Textbook of Periconceptional Medicine (Reproductive Medicine and Assisted Reproductive Techniques)

Periconceptional Medicine CONTENTS: PRECONCEPTION: Genetics and Conception • Lifestyle and Conception • Preconceptional...

Author: Macklon N. (ed.) | Greer I. (ed.) | Steegers E. (ed.)

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Periconceptional Medicine

CONTENTS: PRECONCEPTION: Genetics and Conception • Lifestyle and Conception • Preconceptional Counselling

ACHIEVING PREGNANCY: How to Conceive: Evidence Based Fertility Investigation • The Anovulatory Patient • The Patient with Endometriosis • The Patient with Poor Sperm Quality • The Patient with Tubal Disease • The Couple with Unexplained Infertility * The Patient from the Developing World • The Older Woman Wishing to Conceive • Psychological Aspects of Fertility Therapy • The Luteal Phase • Implantation Failure MANAGEMENT OF EARLY PREGNANCY: Early Placental Development • The Immunology of Early Pregnancy • Mechanisms and Nomenclature of Early Pregnancy Loss • Antiphospholipid Syndrome, Heritable Thrombophilia and Early Pregnancy Loss • Ultrasound in Early Pregnancy • Evidence Based Investigation and Management of Miscarriage • Ectopic Pregnancy after Fertility Treatment • Molar Pregnancy • Multiple Pregnancy • Cervical Cerclage and Pregnancy Loss • Are Pregnancies Conceived by IVF ‘High Risk’?

Nick S Macklon, MD, FRCOG, is Professor of Infertility and Periconceptional Medicine and Head of Reproductive Medicine and Gynaecology at the University Medical Center, Utrecht, The Netherlands: his previous publications include IVF in the Medically Complicated Patient (Informa 2005). Ian A Greer, MD, FRCP(Glas), FRCPE, FRCP, FRCPI, FRCOG, FFFP, FMedSci, is Professor of Obstetric

Medicine and Dean, Hull York Medical School, UK: his most recent publications include Maternal Medicine (Mosby 2008), Fertility and Conception (Collins 2007), Women’s Vascular Health (Arnold 2007), Practical Obstetric Hematology (Informa 2006), and Prevention of Preterm Labor (Cambridge University Press 2005).

Eric AP Steegers, MD, is Professor, Obstetrics and Prenatal Medicine, Erasmus Medical Center, University Medical Center Rotterdam, The Netherlands: his previous publications include Preventive Care in Obstetrics (Baillière Tindall 1995).

Cover design and image by Oxmed

www.informahealthcare.com

Periconceptional Medicine

PREPARING THE HIGH-RISK PATIENT: The Patient with Renal Disease • The Patient with an Organ Transplant • The Patient with Hypertension • The Patient with Cardiac Disease • The Patient with Thyroid Disease • The Patient with Diabetes • The Patient with Epilepsy • The Patient at risk from Thrombosis and Bleeding Disorders • The Patient with Polycystic Ovary Syndrome • The Patient with HIV • The Patient with Cystic Fibrosis • The Patient with Inflammatory Bowel Disease • The Patient with Prolactinoma • The Patient at Risk with Severe Mental Illness • The Patient with Myotonic Dystrophy

Textbook of

It is inceasingly recognized that the outcome of pregnancy is largely determined during the periconceptional period. Both Perinatologists and Reproductive Endocrinologists treating couples with infertility have an important role in ensuring optimal management of this crucial, and sometimes complex, phase. At the interface between reproductive medicine, perinatology, internal medicine and genetics, the new field of Periconceptional Medicine is now emerging. This major new textbook from respected international experts provides the first major and definitive collection of work in this area, and will be of value to all those working with or advising patients planning a pregnancy.

Macklon • Greer • Steegers

Textbook of

Textbook of

Periconceptional Medicine

Edited by

Nick S Macklon Ian A Greer • Eric AP Steegers

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Textbook of Periconceptional Medicine

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Reproductive Medicine and Assisted Reproductive Techniques Series Series editors David Gardner, University of Melbourne, Australia Jan Gerris, University Hospital Ghent, Belgium Zeev Shoham, Kaplan Hospital, Rehovot, Israel Titles 1 Jan Gerris, Annick Delvigne, François Olivennes Ovarian Hyperstimulation Syndrome, ISBN: 9781842143285 2 Alastair G Sutcliffe Health and Welfare of ART Children, ISBN 9780415379304 3 Seang Lin Tan, Ri-Chen Chian, William Buckett In-vitro Maturation of Human Oocytes, ISBN: 9781842143322 4 Christoph Keck, Clemens Tempfer, Jen-Noel Hugues Conservative Infertility Management, ISBN: 9780415384513 5 Carlos Simon, Antonio Pellicer Stem Cells in Human Reproduction, ISBN: 9780415397773 6 Kay Elder, Jacques Cohen Human Preimplantation Embryo Selection, ISBN: 9780415399739 7 Michael Tucker, Juergen Liebermann Vitrification in Assisted Reproduction, ISBN: 9780415408820 8 John D Aplin, Asgerally T Fazleabas, Stanley R Glasser, Linda C Giudice The Endometrium, Second Edition, ISBN: 9780415385831 9 Adam H Balen Infertility in Practice, Third Edition, ISBN: 9780415450676 10 Nick Macklon, Ian Greer, Eric Steegers Textbook of Periconceptional Medicine, ISBN: 9780415458924 Forthcoming 11 Carlos Simon, Antonio Pellicer Stem Cells in Human Reproduction, Second Edition, ISBN: 9780415471718 12 Andrea Borini, Giovanni Coticchio Preservation of Human Oocytes, ISBN 9780415476799

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Textbook of Periconceptional Medicine Edited by Nick S Macklon Department of Reproductive Medicine and Gynaecology University Medical Center Utrecht, The Netherlands Ian A Greer Department of Obstetrics and Gynaecology Hull York Medical School UK and Eric AP Steegers Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands

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© 2009 Informa UK Ltd First published in the United Kingdom in 2008 by Informa Healthcare, Telephone House, 69-77 Paul Street, London EC2A 4LQ. Informa Healthcare is a trading division of Informa UK Ltd. Registered Office: 37/41 Mortimer Street, London W1T 3JH. Registered in England and Wales number 1072954. Tel: +44 (0)20 7017 5000 Fax: +44 (0)20 7017 6699 Website: www.informahealthcare.com All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. Library of Congress Cataloging-in-Publication Data Data available on application ISBN-13: 978–0–415–45892–4 Distributed in North and South America by Taylor & Francis 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, USA Within Continental USA Tel: 1 (800) 272 7737; Fax: 1 (800) 374 3401 Outside Continental USA Tel: (561) 994 0555; Fax: (561) 361 6018 Email: [email protected] Book orders in the rest of the world Paul Abrahams Tel: +44 (0)20 7017 4036 Email: [email protected] Composition by C&M Digitals (P) Ltd., Chennai, India Printed and bound in the United States of America

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Contents

List of contributors Preface

vii xi

SECTION A: PRECONCEPTION 1 2 3

The genetics of conception JPM Geraedts Lifestyle and conception S Temel, JS Laven, and RPM Steegers-Theunissen Preconception care K Boer, RPM Steegers-Theunissen, and EAP Steegers

1 13 23

SECTION B: PREPARING THE HIGH RISK PATIENT 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

The patient with renal disease RJA Sims and M Ramsay The patient with organ transplantation S Winfield and JM Davison The patient with hypertension C Nelson-Piercy The patient with cardiac disease Y Karamermer and JW Roos-Hesselink The patient with thyroid disease W Visser The patient with diabetes mellitus JJN Oats The patient with epilepsy J Craig The patient at risk from thrombosis and bleeding disorders SM Nelson and IA Greer The patient with polycystic ovary syndrome RJ Norman and S Lim The patient with HIV K Boer and MH Godfried The patient with cystic fibrosis GCML Page-Christiaens and F Teding van Berkhout The patient with inflammatory bowel disease S Kane and R Kowalczyk The patient with prolactinoma ME Molitch Periconceptional issues in neuromuscular disorders W Verpoest and M De Vos The patient with, or at risk of, severe mental illness R Cantwell

41 57 69 77 89 99 107 121 137 143 159 173 179 191 199

SECTION C: ACHIEVING PREGNANCY 19

How to conceive: evidence-based fertility investigation BW Mol, JW van der Steeg, HR Verhoeve, and F van der Veen

205

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20 21 22 23 24 25 26 27 28 29

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Achieving pregnancy in the anovulatory woman RS Legro and A Dokras The patient with endometriosis: achieving pregnancy A Vodolazkaia and TM D’Hooghe The patient with poor sperm quality BJ Cohlen and H Tournaye The patient with tubal disease A Strandell The couple with unexplained infertility GI Serour and M Aboulghar The patient from the developing world W Ombelet and G Nargund The older woman wishing to conceive CB Lambalk and FJ Broekmans Psychological issues in periconceptional care L Bunting and J Boivin The luteal phase HM Fatemi, B Fauser, P Devroey, and NS Macklon Implantation failure JA Garcia-Velasco and E Sánchez

215 223 233 241 251 261 273 287 297 309

SECTION D: MANAGEMENT OF EARLY PREGNANCY 30 31 32 33 34 35 36 37 38 39 40

Early placental development and pregnancy outcome GJ Burton and E Jauniaux The immunology of early pregnancy S Scherjon Nomenclature and mechanisms of early pregnancy loss R Farquharson and N Exalto Antiphospholipid syndrome, heritable thrombophilia and early pregnancy loss B Brenner, A Aharon, and G Sarig Ultrasound in early pregnancy S Suri, J Johns, and E Jauniaux Evidence-based investigations and treatments of recurrent miscarriage OB Christiansen Ectopic pregnancy after fertility treatment B Refaat, M Al-Azemi, and W Ledger Molar pregnancy: pathology and management RS Berkowitz and DP Goldstein Multiple pregnancy DLH Moore, NM Fisk, and J Hyett Cervical cerclage and pregnancy loss M Chandiramani and AH Shennan Are pregnancies conceived by IVF ‘high risk’? CE Fox and MD Kilby

Index

317 329 341 349 357 367 379 393 405 419 433

441

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List of contributors

M Aboulghar Egyptian IVF-ET Center Cairo, Egypt A Aharon Thrombosis and Hemostasis Unit Rambam Health Care Campus Faculty of Medicine Tecnion Haifa, Israel M Al-Azemi Academic Unit of Reproductive and Developmental Medicine Royal Hallamshire Hospital Sheffield, UK RS Berkowitz Dept of Obstetrics, Gynecology, and Reproductive Medicine Division of Gynecologic Oncology Brigham & Women’s Hospital Harvard Medical School Boston, MA, USA K Boer Department of Obstetrics and Gynecology Academic Medical Center University of Amsterdam Amsterdam, The Netherlands J Boivin School of Psychiatry Cardiff University Cardiff, UK B Brenner Thrombosis and Hemostasis Unit Rambam Health Care Campus Faculty of Medicine Tecnion Haifa, Israel FJ Broekmans Department of Reproductive Medicine & Gynecology Division of Perinatology & Gynecology University Medical Center Utrecht, The Netherlands L Bunting School of Psychiatry Cardiff University Cardiff, UK

GJ Burton Centre for Trophoblast Research University of Cambridge Cambridge, UK R Cantwell Perinatal Mental Health Service Glasgow, UK M Chandiramani Maternal and Fetal Research Unit King’s College London Division of Reproduction and Endocrinology London, UK OB Christiansen Fertility Clinic Rigshospitalet Copenhagen, Denmark BJ Cohlen Division of Reproductive Medicine Department of Obsterics and Gynaecology Isala Clinics Zwolle Zwolle, The Netherlands J Craig Department of Neurology Royal Group of Hospitals Belfast, UK JM Davison Department of Obstetrics and Gynaecology Royal Victoria Hospital Queen Victoria Road Newcastle-upon-Tyne, UK M De Vos Centre for Reproductive Medicine Universitair Ziekenhuis Brussel Vrije Universiteit Brussel Brussels, Belgium P Devroey Centrum voor Reproductieve Geneeskunde Universitaire Ziekenhuis Brussel Brussel, Belgium TM D’Hooghe Leuven University Fertility Center Department of Obstetrics and Gynecology UZ Gasthuisberg Leuven, Belgium

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A Dokras Department of Obstetrics and Gynecology University of Pennsylvania Philadelphia, PA, USA N Exalto Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands R Farquharson Liverpool Women’s Hospital Liverpool, UK HM Fatemi Centrum voor Reproductieve Geneeskunde Universitaire Ziekenhuis Brussel Brussel, Belgium BC Fauser Department of Reproductive Medicine & Gynecology Division of Perinatology & Gynecology University Medical Center Utrecht, The Netherlands N Fisk University of Queensland Centre for Clinical Research Brisbane, Queensland, Australia CE Fox Department of Obstetrics and Gynaecology Birmingham Women’s Hospital University of Birmingham Birmingham, UK JA Garcia-Velasco IVI-Madrid Rey Juan Carlos University Madrid, Spain JPM Geraedts Genetics and Cell Biology Academic Hospital Maastricht Universiteit Maastricht Maastricht, The Netherlands MH Godfried Department of Internal Medicine Academic Medical Center University of Amsterdam Amsterdam, The Netherlands

DP Goldstein Dept of Obstetrics, Gynecology, and Reproductive Medicine Division of Gynecologic Oncology Brigham & Women’s Hospital Harvard Medical School Boston, MA, USA IA Greer Department of Obstetrics and Gynaecology Hull York Medical School UK J Hyett Department of Obstetrics and Gynaecology Royal Prince Alfred Hospital University of Sydney Sydney, New South Wales, Australia E Jauniaux Academic Department of Obstetrics and Gynaecology Royal Free Hospital and University College Hospital London, UK J Johns Academic Department of Obstetrics and Gynaecology University College London London, UK S Kane Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA Y Karamermer Department of Cardiology Thoraxcenter Erasmus Medical Center University Medical Center Rotterdam, The Netherlands M Kilby Maternal and Fetal Medicine College of Medicine and Dentistry University of Birmingham Birmingham Women’s Hospital Birmingham, UK R Kowalczyk Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, MN, USA

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CB Lambalk Department of Reproductive Medcine Vrije Universiteit Medical Center Amsterdam, The Netherlands W Ledger Academic Unit of Reproductive and Developmental Medicine Royal Hallamshire Hospital Sheffield, UK RS Legro Department of Obstetrics and Gynecology Pennsylvania State University College of Medicine Hershey, PA, USA S Lim Research Centre for Reproductive Health School of Paediatrics and Reproductive Health Discipline of Obstetrics and Gynaecology, University of Adelaide and CSIRO Human Nutrition, Adelaide, Australia NS Macklon Department of Reproductive Medicine and Gynaecology University Medical Center Utrecht, The Netherlands BW Mol Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands ME Molitch Division of Endocrinology, Metabolism & Molecular Medicine Chicago, IL, USA DLH Moore Department of Obstetrics and Gynaecology Royal Brisbane & Women’s Hospital Herston, Queensland, Australia G Nargund Department of Obstetrics & Gynecology St George’s Hospital Medical School London, UK SM Nelson Reproductive and Maternal Medicine University of Glasgow Glasgow Royal Infirmary Glasgow, UK

ix

C Nelson-Piercy Guy’s & St Thomas’ NHS Foundation Trust and Queen Charlotte’s Hospital, Imperial College Healthcare NHS Trust London, UK RJ Norman Research Centre for Reproductive Health School of Paediatrics and Reproductive Health Discipline of Obstetrics and Gynaecology, University of Adelaide and CSIRO Human Nutrition, Adelaide, Australia JJN Oats Clinical Director Women's Services The Royal Women's Hospital Carlton, Victoria, Australia W Ombelet Genk Institute for Fertility Technology Department of Obstetrics & Gynecology Ziekenhuis Oost-Limburg Genk, Belgium GCML Page-Christiaens Maternal-Fetal Department University Medical Center Utrecht, The Netherlands M Ramsay Queen’s Medical Centre Campus Nottingham University Hospitals Nottingham, UK B Refaat Academic Unit of Reproductive and Developmental Medicine Royal Hallamshire Hospital Sheffield, UK J Roos-Hesselink Department of Cardiology Thoraxcenter Erasmus Medical Center University Medical Center Rotterdam, The Netherlands E Sánchez IVI-Madrid, Rey Juan Carlos University Madrid, Spain

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List of contributors

G Sarig Thrombosis and Hemostasis Unit Rambam Health Care Campus Faculty of Medicine Tecnion Haifa, Israel S Scherjon Department of Obstetrics and Gynecology Leiden University Medical Center Leiden, The Netherlands GI Serour Al-Azhar University Cairo, Egypt AH Shennan Maternal and Fetal Research Unit King’s College London Division of Reproduction and Endocrinology London, UK RJA Sims Queen’s Medical Centre Campus Nottingham University Hospitals Nottingham, UK JW van der Steeg Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands EAP Steegers Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands RPM Steegers-Theunissen Depts of Obstetrics & Gynaecology, Epidemiology & Biostatistics, Paediatrics / Division of Paediatric Cardiology and Clinical Genetics, Erasmus Medical Center University Medical Center Rotterdam, The Netherlands A Strandell Reproductive Medicine Department of Obstetrics and Gynecology Sahlgrenska University Hospital Göteborg, Sweden

S Suri Academic Department of Obstetrics and Gynaecology University College London London, UK F Teding van Berkhout Department of Heart and Lungs University Medical Center Utrecht, The Netherlands H Tournaye Center for Reproductive Medicine AZ-Vrije Universiteit Brussels Brussels, Belgium F van der Veen Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands HR Verhoeve Department of Obstetrics and Gynaecology AMC Amsterdam Amsterdam, The Netherlands W Verpoest Centre for Reproductive Medicine Academisck Ziekenhuis Vrije Universiteit Brussel Brussels, Belgium W Visser Department of Obstetrics and Gynecology Erasmus Medical Center University Medical Center Rotterdam, The Netherlands A Vodolazkaia Leuven University Fertility Center Department of Obstetrics and Gynecology UZ Gasthuisberg Leuven, Belgium S Winfield Department of Obstetrics and Gynaecology James Cook University Hospital Middlesbrough, UK

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Preface

The introduction of in vitro fertilization into fertility practice revolutionized the field of Reproductive Medicine, invigorating its emergence as a new subspecialty distinct from, but associated with, Obstetrics or Gynaecology. Over the past 20 years we have observed increasing divergence of these subspecialties. However, increasing recognition that periconceptional events determine not only fertility, but also pregnancy outcome and the long term health of mother and offspring, is causing a reverse in this trend. As perinatologists acknowledge that the outcome of pregnancy is largely determined during the periconceptional period, their focus is increasingly turning to optimizing early pregnancy and preconceptional health. At the same time, the improved prognosis associated with illnesses such as cystic fibrosis mean that many chronically ill women are now achieving reproductive age and wishing to have children. In addition, the increasing age of women presenting for fertility treatment is placing new demands on reproductive endocrinologists to ensure safe and effective treatment of the subfertile couple and the establishment of a healthy pregnancy. Reproductive endocrinologists are

now taking responsibility for optimizing preconceptional conditions in their patients and are working closely with perinatologists and other disciplines to ensure that optimal pregnancy outcomes are achieved. At this interface between Reproductive Medicine, Perinatology, Internal Medicine and Genetics, the new field of Periconceptional Medicine is emerging. As three clinicians approaching this area from the different perspectives of Reproductive Medicine and Perinatology, we recognized the need for a single integrated and authoritative textbook to provide a theoretical and clinical basis to this new field of medicine. In drawing together the different strands of knowledge into a single text, we have been fortunate to engage the services of diverse leading authorities from around the world. We hope that the result of their efforts will provide a sound theoretical basis for those practising in this new and exciting field of Periconceptional Medicine. Nick Macklon Ian Greer Eric Steegers

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1 The genetics of conception Joep Geraedts

Introduction

Meiosis

Genetic variability and epigenetic factors affect reproduction and fertility from one generation to the next. This starts with sex determination and the onset of gametogenesis and finishes at the end of the reproductive period. From each generation to the next, the haploid complement of the human genome is transmitted. The diploid complement contains 23 pairs of chromosomes, each containing hundreds or thousands of genes. The estimated 25 000 genes each make on average several proteins. The nuclear genome involves three billion base pairs which are subject to countless variations that may affect health and disease. Furthermore, there is a small mitochondrial genome. Sexual reproduction and genetics are firmly connected. Sex determination, which takes place during embryogenesis, is determined by the chromosomal sex. Sexual reproduction is characterised by the formation of haploid gametes which combine at fertilisation to give rise to a new diploid individual. The gametes are all genetically unique. During meiosis new combinations of the genetic characteristics are formed, which are present on the homologous chromosomes.

Meiosis consists of two sequential divisions: meiosis I and II. The first is a real reduction division: the diploid number is halved. The second division resembles mitosis since the two chromatids of each chromosome are separated. The first meiotic division is divided into several phases. During the prophase the homologous chromosomes start to pair and to become thicker and shorter. At the pachytene phase there is an exchange of homologous material between the chromatids. This process is directly visible down the microscope as chiasmata formation and genetically as crossing-over between linked genes or genetic markers. It eventually results in recombination. Furthermore, new combinations arise from segregation of maternal and paternal chromosomes.

Gametogenesis Before the onset of meiosis a number of successive mitotic divisions leads to the production of sufficient cells to enter meiosis. This process is completely different in both sexes. Before the onset of spermatogenesis in the male, at least 30 cell divisions have taken place between the embryonic age and puberty. The spermatogonia that are formed are stem cells that will continuously divide during the entire life of the adult male. Approximately 23 divisions take place each year. This means that at the age of 28 years already 335 cell divisions and at the age of 35 almost 500 have occurred before these cells enter meiosis. In the female all mitotic divisions take place in the foetal ovary. Already at the end of the first trimester some 8 million primary oocytes are present, which enter meiosis simultaneously.

Inheritance patterns The behaviour of the chromosomes and the genes during meiosis is most easily studied in pedigrees of inherited diseases. These may be caused at the level of the gene and the chromosome. In principle single gene mutations can lead to genetic diseases which can be distinguished on the basis of five simple modes of inheritance: autosomal dominant, autosomal recessive, X-linked recessive, X-linked dominant and Ylinked. In practice, only the first three are clinically relevant. At the chromosome level a distinction can be made between numerical and structural chromosomal abnormalities. The first usually result from meiotic non-disjunction and are sporadic in the vast majority of cases. Chromosomal rearrangements are carried by a parent and can lead to the production of genetically unbalanced gametes. Besides these modes of nuclear inheritance, there is also mitochondrial inheritance which shows completely maternal inheritance. In recent literature, the term “complex” disorders is preferred for all genetic conditions that are not strictly Mendelian or chromosomal in nature. Complex disorders might result from two or more genes (polygenic inheritance) as well as from more than one gene in combination with environmental factors. Disorders such as diabetes and schizophrenia are caused by the

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interaction of many different genes together with environmental influences. The latter situation is sometimes called multifactorial inheritance.

(a)

Gene mutations and polymorphisms Mutation simply means change. Change in gene function can be brought about by loss of the whole or part of the coding sequence of the gene (deletion) or by alteration in the bases that make up the DNA molecule (substitution). More rarely, gene duplication can cause disease. Surrounding each gene are modifying sequences that affect gene expression; these too can mutate. Mutations also affect non-coding DNA sequences, usually regions of repetitive DNA that are associated with each gene. Mutations in these regions are unlikely to be disease causing. Several forms of these variants may exist in the population and if they are common enough to be found in at least 1% of people they are known as polymorphisms. Polymorphisms are very useful as genetic markers since a particular variant will tend to be inherited along with the gene mutation in each family.1

(b)

(c)

Mendelian inheritance of monogenic disorders The relevant genes may be carried either on the X chromosome or on the non-sex chromosomes (the autosomes). Autosomal conditions are either dominant or recessive. At the outset it is important to remember that chromosomes exist in pairs, one from each parent, which in turn means that a gene for a particular character is also present twice in each cell. The exception is the pair of sex chromosomes. In females one of both X chromosomes is inherited from each parent. The X chromosome in males, which comes from the mother, has no counterpart. The Y chromosome, which is inherited from the father, is much smaller and carries few expressed genes, which are different from those on the X chromosome. It carries genes which are important for sex determination and fertility. The loss of part of this chromosome or of the function of one or more of these genes is therefore harmful. During the formation of the gametes recombination takes place between paired chromosomes after which both parental chromosomes segregate. This means that half of the genome becomes incorporated in the oocyte or sperm. At fertilisation new combinations of maternal and paternal chromosomes will always be formed. Examples of pedigrees with these typical patterns of inheritance are shown in Figure 1.1. An autosomal recessive mode of inheritance is suggested when there are affected children in a family with no known history of the disease. This happens when a gene carrier “marries” into the family. In dominant conditions affected children can be seen in every generation since the parent has a one in two chance of passing on the condition

Key Male

Female

Carrier

Affected

Fig 1.1 Modes of inheritance. (a) Autosomal recessive. (b) Autosomal dominant. (c) X-linked recessive.

irrespective of the genetic status of his/her partner. In families with an X-linked recessive condition only males are affected and they may appear in every generation because some of the mothers will be carriers of the gene but there is no male to male transmission.

Autosomal recessive inheritance In recessive single gene disorders a person who is a gene carrier has one abnormal copy of a particular gene in each of the cells along with one normal copy on the other chromosome. This carrier will not manifest the disease. This person is a heterozygote. If the

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The genetics of conception

partner is not a carrier the couple can safely produce children who will be unaffected. If by chance the partner is also a carrier for the same abnormal gene then the couple has a one in four chance of having a child with two copies of the abnormal gene. This child will then be affected by the disease in question. On average, half of the children of the couple with both parents being carriers of the same abnormal gene will be gene carriers like themselves and a quarter will have two normal genes (Fig 1.1). The commonest autosomal recessive disorder in Caucasian populations is cystic fibrosis (CF).2 Therefore, in Europe this is by far the most frequent reason for referral to a centre offering preimplantation genetic diagnosis (PGD). More than 1000 different mutations are known. In the majority of cases the mutation in this gene is a three base pair deletion known as p.F508del. In most cases both parents of an affected child are likely to be carrying this mutation (Fig 1.2a). This situation makes single cell diagnosis relatively straightforward. However, there are a number of rare CF mutations that are not so easily detected. If the parents carry different mutations the child who inherits these two different abnormal genes will be affected. Such a child is called a “compound heterozygote” (Fig 1.2b). Worldwide, the commonest autosomal recessive disease is β-thalassaemia.3 In contrast to CF, there are numerous different common mutations in this gene. Certain types predominate in different populations, but it is still the case that most parents of affected children will be carriers of different mutations. Many inborn errors of metabolism are autosomal recessive.4 Since one gene is responsible for the production of one enzyme, these diseases cause enzyme deficiency. If one gene coding for an enzyme is affected, 50% of the enzyme will still be produced from the wild type gene. In general this level of enzyme activity is sufficient for normal life. Therefore, both copies of the gene need to be affected in order to result in a severe clinical phenotype.

Autosomal dominant inheritance Autosomal dominant disorders require only one copy of the abnormal gene to be present in each cell for the disease to be expressed. The presence of a normal copy on the other chromosome is not sufficient to ensure normality. Generally, at birth dominant disorders are not so severe or life threatening as recessive disorders. In dominant disease, usually the gene carriers are able to have children either despite being affected, as in the case of achondroplasia (dwarfism) or because the disease itself is of late onset (e.g. Huntington’s disease). On average, half the children of an affected mutant gene carrier will also be affected. From this it might be concluded that diseases which, when studying the pedigree, seem to follow a more complex pattern cannot result from simple point

3

(a)

Normal

Carrier

Normal

Normal

Carrier

Normal

Carrier

Carrier

Normal

Carrier

Carrier

Cystic fibrosis (CF)

(b)

Normal

Carrier

Normal

Normal

Carrier

Carrier

Carrier

CF (compound heterozygote)

Key Male

Female

p.F508del mutation

? Mutation

Chromosome 7

Fig 1.2 Cystic fibrosis (CF) family pedigree illustrating the typical inheritance of an autosomal recessive gene defect. (a) In this family the common CF mutation p.F508del is passed through healthy carriers in the grandparents’ and parents’ generations to the grandchildren, one of whom is affected by the disease. (b) In this case the father carries the p.F508del mutation whilst the mother carries a different, much rarer mutation of the CF gene. The child affected by cystic fibrosis who has inherited both defective copies is essentially a carrier of each mutation and is termed a compound heterozygote.

mutations in individual genes. However, complexity might result from incomplete penetrance and variable expression. Incomplete penetrance means that a number of genotypically affected carriers do not demonstrate any symptoms of the condition. Variable expression means that not all disease carriers show the

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Queen Victoria of England

2 Emperor Frederick III of Germany

King Edward VII of England

Leopold of Albany

Frederik of Hesse

Tsar Nicholas of Russia

Leopold of Battenberg

4 Waldemer of Prussia

Henry of Prussia

2

Tsarewitsch Alexis of Russia

Carrier

Fig 1.3

Maurice of Battenberg

Rupert

Alfonso of Spain

Gonzalo of Spain

Patient with haemophilia

Pedigree of a Royal Family with X-linked disease Haemophilia.

same severity of the condition and suggests that environmental factors or other genes are also involved. Furthermore pleiotropy occurs, in which one mutation can cause more than one effect on development. It should always be kept in mind that new mutations arising during gamete formation may be responsible for sporadic cases in a family. It is also possible that the legal father is not the biological father. Sometimes an individual is mosaic for the mutation. In that case it must have arisen as a somatic event after fertilisation. Sometimes the mutation is confined to the germline. The breast cancer mutations BRCA1 and 2 can either have no effect at all (non-penetrance) or result in breast cancer on the one hand or ovarian cancer on the other with variable risks5 as follows:

an expansion in the number of copies of a CTG repeat in the 3′ untranslated part of the DM1 kinase gene on chromosome 19. The repeat copy number varies from 5 to 37 in normal individuals and from 50 to several thousands in people affected with the disease. Intermediate repeat numbers result in an unstable, permutation state. The expansion of the triplet repeat may lead to the phenomenon of anticipation, which means that the disorder starts at a younger age and becomes more severe with each generation. Mildly affected mothers can give birth to severely affected offspring with the congenital form of the disease.6

X-linked inheritance

A special category of dominant disorders is caused by a variable increase in the number of copies of a particular trinucleotide repeat sequence (i.e. three base pairs, for example cytosine, guanine, guanine (CGG) and their paired bases on the opposite DNA strand) within the vicinity of a gene. Myotonic dystrophy and Huntington’s disease belong to this category.

X-linked disorders (caused by mutation in genes that are carried on the X chromosome) can be either recessively or dominantly inherited. The vast majority are recessives and are carried by females who are themselves unaffected or only mildly so, because of the normal copy of the gene on their second X chromosome (Fig 1.3). Distorted X chromosome inactivation can result in symptoms in females, although much milder than those that occur in males. Half the sons (who get their single X chromosome from their mother) will be normal, however, the others will be affected with the disease as their Y chromosome will not have the normal gene. Common X-linked recessives include Duchenne muscular dystrophy and haemophilia. There are well over 1000 known X-linked disorders and for most of them the molecular basis is not yet known.7

Myotonic dystrophy

Fragile X syndrome

Myotonic dystrophy, DM1, also known as Steinert’s disease, is a progressive muscular dystrophy caused by

Fragile X syndrome is a form of X-linked mental retardation caused by unstable expansion of a CGG repeat in

(1) Risk of female carriers of a mutation in BRCA1/2 to develop breast cancer before the age of 70: 60–80%; (2) Risk of female carriers of a mutation in BRCA1 to develop ovarian cancer before the age of 70: 30– 60%; (3) Risk of female carriers of a mutation in BRCA2 to develop ovarian cancer before the age of 70: 5–20%.

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the 5′ untranslated region of the FMR1 gene. In the normal population the number of repeats is polymorphic with different individuals possessing between 6 and 54 copies and is usually inherited unchanged from parent to child. In families with fragile X syndrome the number of copies of the repeat has a tendency to expand with each generation, which is an unstable, premutation, situation. Once the number of repeats exceeds 200 excessive methylation occurs leading to transcriptional inactivation and absence of gene product. Males with repeat copy numbers in excess of 200 will show symptoms and females, who also have a transcriptionally active copy of the gene, show variable disease manifestation. Fragile X syndrome shows a 10-fold increase in premature ovarian failure.8

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Chromosome abnormalities Chromosome abnormalities are normally divided in numerical abnormalities, structural abnormalities and mosaicism. Numerical chromosome abnormalities are abnormalities which deviate in number from the normal karyotype, which has 2n=46 chromosomes, that is, two haploid sets (Fig 1.4). They are the result of simultaneous chromosome breakage either within the same chromosome or in different chromosomes and subsequent rejoining in an abnormal fashion. Mosaicism means that there is more than one cell line present.

Numerical chromosome abnormalities Numerical chromosome abnormalities can be divided into aneuploidy, an extra (trisomy) or missing (monosomy) chromosome of a pair, and ploidy abnormalities, in which the number of haploid sets of chromosomes is abnormal. An embryo may be haploid (1n=23), triploid (3n=69) or tetraploid (4n=96). Aneuploidy is not normally inherited. Typically the imbalance arises at meiosis I in the mother when two homologous chromosomes pass to the same pole of the spindle at anaphase. The mature oocyte formed after meiosis II will have either an extra or missing copy of the chromosome which will result in trisomy or monosomy in the embryo after fertilisation. The most common numerical chromosome abnormalities are trisomies and monosomies, arising de novo as a result of meiotic non-disjunction during gametogenesis in parents with a normal karyotype. For all chromosomes, except the largest, the non-disjunction rate increases with maternal age. The cause of nondisjunction in oocytes of older women is largely unknown. An increase in maternal age results in an increased embryonic aneuploidy rate as well as an increased frequency of spontaneous abortion. This is not only reflected in a higher miscarriage rate but also in a lower success rate for in vitro fertilisation (IVF). The most frequent abnormality in spontaneous abortions is trisomy 16, representing about 30% of all such trisomies; however, in cleavage stage embryos

Fig 1.4

21

22

X

Y

Human karyotype.

trisomies for chromosomes 13, 21 and 22 are the most common. Trisomies for all chromosomes have been observed in spontaneous abortion, except trisomy 1. Autosomal monosomies are practically unknown in human miscarriages, since they stop development before or soon after implantation.9 On the other hand, monosomy X is a frequent finding in abortions. Nondisjunction may occur at either meiotic division. Trisomy 16, for example, always shows a maternal meiosis I error. Trisomy 18, on the other hand, results predominantly from errors during the second division. Premature centromere division at meiosis I leading to separated chromatids, is an alternative mechanism for trisomy formation, occurring as frequently as whole chromosome non-disjunction.10 The abnormality most frequently resulting from abnormal fertilisation is triploidy. There seems to be no effect of maternal age on triploidy and tetraploidy, the latter of which originates during preimplantation development. Only three autosomal trisomies are regularly observed at birth: trisomies 13, 18 and 21. They have an estimated prenatal survival of 3, 5 and 20%, respectively. The other autosomal trisomies have an estimated survival to term of less than one in 1000. Sex chromosome aneuploidies survive normally with the exception of 45,X which is lethal in about 98% of conceptions.9

Aneuploidy and gonadal mosaicism Occasionally couples present with a history of repeated conceptions involving trisomy for the same chromosome. The reason for this may be mosaicism in a parent with a second, trisomic, cell line present in addition to the normal population of cells. When the trisomic cells are present in the gonads this results

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in a high frequency of gametes which are unbalanced for the involved chromosome. Aneuploidy for the sex chromosomes, leading to Klinefelter syndrome (47,XXY), triple X or Turner syndrome (45,X), has a less severe effect on the phenotype of surviving individuals (in addition to the almost total lethality of 45,X conceptions, 50% of 47,XXY foetuses abort). Full Klinefelter syndrome leads to azoospermia but epididymal sperm may sometimes be recovered and used for fertilisation. Any embryos generated using this method should be checked for sex chromosome aneuploidy by PGD. Also, some infertile males are mosaic for a 47,XXY cell line; if this is discovered their embryos should undergo PGD as there is an increased risk of the production of XY sperm.

Structural chromosomal rearrangements Structural chromosomal rearrangements are common in the human population. They usually occur before or during gamete formation so that every cell of the embryo that results from fertilisation with that gamete carries the same rearrangement. Providing that the breakage in the chromosomes has not affected gene transcription the individual carrying the rearrangement will develop normally. The problems occur in oogenesis or spermatogenesis when the rearranged chromosomes have to pair with their normal homologues and abnormal products of segregation result.11

Chromosomal translocations The most common type of chromosome rearrangement is a translocation which is the movement of a segment of chromosome from its normal position to a new site. Reciprocal translocations involve breaks along the arms of two chromosomes and exchange of material with reunion creating two abnormal derivatives (Fig 1.5a). Robertsonian translocations involve breakage and reunion around the centromere of the “acrocentric” chromosomes; the minute short arms of these chromosomes are normally lost in the process so that the chromosome number per cell is reduced to 45,

Fig 1.5 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). (a) Reciprocal translocation – reciprocal exchange of material between two nonhomologous chromosomes. (b) Cross-shaped arrangement (quadrivalent) adopted by reciprocal translocations during early meiosis allows pairing of homologous chromosomes.

again with no phenotypic effect (Fig 1.6a). Robertsonian translocations are unusual in that identical types occur repeatedly in humans, whereas reciprocal translocations are normally unique to the family. In the case of reciprocal translocations a group of four chromosomes is formed at meiosis in the parental carrier and this group can separate into two groups of two in four ways, only one of which will be balanced genetically (Fig 1.5b). It is also possible for three of the four chromosomes to go to one daughter cell and only one to the other (3:1 segregation). It is clear that there is a high risk of producing chromosomally unbalanced gametes but the exact risk depends on several factors including the chromosomes involved, the position of the breakpoints and the sex of the parent with the translocation.12 In Robertsonian translocation carriers a group of three chromosomes is formed when pairing occurs in meiosis but in the same way as for reciprocals this group can segregate in three ways, only one of which is balanced (Fig 1.6b). An example of a typical family with an inherited Robertsonian translocation is shown in (Fig 1.7).

Insertions Much rarer types of translocation occur which are known as insertions. These involve three simultaneous breaks, either within one chromosome or involving two different chromosomes. The segment freed by two of the breaks within one chromosome is then inserted into a new position within the same chromosome or into a second one (Fig 1.8). In the case of intrachromosomal insertions unbalanced gametes can be formed merely by recombination between the paired homologous chromosomes in the prophase of meiosis I, whereas for interchromosomal insertions the involved chromosomes come together as a group of four in a similar way to reciprocal translocations and the type of gametes formed is again dependent on the segregation pattern.

Inversions When two breaks occur within one chromosome the free segment may rotate through 180 degrees before rejoining (Fig 1.9). This produces an inversion of genetic material

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(b)

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Normal

Fig 1.6 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). (a) Robertsonian translocation – fusion of two acrocentric chromosomes with varying loss of centromeric and short-arm material. (b) Pairing arrangement (trivalent) adopted by Robertsonian translocations during early meiosis allowing pairing of most homologous regions.

Carrier

Normal

Carrier

Down syndrome

Normal

Carrier

Down syndrome

Normal

Key Male Miscarriage

Female Chromosome 21

Robertsonian translocation der(13;21)(q10;q10)

Chromosome 13

Fig 1.7 Pedigree of a family with a Robertsonian translocation between chromosomes 13 and 21. This balanced chromosome rearrangement was only detected in the healthy mother after the birth of two children with Down syndrome.

between the breakpoints which usually has no phenotypic effect in heterozygous form when only one of a pair of chromosomes is involved. The problems for carrier parents occur in gamete formation.12 The genetic effects are different depending upon whether the centromere is included within the inverted segment. Classically, when the inverted chromosome pairs with its normal homologue there is loop formation. If crossing over takes place within this loop the chromatids involved will be genetically unbalanced due to deletion of some genetic loci and duplication of others. Cross-over chromatids from inversions that include the centromere (pericentric) may lead to viable but congenitally abnormal embryos, whereas those from paracentric inversions (without the centromere) will either have two centromeres or none, a condition that is incompatible with further development of the gamete as the chromosomes will be lost or broken.

For this reason paracentric inversions usually pass undetected from one generation to another as no affected offspring are born. However, couples with repeated births of chromosomally abnormal children as a result of a pericentric inversion in one parent have come forward to request PGD.

Ring chromosomes Ring chromosomes are formed when genetic material is lost from both ends of a chromosome, creating an unstable situation which is resolved by the fusion of the broken ends (Fig 1.10). It is unusual to find ring chromosomes in a normal adult but they do occasionally occur as ring X chromosomes or affecting an autosome if only the telomeres themselves are lost. Ring chromosomes are unstable during cell division as interlocking chromatids

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Fig 1.8 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). Insertions – translocation of a chromosome segment to another chromosome (interchromosomal) or to another position on the same chromosome (intrachromosomal), either in the same orientation with respect to the centromere (direct) or reversed (inverted). Inserted segment is shown cross-hatched. (a) Within-arm intrachromosomal insertion. (b) Between-arm intrachromosomal insertion. (c) Interchromosomal insertion.

(b)

(a)

A

derA

A

derA

Fig 1.9 Chromosome rearrangements showing the normal homologues (A, B) with the rearranged or derivative chromosomes (der A, der B). Inversions – inversion of a chromosome segment with (pericentric) or without (paracentric) involvement of the centromere. Inverted segment is shown cross-hatched. (a) Pericentric inversion. (b) Paracentric inversion.

may be formed leading to breakage and loss. Adult carriers are usually mosaics with a monosomic cell line in the case of the X chromosome or a normal line if an autosome is involved. PGD has been requested in at least one case involving an autosome.

Mitochondrial disorders Mitochondrial disorders are a group of diseases and syndromes commonly defined by lack of energy due to defects in oxidative phosphorylation (OXPHOS). They affect at least one in 8000 of the general population, making them the most common inherited metabolic diseases. Clinical manifestations of OXPHOS diseases are extremely variable and range from a single affected tissue, like the loss of vision in Leber’s hereditary optic neuropathy (LHON), to multisystemic syndromes like Leigh syndrome (subacute necrotising encephalomyelopathy, LS), mitochondrial encephalopathy lactic acidosis and stroke-like

A

derA

Fig 1.10 Ring chromosome – loss of telomeric material with fusion of the resulting free ends.

episodes (MELAS), neuropathy, ataxia and retinitis pigmentosa (NARP) and myoclonic epilepsy with ragged red fibres (MERRF).13 The mitochondrial DNA is double stranded, circular and consists of 16 569 base pairs. The mtDNA encodes 37 genes, of which 13 genes encode proteins. Furthermore, there are 22 tRNA and two rRNA genes, required for mitochondrial translation.14 Several unique characteristics discriminate mitochondrial from nuclear DNA: (1) The mtDNA is a multicopy genome. A cell contains hundreds of mitochondria and each mitochondrion contains five to ten copies of mtDNA. Dependent on the tissue and energy demand each cell contains between 500 and 10 000 mtDNA molecules, except for mature oocytes which contain between 100 000 and 600 000 mtDNA molecules. (2) In a cell all mtDNA molecules can be identical (homoplasmy), or two types of mtDNA molecules, that differ in sequence, in the same cell, tissue or even in the same organelle can coexist. (3) The mtDNA is transmitted entirely through the maternal line.

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Segregation of mtDNA diseases in families The segregation of mtDNA disease in families is not straightforward and is highly dependent on the nature and amount of the mtDNA mutation. A woman carrying an mtDNA mutation will transmit a variable amount of this mutation to her offspring. The percentage heteroplasmy of point mutations in the offspring is related to the mutation percentage in the mother, although extreme shifts in mutation percentages occur. The ‘mtDNA bottleneck’ is a restriction in the number of mtDNA molecules to be transmitted followed by an amplification of these founder molecules. The exclusive maternal transmission of mtDNA, the high mutation rate and the lack of a good repair mechanism and recombination would lead to decay of the mtDNA. The stringent bottleneck has an evolutionary advantage as a sort of reset and acts to maintain a healthy mtDNA by filtering out mutations and minimising heteroplasmy. Because this filtering happens very early during the development the chance to preserve age-related mutations in the early oocyte is small, although the low amount of mtDNA copies per mitochondria in the early developmental stages of the oocytes renders these oocytes vulnerable for mutational events. Besides the variation which is present in the DNA sequence, epigenetic changes play an important role in the regulation of gene expression. Several epigenetic mechanisms are operative, including, among others, histone modifications and DNA methylation, RNA associated gene silencing and chromosome inactivation, and genomic imprinting.15

9

defined as regions of more than 500 base pairs in size and with a GC content greater than 55%. They are located within the promoter regions of about 40% of mammalian genes. These CpG islands are normally kept free of methylation and are targets for proteins that bind to unmethylated CpGs and initiate gene transcription. However, methylated CpGs are associated with silent DNA and cause stable heritable transcriptional silencing. The establishment and maintenance of DNA methylation patterns is maintained by DNA methyl transferases (DNMTs).16 The folate-methylation cycle demethylates homocysteine to produce methionine and then S-adenylmethionine (SAM), which is a prime source of methyl groups for DNA methylation and for the synthesis of nucleic acids, proteins and lipids. Deficiencies in the enzyme methylenetetrahydrofolate reductase (MTHFR), which is central to the methylation pathway, cause DNA hypomethylation and could be related to imprinting disorders.17

X-chromosome inactivation

Histone modifications influence the organisation of the chromatin. DNA is wrapped around clusters of histone proteins to form nucleosomes. These structures contain eight histone molecules. Per nucleosome there are two of each of H2A, H2B, H3 and H4. These basic histone proteins allow interaction with acidic DNA. The nucleosomes of DNA and histones are the building blocks of chromatin and influence gene expression. Transcriptionally inactive DNA is characterised by chromatin, which is condensed and is associated with regions of the genome that undergo late replication during S phase of the cell cycle. Transcriptionally active chromatin is more open and replicated early in S phase. These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modifications, such as (combinations of) acetylation, methylation, and other post-translational modifications such as phosphorylation.16

In mammals, one of the two X chromosomes in females (XX) will undergo a process of inactivation early in embryo development in order to ensure an equal gene dosage as in males (XY). In the mouse, a dynamic multistep process of X-chromosome inactivation has been proposed.18,19 After fertilisation, during the early cleavage stages, the paternal X chromosome, after being initially active, undergoes imprinted inactivation. Initiation of this imprinted X-chromosome inactivation was shown to occur at the 4-cell stage.19 At the 32-cell stage, the paternal X chromosome is inactivated in all cells of the embryo and this inactive state was found to be maintained up to the early blastocyst stage, including in the cells of the inner cell mass (ICM).19 At the late blastocyst stage, this inactive state of the paternal X chromosome is reversed in all cells and the process of inactivating one of the X chromosomes in females is repeated. In epiblast cells derived from the ICM and giving rise to the embryo proper, the imprint is erased and selection of the X chromosome to be inactivated is random. In the extraembryonic tissues such as trophectoderm and yolk sac endoderm, the imprint is retained and the paternal X chromosome is preferentially silenced. The X-chromosome inactivation process starts with the expression of a non-coding RNA (XIST) that, from there, will coat one of the X chromosomes and will lead to its inactivation. Immediately after coating with XIST, lysines 9 (K9) and 27 (K27) of histone H3 are methylated. These changes in the nucleosomal core histones play an important role in the changes of the chromatine structure: locally, binding sites for several repressive protein complexes are formed by methylation.

DNA methylation

Genomic imprinting

Another epigenetic mechanism is methylation of the C5 position of cytosine/guanine pairs (CpG). CpG islands are

For the majority of the autosomal genes there is no discrimination between the capacity of the two

Histone modifications

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parental alleles to be expressed, other than that caused by genetic mutational difference between them. However, several genes are known in which the expression of one parental allele, either the paternal or the maternal allele but not both, is normally repressed in some cells (allelic exclusion), although the sequences of both parental alleles are normal. In some cases, the choice of which of the two inherited copies is expressed is not random, and the allele the expression of which is repressed is always the paternally inherited allele; in others, it is always the maternally inherited allele. This process, known as imprinting, involves the reversible modification of gene activity depending on the sex of the parent that transmits it.15 Well-known examples of imprinting diseases, are Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS) and Prader-Willi syndrome (PWS). Several studies have suggested a possible association between assisted reproductive technologies (ART) and genomic imprinting defects. In several studies an increase in the risk of imprinting disorders such as for children conceived by ART has been reported.20,21 It has been suggested that, besides in vitro culture, the intracytoplasmic sperm injection (ICSI) technique could be a possible causal factor.22

Complex genetic inheritance Many of the differences between individuals reflect features that show continuous quantitative variability. The inheritance of such features does not follow the rules of simple, monogenic heredity. Complex genetic inheritance of disease is characterised by familial clustering and a recurrence risk which is higher than the population risk. The incidence is always less than that with Mendelian disorders and can be estimated only by observations among families and population samples. In genetic terms the complexity results from the interaction of endogenous (genetic) and exogenous (environmental) factors. Such a pedigree pattern might also result, however, from the interaction of more than one genetic factor. Family and population data help to explain diseases with complex genetic inheritance, but heritability estimates obtained from twin studies are of special importance.

Conclusions Even for professional human geneticists it is impossible to keep up to date with the rapid progress that is being made in working out the molecular basis of inherited disease. Because of the widespread interest and importance of the subject textbooks (such as the one listed below) are regularly revised and provide a good introduction to the field. The professionals rely on McKusick’s Mendelian Inheritance in Man,7 now available online (OMIM), a comprehensive catalogue of known single gene disorders. Each described condition

is given a number (the OMIM number) enabling geneticists to be sure which disease has been diagnosed, rather than relying on the name of the syndrome.

References 1. Wang L, Luhm R, Lei M. SNP and mutation analysis. Adv Exp Med Biol 2007; 593: 105–16. 2. Sermon KD, Michiels A, Harton G et al. ESHRE PGD Consortium data collection VI: cycles from January to December 2003 with pregnancy follow-up to October 2004. Hum Reprod 2007; 22: 323–36. 3. Kornblit B, Hagve TA, Taaning P, Birgens H. Phenotypic presentation and underlying mutations in carriers of beta-thalassaemia and alpha-thalassaemia in the Danish immigrant population. Scand J Clin Lab Invest 2007; 67: 97–104. 4. Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Basis of Inherited Disease, 8th edn. New York: McGraw-Hill, 2001. 5. Sinilnikova OM, Mazoyer S, Bonnardel C et al. BRCA1 and BRCA2 mutations in breast and ovarian cancer syndrome: reflection on the Creighton University historical series of high risk families. Fam Cancer 2006; 5: 15–20. 6. Harper P. Myotonic dystrophy, 3rd edn. USA: Oxford University Press, 2002. 7. McKusick VA. Mendelian Inheritance in Man, 12th edn. Baltimore: Johns Hopkins Univerity Press, 1998. Also available Online: OMIM http://www.ncbi.nlm. nih.gov/Omim/ 8. Hundscheid RD, Smits AP, Thomas CM, Kiemeney LA, Braat DD. Female carriers of fragile X premutations have no increased risk for additional diseases other than premature ovarian failure. Am J Med Genet A 2003; 117: 6–9. 9. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 2002; 8: 333–43. 10. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001; 2: 280–91. 11. Passarge E. Color Atlas of Genetics. Stuttgart-New York: Thieme, 2001. 12. Kayser-Rogers K, Rao K. Structural chromosome rearrangements. In: Gersen SL, Keagle MB, eds. The Principles of Clinical Cytogenetics. Totowa, NJ: Humana Press, 2005. 13. Jacobs LJ, de Wert G, Geraedts JP, de Coo IF, Smeets HJ. The transmission of OXPHOS disease and methods to prevent this. Hum Reprod Update 2006; 12: 119–36. 14. Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1999; 1410: 103–23. 15. Waggoner D. Mechanisms of disease: epigenesis. Semin Pediatr Neurol 2007; 14: 7–14. 16. Egger G, Liang G, Aparicio A et al. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429: 457–63. 17. Dobson AT, Davis RM, Rosen MP et al. Methylenetetrahydrofolate reductase C677T and A1298C variants do not affect ongoing pregnancy rates following IVF. Hum Reprod 2007; 22: 450–6.

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syndrome and epigenetic alterations of LIT1 and H19. Am J Hum Genet 2003; 72: 156–60. 21. Allen C, Reardon W. Assisted reproduction technology and defects of genomic imprinting. Br J Obstet Gynaecol 2005; 112: 1589–94. 22. Devroey P, Van Steirteghem A. A review of ten years experience of ICSI. Hum Reprod Update 2004; 10: 19–28.

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2 Lifestyle and conception Sevilay Temel, Joop S Laven, Régine PM Steegers-Theunissen

Introduction It is clear from epidemiological and experimental studies that adverse periconceptional lifestyles significantly contribute to reproductive health and performance.1 During the periconceptional period, defined as the time span before and surrounding the conception, gametes further develop and are being programmed by epigenetic mechanisms in order to achieve successful conception and subsequent embryogenesis.2 Adverse lifestyles, such as alcohol use and malnutrition, may induce alterations in the DNA sequence and in the epigenetic (re)programming of the genome.3,4 Thus, adverse periconceptional lifestyles may irreversibly affect the gametes of parents-to-be and the subsequent embryonic genome with consequences for its future health and late-onset diseases.5,6 Failure of conception due to compromised quality of the gametes or early embryo presents in the pre-conceptional period as subfertility and is defined as a failure of conception after 1 year of regular, unprotected intercourse with the same partner. Nowadays, approximately 15% of all couples experience primary or secondary subfertility at some time during reproductive life. In around 58% the cause of subfertility predominantly originates from the woman, in 22% from the man, in 5% from both partners and in the remaining 15% no clear cause can be identified.7 In the past decade it has become apparent that subfertility is an increasing problem particularly in rich countries.8 Besides the rising age of primiparae, the adverse lifestyles of the couples exerted by the increasing demands and stresses from jobs and social obligations may significantly contribute to this problem. Recent figures show that 25% and 35% of women and men in reproductive age are smoking, and 80% and 85% use alcohol, respectively.9 Furthermore, unhealthy diets, characterised by low intakes of fruits and vegetables, and high intakes of saturated fats, are also increasingly used in this age group.10 It is well known that the aforementioned lifestyles significantly contribute to the epidemic of complex diseases such as cardiovascular disease, cancer and obesity by epigenetic mechanisms.11 However, the emerging concept that the same adverse lifestyles in the periconceptional period significantly affect conception and reproductive performance with

short- and long-term effects for the newborn, can no longer be neglected. Therefore, this chapter gives an overview of several adverse lifestyles and phenotypes of lifestyles that impact conception and some preconceptional advice.

Lifestyle factors Table 2.1 depicts the associations between the lifestyle factors cigarette smoking, (social) alcohol use, recreational drug use, malnutrition with a focus on low folate and zinc intake, and exercise in women and men, and the conception parameters fertility, fecundity and semen.

The effects of smoking The strongest lifestyle factor that compromises conception is cigarette smoking. Because one-third of the world’s population over 15 years of age smokes, its impact on reproduction is substantial. Cigarette smoke contains more than 3000 different chemical compounds, such as nicotine, nitrosamine, polycyclic hydrocarbons, cadmium and carbon monoxide. Some of these toxins enter the blood circulation of the gonads and can have direct cytotoxic and genotoxic effects on the gametes. There is some evidence that cigarette compounds have an effect only after biotransformation into reactive products or via alterations of hormone levels.47 Several of these compounds may also interact with the hypothalamic–pituitary– ovarian axis possibly by epigenetic mechanisms, such as the demethylation of CpG islands, thereby influencing gametogenesis and conception.48,49 In the woman, the tobacco compounds cadmium and cotinine, as biomarker of nicotine, accumulate in a doserelated manner in follicular fluid.48 These toxins either damage the oocytes resulting in an average 30% reduced fecundity or a 1.5–1.7- fold increased risk of reduced fecundity, defined as the probability of pregnancy in each cycle, or completely destroy the otherwise healthy oocytes with a subsequent up to 4 years shorter reproductive life span.12–15 One of the possible explanations for these findings is that cigarette smoke disrupts the meiotic spindle function of

1.6 (1.3–1.9)12

1.7 (1.3–2.1)13 1.5 (1.2–2.0)14 0.9 (0.8–1.0)15

3% morphology18

18% count17,18

15% Sperm concentration17 17% motility17

12%15,16

0.7 (1.3–1.9)12

Man

0.3 (0.2–0.5)19 0.4 (0.3–0.8)20

sperm morphology23–25

sperm quality23–25 sperm motility23–25

0.6 (0.4–0.9)19 No effect15,19,21,22

Woman

Alcohol

20–30% acrosome reaction28

ovulation27

LH26

Woman

20–30% motility28

Man

Marijuana

oocyte quality29,30 oocyte maturity29,30

follicle diameter29,30

Woman

70% sperm count31,32 seminal plasma folate:30 aneuploidy

Man

Folic acid

Subfertility33,34

sexual maturation33

Woman

morphology count, motility

Oligozoo s-permia35–38 Zinc treatment:32,39–42

Man

Zinc

Excessive: 5–7% subfertility43

Moderate: no association43

Woman

morphology concentration motility

No effects44 Short-term exhaustive Endurance:45,46

Man

Exercise

--

LH, luteinising hormone.

Semen parameters

Fertility

Fecundity

Man

Woman

Smoking

Periconceptional lifestyles in association with fecundity, fertility and semen parameters.

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Table 2.1

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the oocyte.50 A meta-analysis demonstrates that smoking increases the risk for subfertility 1.6-fold.12 Cohort and case–control studies strongly support this association by showing risk estimates of around 1.6.13,51,52 Although in some studies the effects of cigarette smoking on fertility were only observed in women who smoked more than 20 cigarettes per day, a significant dose-response relationship was identified. Besides the direct effects on the oocytes, cigarette smoke also influences tubal and cervical function, thereby detrimentally affecting the migrating spermatozoa as well. It is important to realise that the effects of cigarette smoke are reversible.51 In men, the cigarette smoke compounds cadmium and cotinine are measured in seminal plasma, indicating that these metabolites pass the blood–testes barrier and hence might induce DNA damage.48 The adverse effects of cigarette smoke might also be due to the suppression of the antioxidant concentrations in blood and semen and as such increase the oxidative DNA damage in sperm.53 In men cigarette smoking resulted in a 12% decrease of fecundity and time to pregnancy of more than 6 months.15,16 However, not all studies substantiate these associations.13,14,17,54 Two meta-analyses reveal also a reduction of 13% in the sperm concentration, 10% in sperm motility and a 3% increase in the abnormal sperm morphology in cigarette smokers.17,18 Although, semen parameters are reduced after smoking, the values often remain within the normal ranges. This has led to the use of new markers for DNA damage in the assessment of semen quality, such as the DNA defragmentation index (DFI).55 So far, the associations between cigarette smoking and DFI are contradictory and need further investigation. Experimental studies largely substantiate the findings of the human studies. Studies in rats exposed to cigarette smoke showed that its constituents and reactive metabolic intermediates directly interact with the DNA of spermatozoa leading to defective spermatogenesis and sperm maturation.56 In addition, shortterm exposure of rats to cigarette smoke resulted in a secretory deficiency of Leydig and Sertoli cells, leading to impaired epididymal sperm maturation and a diminished capacity of spermatozoa to penetrate the oocyte.57 This is very interesting because it may imply that during conception, DNA damage of the spermatozoa might also be directly transmitted to the oocyte. Subsequently this may compromise the epigenetic (re)programming of the early embryo resulting in failed implantation, early pregnancy loss, birth defects and childhood cancers in the offspring.2,58,59 In conclusion, there is enough evidence that pre-conceptional cigarette smoking has a significant impact on oocyte and semen quality. However, whether it also affects the success of conception is not clear. Most interesting, but also worrying, are first indications that early paternal cigarette smoking may exert transgenerational effects.60

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The effects of alcohol Periconceptional excessive alcohol use is detrimental for conception.61 However, less is known about the effects of social alcohol use. This is relevant because around 80% of the reproductive population uses social alcohol. Alcohol consumption causes direct cellular injury. Moreover, recent developments also indicate that ethanol induces epigenetic alterations, particularly the acetylation and the methylation of histones and hypo- and hypermethylation of DNA.3 The epigenetic effects are mainly attributable to ethanol metabolic stress generated by the oxidative and nonoxidative metabolism of ethanol, and dysregulation of methionine metabolism. In women, the frequent use of alcoholic drinks results in more menstrual disorders, such as amenorrhoea, dysmenorrhoea and irregular menstrual periods.62 Hence, the probability of conception in these women might be diminished. A 40% and 70% reduced fecundity has been reported in women with any alcohol intake and intakes above ten drinks per week, respectively.19 Social alcohol use revealed an approximately 60% reduced fecundity.20 This association was not found in subfertile women.15,21,63 Thus, there is some evidence that social alcohol use in the periconceptional period is not absolutely safe. In men, excessive alcohol consumption leads to significant morphological changes in ejaculated spermatozoa thereby reducing sperm quality, motility and sperm count.23–25 In an in vitro study the percentages of progressive motility and morphology were significantly decreased in a dose-dependent manner after exposure to high amounts of alcohol.64 However, several studies did not show a significant effect of alcohol intake on fecundity.15,19,21,22 The hamster ovum test has shown that the fertilisation rate was only 16.7% in men using alcohol compared with 50% in nonusers. In vitro and in vivo studies also showed that alcohol exposure resulted in a reduced ability of sperm to fertilise oocytes.65,66 Thus, there is some evidence that pre-conceptional excessive and social alcohol use affect the quality of the gametes and the success of conception. The potential epigenetic effects of alcohol use are intriguing and certainly warrant further investigations.

The effects of recreational drug use Recreational drug use is particularly high in teenage pregnancies. The effects of these drugs on conception, however, have been scarcely investigated. Marijuana, i.e. cannabis, is the most commonly used recreational drug worldwide. It contains at least 20 active cannabinoids including delta-9-tetrahydocannabinol (THC).67 It is known that the endocannabinoid system regulates many functions in the human body, including the reproductive tract. Two cannabinoid receptors CB1 and CB2 have been identified, that can be bound by THC. The binding of these receptors by THC antagonises the

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endocannabinoid system and as such exerts reproductive dysfunction in both women and men. In women, it has been shown that depending on the menstrual phase of the cycle the administration of the marijuana metabolite THC immediately suppresses the secretion of luteinising hormone (LH) in a dosedependent manner.26 In experimental studies in mice the cannabinoid receptors CB1 and CB2 are expressed in the uterus. Of interest is that the uterine embryo receptivity for embryo implantation can be influenced by interference with these cannabinoid receptors.68 Due to interactions between marijuana and the receptors, the oestrous preovulatory LH surge can also be blocked and hence ovulation possibly by interactions with the oestrogen receptors.27 In men, a cannabinoid receptor which is expressed in the human testes has been identified and cloned.69 Cannabinoid receptors have also been found in rat testes, the mouse vas deferens and sperm from sea urchins.28,70 It was shown that pretreatment of sperm with the marijuana metabolite THC reduces sperm motility and inhibits the acrosome reaction in a dosedependent manner thereby reducing fertilisation capacity by 20–30%.28 Of interest is that the adverse effects of THC on sperm-fertilising capacity are reversible. Despite the reported reduction of testosterone levels by marijuana use, the detrimental effects on semen parameters are still contradictory.71,72

The effects of nutrition In recent decades, in women and men of reproductive age the intake of vegetables and fruits has dramatically decreased and the intake of saturated fats, proteins and carbohydrates has increased.73 This has resulted in marginal to severe deficiencies of several micronutrients of which the most important investigated in regard to conception are folate and zinc. The B vitamin folate is important for the synthesis of DNA, transfer RNA and the amino acids cysteine and methionine as well as the methylation of DNA and histones, lipids and proteins. DNA synthesis and DNA and histone methylation (epigenetic modification) play an important role in gametogenesis, conception and (re)programming of the early embryo. Furthermore, folate serves as a substrate in the homocysteine pathway. A folate deficiency leads to hyperhomocysteinaemia of which several detrimental effects have been reported in association with reproductive outcomes.74 Zinc is a trace element that serves as cofactor for more than 80 metalloenzymes involved in DNA transcription and protein synthesis. The zinc finger proteins are implicated in the genetic expression of steroid hormone receptors.75 Zinc also has anti-apoptotic and antioxidant properties important in gametogenesis and conception.74,76,77 Evidence for the role of periconceptional nutrition on the intrauterine programming by epigenetic mechanisms, such as DNA methylation, is increasing.59,78–80

In women, beside the preventive effect of periconceptional folic acid supplementation on several congenital malformations, other effects on fertility, twinning rate and spontaneous miscarriages have been suggested.81 Folate is present in ovarian follicular fluid and as such influences the homocysteine pathway in the microenvironment of the follicle.29,82,83 Women receiving folic acid supplementation demonstrated a larger follicular diameter, a better oocyte quality and a higher degree of oocyte maturation.29,30 Moreover, it has been demonstrated that embryo quality was significantly lower in women undergoing in vitro fertilisation (IVF) treatment with a high homocysteine concentration in ovarian follicular fluid.84 Mouse preimplantation embryo studies substantiate these findings by showing that folate is essential for fertilisation and early embryo development.85 In men, folic acid supplementation increased sperm count by up to 70%.31,32 The effects are observed in dosages 20– 60 times higher than can be reached by a regular diet and are dependent on the duration of treatment and the combination with other minerals, such as zinc. This is supported by the finding that the sperm concentrations in men carrying the 677CC MTHFR wild type, leading to a normal folate state, significantly improved after folic acid and zinc sulphate intervention and that 677T MTHFR homozygotes with a lower folate state are at risk for subfertility.86,87 Of interest is also the finding that a low folate concentration in seminal plasma resulted in more sperm aneuploidy in fertile males.30 In women, a delay in sexual maturation and longstanding subfertility has been described in association with zinc deficiency.33,34 In contrast, normal menstrual cycles have been reported in subfertile and fertile women with low plasma zinc levels. So far, no significant correlation has been found between ovarian follicular fluid zinc concentrations and follicular volume, the presence of an oocyte in the follicle, or subsequent fertilisation.88 In female animals, however, a zinc deficiency resulted in disinterest in their male counterparts, failure of abnormal oestrous cycles with subsequent anovulation and lower pregnancy rates.89,90 Zinc is very important in male fertility because it directly affects testicular steroidogenesis, the oxygen consumption of spermatozoa in seminal plasma, nuclear chromatin condensation, acrosome reaction, acrosin activity and sperm chromatin stabilisation.75,91–94 Zinc deficiency leads to oligozoospermia, impotence, reduced sexual drive and hypogonadism in males and rats possibly due to a decreased testosterone synthesis by the Leydig cells.35–38 Zinc treatment, however, significantly increases testosterone and dihydrotestosterone in subfertile males.38 Correlations between low seminal zinc levels and low sperm count or subfertility are contradictory.95,96 Zinc treatment may improve sperm count, sperm motility and morphology, testosterone concentration and sexual potency in subfertile males.32,39–42 However, the

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associations between zinc concentrations in seminal plasma and conception are not very clear.32,41,42,74,96 Zinc finger proteins are transcription factors and as such may be involved in periconceptional epigenetic mechanisms.

The effects of exercise Evidence of the influence of periconceptional exercise on conception is limited. It is known that physical exercise affects general health and well-being and probably provides some protection from obesity, chronic diseases and psychological stress that may influence conception. Most research in relation to physical exercise and reproduction is primarily focused on athletes rather than on women and men who have a moderate level of exercise. In women, intensive physical exercise leads to anovulation and concomitant disorders of the menstrual cycle and subfertility. It is not clear whether moderate exercise also affects reproductive functions.97 The Nurses’ Health Study II conducted in normo-ovulatory women shows that each hour of vigorous exercise was associated with a 5–7% reduction of anovulatory subfertility independent of body mass index (BMI).43 No association was found with moderate activity. In a case–control study of subfertile women and pregnant controls, women with less than 60 minutes of vigorous exercise per day in the preconception period showed a significant reduction of anovulatory subfertility.98 This is in line with the findings in patients with polycystic ovary syndrome in whom weight loss improved physiological wellbeing, ovulation and pregnancy rates.99 One theory that needs further investigation is that exercise increases insulin sensitivity, which improves ovarian function and thereby fertilisation.100 In men, no significant effects of exercise on semen parameters or conception have been reported.44 Several studies evaluated the effects of endurance exercise on total testosterone levels with contradictory results.101,102 It has been reported that LH levels were inadequate in trained males.44,103 Furthermore, short-term exhaustive endurance training detrimentally affected spermatogenesis by reducing ejaculate volume, sperm concentration and total number of sperm.45 These findings are in line with those of others showing a reduction of sperm concentrations, total numbers of motile sperms and percentage of normal forms.46 Thus, more research is needed with regard to the effects of periconceptional moderate and low-level exercise on fertility parameters.

Some phenotypes of lifestyles Age and BMI are individual characteristics that can affect lifestyle but can also be used as a proxy of certain lifestyles. Although there are many other factors

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that affect lifestyle, such as ethnicity and religion, this section is focused on age and BMI, being the bestinvestigated characteristics in association with conception (Table 2.2). In the woman, the number and quality of oocytes sharply decrease around the age of 35 years. As a result fecundity declines from the late 20s onwards with women aged 35–39 years being half as fecund as women of 19–26 years.8,104 It was shown that in a period of 3 months 71% of conceptions occurred in women aged <30 years compared with only 41% in women more than 36 years of age.105 The age of the woman is also associated with more conceptuses with genetic abnormalities, aneuploidy and early miscarriages.115,116 It seems that the endometrium retains its receptivity regardless of age. Because ageing goes together with hypomethylation, this might be one of the epigenetic mechanisms involved.117 In men, during puberty spermatogenesis increases and reaches a plateau phase at the age of 55 years, after which it decreases gradually without a sudden age threshold.118 Ageing is accompanied by changes in the testes and alterations of the neuroendocrine regulation of Leydig cell function resulting in a reduced testosterone secretion, and a decline in sperm production, motility and morphology.108 Men of 30–35 years, as those above 55 years of age, showed a decrease of 3– 37% in semen volume, 3–53% in sperm motility and 4–18% of normal semen morphology.109–111 There is no strong evidence that sperm concentration decreases with ageing.109–111 Thus, the best sperm parameters are observed between 30 and 35 years of age, while the most significant reduction in sperm parameters occurs after the age of 55 years. Ageing has also been associated with a decline of fertility and fecundity of 11% and 250% respectively and 1.2–5fold increased of the time to pregnancy.106,107 The age effect of men, however, is less prominent than that of women, but becomes particularly relevant if the woman is also at an advanced age. An explanation is that in men the germ cells divide continuously and DNA damage can be repaired until ejaculation. In women with a BMI below 20 the reported conception rates are 44% and 30% after 3 and 6 months, respectively, compared with 37% and 17%, respectively, in women with a BMI above 25. In addition, a high BMI together with cigarette smoking more than 11–fold decreased the chance of conception.112 The Nurses’ Health Study revealed that the relative risk of ovulatory subfertility was 1.3 in women with a BMI between 24 and 31, and 2.7 in women with a BMI >32 kg/m2.43 Because it takes a woman with central obesity longer to become pregnant, fat distribution may play a role in the chance of conception.119 This is in line with the findings that a waist-to-hip ratio equal to or above 0.8 was associated with a 66% reduced fecundity in women undergoing IVF treatment.113 A modest weight loss of approximately 10% in obese women can improve conception by restoring the

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Table 2.2

Phenotypes of lifestyles in association with fecundity, fertility and semen parameters. Age Woman

Fecundity

Weight Man

Woman

35–39 years50%8,104

Man

BMI <20: 44% conceived <3 months 30% conceived

<30 years 71% conceived <3 months105 >36 years 41% conceived <3 months105

<6 months112 BMI >25: 37% conceived <3months 17% conceived <6months112 WHR ≥0.8:66% IVF pregnancies113

Fertility

Semen parameters

11–250%106,107

production108 motility, morphology108 30–35 years and >55 years:109–111 3–37% semen volume 3–53% motility 4–18% normal morphology

BMI 24–31: 1.3 RR subfertility43 BMI >32: 2.7 RR subfertility43 BMI <20:28% concentration BMI >25:22% concentration114

BMI, body mass index; WHR, waist-to-hip ratio; IVF, in vitro fertilisation; RR, relative risk.

hormonal profiles resulting in menstrual regularity, ovulation and pregnancy.120 Less is known about the influence of BMI on semen parameters and conception. A first study showed that a BMI below 20 or above 25 is associated with a 28% and 22% reduction in sperm concentration.114 It may be that a BMI above 25 kg/m2 leads to fewer chromatin-intact normalmotile sperm cells per ejaculate. Sperm chromatin is a highly organised and compact structure that maintains genetic integrity. However, more studies have to be performed to substantiate the influence of BMI of the man on fertility.

Summary From the available biological, experimental and epidemiological data it can be concluded that adverse periconceptional lifestyles of the couple, such as smoking, excessive and social alcohol use, a low dietary folate and zinc intake, and the use of marijuana significantly contribute to the failure of conception and subsequently subfertility. The effects of other recreational drugs and exercise have scarcely been investigated and therefore their contributions are difficult to estimate. Pre-conceptional age and BMI are important phenotypes for the success of conception, but most importantly in women.

So far less is known about the adverse effects of lifestyles on periconceptional epigenetic mechanisms altering the (re)programming of gametes, blastocyst and early embryo thereby permanently affecting the structures of organs, placenta and functional capacity of adult organs in later life.121 It is hypothesised that derangements in epigenetic mechanisms induced by adverse lifestyles are also implicated in the failure of conception. Therefore, it is important that the practical pre-conceptional advice presented in Table 2.3 is included in pre-conceptional care. Cigarette smoking, social alcohol use and a low intake of fruits and vegetables is highly prevalent in the reproductive population. Therefore, sizeable preventive health benefits of pre-conceptional interventions can be expected. The health benefits could even be larger if the lifestyle changes are maintained after the child wish is fulfilled. Therefore, couples of reproductive age form a highly motivated target group and the planning of pregnancy is an excellent “window of opportunity” for lifestyle modifications.122 This strongly emphasises the importance of pre-conceptional care, in which, besides medical risk assessment and treatment, adverse lifestyles can be identified by a web-based program,123 and modified by interventions.122 It is expected that pre-conceptional care initiatives will improve reproduction and counteract the use of artificial reproductive techniques resulting in a

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Table 2.3 Preconception advises to improve reproductive health and performance. Smoking:

Cigarette smoking cessation by women and men

Alcohol:

Excessive and social alcohol use should be stopped by both women and men

Marijuana:

Women and men should stop the use of recreational drugs

Folate and Zinc:

Women and men should use a folate and zinc rich dietary pattern. In addition, women are recommended to use a folic acid supplement of 0.4 mg per day until the 10th week of pregnancy. Men are advised on indication only to use a folic acid supplement of 0.4 mg per day or zinc of a maximum of 15 mg per day

Exercise:

Mild to moderate exercise is stimulated in women and men

Age:

Women should plan pregnancy in their twenties and early thirties Men should plan pregnancy between their twenties and forthies.

BMI:

Women should preconceptionally reduce BMI below 25. To ensure maximum fertility potential also men may reduce weight in the preconceptional period.

lowering of the psychological and physical burden for the couples and significant reduction of the medical health care costs. Hopefully, this overview will stimulate the further development of pre-conceptional medicine aimed at improving the reproduction and health of the current and future generations.

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45. Vaamonde D, Da Silva ME, Poblador MS, Lancho JL. Reproductive profile of physically active men after exhaustive endurance exercise. Int J Sports Med 2006; 27: 680–9. 46. De Souza MJ, Arce JC, Pescatello LS, Scherzer HS, Luciano AA. Gonadal hormones and semen quality in male runners. A volume threshold effect of endurance training. Int J Sports Med 1994; 15: 383– 91. 47. Field AE, Colditz GA, Willett WC, Longcope C, McKinlay JB. The relation of smoking, age, relative weight, and dietary intake to serum adrenal steroids, sex hormones, and sex hormone-binding globulin in middle-aged men. J Clin Endocrinol Metab 1994; 79: 1310–16. 48. Zenzes MT. Smoking and reproduction: gene damage to human gametes and embryos. Hum Reprod Update 2000; 6: 122–31. 49. Liu H, Zhou Y, Boggs SE, Belinsky SA, Liu J. Cigarette smoke induces demethylation of prometastatic oncogene synuclein-gamma in lung cancer cells by downregulation of DNMT3B. Oncogene 2007; 26: 5900–10. 50. Zenzes MT, Wang P, Casper RF. Cigarette smoking may affect meiotic maturation of human oocytes. Hum Reprod 1995; 10: 3213–17. 51. Howe G, Westhoff C, Vessey M, Yeates D. Effects of age, cigarette smoking, and other factors on fertility: findings in a large prospective study. Br Med J (Clin Res Ed) 1985; 290: 1697–700. 52. Hartz AJ, Kelber S, Borkowf H et al. The association of smoking with clinical indicators of altered sex steroids—a study of 50,145 women. Public Health Rep 1987; 102: 254–9. 53. Shen HM, Chia SE, Ni ZY et al. Detection of oxidative DNA damage in human sperm and the association with cigarette smoking. Reprod Toxicol 1997; 11: 675–80. 54. Martini AC, Molina RI, Estofan D et al. Effects of alcohol and cigarette consumption on human seminal quality. Fertil Steril 2004; 82: 374–7. 55. Smit M, Dohle GR, Hop WC et al. Clinical correlates of the biological variation of sperm DNA fragmentation in infertile men attending an andrology outpatient clinic. Int J Androl 2007; 30: 48–55. 56. Fraga CG, Motchnik PA, Wyrobek AJ, Rempel DM, Ames BN. Smoking and low antioxidant levels increase oxidative damage to sperm DNA. Mutat Res 1996; 351: 199–203. 57. Kapawa A, Giannakis D, Tsoukanelis K et al. Effects of paternal cigarette smoking on testicular function, sperm fertilizing capacity, embryonic development, and blastocyst capacity for implantation in rats. Andrologia 2004; 36: 57–68. 58. Feil R. Environmental and nutritional effects on the epigenetic regulation of genes. Mutat Res 2006; 600: 46–57. 59. Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 2004; 20: 63–8. 60. Pembrey ME, Bygren LO, Kaati G et al. Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet 2006; 14: 159–66.

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Lifestyle and conception 61. Commenges-Ducos M. Clinical assessment of toxics deleterious to fertility. Gynecol Obstet Fertil 2006; 34: 985–9. [in French] 62. Bahamondes L, Bueno JG, Hardy E et al. Identification of main risk factors for tubal infertility. Fertil Steril 1994; 61: 478–82. 63. Juhl M, Nyboe Andersen AM, Gronbaek M, Olsen J. Moderate alcohol consumption and waiting time to pregnancy. Hum Reprod 2001; 16: 2705–9. 64. Donnelly GP, McClure N, Kennedy MS, Lewis SE. Direct effect of alcohol on the motility and morphology of human spermatozoa. Andrologia 1999; 31: 43–7. 65. Donnelly ET, Lewis SE, McNally JA, Thompson W. In vitro fertilization and pregnancy rates: the influence of sperm motility and morphology on IVF outcome. Fertil Steril 1998; 70: 305–14. 66. Barratt CL, Tomlinson MJ, Cooke ID. Prognostic significance of computerized motility analysis for in vivo fertility. Fertil Steril 1993; 60: 520–5. 67. Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 2001; 178: 101–6. 68. Schmid PC, Paria BC, Krebsbach RJ, Schmid HH, Dey SK. Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. Proc Natl Acad Sci USA 1997; 94: 4188–92. 69. Gerard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 1991; 279: 129–34. 70. Pertwee RG, Ross RA, Craib SJ, Thomas A. (–)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol 2002; 456: 99–106. 71. Kolodny RC, Masters WH, Kolodner RM, Toro G. Depression of plasma testosterone levels after chronic intensive marihuana use. N Engl J Med 1974; 290: 872–4. 72. Hembree WC 3rd, Nahas GG, Zeidenberg P, Huang HF. Changes in human spermatozoa associated with high dose marihuana smoking. Adv Biosci 1978: 429–39. 73. Kreijl CF, Knaap AGAC, Busch MCM et al. Ons eten gemeten. Gezonde voeding en veilig voedsel in Nederland. RIVM Rapport 270555007. Volksgezondheid Toekomst Verkenning 2004. 74. Ebisch IM, Thomas CM, Wetzels AM et al. Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility. Fertil Steril 2008; in press. 75. Favier AE. The role of zinc in reproduction. Hormonal mechanisms. Biol Trace Elem Res 1992; 32: 363–82. 76. Chimienti F, Aouffen M, Favier A, Seve M. Zinc homeostasis-regulating proteins: new drug targets for triggering cell fate. Curr Drug Targets 2003; 4: 323–38. 77. Zago MP, Oteiza PI. The antioxidant properties of zinc: interactions with iron and antioxidants. Free Radic Biol Med 2001; 31: 266–74. 78. McKay JA, Williams EA, Mathers JC. Folate and DNA methylation during in utero development and aging. Biochem Soc Trans 2004; 32: 1006–7. 79. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC. Dietary protein restriction of pregnant

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rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 2005; 135: 1382–6. Timmermans S. Periconceptional folic acid supplementation significantly affects intrauterine fetal growth (Abstract). J Reprod Sci 2008; 15: (S2), 124A. Muggli EE, Halliday JL. Folic acid and risk of twinning: a systematic review of the recent literature, July 1994 to July 2006. Med J Aust 2007; 186: 243–8. Steegers-Theunissen RP, Steegers EA, Thomas CM, et al. Study on the presence of homocysteine in ovarian follicular fluid. Fertil Steril 1993; 60: 1006–10. Brouns R, Lindemans J, Eijkemans R, De Jonge R, Macklon N, Steegers-Theunissen R. Follicular folate and cobalamin status and fertilization rate and pregnancy after human ovarian hyperstimulation. TFO 2003; 2: 51–2. Ebisch IM, Peters WH, Thomas CM et al. Homocysteine, glutathione and related thiols affect fertility parameters in the (sub)fertile couple. Hum Reprod 2006; 21: 1725–33. O’Neill C. Endogenous folic acid is essential for normal development of preimplantation embryos. Hum Reprod 1998; 13: 1312–16. Ebisch IM, van Heerde WL, Thomas CM et al. C677T methylenetetrahydrofolate reductase polymorphism interferes with the effects of folic acid and zinc sulfate on sperm concentration. Fertil Steril 2003; 80: 1190–4. Bezold G, Lange M, Peter RU. Homozygous methylenetetrahydrofolate reductase C677T mutation and male infertility. N Engl J Med 2001; 344: 1172–3. Ng SC, Karunanithy R, Edirisinghe WR et al. Human follicular fluid levels of calcium, copper and zinc. Gynecol Obstet Invest 1987; 23: 129–32. Shaw NA, Dickey HC, Brugman HH, Blamberg DL, Witter JF. Zinc deficiency in female rabbits. Lab Anim 1974; 8: 1–7. Swenerton H, Hurley LS. Zinc deficiency in rhesus and bonnet monkeys, including effects on reproduction. J Nutr 1980; 110: 575–83. Huacuja L, Sosa A, Delgado NM, Rosado A. A kinetic study of the participation of zinc in human spermatozoa metabolism. Life Sci 1973; 13: 1383– 94. Kvist U, Kjellberg S, Bjorndahl L, Soufir JC, Arver S. Seminal fluid from men with agenesis of the Wolffian ducts: zinc-binding properties and effects on sperm chromatin stability. Int J Androl 1990; 13: 245–52. Riffo M, Leiva S, Astudillo J. Effect of zinc on human sperm motility and the acrosome reaction. Int J Androl 1992; 15: 229–37. Steven FS, Griffin MM, Chantler EN. Inhibition of human and bovine sperm acrosin by divalent metal ions. Possible role of zinc as a regulator of acrosin activity. Int J Androl 1982; 5: 401–12. Saaranen M, Suistomaa U, Kantola M, Saarikoski S, Vanha-Perttula T. Lead, magnesium, selenium and zinc in human seminal fluid: comparison with semen parameters and fertility. Hum Reprod 1987; 2: 475–9. Carpino A, Siciliano L, Petroni MF et al. Low seminal zinc bound to high molecular weight proteins in asthenozoospermic patients: evidence of increased

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Textbook of Periconceptional Medicine sperm zinc content in oligoasthenozoospermic patients. Hum Reprod 1998; 13: 111–14. Ellison P. Human ovarian function and reproductive ecology: new hypothesis. Am Anthropol 1990; 92: 933–52. Green BB, Daling JR, Weiss NS, Liff JM, Koepsell T. Exercise as a risk factor for infertility with ovulatory dysfunction. Am J Public Health 1986; 76: 1432–6. Clark AM, Ledger W, Galletly C et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995; 10: 2705–12. Palomba S, Giallauria F, Falbo A et al. Structured exercise training programme versus hypocaloric hyperproteic diet in obese polycystic ovary syndrome patients with anovulatory infertility: a 24week pilot study. Hum Reprod 2008; 23: 642–50. Viru AM, Hackney AC, Valja E et al. Influence of prolonged continuous exercise on hormone responses to subsequent exercise in humans. Eur J Appl Physiol 2001; 85: 578–85. White LJ, Dressendorfer RH, Ferguson MA, Wade CE. Maintenance of testosterone status in fitness joggers after increased training mileage. Eur J Appl Physiol 2002; 86: 498–502. Hackney AC, Sinning WE, Bruot BC. Hypothalamicpituitary-testicular axis function in endurancetrained males. Int J Sports Med 1990; 11: 298–303. Dunson DB, Colombo B, Baird DD. Changes with age in the level and duration of fertility in the menstrual cycle. Hum Reprod 2002; 17: 1399–403. Kaplan B, Nahum R, Yairi Y et al. Use of various contraceptive methods and time of conception in a community-based population. Eur J Obstet Gynecol Reprod Biol 2005; 123: 72–6. Hassan MA, Killick SR. Effect of male age on fertility: evidence for the decline in male fertility with increasing age. Fertil Steril 2003; 79(Suppl 3): 1520–7. Mathieu C, Ecochard R, Bied V, Lornage J, Czyba JC. Cumulative conception rate following intrauterine artificial insemination with husband’s spermatozoa: influence of husband’s age. Hum Reprod 1995; 10: 1090–7. Vermeulen A, Kaufman JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res 1995; 43: 25–8.

109. Fisch H, Golubuff ET, Olson JH et al. Semen analyses in 1283 men from United States over a 25-year period: no decline in quality. Fertil Steril 1996; 65: 1009–14. 110. Andolz P, Bielsa MA, Vila J. Evolution of semen quality in North-eastern Spain: a study in 22,759 infertile men over a 36 year period. Hum Reprod 1999; 14: 731–5. 111. Rolf C, Behre HM, Nieschlag E. Reproductive parameters of older compared to younger men of infertile couples. Int J Androl 1996; 19: 135–42. 112. Bolumar F, Olsen J, Rebagliato M, Saez-Lloret I, Bisanti L. Body mass index and delayed conception: a European Multicenter Study on Infertility and Subfecundity. Am J Epidemiol 2000; 151: 1072–9. 113. Wass P, Waldenstrom U, Rossner S, Hellberg D. An android body fat distribution in females impairs the pregnancy rate of in-vitro fertilization-embryo transfer. Hum Reprod 1997; 12: 2057–60. 114. Jensen TK, Andersson AM, Jorgensen N et al. Body mass index in relation to semen quality and reproductive hormones among 1,558 Danish men. Fertil Steril 2004; 82: 863–70. 115. Sauer MV, Paulson RJ, Lobo RA. Reversing the natural decline in human fertility. An extended clinical trial of oocyte donation to women of advanced reproductive age. JAMA 1992; 268: 1275–9. 116. Smith KE, Buyalos RP. The profound impact of patient age on pregnancy outcome after early detection of fetal cardiac activity. Fertil Steril 1996; 65: 35–40. 117. Burzynski SR. Aging: gene silencing or gene activation? Med Hypotheses 2005; 64: 201–8. 118. Junqueira LC, Carneiro J. Basic Histology: Norwalk: Appleton & Lange, 1989. 119. Zaadstra BM, Seidell JC, Van Noord PA et al. Fat and female fecundity: prospective study of effect of body fat distribution on conception rates. BMJ 1993; 306: 484–7. 120. Norman RJ, Clark AM. Obesity and reproductive disorders: a review. Reprod Fertil Dev 1998; 10: 55–63. 121. Gluckman PD, Hanson MA. Maternal constraint of fetal growth and its consequences. Semin Fetal Neonatal Med 2004; 9: 419–25. 122. Steegers EA. Begin bij’t begin. Oratiereeks Erasmus MC 2005. Demmenie Grafimedia, Leiden. 123. www.zwangerwijzer.nl.

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3 Pre-conception care* Kees Boer, Regine PM Steegers-Theunissen, Eric AP Steegers

Introduction From the early 20th century onwards, obstetric care has been directed to achieve an optimum outcome of pregnancy for both mother and child. To qualify the quality of obstetric care, the maternal mortality rate during and shortly after pregnancy, and the perinatal mortality rate are used as rough indicators. After antibiotics became available in the 1930s and blood transfusions in the 1940s and 1950s, maternal mortality sharply decreased.1–3 Perinatal mortality decreased, particularly during the second half of the previous century, due to improved living conditions, the introduction of vaccination policies, Rhesus D sensibilisation prophylaxis and paediatric care immediately after delivery.1,4–6 During the past decades, however, perinatal and maternal mortality have not further decreased.3,7 The most common causes of perinatal mortality and morbidity are major congenital malformations,8 premature birth9 and foetal growth restriction.10 The improvement of obstetric care begins with new knowledge. It is becoming increasingly clear that the causes of many of the problems for mother and child reside in the first 12 weeks of pregnancy. It is largely during this particular period, when the woman often is not aware of being pregnant, that it is determined whether the child will be born with a congenital malformation, prematurely or with a growth restriction and whether the mother will develop pre-eclampsia a few months later. Embryogenesis and early placentation take place in this period, in which the embryonic and placental tissues are most vulnerable to (un)healthy parental lifestyles and other harmful environmental exposures that interact with a genetic background derived from both parents. A few examples of lifestyles amenable to change with significant effect are smoking, vitamin supplement use and nutrition. In order to be able to improve the health for mother and child in the future, both scientific research and the organisation and content of obstetric care should focus much more on the first 12 weeks of pregnancy. The principle that current care begins after early pregnancy originates from a century ago when early check-ups

were not considered advisable because there was still a relatively large chance of a miscarriage. If one wants to make this neglected portion of the pregnancy part of prenatal care, then that care must begin even before the pregnancy. This is called pre-conception care. The objective of pre-conception care is the prevention of defects and disease in mother and child by detecting and, if possible, eliminating the risk factors before conception.11 Moos, together with Cefalo, one of the founding fathers of pre-conception care in America, described it as the active preparation for a pregnancy such that the youngest embryonic cells are offered as healthy an environment as possible.12 The Health Council of The Netherlands defined pre-conception care as “the entire range of measures designed to promote the health of the expectant mother and her child, which, in order to be effective, must preferably be adopted prior to conception”.13 Because of increasing evidence of the importance of not only the paternal genetic contribution, but also the lifestyle of the father-to-be, pre-conception counselling of both parents is now beginning.14,15 Follow-up of preconception recommendations by both parents-to-be may not only result in relatively short-term achievements – an uncomplicated pregnancy and a healthy child – but also improved future general health as they may be more receptive to information on risky lifestyles during that time period. Pre-conception care may, therefore, also be an excellent instrument to improve public health.16 In this chapter an outline is given of the content and organisation of pre-conception care. Pre-conception care entails risk assessment, health promotion, counselling and intervention.17 Moreover, in the overview, harmful exposures on reproductive outcome are presented. The effects of these exposures on fertility have been dealt with in Chapter 2.

Risk assessment The screening of risk factors in couples comprises the collection of information on the medical, obstetric, andrological and family histories; possible infections;

* Partly derived from: Boer K, Steegers EAP. Preconceptiezorg. In. Heineman MJ, Evers JLH, Massuger LFAG, Steegers EAP, eds. Obstetrie en Gynaecologie De Voortplanting van de Mens. Maarsen: Elsevier Gezondheidszorg, 2007: 203–25.

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genetic disorders; medication use; lifestyles such as smoking, use of alcohol, drugs and vitamin supplements; quality of diet; and environmental and occupational exposures (Table 3.1).18

Health promotion Health promotion deals with not only the avoidance of the aforementioned harmful lifestyles, medicines and environmental exposures, but also the prevention of specific diseases such as toxoplasmosis and the use of a healthy balanced diet. Moreover, attention can be paid to working conditions. It also offers the opportunity to discuss prenatal screening and diagnosis in a future pregnancy and the importance of timely prenatal care.

Smoking Smoking is one of the strongest lifestyle risk factors with a number of detrimental effects on reproduction. Evidence is available that smoking, including sometimes passive smoking, increases the risk of extrauterine pregnancy, congenital malformations (oral clefts, club foot and gastroschisis), multiple births, premature birth, intrauterine growth restriction (girls more than boys), placenta praevia (girls more than boys), premature rupture of membranes and abruptio placentae, resulting in increased perinatal and neonatal mortality and morbidity.20–37 These detrimental effects can be partially explained by nicotine induced vasoconstriction, through which the placental blood flow is reduced,38 although not acutely39 and the reduced oxygen supply as a consequence of the competition with carbon monoxide in the binding of haemoglobin.40,41 Both effects lead to a decreased supply of nutrients and oxygen to the embryonic, foetal and placental tissues.11,42,43 It appears, however, that differential sensitivity to smoking exists, which is probably due to differences in the individual genetic profile of detoxification genes. This is substantiated by the 2- to 6-fold increased risks for cleft lip and/or palate observed by interactions between maternal and/or paternal smoking and polymorphisms in genes of detoxification enzymes like glutathione-S transferases and N-acetyltransferases.22,23 Comparable interactions are observed between smoking and the polymorphisms in the CYP1A1 and GSTT1 genes and a decrease in birth weight of up to 520 g and 642 g, respectively.44,45 Moreover, recently three single nucleotide polymorphisms involved in gastroschisis were found to strongly interact with maternal smoking: NOS3 odds ratio (OR) 5.2, 95% confidence interval (CI) (2.4–11.4); ICAM1 (OR 5.2, 95% CI 2.1–12.7); and NPPA (OR 6.4, 95% CI 2.8–14.6).24 Intriguing are the long-term effects of smoking during pregnancy on the neurological development of the child, the increased risks of asthma or bronchial infections,46 obesity,47 hyperactivity,48 aggressive behaviour49 and

Table 3.1

Preconception anamneses.18

Medical Previous History Diabetes Thyroid disease Asthma Cardiac disorders High blood pressure Deep venous thrombosis Kidney disease Systemic lupus erythematosus Epilepsy Sickle cell anaemia Malignant disorders Reproductive Past History Defects of uterus and cervix Two or more miscarriages Premature birth One or more intrauterine deaths (IUD) Previous child with birth weight of < 2500 g Previous child admitted to neonatal intensive care unit Previous child with congenital defect Previous child with sickle cell disease Nutritional History Vegetarian/vegan Frequent snacks or pica Bulimia/anorexia nervosa Special diet Use of vitamin supplements Milk intolerance Previous Infectious Disease History SOA Herpes simplex virus infection Chlamydia infection Human papilloma virus infection Gonorrhoea Viral hepatitis (or risk behaviour) HIV (or risk behaviour) Professional exposure to blood products Blood transfusion Cat owner Vaccination against rubella Family History Congenital defects/genetic disorders Consanguinity Ethnic background Social History/Lifestyle Alcohol use (number of glasses per day) Smoking behaviour (number of cigarettes per day) Marijuana, cocaine or other drug use Exposure to chemicals at home or at work Exposure to radiation at work Actively exercising Age Height and weight Medication history Use of prescription medication Use of “over-the-counter” medication

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smoking patterns of young adult offspring.50 Influences of tobacco smoke on the foetal dopaminergic system could play a role in the development of the behavioural problems.51 When confounding factors were taken into account, smoking during pregnancy did not remain an independent predictor of IQ or neurological soft signs in 9-year-old children.52 Whether epigenetic interference of the tobacco compounds in combination with related lifestyles, such as malnutrition, is involved should be determined in future studies. The pre-conception advice to the couple is to quit smoking. If the woman is a heavy smoker, a nicotinereplacement therapy, such as nicotine patches (category D) and nicotine chewing gum (category C), can be helpful. The effect and side-effects of these drugs during pregnancy however, have hardly been studied. Although, these alternatives are, indeed, less harmful than cigarettes, they still contain the harmful substance nicotine. Therefore, the use of these replacement therapies immediately before or during pregnancy is not advised as long as there is no evidence that nicotine replacement therapy is actually effective for smoking cessation in pregnancy.53 Buproprione (Zyba, category B) has been approved by the Food and Drug Administration (FDA) as a substance to be used to stop smoking, it should, however, only be used before conception.53

Caffeine Coffee is used even more than alcohol or tobacco. It is remarkable, that pregnant women quite often discontinue to drink coffee in early pregnancy, because they do not like it anymore. Maybe that this serves as a natural protection against the negative effects of coffee or the caffeine within coffee on pregnancy outcome or foetal well-being. Many studies have been undertaken on the relation between coffee intake and the incidence of miscarriage or foetal death. An inconsistently positive association was reported, but a review in 2004 of the results of 15 epidemiological studies concluded that the evidence must be considered to be equivocal, given the biases which are probably present and the fact that most of the potential biases would tend to overestimate any association.54 However, a population-based prospective cohort study found that an increasing dose of daily caffeine intake during pregnancy was associated with an increased risk of miscarriage, compared with no caffeine intake, with an adjusted hazard ratio (aHR) of 1.42 (95% CI 0.93–2.15) for caffeine intake of <200 mg/day, and aHR of 2.23 (1.34–3.69) for intake of 200 mg/day or more. The intake of 100 mg caffeine equals about 150 ml coffee.55 Interestingly, the magnitude of the association appeared to be stronger among women without a history of miscarriage (aHR 2.33, 1.48–3.67) than among women with such a history (aHR 0.81, 0.34–1.94). Even more dramatic is a recent report from Uruguay, where a large case–control study

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showed a significantly increased risk of foetal death (>20 weeks and birth weight >350 g) (OR 2.33, 95% CI 1.23–4.41) at a mean caffeine intake of ≥300 mg/day compared with no caffeine consumption during pregnancy.56 A positive relation between the use of coffee/caffeine and miscarriage seems also likely because of the reported association between a CYP1B1 polymorphism with first-trimester miscarriage, and the interaction of this polymorphism and caffeine intake.57 CYP1B1 is involved in the metabolism of key steroid hormones including oestradiol and progesterone, but it is also known to take part in the metabolism of theophylline, caffeine and other xenobiotics.57 CYP1B1 is induced by smoking and the enzyme activity may be altered among smokers. Thus, an interaction between smoking and drinking coffee on the incidence of miscarriage must be considered. Furthermore, a case–control study of 58 cases with two or more recurrent pregnancy losses (RPL) and fertile 147 controls found that the RPL risk significantly increased only among women who had homozygous CYP1A21F alleles with a dosage effect of daily caffeine intake (<100 mg (reference); 100–299 mg: OR 1.94, 95% CI 0.57–6.66; 300 mg or more: OR 5.23, 95% CI 1.05–25.9; p for trend 0.03).58 CYP1A2 is an enzyme primarily responsible for caffeine metabolism, and caffeine clearance rates differ among individuals through genetic propensity. In conclusion, in coffee drinking individual factors, in particular genotype and lifestyle, may determine negative effects on pregnancy outcome.

Alcohol In The Netherlands, approximately 80–90% of the women and men of child-bearing age use alcohol. Unfortunately, binge-drinking behaviour, i.e. consuming five or more alcoholic drinks at one time, is increasing, especially among young people. In 2005 in The Netherlands, 75% of 11–16-year-old young people – in particular girls – who used alcohol, admitted binge drinking. Binge drinking in the pre-conception period appeared to be associated with unintended pregnancies resulting in a live birth among white women, but not among black women in the US.59 Preconception binge drinkers were also more likely to engage in other risky behaviours, including drinking during pregnancy. Although, many women stop drinking alcohol as soon as they are pregnant, most do not stop when they are planning pregnancy. An estimated 35–50% of the pregnant women in The Netherlands continue to consume alcoholic drinks. It is well known that excessive use of alcohol during pregnancy is harmful to the foetus.60 In 1973, the foetal alcohol syndrome (FAS) was documented for the first time. It has been demonstrated that during the first trimester of pregnancy the use of an average of six to nine glasses of alcohol per day leads to facial

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deformities characteristic for FAS.61–63 However, an average use of one glass per day can also be harmful for the psychomotor development of the child.64,65 Binge drinking is probably more dangerous than the chronic use of alcohol during meals.66,67 In the case of binge drinking, the risk of FAS appears to increase with less than six glasses per day. Alcohol use at the time of conception, also by the biological father-to-be, can lead to a reduced chance of conception.68,69 Furthermore, alcohol use enhances the risks of miscarriage,70 intrauterine foetal death71 and, apart from the FAS malformations, congenital malformations such as a cleft lip and/or cleft palate72,73 and kidney defects.67 In addition, during lactation, maternal alcohol use decreases milk production and the intake of milk by the child.74,75 The causes of these adverse reproductive outcomes are not completely understood. Possible explanations are that alcohol causes direct cell damage through oxidative stress and the formation of free oxygen radicals,76,77 the induction of chromosomal defects, interaction with polymorphisms in detoxification enzymes and possible interference with epigenetic mechanisms.78,79 Excessive alcohol is often accompanied by other unhealthy lifestyles, such as malnutrition, vitamin and nutritional deficiencies (folic acid, thiamine, zinc and magnesium) that could also play a role, more so because antioxidants have been shown to diminish ethanol induced congenital malformations.80 Therefore, both women and men planning pregnancy are advised to stop alcohol use. This advice also applies to pregnant and lactating women. During antenatal care, the use of alcohol should be verified in every trimester and followed up with information or the offer of help to stop drinking because cessation at any given moment during the pregnancy prevents further damage. Psychotherapy must be given in the case of alcoholism. Medication, such as disulfiram (Refusal®, Antabus®) inhibits the breakdown of acetaldehyde after alcohol consumption, which results in an increase in the acetaldehyde level and adverse reactions. The use of this drug during the first trimester of pregnancy, however, is contraindicated, because it is shown to be more teratogenic than ethanol.81 Finally, it is very important that vitamin or nutritional deficiencies are diagnosed and treated with vitamin supplements or parenteral treatment.

Drugs The prevalence of the use of recreational drugs by women and men of reproductive age varies between countries. In The Netherlands recent use in the whole population of cannabis (5.4%) or cocaine, opiates, ecstasy, amphetamine totalled 7.6%, whereas actual use was 4.2%, however, in the younger population (12–18 years) it was 12.3%.82 The division between hard drugs, soft drugs and other substances is particularly determined by the realistic or feared social effects. Therefore, there is an important overlap between the

use of hard and soft drugs, and illegality, such that use is often related to poor socioeconomic circumstances that already provide a poor environment for the developing foetus. Professional guidance is necessary throughout and after pregnancy in order to change living conditions and monitor the child after delivery to protect them from malnourishment. The question concerning drug use must be included in pre-conception risk assessment. Prenatal care must always take place in a specialised centre with a programme to care for drug users. Drug use by the partner must also be verified and included in the treatment, because it is relevant for the parenting of the child and for the creation of a situation in which the woman does not slide back into drug use. Unfortunately, an addicted woman will not visit a pre-conception care clinic. Therefore, it is important that pre-conception care is given proactively by, for example, the general practitioner, in which case information is also given about the use of reliable contraconception and protection against venereal diseases. In particular, in the case of heroin addiction, the woman sometimes relies on the secondary amenorrhoea as a side-effect of heroin use. When following a methadone programme, there is a realistic chance that her ovulatory cycle will be restored with subsequent unexpected pregnancy as a result. Whether addicted mothers should breast-feed is a controversial issue. Because of the lack of clarity concerning the effect of drugs in breast milk, breast feeding should certainly be advised against in case of heroin or cocaine use.

Opiates Opiates interfere with the opioid receptors in the central nervous system and the neurons of the digestive tract. These drugs are effective analgesics, cause euphoria (a “high”) and have a calmative effect. Tolerance and dependence do not occur except when the opiates are used as pain killers when there is no pain and the other effects are pursued. When habituation occurs, more of the substance must be used to achieve the same effect, while abstinence results in symptoms such as nausea, diarrhoea, muscle pain, agitation, sleeplessness, hypertension, fever, tremors, dysphoria, oversensitivity for pain, tachycardia and poor appetite. Heroin is the most widely trafficked opiate, but its intravenous use in particular has declined. This may be due to the availability of cocaine and amphetamines and the concomitant disease risks due to intravenous use. In 2001 in The Netherlands 0.4% of the population of 12 years old and older had ever been in contact with heroin, hardly more than in 1997.83 The majority of the heroin-addicted women also use other drugs, such as cocaine and cannabis. Heroin and methadone are the most widely used drugs and are accompanied by menstrual disorders, anovulation and, therefore, infertility. Both drugs are not associated with an increased risk of congenital malformations in the offspring. However, the risk is enhanced for miscarriage, perinatal mortality, foetal growth restriction,

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prematurity, microcephaly and behavioural teratogenicity (hyperactivity) (Table 3.2).84–89 From meta-analysis it was determined that the relative risk of low birth weight is 4.6 for the combined use of heroin and methadone and 1.4 for methadone use only.90 The use of opiates during pregnancy and delivery can cause respiratory depression in newborn or neonatal abstinence syndrome (NAS, symptoms as in adults).91 NAS has been traced in one retrospective study to 12–90% of the newborns who were exposed to methadone in utero, the highest percentage being reached in those with >40 mg methadone per day,92 although this dosage related occurrence of NAS was not found in other studies.89,93 Neonates were more likely to experience withdrawal if their mothers were treated with heroin.92 However, methadone notably protracts the newborn’s abstinence syndrome.94,95 Tobacco use in conjunction with methadone increases the interval to and severity of NAS.96 In case of opiate exposure during pregnancy, the newborn should be observed and treated in the neonatal ward. Because of the shorter half-life of heroin, NAS occurs sooner after birth than with methadone use, the time to onset of withdrawal symptoms being 2.8 (1–13) days in an Irish study.97 Preterm children of opiate-addicted mothers show less NAS.98 Acute abstinence of heroin is contraindicated during pregnancy. If detoxification before pregnancy is not possible, the pregnant women should be admitted as early as possible in the pregnancy to a methadonedistribution programme.87 Through this, the day-andnight rhythm is normalised once again, money ceases to be a problem and an assessment can be made to determine whether she is capable of organising a normal pattern of life, which is important for being able to care for a child. The advantage of methadone over heroin is that it can be taken orally, has a longer halflife and provides a more constant concentration in the blood, which prevents withdrawal symptoms in the pregnant woman. Detoxification during the second trimester is allowed in women who are self-motivated, but must be performed under strict supervision. The greatest danger for both the pregnant woman and the foetus is failed detoxification and relapse. During delivery, narcotics with an agonist-antagonist effect are contraindicated in addicted women. One must be aware that such a woman going into labour will either take an extra dosage of opiates or take the dosage too quickly after the previous dosage. This can cause respiratory depression in the newborn and the pregnant woman should therefore be warned about this. She must be put at ease concerning pain relief. Pain relief is not contraindicated, but should be given separately from the maintenance medication.

In 2001, among Dutch youth over the age of 12 years, 2.9% had ever used cocaine, in contrast to 2.1% in 1997, while the actual usage in the reproductive population was between 1% and 0.5%.83 Around 25% of them are regular users and in particular in the municipal areas these percentages are higher. The use of cocaine increases the chance of maternal morbidity and mortality through cerebrovascular accidents, subarachnoid haemorrhage, hypertension, convulsions, pre-eclampsia and lung oedema.99–101 Underlying vascular malformations, however, appear to be present in most cerebral accidents following street drug use.102 The use of cocaine during pregnancy was also reported to increase the risk of offspring affected with urogenital, cardiovascular malformations, gastrointestinal disorders, including necrotising enterocolitis, intestinal atresia and spontaneous colon perforation as well as deformities of the extremities,103–107 although this was not confirmed in a recent study on a total of 717 cocaine-exposed infants and 7442 nonexposed infants108 and an earlier prospective, longitudinal cohort of 272 offspring of 154 prenatally identified crack/cocaine users and 154 non-using controls that were matched on race, parity, location of prenatal care and socioeconomic status.109 One meta-analysis suggested that the cocaine attributable risks of congenital malformations do not exceed the risks due to other hard drugs (Table 3.2).110 Another meta-analysis on the effect of in utero exposure to cocaine on infant neurobehavioural outcome showed a small effect.111 The largest reliable differences appeared for the motor performance and abnormal reflexes clusters. Also, in a more recent study, heavier prenatal cocaine exposure appeared not to be an independent risk factor for depressed scores on the Bayley Scales of Infant Development up to 24 months age when term infants are compared with lighter exposed or unexposed infants of the same demographic background.112 Cocaine, however, does pose an extra risk of premature rupture of the membranes, prematurity and in particular abruptio placentae.110,113 The problem with cocaine addiction is that it is often accompanied by smoking and alcohol use. Therefore, the independent effects of cocaine on reproductive outcome are difficult to establish. Nevertheless, it has emerged from a case–control study that adopted children who had been exposed to cocaine had a significant decreased head circumference, a lower IQ and poorer language development.114 Unfortunately, there is no effective drug medication therapy for cocaine addiction. Symptoms of co-morbidity, such as depression, can be treated with medication.

Cocaine

The use of amphetamines increases the feeling of energy or vitality, and sometimes even euphoria. A causal relationship between the use of amphetamines during pregnancy and congenital malformations in the offspring has been suggested.115 This could not be confirmed in a

Cocaine is an alkaloid that causes a stimulating effect. It can be used in various forms but is generally snorted and in 10% injected intravenously.

Amphetamines

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Table 3.2

Risks of use of cocaine and other drugs.110

Malformations (RR) Birth weight <2500 g (RR) Preterm (RR) Preterm premature rupture of membranes (RR) Abruptio placentae (RR) Pregnancy duration (weighted ∆) (days) Head circumference (weighted ∆) (cm) Birth weight (weighted ∆) (g) Length at birth (weighted ∆) (cm)

Cocaine vs drugs free

Cocaine + drugs vs drugs free

Cocaine vs cocaine + drugs

Cocaine vs other drugs

Cocaine + drugs vs other drugs

1.70 2.85 2.48 1.85

2.1 4.28 3.19 3.18

0.9 0.88 0.86 0.51

3.0 1.02 1.73 2.84

1.08 1.55 1.85 4.40

4.55 1.83

4.95 1.65

0.88 0.08

4.72 2.40

4.28 0.25

1.72

1.21

0.58

0.50

0.19

495.59 2.57

512.98 2.17

26.16 0.38

16.15 1.20

38.01 0.54

This table, based on the meta-analysis by Addis et al, 2001,110 provides the calculated relative risks (RR) or weighted average difference between the groups (weighted ∆) of pregnant women with only cocaine usage, cocaine usage with other drug usage, only other drug usage or no drug usage.

smaller Dutch study.116 Ecstasy (XTC or methylenedioxymethamphetamine (MDMA)) belongs to the family of amphetamines. So far, little research on the consequences of usage during pregnancy has been performed. In one study, the incidence of small for gestational age (SGA) infacts (birth weight <10th centile) was higher in the methamphetamine-exposed neonates (19%) than in the unexposed group (8.5%) and logisticregression analysis showed the methamphetamineexposed group to be 3.5 times more likely to be SGA.117 In addition, in a longitudinal follow-up of 74 neonates following prenatal amphetamine exposure versus 92 controls, exposure was associated with neurobehavioural patterns of decreased arousal, increased stress and poor quality of movement.118 Whether this has longterm consequences has yet to be established.

Cannabis Cannabis includes hash and marijuana (weed/grass) of which tetrahydrocannabinol is the most important psychoactive ingredient. Cannabis is generally smoked in cigarettes, with or without tobacco and sometimes via a humidifier. It has calming, relaxing and hallucinogenic effects, but in high doses it can cause anxiety, panic and psychotic symptoms. The incidence of one-time use of cannabis among young people of 12 years of age and older is approximately 17%.83 In some cultures cannabis is used during pregnancy to alleviate symptoms of nausea and hyperemesis gravidarum.119,120 although cannabis itself can lead to hyperemesis.121 The use of cannabis seems to enhance the teratogenic effect of stimulants, such as ethanol.122 Its effects on birth weight, short stature, prematurity, head circumference and visual memory, are contradictory.113,122–126 As with smoking prenatal exposure to cannabis appeared in one study to be a significant predictor of marijuana use at age 14.127

As long as research has not unequivocally proven that cannabis use during pregnancy is safe for mother and child, its use should be stopped before and during pregnancy. Addicted pregnant women should, therefore, be referred to a centre with experience in the counselling of addicted pregnant women. It must be realised, however, that ceasing to smoke cigarettes is probably more important for the foetal development than ceasing to smoke cannabis.

Hallucinogens This group of drugs induces hallucination and perception disorders. The strongest substance is lysergic acid diethylamide (LSD). Ecstasy also has a hallucinogenic effect, but is an amphetamine. Literature on LSD is limited and usually from before 1990. From animal studies it has emerged that hallucinogens may be weakly or not teratogenic.128,129 It is, however, not clear whether this also applies to humans. In various case reports, congenital malformations of the extremities and the nervous system have been reported after exposure to LSD in utero.129 There is little or no information available on the consequences for the pregnancy of other popular substances, including magic mushrooms. In general, the use of these possible teratogenic substances in the first 2 weeks after conception have an all or nothing effect. Use may lead to either a miscarriage or no damage. Therefore, pregnant women who used such substances in very early pregnancy can be reassured, thereby preventing unnecessary abortions.

Eating disorders and obesity Eating disorders Eating disorders generally occur among women in puberty and during the reproductive phase of life.

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Approximately 0.5% of young women have an eating disorder.130 Anorexia nervosa and bulimia nervosa are complex disorders in which genetic, environmental and psychological causes are present. Although anorexia nervosa is generally characterised by a abnormally low body mass index (BMI), women suffering from bulimia nervosa can have a normal or low BMI. Both eating disorders influence fertility. A BMI of less than 19 is often complicated by anovulation and amenorrhoea.130 Evidence about the effects of anorexia and bulimia on pregnancy course and outcome is scarce. The prevalence of miscarriages and low birth weight seems to be slightly increased.131–133 During pregnancy, the majority of women with bulimia stop or interrupt the vomiting and impulsive bingeing. However, it has been reported that pregnant women with bulimia have an increased risk of hyperemesis gravidarum, Caesarean section and, possibly,134 postpartum depression.135 Pre-conception professional help from a psychotherapist or psychiatrist is indicated for eating disorders. Cognitive training is sometimes valuable. Although in some cases antidepressants are indicated, treatment with medication is generally not advised. When selective serotonin reuptake inhibitor (SSRI) medication is prescribed, the child must be placed in observation after birth. Referral to a dietician is also important in order to optimise the quality and quantity of the diet. Besides the standard folic acid supplement, a multivitamin preparation must be given if nutritional deficiencies are present. Furthermore, attention should be given to the importance of a healthy and balanced diet in the pre-conception period for both parents-to-be, but in particular for the woman, in order to decrease the risk of miscarriages, congenital malformations, premature birth and low birth weight. Sometimes pregnancy should be postponed until the woman has recovered from the eating disorder and has achieved a BMI of at least 19. If medication is used, it must be verified whether this can be stopped before pregnancy. Otherwise, specific information must be provided on the effects on the pregnancy and on the effects on breast feeding. For questions on the heredity of the eating disorders, patients should be referred to a clinical genetic centre. During pregnancy, the weight of these mothers-to-be must be measured without heavy objects in their pockets and during every visit.

Obesity Obesity, defined by a BMI of more than 30, is complicated by a 1.6–6.4-fold increased risk of spontaneous miscarriage.136 The risk of having a child with spina bifida and other congenital malformations is increased,137,138 as well as the chance of missing its prenatal diagnosis by ultrasonography.139 For that reason amniocentesis is recommended in case the risk of Down syndrome is increased. In a large London study, the following outcomes were significantly more common in

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obese pregnant women (OR (99% CI) for BMI 25–30 and BMI >30, respectively) compared with women with normal BMI: gestational diabetes mellitus (1.68 (1.53–1.84), 3.6 (3.25–3.98)); proteinuric pre-eclampsia (1.44 (1.28–1.62), 2.14 (1.85–2.47)); induction of labour (2.14 (1.85–2.47), 1.70 (1.64–1.76)); delivery by emergency Caesarean section (1.30 (1.25–1.34), 1.83 (1.74–1.93)); postpartum haemorrhage (1.16 (1.12–1.21), 1.39 (1.32–1.46)); genital tract infection (1.24 (1.09–1.41), 1.30 (1.07–1.56)); urinary tract infection (1.17 (1.04– 1.33), 1.39 (1.18–1.63)); wound infection (1.27 (1.09– 1.48), 2.24 (1.91–2.64)); birth weight above the 90th centile (1.57 (1.50–1.64), 2.36 (2.23–2.50)), and intrauterine death (1.10 (0.94–1.28), 1.40 (1.14–1.71)).140 Obesity and pregestational diabetes are independently associated with an increased risk of the delivery of a child that is large for gestational age and the impact of abnormal body habitus on birth weight grows as BMI increases.141,142 The child with macrosomia is at increased risk for obesity in childhood, adolescence and later life which also contributes to the development of type 2 diabetes. Women with a high BMI have an increased Caesarean section rate,140,143 particularly due to delayed cervical dilatation and increased birth weight.144 The success rate of vaginal birth after Caesarean delivery is very low in extremely obese women.145 Macrosomia increases the risk of asphyxia as well as failure to progress, prolonged second stage of labour and shoulder dystocia. Anaesthesia is more difficult in obesity due to technical problems in the placement of a regional block with a spinal or epidural catheter or with general anaesthesia through intubations.146 Moreover, in the postoperative phase, apnoea is of concern.147 There is also increased disturbed wound healing and deep venous thrombosis. These complications contribute to a higher maternal mortality. In England, where one in five women is obese, obesity between 2000 and 2002 was related to one-third of maternal deaths.148 It is important to determine BMI preconceptionally. A woman with a BMI of 30 or more should be advised to lose weight before becoming pregnant, especially if fertility treatment with IVF is involved which decreases the success rate. To lose weight safely and successfully, it is often necessary to consult a dietician. In the battle against obesity, surgical interventions such as the jejunoileal bypass and the laparoscopic adjustable gastric banding, are increasingly carried out. It was advised not to plan a pregnancy within 12–18 months of such surgery, because several complications are documented. Several studies, however, have shown that it is quite safe to be pregnant with a gastric band and that the risks of macrosomia, gestational diabetes, high blood pressure and Caesarean section are reduced in severely obese women.149,150 Besides routine folic acid supplementation, in all these patients iron, vitamin B12 and calcium levels should be monitored during pregnancy and supplemented if necessary.

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The best manner to lose weight is to combine dieting with exercise. However, so far the Cochrane reviews are inconclusive about the beneficial or harmful effects of regular exercise during pregnancy.151–153 Therefore, we have to wait for the results of largescale trials before regular exercise can be recommended for these reasons. However, overweight women with diabetes (prepregnant BMI >25) may need less insulin use when they exercise.154 There are, however, also other reasons to promote exercise during pregnancy. Among pregnant women who are overweight, aerobics has proven to have a favourable effect on oxygen uptake at the anaerobic threshold.155 Moreover, exercises to train the pelvic muscles appear to have a favourable effect on pelvic pain and the second stage of labour,156 but not on an earlier postpartum resolvement of pelvic girdle pain.157

Nutrition It is becoming increasingly clear that in the periconception period and during pregnancy not only the quantity but also especially the quality of maternal nutrition is important. A suboptimal nutritional status has proven to be a risk factor for various congenital malformation and placenta-related vascular complications during pregnancy.158–163 Some studies suggest that in about half of women planning pregnancy, the quality of the nutrition is suboptimal.164 Qualitative malnutrition is caused by a shortage of micronutrients, such as vitamins and trace elements. The use of fast ready-made meals and snacks, which are in general rich in calories and relatively poor in vitamins, is one of the reasons that even in rich countries malnutrition occurs more frequently than previously assumed. Some details are given regarding the most important nutrients studied in reproduction. Folic acid is a B vitamin, that is present in green, leafy vegetables and grains. Since the 1960s this vitamin has received a great deal of attention. Increasing evidence has shown that a folate deficiency in the periconception period significantly increases the risk of a child with a neural tube defect (anencephaly, spina bifida, encephalocele), cleft lip and/or palate, possibly conotruncal heart defects and omphalocoele.165 A folic acid deficiency is also associated with an increased risk of miscarriages and abruptio placentae). In 1992 and 1993, the Health Council of The Netherlands formulated recommendations for the primary prevention of neural tube defects by folic acid administration to women with a normal population risk, an increased risk and a recurrence risk of a child with such malformation (Table 3.3).166,167 These recommendations were based on the findings of randomised controlled trials showing that additional folic acid administration in the periconception period significantly reduced the risk of having a first child (daily dosage of 0.4–0.5 mg) with a neural tube defect as well as the recurrence risk (daily dosage 4–5 mg).168

Table 3.3 Governmental advice with respect to the prevention of neural tube defects (NTD).166,167

Recurrence Risk Women who have previously had an NTD child are advised to take a daily preparation with 4.0–5.0-mg folic acid from at least 4 weeks before conception to at least 8 weeks after conception. This should be done under medical supervision, because a vitamin B12 deficiency must be ruled out Increased Risk Women who use anticonvulsives, ovulation stimulating drugs or antifolates, suffer from diabetes mellitus or have NTD in the family are advised to optimise the folic acid status from at least 4 weeks before conception to at least 8 weeks after conception by increasing the daily dose of folic acid rich foods, if available, the use of folic acid enriched or restored foods or the daily use of a dietary supplement with 0.4–0.5-mg folic acid Normal Population Risk These women are advised to optimise the folic acid status – from at least 4 weeks before conception to at least 8 weeks after conception – by increasing the daily dose of folic acid rich foods, if available, the use of folic acid enriched or restored foods or the daily use of a dietary supplement with 0.4–0.5-mg folic acid

Alternative strategies, such as personal lifestyle programmes and selective folic acid fortification of foods with long-term monitoring on beneficial and sideeffects should also be considered. In contrast to the Third World countries where visual disorders in newborns occur as a result of maternal vitamin A deficiency, such deficiencies are hardly ever observed in developed countries. Vitamin A as retinol and beta carotene is present in liver, fruits and vegetables. Hypervitaminosis A is the minimum amount of vitamin A that can cause teratogenic effects in humans. This concentration probably varies between 10 000–50 000 IU per day. Depending upon the moment of exposure during pregnancy, hypervitaminosis A can increase the risk of congenital malformations and neurological developmental disorders.169 Because of the high concentrations of vitamin A present in liver and liver products, the Dutch government has advised against the use of certain nutritional supplements and medications based on vitamin A derivatives for all pregnant women and women planning pregnancy.170 Zinc is a trace element that is present in animal products and involved in the regulation of most metabolic processes in the body. A zinc deficiency during the periconception period and during pregnancy increases the risk of miscarriage, congenital malformation and foetal growth restriction. Although research carried out in Third World countries has shown favourable effects of the use of zinc supplements by pregnant women,171 in developed countries

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zinc supplementation is not yet advised and more attention is being given to a good overall diet.172

Radiation A differentiation should be made between exposure to electromagnetic and ultrasound waves. Electromagnetic waves with a short wavelength, such as X-ray and gamma radiation, can generate harmful ionising radiation. Microwaves, radar and diathermia, on the other hand, are electromagnetic waves with a long wavelength that do not generate any harmful ionising radiation. Ionising radiation occurs naturally in relatively low doses in the environment. Depending upon the dosage and the moment of exposure during pregnancy, ionising radiation of the mother and the foetus (medical diagnostics and treatment, equipment and nuclear disasters) can induce abnormal cell death and cause cytogenetic defects and somatic mutations. This can cause congenital malformations, intrauterine foetal death and foetal growth restriction. In particular, exposure to high dosages of ionising radiation should, therefore, be avoided throughout pregnancy, but especially during the pre-conception period and the first trimester. Monitors or television screens also cause ionising radiation. They can be considered to be safe because during normal use the exposure to radiation is extremely small. The amount of cosmic radiation that a passenger receives during a trans-Atlantic flight is also very small and therefore a pregnant woman can safely take an incidental plane trip.173,174 Ultrasound waves, that fall outside of the auditory range and that are used with an energy level comparable to that used in prenatal diagnosis, do not pose any increased risk for mother and child.175

Infections Infectious diseases can play a major role in pregnancy. Many of the primary infections lead to immunity and include rubella, chicken pox, herpes simplex (HSV), tuberculosis and toxoplasmosis, and thereby any subsequent pregnancy is not endangered. When the immune system is severely compromised, however, such as with AIDS, a revival of these pathogens can cause recurrence of the disease. This applies in particular to toxoplasmosis, HSV, tuberculosis and cytomegalovirus (CMV) infections. There are infections in which a primary infection results in the host becoming a carrier of the pathogen such as in cases of HIV (always), hepatitis C, and group B streptococcus (GBS) (often) and hepatitis B (sometimes). This may result in infection of the child during pregnancy or delivery. Infections against which no, or insufficient, permanent immunity can be achieved are gonorrhoea, syphilis and CMV. A re-infection with these pathogens can cause congenital infections. Pre-conception information about infections, therefore, serves both primary and secondary preventive goals. With regard to

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the primary prevention of infections before and during pregnancy a medical history is taken directed towards infectious diseases in the past and vaccinations. For some infections, such as rubella, antibodies can be measured to verify the primary infection or previous vaccination. Furthermore, general guidelines must be provided to prevent a primary infection with toxoplasmosis and listeria. Secondary prevention is concerned with the pre-conception carrier of infectious diseases and to prevent that the infection being passed to the foetus or neonate. These could include not only HIV, hepatitis B, GBS and herpes genitalis, but also toxoplasmosis and chicken pox. A few infectious diseases that could be brought up during a pre-conception consultation or for which pre-conception testing is advisable are discussed in more detail below.

Syphilis Testing for syphilis at the first prenatal visit is costeffective. Because the treatment of parents-to-be will prevent a congenital syphilis infection, the screening, by determination of TPPA and VDRL, should be carried out preferably in the pre-conceptional period. To exclude false-positive results with other treponema, confirmation testing must always be performed.176

Toxoplasmosis A primary infection with toxoplasmosis a month before the conception can lead to placental infection and, thus, to vertical transmission. In contrast to countries like France, in The Netherlands and the UK, there is no policy for toxoplasmosis testing, but instead a universal policy of preventive measures.177,178 Therefore, the same advice to primarily prevent infection by toxoplasmosis as given during pregnancy should be given pre-conceptionally. This is most important as it appears that the general knowledge of how toxoplasmosis is transmitted is low in a developed country like the US.179

Rubella If women planning pregnancy have not received a rubella vaccination, in the past, in particular nonWestern immigrant women, vaccination before pregnancy is strongly advised. After being vaccinated pregnancy should be delayed for 3 months, although in case of a pregnancy in this period “vaccination is not ordinarily an indication to terminate the pregnancy”, because foetal infection is rare.180

HIV For HIV as with other sexually transmitted diseases, it is important to diagnose the disease as early as possible in order to prevent horizontal infection. Detailed information is provided in Chapter 13.

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Hepatitis B Pre-conception testing of a couple for hepatitis B virus (HBV) is advisable if they intend to have unprotected sex. If there is a HBV carrier in the family, the rest of the family members will be vaccinated.181,182 If a pregnant woman is a carrier, the neonate will be vaccinated in order to prevent infection and, thus, in many cases, prevent carrier in the next generation.183–186

(3)

(4)

Other infections A history of intravenous drug use or a previous blood transfusion before 1991 in The Netherlands is indication for testing for hepatitis C (HCV). Testing is advisable before pregnancy because, if treatment is necessary it should be provided before pregnancy. Couples from Third World countries and a history of coughing should always be tested for tuberculosis. Everyone who comes for pre-conception counselling must be given specific information concerning the prevention of listeria infection during pregnancy. Listeria is transmitted via raw milk and soft cheeses made from raw milk. Pre-conception advice is of little value for other infectious diseases, such as parvovirus B12, herpes simplex genitalis and GBS, because there are no specific measures that can be taken before pregnancy. An exception must certainly be made for couples who had a related problem in a previous pregnancy and who are concerned about a subsequent pregnancy. It is then often advisable to refer them for specialised pre-conception care.

Counselling Specialised pre-conception care is required when there are obvious risks of an adverse pregnancy course or outcome.17 Counselling offers those couples the opportunity to make a conscious decision whether to pursue a pregnancy based on good information and risk assessment. This group includes women with a seriously disturbed obstetric history, chronic illnesses, maternal congenital malformations, previous organ transplantation and the use of prescribed medicines. Ethnic minorities sometimes belong to this group, because of consanguinity and the presence of haemoglobinopathies. In the past many of these women were counselled to refrain from pregnancy. However, nowadays after specialised pre-conception counselling this applies only to a very small group. The following issues should be evaluated: (1) The seriousness of the condition. Effective contraconception is often important in order to have enough time to provide adequate pre-conception care so that the pregnancy can be optimally planned. (2) Influence of the condition on the pregnancy. Risks should be discussed as due to chronic hypertension, renal disease and diabetes, such as

(5)

(6)

the occurrence of miscarriages, congenital malformations, premature birth, foetal growth restriction, intrauterine fetal death, pre-eclampsia and operative delivery. Influence of the pregnancy on the condition and maternal morbidity and mortality. For example, pregnant women with a congenital heart defect can develop a variety of complications due to the haemodynamic changes of pregnancy. Risks due to previous surgical interventions for extrauterine pregnancy or intraabdominal complications in case of Caesarean section. Teratogenic and other risk evaluation of medication. Switching before pregnancy to other, more safe, preparations should be considered. Chance of recurrence of pregnancy complications like severe pre-eclampsia or adverse pregnancy outcome such as congenital abnormalities, hereditary conditions or foetal growth restriction. Referral to a clinical geneticist is sometimes advised.

A pre-conception consultation also offers the unique opportunity to discuss the associations of some pregnancy complications with future maternal disease in later life. Maternal pregnancy complications, such as early-onset pre-eclampsia and gestational diabetes, are early predictors for the development of cardiovascular disease and type 2 diabetes.188,189 Pregnancy can, therefore, be considered as a stress test for the metabolic and cardiovascular constitution of women.190 This offers new opportunities for secondary prevention of disease at a relatively young age. It is of major importance to set up a good pre-conception plan for the management of conception, pregnancy, delivery and puerperium in these women. This should be coordinated by an obstetrician, consulting other specialists.

Preconception intervention During pre-conception counselling, there is also an opportunity for active health-promoting intervention. A well known example of this is the pre-conception use of folic acid supplements to prevent the development of neural tube defects in the offspring. It emerges that a single consultation in which this advice is given is very effective.187 Moreover, infections can be treated and vaccinations can be given. It also offers the opportunity to help people with intervention programmes that have proven effective in smoking cessation, weight loss and improvement of the quality of the diet. Moreover, the regular medication for women with chronic diseases can be changed for medication that is relatively safe for the unborn child.

Medication In The Netherlands nearly 50% of the women take one or more medications during the first trimester of pregnancy (not including vitamins and iron preparations).191,192

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Table 3.4

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Drugs with a teratogenic effect in humans.193

Drug

Teratogenic effect

Methotrexate ACE inhibitors

CNS and limb deformities Neonatal kidney insufficiency, decreased ossification of skull, kidney tubular dysgenesis Neonatal meconium ileus Foetal and neonatal struma and hypothyroidism, aplasia cutis Neural tube defects CNS defects, cancer Masculinisation of female foetus Vagina carcinoma and other urogenital defects in female and male progeny Neonatal hypoglycaemia Ebstein’s anomaly Moebius sequence (6th and 7th nerve paralysis), limb defects Constriction ductus arteriosus, necrotising enterocolitis foetal growth recession, CNS defects Neonatal withdrawal symptoms with opiates, use late in pregnancy CNS, craniofacial, cardiovascular and other defects Teeth and bone defects Limb and organ defects Facial and CNS defects Skeletal and CNS defects, Dandy-Walker syndrome

Anticholinergic drugs Thyreostatic drugs (propylthiouracil and methimazol) Carbamazepine Cyclofosfamide Danazol and other androgenic drugs Diethylstilbestrol Blood sugar-lowering drugs Lithium Misoprostol Prostaglandin synthetase-inhibitors (NSAIDs) Phenytoine Psychoactive drugs (including barbiturates, benzodiazepines) Retinoid Tetracycline Thalidomide Valproic acid Acenocoumarol

ACE, angiotensin converting enzyme; CNS, central nervous system.

Approximately 65% of the medication that is used by non-pregnant women in the same age category appeared not to be safe during pregnancy.191 The prescription of medication during pregnancy reflects a therapeutic dilemma. Most of the medicines are intended to treat the mother, but can often reach the embryo during the first weeks of pregnancy via the yolk sac and amniotic fluid, and thereafter via the placenta. This can lead to harmful effects for the developing child (Table 3.4).193 This information should not, however, lead to a “therapeutic nihilism” because various diseases of the pregnant woman can, in themselves, negatively influence pregnancy. In the case of chronic diseases, such as renal or autoimmune disease or chronic hypertension, the woman should be counselled pre-conceptionally on the risks of the use of certain medications during pregnancy. It can be decided to stop the medication, lower the dosage or change it to a different drug. The knowledge of possible teratogenic effects of medicines is therefore of great importance and the medicines should only be allowed during pregnancy for strict purposes. Unfortunately, information on possible teratogenic effects of (often new) drugs is often insufficiently available. This also has to do with the fact that, upon admittance to the market by the US FDA, only preclinical animal experimental research is done and practically no information is available on the possible teratogenic effects in human pregnancy. Moreover, it has been shown that, even after the introduction of drugs, the teratogenic risk is generally unknown. In analogy to an Australian model, the risks for the

foetus can be indicated by specific codes. The codes A, C, D and X are related to data in humans and the codes B1, B2 and B3 originate from animal experimental research. This classification is largely in agreement with the FDA pregnancy classification. The five categories are defined as follows: Category A

Category C

Category D

Category X

Category B

Drugs that are used by a large number of women with no observed harmful effects to the foetus Drugs that may cause reversible damage to the unborn child without malformations Drugs for which it is known that they increase the risk of congenital malformations or irreversible damage Drugs for which it is known that they provide such a high risk of foetal malformations that they must not be used during pregnancy and during reproductive age Drugs for which there is still insufficient experience obtained to be able to assume that they are harmful (B1, harmless in animal studies; B2, insufficient animal experimental data as yet known; B3, harmful in animal studies).

This classification is subject to two serious shortcomings. First, it gives the incorrect impression that the risk gradually increases from A, B, C, D to X. Second, it is not the case that drugs within a category all have the

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same degree of risk. This is particularly applicable to category C. In the American Physicians Desk Reference 66% of the drugs were clustered under category C and only 0.7% and 7% under A and D, respectively. From this, it becomes clear that the information in this classification is actually insufficient for effective advice. The “FDA Pregnancy Labeling Taskforce” is, at the moment, working on a revision of the information for medications which will include more clinically relevant information and a summary of the available knowledge on possible teratogenicity. The collection of post-marketing data on not only the possible teratogenic risks, but also on the possible long-term effects of drugs on development and behaviour must be given a much higher priority (functional teratogenicity). The individual health-care worker must be aware of the available information, so that use can be made of known international sources and organisations such as the Motherrisk Program (Hospital for Sick Children, Toronto) or the Teratologie_Information Service (RIVM, Bilthoven, The Netherlands).

11

12

13 14

15 16

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birth size in Japanese subjects. Mol Hum Reprod 2006; 12: 77–83. Gold DR, Burge HA, Carey V et al. Predictors of repeated wheeze in the first year of life: the relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking. Am J Respir Crit Care Med 1999; 160: 227–36. Gillman MW, Rifas-Shiman SL, Kleinman K et al. Developmental origins of childhood overweight: potential public health impact. Obesity (Silver Spring) 2008; 16: 1651–6. Obel C, Linnet KM, Henriksen TB et al. Smoking during pregnancy and hyperactivity-inattention in the offspring – comparing results from three Nordic cohorts. Int J Epidemiol 2008; in press. Huijbregts SC, Séguin JR, Zoccolillo M et al. Maternal prenatal smoking, parental antisocial behavior, and early childhood physical aggression. Dev Psychopathol 2008; 20: 437–53. Al Mamun A, O’Callaghan FV, Alati R et al. Does maternal smoking during pregnancy predict the smoking patterns of young adult offspring? A birth cohort study. Tob Control 2006; 15: 452–7. Slotkin TA. Nicotine and the adolescent brain: insights from an animal model. Neurotoxicol Teratol 2002; 24: 369–84. MacArthur C, Knox EG, Lancashire RJ. Effects at age nine of maternal smoking in pregnancy: experimental and observational findings. BJOG 2001; 108: 67–73. Coleman T. Recommendations for the use of pharmacological smoking cessation strategies in pregnant women. CNS Drugs 2007; 21: 983–93. Signorello LB, McLaughlin JK. Maternal caffeine consumption and spontaneous abortion: a review of the epidemiologic evidence. Epidemiology 2004; 15: 229–39. Weng X, Odouli R, Li DK. Maternal caffeine consumption during pregnancy and the risk of miscarriage: a prospective cohort study. Am J Obstet Gynecol 2008; 198: 279.e1–8. Matijasevich A, Barros FC, Santos IS, Yemini A. Maternal caffeine consumption and fetal death: a case-control study in Uruguay. Paediatr Perinat Epidemiol 2006; 20: 100–9. Karypidis AH, Söderström T, Nordmark A et al. Association of cytochrome P450 1B1 polymorphism with first-trimester miscarriage. Fertil Steril 2006; 86: 1498–503. Sata F, Yamada H, Suzuki K et al. Caffeine intake, CYP1A2 polymorphism and the risk of recurrent pregnancy loss. Mol Hum Reprod 2005; 11: 357–60. Naimi TS, Lipscomb LE, Brewer RD, Gilbert BC. Binge drinking in the preconception period and the risk of unintended pregnancy: implications for women and their children. Pediatrics 2003; 111: 1136–41. Hannigan JH, Armant DR. Alcohol in pregnancy and neonatal outcome. Semin Neonatol 2000; 5: 243–54. Jones KL, Smith DW, Ulleland CN, Streissguth P. Pattern of malformation in offspring of chronic alcoholic mothers. Lancet 1973; 1: 1267–71. Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet 1973; 2: 999–1001.

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to cocaine: the Toronto Adoption Study. Clin Invest Med 2001; 24: 129–37. McElhatton PR, Bateman DN, Evans C et al. Congenital anomalies after prenatal ecstasy exposure. Lancet 1999; 354: 1441–2. van Tonningen-van Driel MM, Garbis-Berkvens JM, Reuvers-Lodewijks WE. Pregnancy outcome after ecstasy use; 43 cases followed by the Teratology Information Service of the National Institute for Public Health and Environment (RIVM). Ned Tijdschr Geneeskd 1999; 143: 27–31. [in Dutch] Smith LM, LaGasse LL, Derauf C et al. The infant development, environment, and lifestyle study: effects of prenatal methamphetamine exposure, polydrug exposure, and poverty on intrauterine growth. Pediatrics 2006; 118: 1149–56. Smith LM, Lagasse LL, Derauf C et al. Prenatal methamphetamine use and neonatal neurobehavioral outcome. Neurotoxicol Teratol 2008; 30: 20–8. Russo EB. History of cannabis and its preparations in saga, science, and sobriquet. Chem Biodivers 2007; 4: 1614–48. Westfall RE, Janssen PA, Lucas P, Capler R. Survey of medicinal cannabis use among childbearing women: patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness’. Complement Ther Clin Pract 2006; 12: 27–33. Wallace D, Martin AL, Park B. Cannabinoid hyperemesis: marijuana puts patients in hot water. Australas Psychiatry 2007; 15: 156–8. Hansen HH, Krutz B, Sifringer M et al. Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity. Ann Neurol 2007; in press. Sherwood RA, Keating J, Kavvadia V et al. Substance misuse in early pregnancy and relationship to fetal outcome. Eur J Pediatr 1999; 158: 488–92. Fergusson DM, Horwood LJ, Northstone K; ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Maternal use of cannabis and pregnancy outcome. BJOG 2002; 109: 21–7. Huizink AC, Mulder EJ. Maternal smoking, drinking or cannabis use during pregnancy and neurobehavioral and cognitive functioning in human offspring. Neurosci Biobehav Rev 2006; 30: 24–41. Cornelius MD, Goldschmidt L, Day NL, Larkby C. Alcohol, tobacco and marijuana use among pregnant teenagers: 6-year follow-up of offspring growth effects. Neurotoxicol Teratol 2002; 24: 703–10. Day NL, Goldschmidt L, Thomas CA. Prenatal marijuana exposure contributes to the prediction of marijuana use at age 14. Addiction 2006; 101: 1313–22. Cohen MM, Shiloh Y. Genetic toxicology of lysergic acid diethylamide (LSD-25). Mutat Res 1977– 1978; 47: 183–209. Dishotsky NI, Loughman WD, Mogar RE, Lipscomb WR. LSD and genetic damage. Science 1971; 172: 431–40. Katz MG, Vollenhoven B. The reproductive endocrine consequences of anorexia nervosa. BJOG 2000; 107: 707–13. Micali N, Simonoff E, Treasure J. Risk of major adverse perinatal outcomes in women with eating disorders. Br J Psychiatry 2007; 190: 255–9.

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132 Ekéus C, Lindberg L, Lindblad F, Hjern A. Birth outcomes and pregnancy complications in women with a history of anorexia nervosa. BJOG 2006; 113: 925–9. 133 Koubaa S, Hällström T, Lindholm C, Hirschberg AL. Pregnancy and neonatal outcomes in women with eating disorders. Obstet Gynecol 2005; 105: 255–60. Erratum in: Obstet Gynecol 2008; 111: 1217. Kouba, Saloua [corrected to Koubaa, Saloua]. 134 Kye SL. Pregnancy in women with eating disorders. Am J Psychiatry 2002; 159: 1249–50; author reply 1250. 135 Franko DL, Blais MA, Becker AE et al. Pregnancy complications and neonatal outcomes in women with eating disorders. Am J Psychiatry 2001; 158: 1461–6. 136 Bellver J, Rossal LP, Bosch E et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 2003; 79: 1136–40. 137 Ray JG, Wyatt PR, Vermeulen MJ et al. Greater maternal weight and the ongoing risk of neural tube defects after folic acid flour fortification. Obstet Gynecol 2005; 105: 261–5. 138 Waller DK, Shaw GM, Rasmussen SA et al. Prepregnancy obesity as a risk factor for structural birth defects. Arch Pediatr Adolesc Med 2007; 161: 745–50. 139 Hendler I, Blackwell SC, Bujold E et al. The impact of maternal obesity on midtrimester sonographic visualization of fetal cardiac and craniospinal structures. Int J Obes Relat Metab Disord 2004; 28: 1607–11. 140 Sebire NJ, Jolly M, Harris JP et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001; 25: 1175–82. 141 Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol 2004; 191: 964–8. 142 Weiss JL, Malone FD, Emig D et al. Obesity, obstetric complications and Cesarean delivery rate – a population-based screening study. Am J Obstet Gynecol 2004; 190: 1091–7. 143 Ehrenberg HM, Durnwald CP, Catalano P, Mercer BM. The influence of obesity and diabetes on the risk of Cesarean delivery. Am J Obstet Gynecol 2004; 191: 969–74. 144 Kabiru W, Raynor BD. Obstetric outcomes associated with increase in BMI category during pregnancy. Am J Obstet Gynecol 2004; 191: 928–32. 145 Chauhan SP, Magann EF, Carroll CS et al. Mode of delivery for the morbidly obese with prior Cesarean delivery: vaginal versus repeat Cesarean section. Am J Obstet Gynecol 2001; 185: 349–54. 146 Soens MA, Birnbach DJ, Ranasinghe JS, van Zundert A. Obstetric anesthesia for the obese and morbidly obese patient: an ounce of prevention is worth more than a pound of treatment. Acta Anaesthesiol Scand 2008; 52: 6–19. 147 Maasilta P, Bachour A, Teramo K et al. Sleeprelated disordered breathing during pregnancy in obese women. Chest 2001; 120: 1448–54. 148 Ngan Kee WD. Confidential enquiries into maternal deaths: 50 years of closing the loop. Br J Anaesth 2005; 94: 413–16.

149 Bar-Zohar D, Azem F, Klausner J, Abu-Abeid S. Pregnancy after laparoscopic adjustable gastric banding: perinatal outcome is favorable also for women with relatively high gestational weight gain. Surg Endosc 2006; 20: 1580–3. 150 Martin LF, Finigan KM, Nolan TE. Pregnancy after adjustable gastric banding. Obstet Gynecol 2000; 95: 927–30. 151 Ceysens G, Rouiller D, Boulvain M. Exercise for diabetic pregnant women. Cochrane Database Syst Rev 2006: CD004225. 152 Meher S, Duley L. Exercise or other physical activity for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2006: CD005942. 153 Kramer MS, McDonald SW. Aerobic exercise for women during pregnancy. Cochrane Database Syst Rev 2006: CD000180. 154 Brankston GN, Mitchell BF, Ryan EA, Okun NB. Resistance exercise decreases the need for insulin in overweight women with gestational diabetes mellitus. Am J Obstet Gynecol 2004; 190: 188–93. 155 Santos IA, Stein R, Fuchs SC et al. Aerobic exercise and submaximal functional capacity in overweight pregnant women: a randomized trial. Obstet Gynecol 2005; 106: 243–9. 156 Salvesen KA, Mørkved S. Randomised controlled trial of pelvic floor muscle training during pregnancy. BMJ 2004; 329: 378–80. 157 Haugland KS, Rasmussen S, Daltveit AK. Group intervention for women with pelvic girdle pain in pregnancy. A randomized controlled trial. Acta Obstet Gynecol Scand 2006; 85: 1320–6. 158 Brown JE. Preconceptional nutrition and reproductive outcomes. Ann N Y Acad Sci 1993; 678: 286–92. 159 Brown JE, Kahn ES. Maternal nutrition and the outcome of pregnancy. A renaissance in research. Clin Perinatol 1997; 24: 433–49. 160 Steegers-Theunissen BP. Maternal nutrition and obstetric outcome. Baillieres Clin Obstet Gynaecol 1995; 9: 431–43. 161 Krapels IP, Vermeij-Keers C, Müller M et al. Nutrition and genes in the development of orofacial clefting. Nutr Rev 2006; 64: 280–8. 162 Steegers-Theunissen RP, Steegers EA. Nutrientgene interactions in early pregnancy: a vascular hypothesis. Eur J Obstet Gynecol Reprod Biol 2003; 106: 115–17. 163 de Weerd S, Steegers-Theunissen RP, de Boo TM et al. Maternal periconceptional biochemical and hematological parameters, vitamin profiles and pregnancy outcome. Eur J Clin Nutr 2003; 57: 1128–34. 164 Weerd de S, Steegers EAP, Heinen MM, van den Eertwegh S, Vehof RMEJ, Steegers-Theunissen RPM. Preconception nutritional intake and lifestyle factors: first results of an explorative study. Eur J Obstet Gynecol Reprod Biol 2003; 111: 167–72. 165 Tamura T, Picciano MF. Folate and human reproduction. Am J Clin Nutr 2006; 83: 993–1016. 166 Health Council of the Netherlands. Primary Prevention of Neural-tube Defects, Combined Committee of the Dutch Food and Nutrition Council and the Health Council. Report. Gezondheidsraad, The Hague; 1992.

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Health Council of the Netherlands. Recommendations of folic acid to prevent neural-tube defects in the Dutch Population, Combined committee of the Dutch Food and Nutrition Council and the Health Council. Report. Gezondheidsraad, The Hague; 1993. Lumley J, Watson L, Watson M, Bower C. Periconceptional supplementation with folate and/or multivitamins for preventing neural tube defects. Cochrane Database Syst Rev 2001; (3): CD001056. Miller RK, Hendrickx AG, Mills JL et al. Periconceptional vitamin A use: how much is teratogenic? Reprod Toxicol 1998; 12: 75–88. Dutch Food and Nutrition Council. The teratogenicity of vitamin A. Report. Gezondheidsraad, The Hague; 1994. Shah D, Sachdev HP. Zinc deficiency in pregnancy and fetal outcome. Nutr Rev 2006; 64: 15–30. Mahomed K, Bhutta Z, Middleton P. Zinc supplementation for improving pregnancy and infant outcome. Cochrane Database Syst Rev 2007: CD000230. Bagshaw M. Cosmic radiation in commercial aviation. Travel Med Infect Dis 2008; 6: 125–7. Chen J, Lewis BJ, Bennett LG et al. Estimated neutron dose to embryo and foetus during commercial flight. Radiat Prot Dosimetry 2005; 114: 475–80. Jensh RP, Brent RL. Intrauterine effects of ultrasound: animal studies. Teratology 1999; 59: 240–51. Genç M, Ledger WJ. Syphilis in pregnancy. Sex Transm Infect 2000; 76: 73–9. Review. Conyn-van Spaendonck MA. Prevention of congenital toxoplasmosis; experience in The Netherlands. Int Ophthalmol 1989; 13: 403–6. Elsheikha HM. Congenital toxoplasmosis: priorities for further health promotion action. Public Health 2008; 122: 335–53. Jones JL, Ogunmodede F, Scheftel J et al. Toxoplasmosis-related knowledge and practices among pregnant women in the United States. Infect Dis Obstet Gynecol 2003; 11: 139–45. Chang S, Ball R, Braun MM. Elective termination of pregnancy after vaccination reported to the Vaccine Adverse Event Reporting System (VAERS): 1990–2006. Vaccine 2008; 26: 2428–32. Craxì A, Vinci M, Almasio P, Pagliaro L. Hepatitis B. vaccination of relatives of hepatitis B virus DNA positive carriers: an experience with plasmaderived vaccine. Eur J Epidemiol 1989; 5: 65–9. Lok AS, Lai CL, Wu PC, Ng MM. Response to hepatitis B vaccine in family members of HBsAg carriers. J Med Virol 1986; 19: 33–9.

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Grosheide PM, Klokman-Houweling JM, Conyn-van Spaendonck MA. Programme for preventing perinatal hepatitis B infection through screening of pregnant women and immunisation of infants of infected mothers in The Netherlands, 1989–92. National Hepatitis B Steering Committee. BMJ 1995; 311: 1200–2. Wong VC, Ip HM, Reesink HW et al. Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis-B vaccine and hepatitisB immunoglobulin. Double-blind randomised placebo-controlled study. Lancet 1984; 1: 921–6. Grosheide PM, del Canho R, Voogd M et al. AntiHBs levels in infants of hepatitis B carrier mothers after delayed active immunization with recombinant vaccine concomitant with DTP-polio vaccine: is there need for a second dose of HBIg? Dutch Study Group on Prevention of Neonatal Hepatitis B. Vaccine 1994; 12: 1059–63. Lee C, Gong Y, Brok J et al. Hepatitis B immunisation for newborn infants of hepatitis B surface antigenpositive mothers. Cochrane Database Syst Rev 2006; (2): CD004790. De Weerd S, Thomas CMG, Cikot RJLM et al. Preconception counseling improves folate status of women planning pregnancy. Obstet Gynecol 2002; 99: 45–50. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Pre-eclampsia and risk of cardiovascular disease and cancer in later life: systematic review and meta-analysis. BMJ 2007; 335: 974. Linné Y, Barkeling B, Rössner S. Natural course of gestational diabetes mellitus: long term follow up of women in the SPAWN study. BJOG 2002; 109: 1227–31. Williams D. Pregnancy: a stress test for life. Curr Opin Obstet Gynecol 2003; 15: 465–71. Schirm E, Meijer WM, Tobi H, de Jong – van den Berg LTW. Drug use by pregnant women and comparable non-pregnant women in The Netherlands with reference to the Australian classification system. Eur J Obstet Gynecol Reprod Biol 2004; 114: 182–8. Bakker MK, Jentink J, Vroom F et al. Drug prescription patterns before, during and after pregnancy for chronic, occasional and pregnancy-related drugs in the Netherlands. BJOG 2006; 113: 559–68. Koren G, Pastuszak A, Ito S. Drugs in pregnancy. N Engl J Med 1998; 338: 1128–37. Perucca E. Birth defects after prenatal exposure to antiepileptic drugs. Lancet Neurol 2005; 4: 781–6.

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4 The patient with renal disease Rebecca JA Sims, Margaret Ramsay

Introduction Physiological changes An appreciation of the anatomical, haemodynamic, renal tubular and endocrine changes that the healthy renal system undergoes during gestation is essential in interpreting the response of the diseased kidney during pregnancy. Dilatation of the ureters and renal pelvis occurs progressively during pregnancy.1,2 This predisposes to urinary stasis and increased risk of urinary tract infections (UTIs). Kidney size increases by 1–1.5 cm, with renal volumes increasing by 70% by the third trimester, probably due to intra-renal fluid and vascular expansion.3 These changes may mimic obstruction and imaging should be interpreted cautiously. The changes persist for around 12 weeks after delivery. In the first two trimesters, there is an increase in renal plasma flow of 50–70%. This gestational hyperfiltration leads to an increase in glomerular filtration rate (GFR), which peaks at the end of the first trimester and remains elevated throughout.4,5 In a study of ten healthy females, mean creatinine levels were 73 mmol/l in non-pregnant state, falling to 60, 54 and 64 mmol/l in successive trimesters.5 Thus, levels of creatinine and urea within laboratory normal parameters may actually represent impaired renal function during pregnancy. Suggested upper limits of normal in pregnancy are 75 mmol/l of creatinine and 4.5 mmol/l of urea. Levels above this should prompt concern.6 Augmented renal haemodynamics, in combination with a variety of other mechanisms, lead to alterations in renal tubular function resulting in hyperuricaemia, glycosuria without hyperglycaemia and proteinuria up to 500 mg/24 h.7–9 The kidney also increases production of erythropoetin, active vitamin D and renin. Progesterone enhances smooth muscle relaxation and decreases peripheral vascular resistance and thus diastolic blood pressure falls approximately 10 mmHg in the first 24 weeks of pregnancy.10 Blood pressure gradually returns to a pre-pregnancy level by term. Pregnancy blood pressure consistently at “normal” or pre-pregnancy levels may therefore suggest a hypertensive disorder. The fall occurs despite significant plasma volume expansion as oestrogen increases renin

levels causing sodium retention and an increase in total body water. Hormones such as prolactin, prostaglandins and growth hormone further contribute to fluid retention. Plasma osmolality is reduced by 8–10 mmol/l, even from the first weeks of the first trimester.11 This is not associated with a diuresis, as in the non-pregnant state, but instead a reset in the osmostat occurs, resulting in increased thirst and decreased serum sodium levels (by approximately 5 mmol/l) compared with non-pregnant females.12,13

Assessing and monitoring renal function There is good correlation between the Cockcroft-Gault formula for creatinine clearance (CG CrCl) (using prepregnancy weights) and 24-hour creatinine clearance in pregnancy in the general population,14 but its use in pregnant patients with chronic kidney disease has not been validated. Whilst it is now standard practice across UK laboratories to calculate estimated GFR using the modified diet in renal disease formula,15 this has been shown to significantly underestimate GFR in gravid women and cannot be recommended for use in pregnancy.16 The gold standard to monitor excretory renal function in pregnancy remains 24-hour urine collections for creatinine clearance. In practice, a pragmatic approach is usually taken with changes in renal function monitored through clinical parameters, serum creatinine levels and the trend seen in calculated CrCl. Further studies are needed to determine the optimum approach.

Proteinuria in pregnancy Proteinuria characterises many primary renal disorders and renal manifestations of systemic disorders. In normal pregnancy without renal disease, proteinuria up to 500 mg/24 h, or equivalent, may be normal. In women who enter pregnancy with established proteinuria, levels may be approaching, or already above, these accepted normal limits. However, proteinuria is one of the cardinal signs of pre-eclampsia. Unless the pre-existing proteinuria and its likely course during pregnancy is appreciated, there is a risk of preeclampsia being over-diagnosed or, more dangerously, missed. Furthermore, the proteinuric conditions

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Table 4.1

Stages of chronic kidney disease.22

Stage

Estimated GFR (ml/min/1.73 m2)

Description

1 2 3

≥90 60–89 30–59 (with or without proteinuria as indicated by suffix “p”) 15–29 <15 or on RRT

Evidence of kidney damage with normal GFR Evidence of kidney damage with mildly low GFR Moderately low GFR

4 5

Severely low GFR End-stage renal disease

GFR, glomerular filtration rate; RRT, renal replacement therapy.

appear to be associated with an increased frequency of superimposed pre-eclampsia (in the order of 25– 50%). The fact that hypertension is a frequent feature of these renal conditions and also characterises preeclampsia adds further to the diagnostic difficulty (see section on Influence of renal disease on pregnancy outcome and Table 4.4). Antenatal screening for proteinuria is routinely performed with a “dipstick” test. This is a useful screening tool, but those with established renal disease or a positive urine dip should have regular quantitative evaluation. Traditionally, this was done by a 24-hour urine collection but this is inconvenient for patients and often incorrectly performed. The urine protein to creatinine ratio (uPCR) is quick, easy and has shown excellent correlation with 24hour urinary protein in ambulant and hospitalised pregnant women without renal disease.17–19 However, some reports suggest a poor negative predictive value in those women otherwise clinically suspected of pre-eclampsia, so uPCR should not be used to exclude this diagnosis and 24-hour collections should be made instead.20 On a pragmatic level, in women with pre-established or at high risk for renal disease, we recommend collecting up to three uPCR samples prior to pregnancy to establish baseline and stability. The uPCR can then be monitored on a monthly basis during the first 20 weeks of pregnancy and at least fortnightly thereafter. If the clinical situation changes, a 24-hour collection can be sent.

Influence of renal disease on pregnancy outcome Chronic Kidney Disease Women entering pregnancy with established renal disease have a broad range of diagnoses. Even in those with the same diagnosis, differing degrees of renal impairment, hypertension and proteinuria are seen, depending on stage and idiosyncratic patient response to pathology. In general, women with chronic kidney disease are less able to respond to the demands of pregnancy with changes such as appropriate excretory

Table 4.2

Classification of severity of renal impairment.

Classification

Plasma creatinine (µmol/l)

Mildly impaired renal function Moderate renal impairment Severe renal impairment

≤125 ≥125 but ≤250 ≥250

hyperfiltration, expanded plasma volume, augmented erythropoeitin and vitamin D production. These changes can result in multiple and variable insults to the pregnancy, for example retention of harmful endogenous or exogenous waste products, inadequate placental perfusion, and anaemia. Kidney disease is an independent risk factor for both adverse fetal and adverse maternal outcomes,21 but in many cases, data are not available to offer robust and specific prognostic statistics regarding pregnancy outcomes.21 Counselling must be individualised to each patient with the extent of predictive uncertainty made clear. In general, prognosis broadly depends on the degree of renal impairment at time of conception and on the presence and degree of hypertension and, to a lesser extent, proteinuria. There are a number of conditions in which special considerations apply, particularly lupus nephritis and diabetic nephropathy. Chronic kidney disease is now widely classified into five stages based on GFR and other clinical features22 (Table 4.1). However, most available data categorise pregnant women by baseline plasma creatinine level. Patients are categorised as having mild, moderate or severe renal impairment, as groups with creatinine ≤125 µmol/l, ≥125 but ≤250 µmol/l, and ≥250 µmol/l respectively (Table 4.2).

Mild Renal Impairment Approximately 3% of women of childbearing age are affected by stage 1 and 2 chronic kidney disease.23 As symptoms rarely develop until GFR declines to less than 25% of normal, this group is often asymptomatic

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and may be undiagnosed. Women with chronic kidney disease but preserved renal function, particularly those without hypertension or proteinuria, may expect a fertility rate approaching that of the general population, with some variations depending on the underlying cause of renal disease. This group may also expect rates of successful obstetric outcome near normal, particularly in the absence of hypertension.24,25 Poorly controlled hypertension and nephrotic range proteinuria appear to be independent risk factors for poor outcome.26

Moderate Renal Impairment There are no published data describing the relationship between fertility and GFR, but practice shows that as GFR falls, fertility decreases. In those that do conceive, obstetric prognosis again depends on the severity of renal impairment and the presence or absence of hypertension and proteinuria.26,27 Once pregnancy has progressed beyond the first trimester, infant survival rates are 90–95%, but preterm delivery rates are around 60% and growth restriction is seen in 40% (see Table 4.3).

Severe Renal Impairment Most women with severe renal impairment (serum creatinine >250 µmol/l) are amenorrhoeic and/or anovulatory31,32 and may suffer from anaemia, fatigue and reduced libido. Whilst conception is possible, the limited data suggest a very poor obstetric prognosis, perhaps in the order of 25% success rate, with a risk of severe maternal complications of around 92%.6,27 More data are needed as these observations are incomplete and were made prior to the introduction of optimal erythropoeitin management and other advances. However, patients with severe renal impairment should be advised to postpone attempts at pregnancy until after successful renal transplantation. It is not known whether the introduction of an intensive renal replacement therapy program alters outcome.

End-stage/Dialysis Dependent renal disease The first case report of successful full term pregnancy in a dialysis patient was published in 1971.33 Since then, around 120 cases of conception in end-stage renal disease (ESRD) patients have been published. With improvements in renal replacement therapy (RRT) and supportive treatments such as erythropoeitin, the frequency of conception on dialysis has increased and the obstetric outcomes are improving.34 ESRD requiring dialysis is associated with a marked reduction in fertility. The exact fertility rate in women of childbearing age on maintenance dialysis is unknown. The largest study is from the United States Registry for Pregnancy in Dialysis Patients, with data from nearly 1000 centres. Amongst 6230 females aged 14–44 years (1699 on peritoneal dialysis and 4531 on

43

haemodialysis), just 2% conceived during a 4-year period.30 This translates to fertility rate of about 0.5% per year in haemodialysis and about one-half to one-third of this in women on peritoneal dialysis. The reason for this apparent difference is unclear. The cause of reduced fertility is probably multifactorial. It is estimated that over 50% of dialysis patients are anovulatory due to hypothalamic– pituitary dysfunction.31,35 Additionally these patients face reduced libido, the fatigue and malaise of chronic intervention, altered hormonal milieu, anaemia, and significant psychosocial issues.36 Should a woman on dialysis become pregnant, her chances of having a healthy baby are, at best, 50%, regardless of dialysis modality.37 Only two-thirds of pregnancies continue beyond 3 months, and of these, around 20% end in spontaneous abortion while around 10% go on to stillbirth.30 Chances of a successful pregnancy are higher in women who have some renal function, or who conceived before starting dialysis, presumably because of the protective effect of even minimal residual renal function.37 In terms of fetal outcome, there are high rates of prematurity, intrauterine growth restriction (IUGR) and neonatal mortality 30 with approximately 85% of the surviving infants being premature, and around 30% small for gestational age (SGA). There are no data to suggest significant morbidities over and above those which might be expected in premature or SGA infants.38

Renal Transplant Recipients A return of fertility is usually seen after renal transplant.39 Pregnancy occurs in up to 12% of these patients and obstetric success rates are good. One series of 3382 pregnancies showed greater than 90% foetal survival rates for those pregnancies proceeding beyond the first trimester.40 However, the incidence of preterm delivery was 50% and IUGR was seen in over 20%. Fetal survival rate is around 96% in patients with a creatinine level of less than 124 µmol/l. A prepregnancy creatinine level of over 124 µmol/l is associated with a risk of renal damage and also with a decreased fetal survival rate of approximately 74%.41

Nephrotic Syndrome Nephrotic syndrome is characterised by nephrotic range proteinuria (>3 g/24 h or equivalent), but also requires hypoalbuminaemia, hyperlipidaemia and oedema. It may be the clinical manifestation of a variety of renal histopathological diagnoses. Nephrotic range proteinuria can occur without nephrotic syndrome if there is no hypoalbuminaemia and if sodium intake does not overwhelm excretion capacity. In pregnancy, the nephrotic syndrome can be caused by pre-existing renal disease, new onset renal disease or, most commonly, pre-eclampsia. Women

30– 33% 17–25% 25% 22% 75–99% 0% 0%

*Deaths in utero after 24 weeks and up to 28 days after birth. IUGR, intrauterine growth restriction; Cr, creatinine.

Preterm delivery <37 weeks IUGR Perinatal mortality* Pre-eclampsia Infant survival in pregnancies >24/40 Sustained decline in maternal renal function Progression to maternal ESRD 59% 37% 5% 40% 93% 20% 2%

Cr <120 µmol/l with renal pathology29 (Based on estimates by Williams and Davison) Cr 120–220 µmol/l29 >90% 65% 10% 60% 90% 50% 35%

Cr >240 µmol/l – ESRD (Based on estimates by Williams and Davison) 40% 15% 54% 75% 50% NA NA

ESRD on RRT30

50% 20% 14% — 94% — —

Renal Transplant–Cr <124 mmol/l (Davison et al)

Pregnancy outcomes with mild, moderate and severe renal impairment in end-stage renal disease (ESRD)/renal replacement therapy (RRT) and in renal transplant recipients.20

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Table 4.3

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Table 4.4 Renal disease versus pre-eclampsia. These features offer guidance but are not absolute. If in doubt, treat as pre-eclampsia which has the potential for rapid onset of very serious complications. Renal disease

Pre-eclampsia

Renal disease known to have been pre-established Proteinuria seen prior to pregnancy or occurring in first 20 weeks of gestation. (Note: there are case reports of pre-eclampsia occurring before 20 weeks but this is a rarity45) Pre-existing hypertension Stability of proteinuria and/or hypertension (or gradual worsening over weeks or months) No systemic manifestations of pre-eclampsia. (Note: uric acid is renally excreted but levels do not tend to rise significantly until GFR is <20 ml/min/m2 Red cell haemolysis may occur in haemodialysis patients) Signs persist after delivery

No pre-established renal disease or risk factors New onset proteinuria after 20 weeks’ gestation.

with established pre-nephrotic proteinuria often progress to nephrotic range proteinuria during the final trimester. This is reported in proteinuric primary glomerulopathies and proteinuric diabetic nephropathy.42–44 There is considerable diagnostic difficulty between late-stage worsening proteinuria and preeclampsia. Timing intervention to avoid unnecessary premature delivery is difficult. However, because of the rapid development of potential and severe complications, pre-eclampsia must often be the presumptive diagnosis with the situation only becoming more certain after delivery (Table 4.4). There are mixed reports and small numbers of data regarding fetal and renal outcomes in the presence of nephrotic syndrome without pre-eclampsia. When combined with renal impairment and hypertension both fetal and renal outcomes are less probably favourable.46–50 Nephrotic syndrome is associated with spontaneous abortion, prematurity and IUGR.51

Specific Renal Diseases The clinical implications of specific renal diagnoses are shown in Table 4.5.

Influence of pregnancy on severity of renal disease In a similar profile to that of obstetric outcome, progression of renal disease during pregnancy generally depends on the degree of renal dysfunction at the time of conception as well as the presence and extent hypertension and proteinuria.

Mild Renal Impairment When the baseline GFR is normal or mildly reduced (plasma creatinine <125 µmol/l), pregnancy is associated with a permanent decline in renal function in

New onset hypertension after 20 weeks’ gestation. Rapid worsening of proteinuria and/or hypertension over days Systemic manifestations of pre-eclampsia such as thrombocytopenia, deranged liver transaminases, evidence of haemolysis, persistent headache or epigastric pain Signs resolve within 4–6 weeks of delivery

0–10% of women.25,57,79,80 During pregnancy, this group may experience a change in clinical manifestations, for example increased proteinuria and worsening of hypertension or a transient decline in renal function.80 These women are likely to show increments in GFR during pregnancy, but to a lesser degree than pregnant women without renal disease.81 After follow-up over up to 30 years of 171 pregnancies in 360 women with chronic glomerulonephritis and both normal and mildly impaired renal function, there was no difference in renal survival between the groups. Patients with hypertension were much more likely to have progressive disease independent of pregnancy status.

Moderate Renal Impairment In women with moderate renal impairment (creatinine 130–250 µmol/l), around half will show a fall in serum creatinine from baseline during the first half of pregnancy, reflecting the same mechanisms of increased GFR seen in women without renal disease. Several small studies suggest that around one-third of patients with moderate pre-pregnancy renal insufficiency will sustain irreversible decline in renal function.27,29 In a multicentre study of 82 pregnancies continuing beyond the first trimester in women with mean early pregnancy serum creatinine of 168 ± 71 µmol/l,29 hypertension increased from 28% at baseline to 48% in the third trimester, and nephrotic range proteinuria from 23% to 41%. Mean creatinine rose to 221±115 µmol/l in the third trimester, with 10% of the pregnancies being associated with acceleration of maternal renal insufficiency. Amongst those with initial creatinine of 124– 168 µmol/l, the risk of exacerbation of renal dysfunction was around 45%.29 In a study of 22 pregnancies in women with creatinine levels 150–240 µmol/l, 25% of the women exhibited a sustained decline in renal function attributable to pregnancy, i.e. greater than predicted from the natural history of their disease.82

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Table 4.5

Clinical implications of specific renal diagnoses.

Renal diagnosis

Primary glomerular disease Chronic glomerulonephritis (GN)

IgA nephropathy

Minimal change GN Focal glomerulosclerosis Membranous nephropathy Mesangiocapillary GN Secondary glomerular disease Diabetic nephropathy

Systemic lupus erythematosus

Effects

Risks are hypertension, proteinuria and pre-eclampsia, recurrent infection. In general, outcome depends on degree of renal impairment and hypertension. With creatinine <150 mmol/l and BP <140/90, obstetric and renal outcomes are likely to be favourable.28 Risk of hypertension probably higher than for other GN52 and obstetric prognosis much worse if hypertensive with 20% fetal loss and 20% preterm delivery. If moderate to severe renal impairment pre-pregnancy, probably high risk of progression after delivery but further research needed.53,54 For women with disease in remission and normal function or only mild renal impairment, renal and obstetric outcomes near normal.55 25% fetal loss, 32% preterm delivery, 18% deterioration in renal function (5% progressive), 42% deterioration in hypertension (10% irreversible).56 15% fetal loss, 35% preterm delivery, 22% reversible worsening of hypertension, 2% progressive deterioration in renal function.56 25% fetal loss, 20% preterm delivery, 14 decline in renal function (2% irreversible), 32% worsening of hypertension (12% irreversible).57 In type 1 diabetes, risk of pre-eclampsia, preterm delivery and SGA baby increases with microalbuminuria and rises further with diabetic nephropathy.58 Diabetic nephropathy does not appear to be an independent predictor of worse foetal outcome in women with type 2 diabetes.59 The renal lesion of diabetic nephropathy is characterised by a progressive reduction in renal function, proteinuria and hypertension. It is seen in both type 1 and type 2 diabetes and is present in approximately 6% of all diabetic women entering pregnancy.60 The impact and progression during pregnancy is a subject of some debate in the literature. Perinatal morbidity and mortality in diabetic pregnancies have improved in parallel with improvements in glycaemic control. Data suggest that the overall perinatal survival in pregnancy complicated by pre-existing diabetic nephropathy is 95%, compared with approximately 99% in the general population.61 In this same small study (27 pregnancies) IUGR and major congenital malformations were observed in 9% of the neonates; 26% of the infants were delivered preterm. Chronic hypertension (77%) and pre-eclampsia (53%) were common maternal complications; 63% of women required delivery by Caesarean section. There is increased incidence of infection, oedema and/or pre-eclampsia. In those patients with established diabetic nephropathy, there appears to be a proportion of patients with an accelerated decline in renal disease, with figures varying from 45–80%, probably attributable to poorly controlled hypertension.62 Again, as in other causes of renal insufficiency, the level of renal impairment at the time of conception is the most important determinant of both pregnancy outcome and the effect of pregnancy on the progression of disease The negative prognostic implications of impaired renal function and hypertension also apply to patients with lupus. There are some conflicting data on whether pregnancy exacerbates lupus per se. Patients who have been in remission for >6 months have a lower risk of disease flare during pregnancy than those who have active lupus at the time of conception (7–33% vs. 61–67%). 63–65 For women with inactive disease, pregnancy is generally well tolerated with good outcomes, with any complications reflecting impairment of renal function, hypertension and presence or degree of proteinuria.66 In women with active disease, severe renal exacerbations can occur.63 The approach to exacerbations of lupus nephritis during pregnancy is not well defined. Oral steroids and azathioprine are first line treatments. In this situation, patients must be counselled regarding the balance between preservation of renal function and preservation of the pregnancy. (Continued)

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Table 4.5

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Continued

Renal diagnosis

Urinary tract pathology Urinary tract infection/ Pyelonephritis

Vesicoureteric reflux (VUR)/reflux nephropathy*

Autosomal dominant polycystic kidney disease*

Autosomal recessive polycystic kidney disease* Other cystic diseases, e.g. medullary cystic kidney disease (MCKD)

Effects

The anatomical and physiological changes of pregnancy mean that urinary tract infections in pregnancy are common in women with normal renal anatomy and without pre-existing renal disease or previous urinary tract infection, with an incidence of about 7%. Urinary tract infection includes the spectrum of asymptomatic bacteriuria, cystitis, and upper tract infection or pyelonephritis. UTIs have been associated with premature labour, SGA babies and intrauterine foetal death.67 There are a number of conditions that predispose to UTI and may increase the risk of more serious complications. These include any abnormality of the urinary tract, diabetes, HIV and previous UTI in pregnancy or UTI at the time of conception. Antibiotic prophylaxis should be offered after more than one UTI during pregnancy and after just one UTI in those with predisposing factors. Prophylaxis may be considered prior to conception. A regimen of cephalexin 500 mg every night and nitrofurantion 100 mg every night for alternate months is effective, well tolerated and reduces risk of resistance. In pregnancy, routine leucocyte-nitrite dipstick screening for bacteriuria in all patients is advocated. Samples testing positive should be sent for microscopy and culture. Asymptomatic bacteriuria is common, with a prevalence of 10% during pregnancy.68,69 Untreated, up to 30% of pregnant patients with asymptomatic bacteriuria and normal anatomy develop pyelonephritis. The risk is presumed higher in abnormal anatomy and predisposing conditions. Treatment with 3–7 days of oral antibiotics is warranted and reduces the incidence of pyelonephritis to <3%.69,70 After treatment, urinalysis with culture should be performed and evaluated on a monthly basis. If bacteriuria is persistent, culture guided suppressive therapy is probably indicated (e.g. Nitrofurantoin 100 mg at night). Cystitis or upper tract infections should be aggressively treated, with antibiotics tailored as urine culture indicates. Severe or systemic symptoms warrant admission. Usually a congenital disorder, caused by displacement of the ureters into the bladder with inadequate valves allowing backflow of urine to the ureters during bladder contraction. It may rarely be acquired through irradiation damage, with bladder disorders or after renal transplantation. It predisposes to recurrent upper tract infection. Renal parenchymal damage may occur. This is reflux nephropathy. Often diagnosed in childhood following recurrent UTIs. In 90%, the problem resolves as the anatomy matures. Providing there was no parenchymal damage, these women have the same pregnancy outcomes as the general population. However, for those with reflux nephropathy or in whom the problem persists, there are increased obstetric and renal risks. In one study of pregnancies in women with reflux, pre-eclampsia occurred in 24%, with the risk being higher in those women with hypertension.71 A third of infants were delivered preterm. Of those babies screened with micturating cystourethrography, 43% had VUR, consistent with autosomal dominant inheritance with reduced penetrance. Recurrent UTI may further increase the risk of premature labour, and daily antibiotic prophylaxis is usually advised. In women with reflux nephropathy and pre-existing mild or moderate renal impairment, deterioration in renal function is experienced in around 20% during pregnancy. Most common inherited kidney disease. Incidence one in 200–1000. Multisystem disorder characterised by progressive cystic dilatation of both kidneys with variable extra renal manifestations. Cysts predominantly develop along the entire nephron. Manifestations evolve at variable speeds, but at childbearing age women usually have preserved renal function and normotension with good pregnancy and renal outcomes. Cysts predominantly develop along the cortical collecting tubule. MCKD is inherited in an autosomal dominant pattern and usually appears with adult-onset renal failure and no extra renal involvement. (Continued)

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Table 4.5

Continued

Renal diagnosis

Effects

Urolithiasis

Incidence of about one in 250 pregnancies. May become symptomatic in the second or third trimester, with most stones passed spontaneously. Pregnancy outcome probably unaffected but may be higher incidence of preterm premature rupture of membranes.72 UTI with attendant risks may be more common. If associated with urinary tract malformations, increased risk of urinary tract infection and associated risks. Risk of obstruction or sphincter disturbance depends on nature of surgery. With normal pre-pregnancy renal function and blood pressure, probably no contraindication but risk of decline in renal function. If pyelonephritis occurs, increased risk of obstetric complications. Pelvic kidneys may have increased risk. of obstruction and infection.73

Previous urinary tract surgery

Solitary kidney

Others Wegener’s granulomatosis Polyarteritis nodosa

Systemic sclerosis

Renal artery stenosis

There is very little information.74 Hypertension and proteinuria are common. Non-cytotoxic immunosuppression can be used with caution. Extremely rare. Very limited data suggesting possibility of successful outcome if conception occurs in disease remission, but of both fetal and maternal deaths in active disease.74–76 Possibility of scleroderma renal crisis or early onset pre-eclampsia. Successful outcome reported even if active disease with management including aspirin, heparin, and nitric oxide donors.77 Even in quiescent disease, risk of growth restriction, preterm delivery (up to 40%) and SGA infants (~50%), worsening with active disease.78 May present as intractable hypertension or recurrent isolated pre-eclampsia. High index of suspicion is needed. Can be suggested by renal ultrasound scan and confirmed with formal CT angiography or MRI. Pre-pregnancy vascular intervention is preferable, but angioplasty can be undertaken during pregnancy if appropriate.

*

Genetic counselling required. BP, blood pressure; SGA, small for gestational age; UGR, intrauterine growth restriction; UTI, urinary tract infection; CT, computed tomography; MRI, magnetic resonance imaging.

Cunningham et al found that patients with moderate renal insufficiency appear to have a normal gestational plasma volume expansion.83 However, this group was much more likely to have accelerated renal impairment sustained beyond pregnancy. In this study, about 20% of pregnant patients with moderate renal insufficiency progressed to end-stage renal failure within 4 years of delivery.

Severe Renal Impairment In those rare patients who do conceive, rates of accelerated renal decline are reported in between one-third and more than half.29 Cunningham et al observed progression to end-stage renal failure within 1 year of delivery in 45% of patients.83

reported, with hypertensive crisis and pulmonary oedema the predominant factors.

Renal Transplant Recipients As with patients with chronic renal impairment, poor pre-pregnancy renal function, uncontrolled hypertension and worsening proteinuria are poor prognostic indicators for renal function deterioration. Rarely, obstruction of the transplant ureter by the pregnant uterus has been reported. Further long-term studies are required. In women with a creatinine level of < 124 µmol/l who are treated with prednisolone and/ or azathioprine, pregnancy is unlikely to adversely affect graft function.84

Summary End-stage Renal Disease/Renal Replacement Therapy Patients Maternal health is put at serious risk, in particular due to volume expansion, worsening hypertension and fluid overload.38 Several maternal deaths have been

It is not entirely clear why some pregnant patients experience accelerated renal impairment. Worsening hypertension is a poor prognostic indicator and probably contributes directly to worsening renal function. Urinary tract infections are more common and

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also probably trigger a decline. Some evidence suggests that proteinuria, which almost always increases in pregnancy with any underlying renal impairment, may have a detrimental effect on the kidneys, probably through hyperfiltration injury. Some investigators have suggested that certain renal diseases may be more prone to accelerated deterioration, in particular focal glomerulosclerosis, membranous glomerulonephritis and reflux nephropathy.57,85 However, most studies appear to shown that if pre-existent hypertension and degree of renal impairment are taken into account, aetiology is probably not important.53 In pregnancy, the diagnosis of gestational hypertension or pre-eclampsia may reveal previously undiagnosed renal disease. In one study, 8% of women developing pre-eclampsia had underlying disease (30% renal disease, 70% essential hypertension), as did 16% of women with gestational hypertension (renal disease 10%, essential hypertension 90%).86

Practical Management Recommendations in Chronic Kidney Disease Pre-conception Counselling Women with renal disease but preserved renal function and normotension can be reassured of a low level risk and pregnancy can be encouraged with standard pre-conceptual advice and plans for regular monitoring, ideally through a multidisciplinary clinic. In patients with moderate to severe renal impairment and hypertension, the outlook must be much more guarded. Whilst there is no clear cut off beyond which risks inevitably outweigh benefit, many units would try to discourage women with a creatinine ≥250 µmol/l from attempting pregnancy (this equates to an estimated GFR of 25–30 ml/min/1.73 m2 in a 60 kg female aged 25–30 years, i.e. chronic kidney disease Stage 4 or 5). Importantly for this group, pregnancy can occasion antibody sensitisation making transplantation more difficult. Counselling of the risk of worsening renal impairment is important as this has implications not only for the progress and outcome of pregnancy but also for the potential health of the mother and her ability to care for the child subsequently should pregnancy be successful. It is difficult to separate the issues of obstetric and renal outcome as maternal health clearly has overwhelming implications for fetal health. Moreover, a pregnancy that accelerates progressive renal impairment might result in a child whose mother is disabled by illness in the formative early months or years. If the mother reaches ESRD there is significant maternal morbidity and mortality associated with renal replacement therapy, as well as the gross psychosocial burden this places on the family and the developing child. Decisionmaking is ethically complex and highly emotive.87 Sensitive and transparent counselling from an experienced multidisciplinary team is essential.

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Those patients who do choose to attempt pregnancy should have any medications rationalised. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists must be withdrawn and, if required, replaced with safer agents. Patients should be prescribed folic acid. If they are not rubella immune they should be immunised as soon as possible before progressive renal disease attenuates the immune response. If a decision not to attempt pregnancy, or to postpone it until transplantation is achieved and established, this should be well supported. Accepting this choice can be a very traumatic stage in the emotional pathway of a progressive chronic illness and professional teams must be sensitive to this. Contraceptive advice should be offered. It is preferable to avoid hormonal contraceptives that may aggravate hypertension.

Management of infertility Women with mild to moderate chronic kidney disease may seek fertility assistance for unrelated problems and must have their cases considered on an individual basis. As yet, there are no available data exploring success rates and outcomes of the various possible fertility interventions and their outcomes in kidney patients to stratify prognosis by baseline renal function. If drugs are used for ovarian stimulation this must be under expert supervision. Ovarian hyperstimulation syndrome is an acknowledged risk of fertility drugs and its prognosis will only be worsened by poor renal reserve. It is also advisable to ensure that only singleton pregnancies are attempted. For women with severe renal impairment or if spontaneous conception is not possible due to poor kidney function, any pregnancy resulting from assisted conception would be exceptionally high risk with elevated chances of a early stage spontaneous abortion or later stage fetal and maternal complications. There are no reports of successful assisted fertility treatments in advanced chronic kidney disease.

Antenatal Care If conception is successful, an experienced multidisciplinary team should care for the patient. Prenatal visits should be frequent with some authorities suggesting visits every 2–4 weeks until 28 weeks’ gestation and then weekly. The usual antenatal observations of blood pressure and urinalysis must be carefully made and interpreted judiciously. Patients should be screened for asymptomatic bacteriuria, and treated with antibiotics if infection is found. Patients with renal disease, hypertension and proteinuria are at increased risk of development of pre-eclampsia.88,89 In view of this, despite limited evidence in renal patients, if there are no contraindications aspirin prophylaxis (50–150 mg) from the second trimester is recommended in patients with renal insufficiency.90,91 One retrospective study of pregnancy in renal disease examined whether heparin plus

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low dose aspirin and/or dipyridamole (44 patients) reduced the prevalence of pre-eclampsia and improved fetal outcome compared with no treatment (76 patients) or low dose aspirin alone (27 patients).92 Preeclampsia was less frequent in the heparin group (2.3%) compared with 27.6% in the no treatment group and 25.9% in the aspirin group. Women who developed pre-eclampsia whilst taking aspirin delivered later than those who developed pre-eclampsia on no treatment (35.4 weeks vs 29 weeks). There were reduced perinatal deaths in the heparin and antiplatelet drug and aspirin groups; 2.3% and 0%, respectively, compared with 11.7% with no treatment. Further investigation in a randomised trial is indicated.

Nephrotic Syndrome Nephrotic syndrome can be disabling if oedema becomes excessive. There is also a significantly increased risk of thromboembolic events. There are discussion papers and case reports in the literature,93–95 but as yet no available data on the absolute risk of thromboembolic event occasioned by the combination of the two hypercoaguable states. Many clinicians would advise prophylactic low molecular weight heparin anticoagulation, particularly in the highest risk period of 6 weeks postpartum. This must be guided by the clinical situation and further studies are needed. The mainstay of oedema management should be salt restriction (e.g. 1.5 g/day) and bed rest. Bed rest reduces pressure on the inferior vena cava and increases renal perfusion, thus potentiating diuresis (although potentially increasing the risk of venous thromboembolism). Cautious use of fluid restriction and/or loop diuretic therapy can be attempted, with the aim being to reduce oedema by no more than 0.5 kg/24 h. The concern is that aggressive diuresis may compromise plasma flow to the placenta. Daily weights must be monitored and regular checks made on urea and electrolytes. Diuretics should not be administered if pre-eclampsia is suspected, as this is a low volume state.

Obstetric management There should be careful foetal monitoring, including serial ultrasound for biometry and Doppler studies of placental and fetal blood flows. If there are no maternal or fetal complications, vaginal delivery should be encouraged.

Recommendations in Dialysis Patients Pre-conception Counselling Dialysis patients wishing to conceive should be fully counselled about the risks both for themselves and the fetus. The bleak outcome statistics should be presented realistically and transparently. The intensive dialysis regimen that would be recommended if a pregnancy is achieved should be fully explained.

If possible, patients should consider pre-emptive live donor transplantation and be advised to postpone conception until a functioning graft is well established. If live donor transplantation is not possible, patients should be listed for cadaveric transplantation at the earliest permitted opportunity. Outcomes in renal transplant recipients are markedly better. Delaying attempts to conceive in anticipation of possible transplant must be balanced against the evidence that the shorter the time on dialysis prior to conception, the better the pregnancy outcome, presumably because of some remaining residual renal function.96 Patients should be encouraged to adhere strictly to their dialysis regimens and renal diets in the pre-conception phase. Dialysis regimens should be optimised, ideally to ensure that predialysis creatinine does not exceed 600 µmol/L. Potentially teratogenic medications, should be discontinued and safer alternatives substituted. All dialysis patients wishing to conceive should be prescribed folic acid supplements to reduce the incidence of neural tube defects. There are no data to support the prescription of high dose folic acid, but as patients with ESRD often suffer folate deficiency, it is common practice in most centres to prescribe 5 mg daily. Again, when pregnancy is unwise or should be deferred, sensitive support and contraceptive advice should be offered.

Diagnosis of Pregnancy The classical presenting symptoms of nausea and fatigue are common in all dialysis patients. Many do not produce any urine to use for the standard urinary β-human chorionic gonadotrophin (β-hCG) levels. Furthermore, both serum and urine levels may give false positive results as β-hCG is renally excreted but poorly cleared by dialysis. Occasionally increased erythropoeitin requirement may suggest pregnancy where it is otherwise unsuspected.97 If pregnancy is suspected, it should be confirmed with ultrasound.

Antenatal Care including Management of Dialysis Dialysis Modality The volume of the uterus changes during haemodialysis, thus peritoneal dialysis might be intuitively expected to be favourable because of the smaller volume fluid shifts. However, understandably there are concerns about the total intraperitoneal volume with an expanding uterus. There are some limited data to suggest a marginally less favourable fertility rate and pregnancy outcome in peritoneal dialysis patients.30 In practice this appears to have an extremely small impact and if a patient successfully conceives on a well tolerated peritoneal dialysis regimen, there is no compelling reason to change to haemodialysis. However, some units might make this recommendation later in pregnancy because it allows more intensive hospital input, potentially tighter volume control and may be more

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comfortable in a patient with a heavily gravid uterus. Additionally, peritonitis is a relatively frequent complication of peritoneal dialysis and if this occurs in pregnancy may cause disastrous diagnostic confusion and a serious risk of premature labour. General Correction of anaemia possibly reduces hypoxemic stress in the foetus and some evidence indicates that carefully judged use of erythropoietin stimulating agents (ESAs) may improve foetal survival.98,99 Recombinant erythropoeitin does not pass through the human placenta and there are no reported cases of ESA-related teratogenicity. Use of intravenous iron sucrose in anaemia of pregnancy in non-renal patients is well established and is extrapolated to renal patients.100,101 The most recent Cochrane review concludes that whilst intravenous iron improves haematological parameters, further studies to evaluate side-effects are desirable.101 In end-stage renal failure, use of intravenous iron is usual practice as these patients rarely absorb adequate oral iron. Haemodialysis Regimen The report of the registry of pregnancy in dialysis patients suggested a trend toward reduced fetal prematurity and higher birth weight in patients with a weekly haemodialysis dose of 20 hours or more.30 Aggressive dialysis to keep urea levels <20 mmol/l appears to reduce fetal mortality and morbidity, probably by reducing the risk of polyhydramnios, controlling hypertension, and improving maternal nutritional status.30,102 Whilst increasing numbers of units have published series data,99 there are as yet no trial data to guide management of the pregnant dialysis patient, and regimens must be individualised. During haemodialysis, regular uterine and fetal monitoring is advised to try to ensure stable uteroplacental and fetal perfusion.103,104 Serial assessments of uterine and umbilical artery blood flow with Doppler velocimetry and continuous fetal heart rate tracings, ideally before, during and after each haemodialysis session are advised. As the amniotic fluid volume reduces after dialytic fluid removal to reflect total volume removed, small volume fluid shifts should be the target.105 Dialysis-induced hypotension should be avoided.

Peritoneal Dialysis Although most units would recommend an intensification of dialysis regimen, there are limited data to support this. In a review of 25 pregnancies, there was no relation of either frequency or volume of peritoneal dialysis exchanges to gestational age or fetal survival.102

Obstetric Management Careful serial maternal and fetal assessment must be made, with particular attention to the development of

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Table 4.6 Pre-conception recommendations for renal transplantion recipients.106

Good general health for approximately 2 years after transplantation. Stable graft function (serum creatinine preferably <133 µmol/l). No recent or on-going episodes of rejection. Normal blood pressure on minimal and non-teratogenic therapy. Absent or minimal proteinuria (<0.5 g/24 h). Normal graft ultrasound – no evidence of obstruction. Recommended immunosuppression prednisolone <15 mg/24 h azathioprine ≤2 mg/kg/24 hours ciclosporin or tacrolimus at therapeutic levels (* it is often necessary to increase doses during pregnancy due to increased GFR). Check immune status for hepatitis B virus, herpes simplex virus (HSV), cytomegalovirus (CMV), and Toxoplasma species. In addition, if rubella titres are low, the patient should be vaccinated before transplant (live virus vaccine is contraindicated after transplantation). * Mycophenolate mofetil (MMF) and sirolimus should be stopped at least 6 weeks before conception is attempted.

hypertension, pre-eclampsia, anaemia, infection, IUGR and preterm labour. Caesarean section should be reserved for usual obstetric indications. As experience of pregnancy in dialysis patients remains relatively limited, these pregnancies should be regarded throughout as high risk and whatever the circumstances of delivery, the baby should be monitored for by experienced paediatricians for the first 24–48 hours.

Recommendations in Renal Transplant Recipients Pre-conception Counselling To optimise renal stability, patients should be strongly encouraged to delay conception for 2 years post-transplant before trying to conceive.106 A longer interval between pregnancy and transplantation is associated with better outcomes.25 Interim contraceptive advice should be offered immediately as ovulatory cycles can occur weeks after transplantation. Pre-pregnancy work-ups should be undertaken by an experienced transplant renal physician. Recommendations are outlined in Table 4.6.

Antenatal Care Despite the optimistic outlook, renal transplant recipient pregnancies should be managed as high risk. Again, use of prophylactic aspirin from the second trimester is recommended to reduce risk of preeclampsia.91,106 Patients should be seen frequently, with monitoring as shown in Table 4.7.

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Table 4.7 Monitoring and management of the pregnant renal transplant recipient.91,106

Pre-transplantation Rubella vaccination. Pre-pregnancy Rhesus compatibility of patient and graft. Microbiology for hepatitis B, C, herpes simplex virus, cytomegalovirus (CMV), toxoplasmosis and rubella Normal blood glucose. Discontinue teratogenic medications, e.g. angiotensin converting enzyme inhibitor angiotensin II receptor antagonists. Discontinue mycophenolate mofetil (MMF) and sirolimus. Standard pregnancy advice to avoid high risk food, contacts and exposure. Monitoring during pregnancy Daily Blood pressure monitoring (home). Aspirin 50–150 mg daily from second trimester.91 Fortnightly/monthly Multidisciplinary team review. Full blood count, urea and electrolytes. Serum creatinine and creatinine clearance. Quantification of proteinuria. Ciclosporin or tacrolimus blood levels. Urine culture. Monthly Transplant ultrasound. Each trimester IgM to toxoplasmosis and CMV for previously seronegative women.

of azathioprine cross the placenta, the immature fetal liver cannot convert it to its active form, 6-mercaptopurine.108 However, azathioprine is associated with prematurity, SGA babies and also fetal dose-related myelosuppression. If azathioprine is continued, the lowest possible doses should be used, ideally 2 mg/ kg/day or less.109 Similarly, ciclosporin has not been associated with an increase in fetal anomalies but has been associated with SGA babies.110 An increased risk of pre-eclampsia is a recognised complication (up to 29%), presumably from thromboxane and endothelin production.111 Therapeutic levels should be maintained using the lowest possible dose. Breastfeeding is not recommended whilst taking ciclosporin. Tacrolimus crosses the placenta and has been associated with hyperkalaemia and renal insufficiency, but there are increasing amounts of registry data to suggest that it is non-teratogenic and its use is becoming widely accepted.106

Fertility Treatment The first reported case of successful in vitro fertilisation in a renal transplant recipient was in 1995.112 Since then a small number of other successful cases have been reported but there are no available series data.113 In another case, ovarian hyperstimulation syndrome resulted in graft obstruction and a deterioration in renal function.114 Despite this the pregnancy was successful. Each case must be assessed on an individual basis, but if patients meet the recommendations as outlined in Table 4.6 then consideration of fertility treatment is probably reasonable.

Final Trimester IgM to herpes simplex for seronegative women. Bi-weekly fetal surveillance. Careful monitoring of blood pressure.

Immunosuppressive Regimens Most pregnant renal transplant recipients are managed using combinations of prednisolone, azathioprine and ciclosporin or tacrolimus, as these established drugs offer enough data to be confident of a relatively safe profile.106 Doses should be minimised and stabilised before conception. Mycophenalate mofetil and sirolimus are contraindicated and should be stopped at least 6 weeks prior to conception.107 Prednisolone crosses the placenta with a maternalto-cord ratio of 1:10. Potential fetal complications from the use of steroids include neonatal adrenal insufficiency and thymic hypoplasia, but these are unlikely to occur if the dose is <15 mg/24 h. However, if acute rejection of the kidney occurs during pregnancy, balance of risk suggests there should be no hesitation in the use of high-dose steroids. Azathioprine is teratogenic in animals, but this has not been found in humans. Although small amounts

Acute Rejection Risk During pregnancy, the incidence of acute rejection is not greater than expected for non-pregnant transplant recipients. Transplant biopsy should be performed before starting antirejection therapy. First line treatment is high dose steroids. There are case reports of the use of the monoclonal T-cell drug OKT3 in corticosteroid resistant cases.107 In the first 3 months after delivery, there is an increased risk of renal function deterioration of around 10–15%.40,107 This may be a rebound phenomenon after the immunoprivileged state of pregnancy. Factors predicting rejection include previous rejection episodes and impaired pre-pregnancy and intrapregnancy graft function.25 Women should be closely followed up during this period. Ciclosporin and tacrolimus levels must be monitored as the dose may need to be reduced to pre-pregnancy levels as GFR returns to normal postpartum.

Obstetric Management Awaiting the natural onset of labour is generally recommended but around 50% require Caesarean section

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because of the high incidence of pre-eclampsia, IUGR, fetal distress, deterioration of graft function, premature rupture of membranes or labour. Positive cervical cultures for herpes simplex virus would also prompt surgical delivery. During vaginal or surgical delivery, steroid doses should be increased (e.g. to 100 mg hydrocortisone/12 h) to cover the stress of labour and reduce postpartum acute rejection. Delivery should occur in a specialist centre with access to experienced obstetricians and transplant physicians and the babies should be monitored by paediatricians.91 However, there is no reported increased incidence of congenital fetal abnormality and overall outcome for children of renal transplant recipient mothers is good.115

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Acknowledgements

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We gratefully acknowledge the guidance and comments of Dr Susan J Carr, Consultant Nephrologist/ Honorary Senior Lecturer, University Hospitals of Leicester, John Walls Renal Unit, Leicester General Hospital, Leicester, UK.

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diagnosis and treatment of asymptomatic bacteriuria in adults. Clin Infect Dis 2005; 40: 643–54. North RA, Taylor RS, Gunn TR. Pregnancy outcome in women with reflux nephropathy and the inheritance of vesico-ureteric reflux. Aust N Z J Obstet Gynaecol 2000; 40: 280–5. Lewis DF, Robichaux AG 3rd, Jaekle RK, Marcum NG, Stedman CM. Urolithiasis in pregnancy. Diagnosis, management and pregnancy outcome. J Reprod Med 2003; 48: 28–32. Jena M, Mitch WE. Rapidly reversible acute renal failure from ureteral obstruction in pregnancy. Am J Kidney Dis 1996; 28: 457–60. Ramsey-Goldman R. The effect of pregnancy on the vasculitides. Scand J Rheumatol Suppl 1998; 107: 116–17. Burkett G, Richards R. Periarteritis nodosa and pregnancy. Obstet Gynecol 1982; 59: 252–4. Owen J, Hauth JC. Polyarteritis nodosa in pregnancy: a case report and brief literature review. Am J Obstet Gynecol 1989; 160: 606–7. Carbonne B, Mace G, Cynober E, Milliez J, Cabane J. Successful pregnancy with the use of nitric oxide donors and heparin after recurrent severe preeclampsia in a woman with scleroderma. Am J Obstet Gynecol 2007; 197: e6–7. Chung L, Flyckt RL, Colon I et al. Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease. Lupus 2006; 15: 595–9. Hayslett JP. Interaction of renal disease and pregnancy. Kidney Int 1984; 25: 579–87. Jungers P, Houillier P, Forget D et al. Influence of pregnancy on the course of primary chronic glomerulonephritis. Lancet 1995; 346: 1122–4. Katz AI, Davison JM, Hayslett JP, Singson E, Lindheimer MD. Pregnancy in women with kidney disease. Kidney Int 1980; 18: 192–206. Hou SH, Grossman SD, Madias NE. Pregnancy in women with renal disease and moderate renal insufficiency. Am J Med 1985; 78: 185–94. Cunningham FG, Cox SM, Harstad TW, Mason RA, Pritchard JA. Chronic renal disease and pregnancy outcome. Am J Obstet Gynecol 1990; 163: 453–9. Rizzoni G, Ehrich JH, Broyer M et al. Successful pregnancies in women on renal replacement therapy: report from the EDTA Registry. Nephrol Dial Transplant 1992; 7: 279–87. Packham D, North R, Fairley K. Pregnancy in women with primary focal and segmental hyalinosis and sclerosis. Clin Nephrol 1988; 29: 185. Reiter L, Brown MA, Whitworth JA. Hypertension in pregnancy: the incidence of underlying renal disease and essential hypertension. Am J Kidney Dis 1994; 24: 883–7. Davison SN. Ethical considerations regarding pregnancy in chronic kidney disease. Adv Chronic Kidney Dis 2007; 14: 206–11. Fink JC, Schwartz SM, Benedetti TJ, StehmanBreen CO. Increased risk of adverse maternal and infant outcomes among women with renal disease. Paediatr Perinat Epidemiol 1998; 12: 277–87. Ramin SM, Vidaeff AC, Yeomans ER, Gilstrap LC 3rd. Chronic renal disease in pregnancy. Obstet Gynecol 2006; 108: 1531–9.

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90. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet 1994; 343: 619–29. 91. Hou S. Pregnancy in chronic renal insufficiency and end-stage renal disease. Am J Kidney Dis 1999; 33: 235–52. 92. North RA, Ferrier C, Gamble G, Fairley KF, Kincaid-Smith P. Prevention of preeclampsia with heparin and antiplatelet drugs in women with renal disease. Aust N Z J Obstet Gynaecol 1995; 35: 357–62. 93. Tien YC, Yang CW, Ng KK et al. Thrombosis of the inferior vena cava in a pregnant woman with nephrotic syndrome–diagnostic and therapeutic dilemma. Nephrol Dial Transplant 1999; 14: 210–13. 94. Tooke JE, McNicol GP. Thrombotic disorders associated with pregnancy and the pill. Clin Haematol 1981; 10: 613–30. 95. Shibolet O, Schwaber MJ, Brezis M. Venous thromboembolism during pregnancy. N Engl J Med 1996; 335: 1846, author reply 1847. 96. Chandna SM, Farrington K. Residual renal function: considerations on its importance and preservation in dialysis patients. Semin Dial 2004; 17: 196–201. 97. Maruyama H, Shimada H, Obayashi H et al. Requiring higher doses of erythropoietin suggests pregnancy in hemodialysis patients. Nephron 1998; 79: 413–19. 98. Sobilo-Jarek L, Popowska-Drojecka J, Muszytowski M et al. Anemia treatment with darbepoetin alpha in pregnant female with chronic renal failure: report of two cases. Adv Med Sci 2006; 51: 309–11. 99. Haase M, Morgera S, Bamberg C et al. A systematic approach to managing pregnant dialysis patients– the importance of an intensified haemodiafiltration protocol. Nephrol Dial Transplant 2005; 20: 2537–42. 100. Bayoumeu F, Subiran-Buisset C, Baka NE et al. Iron therapy in iron deficiency anemia in pregnancy: intravenous route versus oral route. Am J Obstet Gynecol 2002; 186: 518–22. 101. Reveiz L, Gyte GM, Cuervo LG. Treatments for irondeficiency anaemia in pregnancy. Cochrane Database Syst Rev 2007: CD003094. 102. Chan WS, Okun N, Kjellstrand CM. Pregnancy in chronic dialysis: a review and analysis of the literature. Int J Artif Organs 1998; 21: 259–68. 103. Malone FD, Craigo SD, Giatras I et al. Suggested ultrasound parameters for the assessment of fetal well-being during chronic hemodialysis. Ultrasound Obstet Gynecol 1998; 11(6): 450–2. 104. Eroglu D, Lembet A, Ozdemir FN et al. Pregnancy during hemodialysis: perinatal outcome in our cases. Transplant Proc 2004; 36: 53–5. 105. Brost BC, Newman RB, Fries M, Calhoun BC. The effects of hemodialysis on total intrauterine volume. Ultrasound Obstet Gynecol 1996; 8: 34–6. 106. ERA-EDTA, Association ERA-EDTA. IV.10 Pregnancy in renal transplant recipients. Nephrol Dial Transplant 2002; 17(Suppl 4): 50–5. 107. Armenti VT, Radomski JS, Moritz MJ et al. Report from the National Transplantation Pregnancy

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112. Lockwood GM, Ledger WL, Barlow DH. Successful pregnancy outcome in a renal transplant patient following in-vitro fertilization. Hum Reprod 1995; 10: 1528–30. 113. Fichez A, Labrousse C, Fromajoux et al. Successful pregnancy outcome after in vitro fertilization in a pancreas-kidney recipient. Fertil Steril 2007. 114. Khalaf Y, Elkington N, Anderson H, Taylor A, Braude P. Ovarian hyperstimulation syndrome and its effect on renal function in a renal transplant patient undergoing IVF treatment: case report. Hum Reprod 2000; 15: 1275–7. 115. Willis FR, Findlay CA, Gorrie MJ. Children of renal transplant recipient mothers. J Paediatr Child Health 2000; 36: 230–5.

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5 The patient with organ transplantation Sarah Winfield, John M Davison

Organ transplantation is a well established option for women with end-stage organ failure. With advances in transplantation surgery and immunosuppressive regimens there has been improved prognosis for patient and graft alike, and the number of transplants in women of reproductive age has increased. Furthermore, the success of transplantation has also meant that children who received organ transplants now reach childbearing age.1 So inevitably pregnancy in women with an organ transplant is increasingly common as part of their total rehabilitation. Pregnancy in renal transplant recipients has been most commonly documented. There are, however, increasing numbers of reports of pregnancies in liver, liver-kidney, pancreas, pancreas-kidney, lung, heart, heart-lung and even intestinal transplant patients.2 Significantly, it is 50 years since that first pregnancy in a renal transplant patient, reported in 1963.3 As the number of pregnancies in all types of transplant recipients has increased worldwide, probably reaching at least 30 000 by now, we have been able to move on from case and small series reports and literature reviews in the quest for clinically useful data, to bigger series and most importantly, to registries, for better information regarding the management of these women.

The value of the literature and Registries The Registration Committee of the European Dialysis and Transplant Association (EDTA) collected data from 1977 to 1986 in 490 pregnancies (88% of which were renal transplants) and publications have ranged from congenital anomaly documentation to long-term experience with repeated successful pregnancies after kidney transplantation.4,5 The UK Transplant Database Pregnancy Registry collected data from 1994 to 2001, mainly in renal transplant patients, with case–controlled survival analysis pointing to an association between significant gestational hypertension and poorer postpregnancy graft survival, and where prepregnancy serum creatinine was >150 µmol/l, a trend towards further postpartum increase was identified.6

The only well established registry which currently regularly publishes data is the US National Transplantation Pregnancy Registry (NTPR) which was inaugurated in 1991, depending on voluntary reporting of pregnancies in women with transplants and pregnancies fathered by transplant recipients.7–10 Long-term followup of the recipients and infants has been undertaken to identify any long-term effects of pregnancy on the recipient or her graft as well as consequences for the offspring. At 2006 1595 pregnancies in 1016 female recipients were registered at the NTPR (Table 5.1). Information on pregnancy outcomes, maternal complications and graft function is similar between the NTPR and the now abandoned UK Registry (see Tables 5.2–5.4), despite different methods of patient ascertainment and different patient populations. As well as these registry data, the Women’s Health Committee of the American Society of Transplantation (AST) convened a Consensus Conference to address potential risks in pregnancy for graft and patient alike as well as long-term fetal sequelae.11 The resultant publications plus some of the better literature reviews form the basis from which to formulate guidelines for the clinical management of pregnancy in all types of solid organ transplant.12–31 There are still controversies, however, and these have also been highlighted. Refinements in management guidelines will inevitably continue as more emphasis is placed on gestational organ specific problems, the role of newer immunosupressants and the potential subtle long-term effect of pregnancy on both graft prognosis and offspring. This chapter focuses on the care of women with all types of solid organ transplant and aims to provide the busy clinician with an “ABC aide mémoire” or “information at a glance” in tabulated form for prepregnancy care and counselling as well as for management during pregnancy, delivery and the puerperium. Such an approach is not meant to belittle recent excellent publications (the sources for this chapter) which provide more detailed coverage for managing these women. Finally, consideration is also given to the specific controversies surrounding these women and their approach to parenthood despite potential risks to their own health and that of their unborn baby.26,32

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Table 5.1

National Transplantation Pregnancy Registry (NTPR): pregnancies in female transplant recipients.b

Organ

Recipients

Kidney Liver Liver-Kidney Pancreas-Kidney Pancreas alone Heart Heart-Lung Lung Totals

Pregnancies

Outcomes*

781 130 4 43 1 39 3 15

1208 219 6 73 4 63 3 19

1245 223 7 75 5 63 3 21

1016

1595

1642

* Includes twins and triplets.

Table 5.2

Kidney registry outcomes.6,14

Number of patients Number of pregnancies Pregnancy outcomes Live birth Miscarriage Therapeutic termination Stillbirth Ectopic pregnancy Caesarean section Gestational age mean ± SD range preterm delivery (<37 weeks) Birth weight mean ± SD range low birthweight (<2500g)

Table 5.3

UK Registry1

NTPR2

176 193 188 79% 11% 6% 2% 1% 72%

327 496 508 76% 12% 8% 3% 1% 52%

35.6 ± 0.3 weeks 25–41 weeks 50% 112 2316 ± 80g 370–5500g 54%

36 ± 3.4 weeks 24–43 weeks 52% 386 2492 ± 757g 510–4536 g 46%

Liver registry outcomes.6,14

Number of patients Number of pregnancies Pregnancy outcomes Live birth Miscarriage Therapeutic termination Stillbirth Ectopic pregnancy Caesarean section Gestational age mean ± SD range preterm delivery (<37 weeks) Birth weight mean ± SD range low birthweight (<2500 g)

UK Registry1

NTPR2

16 18 16 69% 13% 13% 0 6% 62%

121 202 205 74% 19% 5% 2% 0 35%

35.4 ± 1.4 weeks 28–40 weeks 50%

37 ± 3.5 weeks 26–42.5 weeks 35%

2629 ± 350 g 1260–3820 g 57%

2687 ± 784 g 680–4338 g 34%

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Table 5.4

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Registry outcomes.6,14 UK Registry1 Cardiothoracic

Heart

Lung

17 18 18 83% 6% 0 6% 6% 45%

36 60 60 70% 18% 8% 2% 2% 33%

15 17 17 59% 12% 29% 0 0 30%

36.8 ± 1.5 weeks 30–40 weeks 33%

37 ± 2.8 weeks 30–41 weeks 33%

35 ± 3.4 weeks 30–40 weeks 60%

10 2458 ± 186 g 1400–3690 g 80%

42 2674 ± 546 g 1191–3813 g 33%

10 2407 ± 805 g 1077– 3884 g 60%

Number of patients Number of pregnancies Pregnancy outcomes Live birth Miscarriage Therapeutic termination Stillbirth Ectopic pregnancy Caesarean section Gestational age mean ± SD range preterm delivery (<37 weeks) Birth weight mean ± SD range low birthweight (<2500 g)

NTPR2

Prepregnancy care

Table 5.5 Transplation and pregnancy: “ABC” of some of the harsh realities.

Assessment and counselling The basic components of assessment and counselling should be analysis of risks, provision of health education and advice as well as interventions of any type that might be deemed helpful, all “held together” by that much used word “counselling”.33 Inevitably, from the literature, the tertiary centre multidisciplinary team has to distil what is important so that “active preparation for pregnancy” is tailored to each woman’s needs, with her being encouraged to involve her consort so that the team is actually working in partnership with them. It is especially important that these women should be counselled from the time of the various treatments for their organ failure and that the potential for optimal rehabilitation is discussed. The patient and her partner should be encouraged to discuss all the implications, including the harsh realities and potential areas of disagreement, even whether infertility treatment, if needed, would be made available (Table 5.5).

Autonomous competent adult woman can decide for herself Bottom line” discussions, even worst case scenario “B Contraindicated – what if this is the situation? Disputes between patient and healthcare providers Ethical issues Future prospects for patient and family Graft lifespan and consequences of failure Health care provision Infertility treatment may need to be considered Joint management at tertiary centre during pregnancy is essential

question “will my pregnancy be complicated?”, moving straight on to the remaining questions. So somehow the team must ensure that all relevant and even “bottom line” information is passed on, based on fact, not anecdote, covering the unasked questions as well.

What the patient needs to understand What the patient wants to know Aside from what the team wants to discuss and achieve for the transplant recipient and her partner, she herself usually has straightforward questions: • • • •

Should I get pregnant? Will my pregnancy be complicated? Will I have a live and healthy baby? Will I have problems after my pregnancy?

Often, however, that first question of “should I get pregnant?” is bypassed, as is possibly even the second

The organ transplant recipient must understand the risks, improve her knowledge, and then be provided with the support she may need to make any necessary changes in her behaviour, attitude and medication(s).34 Knowledge of and even understanding risks, however, may not be sufficient to ensure that the patient makes changes because many other factors influence behaviour. Even when there is an element of self-management, perhaps best exemplified with dialysis and/or diabetes, this will also be influenced by the woman’s repertoire of beliefs, skills, intuition,

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motivation and not just her so-called knowledge, however gained. The key is a strong, unwavering, positive, supportive relationship with the team which allows prepregnancy advice to be included in the overall care agenda as a goal-orientated process.26 Thus, a planned pregnancy is one that is desired before conception, occurs when contraception is discontinued in order to get pregnant and where the woman does try to achieve optimal health beforehand (Table 5.6). Furthermore, it should be remembered, that even if some of the answers are not favourable, a woman, being an autonomous adult, may choose to go ahead for a pregnancy (or with a pregnancy), in an effort to re-establish a normal life in the face of chronic illness. In some cases this may cause a breakdown in communication with the team and, indeed, some women may not seek advice until already pregnant. This may lead to ethical dilemmas regarding clinicians’ duties of care towards women who ignore advice. Attempts are being made to differentiate “healthy” and “pathological” levels of assumed risk and to understand the psychology of women who pursue parenthood despite substantial risk to their own health and that of their unborn child.32

Timing of a pregnancy As mentioned earlier, the most commonly documented pregnancies are in renal transplant recipients and in 1958 it was such a patient who was the first to deliver a baby, having earlier received her graft from her identical twin sister, so that immunosuppression was never a concern.3 In 1976, prepregnancy guidelines were published for assessing and managing renal transplant patients with the recommendation of a wait of 2 years post-transplant,36 an approach endorsed by the best available literature at that time. Those criteria have been modified further for renal recipients (Table 5.7) but importantly have also been used as a framework for prepregnancy counselling for all organ transplant recipients considering pregnancy (Table 5.8). It is now agreed that 1 year post-transplant seems a reasonable interval – surgical recovery being complete, graft function stabilised, comorbid conditions under control and immunosuppression at maintenance levels.11,31 However, it should be borne in mind that not all recipients will have satisfactory and stable graft function in that first year and significant transplantrelated problems can still occur. Also, a patient outside the guidelines, who is “not meeting the criteria” still has to be managed.32

Immunosuppressive therapy Women do worry about immunosuppressive therapy but it is safe to say that it is usually maintained at prepregnancy levels and there are many encouraging registry and single centre reports of non-complicated

Table 5.6

Transplation and pregnancy: “ABC” for

prepregnancy counselling. Awareness and honesty about basic facts and figures Bacterial and viral infection status Comorbidities optimally managed Different counselling for different organs Evaluate all medications Folic acid should be commenced Graft function must be stable Hypertension optimally managed Immunosuppression at maintenance levels with agents not contraindicated in pregnancy

Table 5.7 Guidelines for prepregnancy counselling of renal transplant recipients.27

Good general health for about 1 year after transplantation Stature compatible with good obstetric outcome No or minimal proteinuria No hypertension* No evidence of graft rejection No pelvicalyceal distension on recent ultrasound or intravenous urogram Stable graft function: serum creatinine ≤160 µmol/l, preferably ≤125 µmol/l Drug therapy at maintenance levels: prednisolone, azathioprine, ciclosporin and tacrolimus are “safe” Mycophenolate mofetil and sirolimus are contraindicated *

Due to the high incidence of hypertension in patients on ciclosporin “well controlled hypertension” is more appropriate. (Newcastle upon Tyne+ 197636 & revised 1987 and 2006)

Table 5.8

Prepregnancy counselling guidelines.

1. Introduce at pretransplant with follow-up evaluation and follow this up into post-transplant management 2. Involve both patient and partner at all times 3. Discuss pregnancy complications, perinatal outcomes, offspring sequelae, graft prognosis and maternal survival 4. Virus “track record” satisfactory with vaccinations pretransplant but certainly prepregnancy 5. Good general health for 1 year post-transplant 6. Adequate and stable graft function 7. No evidence of graft rejection 8. “Tailored” maintenance immunosuppression 9. “Well controlled” co-morbid medical conditions, e.g. hypertension, diabetes, anaemia, hyperlipidaemia 10. Serum creatinine ≤180 µmol/l (2 mg/dl) but preferably ≤125 µmol/l (1.4 mg/dl) 11. Stature compatible with good obstetric outcome

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Table 5.9

Pregnancy safety information for immunosuppresive drugs used in transplantation.

Corticosteroids (prednisolone, methylprednisolone, others) Azathioprine (Imuran) Ciclosporin A (Sandimmune, Neoral, others) Tacrolimus, FK506 (Prograf) Antithymocyte globulin (Atgam, ATG) Antithymocyte globulin (Thymoglobulin) Orthoclone (OKTS3) Mycophenolate mofetil (CellCept) (MMF) Mycophendic acid (Myfortic) Basiliximab (Simulect) Daclizumab (Zenapax) Sirolimus (Rapamune) *

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Animal reproductive data

Pregnancy category*

Y Y Y Y N N N Y Y Y N Y

B D C C C C C D D B C C

B, no fetal risk, no controlled studies; C, fetal risk cannot be ruled out; D, evidence of fetal risk.

pregnancies in patients taking steroids, azathioprine, cyclosporine and tacrolimus (FK506 or Prograf).6,7 Although numerous adverse effects are attributed to calcineurin inhibitors in non-pregnant transplant recipients, including renal toxicity, hepatic dysfunction, chronic hypertension, tremor, convulsions, diabetogenic effects, haemolytic uraemic syndrome and neoplasia, these are no more common in pregnancy. Theoretically, however, in pregnancy, some of the maternal adaptations that normally occur may be blunted or abolished by cyclosporine or tacrolimus, especially plasma volume expansion and renal haemodynamic augmentation. Congenital anomalies are not more prevalent but there is evidence to suggest that patients have more “gestational” hypertension and smaller babies. Most agents used in pregnancy are category C (Food and Drug Administration (FDA) classification), where harm in humans cannot be excluded (Table 5.9). In pregnancy serum concentrations can be affected by various factors – increased glomerular filtration rate (GFR), enhanced volume of distribution and even reduced gastrointestinal motility, so levels must be monitored with dose adjustments if and when needed. Newer agents such as mycophenolate mofetil (MMF/CellCept), antithymocytic globulin, antithymocyte globulin (ATG/Atgam) and orthodione (OKTS) are being prescribed more frequently for transplant recipients. Some were originally considered only to have a “rescue role” in kidney and kidney-pancreas transplants but are nowadays being used as primary immunosuppressive agents. Based on registry reports plus post-marketing data which show an increased incidence and specific types of malformation, as well as a higher incidence of spontaneous abortions in female transplant recipients exposed to MMF during pregnancy, the FDA has

changed the MMF pregnancy category from category C to D (Table 5.9). A predominance of a particular type of birth defect had not been reported with previous immunosuppressive regimens and successful pregnancies with MMF exposure have also been reported but the conclusion cannot be avoided that there is a characteristic pattern of malformation after in utero exposure to MMF.37 Indeed, the existence of a MMF-associated embryopathy has been proposed with consistent main features: cleft lip and palate, microtia with atresia of the external auditary canal, micrognathia and hypertelorum. Occular anomalies, corpus callosum agenesis, heart defects, kidney malformations and diaphragmatic hernia could also be a part of the phenotypic spectrum, which is supported by experimental animal studies.38 To date, in the babies, psychomotor development and growth have been reported as normal. Thus, a management dilemma might be what to do about MMF, a drug with proven efficacy, because of potential fetal harm. Alternative immunosuppression may either be less effective (e.g. azathioprine) or have limited experience in this context (e.g. sirolimus). So, should the clinician recommend prepregnancy changes to immunosuppression, potentially increasing rejection risk and in the absence of data on the efficacy of such switches or should the clinician recommend continuation of an efficacious regimen with potential teratogenic risk?39

Comorbid conditions Hypertension can be a common problem after solid organ transplantation and renal dysfunction may also be present, and not just in renal recipients, but also in all organ recipients, again as a result of immunosuppressant therapy. Importantly, normal prepregnancy blood pressure and serum creatinine are associated

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with successful pregnancy outcome.6,40,41 Hypertension should be treated as it impinges on graft function, and poorly controlled hypertension can be associated with poor obstetric outcome. Prepregnancy angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blockers (ARBs) should be discontinued because of possible adverse fetal effects.42 Where there is established diabetes or it is likely to develop due to immunosuppressive usage, tight prepregnancy glycaemic control leading into the first trimester is advisable. Cognisance should also be taken of bone disease and autoimmune, haematological, cardiac and renal problems in these women and if/as needed medications adjusted or commenced de novo at doses acceptable for pregnancy.

Immunisation and significant infections Cytomegalovirus (CMV) infection has a high prevalence in transplant recipients. Furthermore, immunosuppressants predispose women to acute infections in pregnancy, so CMV, rubella, varicella, herpes simplex, toxoplasmosis, parvovirus and hepatitis titres should be determined. Susceptible women should be vaccinated against varicella before transplantation if at all possible as live virus vaccine administration is contraindicated in transplant recipients receiving immunosuppressive agents. Hepatitis, pneumococcal, tetanus and influenza vaccines may be given prior to or during pregnancy and, again, before transplantation. Immune conversion must always be ascertained after vaccine administration.43 It should be remembered that the lifelong infection associated with CMV can be reactivated by long-term immunosuppression and both maternal and fetal sequelae are not insignificant. Fetal CMV infection is not open to treatment as maternal administration of appropriate antiviral agents is unproven in pregnancy. Human papillomavirus (HPV) infection and cervical neoplasia are more common in female organ transplant recipients, so cervical smear cytology needs to be regularly undertaken. Theoretically HPV vaccine should be considered in young women awaiting a transplant or afterwards. This vaccine is non-infectious, but its efficacy may be reduced in an immunocompromised recipient.

Antenatal care Patients must be monitored as high risk cases (Table 5.10). Management requires attention to serial assessment of graft function, diagnosis and treatment of rejection, blood pressure control, monitoring renal function (in non-kidney recipients), early diagnosis and prevention of anaemia, diagnosis and treatment of any infection and meticulous surveillance of fetal well-being.14,44 Antenatal visits should be every 2 weeks up to 32 weeks, and weekly thereafter.

Table 5.10

Transplation and pregnancy: “ABC for

antenatal care”. Accurate dating and early diagnosis of pregnancy Bacterial and viral infections diagnosed and treated Comorbidities optimally managed Delivery – decisions on timing and route Effects of all medications to be considered Fetal surveillance essential Graft function/rejection must be monitored Hypertension/pre-eclampsia must be watched for Immunosuppression monitored and reviewed

Comorbid conditions These women are at greater risk of hypertension and/or pre-eclampsia and preterm delivery is common, with or without fetal growth restriction. Lower birth weights are seen in infants born to recipients of less than 1 year post-transplant and calcineurin inhibitors can be associated with significant fetal growth restriction.7,14,31,39 If changes to hypertensive agents are needed these should have been made in anticipation of pregnancy.19 Dose adjustments may be needed during pregnancy too. Attention should also be focused on other comorbid conditions, including anaemia, infections and gestational diabetes, the latter being more common in recipients taking steroids and/or tacrolimus.

Immunosuppressive therapy Unless obvious immunosuppressive toxicity or rejection occurs, it is best to maintain baseline dosing.12,39,44 As mentioned earlier, blood concentrations are likely to decrease slightly during pregnancy but this must not blind the clinician to the fact that some recipients become variably compliant, choosing to stop or reduce immunosuppressive agents during pregnancy for fear of harming the fetus. Significant unexplained deterioration in graft function should be assessed with biopsy. There are special considerations for each organ group. In the renal transplant group, the group with the most data, the usual pattern for the serum creatinine level is a slight decrease in early pregnancy, with a return to baseline postpartum. Increases during pregnancy and postpartum should be evaluated. Pancreas-kidney recipients usually can tolerate pregnancy without problems with glucose control, but additional comorbid conditions caused by cardiovascular disease must be considered. Lung recipients appear to have a higher incidence of peripartum problems in terms of both graft function and patient survival. For heart recipients to avoid X-ray exposure, biopsy can be done with echocardiographic guidance. In liver recipients, worsening liver function with chronic rejection or hepatitis C has been noted, with further deterioration in subsequent pregnancies. Whether such deterioration is time-linked or pregnancy-induced

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Table 5.11

Pregnancy-transplation interaction: problems

Table 5.14

Transplation and pregnancy: “ABC for

and decisions.

post-delivery care”.

Pregnancy complications/transplant deterioration? Delivery needed Gestational age at onset of problems Severity and progression of problems ± response to treatment Beware of “treating a sign” without modifying the basic disorder so as to “buy time” Fetal surveillance information Comorbidity problems to be considered Timing of delivery decision balances maternal and fetal “interests”

Anaemia may be a problem Breast feeding issues Contraception to be discussed Delivery “debrief” is essential Evaluate medications, adjust dosages if/as needed Follow-up of mother and baby in appropriate clinics Graft assessment Hypertension must be optimally controlled, especially if “troublesome” antenatally or at delivery Immunosuppression monitored and reviewed

Table 5.12

Reasons to consider delivery of a transplant

patient. Worsening hypertension/pre-eclampsia Deteriorating transplant function Fetal compromise Comorbidity problems

63

membranes and pre-eclampsia, most commonly. The judicious moment to deliver may be decided for a variety of reasons (Tables 5.11–5.13). After delivery, vigilance for graft rejection is needed and immunosuppressant levels should be monitored as fluid shifts may cause changes. If rejection is suspected then a biopsy is indicated (Table 5.14).

Care of the offspring Table 5.13

Transplantion and pregnancy “ABC for

Immediate problems

delivery”. Analgesia, anaesthesia, asepsis – all very important Back-up” from all relevant specialist personnel “B Cover with steroids (if appropriate) and antibiotic(s) always Delivery route dependent on obstetric factors Evaluate progress regularly Fluid balance is very important Graft assessment Hypertension optimally managed at all times Immunosuppression to be maintained

requires further study. Recipients with stable graft function have tolerated subsequent pregnancies. Whenever the diagnosis of acute rejection is made, then the appropriate anti-rejection regimens are necessary.

Delivery and immediately afterwards Vaginal delivery can be achieved and in the case of kidney grafts there are rarely any obstructive problems and/or mechanical injury to the transplant.14,28,44–46 Unless there are specific obstetric problems then spontaneous onset of labour can be awaited. Pain relief can be conducted as for healthy women. Augmentation of steroids (where relevant), antibiotic prophylaxis and continuation of immunosuppressants should not be overlooked.39 Caesarean section should only be undertaken for obstetric reasons. The main reason for the much higher than average Caesarean section rates in all transplant recipients is the increased complication rate – fetal growth restriction, preterm rupture of

More than 50% of liveborns have no neonatal problems.6,7,30,31 Preterm delivery is common (45–60%), growth restricted infants are delivered in 30–50% of cases, and occasionally the two factors coexist. Although management is the same as in the neonates of other mothers, some specific problems exist.21 Adrenocortical insufficiency due to the maternal steroid therapy potentially increases the risk of overwhelming neonatal infection. Finally, there are data associating tacrolimus with oligoanuria, hypokalaemia, myocardial hypertrophy and cardiomyopathy in neonates and thorough assessment is needed in these babies.

Breast feeding There are substantial benefits to breast feeding.12,47 It could be argued that because the baby has been exposed to immunosuppressive agents and their metabolites in pregnancy, breast feeding should not be allowed.47,48 Little is known, however, about the quantities of these agents and their metabolites in breast milk and whether the levels are biologically trivial or substantial. Azathioprine does not appear in breast milk but cyclosporine and tacrolimus do, although a wide range of fetal drug levels have been demonstrated. In women who choose to breast feed infant immunosuppressive agent levels should probably be evaluated.21 There are theoretical worries about in utero exposure to immunosuppressives with eventual development of malignant tumours in affected offspring, exaggerated or inadequate responses to vaccines,

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autoimmune complications, abnormalities in the reproductive performance and/or worries about neurocognitive development in the next generation.12,39 Thus, evaluation of the immune system and paediatric follow-up are needed. To date, information about general progress in early childhood has generally been good, although in 5–12 year olds exposed to cyclosporine in utero one study has identified a 16– 24% incidence of developmental delay.49

Maternal follow-up after pregnancy Theoretically, pregnancy is a “test of the graft” and the ultimate measure of success is the long-term survival of the patient and the graft (Table 5.15). A major concern is that the mother may not survive or remain well enough to rear the child she bears. Pregnancy occasionally and sometimes unpredictably causes irreversible declines in graft function. However, the consensus is that pregnancy has no effect on graft function or survival provided graft function prepregnancy is satisfactory (Table 5.16). Also, repeated pregnancies do not adversely affect graft function or fetal development again, provided that renal function is well preserved at the time of conception. Registry data, however, do indicate that graft loss rates within 2 years of pregnancy are significantly higher among kidney-pancreas, lung and lung-heart recipients (Table 5.17).7,50

Table 5.15

`Can the graft in pregnancy “pass the test?”

Yes, if there are: 1. An adequate and maintained graft response to pregnancy 2. No graft or associated complications during pregnancy 3. Successful maternal and fetal outcomes 4. No differences between pre- and post-pregnancy graft function 5. No long-term adverse graft outcomes

Contraception It is unwise to offer the option of sterilisation at the time of transplantation; this decision should not take place at this time. Oral contraceptives may cause or aggravate hypertension or thromboembolism and can produce subtle changes in the immune system, but this does not necessarily contraindicate their use.40 Careful surveillance is important.41 An intrauterine contraceptive device (IUD) may aggravate menstrual problems, which in turn may obscure signs and symptoms of abnormalities of early pregnancy, such as threatened abortion and ectopic pregnancy. The increased risk of pelvic infection associated with the IUD in an immunosuppressed patient makes this method worrisome. As insertion or replacement of an

Table 5.16 Prepregnancy renal function (SCr) in renal transplant recipients with estimates for pregnancy outcome (>24 weeks) and impact on maternal renal function. Estimates based on literature from 1991–2007, with all pregnancies attaining at least 24 weeks’ gestation. Loss of >25% renal function SCr µmol/l (mg/dl) <125 (<1.4) 125–160 (1.4–1.85) >160 (>1.85)

Fetal growth restriction (%)

Preterm delivery (%)

Pre-eclampsia (%)

Perinatal deaths (%)

Pregnancy (%)

Persists post-partum (%)

ESRF in 1 year (%)

30 50

35 70

24 45

3 7

15 20

4 7

— 10

60

90

60

12

45

35

70

ESRF, end stage renal failure.

Transplant patients and pregnancy: prospects and outcomes (%). Estimates based on literature review up to December 2006 (unpublished).

Table 5.17

Organ

Kidney Liver Heart/Heart-Lung Kidney-Pancreas

First Trimester pregnancy loss

Problems in pregnancy

Rejection in pregnancy

Infection(s) in pregnancy

Successful Outcome if > more than first trimester

Neonatal problems

Graft loss at 2 years

24 25 40 23

50 50 60 80

4 10 25 10

30 25 15 50

96 95 90 90

40 30 25 50

<10 <10 15–30 20

Antenatal

Early diagnosis and dating of pregnancy Clincial and laboratory monitoring of the graft and immunosuppressive drug levels every 4 weeks until 32 weeks every 2 weeks until 36 weeks then weekly until delivery Surveillance for rejection, with transplant biopsy considered if it is suspected Surveillance for bacterial or viral infection (e.g. cytomegalovirus, toxoplasmosis, hepatitis in first trimester and repeat if signs of rejection or tenderness over graft site) Monthly urine cultures Fetal surveillance after 32 weeks (e.g. nonstress test, sonographic evaluation) Monitoring of hypertension and man agement Surveillance for pre-eclampsia (and nephropathy) optimal Screening for gestational diabetes For kidney recipients proteinuria is common For liver recipients upper abdominal discomfort is common liver enzyme changes may be difficult to interpret For kidney-pancreas recipients Immunosuppressives may augment diabetogenic effect of pregnancy all infections must be taken very seriously For lung recipients 1 in 4 have rejection episodes

Patients should defer pregnancy for at least 1 year post-transplant, with appropriate and reliable contraception Assessment of graft function recent biopsy and/or organ-specific tests proteinuria creatinine level Hepatitis B and C, cytomegalovirus, toxoplasmosis, and herpes simplex status Maintenance immunosuppression azathioprine ciclosporin tacrolimus corticosteroids mycophenolate mofetil (MMF) and sirolimus very careful review needed Comorbidities (e.g. diabetes, hypertension) should be optimally managed; non-renal recipients must always have baseline kidney function assessed as well Vaccinations should be given, if needed (e.g. hepatitis, tetanus, pneumococcus, HPV and influenza Discuss the aetiology of the original disease and genetic issues, if appropriate Discuss the effect of pregnancy on graft function Discuss the risks of fetal growth restriction, preterm delivery and low birth weight

Summary of management for the patient with organ transplantation.14

Prepregnancy

Table 5.18

Caesarean delivery for obstetric reasons. For kidney recipients episiotomy on side opposite to graft Caesarean section may not be “easy” For heart, lung or heart-lung recipients continuous cardiac monitoring vigilance for poor or absent cough reflex and the need for airway protection due to denervation can be unpredictable responses to vasoactive medications judicious use of intravenous fluids

Delivery

Monitor immunosuppressant levels for 3–4 weeks’ postpartum, with adjust ment as needed Surveillance for rejection and consider biopsy if it is suspected Breast feeding is appropriate; monitor fetal drug levels Contraception counselling is essential

Postpartum

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IUD can be associated with bacteraemia of vaginal origin, antibiotic coverage is essential at this time. The efficacy of the IUD may be reduced by immunosuppressive and anti-inflammatory agents, possibly because of modification of the leukocyte response. Careful counselling and follow-up are essential.

Gynaecological problems Transplant recipients receiving immunosuppressive therapy have a malignancy rate estimated to be 100 times greater than normal, and the female genital tract is no exception.53 This association is probably related to factors such as loss of immune surveillance, chronic immunosuppression allowing tumour proliferation, and prolonged antigenic stimulation of the reticuloendothelial system. Therefore, regular gynaecological assessment is essential.52,54 Management should be on conventional lines, with the outcome unlikely to be influenced by stopping or reducing immunosuppression.

Summary (Table 5.18) Successful pregnancy is possible after an organ transplant but before becoming pregnant, a recipient should have stable graft function and optimal control of comorbid conditions. The shortest safe interval between transplant and pregnancy has not been established but 1 year is reasonable, given the prerequisites of stable, adequate graft function and maintenancelevel immunosuppression. Stable medical regimens should be changed as little as possible during pregnancy and close maternal and fetal surveillance is mandatory because these pregnancies are high risk and require tertiary centre care by perinatal specialists and the transplant team.

References 1. Armenti VT, Moritz MJ, Davison JM. Pregnancy in female pediatric solid organ transplant recipients. Pediatr Clin North Am 2003; 50: 1543–60. 2. Kosmach-Park B, Doshi B, Seward L et al. Successful pregnancy following intestine transplant in a longterm survivor. Transplantation 2006; 77: 430. 3. Murray J, Reid DE, Harrison JH et al. Successful pregnancies after human renal transplantation. N Engl J Med 1963; 269: 341–3. 4. Registration Committee of the European Dialysis and Transplant Association: Successful pregnancies in women treated by dialysis and kidney transplantation. Br J Obstet Gynaecol 1980; 87: 839–45. 5. Ehrlich JH, Loirat C, Davison JM et al. Repeated successful pregnancies after kidney transplantation in 102 women (Report by the EDTA Registry). Nephrol Dial Transplant 1996; 11: 1314–17. 6. Sibanda N, Briggs D, Davison J et al. Pregnancy after organ transplantation: a report from the UK Transplant Pregnancy Registry. Transplantation 2007; 83: 1301–7.

7. Armenti VT, Daller JA, Constantinescu S et al. Report from the National Transplantation Pregnancy Registry (NTPR): Outcomes of pregnancy after transplantation. In: Terasaki PI, ed. Clin Transpl. Los Angeles: Terasaki Foundation Laboratory, 2007; 57–70. 7. Armenti VT, Moritz MJ, Davison JM. Pregnancy following transplantation. In: James DK, Steer PJ, Weiner CP, Gonik B, eds. High Risk Pregnancy: Management Options, 3rd edn. Philadelphia, PA: Elsevier Science, 2006; 1174–86. 8. McGrory CH, McCloskey LJ, DeHoratius RJ et al. Pregnancy outcomes in female renal recipients: a comparison of systemic lupus erythematosus with other Diagnoses. American J of Transplantation 2003; 3: 35–42. 9. Gilbert-Hayn L, Sifontis NM, McGrory CH, et al. Pregnancy outcomes in female pancreas-kidney (PK) transplant recipients. American J of Transplantation 2007; S2: 399A. 10. Ohler L, Cosicia LA, McGrory CH, et al. National Transplantation Pregnancy Registry (NTPR): Pregnancy outcomes in female thoracic transplant recipients. J Heart and Lung Transplant 2007; 2(S1): 273A. 11. McKay DB, Josephson MA, Armenti VT, August P et al. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive issues and Transplantation. Am J Transplant 2005; 5: 1592–9. 12. Armenti VT, Moritz MJ, Cardonick EH, Davison JM. Immunosuppression in pregnancy: choices for infant and maternal health. Drugs 2002; 62: 2361–75. 13. Armenti VT, Herrine SK, Radomski JS, Moritz MJ. Pregnancy after liver transplantation. Liver Transpl 2000; 6: 671–85. 15. Cardonick E, Moritz M, Armenti V. Pregnancy in patients with organ transplantation: a review. Obstet Gynecol Surv 2004; 59: 214–22. 16. Davison JM, Bailey DJ. Pregnancy following renal transplantation. J Obstet Gynaecol Res 2003; 29: 227–33. 17. Guidelines for vaccination of solid organ transplant candidates and recipients. Am J Transplant 2004; 4 (Suppl 10): 160–3. 18. Hou S. Pregnancy in renal transplant recipients. Adv Ren Replace Ther 2003; 10: 40–7. 19. Josephson JA, McKay DB. Considerations in the medical management of pregnancy in transplant recipients. Adv Chronic Kidney Dis 2007; 14: 56–67. 20. Mastrobattista JM, Katz AR. Pregnancy after organ transplant. Obstet Gynecol Clin North Am 2004; 31: 415–28. 21. McKay DB, Josephson MA. Pregnancy in recipients of solid organs – effects on mother and child. N Engl J Med 2006; 354: 1281–93. 22. Nagy S, Bush M, Berkowitz R, Fishbein T, GomezLobo V. Pregnancy outcome in liver transplant recipients. Obstet Gynecol 2003; 102: 121–8. 23. Thompson BC, Kingdon EJ, Tuck SM et al. Pregnancy in renal transplant recipients: the Royal Free Hospital experience. Q J Med 2003; 96: 837. 24. Wu A, Nashan B, Messner U et al. Outcome of 22 successful pregnancies after liver transplantation. Clin Transplant 1998; 12: 454–64.

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The patient with organ transplantation 25. Wu D, Wilt J, Restaino S. Pregnancy after thoracic organ transplantation. Semin Perinatol 2007; 31: 354–62. 26. Ross LF. Ethical considerations related to pregnancy in transplant recipients. N Engl J Med 2006; 354: 1313. 27. EBPG Expert Group on Renal Transplantation. European best practice guidelines for renal transplantation. Nephrol Dialy Transplant 2002; 17(S4): 50. 28. Jabiry-Zieniewicz Z, Bobrowska K, Pietrzak B, et al. Mode of delivery in women after liver transplantation. Transplant Proc 2007; 39: 2796–99. 29. Oliveira LG, Sass N, Sato JL et al. Pregnancy after renal transplantation - a five-year single-center experience. Clinical Transplantation 2007; 21: 301–4. 30. del Mar Colon M, Hibbard JU. Obstetric considerations in the management of pregnancy in kidney transplant recipients. Ad Chr Kid Dis 2007; 14:(2): 168–77. 31. Kim HW, Seok HJ, Kim TH et al. The experience of pregnancy after renal transplantation: Pregnancies even within postoperative 1 year may be tolerable. Transplantation 2008; 85: 1412–19. 32. Stotland NL, Stotland NE. The mother and the burning building syndrome. Obstet Gynecol Surv 1997; 53: 1–2. 33. Muchowski K, Paladine H. An ounce of prevention: the evidence supporting periconception health care. J Fam Pract 2004; 53: 126–33. 34. Hellerstedt WL, Pirie PL, Lando HA, Curry SJ. Differences in preconceptual and prenatal behaviours in women with intended and unintended pregnancies. Am J Public Health 1998; 88: 663–7. 35. Coustan D. Preconception planning. The relationship is the thing. Diabetes Care 1998; 21: 8887–8. 36. Davison JM, Lind T, Uldall PR. Planned pregnancy in a renal transplant recipient. Br J Obstet Gynaecol 1976; 83: 518–27. 37. Sifontis NM, Coscia LA, Constantinescu S et al. Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus. Transplantation 2006; 82: 1698–702. 38. Perez-Aytes A, Ledo A, Boso V et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am J Med Genet A 2007; 146A-1–7. 39. Armenti VT, Moritz M, Davison JM. Drug safety issues in pregnancy following transplantation and immunosuppression: effects and outcomes. Drug Safety 1998; 19: 219–32. 40. Armenti VT, Moritz MJ, Davison JM. Parenthood post transplantation: 50 years later. Transplantation 2008; 85: 1389–90.

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41. Davison JM. Prepregnancy care and counselling in chronic renal disease. Eur Clin Obstet Gynaecol 2006; 3: 8–15. 42. Quan A. Fetopathy associated with exposure of angiotensin converting enzyme inhimitors and angiotensin receptor antagonists. Early Hum Dev 2006; 82.1: 23(6). 43. Duchini A, Goss JA, Karpen S, Pockros PJ. Vaccinations for adult solid-organ transplant recipients: current recommendations and protocols. Clin Microbiol Rev 2003; 16: 357–64. 44. Davison JM, Baylis C. Pregnancy in patients with underlying renal disease. In: Davison AM, Cameron JS, Grünfeld J-P, Ponticelli C, Ritz E, Winnearls CG, van Ypersele C, eds. Oxford Textbook of Clinical Nephrology. 3rd edn. 2005. Oxford: Oxford University Press, 2243–60. 45. Jain AB, Reyes J, Marcos A et al. Pregnancy after liver transplantation with tacrolimus immunosuppression: a single center’s experience update at 13 years. Transplantation 2003; 76: 827–32. 46. Rigg CD, Bythell VE, Bryson MR, Halshaw J, Davison JM. Caesarean section in patients with heart-lung transplants: a report of 3 cases and review. Int J Obstet Anesth 2000; 9: 125–32. 47. Gardiner SJ, Begg EJ. Breastfeeding during tacrolimus therapy. Obstet Gynecol 2006; 107: 453–5. 48. Moretti ME, Sgro M, Johnson DW et al. Cyclosporine excretion into breast milk. Transplantation 2003; 75: 2144–6. 49. Stanley CW, Gottlieb R, Zager R, Eisenberg J et al. Developmental well-being in offspring of women receiving cyclosporine post-renal transplant. Transplant Proc 1999; 31: 241–2. 40. Armenti VT, Moritz M, Davison JM. Drug safety issues in pregnancy following transplanation and immunosuppression: effects and outcomes. Drug safety 1998; 19: 219–32. 50. Davison JM, Nelson-Piercy C, Kehoe S, Baker P, eds. Renal Disease in Pregnancy. London: RCOG Press, 2008. 51. Estes CM, Westhoff C. Contraception for the transplant patient. Semin Perinatol 2007; 31: 372–7. 52. Framarino Dei Malatesta M, Rossi M, Rocca B et al. Fertility following solid organ transplantation. Transplant Proc 2007; 39: 2001–4. 53. Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplanation in the United States. Am J Transplant 2004; 4: 905–13. 54. Sucato GS, Murray PJ. Gynecologic health care for the adolescent solid organ transplant recipient. Pediatr Transplantation 2005; 9: 346–56.

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6 The patient with hypertension Catherine Nelson-Piercy

Introduction Hypertension is one of the commonest pre-existing medical conditions encountered in women of childbearing age. Chronic or pre-existing hypertension complicates 3–5% of pregnancies, although this figure may rise with the trend for women to postpone childbirth into their 30s and 40s.1 Pre-existing hypertension has implications for pregnancy outcome and the woman’s long-term health. Some drugs used to treat hypertension are teratogenic or ill advised in pregnancy and alterations to medication regimens may be required pre-conception. There are three types of hypertension in pregnancy: pre-existing hypertension, gestational or pregnancyinduced hypertension (PIH), and pre-eclampsia. This chapter focuses on pre-existing hypertension, although women with previous PIH or pre-eclampsia also require pre-pregnancy counselling regarding recurrence risks. Women with pre-existing hypertension may have essential hypertension, often in association with a family history of hypertension, or they may have hypertension that is secondary to renal, cardiac or endocrine disease or associated with co-morbidities such as obesity, diabetes or polycystic ovarian syndrome. One of the important roles of periconceptional medicine in women with hypertension is to establish the underlying cause of the hypertension, and specifically to exclude secondary causes. These may be serious medical conditions, associated with adverse pregnancy outcomes and serious maternal morbidity such as reflux nephropathy, phaeochromocytoma or aortic coarctation, or medical conditions that themselves influence fertility, such as renal failure or Cushing’s syndrome. The hypertension may be curable or ameliorated by treatment of the underlying cause such as renal artery stenosis. If the woman has been previously appropriately and thoroughly investigated to exclude secondary causes of hypertension, then it is not necessary to repeat these investigations. However, hypertension in any young person should not be attributed to essential (idiopathic) hypertension before secondary causes such as renal and cardiac disease, and rarely endocrine disorders

Table 6.1

Secondary causes of hypertension.

Renal disease Reflux nephropathy Adult polycystic kidney disease Glomerulonephritis Renal disease Any chronic kidney disease (CKD) Cardiac disease Coarctation of the aorta Endocrine disease Conn’s syndrome/hyperaldosteronism Cushing’s syndrome Phaeochromocytoma Hyperparathyroidism

have been excluded. Hypertension that is newly diagnosed, that is not associated with a family history, that is discovered in a particularly young woman (e.g. age <30 years) or that has not been previously investigated warrants thorough investigation prior to pregnancy. The secondary causes of hypertension are shown in Table 6.1. Of these the commonest secondary cause encountered is renal disease, including, particularly in women of child-bearing age, reflux nephropathy, glomerulonephritis and renal artery stenosis. Women presenting with hypertension should be examined for clues to a possible secondary cause. This should include examination of the femoral pulses (looking for radiofemoral delay, suggesting coarctation of the aorta) and a search for renal bruits (possible renal artery stenosis) and features of Cushing’s syndrome. Women with hypertension should also have urinalysis performed to identify proteinuria or haematuria that may suggest underlying renal disease, or glycosuria suggesting diabetes. A simple screen with serum creatinine and urea (to exclude renal impairment), and electrolytes (to exclude hypokalaemia, which may suggest Conn’s syndrome) should be performed. Liver function tests and a serum calcium are required to calculate a corrected calcium to exclude hypercalcaemia as a cause of hypertesion. Urinary catecholamines should be

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Table 6.2 outcome.

Adverse effects of hypertension on pregnancy

Maternal Increased risk of pre-eclampsia Increased risk of placental abruption Increased risk of Caesarean section Fetal Increased risk of fetal growth restriction/small for gestational age Increased risk of preterm delivery Increased perinatal mortality Increased risk of miscarriage

measured in cases suggestive of phaeochromocytoma (labile hypertension, palpitations). A renal ultrasound will exclude polycystic kidney disease or may suggest another chronic kidney disease (e.g. scarring in reflux nephropathy or small kidneys in chronic renal failure). An ultrasound of the abdomen may also diagnose adrenal tumours (e.g. Conn’s syndrome). Consideration and counselling regarding co-morbidities, particularly obesity, diabetes, and polycystic ovarian syndrome, are also important in women with hypertension since these conditions are associated with their own implications for fertility, pregnancy outcome and long-term health. These comorbidities may add to the already elevated risk of pre-eclampsia associated with hypertension. For example, obese women are more likely to be hypertensive. Comorbidities affecting fertility result in a delay before child bearing or longer inter-birth interval, both of which increase the risk of pre-eclampsia. For example, women with renal failure have reduced fertility. It is the individualised cumulative risk of these various factors that is important for clinical practice. Thus, an obese 40-year-old women with hypertension in her first pregnancy is at higher risk of superimposed preeclampsia than a multiparous hypertensive woman aged 24 with a normal body mass index.

Effect of pre-existing hypertension on pregnancy outcome The adverse effects of pre-existing hypertension on pregnancy outcome are summarised in Table 6.2. Women with pre-existing hypertension from whatever cause are at increased risk of superimposed pre-eclampsia,2 small for gestational age (SGA) infants, and placental abruption. Consequently, the perinatal mortality and preterm delivery rates are increased in this population. If a woman is sufficiently hypertensive to require treatment before pregnancy, the risk of pre-eclampsia in pregnancy is approximately doubled. These women are also at particular risk of severe or early-onset preeclampsia.3 In a recent Danish study pre-existing hypertension, diabetes, obesity or multiple gestation

were present in 34% of cases of early pre-eclampsia in nulliparous women and 50% of early pre-eclampsia in multiparous women. For severe pre-eclampsia the percentages were 23% in nulliparous and 59% in multiparous women.3 A Canadian study found an incidence of preeclampsia of 21.2% in 337 women with chronic hypertension compared with an incidence of 2.3% in the control population. (p<0.01).4 In a study of 169 pregnancies in 156 women with chronic hypertension 34.3% developed superimposed pre-eclampsia.5 More recent studies have confirmed these observations. A large cross-sectional study from South America found that chronic hypertension was associated with a doubling of the risk of pre-eclampsia (relative risk (RR) = 1.99, 95% confidence interval (CI) 1.78–2.22).6 In a study from South Australia superimposed preeclampsia occurred in approximately 40% of pregnancies of women with pre-existing hypertension.7 In a recent large prospective study from London of 822 women with pre-existing hypertension, the incidence of superimposed pre-eclampsia was 22%, but early-onset pre-eclampsia (≤34 weeks’ gestation) accounted for almost half of the cases.8 Using multiple logistic regression, this group showed that in women with hypertension, black ethnic origin, raised body mass index, present smoking, booking systolic blood pressure of 130–139 mmHg, diastolic blood pressure of 80–89 mmHg, a previous history of pre-eclampsia or eclampsia and chronic renal disease were identified as risk factors for superimposed pre-eclampsia.8 The increased risk of pre-eclampsia is related to the degree of hypertension. In a study of 211 women with mild hypertension (diastolic blood pressure 90–110 mmHg) the incidence of superimposed preeclampsia was 10%.9 In those women with severe hypertension, defined as a diastolic blood pressure of 110 mmHg or higher before 20 weeks’ gestation, a study from New Zealand of 155 hypertensive women demonstrated a risk of superimposed pre-eclampsia of 46% compared with 14% for women with mild hypertension (odds ratio 5.2, 95% CI 1.5–17.2).10 Both diastolic and systolic hypertension increase the risk of superimposed pre-eclampsia. In an analysis of risk factors for pre-eclampsia in nulliparous women11 the odds ratio for a systolic blood pressure in early pregnancy of 120 mmHg or more compared with <101 mmHg was 2.66. Similarly the odds ratio for a diastolic blood pressure of greater than 60 mmHg compared with less than 60 mmHg was 1.72. In the South Australian study, pre-existing hypertension and superimposed pre-eclampsia were significantly associated with elective Caesarean section as well as induction of labour and emergency Caesarean section.7 Pre-existing hypertension is an independent risk factor for perinatal death. In another more recent study from South Australia, the adjusted odds ratio for pre-existing hypertension was 1.72.12 Of particular relevance, assisted

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reproductive technology was also an independent risk factor (adjusted odds ratio (AOR) 3.16).12 In a sample of 305 women with non-proteinuric hypertension that was either pre-existing (n=133 (43.6%)) or gestational (n=172 (56.4%)), 16.4% (n=50) of pregnancies were complicated by birth weight less than the 3rd centile or one or more serious perinatal complications, 33% (n=100) by preterm birth, 30.8% (n=94) by pre-eclampsia, and 2.0% (n=6) by serious maternal complications.13 Multivariate analysis of outcomes of pregnancy in women with hypertension in pregnancy in Adelaide has shown that pre-existing hypertension was an independent risk factor for requirement for level II/III care, preterm birth, (SGA) birth and length of maternal hospital stay greater than 7 days, odds ratio 1.26–2.90.14 The recent study by Chappell et al showed that in a cohort of women with pre-existing hypertension, 21% of women without superimposed pre-eclampsia delivered a baby with less than the 10th customised birthweight centile but this figure rose to 48% in those with superimposed pre-eclampsia.8 Preterm delivery (<37 weeks) was also more common, occurring in 51% of those with superimposed pre-eclampsia (98% of these iatrogenic) and 15% of those without superimposed pre-eclampsia (66% iatrogenic).

Effect of pregnancy on severity of hypertension Women with pre-existing hypertension will usually exhibit the normal physiological responses to pregnancy with regards to changes in blood pressure. Early in the first trimester there is a fall in blood pressure caused by vasodilatation. This is due to local mediators, such as prostacyclin and nitric oxide. This reduction in blood pressure primarily affects the diastolic pressure, and a drop of 10 mmHg is usual by 13– 20 weeks’ gestation.15 Blood pressure continues to fall until 22–24 weeks. After this, there is a gradual increase in blood pressure until term, when blood pressure returns to the level it was before pregnancy. Immediately after delivery blood pressure usually falls and then increases over the next 5 days.15 Women with pre-existing hypertension that has not been diagnosed may appear normotensive in early pregnancy because of the normal fall in blood pressure starting in the first trimester. This may mask the pre-existing hypertension. Sometimes the diagnosis only comes to light several months after the birth, when the blood pressure fails to return to normal as one would expect with gestational hypertension. Even women whose blood pressure was normal throughout pregnancy may experience transient hypertension in the early period postpartum. This perhaps reflects a degree of vasomotor instability. The conventional definition of hypertension in pregnancy is systolic pressure >140 µmHg or diastolic

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>90 mmHg. A diastolic blood pressure of 90 mmHg is, 3 standard deviations above the mean for mid-pregnancy, 2 standard deviations at 34 weeks and 1.5 standard deviations at term. The definition for a relative rise in blood pressure incorporates a rise in systolic pressure of >30 mmHg or a rise in diastolic pressure of >15 mmHg above blood pressure at booking. Women with pre-existing hypertension who develop superimposed pre-eclampsia will exhibit worsening hypertension from anytime after 20 weeks’ gestation. It may be difficult to differentiate superimposed preeclampsia from the normal physiological rise in blood pressure that occurs in the third trimester. Thus, regular assessment for the development of proteinuria or other features of pre-eclampsia is imperative. There is no evidence that pregnancy itself worsens pre-existing hypertension in the long term. However, superimposed pre-eclampsia or severe hypertension in pregnancy in women with hypertension related to kidney disease can worsen underlying renal disease and therefore the hypertension. There is also a well described association of preeclampsia and the subsequent development of hypertension later in life. Systematic review and meta-analysis have shown that after pre-eclampsia women have a relative risk of hypertension of 3.70 (95% CI 2.70–5.05) after 14.1 years weighted mean follow-up.16

Summary of pre-conception advice Pre-conception advice In women with pre-existing hypertension, assessment before conception should include: (1) Exclusion of secondary causes of hypertension (for example, renal and endocrine causes); (2) Ensuring optimal blood pressure control; (3) Discussion of the increased risks of pre-eclampsia and other adverse pregnancy outcomes; (4) Education about drug alterations that should be made prior to pregnancy or in the first trimester if the woman becomes pregnant. Optimal pre-conception control of hypertension may reduce the risk of adverse outcomes. It is important that women with pre-existing hypertension are counselled, ideally prior to pregnancy, about the associated increased risks of pre-eclampsia and the related complications of fetal growth restriction and preterm delivery.

Medication Antihypertensives A Cochrane review of the treatment of mild to moderate hypertension in pregnancy included 46 trials, 4282 women17 and showed that antihypertensive therapy

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given in pregnancy does not prevent superimposed pre-eclampsia (RR 0.97, 95% CI 0.83–1.13). Similarly, there is no clear effect on the risk of the baby dying (RR 0.73, 95% CI 0.50–1.08), preterm birth (RR 1.02, 95% CI 0.89–1.16), or SGA babies (RR 1.04, 95% CI 0.84– 1.27). However, treatment of hypertension halves the risk of severe hypertension (RR 0.50, 95% CI 0.41– 0.61, risk difference (RD) −0.10 (−0.12 to −0.07), number needed to treat (NNT) 10 (8–13)) and therefore reduces the risk of dangerous complications such as maternal cerebral haemorrhage. There is consensus that blood pressures above 160/110 mmHg should be treated18 and it has been shown that a systolic blood pressure of 155 mmHg or greater was present immediately before stroke that occurred in the context of pre-eclampsia in 100% (n=24) of women and a systolic blood pressure of 160 mmHg or greater in 96% of women.19 Because of the risks of severe hypertension, most clinicians would agree that blood pressures above 150/100 mmHg should be treated. However, a randomized controlled trial of less tight (target diastolic blood pressure 100 mmHg) or tight (target diastolic blood pressure 85 mmHg) blood pressure control in pregnancy showed that tight control of blood pressure was associated with a higher risk of preterm birth (40% versus 36.4%), neonatal intensive care unit admissions (34.4% versus 22.7%) and serious perinatal complications (21.5% versus 13.6%).20 So overzealous control of blood pressure in pregnancy is not appropriate either. Choice of antihypertensive agent Most of the many antihypertensive drugs used in routine practice have not been shown to be teratogenic and women can safely conceive while taking medication. The exceptions are angiotensin converting enzyme (ACE) inhibitors (e.g. ramipril, enalapril, lisinopril) and angiotensin receptor blockers (ARBs) (e.g. Losartan) which should be discontinued prepregnancy or early in the first trimester because they are teratogenic and foetotoxic.21 In a cohort of almost 30 000 infants from Tennessee, a retrospective study has shown an increased risk of major congenital malformations (RR 2.71, 95% CI 1.72–4.27) in infants exposed to ACE inhibitors in the first trimester. The increased risk was for malformations of the cardiovascular system (RR 3.72, 95% CI 1.89–7.30) and the central nervous system (RR 4.39, 95% CI 1.37–14.02).21 The foetotoxic effects include oligohydramnios, renal failure and hypotension. The use of ACE inhibitors has also been associated with decreased skull ossification, hypocalvaria and renal tubular dysgenesis, and there is also a risk of intrauterine death. No similar risk has been shown for other classes of antihypertensive drugs.21 It is not therefore necessary to switch women’s medication prior to conception unless they are receiving ACE inhibitors or ARBs. For women taking these drugs, an individual risk–benefit

assessment should be undertaken and discussed. If the woman is receiving these drugs for control of blood pressure alone, then it is appropriate to swap the drugs for a ‘pregnancy-friendly’ alternative, such as the calcium antagonist amlodipine (see below). However, in some cases women will be receiving ACE inhibitors or ARBs for control of proteinuria with or without hypertension. This is a common strategy in women with diabetes and in those with renal disease, since blockade of the rennin–angiotensin–aldosterone system (RAAS) has an additive renoprotective effect over reduction of blood pressure alone, both in diabetic and nondiabetic renal diseases. The main evidence for the renoprotective action of RAAS blockade is provided by its consistent antiproteinuric action, which cannot completely be attributed to the reduction in blood pressure.22 Therefore, in women with renal disease it may be judged that rapid cessation of ACE inhibitors or ARB therapy on confirmation of pregnancy (before fetal cardiac development occurs) is preferable to elective discontinuation prior to conception that may not occur for many months and will result in loss of valuable renoprotection. The importance of rapid cessation on confirmation of pregnancy should be discussed with the woman prior to pregnancy. The drug of choice to treat pre-existing hypertension in pregnancy is methyldopa, based on its long and robust safety record.23 Beta-blockers have fewer maternal sideeffects than methyldopa, causing less sedation and postural hypotension. Furthermore, in a Cochrane review17 beta-blockers were superior to methyldopa for reducing the risk of severe hypertension (ten trials, 539 women, RR 0.75 (95% CI 0.59–0.94), RD −0.08 (−0.14–0.02), NNT 12 (6–275)). However, the safety of beta-blockers in the fetus is not so well established. There is concern that beta-blockers may inhibit fetal growth when used longterm (and started in the first trimester) or in large doses throughout pregnancy. A retrospective cohort study from the UK of 491 pregnancies in 380 women with essential or secondary hypertension24 showed that babies of women taking atenolol at conception or during the first trimester had significantly lower birth weights (by 139–512 g, p<0.01) than women on calcium channel blockers or no medication. Likewise, the ponderal index was also significantly reduced, p<0.01. In addition most of these babies were SGA with 70% on or below the 10th centile and 40% below the 3rd centile.24 Claims of betablockers causing neonatal hypotension and hypoglycaemia have not been substantiated in the randomised controlled trials performed. There is no evidence for the superiority of any one beta-blocker over the others. Betablockers should not be given to women with a history of asthma. Guidelines of the International Society for the Study of Hypertension in Pregnancy (ISSHP) do not recommend the use of oral beta-blockers for mild hypertension in pregnancy.1 Second-line drugs for the treatment of hypertension in pregnancy include calcium antagonists (e.g. slowrelease nifedipine, or amlodipine), and labetalol.

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These should be used in conjunction with methyldopa in those women who fail to respond to monotherapy, or to replace methyldopa in the minority of women who are unable to tolerate it. As data regarding the safety and tolerability of calcium antagonists in pregnancy accumulate, it would seem preferable to use these in preference to methyldopa for women who need to change their therapy prior to pregnancy. Side-effects of vasodilators include headache, facial flushing and oedema, and may necessitate withdrawal in some patients. Labetalol, a combined alphaand beta-blocker, should not be given to women with asthma. Alpha-adrenergic blockers are also safe and can be used as second- or third-line therapy. Diuretics should only be used in pregnancy for the treatment of heart failure and pulmonary oedema. They are particularly hazardous and relatively contraindicated in pre-eclampsia because they cause further depletion of a reduced intravascular volume.25 In summary, it is acceptable for women to conceive while continuing to take their usual antihypertensive medication, (except ACE inhibitors, ARBs and atenolol). Once pregnancy is confirmed, if a woman only requires one antihypertensive agent to control her blood pressure outside pregnancy and the blood pressure is <140/90 mmHg when first seen in pregnancy, it is usually possible to discontinue the antihypertensive medication because of the physiological fall of blood pressure in early pregnancy. Women with severe hypertension (>170/110 mmHg) and those requiring more than one agent should continue their medication if they are receiving calcium antagonists, methyldopa, labetalol or alpha-blockers. Women receiving diuretics, atenolol, ACE inhibitors or ARBs should be converted directly to methyldopa.

Treatments to prevent pre-eclampsia As discussed above, much of the increase in adverse maternal and fetal outcomes in women with pre-existing hypertension is due to superimposed pre-eclampsia. Therefore, any agents that reduce the risks of pre-eclampsia should be used in hypertensive women, particularly those who have experienced poor obstetric outcomes in previous pregnancies because of severe pre-eclampsia. In the most recent Cochrane systematic review of almost 38 000 women in 59 trials,26 prophylactic antiplatelet agents, most commonly low dose aspirin, reduced the risk of pre-eclampsia by 17% (RR 0.83, 95% CI 0.77–0.89), NNT 72 (52–119)). High risk women (such as women with hypertension) benefit most, and the review found a significant increase in the absolute risk reduction of pre-eclampsia for high risk (RD −5.2% (−7.5 to −2.9), NNT 19 (13–34)) compared with moderate risk women (RD −0.84 (−1.37 to −0.3), NNT 119 (73–333)). Antiplatelet agents were also associated with an 8% reduction in the relative risk of preterm birth (RR 0.92, 95% CI 0.88–0.97; NNT

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72 (52–119)), a 14% reduction in fetal or neonatal deaths (RR 0.86, 95% CI 0.76–0.98, NNT 243 (131– 1666)) and a 10% reduction in SGA babies (RR 0.90, 95% CI 0.83–0.98). It is not known if commencing aspirin pre-pregnancy is more effective than starting it after conception, or whether 150 mg is more effective than 75 mg. Because pre-eclampsia involves endothelial dysfunction and oxidative stress, there has been interest in giving antioxidant vitamin C and E supplements in the second trimester. A preliminary trial of antioxidant vitamins in women at high risk reported improvements in biochemical markers of endothelial activation and a reduction in pre-eclampsia.27 However, a large, nationwide, randomised trial showed no reduction in the incidence of pre-eclampsia in women treated with vitamins and indeed the risk of low birth weight babies was increased.28 A randomised double blind placebo controlled trial in over 8000 primiparous women with low dietary calcium intakes29 has shown that supplements of calcium of 1.5 g/day significantly reduced severe gestational hypertension (RR 0.71, 95% CI 0.61–0.82). Calcium also reduced the severe pre-eclamptic complications index (RR 0.76, 95% CI 0.66–0.89, life-table analysis, log rank test, P= 0.04). The severe maternal morbidity and mortality index was also reduced in the supplementation group (RR 0.80, 95% CI 0.70–0.91). The neonatal mortality rate was also significantly lower (RR 0.70, 95% CI 0.56–0.88) in the calcium group. The authors concluded that although a 1.5 g calcium/day supplement did not prevent pre-eclampsia it did reduce its severity, maternal morbidity and neonatal mortality.29 More recently, a meta-analysis of 12 studies including 15 528 women showed that calcium supplementation reduced blood pressure and the risk of pre-eclampsia (12 trials, 15 206 women: RR 0.48, 95% CI 0.33–0.69). The effect was greatest for women at high risk (five trials, 587 women: RR 0.22, 95% CI 0.12–0.42) and for those with low baseline calcium intake (seven trials, 10 154 women: RR 0.36, 95% CI 0.18–0.70). The composite outcome maternal death or serious morbidity was also reduced (four trials, 9732 women: RR 0.80, 95% CI 0.65–0.97).30 Therefore, calcium supplementation would seem sensible in women with low calcium intake and may reduce the severity of pre-eclampsia.

Management of pregnancy Most women with controlled chronic hypertension will, under close supervision and management, have a successful pregnancy outcome. However, poorly controlled hypertension in the first trimester significantly increases maternal and fetal morbidity and mortality. Early booking with access to specialist care for high risk pregnancies is therefore important. Antenatal care for women with pre-existing hypertension centres around surveillance for pre-eclampsia31 and fetal

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growth restriction. Antenatal care should include regular checks of blood pressure (every 2–4 weeks, depending on blood pressure levels and gestational age). Measurements of blood pressure should be made with the woman seated and using the appropriate cuff size. Late in the second trimester and in the third trimester, the pregnant uterus may obstruct venous return. If the blood pressure is taken while she is lying down, she should be lying on her side. Korotkoff V (disappearance) rather than phase IV (muffling) should be used because it is more reproducible and shows better correlation with true diastolic blood pressure in pregnancy or alternatively an automated device that is validated for use in pregnancy.32,33 As discussed above, the optimal level of blood pressure in pregnancy has not been established. Lowering the blood pressure too much may lead to placental hypoperfusion because placental blood flow is not autoregulated. This will affect the growth of the fetus. In one meta-analysis it was demonstrated that a greater fall in mean arterial blood pressure with antihypertensive therapy was associated with a higher proportion of SGA infants and lower mean birth weight.34 Also, women with chronic hypertension may have reset their cerebral autoregulation and be able to withstand higher blood pressures than previously normotensive women who develop pre-eclampsia. A reasonable target would seem to be a systolic blood pressure 140– 150 mmHg and a diastolic 90–95 mmHg.19,20 Pre-eclampsia is one of the most common causes of maternal death in the UK35 and usually occurs after 20 weeks’ gestation, but can occasionally present before 20 weeks’ gestation.36 Overall, pre-eclampsia complicates 5–6% of pregnancies,37 but this figure increases to up to 25% in women with pre-existing hypertension. Correct identification of women at increased risk of pre-eclampsia such as those with pre-existing hypertension allows appropriate channelling of antenatal care and allocation of resources to maximise the chances of early diagnosis and appropriate management. In addition, strategies to screen for and prevent pre-eclampsia are often more effective in high-risk women. Doppler ultrasound of the uterine arteries around the time of the fetal anomaly scan at 20–24 weeks can be useful particularly because of its high negative predictive value in predicting severe early-onset (requiring delivery before 34 weeks’ gestation) preeclampsia and growth restriction. A meta-analysis concluded that increased impedance to flow in the uterine arteries in pregnancies attending for routine antenatal care identifies about 40% of those who subsequently develop pre-eclampsia and about 20% of those who develop fetal growth restriction. Following a positive test, the likelihood of pre-eclampsia is increased about 6 fold and fetal growth restriction 3.5 fold.38 Diagnosis of pre-eclampsia in women with preexisting hypertension relies on the development of

new-onset significant proteinuria and worsening hypertension. The onset of significant proteinuria, in the absence of renal disease, is one of the best indicators of pre-eclampsia. If the women develops 1+ or greater of proteinuria on dipstick, formal quantification of proteinuria with a 24-hour urine collection or protein:creatinine ratio is needed. Significant proteinuria in pregnancy is greater than 0.3 g per 24 hours. If the woman already has proteinuria because of underlying renal disease, then diagnosis of pre-eclampsia is even more problematic and is dependent on the degree of worsening of the hypertension and proteinuria as well as trends in the blood parameters. Laboratory blood tests that should be carried out include serum creatinine, platelets, uric acid and transaminases. Abnormalities in these blood parameters are an aid to diagnosis of pre-eclampsia but are neither specific nor sensitive enough in isolation.

Management of delivery It is important to continue antihypertensive therapy throughout labour and delivery. For women who develop superimposed pre-eclampsia, it may become necessary to use parenteral therapy with either intravenous labetalol or hydralazine. The clinician should use an agent with which they are familiar.18 Hydralazine and labetalol are equally effective but hydralazine has more side-effects, particularly headache and palpitations.39 The systolic blood pressure should be kept below 160 mmHg.19,35

Management of puerperium As discussed above, the blood pressure tends to fall after delivery but to rise again by day 3–4. Women with pre-existing hypertension who required treatment prior to pregnancy will require treatment after the pregnancy as well. Higher doses may be needed for 4–6 weeks following a pregnancy, particularly if the pregnancy was complicated by superimposed pre-eclampsia. All commonly used oral antihypertensive agents are safe to use in women who are breast feeding.40 A pragmatic approach is to recommence the therapy on which women were stable prior to pregnancy. Women who were transferred to methyldopa, should discontinue this because of the possible side-effect of depression and because once the pregnancy is over there is no longer any indication to use this drug. Drugs with a long and established safety record in lactating mothers include atenolol, labetalol and nifedipine, but ACE inhibitors and amlodipine are also probably safe. Doxazocin accumulates in breast milk and should probably be avoided41 and there are few data for ARBs in breast feeding. Diuretics, although not harmful are usually avoided since they may exacerbate thirst which is a common complaint in breast feeding mothers.

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It is important to arrange postpartum follow-up for women with pre-existing hypertension. This will usually be with the woman’s general practitioner. Counselling regarding the importance of long-term control of blood pressure and assessment for other cardiovascular risk factors, particularly those that are modifiable with lifestyle changes such as cessation of smoking, weight reduction and exercise, is also important. Statin therapy if introduced should be discontinued prior to a subsequent pregnancy. For women with superimposed pre-eclampsia, the increased subsequent risks of ischaemic heart disease (RR 2.16, 95% CI 1.86–2.53 after 11.7 years of followup) and cerebrovascular disease (RR of stroke 1.81, 95% CI 1.45–2.27) after 10.4 years16 should be explained.42,43

Conclusion Pre-existing hypertension is associated with significant risks to both the mother and her fetus. These risks are lower with milder degrees of hypertension and in the absence of other comorbidities and may be minimised by optimal control of the blood pressure prior to conception. Preparation for pregnancy should include informed counselling regarding potential risks in pregnancy and longer-term health, and specific advice regarding necessary adjustment of drug therapy and a plan for care during the pregnancy.

References 1. Magee LA, Ornstein MP, von Dadelszen P. Management of hypertension in pregnancy. BMJ 1999; 318: 1332–6. 2. Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ 2005; 330: 565. 3. Catov JM, Ness RB, Kip KE, Olsen J. Risk of early or severe pre-eclampsia related to pre-existing conditions. Int J Epidemiol 2007; 36: 412–19. 4. Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. AMJ Obstet Gynecol 1994; 171: 410–16. 5. Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol 1986; 67: 197– 205. 6. Conde-Agudelo A, Belizan JM. Risk factors for preeclampsia in a large cohort of Latin American and Caribbean women. BJOG 2000; 107: 75–83. 7. Heard AR, Dekker GA, Chan A et al. Hypertension during pregnancy in South Australia, part 1: pregnancy outcomes. Aust N Z J Obstet Gynaecol 2004; 44: 404–9. 8. Chappell LC, Enye S, Seed P et al. Adverse perinatal outcomes and risk factors for preeclampsia in women with chronic hypertension. A prospective study. Hypertension 2008; 51: 1002–9. 9. Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic hypertension. Obstet Gynecol 1983; 61: 571–6.

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10. McCowan L.M.E, Buist R.G, North R.A, Gamble G. Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996; 103: 123–9. 11. Sibai BM, Ewell M, Levine RJ et al. Risk factors associated with preeclampsia in healthy nulliparous women. The Calcium for Pre-eclampsia Prevention (CPEP) Study Group. Am J Obstet Gynecol 1997; 177: 1003–10. 12. de Lange TE, Budde MP, Heard AR et al. Avoidable risk factors in perinatal deaths: A perinatal audit in South Australia. Aust N Z J Obstet Gynaecol 2008; 48: 50–7. 13. Magee LA, Von Dadelszen P, Bohun CM et al. Serious perinatal complications of non-proteinuric hypertension: an international, multicentre, retrospective cohort study. J Obstet Gynaecol Can 2003; 25: 372–82. 14. Vreeburg SA, Jacobs DJ, Dekker GA et al. Hypertension during pregnancy in South Australia, part 2: risk factors for adverse maternal and/or perinatal outcome – results of multivariable analysis. Aust N Z J Obstet Gynaecol 2004; 44: 410–18. 15. Sibai BM. Treatment of hypertension in pregnancy. N Engl J Med 1996; 335: 257–65. 16. Bellamy L, Casas JP, Hingorani AD, Williams DJ. Preeclampsia and risk of cardiovascular disease and cancer in later life: systematic review and metaanalysis. BMJ 2007; 335: 974. 17. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for mild to moderate hypertension in pregnancy (Cochrane Review). Cochrane Database Syst Rev 2007; (1): CD002252. 18. RCOG green top guideline. The management of severe pre-eclampsia/eclampsia. Number 10(A). 2006 http://www.rcog.org.uk/resources/Public/pdf/ management_pre_eclampsia_mar06.pdf 19. Martin JN Jr, Thigpen BD, Moore RC et al. Stroke and severe preeclampsia and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet Gynecol 2005; 105: 246–54. 20. Magee LA, von Dadelszen P, Chan S et al. CHIPS Pilot Trial Collaborative Group. The Control of Hypertension In Pregnancy Study pilot trial. BJOG 2007; 114: 770, e13–20. 21. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443–51. 22. Vogt L, Kocks MJ, Laverman GD. Renoprotection by blockade of the renin-angiotensin-aldosterone system in diabetic and non-diabetic chronic kidney disease. Specific involvement of intra-renal angiotensinconverting enzyme activity in therapy resistance? Minerva Med 2004; 95: 395–409. 23. Cockburn J, Moar VA, Ounsted M et al. Final report of study on hypertension during pregnancy: the effects of specific treatment on the growth and development of the children. Lancet 1982; i: 647–9. 24. Bayliss H, Churchill D, Beevers M, Beevers DG. Anti-hypertensive drugs in pregnancy and foetal growth: evidence for “pharmacological programming” in the first trimester? Hypertens Pregnancy 2002; 21: 161–74. 25. Nelson-Piercy C. Handbook of Obstetric Medicine, 3rd edn. London: Taylor & Francis 2006.

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26. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev 2007; (2): CD004659.Update of: Cochrane Database Syst Rev 2004; (1): CD004659. 27. Chappell LC, Seed PT, Briley AL et al. Effects of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet 1999; 354: 810–16. 28. Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH: Vitamins in Pre-eclampsia (VIP) Trial Consortium. Vitamin C and vitamin E in pregnant women at risk for pre-eclampsia (VIP trial): randomised placebocontrolled trial. Lancet 2006; 367: 1145–54. 29. Villar J, Abdel-Aleem H, Merialdi M et al. World Health Organization Calcium Supplementation for the Prevention of Preeclampsia Trial Group World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. Am J Obstet Gynecol 2006; 194: 639–49. 30. Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for prevention of pre-eclampsia and related problems: a systematic review and commentary. BJOG 2007; 114: 933–43. 31. Milne F, Redman C, Walker J et al. The pre-eclampsia community guideline (PRECOG): how to screen for and detect onset of pre-eclampsia in the community. BMJ 2005; 330: 576–80. 32. Shennan A, Gupta M, Halligan A et al. Lack of reproducibility in pregnancy of Korotkoff phase IV measured by mercury sphygmomanometry. Lancet 1996; 347: 139–42. 33 Brown MA, Reiter L, Smith B et al. Measuring blood pressure in pregnant women: a comparison of direct

34.

35.

36. 37. 38.

39.

40.

41. 42.

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and indirect methods. Am J Obstet Gynecol 1994; 171: 661–7. Von Dadelszen P, Ornstein MP, Bull SB et al. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis. Lancet 2000; 355: 87–92. CEMACH. Saving Mothers Lives. http://www. cemach.org.uk/getattachment/ee9ca316-2a9a-4de69d48-ecaf5716e2b4/Why-Mothers-Die-20002002.aspx Walker JJ. Pre-eclampsia. Lancet 2000; 356: 1260-5. Broughton Pipkin F. Risk factors for pre-eclampsia. N Engl J Med 2001; 344: 925–6. Papageorghiou AT, Yu CK, Cicero S, Bower S, Nicolaides KH. Second-trimester uterine artery Doppler screening in unselected populations: a review. J Matern Foetal Neonatal Med 2002; 12: 78–88. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P. Hydralazine for treatment of severe hypertension in pregnancy: meta-analysis. BMJ 2003; 327: 955–60. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Foetal and Neonatal Risk, 6th edn. Philadelphia: Lippincott Williams and Wilkins, 2002. British National Formulary. http://www.bnf.org/bnf/ Wilson BJ, Watson MS, Prescott GJ et al. Hypertensive diseases of pregnancy and risk of hypertension and stroke in later life: results from cohort study. BMJ 2003; 326: 845–9. Smith GCS, Pell JP, Walsh D. Pregnancy complications and maternal complications of ischaemic heart disease: a retrospective cohort study of 129 290 births. Lancet 2001; 357: 2002–6.

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7 The patient with cardiac disease Yusuf Karamermer, Jolien W Roos-Hesselink

Cardiac disease is present in approximately 1% of pregnancies and poses an increased risk to both mother and foetus. About 10–15% of all maternal mortality is due to cardiovascular disease. Surprisingly, there have been no signs of decline of this incidence over the past decades.1 The patient with cardiac disease is known to have an increased risk of developing cardiac complications during pregnancy. Adverse foetal and neonatal outcome occurs frequently. Although the majority of women with cardiac disease tolerate pregnancy well, thorough preconceptional counselling is warranted to estimate the risks and to take necessary preparations. Occasionally, pre-conceptional counselling is not possible since cardiac disease becomes manifest first during pregnancy. Symptoms of cardiac disease may be very subtle, mimicking the signs and symptoms of normal pregnancy. Dyspnoea, decreased exercise tolerance, chest pain, peripheral oedema, systolic ejection murmurs and even a third heart sound can occur in the course of normal pregnancy and cardiac disease may be overlooked. Improved survival into adulthood after neonatal surgery for congenital heart disease has resulted in increasing numbers of women with congenital heart disease contemplating pregnancy.2 Congenital heart disease is currently the leading cause of maternal cardiac problems during pregnancy in Western countries. Also, cardiac diseases such as rheumatic valvular disease, dilated and hypertrophic cardiomyopathies are still frequently encountered during pregnancy. The

Table 7.1

haemodynamic changes elicited by pregnancy may expose a limited cardiac reserve, or may instigate arrhythmias and heart failure. Pregnancy also increases the risk of coronary events. A comprehensive knowledge of the nature of the cardiac lesion, as well as an interdisciplinary approach of obstetrician, cardiologist and anaesthetist is imperative in the management of pregnancy in patients with heart disease. Information must be given regarding the frequency of follow-up and level of care during pregnancy and the mode and setting of delivery. In case of hereditary cardiac disease, the risk of recurrence of cardiac disease in the offspring should also be discussed.

Cardiac evaluation Counselling of the cardiac patient should begin early in childhood in order to prevent (accidental) pregnancies in women with high-risk cardiac diseases. At the time of actual “child wish” a careful assessment and discussion of maternal and foetal risks during pregnancy should be made and advisability of pregnancy should be given. A comprehensive history-taking and physical examination of the pre-conceptional physical condition is mandatory to have a reference when changes in cardiopulmonary signs and symptoms arise during pregnancy and which may indicate worsening of cardiac disease. Pre-conceptional New York Heart Association (NYHA) functional classification (Table 7.1) must be determined and prosecuted throughout

New York Heart Association (NYHA) classification.

Class

NYHA functional classification

I

Patients have cardiac disease but without the resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnoea or anginal pain Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or anginal pain Patients have cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes fatigue, palpitation, dyspnoea or anginal pain Patients have cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of cardiac insufficiency or of the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased

II III IV

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pregnancy. In patients who are taking cardiovascular medication, potentially hazardous medication (such as angiotensin converting enzyme (ACE) inhibitors) must be discontinued or switched to an alternative drug before pre-conceptional evaluation with exercise testing and echocardiography 3 months thereafter.

Pre-pregnancy exercise testing Pre-conceptional exercise testing can be helpful in revealing a diminished functional capacity. In general, women who can achieve more than 70–80% of their predicted capacity and those who can increase their blood pressure or heart rate adequately are likely to tolerate pregnancy.

Echocardiography The safety and feasibility aspects of transthoracic echocardiography make it the cornerstone of cardiac evaluation before and during pregnancy. Echocardiography plays an important role in assessing left ventricular function. During normal pregnancy the ventricular function remains preserved. Left ventricular end-diastolic volume increases but stays within normal range, as well as the atrial volume and left ventricular mass. As a result of the increased cardiac output, flow velocities across the aortic and pulmonic valve increase and may resemble an increased gradient. Trivial mitral, tricuspid and pulmonic valve regurgitation are expected findings and may be considered normal.

Physical examination The haemodynamic adaptation of normal pregnancy results in altered physical findings, making the diagnosis of heart disease in pregnant women more difficult. These findings include a slightly increased resting heart rate and a bounding pulse. The jugular venous pressure becomes slightly elevated and peripheral oedema is usually present. The apical impulse is displaced laterally, represented by a slight leftward deviation of the electrical axis on the electrocardiogram. The first heart sound is loud and as the pregnancy progresses there is a persistent physiological splitting of the second heart sound. A third heart sound is usually present by 20 weeks of gestation. A mid-systolic ejection murmur is heard in nearly all women at the left sternal border and is secondary to increased blood flow through the right and left ventricular outflow tract. In addition, continuous murmurs may also be heard indicating a venous hum or a mammary souffle. However, there should be no diastolic murmur at all or systolic and continuous murmurs louder than grade III in intensity and hence any evidence of such requires further evaluation with echocardiography.

Adaptation to pregnancy Pregnancy elicits already early in the first trimester major haemodynamic changes. The initial step in the cardiovascular adaptation to pregnancy is a decline in

total peripheral vascular resistance (TPVR), in response to increased circulating levels of gestational hormones and vasodilating peptides in combination with the low vascular resistance of the placenta and uterus.3,4 In the first weeks of pregnancy, TPVR falls to 40–70% of initial pre-pregnancy levels. In the second half of pregnancy, TPVR shows a small increase until the end of pregnancy. The fall in TPVR creates a relatively underfilled vascular state, which is reflected by a fall in blood pressure. Probably in response to the relative vascular underfill, there is an expansion of plasma volume. Blood volume increases with 1–1.5 l, a rise of 30–50%. The blood volume expands rapidly until the 34th week, after which there is only a modest rise. Red cell mass increases to a lesser extent than blood volume, thereby resulting in a physiological anaemia and a decreased blood viscosity.5 The fall in vascular resistance gives a reduction in cardiac afterload while the rise in blood volume increases the cardiac preload. In addition, there is an increase in heart rate of 10–20 beats per minute. These changes result in an increase of cardiac output with a maximum of 30–50% above pre-pregnancy levels at approximately the 20th week of pregnancy.3,6,7 Thereafter, cardiac output remains stable until delivery. During and immediately after delivery, an extra effort of the cardiac function is demanded. Uterine contractions during labour cause an extra increase in cardiac output. Together with anxiety and physical effort during labour, cardiac output may further increase up to 80% of pre-pregnancy levels.8 The period most at risk for developing heart failure is the puerperium. Decompression of the inferior caval vein and the return of uterine blood into the systemic circulation (autotransfusion) results in a relatively overfilled state. Intravascular volume is further increased by reabsorption of extracellular fluids into the circulation.9 In order to maintain placental function during pregnancy and prevent excessive bleeding at delivery, the maternal coagulation becomes activated. Physiological changes in both the coagulation and fibrinolytic systems occur.10 The coagulation factors V, VII, VIII, IX, X and XII and von Willebrand factor increases. Resistance to activated protein C increases in the second and third trimester.11 Protein S decreases through the entire pregnancy. Plasma activator inhibitors increase during pregnancy.12 The hypercoagulable state is partly counteracted by the activation of the fibrinolytic system and the physiological haemodilution.10,13 At the time of delivery coagulability is further enhanced through the release of tissue plasminogen activator inhibitors from the placenta and myometrium. The plasma concentrations of the plasminogen-activator system return to normal 6 weeks after pregnancy. Due to the hypercoagulability, pregnant women are particularly in the puerperium more likely to have thromboembolic events. Hormonal changes during pregnancy induce alterations in the extracellular matrix of the aortic media. There is hypertrophy and hyperplasia of smooth muscle

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cells, loss of normal corrugation of elastic fibres and a small increase in aortic diameter, which increases its compliance.14,15 This improves aortic function, which is not only a conduit delivering arterial blood to the tissues, but also an important modulator of the entire cardiovascular system, buffering the intermittent pulsatile output from the heart to provide steady flow to capillary beds.

Risk stratification Maternal risks Maternal cardiac risk can be predicted by the use of a risk score designed for women with mainly congenital heart disease.16 Four predictors of adverse maternal outcome are: (1) a history of cardiac event (e.g. stroke, transient ischaemic attack, heart failure or symptomatic arrhythmia); (2) baseline NYHA-class higher than II or cyanosis (oxygen saturation <90%); (3) left-sided heart obstruction (mitral valve area below 2 cm2, aortic valve area below 1.5 cm2 or left ventricular outflow gradient higher than 30 mmHg by Doppler); and (4) impaired systemic ventricular systolic function (ejection fraction below 40%). Each predictor is assigned one point. The estimated risk of occurrence of cardiac events during pregnancy with zero or one point is 5 and 27%, respectively. The presence of more than one predictor estimates a cardiac complication rate of 75%. The recommendations from this risk score include the advice that patients with a low-risk pregnancy (risk score 0) could safely deliver in a community hospital. Those with an intermediate or high risk are recommended to deliver in a regional or tertiary care centre. It must be noted that some high-risk conditions are not, or insufficiently, represented in this risk score and the risk in these conditions might be underestimated. International guidelines on pregnancy and cardiac disease define highrisk pregnancies, in addition to left-sided heart obstruction and impaired left ventricular function, as Marfan syndrome or associated conditions with a dilated aorta more than 40 mm, mechanical valvular prosthesis or pulmonary hypertension (pulmonary systolic pressure higher than 75% of systemic pressure) (Table 7.2).17,18

Foetal risks Cardiac disease in pregnant women poses a substantial increased risk for adverse foetal and neonatal outcome. Most experience has been gained in women with congenital heart disease. The incidence of preterm delivery, growth retardation and spontaneous abortions is increased (Table 7.3). Overall foetal and neonatal mortality approximates 4%, which is a fourfold increase compared with the general population. Predictors of neonatal events have been depicted to be maternal baseline NYHA class higher than II or cyanosis (oxygen saturation >90%), maternal leftsided heart obstruction (mitral valve area below 2 cm2, aortic valve area below 1.5 cm2 or left ventricular outflow gradient higher than 30 mmHg by Doppler),

Table 7.2

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Low, intermediate and high risk lesions.17,18

Low risk Mild to moderate aortic stenosis Asymptomatic aortic or mitral regurgitation with preserved ventricular function Aortic coarctation Atrial septal defect Ventricular septal defect Intermediate risk Mechanical valve in aortic position with normal ventricular function Cyanotic lesions without pulmonary hypertension Systemic right ventricle Mild to moderate mitral stenosis High risk Marfan syndrome or associated conditions with aortic diameter >40 mm Mechanical valve in mitral, tricuspid or pulmonic position Pulmonary hypertension Severe aortic stenosis Pulmonary hypertension (>60 mmHg) Impaired systemic ventricular function (<40%) Univentricular heart

Table 7.3 Overall occurrence of cardiac and obstetric complications during completed pregnancies in 2491 patients with congenital heart disease.31 Incidence (normal)

Cardiac complications Arrhythmias Heart failure Cardiovascular events Endocarditis Obstetric complications Pregnancy induced hypertension Pre-eclampsia Thromboembolic complications Premature rupture of membranes Premature labour Postpartum haemmorhage Premature delivery Small for gestational age Foetal mortality Perinatal mortality

4.5% (<0.5%) 4.8% (<0.5%) 1.9% (<0.5%) 0.5% (<0.01%) 5.5% (∼5%) 3.2% (∼2%) 2.2% (0.1%) 3.9% (3.5%) 11% (∼10%) 8.4% 15.9% (∼10%) 8.0% (∼10%) 1.7% (<0.5%) 2.3% (<0.5%)

smoking during pregnancy, multiple gestations and the use of oral anticoagulation during pregnancy (Table 7.4). Nevertheless, in the absence of any of these predictors, foetal and neonatal mortality in this population is still 2%.

Risk of recurrence In women with hereditary cardiac diseases, the risk for recurrence of the heart defect is a major concern. The

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Table 7.4

heart disease is still prevalent in other parts of the world. Some patients will present for the first time in pregnancy with symptoms of new-onset or previously undetected cardiac disease.

Foetal risk factors/score.16

Predictors of foetal/neonatal events in patients with congenital heart disease∗ Maternal NYHA functional class >II or cyanosis (before pregnancy) Left heart obstruction (mitral valve area <2 cm2, aortic valve area <1.5 cm2 or left ventricular outflow obstruction >30 mmHg, measured with Doppler) Smoking during pregnancy Multiple gestations Use of anticoagulation throughout pregnancy ∗

Number of risk factors: 0, estimated risk of foetal or neonatal mortality 2%; 1 or more 4%. NYHA, New York Heart Association.

Table 7.5

Recurrence risk of congenital heart disease.22

Type of heart disease

Acyanotic defects Atrial septal defect Ventricular septal defect Atrioventricular septal defect Patent ductus arteriosus Pulmonary stenosis Left ventricular obstruction Aortic coarctation Cyanotic lesions Tetralogy of Fallot Transposition of great arteries

Mother affected Total risk (%) (%)

Father affected (%)

3–5 4–8 10–15

4.5–6 6–9.5 7.5–15

1.5 2–2.5 1–7

3–4 4 11–15

4 6.5 10–11

2 2 3

6

4

2.5

2.2–3.1 0.5

2.5

1.5

overall recurrence risk of congenital heart disease in patients with an affected parent is 4%, while in the general population the incidence is 0.8%.19 The risk of recurrence is higher if the mother (5%) rather than the father (2%) has congenital heart disease. If recurrence occurs, approximately half of the children will have the same or a related defect, suggesting a complex (polygenic or multifactorial) form of heredity.20 Over the past decade various genetic causes for cardiac lesions have been identified. Some result in isolated cardiac lesions, while others are cardiac manifestations of genetic syndromes such as Turner, Noonan and Holt-Oram syndrome. Autosomal dominant inherited syndromes, such as Marfan, Noonan and Holt-Oram, carry a 50% recurrence risk. For an atrial septal defect, the risk of recurrence is about 5%.21 Left ventricular outflow obstruction has the highest risk up to 11–15% (Table 7.5)22

Cardiac diseases Most maternal cardiac disease in the Western world nowadays is congenital in origin, while rheumatic

Congenital heart disease Cyanotic lesions The risk in patients with unrepaired cyanotic lesions (such as ventricular septal defects/tetralogy of Fallot, a large patent arterial duct or atrioventricular septal defects) depends on the degree of maternal oxygenation and additional increase in maternal haematocrit and haemoglobin levels. The latter increases the risk of thromboembolic complications. Cyanotic lesions have great impact on foetal outcome. Premature delivery and growth retardation occur in up to 50–70%.23 Maternal oxygen saturation below 90% leads to foetal growth retardation and even may result in foetal mortality. The chance of live birth is minimal (12%) with maternal arterial oxygen saturation below 85%. Oxygen saturation between 85 and 90% and over 90% is associated with a foetal mortality of 55% and 8%, respectively. Maternal and/or foetal mortality in Eisenmenger syndrome is estimated to be 30–50%. Therefore, pregnancy should be discouraged in these patients.18,24 In patients with Eisenmenger syndrome, the fall in systemic vascular resistance and increase in right ventricular workload during pregnancy causes an increased right-to-left shunt with a further decrease in oxygen saturation. In a large series with 112 pregnancies in patients with mainly repaired tetralogy, the occurrence of adverse maternal events was rare. However, there was a high rate of miscarriages (27%). Children of patients with an unrepaired tetralogy had a significant lower birth weight compared with repaired tetralogy of Fallot (2.6 kg versus 3.3 kg).25 In patients with atrioventricular septal defects, cardiovascular complications were present in almost 40% of the 48 completed pregnancies. Persistent functional deterioration, deterioration of valvular regurgitation and arrhythmias were the most common complications.26 Foetal outcome was affected by growth retardation (10.4%), premature delivery (6.3%) and a high recurrence of congenital heart disease (12.5%). Neonatal mortality within the first year of life was 4% (n=2) and all due to recurrence of congenital heart disease.

Transposition of the great arteries The risk of complications is increased in patients with a transatrial repair (Mustard or Senning repair) for transposition of the great arteries (TGA). The impaired systemic ventricle is prone to deterioration during pregnancy. Up to 10–20% of the patients will have an irreversible decrease of their ventricular systolic function.27 The large intra-atrial surgical scars and suture lines are

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potential substrates for arrhythmias. In a Dutch study, the most important cardiac complication was clinically significant arrhythmia (mainly of supraventricular origin), occurring in 22% of the 69 pregnancies.28 Thromboembolic complications were present in 4%. In TGA the incidence of pregnancy related hypertensive disorders is increased, with 8% hypertension and 10% pre-eclampsia. Other complications were premature rupture of membranes (14%), premature labour (24%) and premature delivery (31%).28,29 In congenitally corrected transposition of the great arteries, complications arise when the systemic right ventricle fails under the circulatory burden of pregnancy and/or the increase in atrioventricular valve regurgitation. Heart failure is the main cardiac complication encountered during pregnancy (7%). Premature delivery is seen in 9%.30,31

Conditions associated with aortic dilatation In conditions associated with aortic dilatation, such as Marfan, Ehler-Danlos, and bicuspid aortic valve, pregnancy poses an increased risk for dissection and rupture, probably due to the aforementioned vascular changes. The risk of these complications increases with the diameter of the root.18 Therefore, pregnancy should be discouraged when the aortic dimension exceeds 40 mm or aortic replacement should be performed before pregnancy. In case of progressive dilatation during pregnancy it is recommended to terminate pregnancy with prompt aortic repair. Pregnancy in women with Marfan syndrome is associated with high rates of spontaneous miscarriage (20%) and increased neonatal mortality (7%), mainly due to premature delivery (15%) and preterm premature rupture of membranes (5%).32 For coarctation of the aorta, cardiovascular complications are infrequent, however, hypertension may be a major problem.33

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mortality. From more recent studies, it seems that despite high morbidity, maternal mortality is rare.34 This probably is due to different patient groups with differences in the severity of stenosis. Important complications of aortic stenosis in pregnant women are heart failure (3.8%), atrial arrhythmias (5.7%), premature delivery (13%) and foetal growth retardation (13%).36,37 An uteroplacental perfusion deficit due to low cardiac output might explian the higher incidence of obstetric complications.38 Although mitral valve stenosis is usually an acquired condition often due to rheumatic heart disease, it may be congenital in origin and it is the commonest valve lesion in pregnant women with great impact on maternal and foetal outcome. The haemodynamic changes in pregnancy result in an increased gradient across the narrowed mitral valve and the physiological tachycardia results in an impaired diastolic filling of the left ventricle. The risk of maternal complications rises from 26% in mild (mitral valve area (MVA) >1.5 cm2) to 38% in moderate (MVA ≥1.1 cm2 to <1.5 cm2) and up to 67% in severe stenosis (MVA <1.0 cm2).37 Despite high maternal morbidity, mortality is rare. Adverse foetal and neonatal outcome is common (30%) and foetal and neonatal mortality may be as high as 4%.34,37 The primary therapy of mitral stenosis is reducing heart rate and improving diastolic filling with beta-blockade. Interventional therapy should be considered if symptoms persist despite optimal medical treatment. Right-sided heart obstructions are in general well tolerated during pregnancy. Maternal complications such as heart failure and arrhythmias are rare. However, severe pulmonary valve stenosis may lead to problems and is also associated with an increased risk of premature labour (14%), premature delivery (15%) and intrauterine growth retardation (10%).39

Valvular regurgitation Valvular heart disease Valvular stenosis The haemodynamic changes during pregnancy, such as increased stroke volume and a fall in peripheral resistance, are responsible for the increase in the gradient across the stenotic aortic valve. Cardiac output and plasma volume reach their maximum at between 24 and 28 weeks of pregnancy duration. For aortic stenosis, this is the time that most complications occur. The clinical consequences of the increased gradient depend on the left ventricular function, the severity of the stenosis and the individual determined rise in cardiac output.34,35 Only one study investigated the impact of aortic stenosis on the physiological changes during pregnancy. In mild aortic stenosis (aortic valve area 1.95–2.4 cm2) normal cardiovascular changes were found, but in moderate to severe aortic stenosis (0.5–1.8 cm2) there was no increase in stroke volume.35 Early studies suggested a high maternal

Valvular regurgitation is usually well tolerated during pregnancy, provided that the ventricular function is preserved. For aortic regurgitation, the decreased systemic vascular resistance may be beneficial in contrast to mitral regurgitation, which may aggravate due to the increased left ventricular dimension. Valvular regurgitation can often be managed medically with diuretics and vasodilator therapy.

Valve prosthesis The risks of pregnancy in patients with valve prostheses depend on the type and position of the valve. Tissue valves have the advantage that anticoagulation is not necessary, however, the long-term effect of pregnancy on the durability of this type of valve is unknown.40 Several studies reported an accelerated deterioration of tissue valves due to pregnancy, while others reported deterioration that fitted in the natural course of tissue valves.41,42

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Mechanical valves are associated with a high rate of foetal mortality. The incidence of spontaneous miscarriages is 32% for mechanical valves versus 11% for tissue valves.43 Most likely this is related to the necessary anticoagulation with coumadins. The risk of foetal and neonatal mortality is highest for mechanical valves in mitral position. Pregnancy loss is reported in up to 59% (including miscarriages before 20 weeks).44 The high thrombogenicity of mechanical valve protheses poses a high risk for thromboembolic complications. Again, mechanical valves in mitral position are at high risk of valvular thrombosis, due to a low flow rate. The presence of a mechanical heart valve implicates the use of anticoagulation with additional risks to both the mother and foetus. These risks should be considered before valve replacement in every young woman, even when there is no child wish yet and the risks of a future pregnancy should be discussed timely.

Cardiomyopathies Hypertrophic obstructive cardiomyopathy Pregnancy is reasonably well tolerated in most women with hypertrophic obstructive cardiomyopathy.45 The increased volume load of pregnancy decreases the pressure gradient of the left ventricular outflow. Although symptoms such as angina, palpitations and dyspnoea are common, maternal mortality is very low and mostly limited to high-risk patients.46 Strenuous exercise should be discouraged because of potential arrhythmias. Preload-reducing medication such as diuretics and vasodilators should be avoided. Instead, if symptoms occur, such as heart failure or angina, beta-blocking drugs are indicated.

Dilated or peripartum cardiomyopathy Patients with idiopathic dilated cardiomyopathy or peripartum cardiomyopathy, which is a diagnosis by exclusion, are advised against pregnancy when the ejection fraction is below 40%. Subsequent pregnancies in women with a history of peripartum cardiomyopathy and persistent left ventricular dysfunction are associated with increased maternal mortality and a high rate of premature deliveries.34

Ischaemic heart disease The incidence of acute coronary syndromes (ACS) is estimated at one per 10 000 pregnancies, a three- to four-fold increase compared with non-pregnant women of similar age.47,48 The increased incidence may be related to haemostatic and hormonal changes. Atherosclerosis is the most common cause of coronary artery disease in the general population. However, ACS in pregnancy often have different aetiologies. Coronary atherosclerosis (with or without a thrombus) is found in only 43% and a thrombus without signs of atherosclerosis in 21% of the patients who underwent

coronary angiography for ACS during pregnancy. Coronary dissection was found in 16%, while normal coronary arteries were reported in 29%. In the postpartum period the primary cause of ACS is dissection.49 Statin-therapy is recommended in patients with coronary artery disease. However, statins are contraindicated in pregnancy due to teratogenic effects. Evidence of foetal abnormalities (mainly skeletal defects) has been found in animal studies.50 All statins are labelled as Food and Drug Administration (FDA) category X and should be stopped before pregnancy.

Arrhythmias Ectopic beats are frequently observed during pregnancy but are usually benign and well tolerated. Isolated arrhythmias are rare during pregnancy and most often related to some identifiable underlying cause, commonly congenital heart disease. Impaired autonomic nervous activity and volume overload contribute to the increased rate of tachyarrhythmias during pregnancy in women with congenital heart disease.51 Management of arrhythmias during pregnancy should be treated as in the non-pregnant situation and therapy is indicated if the systolic function of the heart becomes impaired or haemodynamic instability occurs. In the selection of antiarrhythmic drugs, however, considerations should include the potential proarrhythmic effects, negative inotropic effects and teratogenic effects of the selected drugs. There are limited data on the effects of most anti arrhythmic drugs on the foetus. The majority of antiarrhythmic drugs are US FDA category C, which means that there are either animal studies suggesting risks but no confirmatory human studies, or no controlled studies in either humans or animals. International guidelines recommend (class I indication) therapy with digoxin, beta-blocker or non-dihydropyridine calcium channel antagonist for rate control in atrial fibrillation (AF). Direct-current cardioversion is the treatment of choice for drug-refractory AF or supraventricular tachyarrhythmias (SVT) and is safe for the foetus. Throughout pregnancy, anticoagulant therapy is a class I indication for AF (often with low-molecular weight heparin (LMWH)). Paroxysmal SVT is usually well tolerated and vagal manoeuvre should be tried to terminate an episode. Subsequently, intravenous adenosine would be the first-choice drug (Table 7.6).52,53

Pharmacological treatment Management of heart failure Heart failure may develop as a consequence of the increased cardiac workload during pregnancy. Advice during pregnancy should include salt and fluid restriction and limitation of physical activity up to complete bed rest in case of manifest heart failure.

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Table 7.6 American College of Cardiology/American Heart Association/European Society of Cardiology recommendations for the treatment of atrial fibrillation (AF) and supraventricular tachycardia (SVT) during pregnancy.51,52 Level of evidence

Classification

Indication

Recommendation

I

Rate control in AF

C

I I

AF with haemodynamic instability Antithrombotic therapy in AF

Digoxin, beta-blocker or non-dihydropyridine calcium channel antagonist Direct-current cardioversion

C

I I

Conversion of SVT Prophylactic therapy of SVT

IIa IIa

Conversion of SVT Prophylactic therapy of SVT

Anticoagulant therapy throughout pregnancy. Choice of therapy according to the stage of pregnancy Vagal manoeuvre, adenosine, direct-current cardioversion Metoprolol Digoxin Metoprolol, propanolol Propanonol, sotalol, flecainide

IIb

Antithrombotic therapy in AF

IIb IIb IIb

Conversion of AF in haemodynamic stable patients Conversion of SVT Prophylactic therapy of SVT

III

Prophylactic therapy of SVT

Administration of dose-adjusted unfractioned heparin in first trimester and last month of pregnancy Administration of low molecular weight heparin in first trimester and last month of pregnancy Administration of oral anticoagulant during second trimester Quinidine, procainamide Verapamil Procainamide Quinidine, propafenone, verapamil Catheter ablation Atenolol Amiodarone

Self-weighing should be encouraged and in case of sudden unexpected weight gain (although pregnant) contacting the physician is recommended.18 Diuretics are given to relieve pulmonary and systemic congestion. Furosemide has been proven safe during pregnancy, however, it should be used with caution to prevent hypovolaemia and subsequent reduction in uteroplacental flow. Furosemide is preferred over thiazide diuretics, since with thiazides the neonate may develop electrolyte imbalance or hypoglycaemia. There are limited data available concerning spironolactone, an aldosterone antagonist that leads to potassium retention. Spironolactone can theoretically cause feminisation of the male foetus due to the known anti-androgenic effects. However, no teratogenic effects have been reported, making spironolactone relatively safe in pregnancy. Beta-blockers are relatively safe during pregnancy and indicated, especially in patients with mitral stenosis, to optimise diastolic filling. The use of beta-blockers is associated with a mildly lower birth weight and can cause some (postpartum) foetal bradycardia. Digoxin has positive inotropic effects and its use is safe during pregnancy. In pregnancy the dose of digoxin must be adjusted for the increased volume of distribution.54 The use of ACE inhibitors can lead to severe teratogenic malformations such as oligohydramnios, renal

C

C B C C B,C B C C C C B C C B C

failure, foetal growth retardation, pulmonary hypoplasia, joint contractures and neonatal renal failure. Teratogenic effects of ACE inhibitors can occur during the entire pregnancy and, therefore, ACE inhibitors should not be used and should be stopped in women contemplating pregnancy.55 There are limited data available regarding the teratogenic effects of angiotensin II inhibitors. However, their mechanism of action is very similar to that of ACE inhibitors. Therefore, it seems likely that they have the same teratogenic effects, making them also contraindicated in pregnancy.56 Hydralazine, just like nitroglycerine, is safe during pregnancy. Both can be used for afterload reduction and as antihypertensive agents.57 In counselling before pregnancy, all medication should be inventorised and it is recommended to discontinue or switch potential teratogenic medication and perform an echocardiographic examination and exercise testing 3 months after discontinuation of the therapy before giving definite advice on pregnancy (Table 7.7).

Anticoagulation The use of low-dose aspirin (<150 mg/day) is considered safe. Higher doses are associated with premature closure of the ductus arteriosus and foetal congenital abnormalities.

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Table 7.7

Safety of cardiovascular drugs in pregnancy.

Relatively safe Aspirin Beta-blockers Calcium channel blockers (in particular nifedipine and verapamil) Low molecular weight and unfractionated heparins Furosemide Digoxin Flecainide Quinidine Not safe HMG-CoA reductase inhibitors (statins) Angiotensin converting enzyme (ACE) inhibitors Angiotensin II receptor antagonists Amiodarone Phenytoin Warfarin (between 6 and 12 weeks of gestation) HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA.

There is no consensus on anticoagulant therapy during pregnancy in women with mechanical valve prostheses. No single treatment strategy is ideal and various regimens have been recommended (Table 7.8).17,18,58 Treatment with heparins is safe for the foetus, as it does not cross the placenta due to their high molecular

weight. No teratogenic effects in the foetus have been reported. Unfractionated heparins have the disadvantage of a short half-life and a variable dose response. Frequent monitoring of activated partial thromboplastin time is a problematic necessity. In addition, alopecia and osteoporosis are unwanted side-effects. Low molecular weight heparin (LMWH) is an alternative for unfractionated heparin; it is easy to use and has a superior bioavailability. The value of monitoring its therapeutic activity by measuring antifactor-Xa level is controversial. It is recommended that it should be administered in a therapeutic dose every 12 hours. The dose must be adjusted so that a 4-hour postinjection antifactor-Xa level is maintained at 1.0–1.2 units/ml. LMWH has been proven safe for several indications such as the prevention and treatment of venous and pulmonary thromboembolisms, nevertheless, in patients with a mechanical valve prosthesis valvular thrombosis still occurs. Large prospective studies are lacking but thromboembolic complications have been estimated to occur in approximately 10–20% of patients treated with unfractionated or LMWH and, therefore, it is not the optimal treatment for the mother.59 Coumadins are the recommended anticoagulant therapy for mechanical valve prosthesis. However, teratogenic effects (nasal and limb hypoplasia, chondromalacia punctata, optic atrophy, mental retardation, microcephaly and growth retardation) of coumadins are

Table 7.8 American College of Cardiology/American Heart Association recommendations for the selection of anticoagulation regimen in pregnant patients with mechanical prosthetic valves.17 Indication class

Recommendation

I I

Continuous therapeutic anticoagulation with frequent monitoring Patients who stop warfarin between weeks 6 and 12 of gestation should receive continuous intravenous UFH, dose-adjusted UFH, or dose-adjusted subcutaneous LMWH The therapeutic choice up to 36 weeks of gestation should be continuous intravenous or dose-adjusted subcutaneous UFH, dose-adjusted LMWH, or warfarin If dose-adjusted LMWH is administered, the LMWH should be administered twice daily subcutaneously to maintain the anti-Xa level between 0.7 and 1.2 U/ml 4 h after administration If dose-adjusted UFH is administered, the aPTT should be at least twice control The INR goal should be 3.0 (range 2.5–3.5) if warfarin is used Warfarin should be discontinued and continuous intravenous UFH or LMWH given, starting 2–3 weeks before planned delivery It is reasonable to avoid warfarin between weeks 6 and 12 of gestation owing to the high risk of foetal defects It is reasonable to resume UFH 4–6 h after delivery and begin oral warfarin in the absence of significant bleeding It is reasonable to give low-dose aspirin (75–100 mg/day) in the second and third trimesters of pregnancy in addition to anticoagulation with warfarin or heparin LMWH should not be administered unless anti-Xa levels are monitored 4–6 h after administration Dipyridamole should not be used instead of aspirin as an alternative antiplatelet agent because of its harmful effects on the foetus

I I

I I I IIa IIa IIa III III

Level of evidence

B C

C

C C C C C C

C C B

UFH, unfractionated heparin; LMWH, low molecular weight heparin; aPTT, activated partial thromboplastin time; INR, international normalised ratio.

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encountered in 6% of the babies when given between 6 and 9 weeks of gestation.60 There is probably a dosedependent relation with minimal risk when the daily dose does not exceed 5 mg of warfarin or an equivalent dose of coumadins (<1.7 mg acenocoumarol).61 The use of coumadins during the entire pregnancy is associated with an increased risk of miscarriage. Thus, the lack of large randomised prospective trials has resulted in poor consensus and disparity among expert recommendations, in particular, regarding anticoagulation therapy in the first trimester. The recommended treatment strategies are: (1) Stop coumadin therapy as soon as the pregnancy test is positive. Start dose-adjusted unfractionated heparins until the 13th week. Switch to coumadins between the 13th and 36th week or 2 days before planned delivery and change back to heparins. Restart coumadin therapy shortly after delivery. Monitor activated partial thromboplastin time. (2) Similar to option (1) but instead of unfractionated heparin, use LMWH and monitor antifactor Xa-level. (3) Continue coumadins throughout pregnancy if low doses are needed to maintain appropriate international normalised ratio. The European Society of Cardiology recommends this strategy. It is not advisable to switch to heparins before pregnancy because heparins are less effective in preventing thrombotic events and it may take considerable time before pregnancy is established.

Percutaneous and surgical management In patients with persistent symptoms despite optimal medical therapy invasive treatment should be considered. The use of radiation is the principal argument against percutaneous interventions during pregnancy. Doses in excess of 50–100 mSv increase the incidence of foetal malformation. The risk of malformations is greatest before the completion of major organogenesis (first 12 weeks after menses). In the second and third trimester, there is a small risk of malformations but high radiation doses (over 500 mSv) increase the risk of childhood cancer and mental retardation. However, only a small amount of the radiation delivered to the thorax reaches the foetus.62 The amount of foetal exposure to radiation during chest radiography in percutaneous interventions is on average 0.01 mSv and has a maximum of 0.02 mSv in difficult procedures (National Council of Radiation Protection and Measurements 1998). Shielding the gravid uterus is of limited value, since this will not prevent internal radiation scatter. The additional risk of fluoroscopy guided cardiac procedures on the development of childhood cancer, hereditary defects and birth defects seems small and therapy should not be withheld for this reason.

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Usually, cardiac surgery can be avoided during pregnancy. Maternal mortality equals mortality in non-pregnant cardiac surgery but foetal mortality risk is high with an incidence of 20%.63 If surgery is required a multidisciplinary approach is warranted to make a careful plan for the optimal timing of cardiac surgery and of delivery.

Delivery Vaginal delivery is preferred in general for patients with heart disease unless there is an obstetrical indication for Caesarean section. The only exception is a dilated aortic root, for instance in Marfan syndrome, which is an indication for Caesarean section. However, no convincing data proclaiming either vaginal delivery or Caesarean section have been reported. Caeserean section leads to more blood loss at delivery and is therefore less preferable. Shortening the second stage of labour and using epidural anaesthesia for the reduction of pain and anxiety can facilitate vaginal delivery.

References 1. Steer PJ, Gatzoulis MA, Baker PN. Heart disease and pregnancy. London: RCOG, 2006. 2. Karamermer Y, Roos-Hesselink JW. Pregnancy and adult congenital heart disease. Expert Rev Cardiovasc Ther 2007; 5: 859–69. 3. Robson SC, Hunter S, Boys RJ et al. Serial study of factors influencing changes in cardiac output during human pregnancy. Am J Physiol 1989; 256: H1060–5. 4. Hunter S, Robson SC. Adaptation of the maternal heart in pregnancy. Br Heart J 1992; 68: 540–3. 5. Whittaker PG, Macphail S, Lind T. Serial hematologic changes and pregnancy outcome. Obstet Gynecol 1996; 88: 33–9. 6. Mabie WC, DiSessa TG, Crocker LG et al. A longitudinal study of cardiac output in normal human pregnancy. Am J Obstet Gynecol 1994; 170: 849–56. 7. Kametas NA, McAuliffe F, Hancock J et al. Maternal left ventricular mass and diastolic function during pregnancy. Ultrasound Obstet Gynecol 2001; 18: 460–6. 8. Robson SC, Dunlop W, Boys RJ et al. Cardiac output during labour. Br Med J (Clin Res Ed) 1987; 295: 1169–72. 9. Robson SC, Hunter S, Moore M et al. Haemodynamic changes during the puerperium: a Doppler and Mmode echocardiographic study. Br J Obstet Gynaecol 1987; 94: 1028–39. 10. Cerneca F, Ricci G, Simeone R et al. Coagulation and fibrinolysis changes in normal pregnancy. Increased levels of procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive fibrinolysis. Eur J Obstet Gynecol Reprod Biol 1997; 73: 31–6. 11. Walker MC, Garner PR, Keely EJ et al. Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 1997; 177: 162–9.

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12. Coolman M, de Groot CJ, Steegers EA et al. Concentrations of plasminogen activators and their inhibitors in blood preconceptionally, during and after pregnancy. Eur J Obstet Gynecol Reprod Biol 2006; 128: 22–8. 13. Uchikova EH, Ledjev, II. Changes in haemostasis during normal pregnancy. Eur J Obstet Gynecol Reprod Biol 2005; 119: 185–8. 14. Manalo-Estrella P, Barker AE. Histopathologic findings in human aortic media associated with pregnancy. Arch Pathol 1967; 83: 336–41. 15. Easterling TR, Benedetti TJ, Schmucker BC et al. Maternal hemodynamics and aortic diameter in normal and hypertensive pregnancies. Obstet Gynecol 1991; 78: 1073–7. 16. Siu SC, Sermer M, Colman JM et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation 2001; 104: 515–21. 17. Bonow RO, Carabello BA, Kanu C et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006; 114: e84–231. 18. Task Force on the Management of Cardiovascular Diseases During Pregnancy of the European Society of Cardiology expert consensus document on management of cardiovascular diseases during pregnancy. Eur Heart J 2003; 2: 761–81. 19. Burn J, Brennan P, Little J et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 1998; 351: 311–16. 20. Gill HK, Splitt M, Sharland GK et al. Patterns of recurrence of congenital heart disease: an analysis of 6,640 consecutive pregnancies evaluated by detailed foetal echocardiography. J Am Coll Cardiol 2003; 42: 923–9. 21. Caputo S, Capozzi G, Russo MG et al. Familial recurrence of congenital heart disease in patients with ostium secundum atrial septal defect. Eur Heart J 2005; 26: 2179–84. 22. Presbitero P, Boccuzzi GG, de Groot CJM et al. Pregnancy and heart disease. In: Camm AJ, Lüscher TF, Serruys PW, eds. The ESC Textbook of Cardiovascular Medicine. Oxford: Blackwell Publishing, 2006: 607–24. 23. Presbitero P, Somerville J, Stone S et al. Pregnancy in cyanotic congenital heart disease. Outcome of mother and foetus. Circulation 1994; 89: 2673–6. 24. Avila WS, Grinberg M, Snitcowsky R et al. Maternal and fetal outcome in pregnant women with Eisenmenger’s syndrome. Eur Heart J 1995; 16: 460–4. 25. Veldtman GR, Connolly HM, Grogan M et al. Outcomes of pregnancy in women with tetralogy of Fallot. J Am Coll Cardiol 2004; 44: 174–80. 26. Drenthen W, Pieper PG, van der Tuuk K et al. Cardiac complications relating to pregnancy and recurrence of disease in the offspring of women with atrioventricular septal defects. Eur Heart J 2005; 26: 2581–7.

27. Guedes A, Mercier LA, Leduc L et al. Impact of pregnancy on the systemic right ventricle after a Mustard operation for transposition of the great arteries. J Am Coll Cardiol 2004; 44: 433–7. 28. Drenthen W, Pieper PG, Ploeg M et al. Risk of complications during pregnancy after Senning or Mustard (atrial) repair of complete transposition of the great arteries. Eur Heart J 2005; 26: 2588–95. 29. Clarkson PM, Wilson NJ, Neutze JM et al. Outcome of pregnancy after the Mustard operation for transposition of the great arteries with intact ventricular septum. J Am Coll Cardiol 1994; 24: 190–3. 30. Connolly HM, Grogan M, Warnes CA. Pregnancy among women with congenitally corrected transposition of great arteries. J Am Coll Cardiol 1999; 33: 1692–5. 31. Drenthen W, Pieper PG, Roos-Hesselink JW et al. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007; 49: 2303–11. 32. Meijboom LJ, Drenthen W, Pieper PG et al. Obstetric complications in Marfan syndrome. Int J Cardiol 2006; 110: 53–9. 33. Beauchesne LM, Connolly HM, Ammash NM et al. Coarctation of the aorta: outcome of pregnancy. J Am Coll Cardiol 2001; 38: 1728–33. 34. Hameed A, Karaalp IS, Tummala PP et al. The effect of valvular heart disease on maternal and fetal outcome of pregnancy. J Am Coll Cardiol 2001; 37: 893–9. 35. Lesniak-Sobelga A, Tracz W, KostKiewicz M et al. Clinical and echocardiographic assessment of pregnant women with valvular heart diseases—maternal and fetal outcome. Int J Cardiol 2004; 94: 15–23. 36. Drenthen W, Pieper PG, Roos-Hesselink JW et al. Outcome of pregnancy in women with congenital heart disease: a literature review. J Am Coll Cardiol 2007. 37. Silversides CK, Colman JM, Sermer M et al. Early and intermediate-term outcomes of pregnancy with congenital aortic stenosis. Am J Cardiol 2003; 91: 1386–9. 38. Yap SC, Drenthen W, Pieper PG et al. Risk of complications during pregnancy in women with congenital aortic stenosis. Int J Cardiol 2007; May 3. 39. Drenthen W, Pieper PG, Roos-Hesselink JW et al. Non-cardiac complications during pregnancy in women with isolated congenital pulmonary valvar stenosis. Heart 2006; 92: 1838–43. 40. Elkayam U, Bitar F. Valvular heart disease and pregnancy: part II: prosthetic valves. J Am Coll Cardiol 2005; 46: 403–10. 41. Avila WS, Rossi EG, Grinberg M et al. Influence of pregnancy after bioprosthetic valve replacement in young women: a prospective five-year study. J Heart Valve Dis 2002; 11: 864–9. 42. El SF, Hassan W, Latroche B et al. Pregnancy has no effect on the rate of structural deterioration of bioprosthetic valves: long-term 18-year follow up results. J Heart Valve Dis 2005; 14: 481–5. 43. Mihaljevic T, Paul S, Leacche M et al. Valve replacement in women of childbearing age: influences on mother, fetus and neonate. J Heart Valve Dis 2005; 14: 151–7. 44. Sadler L, McCowan L, White H et al. Pregnancy outcomes and cardiac complications in women with

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45.

46.

47.

48.

49.

50.

51.

52.

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mechanical, bioprosthetic and homograft valves. BJOG 2000; 107: 245–53. Maron BJ, McKenna WJ, Danielson GK et al. American College of Cardiology/European Society of Cardiology clinical expert consensus document on hypertrophic cardiomyopathy. A report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents and the European Society of Cardiology Committee for Practice Guidelines. J Am Coll Cardiol 2003; 42: 1687–713. Thaman R, Varnava A, Hamid MS et al. Pregnancy related complications in women with hypertrophic cardiomyopathy. Heart 2003; 89: 752–6. James AH, Jamison MG, Biswas MS et al. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation 2006; 113: 1564–71. Ladner HE, Danielsen B, Gilbert WM. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet Gynecol 2005; 105: 480–4. Roth A, Elkayam U. Acute myocardial infarction associated with pregnancy. Ann Intern Med 1996; 125: 751–62. Pollack PS, Shields KE, Burnett DM et al. Pregnancy outcomes after maternal exposure to simvastatin and lovastatin. Birth Defects Res A Clin Mol Teratol 2005; 73: 888–96. Niwa K, Tateno S, Akagi T et al. Arrhythmia and reduced heart rate variability during pregnancy in women with congenital heart disease and previous reparative surgery. Int J Cardiol 2007; 122: 143–8. Blomstrom-Lundqvist C, Scheinman MM, Aliot EM et al. ACC/AHA/ESC guidelines for the management of patients with supraventricular arrhythmias—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Supraventricular Arrhythmias). Circulation 2003; 108: 1871–909. Fuster V, Ryden LE, Cannom DS et al. ACC/ AHA/ESC 2006 guidelines for the management of

54. 55.

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patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J 2006; 27: 1979–2030. Montan S. Drugs used in hypertensive diseases in pregnancy. Curr Opin Obstet Gynecol 2004; 16: 111–15. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443–51. Alwan S, Polifka JE, Friedman JM. Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin Mol Teratol 2005; 73: 123–30. Vigil-De Gracia P, Lasso M, Ruiz E et al. Severe hypertension in pregnancy: hydralazine or labetalol. A randomized clinical trial. Eur J Obstet Gynecol Reprod Biol 2006; 128: 157–62. Bates SM, Greer IA, Hirsh J et al. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 627S–44S. James AH, Brancazio LR, Gehrig TR et al. Low-molecular-weight heparin for thromboprophylaxis in pregnant women with mechanical heart valves. J Matern Fetal Neonatal Med 2006;19: 543–9. Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med 2000; 160: 191–6. Vitale N, De Feo M, De Santo LS et al. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol 1999; 33: 1637–41. Damilakis J, Theocharopoulos N, Perisinakis K et al. Conceptus radiation dose and risk from cardiac catheter ablation procedures. Circulation 2001; 104: 893–7. Arnoni RT, Arnoni AS, Bonini RC et al. Risk factors associated with cardiac surgery during pregnancy. Ann Thorac Surg 2003; 76: 1605–8.

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8 The patient with thyroid disease Willy Visser

Thyroid disease is the second most common endocrine disorder (after diabetes) affecting women of reproductive age.1 Two forms of thyroid pathology can be distinguished. The first is abnormal thyroid function, with or without clinically apparent changes in thyroid volume such as goitre or noduli. The second deals with changes in thyroid volume without abnormal thyroid function. Thyroid dysfunction is usually an expression of an autoimmune disorder. Thyroid dysfunction may lead to clinically apparent signs and symptoms but it may also remain subclinical, with the diagnosis based only on abnormal thyroid function tests. Untreated overt as well as subclinical thyroid disorders in women are associated with medical complications and impaired fertility. The physiological changes of pregnancy affect maternal thyroid function and the interpretation of results of thyroid function tests when pregnancy occurs in a woman with thyroid disease or when the thyroid problem develops during gestation. Conversely, thyroid diseases and their management may affect the course of pregnancy, the developing foetus, and the neonate. Diagnosis, counselling and successful management of pregnant women with thyroid disease requires an understanding of the potential effects on the mother and foetus, and their pathophysiological background and management.

The maternal thyroid in pregnancy Synthesis and secretion of thyroid hormones thyroxine (T4) and tri-iodothyronine (T3) are physiologically increased in pregnancy. By the 5th week of gestation the demand for thyroxine is already 30–50% higher than before pregnancy.2 The increased production of thyroid hormones requires a higher dietary intake of iodine. Additional iodine intake is also needed to compensate for the transfer of iodide to the foetus and for the increased renal clearance. Dietary iodine deficiency is associated with maternal and foetal goitre, and maternal and foetal hypothyroidism may develop. The requirement for an augmented production of thyroid hormones in pregnancy is explained, at least in part, by a rise in production of their carrier protein

thyroxin binding globulin (TBG), by the increased distribution volume caused by the rise in plasma volume, by the inactivation of T4 and T3 due to expression of the enzyme iodothyronine deiodinase type III in the placenta, and by some placental transfer to the foetus. The increased synthesis of TBG by the liver is induced by placental oestrogens. TBG is the most important thyroid hormone binding globulin, and, therefore, circulating levels of total thyroxine (tT4) and total tri-iodothyronine (tT3) increase about 1.5 fold during pregnancy.3 However, only free, nonprotein bound, T4 and T3 exert biological activity and their concentrations show a different pattern of change during pregnancy. Free T4 (fT4) levels increase during the first trimester, return to normal by about 20 weeks’ gestation and may fall in the third trimester below the reference range for non-pregnant women.4–6 The rise in fT4 during the first trimester is attributed to the increasing level of human chorionic gonadotrophin (hCG) which shares a common α-subunit with TSH (thyroid-stimulating hormone or thyrotropin) capable of stimulating the TSH receptors.7 Serum TSH is reduced in early pregnancy followed by a slight rise in the last two trimesters, but serum levels remain reduced in comparison with the nonpregnant range.8,9 Free T3 ( fT3) concentrations also show a slight reduction in the second and third trimester, whereas the level of the metabolically inactive reverse T3 increases.5,6 Thyroglobulin and thyroid volume remain unchanged.5,6 After delivery levels of thyroid hormones and TSH return to the prepregnant state.5,6

The foetal thyroid Before gestational week 10–12, when the foetal thyroid starts concentrating iodine and synthesizing thyroid hormones, the foetus depends entirely on transfer of maternal thyroxine across the developing placenta.10,11 Later in pregnancy, the fully developed placenta becomes relatively impermeable to maternal thyroid hormones, and the foetal hypothalamus– pituitary–thyroid axis becomes essentially independent

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of the mother. Maternal thyroid hormones T3 and T4 and TSH cross in small amounts, and part of the T3 and T4 is inactivated by the placental enzyme iodothyronine deiodinase type III before reaching the foetus. When the maternal–foetal T4 concentration gradient is high, significant transfer of maternal T4 to the foetal circulation can occur.3 For example, in infants with congenital hypothyroidism a substantial, albeit subnormal, concentration of T4 is detected in cord blood and in women with severe hyperthyroidism, increased amounts of maternal T4 pass across the placenta and may inhibit the development of the foetal hypothalamus–pituitary–thyroid axis and cause a central hypothyroidism in the neonate.12,13 Thyrotrophin releasing hormone (TRH) passes the placenta without difficulty, but it seems to have no effect on the foetal thyroid. Maternal TSHreceptor antibodies (TSHrAb) are easily transferred across the placenta and may affect the foetal thyroid. Maternal thyroid peroxidase (TPO) antibodies (TPOAb) also pass across the placenta but do not have an effect on the foetal thyroid. Drugs used for diagnosis or treatment of maternal thyroid diseases cross the placenta readily in amounts sufficient to exert biological effects on the foetus. This includes the thionamides, beta-adrenergic antagonists, and radioactive and non-radioactive iodine.

Measurement and interpretation of maternal thyroid function in pregnancy Laboratory assessment of thyroid function in pregnancy remains a debated issue.8,14 Because the physiological changes of pregnancy may influence methods of estimation, non-pregnant reference values should be modified. For serum TSH trimester-related reference ranges should be used, but there is no need for methodspecific reference ranges.14 Recommended target TSH values for pregnancy are: first trimester 0.03–2.5 mIU/l; second trimester 0.03–3 mIU/l; third trimester 0.13–3 mIU/l.8 Because of the rise in tT4 concentration during pregnancy it was generally recommend to use fT4 instead of tT4. However, it turned out that serum fT4 levels show a variable pattern of change, and their estimation is problematic in that levels are sensitive to the TBG and albumin changes of pregnancy in a methodspecific and unpredictable manner.14 Therefore, if fT4 estimation is used, gestational and method-specific reference intervals should be determined for the pregnant population. In contrast to fT4, tT4 methodology is more reliable and not method dependent. Until trimester-specific and method-specific reference ranges for fT4 are available some authors advocate to use tT4 in preference to fT4 provided that the non-pregnant reference limits are adjusted by a factor of 1.5.8,14

Hypothyroidism Introduction Hypothyroidism is relatively common in women of reproductive age. The prevalence of hypothyroidism during pregnancy varies from 0.3–0.5% for overt hypothyroidism to 2–3% for subclinical hypothyroidism.8,15–18 Hypothyroidism in pregnancy is usually mild or subclinical since severe disease leads to anovulation and infertility. Almost all cases of hypothyroidism during pregnancy concern primary hypothyroidism characterised by an elevated serum TSH concentration. On a worldwide basis iodine deficiency remains the most important cause of thyroid insufficiency.8,19 In areas of the world in which dietary iodine is sufficient chronic autoimmune thyroiditis or Hashimoto’s disease is the most important cause of hypothyroidism followed by ablative treatment of Graves disease.8,19 The clinical manifestations of hypothyroidism in pregnancy are characterised by vague, non-specific symptoms that are often insidious in onset and easily confused with complaints attributable to pregnancy itself. Symptoms include fatigue, weight increase, sensitivity to cold, dry skin, constipation, asthenia and drowsiness. These are all less specific symptoms. Obvious signs like myxoedema, low body temperature and hoarse voice are an exception in pregnant women, even with overt hypothyroidism. Many women remain asymptomatic. A diagnosis of hypothyroidism cannot be established or excluded without laboratory tests. Thyrotropin (TSH) is a reliable marker for hypothyroidism in pregnancy, except when there is iodine deficiency, usually evidenced by elevated serum thyroglobulin. The serum TSH concentration will be elevated above the trimester-related upper-limit reference value even in subclinical hypothyroidism in which serum tT4 and fT4 may fall within their reference range. Since serum TSH levels are reduced in the first trimester of normal pregnancy a diagnosis of hypothyroidism may easily be missed in a woman with a TSH in the high-normal nonpregnant range. In overt cases serum fT4 will be low but tT4 may still be in the normal range for non-pregnant women. In Hashimoto’s disease TPOAb are found. They are of the IgG class and pass across the placenta. These antibodies appear to be a secondary response to thyroid injury and are not thought to cause disease themselves.3 TPOAb do not have an effect on the foetal or neonatal thyroid, but TPOAb in euthyroid women were shown to be associated with recurrent pregnancy loss, foetal death, postpartum thyroiditis and postpartum depression.19–23 The pathophysiology of these associations remains to be elucidated. The benefits of prophylactic immunoglobulin treatment and thyroid hormone substitution are as yet uncertain.24–26 At present general screening for TPOAb, and possible

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treatment, cannot be recommended.8 In women with a former Graves’ disease TSHrAb may still be present, especially in women who have been treated by radioiodine ablation or surgery. 27,28

The influence of hypothyroidism on pregnancy outcome In addition to the complications of untreated hypothyroidism in non-pregnant women that are described in standard texts on endocrinology, overt and even subclinical hypothyroidism have several adverse effects on pregnancy outcome.

Maternal complications Maternal complications of untreated hypothyroidism are decreased fertility, increased risk of miscarriage, anaemia, pregnancy-induced hypertension, placental abruption and postpartum haemorrhage.16,29,30 Even euthyroid women with elevated TPOAb have an increased risk of miscarriage and preterm birth.20,24,29,31 The risk of miscarriage can be reduced with thyroxine treatment.24–26,31 Women with TPOAb also have an increased risk of developing postpartum thyroiditis (PPT).21,32

Foetal and neonatal complications Untreated overt as well as subclinical maternal hypothyroidism are associated with adverse neonatal outcome including preterm birth, foetal growth restriction, neonatal respiratory distress and impaired brain development.16,19,29,33,34 An increased risk of perinatal death is also reported.29,35 There is no evidence that TPOAb have an effect on the foetal thyroid, but they appear to be associated with preterm birth and impaired brain development of the offspring.29 In women with hypothyroidism after treatment for Graves’ disease with ablation radiotherapy or surgery, TSHrAb may still be present and may cause foetal or neonatal hyperthyroidism or in very rare cases even hypothyroidism.27,28,36 Several recent studies have shown impaired neuropsychological development in children of women with unrecognised or suboptimally treated maternal hypothyroidism or maternal hypothyroxinaemia. 29,33,34 Because foetal production of thyroid hormones does not become efficient until midgestation, an adequate maternal thyroid hormone supply across the placenta is especially important during early pregnancy, although a low T4 later in gestation may also impair brain development of the offspring.29 Iodine deficiency exposes both mother and foetus to thyroid underfunction. Children of mothers from iodine deficient areas show neuropsychiatric and intellectual deficits.8,37,38

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The influence of pregnancy on the severity of hypothyroidism Because of the immune modulation of pregnancy, the level of TPOAb decreases during pregnancy, but may increase after pregnancy, which may lead to further destruction of the thyroid. Women with TPOAb who are euthyroid in early pregnancy carry a significant risk of developing hypothyroidism progressively during gestation.39 Because T4 requirement increases already early in pregnancy, hypothyroid pregnant women require larger thyroxine replacement doses than do non-pregnant patients. In pregnant women, the full replacement thyroxine dose is estimated at 2.0–2.4 µg/kg/day.8 Women already on thyroid hormone treatment should increase their dose of levothyroxine as early in pregnancy as possible.2 Women without residual functional thyroid tissue (after radioiodine ablation, total thyroidectomy, or due to congenital agenesis of the gland) require a greater increment in thyroxine dosage than women with Hashimoto’s thyroiditis, who usually have some residual thyroid tissue, with the ability to compensate for the increased requirements in thyroid hormone associated with pregnancy.2,40

Pre-conception advice and management of women with hypothyroidism Iodine nutrition status should be adequate. During pregnancy and lactation a daily iodine intake of approximately 250 µg is recommended.8,41,42 Levothyroxine is the treatment of choice for maternal hypothyroidism. Known hypothyroidism should be corrected before initiation of pregnancy. The replacement dose of thyroxine should be titrated to reach a TSH level not higher than 2.5 µU/ml.8 Maternal euthyroidism should be maintained, especially during early pregnancy. When a woman receiving thyroxine replacement therapy becomes pregnant the levothyroxine dose should be increased as early as possible to maintain the TSH level below target values of 2.5 mU/ml in the first trimester and below 3 mU/ml in the second and third trimester.2,8 A 30–50% increment in dosage may be required.2 TSH levels should be measured within 1 month after the initiation or adjustment of treatment and monitored every 6–8 weeks after stabilisation. After pregnancy the dose of thyroxine can usually be reduced to the prepregnancy level. Serum TSH should be checked in 6 weeks. A minute amount of thyroxine is transferred into breast milk, and breast feeding does not pose a risk to the neonate.43

Hyperthyroidism Introduction Hyperthyroidism is the sustained overproduction of hormone by the thyroid gland, of which Graves’ disease

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is the most common cause. The clinical syndrome caused by excessive quantities of the thyroid hormones is indicated with the term thyrotoxicosis and is encountered in approximately 0.2% of pregnancies.10,11 The term thyrotoxicosis not only refers to hyperthyroidism, but also to thyroiditis and exogenous excess of thyroid hormone. Severe hyperthyroidism is uncommon during pregnancy, because hyperthyroidism is associated with reduced fertility and if conception occurs, there is an increased risk of miscarriage. Once the disease is under control, fertility is normal. The clinical diagnosis of thyrotoxicosis in pregnancy may be difficult because pregnancy and hyperthyroidism are both accompanied by thyroid stimulation, a hyperdynamic circulation and a hypermetabolic state. Many signs and symptoms of hyperthyroidism such as tachycardia, palpitations, heat intolerance, warm moist skin, tremor, systolic murmur and emotional lability are often present during normal pregnancy. On the other hand, a sustained resting tachycardia, failure to gain weight or weight loss despite an adequate dietary intake, ophthalmological signs of Graves’ disease, and an obvious goitre should alert the physician to the possibility of thyrotoxicosis. The diagnosis of overt hyperthyroidism is made by demonstrating a serum fT4 or tT4 concentration above the trimester-related reference value combined with a suppressed TSH. An asymptomatic patient with a repeat subnormal TSH but a serum fT4 or tT4 in the normal range is classified as having subclinical hyperthyroidism. If a patient is clearly thyrotoxic but has normal fT4 values, the possibility of T3 thyrotoxicosis should be considered. In interpreting the laboratory tests it is important to realise that serum TSH values are physiologically reduced in pregnancy, in particular in the first trimester.8,9 One might suspect hyperthyroidism in a healthy pregnant woman with a physiologically blunted serum TSH value. About 85% of the cases of hyperthyroidism during pregnancy are caused by Graves’ disease.8 Other causes of thyrotoxicosis during pregnancy, such as transient gestational hyperthyroidism, single toxic adenoma, multinodular toxic goitre, thyroiditis, factitious thyrotoxicosis and gestational trophoblastic disease are far less common. The hyperthyroidism of Graves’ disease is the result of circulating TSHrAb (IgG class) that bind to the TSH receptors on the thyroid follicular cells and stimulate thyroid hormone synthesis and secretion. The prevalence of maternal Graves’ disease, past or present, varies from 0.5 to 1%.8,27 Transient gestational thyrotoxicosis is a form of hyperthyroidism that is unique for pregnancy. It is particularly seen in the first trimester and usually associated with hyperemesis gravidarum. It may be caused by high levels of hCG which lead to TSH receptor stimulation and temporary hyperthyroidism. Also, hydatiform mole may produce enough hCG to stimulate the thyroid and

produce transient hyperthyroidism. Women with transient gestational thyrotoxicosis are rarely symptomatic and, in general, treatment with antithyroid drugs is not necessary.

The influence of hyperthyroidism on pregnancy outcome Apart from the complications of hyperthyroidism in non-pregnant women that are described in standard texts on endocrinology, overt hyperthyroidism has several adverse effects on pregnancy outcome. In contrast with subclinical hypothyroidism, there is no evidence that subclinical hyperthyroidism is associated with adverse pregnancy outcomes.44

Maternal complications Maternal thyrotoxicosis is associated with an increased risk of miscarriage, maternal heart failure and preeclampsia.45–47 Thyroid storm or crisis, a rare emergency consisting of an exaggerated state of hypermetabolism with hyperpyrexia, cardiovascular manifestations and delirium, may occur in pregnancy or during labor and delivery in the undiagnosed or insufficiently treated patient.47–49

Foetal and neonatal complications Foetal and neonatal risks associated with maternal hyperthyroidism are related to the disease itself or to the medical treatment of the disease, or to both. There is good evidence that poorly or uncontrolled maternal thyrotoxicosis is associated with intrauterine growth restriction, preterm delivery, foetal congestive heart failure and hydrops, low birth weight, intrauterine death, foetal goitre, and foetal and neonatal hypothyroidism.8,36,45,50 Maternal thyroid disease (most likely Graves’ disease) or its treatment may be associated with craniosynostosis in the infant.51 The exposure of the foetal hypothalamic–pituitary– thyroid system to high thyroid hormone concentrations transferred across the placenta may impair its physiological maturation during intrauterine life. Initially, it was thought that this type of central hypothyroidism was transient, but Kempers et al showed that at least some of these children had a persistent loss of integrity of the thyroid morphology at the age of about 3 years with a presumably permanent loss of the patients’ capacity to maintain euthyroidism.52 In women with adequately treated and controlled hyperthyroidism or with previously medically treated Graves’ disease in remission, foetal and neonatal outcomes are usually good. TSHrAb in women with a past or present Graves’ disease freely cross the placenta. These antibodies, which may still be present after ablative treatment of hyperthyroidism, can stimulate the foetal thyroid and, if the titre is sufficiently high, may cause a foetal or transient neonatal thyrotoxicosis. Signs of foetal

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hyperthyroidism are foetal tachycardia, goitre and intrauterine growth retardation. Foetal hyperthyroidism may cause serious complications such as premature delivery, craniosynostosis, intellectual impairment, foetal cardiac failure and hydrops and death.8,36,53 Fortunately, severe symptomatic foetal hyperthyroidism requiring treatment is rare, occurring in less than 0.01% of pregnancies, but if left untreated the mortality rate may reach 50%.8,45 Maternal antibodies are cleared less rapidly than antithyroid drugs in the neonate, which may result in delayed presentation of neonatal Graves’ disease.8,36 Without treatment the mortality rate of neonatal hyperthyroidism is about 15%, and 25% of the children who remain alive have neurological deficiency.45 Neonatal thyrotoxicosis resolves with clearance of the maternal antibodies and clinical signs usually disappear during the first 4 months of life Because the foetal thyroid is unable to respond to these passively acquired maternal antibodies before 20 weeks’ gestation, foetal hyperthyroidism does not occur before a gestational age of 20 weeks. The risk depends primarily on the level of TSHrAb in maternal serum. If antibodies are absent, or the level is low, the estimated risk is low.27 Recently, new generations of TSHrAb assays have been developed, which show high sensitivity and specificity. Therefore, further studies are needed to determine at which level of TSHrAb determined with these new assays the risk of foetal or neonatal hyperthyroidism is negligible. It is estimated that approximately 1–5% of neonates of mothers with Graves’ disease have transient hyperthyroidism as a result of the transplacental passage of maternal TSHrAb.54 Occasionally, maternal antibodies against the TSH receptor bind to the foetal receptor without stimulation, but block the normal effect of TSH. This may cause a primary hypothyroidism in the foetus, and transient hypothyroidism in the neonate. The condition is very rare; it has been detected in 1 in 180 000 newborns in North America.55 Overtreatment of the mother with antithyroid agents can result in iatrogenic foetal goitre and hypothyroidism. For that reason women on a “block and replace” regimen who become pregnant should be changed immediately to a maintenance dose of a single antithyroid drug. A large foetal goitre may cause polyhydramnios due to oesophagial obstruction or neck extension and subsequent malposition during delivery and respiratory embarrassment and feeding difficulties in the neonate. Maternal treatment with methimazole in early pregnancy has been associated with aplasia cutis, choanal and oesophagial atresia and facial anomalies but data supporting these associations are controversial.56–58 Any pregnant woman, with or without hyperthyroidism, taking medical doses of iodide runs the risk of inducing a large foetal goitre. The use of radioactive131 I is contraindicated in pregnancy because it leads to significant radiation to the foetal thyroid, which can induce thyroid ablation.8

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β-blockers pass through the placenta and their symptomatic use in late pregnancy may induce neonatal hypoglycaemia, apnoea and bradycardia. It has also been suggested that the use of β-blockers may be associated with the development of intrauterine growth restriction.8

The influence of pregnancy on the severity of hyperthyroidism Graves’ disease usually becomes quiescent or less active during pregnancy, because of the immunosuppression associated with pregnancy. Occasionally the onset of Graves’ disease occurs in pregnancy. Rebound from immunosuppression after delivery may cause a relapse of Graves’ hyperthyroidism in the postpartum period.8 Pregnancy is a major risk factor for development of Graves’ disease in susceptible women. As many as 30–40% of young women give a history of pregnancy in the 12 months before the onset of Graves’ disease.3

Pre-conception advice and management in women with hyperthyroidism In patients with Graves’ disease who are in early remission after antithyroid treatment or who are on antithyroid drugs and want to become pregnant in the near future, definitive treatment (radioiodine or surgery) is often recommended before they become pregnant to forestall the complexities of managing hyperthyroidism during pregnancy.59 This advice is open to question because a recent study of Laurberg et al showed that radioiodine therapy led to a 1-year long worsening of autoimmunity against the TSH receptor.28 Also, the number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TSHrAb from serum during the following years was considerably lower than with treatment with antithyroid agents or surgery.28 Moreover, in pregnant women with a high maternal level of TSHrAb, the development of foetal Graves’ disease can usually be prevented with maternal antithyroid treatment. Therefore, the recommendation of definitive treatment with radioiodine prior to pregnancy needs re-evaluation. Preferably before pregnancy and otherwise as soon as possible during pregnancy, thyroid function and the concentration of TSHrAb need to be determined. Information should be obtained about present and previous treatments. The level of TSHrAb in the first trimester is a predictor of foetal Graves’ disease, the TSHrAb concentration in the third trimester is a predictor of neonatal Graves.8,27 Subclinical hyperthyroidism during pregnancy needs no treatment. It has no adverse pregnancy outcome and maternal antithyroid drugs cross the placenta and may lead to foetal hypothyroidism and goitre.44 Medical therapy with antithyroid drugs is the treatment of choice during pregnancy. Partial or total

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thyroidectomy may be considered for failure or allergy to medical therapy. If necessary, surgery is preferably performed in the second trimester, when organogenesis is complete and thus the foetus is at minimal risk for teratogenic effects of medications and the uterus is relatively resistant to contraction stimulating events.8 Radioactive iodine (RAI) therapy is contraindicated during pregnancy and lactation.8 The recommended therapy for Graves’ disease during pregnancy is monotherapy with one of the antithyroid agents propylthiouracil (PTU), methimazole, or carbimazole. Although the data are not conclusive, there is a possible association between methimazole or carbimazole exposure with foetal development abnormalities.56–58 PTU also crosses the placenta, but there are no data to support an association between congenital anomalies in PTU. For that reason PTU is preferred as the initial therapy for maternal hyperthyroidism during pregnancy, especially during first trimester organogenesis.58 Because all antithyroid agents easily cross the placenta and placental transfer of T4 is not efficient, the “block and replace” treatment that is generally applied in non-pregnant patients, in which a high dose of an antithyroid drug is combined with replacement thyroxine, should be changed immediately in pregnancy to a maintenance dose of an antithyroid drug only. A balance between stimulating antibodies and antithyroid drugs which keeps the mother euthyroid will also maintain euthyroidism in the foetus. Maternal thyroid function should be determined every 4–6 weeks and the dose of the antithyroid drug should be titrated to the lowest possible dose to maintain maternal serum fT4 levels at the upper end of the normal non-pregnant reference range.8 With that regimen normal serum fT4 levels are found in more than 90% of neonates. However, if the maternal fT4 is kept in the lower two-thirds of the non-pregnant reference range, 36% of neonates have a decreased fT4.8 Maternal overtreatment carries a significant risk of foetal hypothyroidism with goitre. Because of the usual improvement in the disease throughout pregnancy, the dosage of the antithyroid drug required to maintain the fT4 at the upper end of the reference range can often be reduced or even stopped in the third trimester. If necessary, β-blockers (especially propranolol) may be used to treat severe symptoms of hyperthyroidism, for example maternal or foetal tachycardia. After 20 weeks’ gestation monthly foetal ultrasonography should be performed to determine foetal growth and detect the possible development of goitre. The foetal heart rate needs to be checked at every visit. Especially pregnancies with elevated levels of TSHrAb or a previous pregnancy complicated by foetal or neonatal hyperthyroidism need close observation. Foetal goitre can be a sign of either foetal hypothyroidism or hyperthyroidism. Usually the diagnosis can be made on medical history, maternal treatment and thyroid function, the presence or absence of foetal tachycardia and the level of TSHrAb. If the goitre is caused by foetal hypothyroidism, usually due to maternal antithyroid

overtreatment, foetal tachycardia will be absent. In these cases the dose of the antithyroid drug should be reduced or stopped after which the goitre will usually disappear. If foetal goitre is caused by foetal hyperthyroidism, a foetal heart rate of >160 beats/min will be present and a high level of TSHrAb. Amniocentesis or cordocentesis can be performed to determine foetal fT4 and TSH, but these procedures are almost never necessary.60 Foetal hyperthyroidism can be treated with maternally administered antithyroid drugs (in euthyroid women in combination with thyroxine). Early delivery should be considered, depending on the duration of gestation at diagnosis and the severity of the foetal symptoms. Women with Graves’ disease are at risk for postpartum aggravation of thyrotoxicosis.61 Postpartum thyrotoxicosis may be accompanied by symptoms similar to postpartum psychosis. Women treated for hyperthyroidism during pregnancy should be monitored postpartum for a possible relapse and followed for 6 months. Infants born to mothers with Graves’ disease should be closely followed by a paediatrician for thyroid dysfunction and treated if necessary. After delivery, maternal antithyroid drugs are cleared from the neonatal circulation within the first few days, whereas TSHrAb disappear much more slowly and may stimulate the thyroid during the first weeks or even months of life.8,36 If the mother uses thionamides until the end of pregnancy the neonate should be followed for a delayed development of neonatal hyperthyroidism. All antithyroid drugs are excreted into breast milk, but they do not seem to pose a significant risk to the infants thyroid function at usual doses. PTU is considered the drug of choice because it is ionised at physiological pH and protein bound, which limits its transfer into breast milk. Preferably the drug is taken by the mother after a breast feeding, and the dose is split throughout the day to minimise exposure to the nursing infant. A study in 11 infants who were exclusively breast-fed and whose mothers took PTU in a doses as high as 750 mg/day did not show any adverse effects in the nursing infants.62 Nevertheless, if high doses of thionamides are used (PTU >150 mg/day, methimaziole >15 mg/day) it is recommended to determine the thyroid function of the nursing infant at frequent intervals.

Non-functional goitre, thyroid nodules and cancer Half of all thyroid cancers occur in women of childbearing age and many present as asymptomatic thyroid nodules.63 Pre-existing nodules often become larger in pregnancy, and new nodules are detected more often as a result of pregnancy associated TSH-mediated growth stimuli, which may be most prominent under conditions of iodine deficiency.8 Thyroid nodules (TN) are

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generally benign hyperplastic nodules or benign follicular adenomas. Outside pregnancy only about 5–10% of nodules coming to medical attention are carcinomas. The conclusion from most available data is that the malignancy rate of a thyroid nodule detected during pregnancy is either similar to or slightly greater than that seen in the general population.8 The most common type of malignancy is papillary thyroid carcinoma.

The influence of thyroid nodules and thyroid cancer on pregnancy outcome With a few exceptions, the outcome for women diagnosed with TN and thyroid cancer during pregnancy is good. No difference in maternal outcome was found between women who underwent surgery during pregnancy or those in whom surgery was delayed until after pregnancy.8,64

The influence of pregnancy on thyroid nodules and thyroid cancer Thyroid nodules often become larger during pregnancy. Pregnancy is not thought to influence the natural course of thyroid malignancy and the risk of relapse after treatment is not increased.8,64

Pre-conception advice and management in women with thyroid nodules and cancer Pregnancy should be avoided for 6 months to 1 year in women with thyroid cancer who have received therapeutic radioactive iodide to ensure stability of thyroid function and confirm remission of thyroid cancer. There are no data that subsequent pregnancy increases the risk for thyroid cancer recurrence.8

Management during pregnancy The principles of diagnosis and management of thyroid nodules in pregnancy should closely follow those already well-defined for TN in the non-pregnant state. Thyroid function should always be determined. An undetectable or suppressed TSH and an increased fT4 suggest a hyperfunctioning nodule, but autonomously functioning thyroid nodules are uncommon in this age group. A rapidly increasing nodule, a history of neck irradiation during childhood, a family history of thyroid cancer or multiple endocrine neoplasia (MEN) 2 are suggestive of malignancy. Radioisotope scans are contraindicated but high resolution ultrasound imaging should be used to assess and to follow TN. Ultrasound scanning is also useful to guide fine-needle aspiration biopsy and assess regional lymph nodes. Management of malignant nodules depends upon how aggressive the tumour is and on the duration of gestation when the diagnosis is made. A diagnosis of thyroid cancer in early pregnancy is not an absolute indication for termination, nor is pregnancy a

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contraindication to necessary surgery. Surgery is preferably performed in the second trimester, or after delivery.8,65 For advanced disease, or disease that shows evidence of progression during pregnancy, immediate intervention should be performed, irrespective of the gestational age. It is appropriate to administer thyroid hormone to achieve a suppressed but detectable TSH in a pregnant woman with previously treated thyroid cancer, or a fine needle aspiration positive for, or suspicious for, cancer, and those who elect to delay surgical treatment until postpartum.

Postpartum thyroiditis Women without overt thyroid disease before pregnancy may develop a postpartum thyroiditis (PPT). It is a form of autoimmune thyroid disease closely related to Hashimoto’s thyroiditis. The pathophysiology is the postpartum increase in thyroid-directed autoimmunity, which causes a destruction of thyrocytes. It causes transient hyperthyroidism due to thyroid cell destruction followed by a transient hypothyroidism. Later, permanent hypothyroidism may develop. In about 30% of the women with PPT, the hyperthyroid phase is asymptomatic. The prevalence of PPT varies globally from as low as 1.1% in Thailand to as high as 21.1% in Canada.8 The prevalence of PPT in women with type 1 diabetes mellitus is three times greater and varies from 18 to 25%.8,66 Women with high TPOAb in early pregnancy are most commonly affected.8,49,67,68 Other risk factors are a previous thyroid dysfunction, a family history of thyroid or other autoimmune disease, a low iodine intake and smoking.8,68 PPT may begin between 6 weeks to 6 months after delivery. It may also be triggered by a miscarriage occurring as early as 6 week’s gestation. PPT is characterised by a near 0% radioactive iodine uptake and a significant elevation of TPOAb. The hyperthyroid phase of PPT occurs between 1 and 6 months’ postpartum and usually lasts 1–2 months. The hypothyroid phase of PPT usually occurs between 3 and 8 months’ postpartum. Most women will return to the euthyroid state within 12 months. Although some studies report an association between the development of a postpartum depression and either the presence of TPOAb or PPT this association has not been confirmed by others.8,22,23,32

Pre-conception advice in women with a previous postpartum thyreoiditis In women who have had a PPT in a previous pregnancy thyroid function should be determined before a next pregnancy, because permanent hypothyroidism may have developed. Women who remain euthyroid after transient thyroid dysfunction have a 75% chance of PPT in a subsequent pregnancy and 20–64% of women develop permanent hypothyroidism during long-term follow-up.8,32,68,69

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The level of TPOAb is the most useful marker for the prediction of PPT. Women known to be TPOAb positive should have a TSH performed at 3 and 6 months’ postpartum, to check for the development of PPT.8 The hyperthyroid phase of PPT should not be treated with thionamides. In women with severe symptoms β-blockers can be used. Treatment decisions for women in the hypothyroid phase of PPT depend on both the degree of hypothyroidism and whether the woman is attempting pregnancy. When treatment with levothyroxine is required, it should be withdrawn slowly approximately 6 months later, because the hypothyroidism is often not permanent.3

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Pre-conceptional screening for thyroid dysfunction The question of whether or not to screen all women for subclinical hypothyroidism before conception or early in pregnancy is fiercely debated.8,70–73 Although there are a few promising data which suggest that thyroxine treatment may improve obstetrical outcome, there is as yet insufficient evidence that treatment modifies longterm neurological development in the offspring. Therefore, population-based screening for subclinical hypothyroidism in all women who are pregnant or planning pregnancy has not yet been recommended in the recent Endocrine Society Guidelines, but targeted case finding is recommended among the following groups of women:8 1. Women with a history of hyperthyroid or hypothyroid disease, postpartum thyroiditis or thyroid lobectomy; 2. Women with a family history of thyroid disease; 3. Women with a goitre; 4. Women with thyroid antibodies; 5. Women with symptoms or clinical signs suggestive of thyroid underfunction; 6. Women with type 1 diabetes; 7. Women with other autoimmune disorders; 8. Women with infertility who should have screening with TSH as part of their infertility work-up; 9. Women with previous therapeutic head or neck irradiation; 10. Women with a history of recurrent miscarriage or preterm delivery.

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References 1. Rashid M, Rashid MH. Obstetric management of thyroid disease. Obstet Gynecol Surv 2007; 62: 680–8. 2. Alexander EK, Marqusee E, Lawrence J et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004; 351: 241–9. 3. Reed Larsen P, Davies TF, Schlumberger M, Hay ID. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Kronenberg HM,

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Melmed S, Polonsky KS, Reed Larsen P, eds. Williams Textbook of Endocrinology, 11th edn. Philadelphia: Saunders Elsevier, 2008: 299–332. Chan GW, Mandel SJ. Therapy Insight: management of Graves’ disease during pregnancy. Nat Clin Pract Endocrinol Metab 2007; 3: 470–8. Berghout A, Endert E, Ross A et al. Thyroid function and thyroid size in normal pregnant women living in an iodine replete area. Clin Endocrinol 1994; 41: 375–9. Berghout A, Wiersinga W. Thyroid size and thyroid function during pregnancy: an analysis. Eur J Endocrinol 1998; 138: 536–42. Kimura M, Amino N, Tamaki H et al. Physiologic thyroid activation in normal early pregnancy is induced by circulating hCG. Obstet Gynecol 1990; 75: 775–8. Abalovich M, Amino N, Barbour L et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol of Metab 2007; 92: S1–47. Dashe JS, Casey BM, Wells CE et al. Thyroid stimulating hormone in singleton and twin pregnancy: importance of gestational age-specific reference ranges. Obstet Gynecol 2005; 106: 753–7. Becks GP, Burrow GN. Thyroid disease in pregnancy. Med Clin North Am 1991; 75: 121–50. Burrow GN, Fisher DA, Larsen PR. Maternal and fetal thyroid function. N Engl J Med 1994; 331: 1072–8. Vulsma T, Gons MH, de Vijlder JM. Maternal fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect of thyroid dysgenesis. N Engl J Med 1989; 321: 13–16. Kemkers MJ, van Tijn DA, van Trotsenburg SP et al. Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 2003; 88: 51–7. Mandel SJ, Spencer CA, Hollowell JG. Are detection and treatment of thyroid insufficiency in pregnancy feasible? Thyroid 2005; 15: 44–53. Klein RZ, Haddow JE, Faix JD et al. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol 1991; 35: 41–6. Casey B, Dashe JS, Wells CE et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005; 105: 239–45. Glinoer D, Abalovich M. Unresolved questions in managing hypothyroidism during pregnancy. BMJ 2007; 335: 300–2. Goldman JC, Malone FD, Lambert-Messerlian G et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008; 112: 85–92. Smallridge RC, Glinoer D, Hollowell JG et al. Thyroid function inside and outside of pregnancy: What do we know and what don’t we know? Thyroid 2005; 15: 54–9. Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. Eur J Endocrinol 2004; 150: 751–5. Amino N, Mori H, Iwatani Y et al. High prevalence of transient post-partum thyrotoxicosis and hypothyroidism. N Engl J Med 1989; 306: 849–52. Harris B, Othman S, Davies JA et al. Association between postpartum thyroid dysfunction and thyroid antibodies and depression. BMJ 1992; 305: 152–6.

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The patient with thyroid disease 23. Kuijpens JL, Vader HL, Drexhage HA et al. Thyroid peroxidase antibodies during gestation are a marker for subsequent depression postpartum. Eur J Endocrinol 2001; 145: 579–84. 24. Negro R, Formoso G, Mangieri T et al. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. J Clin Endocrinol Metab 2006; 91: 2587–91. 25. Vaquero E, Lazzarin N, De Carolis C et al. Mild thyroid abnormalities and recurrent spontaneous abortion diagnostic and therapeutic approach. Am J Reprod Immunol 2000; 43: 204–8. 26. Glinoer D. Miscarriage in women with positive antiTPO antibodies: Is thyroxine the answer? J Clin Endocrinol Metab 2006; 91: 2500–2. 27. Laurberg P, Nygaard B, Glinoer D et al. Guidelines for TSH-receptor antibody measurements in pregnancy: results of an evidence – based symposium organized by the European Thyroid Association. Eur J Endocrinol 1998; 139: 584–6. 28. Laurberg P, Wallin G, Tallstedt L et al. TSH–receptor autoimmunity in Graves’ disease after therapy with anti-thyroid drugs, surgery, or radiodine: a 5-year prospective randomised study. Eur J Endocrinol 2008; 158: 69–75. 29. LaFranchi SH, Haddow JE, Hollowell JG. Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes? Thyroid 2005; 15: 60–71. 30. Abramson J, Stagnaro-Green A. Thyroid antibodies and fetal loss: An evolving story. Thyroid 2001; 11: 57–63. 31. Negro R, Mangieri T, Coppola L et al. Levothyroxine treatment in thyroid peroxidase antibody-positive women undergoing assisted reproduction technologies: a prospective study. Hum Reprod 2005; 20: 1529–33. 32. Lucas A, Pizarro E, Granada ML et al. Postpartum thyroiditis: long-term follow-up. Thyroid 2005; 15: 1177–81. 33. Haddow JE, Palomaki GE, Allan WC et al. Maternal Thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999; 341: 549–55. 34. Pop VJ, Brouwers EP, Vader HL et al. Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3 year follow-up study. Clin Endocrinol 2003; 59: 282–8. 35. Allan WC, Haddow JE, Palomaki GE et al. Maternal thyroid deficiency and pregnancy complications: implications for population screening. J Med Screen 2000; 7: 127–30. 36. Polak M, Le Gac I, Vuillard E et al. Fetal and neonatal thyroid function in relation to maternal Graves’ disease. Baillieres Clin Endocrinol Metab 2004; 18: 289–302. 37. Glinoer D, Delanfe F. The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny. Thyroid 2000; 10: 871–87. 38. Vermiglio F, Lo Presti VP, Moleti M et al. Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder

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in developed countries. J Clin Endocrinol Metab 2003; 89: 6054–60. Glinoer D, Rihai M, Grun JP et al. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. J Clin Endocrinol Metab 1994; 79: 197–204. Kaplan MM. Monitoring thyroxine treatment during pregnancy. Thyroid 1992; 2: 147–54. Glinoer D. Iodine nutrition requirements during pregnancy. Thyroid 2006; 16: 947–8. The Public Health Committee of the American Thyroid Association. Iodine supplementation for pregnancy and lactation – United States and Canada: Recommendations of the American Thyroid Association. Thyroid 2006; 16: 949–51. Franklin R, O’Grady C, Carpenter L. Neonatal thyroid function: comparison between breast-fed and bottle-fed infants. J Pediatr 1985; 106: 124–6. Casey BM, Dashe JS, Wells CE et al. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006; 107: 337–41. Davis LE, Lucas MJ, Hankins GDV et al. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989; 160: 63–70. Millar LK, Wing DA, Leung AS et al. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994; 84: 946–9. Mestman JH. Hyperthyroidism in pregnancy. Best Pract Res Clin Endocrinol Metab 2004; 18: 267–88. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 1993; 22: 263–77. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006; 108: 1283–92. Hamburger JI. Diagnosis and management of Graves’ disease in pregnancy. Thyroid 1992; 2: 219–24. Rasmussen SA, Yazdy MM, Carmichael SL et al. Maternal thyroid disease as a risk factor for craniosynostosis. Obstet Gynecol 2007; 110: 369–77. Kempers MJ, van Trotsenburg SP, van Rijn RR et al. Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves’ disease. J Clin Endocrinol Metab 2007; 92: 2984–91. Smith C, Thomsett M, Choong C et al. Congenital thyrotoxicosis in premature infants. Clin Endocrinol 2001; 54: 371–6. Weetman AP. Graves’ disease. N Engl J Med 2000; 26: 1236–48. Brown RS, Bellisario RL, Botero D et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab 1996; 81: 1147–51. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001; 86: 2354–9. Wolf D, Foulds N, Daya H. Antenatal carbimazole and choanal atresia. A new embryopathy. Arch Otolaryngol Head Neck Surg 2006; 132: 1009–11. Chattaway JM, Klepser T. Propylthiouracil versus methimazole in treatment of Graves’ disease during pregnancy. Ann Pharmacother 2007; 41: 1018–22.

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59. Brent GA. Graves’ disease. N Engl J Med 2008; 358: 2594–605. 60. Kilpatrick S. Umbilical blood sampling in women with thyroid disease in pregnancy: Is it necessary? Am J Obstet Gynecol 2003; 189: 1–2. 61. Marx H, Amin P, Lazarus JH. Hyperthyroidism and pregnancy. BMJ 2008; 336: 663–7. 62. Monotani N, Yamashita R, Makino F et al. Thyroid function in wholly breast-feeding infants whose mothers take high doses of propylthiouracil. Clin Endocrinol 2000; 53: 177–81. 63. Rosen IB, Korman M, Walfish PG. Thyroid nodular disease in pregnancy: current diagnosis and management. Clin Obstet Gynecol 1997; 40: 81–9. 64. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed in pregnant women. J Clin Endocrinol Metab 1997; 82: 2862–6. 65. Sam S, Molitch ME. Timing and special concerns regarding endocrine surgery during pregnancy. Endocrinol Metab Clin North Am 2003; 32: 337–54. 66. Robert P, Gallas J, Stolk RP et al. Thyroid dysfunction during pregnancy and in the first postpartum year in women with diabetes mellitus type 1. Eur J Endocrinol 2002; 147: 443–51. 67. Premawardhana LD, Parkes AB, Ammari F et al. Postpartum thyroiditis and long-term thyroid status:

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prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000; 85: 71–5. Mulller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care. Endocr Rev 2001; 22: 605–30. Lazarus JH, Kokandi A. Thyroid disease in relation to pregnancy: A decade of change. Clin Endocrinol 2000; 53: 265–78. Glinoer D. The systematic screening and management of hypothyroidism and hyperthyroidism during pregnancy. Trends Endocrinol Metab 1998; 9: 403–11. U.S. Preventive Services Task Force. Screening for thyroid disease: Recommendation Statement. Ann Intern Med 2004; 140: 125–7. Dosiou C, Sanders GD, Araski SS, Capro LM. Screening pregnant women for autoimmune thyroid disease: a cost-effectiveness analysis. Eur J Endocrinol 2008; 158: 841–51. Vaidya B, Anthony S, Bilous M et al. Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 2007; 92: 203–7.

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9 The patient with diabetes mellitus Jeremy JN Oats

Introduction The epidemic of diabetes is affecting all ethnic groups as changing habits with increased calorific intake and reduced energy expenditure spread worldwide. The impact of this now affects increasing numbers of women in the child bearing age group, so that more women are entering pregnancy with diagnosed diabetes, i.e. pre-gestational diabetes, and more are developing gestational diabetes. This rise in all forms of diabetes and particularly of type 2 is well established. In the US the incidence of type 2 diabetes in the 30–39-year-old age range increased by 70% between 1990 and 1998, double the rate for the population as a whole.1 Onkamo et al2 reported in 1999 that there was an average annual increase in the incidence of type 1 diabetes of 3% (95% confidence interval (CI) 2.6–3.3) from studies conducted in 27 countries and this dated from the middle of the 20th century. In the US the proportion of pregnancies in women with type 2 diabetes compared with those with type 1 diabetes virtually trebled between 1980 and 1988, increasing from 26 to 65%. In the UK there has been up to a 6-fold increase in the incidence of pregnancies in women with type 2 diabetes, from 0.2 per 1000 pregnancies in 1996–98 to 1.2 per 1000 in 2002–4. The incidence of women with type 1 diabetes rose from 2.9 per 1000 to 3.5 per 1000 in the same time interval.3 The implication of this is that more women with pre-existing type 1 diabetes are now entering the child bearing years. The obesity epidemic is also affecting both developed and developing societies. In the US the proportion of the population with a body mass index (BMI) of >30 rose from 22.9% in 1994 to 30.5% in 2000.4 Of even more concern is that the prevalence of overweight in adolescents increased by 11.3%.5 In Australia, the prevalence of obesity was 2.5 times higher in 2000 than in 1980, affecting 34% of women, and overall 60% of the population were overweight or obese.6 Pregnancy is accompanied by an increase in insulin resistance thought to be due to the inhibition of insulin receptor activity by agents released by the

placenta such as tumour necrosis factor (TNF)-α.7 Most pregnant women can secrete additional insulin to overcome this, but a small percentage with diminished pancreatic β-islet cell activity cannot and, consequently, become hyperglycaemic either throughout the day or when specifically challenged with a glucose load, i.e. a glucose tolerance test. Others at increased risk are those who are already insulin resistant because of polycystic ovarian syndrome (PCOS) and/or those who are significantly overweight. Consequently, women with PCOS who have not been recently tested for glucose intolerance should be screened pre-pregnancy and ideally women with a strong family history of diabetes and those who are significantly overweight should also be tested. The opportunity provided by seeing women with diabetes before they become pregnant, so that their control can be optimised and thus reduce the adverse outcomes that particularly affect early pregnancy, has been recognised for many years. Steel et al8 reported the improved outcomes from their pre-pregnancy care strategies in Aberdeen, Scotland in the 1970s. Fuhrmann et al9 in 1983 published the results from their East German clinic where the incidence of major malformations was 0.8% in those who achieved “tight control” pre-pregnancy, compared with 7.5% in those who only achieved this after 8 weeks’ gestation. The UK 2007 CEMACH (Confidential Enquiry into Maternal and Child Health) report10 entitled “Diabetes in pregnancy: are we providing the best care?” concluded that “Suboptimal preconception care, glycaemic control before and during pregnancy and approach of the woman to managing her diabetes were all associated with poor pregnancy outcome”. Women with pre-gestational diabetes who had poor pregnancy outcomes were more likely to have an unplanned pregnancy (OR 1.7, 95% CI 1.1–2.7), not used contraception in the 12 months before conception (OR 2.4, 95% CI 1.4–4.1), not taken folic acid (OR 2.2, 95% CI 1.3–3.8), smoked (OR 1.7, 95% CI 1.0–2.6), or were assessed as having a suboptimal approach to the management of their diabetes prepregnancy (OR 4.0, 95% CI 2.6–6.3).

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The enquiry found that the main factors contributing to suboptimal pre-conception care were (1) Health service providers’ failure to provide (a) (b) (c) (d)

Pre-conception counselling; Contraceptive advice; High dose folic acid therapy; Appropriate screening and management of diabetic complications.

(2) Social and lifestyle issues including (a) Non-attendance of women at planned appointments; (b) Non-adherence to medical advice about diabetes management; (c) Unplanned pregnancy; (d) Language difficulties; (e) Difficult domestic circumstances; (f) Erratic or busy lifestyles. Furthermore, there was poor documentation of preconception care and the advice given. Overall 79% of the women had suboptimal glycaemic control before and during the first trimester of pregnancy and less than half had documentation that they were taking high dose (5 mg) folic acid. The women with suboptimal control were more likely to have a poor pregnancy outcome (OR 3.89, 95% CI 2.14–7.02 adjusted for maternal age and social deprivation). The enquiry also found that in the 12 months before becoming pregnant (1) Just over half of the women had a retinal and renal function test; (2) A quarter had evidence of having glycaemic controls set; (3) Half had had documented discussion about glycaemic control; (4) Less than half had evidence that diet, contraception or diabetes complications had been discussed; (5) Less than half had been informed about fetal risks, increased chances of induction of labour and caesarean delivery.10 The challenge for the maternity health care providers is to identify these women pre-pregnancy and encourage them to seek medical attention and advice before they become pregnant. The in utero effects of maternal hyperglycaemia permanently damaging the developing fetal islet cells resulting in diabetes in later life, can be minimised thereby breaking the “diabetes begets diabetes cycle”.11 The CEMACH recommendations regarding the patient with diabetes are outlined in Table 9.1.

Influence of the disease/disorder on pregnancy outcome The increased risks to the developing fetus posed by maternal diabetes, especially in pregnancies where there is suboptimal control, are well documented.

Table 9.1

CEMACH recommendations.10

1. Pre-conception and maternity services related to pregnancy should be easily accessible and responsive to all women with diabetes, and provide appropriate care and information 2. There should be mechanisms in place to identify vulnerable communities and individuals, so that additional services can be provided as appropriate to women of child bearing age with diabetes, thereby ensuring optimal preconception care 3. Providers of diabetes care should develop educational strategies that will enable women of child bearing age with diabetes to prepare adequately for pregnancy

Fetal malformations The risk of congenital anomalies in the offspring of women with diabetes is from two to five times greater than in those of women without diabetes,12 with the frequency of malformations in the neonatal period being reported from 4 to 13%.13 In a large study of 22 843 pregnancies in Hungary, Nielsen et al12 reported that the prevalence odds ratios (POR) of congenital abnormalities compared with controls, was 2.1 (95% CI 1.5–3.1) with the strongest associations with maternal diabetes being for renal agenesis (POR 14.8, 95% CI 3.5–62.1), obstructive lesions of the urinary tract (POR 4.3, 95% CI 1.3–13.9), cardiovascular abnormalities (POR 3.4, 95% CI 2.0–5.7) and multiple anomalies (POR 5.0, 95% CI 2.4–10.2).

Miscarriage Whilst the absolute risk of miscarriage for women with diabetes is debated, the rates of spontaneous miscarriage in women with diabetes are strongly influenced by the degree of diabetic control. In the Diabetes in Early Pregnancy Study (DIEP), the rates rose from 9% in those with good control to 45% with poor control.14

Fetal growth The principal association between fetal growth and diabetes is with accelerated growth resulting in macrosomia, however, in women with microvascular involvement (especially renal and retinal) there may be growth restriction.15 The accelerated growth occurs primarily in the subcutaneous adipose tissue and in the liver, heart, lungs and the adrenal glands plus a modest growth in skeletal tissue.16 After birth the relative weight of the affected child returns to the normal range, but by 4 years of age Silverman et al17 reported that the growth was significantly greater than that of the offspring of women with

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101

Symmetry index

1.3

1.2

1.1

1

0.9 0

0.5

1

2

3 4 Age in years

5

6

7

8

Fig 9.1 Emergence of obesity in offspring of diabetic women. Reproduced from reference 17, with permission.

80 Prevalence of obesity (%)

70 60 50 40 30 20 10 0 5–9

10–14

15–19

20–24

25–29

Age (years)

Non-diabetic

Prediabetic

normal glucose tolerance during pregnancy (Fig 9.1). Similar findings have been reported from the Pima Indian studies by Pettitt et al. Children who were born to diabetic mothers, compared with the offspring of women who later developed diabetes and those who remained normoglycaemic, were significantly more obese by the age of 5 years; confirming that this effect is due to the in utero effect of maternal diabetes rather than a genetic predisposition (Fig 9.2).18 The increased occurrence of intrauterine growth restriction (IUGR) associated with progressive retinopathy was found by McElvy et al to be independent of the association with hypertension, itself a factor in the genesis of IUGR.19

Diabetic

Fig 9.2 Prevalence of severe obesity according to mother’s diabetes during and following pregnancy in 5–29-year-old Pima Indians. Reproduced from reference 18, with permission.

Perinatal mortality The perinatal mortality rate in women with well controlled diabetes approaches that of the background population,22 although a number of studies have reported that the perinatal mortality especially for women with type 2 remains significantly worse than for both women with type 1 diabetes and the background population. In an Australian population, McElduff et al reported that the perinatal mortality rate (PNMR) for women with type 2 was 5.1%, for type 1 was 1.2% and for the background population was 0.7%.23 Similarly, Clausen et al reported PNMRs of 6.7%, 1.7% and 0.8% in a Danish survey.24

Early neonatal problems Shoulder dystocia and birth trauma The frequency of shoulder dystocia, brachial plexus injury and clavicular fracture in the offspring of women with diabetes is two to three times greater for any given birth weight compared with women with normal glucose tolerance20 and 84% of cases in diabetic pregnancies occur in babies with birth weights greater than 4000 g.21

The prevalence of neonatal hypoglycaemia is influenced strongly by maternal control particularly in the later stages of pregnancy and labour. Using a cut-off of 2.6 mmol/l, Merlob and Hod reported an incidence of 26.3% in infants whose mothers maintained strict control.25 This contrasted with Cordero et al’s report of 47% hypoglycaemia in macrosomic infants compared with 20% in normal weight infants.26

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Hyperbilirubinaemia defined as total serum bilirubin level of >205 mmol/l occurs in 20–25% of infants of pre-gestational diabetics. It is thought to be due to the haemolysis of excessive red cells that result from the polycythaemia associated with the diabetic pregnancy.25 Respiratory distress syndrome (RDS) is closely related to both the tightness of maternal glycaemic control and prematurity. Improvements in management of the maternal diabetes and the avoidance of iatrogenic premature delivery plus the administration of corticosteroids to stimulate surfactant production has resulted in a 10-fold fall in RDS from 31 to 3%.25 Ventricular septal hypertrophy is more common in macrosomic infants (8.3% versus 1.8%) and again the overall incidence is reduced by tight maternal glucose control.25

Influence of pregnancy on severity of the disease/disorder The interaction between the complex metabolic and pathological complications of diabetes mellitus and pregnancy per se is complex and debated.

Progressive increase in insulin requirements With the increasing insulin resistance of pregnancy, insulin requirements average 0.7 units/kg/day for weeks 5–12, 0.8 for weeks 12–26, 0.9 for weeks 26–36 and 1.0 for weeks 36–40. There are reports of falling requirements late in the first trimester but this is probably due to overinsulinisation.27 Falling requirements for insulin late in pregnancy have been attributed to a “failing pregnancy”, however, Steel et al showed that in those women experiencing a fall of >30% in 1 week in late pregnancy, there was no association with fetal outcome, only with the duration of the maternal diabetes.28

Early hypoglycaemia and awareness of hypoglycaemia During pregnancy in women with type 1 diabetes, the counter regulatory mechanisms associated with hypoglycaemia are further impaired so hypoglycaemia is a common complication. Rosenn et al found that the peak incidence of significant hypoglycaemia that required assistance from another person was between 10 and 15 weeks and that overall 71% were affected.29 Women who use insulin pumps have been reported to have a reduced incidence of hypoglycaemic episodes.30

Microvascular complications of diabetes

Nephropathy A review of the current literature summarised by Rosen and Miodovnik concludes that pregnancy is not associated with the development of diabetic nephropathy or with acceleration of existing nephropathy. However, in women with advance renal disease, pregnancy may hasten progression to end stage renal disease.32

Summary of preconception advice Management of glycaemic control The current recommendations from the American Diabetes Association are that haemoglobin A1C (HbA1C) levels should be as close to normal as possible (<7%) before conception is attempted.33 There is evidence that there is further benefit from maintaining the HbA1C within the normal reference range and the Australasian Diabetes in Pregnancy Society recommends that this should be the target.34

Oral agents There has been considerable debate in the medical literature about the use of oral hypoglycaemic agents in pregnancy. The first concern has been about potential teratogenicity. A meta-analysis of oral agents concluded that they did not pose a risk to the developing fetus.35 Two agents have been subjected to clinical trials in later pregnancy. Both glyburide (also known as glibenclamide and glybenzcyclamide)36 and metformin37 were both found to be effective treatments for the majority of women with gestational diabetes. However, there are limited data available about their possible long-term effects on the fetus, so caution is still counselled until this aspect of their safety is determined.34 Women taking oral agents should preferably be changed over to insulin before conception so that they can achieve optimal glycaemic control before the fetus is exposed to the proven teratogenic effects of hyperglycaemia.

Insulin analogues Lispro and aspart have not been shown to be associated with fetal malformations or other adverse effects during pregnancy and are widely used in clinical practice.38,39 There are theoretical toxicological implications of glargine’s effect on increasing insulin-like growth factor (IGF)-1 receptor activity and mitogenic potencies and, consequently, current consensus would caution against its use in pregnancy.39

Retinopathy Abrupt institution of tight glycaemic control in poorly controlled diabetes can lead to worsening of existing retinopathy, however, the majority of studies including Rosenn et al suggest that the retinopathy regresses postpartum.31

Other medications Antihypertensive medication Angiotensin-converting enzyme (ACE) inhibitors in the first trimester have been linked to an increased

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risk of major congenital malformations (RR 2.71, 95% CI 1.72–4.27). These malformations were cardiovascular (RR 3.72; 95% CI 1.89–7.30) and central nervous system (RR 4.39, 95% CI 1.37–14.02).40 Later in pregnancy ACE inhibitors are associated with fetal growth restriction and renal failure.41,42 For similar theoretical reasons angiotensin 2 receptor blockers (ARB) should also be avoided.

Lipid lowering agents Lipophilic statins – cerivastatin, simvastatin, lovastatin and atorvastatin – readily cross the placenta and have been associated with skeletal and central nervous malformations. Although there are no reports of malformations associated with the hydrophilic statin, pravastatin, in either human or animal studies,43 data are limited and therefore all statins should be ceased in women who are planning to conceive.

Table 9.2

103

Obstetric risks associated with maternal obesity.

Early gestation Miscarriage Malformations neural tube defects spina bifida heart defects omphalocele

OR 1.2, 95% CI 1.01–1.46 OR 1.8, 95% CI 1.1–3.0 OR 2.6, 95% CI 1.5–4.5 OR 1.18, 95% CI 1.09–1.27 OR 3.3, 95% CI 1.0–10.3

Late gestation Gestational hypertension 2.5 times greater risk Pre-eclampsia 10.8% compared with normal weight 8.2% Intrauterine fetal death 28–36 weeks 37–39 weeks ≥40 weeks

HR 2.1, 95% CI 1.0–4.4 HR 3.5, 95% CI 1.9–6.4 HR 4.6, 95% CI 1.6–13.4

Peripartum Caesarean delivery

Folic acid The recommended dose of folic acid to prevent neural tube defects is 5 mg in women with diabetes.34

BMI ≤29.9 BMI 30–34.9 BMI 35–39.9

20.7% 33.8% 47.7%

Operative morbidities anaesthesia complications

Weight control The obstetric risks associated with maternal obesity are summarised in Table 9.2 and are detailed in the review article by Catalano.44 Women who are overweight/obese should be counselled about these risks and the assistance of dietitians, psychologists, etc. with expertise in both weight control and the requirements of pregnancy should be sought. Limited or no weight gain during pregnancy in obese women carries a significant reduction in the risk of pre-eclampsia, Caesarean delivery and large for gestational age infants. Weight loss of 5 kg or more was associated with a modest rise in the incidence of small for gestational age infants of 14% compared with 10% for those whose weights remained static throughout pregnancy.45

postpartum endometritis wound breakdown thromboembolism Fetus/Neonate Macrosomia Fetal obesity Childhood obesity HR, hazard ratio; BMI, body mass index.

Diabetes education Instruction on the self management of diabetes including sick days, expected nausea of pregnancy, hypoglycaemia plus exercise regimens are all important facets of pre-pregnancy care.

Assessment for complications of diabetes

Management of pregnancy

Retinal examination should be conducted by a person skilled in retinal examination. Screening for nephropathy by an overnight or 24 hour urine collection to measure albumin excretion should be undertaken. Evidence of macrovascular disease should be sought by history and relevant examination and investigations.33,34 Thyroid function should be checked in women with type 1 diabetes as coexisting thyroid dysfunction is common and also the presence coeliac disease should be considered.34

The key features are continuation of tight glycaemic control with management by the multidisciplinary team co-ordinated by the diabetes educator and including the dietitian, endocrinologist, obstetrician, midwife and neonatal paediatrician. Early confirmation of a viable pregnancy by ultrasound that in addition establishes an accurate gestational age will assist with management decisions that are gestation-influenced. As for any pregnant woman, screening for chromosome anomalies can be facilitated by first trimester serum screening of pregnancy associated plasma protein-A and human chorionic

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gonadotrophin coupled with a nuchal translucency measurement around 11–13 weeks. Further detailed anomaly screening by ultrasound around 18–20 weeks’ gestation will identify/exclude congenital abnormalities associated with diabetes. Growth assessment again by ultrasound can be performed at indicated intervals, the frequency and timing depending on the presence of any diabetic complications or the emergence of obstetric associated complications such as the hypertensive disorders of pregnancy. Timing and route of delivery will be influenced by the emergence of any particular obstetric complication including abnormal fetal growth. Common practice is to recommend delivery around 38 weeks’ gestation if there is fetal macrosomia, polyhydramnios or poor metabolic control and maternal obesity because of the increased risk of later fetal deaths with these complications. Elective Caesarean section if the estimated fetal weight is in excess of 4–4.25 kg to avoid the risk of shoulder dystocia leading to brachial plexus palsy is also widely recommended. After delivery insulin requirements rapidly return to pre-pregnancy levels so that women with type 2 diabetes previously well controlled on oral agents can return to their previous medication. The infant requires close monitoring particularly for early hypoglycaemia and for the other diabetes related neonatal complications listed above.34

References 1. Mokdad AH, Ford ES, Bowman BA et al. Diabetes trends in the US: 1990–1998. Diabetes Care 2000; 23: 1278–83. 2. Onkamo P, Vaananen S, Karvonen M, Tuomilehto J. Worldwide increase in incidence of type 1 diabetes: the analysis of the data on published incidence trends. Diabetologia 1999; 42: 1395–403. 3. Bell R, Bailey K, Cresswell T et al. Trends in prevalence and outcomes of pregnancy in women with pre-existing type 1 and type 2 diabetes. BJOG 2008; 115: 445–52. 4. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 1723–7. 5. Ogden CL, Flegal KM, Carroll MD, Johnson CL. Prevalence and trends in overweight among US children and adolescents. JAMA 2002; 288: 1728–32. 6. Cameron AJ, Welborn TA, Zimmet PZ et al. Overweight and obesity in Australia: the 1999–2000 Australian Diabetes, Obesity and Lifestyle Study (AusDiab). Med J Aust 2003; 178: 427–32. 7. Kirwan JP, Hauguel-de Mouzon S, Lepercq J et al. TNFα is a predictor of insulin resistance in pregnancy. Diabetes 2002; 51: 2207–13. 8. Steel JM, Parboosingh J, Cole RA, Duncan LJ. Prepregnancy counselling: a logical prelude to the management of the pregnant diabetic. Diabetes Care 1980; 3: 371–3.

9. Fuhrmann K, Reiher H, Semmler K et al. Prevention of congenital malformations in infants of insulindependent diabetic mothers. Diabetes Care 1983; 6: 219–23. 10. Confidential Enquiry into Maternal and Child Health. Diabetes in Pregnancy: Are we Providing the Best Care? Findings of a National Enquiry: England, Wales and Northern Ireland. CEMACH: London, 2007. 11. Metzger BE, Cho NH, Brickman WJ. The rising tide of diabetes mellitus: implications for women of all ages. In: Reece EA, Coustan DR, Gabbe SG, eds. Diabetes in Women Adolescence, Pregnancy and Menopause, 3rd edn. Philadelphia: Lippincott Williams and Wilkins, 2004, 17. 12. Nielsen GL, Nørgard B, Puho E et al. Risk of specific congenital abnormalities in offspring of women with diabetes. Diabetes Med 2005; 22: 693–6. 13. Reece EA, Eriksson UF. Congenital malformations: epidemiology, pathogenesis, and experimental methods of induction and prevention. In Reece EA, Coustan DR, Gabbe SG, eds. Diabetes in Women Adolescence, Pregnancy and Menopause, 3rd edn. Philadelphia: Lippincott Williams and Wilkins, 2004: 170. 14. Mills JL, Simpson JL, Driscoll SG et al. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med 1988; 319: 1617–23. 15. Dicker D, Goldman J, Yeshaya A et al. Umbilical artery flow velocity waveforms in diabetic pregnancies. J Perinat Med 1990; 18: 391–5. 16. Naeye RL. Infants of diabetic mothers: a quantitative morphological study. Pediatrics 1965; 35: 980–8. 17. Silverman BL, Rizzo TA, Cho NH, Metzger BE. Long-term effects of the intrauterine environment. The Northwestern University Diabetes in Pregnancy Centre. Diabetes Care 1998; 21 (Suppl 2): B142–9. 18. Pettitt DJ, Nelson RG, Saad MF et al. Diabetes and obesity in the offspring of Pima Indian women with diabetes during pregnancy. Diabetes Care 1993; 16: 310–14. 19. McElvy S, DeMarini S, Miodovnik M et al. Fetal weight and progression of diabetic retinopathy. Obstet Gynecol 2001; 97: 587–92. 20. Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic born in California. Am J Obstet Gynecol 1998; 179: 476–80. 21. Langer O, Berkus MD, Huff RW, Samueloff A. Shoulder dystocia: should the fetus weighing ≥ 4,000g be delivered by Cesarean section? Am J Obstet Gynecol 1991; 165: 928–30. 22. Whylie BR, Kong J, Kozak SE et al. Normal perinatal mortality in type1 diabetes mellitus in a series of 300 consecutive pregnancy outcomes. Am J Perinatol 2002; 19: 169–76. 23. McElduff A, Ross GP, Lagstrom JA et al. Pregestational diabetes and pregnancy: an Australian experience. Diabetes Care 2005; 28: 1260–1. 24. Clausen TD, Hellmuth E, Mathiesen E et al. Poor pregnancy outcome in women with type 2 diabetes. Diabetes Care 2005; 28: 323–8.

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The patient with diabetes mellitus 25. Merlob P, Hod M. Short-term implications: the neonate. In Hod, M, Jovanovik L, Di Renzo GC, de Leiva A, Langer O, eds. Textbook of Diabetes and Pregnancy. London: Martin Dunitz, 2003: 289–304. 26. Cordero L, Treuer SH, Landon M, Gabbe S. Management of infants of diabetic mothers. Arch Pediatr Adolesc Med 1998; 152: 249–54. 27. Jovanovik L, Mills JI, Knopp RH et al. Declining insulin requirements in the late first trimester of pregnancy. Diabetes Care 2001; 24: 1130–6. 28. Steel JM, Johnstone FD, Hume R, Mao J-H. Insulin requirements during pregnancy in women with type 1 diabetes. Obstet Gynecol 1994; 83: 253–8. 29. Rosenn B, Miodovnik M, Holcberg G et al. Hypoglycemia: the price of intensive insulin therapy in insulin-dependent diabetes mellitus pregnancies. Obstet Gynecol 1995; 85: 417–22. 30. Gabbe SG, Holing E, Temple P, Brown ZA. Benefits, risks, costs, and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus. Am J Obstet Gynecol 2000; 182: 1283–91. 31. Rosenn B, Miodovnik M, Kranias G et al. Changes in diabetic retinopathy during pregnancy. Am J Obstet Gynecol 1992; 166: 1214–18. 32. Rosenn BM, Miodovnik M. Diabetic vascular complications in pregnancy: nephropathy. In Hod, M, Jovanovik L, Di Renzo GC, de Leiva A, Langer O, eds. Textbook of Diabetes and Pregnancy. London: Martin Dunitz, 2003: 486–94. 33. American Diabetes Association. Clinical practice recommendations 2008. Diabetes Care 2008; 31: S36. 34. McElduff A, Cheung NW, McIntyre HD et al. The Australasian Diabetes in Pregnancy Society consensus guidelines for the management of type 1 and

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44. 45.

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type 2 diabetes in relation to pregnancy. Med J Aust 2005; 183: 373–7. Gutzin SJ, Kozer E, Magee LA. The safety of oral hypoglycaemic agents in the first trimester of pregnancy: a meta-analysis. Can J Clin Pharmacol 2003; 10: 179–83. Langer O, Conway DL, Berkus MD et al. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343: 1134–8. Rowan JA, Hague WM, Gao W et al. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008; 358: 2003–15. Simmons D. The utility and efficacy of the new insulins in the management of diabetes and pregnancy. Curr Diab Rep 2002; 2: 331–6. Hirsch IB. Insulin analogues. N Engl J Med 2005; 352: 174–83. Cooper WO, Hermandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med 2006; 354: 2443–51. Briggs GG. Drug effects on the fetus and breast-fed infant. Clin Obstet Gynecol 2002; 45: 6–21. Tabacova S, Little R, Tsong Y et al. Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmacoepidemiol Drug Saf 2003; 12: 633–46. Edison RJ, Muenke M. Central nervous system and limb anomalies in case reports of first-trimester statin exposure. N Engl J Med 2004; 350: 1579–82. Catalano PM. Management of obesity in pregnancy. Obstet Gynecol 2007; 109: 419–33. Kiel DW, Dodson EA, Artal R et al. Gestational weight gain and pregnancy outcomes in obese women – how much is enough? Obstet Gynecol 2007; 110: 752–8.

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10 The patient with epilepsy John Craig

Epilepsy is defined as the condition, or more accurately the set of conditions, in which individuals have a tendency to recurrent, usually unprovoked epileptic seizures. These can be of many types (Table 10.1), of multiple aetiologies and associated with markedly differing responses to treatment. It is the most common chronic serious neurological disorder and affects four to ten out of every 1000 people, in the developed world.1 Although the fundamental principles of managing women and men with epilepsy are similar, epilepsy can have special implications for women. While women with epilepsy have particular considerations, which differ throughout their lives, and which must be taken account of if their care is to be optimised, it is usually when a woman with epilepsy becomes of childbearing age and, in particular, when she is contemplating pregnancy that the differences between managing men and women with epilepsy become most obvious. Since women with epilepsy of childbearing age account for about 25% of people with epilepsy and it has been estimated that up to three to four pregnancies in every thousand occur in women with active epilepsy,2,3 and it is recognised that women with epilepsy are a high-risk group in pregnancy, it is of concern that recent surveys have shown that the care of women with epilepsy is less than ideal,4 with specialists caring for them not always being informed of the important issues.5,6

Table 10.1

Classification of seizures.

Partial (focal onset) seizures Simple partial seizures (consciousness preserved) Complex partial seizures Partial seizures evolving to secondarily generalised seizures Generalised seizures Absence seizures (typical, atypical) Myoclonic seizures Clonic seizures Tonic seizures Tonic–clonic seizures Atonic (astatic) seizures

Table 10.2 Areas for consideration for women with epilepsy of childbearing age.

Effects of AEDs on appearance Effect of female hormones on seizure control Effects of epilepsy and seizures and AEDs on fertility Effects of AEDs on contraception and vice versa Effects of epilepsy and AEDs on pregnancy Effects of pregnancy on AEDs and seizure control Effects of epilepsy and in particular seizures on the developing embryo/foetus Effects of AEDs on the developing embryo/fetus AED, antiepileptic drug.

There are many areas that need to be considered when caring for women with epilepsy of childbearing age (Table 10.2). These include the potential effects of antiepileptic drugs (AEDs) on appearance, of female hormones on seizure control, of epilepsy and seizures and AEDs on fertility, and of AEDs on contraception and vice versa. The effects of epilepsy and AEDs on pregnancy, of pregnancy on AEDs and seizure control, of epilepsy and in particular seizures on the developing embryo/foetus, and of AEDs on the developing embryo/foetus are also considered in this chapter.

Influence of epilepsy and seizures and antiepileptic drugs on pregnancy outcome The effects on pregnancy Data on whether women with epilepsy are at increased risk of obstetric complications are conflicting. Complications that have been reported as being increased compared with control mothers are vaginal bleeding, spontaneous abortion, pre-eclampsia and premature or prolonged labour.7 A higher frequency of labour induction and artificial labour have also been reported,8 but whether this is due to a greater frequency of medical indications or to increased concern on the part of obstetricians or the mothers is uncertain.9 The adverse outcomes most consistently reported as

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being increased are stillbirth and neonatal death,10,11 although there is some evidence that rates of the latter have been improving.12 The confidential enquiries into maternal deaths in the UK, covering the period from 1985 to 1999 (in which epilepsy is classified as an indirect cause of death) has identified that epilepsy is over-represented with over a ten-fold increased risk compared with what might be expected considering the prevalence of epilepsy. The reasons for the increased risk are unknown. It has been recommended from these reports that there is a need for regular review of epilepsy control and optimisation of treatment prior to and during pregnancy.

The effects on the developing embryo/foetus The effects of seizures The foetus seems relatively resistant to the effects of seizures, although anecdotal evidence suggests that tonic–clonic seizures may cause foetal bradycardia13 or miscarriage. There is no evidence that simple partial, complex partial, absence or myoclonic seizures are harmful to the foetus.14 Likewise, prospective studies have not shown an association between tonic–clonic seizures and malformations.15,16 Nevertheless, the risk of seizure recurrence, injury, status epilepticus or even death needs to be considered. Status epilepticus in pregnancy has been felt to be particularly dangerous to both mother and baby. This was highlighted by Teramo and Hiilesmaa who compiled 29 cases from the literature, finding that nine of the mothers and 14 of the foetuses died.17 In contrast, in a prospective study of seizure control during pregnancy, the EURAP study group did not find such an effect. Out of 1956 pregnancies there were 36 cases (1.8%) cases of status epilepticus, of which one-third were convulsive in type.18 Overall, there was one stillbirth which occurred around the time of status epilepticus, one spontaneous abortion occurring long after the period of status epilepticus and no cases of maternal mortality.

The effects of antiepileptic drugs (Table 10.3) There is some evidence from human pregnancies, albeit largely indirect, that AEDs can have an effect on foetal and embryonic development. For example, it is a consistent finding that women with epilepsy who are not on AEDs have a lower risk of having a child with a major congenital malformation (MCM) than those who are taking AEDs.19 However, whether the two groups are directly comparable is controversial, as women reported as having epilepsy, but who do not require AEDs usually either have very mild epilepsy or epilepsy in remission. It has also been consistently reported that women who take more than one AED are more at risk than those who take a single AED.20–22 Again this could be argued as simply being a reflection of the severity of the epilepsy. Finally, animal studies

Table 10.3 Antiepileptic drugs (AEDs) available in UK with years of registration. Newer AEDs are shown in bold.

Phenobarbitone Phenytoin Primidone Ethosuximide Carbamazepine Na valproate Vigabatrin Lamotrigine Gabapentin Topiramate Tiagabine Oxcarbazepine Levetiracetam Pregabalin Zonisamide

1912 1938 1952 1960 1962 1973 1989 1991 1993 1995 1998 2000 2000 2004 2005

Table 10.4 Major congenital malformation (MCM) rates for in utero exposure to any antiepileptic drug taken as monotherapy. Exposed n

Samren et al, 199724 1221 Olafsson et al, 19983 266 Canger et al, 199925 444 Kaneko et al, 199926 885 Samren et al, 199919 1441 Holmes et al, 200122 223 Kaaja et al, 200327 740 Morrow et al, 200628 2468

Controls

MCM (%)

n

MCM (%)

9.0 5.9 5.6 9.0 3.7 5.7 3.8 4.2

158 82 483 — 98 2000 508 239 227

8.0 2.2 — 3.1 1.5 1.8 0.8 3.5

have demonstrated teratogenicity with all of the older AEDs.23 It is generally accepted that women with epilepsy who are taking a single AED have at least a two to three times increased risk over the background population of having an infant with a MCM. This is equivalent to a 4–9% chance of a MCM.3,19,22,24–28 (Table 10.4). Since the risk of MCMs seems to be higher for women taking more than one AED, the message is therefore to use one AED whenever possible in this situation.3,19,22,24,26–28 (Table 10.5). With regard to individual AEDs, taken as monotherapy, there is emerging evidence from various quarters that there are differences between AEDs for the risks of MCMs. Information is now also becoming available for the more recently introduced AEDs, with the greatest number of outcomes thus far being reported for lamotrigine.29 However, it is important to stress that the information available for all pregnancy outcomes in women with epilepsy is imperfect. Older studies reporting on the effects of AEDs were often retrospective and hence may contain inherent biases. They were also frequently

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Table 10.5 exposures.

109

Major congenital malformation (MCM) rates for antiepileptic drugs (AEDs) comparing monotherapy and polytherapy

Monotherapy MCM (%)

Polytherapy MCM (%)

Samren et al, 199724 Olafsson et al, 19983 Canger et al, 199925 Kaneko et al, 199926

8.0 3.4 5.7 7.8

Samren et al, 199919

3.3

Holmes et al, 200122 Kaaja et al, 200327

4.5 3.2

Morrow et al, 200628

3.7

9.8 8.7 5.3 9.6 (2 AEDs), 11.5 (3AEDs), 13.5 (4 AEDs), 15.4 (5 AEDs) 4.7 (2 AEDs), 4.4 (3 AEDs), 8.3 (4 + AEDs) 8.6 5.8 (2 AEDs), 8.3 (3 + AEDs) 6.0

Table 10.6

Epilepsy and pregnancy registers.

Registers Pharmaceutical company (e.g. Glaxo Smith Kline, UCB Pharma) National (USA, UK, Australia, Ireland, India) Multinational (EURAP) Potential disadvantages Not randomised No control population Selective reporting Heterogeneous populations Incomplete confounding variables studied Potential advantages Prospective/observational Reflect current practice Broad-based Adequate numbers recruited Homogeneous population

carried out in specialised epilepsy centres, making them poorly generalisable. In an attempt to solve some of the above problems pregnancy registries, sponsored by the pharmaceutical industry or representing outcomes from individual regions or countries or even being internationally based have been formed. (Table 10.6). While collecting information on large numbers of pregnancies exposed to AEDs some of the problems highlighted from older studies are also applicable to registries. However, bearing in mind that information is never likely to be available from randomised controlled trials they offer the best chance of identifying differences between AEDs. Barbiturates (phenobarbital, primidone) and phenytoin have been associated with congenital heart defects and facial clefts.30–32 A few studies have found a positive dose–response relationship for barbiturates.

Phenytoin has also been implicated as causing urogenital defects,30 and dysmorphic facial and other features such as distal phalangeal hypoplasia.33 The North American AED Pregnancy Registry has published data on 146 women who used phenobarbital as monotherapy during the first trimester of pregnancy. The incidence of major birth defects in infants born to the 77 women who were felt to be truly prospective was 6.5%, which was significantly higher than the background rate of 1.62%.34 In a case–control study the rate of MCMs for infants exposed to carbamazepine was approximately twice that in the control group (relative risk 2.24, 95% confidence interval (CI) 1.1–4.56).35 Such an increase was not found by the UK Epilepsy and Pregnancy Register where the MCM rate for 927 pregnancies exposed to carbamazepine as monotherapy was only 2.2%.28 With regard to specific MCMs, carbamazepine has been reported as being associated with neural tube defects, at a rate varying between 0.2% and 1.0%.36 Cardiovascular problems, inguinal hernias, hypospadias and hip dislocations have also been reported.37 There have also been reports of reduced head circumference, weight and length at birth.38,39 Valproate is the AED that has most often been shown to be associated with the highest risk for MCMs. Results from the North American Pregnancy Registry described 16 MCMs among 149 valproateexposed women (MCM rate 10.7%).40 Results from Australia have been even more concerning, with 16.0% of 97 exposed pregnancies having a MCM, although both monotherapy and polytherapy exposures were recorded.41 In a much bigger cohort (762 outcomes) the UK Epilepsy and Pregnancy Register found that valproate had the highest MCM rate for any monotherapy exposure, with 6.2% having a MCM.28 A higher risk for valproate compared with other AEDs was also shown by the Neurodevelopmental Effects of

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Table 10.7

Features of foetal valproate syndrome.

Tall forehead Medial eyebrow deficiency Flat nasal bridge Broad nasal root Long philtrum Long upper lip Thin vermillion border

Antiepileptic Drugs study in which 12 of 69 (17.4%) prospectively recruited pregnancies that had been exposed to valproate had a MCM.42 With regard to specific MCMs, exposure to valproate has been associated with a significantly increased risk for spina bifida aperta (1–2%),43 with the greatest risk seeming to be for those exposed to doses of >1000 mg/day.44 It has also been reported that there is a greater risk of cardiovascular and urogenital malformations, skeletal defects including radial ray aplasia and rib and vertebral anomalies.45 A combination of facial dysmorphic features, which has been called the foetal valproate syndrome,46 and which is felt by some to be distinct from that seen with other AEDs such as phenytoin, has also been described (Table 10.7). However, the dysmorphic features such as epicanthal folds, long philtrum, flat nasal bridge, and hypertelorism occur with other AEDs. More importantly their significance in terms of whether they are markers for other problems including longterm development is unknown. There is evidence of a pharmacogenetic susceptibility to the teratogenic effects of valproate from both human reports47,48 and preclinical studies.49 There is also a suggestion from preclinical studies that for valproate, at least, high peak plasma concentrations are associated with an increased risk of malformations.50 This finding was replicated in the Australian study where the mean daily dose of valproate was higher in those with a MCM. Thus, it has been suggested that a sustained release preparation may be preferable, with the total daily dose being divided into two or three administrations per day. Considering the new AEDs, most human data are available for lamotrigine. Until recently human data have been lacking with only a few case reports51,52 and one case series53 reporting outcomes of pregnancies exposed to lamotrigine. The International Lamotrigine Pregnancy Registry reported the outcomes of 414 first trimester lamotrigine-exposed pregnancies.54 The percentage of major birth defects after exposure to lamotrigine monotherapy was 2.9% (95% CI 1.6–5.1%). For polytherapy containing lamotrigine, the occurrence of birth defects varied according to whether sodium valproate was included in the polytherapy regimen. For combinations containing sodium valproate in addition to lamotrigine (n=88) the rate of major birth defects was 12.5% (95% CI 6.7–21.7%). This compared with a

rate of 2.7% (95% CI 1.0–6.6%) for polytherapy combinations which included lamotrigine but not sodium valproate (n=182). No distinctive pattern of malformations was reported in this study. Data from the UK Epilepsy and Pregnancy Register revealed a similar MCM rate for pregnancies exposed to lamotrigine alone, with 21 of 647 (3.2%) infants having a major MCM. A positive drug response was seen with 5.4% of pregnancies exposed to >200 mg/day of lamotrigine having a MCM.28 Reported data on the other new AEDs are sparse. A report of 55 exposures to oxcarbazepine (35 monotherapy and 20 polytherapy) noted only one MCM.55 Six MCMs from 248 pregnancies (2.4%) exposed solely to oxcarbazepine have also been reported.56 In a postmarketing surveillance study of gabapentin as add-on therapy for 3100 patients in England no congenital abnormalities were seen in the 11 infants born to women who used gabapentin in the first trimester of pregnancy.57 In the tiagabine clinical trials 22 patients who received the drug became pregnant, of whom nine carried to term. In one of these a hip displacement was noted, although this was a breech delivery.58 In a small study of five women who received topiramate during pregnancy and lactation all women had uneventful deliveries and gave birth to healthy children, although one had a premature delivery at 36 weeks’ gestation.59 Two small reports of pregnancies exposed to levetiracetam have not raised any concerns with regard to MCMs, with preliminary experience from the UK Epilepsy and Pregnancy Register finding no MCMs in 39 pregnancies exposed to levetiracetam alone.60 While presenting some concerns, preclinical models are of interest for the more recently introduced AEDs. In these studies, topiramate at high doses was noted to cause limb and digital malformations in mice, rats and rabbits, including right-sided ectrodactyly in rats and rib and vertebral malformations in rabbits. Vigabatrin was also shown to be teratogenic in rabbits, inducing cleft defects.61 Gabapentin was associated with skeletal malformations, including delayed ossification of the calcaneus and hindlimb digits in mice, and incomplete fusion of skull bones and sternabrae in rats. However, the type and incidence of these abnormalities were not felt to be indicative of developmental toxicity.62 Tiagabine, oxcarbazepine and levetiracetam have not been found to be associated with abnormalities in preclinical models studied to date. When considering the effect of AEDs on embryonic and foetal development, most of the emphasis to date has been on the risk of MCMs. However, there is emerging evidence that minor anomalies, learning difficulties and other problems may also be related to AED therapy. It has been found that the children of women with epilepsy, regardless of whether they are taking AEDs, are at increased risk of minor anomalies,63 and specific AED-related foetal syndromes have

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been suggested for most of the older AEDs.33,46,64 The types of abnormalities found have included minor craniofacial and digital anomalies and growth retardation. However, possibly except for valproate,46,65 there is no real convincing evidence that specific syndromes are associated with specific AEDs, hence the term “foetal-AED” syndrome may be more appropriate. Furthermore, it is unclear what is the influence of other variables, such as maternal epilepsy and hereditary factors. Nonetheless, such abnormalities, although undesirable, have usually been felt in themselves to cause little disability. However, whether they are markers for more diffuse problems, in particular cognitive and behavioural upset, is increasingly being questioned. Long-term follow-up studies of children exposed to AEDs in utero have been limited, with a Cochrane review concluding that the majority of studies in this area are of limited quality with there being little evidence overall to implicate one drug over another with respect to a detrimental effect on development.66 While previous studies have shown mean IQ to be significantly lower in the children of women with epilepsy,10,67,68 it is suggested that this is independent of AED exposure. However, a growing number of retrospective and prospective studies have found that developmental delay is more common in children born to mothers or fathers with epilepsy. What the influence of the AEDs is, and whether there are differences between the drugs requires further study. One recent study found that 16% of 224 children who had been exposed to AEDs prenatally had additional educational needs compared with 11% of 176 exposed to no drugs (odds ratio 1.49, 95% CI 0.83–2.67).69 Thirty per cent of those exposed to valproate, and 20% exposed to polytherapy containing valproate, had additional educational needs. This compared with 3.2% and 6.5% exposed to carbamazepine and other monotherapy regimens, respectively. In a more thorough investigation, of partly the same cohort of children, the authors found that verbal IQ was significantly lower in children exposed to valproate monotherapy (mean 83.6, 95% CI 78.2–89.0; n=41) than in unexposed children (90.9, 95% CI 87.2–94.6; n=80) or in children exposed to carbamazepine (94.1, 95% CI 89.6–98.5; n=52) or phenytoin (98.5, 95% CI 90.6–106.4; n=21).70 Multiple regression analysis revealed exposure to valproate, five or more tonic–clonic seizures in pregnancy and low maternal IQ to be associated with lower verbal IQ after adjustment for confounding variables. Doses of valproate over 800 mg/day were associated with lower verbal IQ than were lower doses. There was also a significant negative correlation between dysmorphic features and verbal IQ, with children exposed to valproate most often having moderate to severe facial dysmorphism.70 Other studies have suggested that the problem may not be confined to valproate, with there also being reports of raised rates of developmental delay for

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infants exposed prenatally to carbamazepine of between 8 and 20%.67,71,72 In another study, 24% of AED exposed infants had a developmental disorder compared with 10.5% of non-exposed siblings. Differences were noted between AEDs. However, infants exposed to carbamazepine, phenytoin and valproate had significantly higher rates of developmental delay than infants not exposed to AEDs.73 The situation for the newer AEDs is even less clear with very limited data being available on their influence on cognitive functioning and other aspects of development.

The effects of pregnancy on epilepsy and seizure control Studies documenting the natural history of epilepsy during pregnancy have given a wide range of results. Three prospective studies from the past couple of decades reported an increased seizure frequency in between 0 and 37% of pregnancies. In a more recent study of 93 pregnancies occurring in 70 women with epilepsy, 61% had unaltered, 24% had improved and 15% worsened seizure frequency.74 In this study there did not appear to be a relationship between AED serum level and outcome. It is usually thought that women with well controlled epilepsy are unlikely to experience a significant change in their seizure frequency during pregnancy. This has been confirmed in a recent report in which the outcomes of 1956 prospectively identified cases were studied. Using first trimester seizure control as a reference, seizure control was found to be unchanged throughout pregnancy in 63.6% of cases. Of these, 92.7% were seizure free during the entire pregnancy.18 Poor compliance with AED treatment because of nausea or fear of the potential risks from AEDs to the foetus can result in loss of control.75 Measuring compliance is problematic and monitoring serum levels or self-reporting may not be reliable. A study comparing longer-term AED ingestion, in pregnant and non-pregnant women, using hair samples is therefore of interest. In this study it was shown that AED levels of carbamazepine and lamotrigine varied more often in women who were pregnant, with 15% of the cohort of pregnant women having little or no AED in their proximal compared with distal hair measurements.76 During pregnancy total serum AED levels may fall with less marked reductions in non-protein bound (free) drug concentrations.77,78 Many factors may contribute to this fall including increased metabolism/ excretion, increased plasma volume and reduced protein binding. Total AED concentrations do not predict response during pregnancy and therefore if serum assessments are to be made measurement of the unbound fraction is the method of choice.79 This is especially relevant for those AEDs, such as valproate and phenytoin, that are moderately or highly protein bound.

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Pronounced alterations in the pharmacokinetics of the newer AEDs have also been shown during pregnancy. For lamotrigine, apparent clearance increases steadily throughout pregnancy, peaking at about the 32nd gestational week, when a 330% increase from baseline has been observed.80 The observed fall in lamotrigine levels during pregnancy has been reported as being associated with deterioration in seizure control in small case series.81 Similar results of falling AED levels have also been found for oxcarbazepine and levetiracetam, although the potential effect on seizure control is less clear.

Management of women with epilepsy before, during and after pregnancy The management of pregnant women with epilepsy82 is becoming of increasing importance as the risk factors for adverse outcomes of pregnancy are becoming more clearly delineated. The majority of women with epilepsy will have a normal pregnancy and delivery, an unchanged seizure frequency and over a 90% chance of a healthy baby. However, considering the prevalence of epilepsy, many pregnancies are still at risk for an adverse outcome. Because of this, pregnancies in women with epilepsy are considered high risk and need careful management by both medical and obstetric teams.

Pre-conception Pre-conception counselling should be available to all women with epilepsy contemplating pregnancy. This should start at the time of diagnosis and at subsequent reviews. While it may not always be appropriate to discuss the many relevant issues (for example in paediatric practice) it should certainly be considered in female adolescents with epilepsy, including those whose care is being transferred from a paediatrician to an adult physician. The fact that the relevant issues have been discussed should always be clearly recorded in the notes. Work has shown that women with epilepsy of childbearing age do not always recall being given relevant information, hence the need to repeat this regularly. For example a survey of women showed that only between 38 and 48% recalled being given information on contraception, pre-pregnancy planning, folic acid and teratogenicity.83 Ideally an organised joint obstetric/neurology preconceptual counselling service should be available to allow rapid assessment of women actively contemplating pregnancy and to co-ordinate care during pregnancy. At present, given the numbers of neurologists and other specialists with an interest in epilepsy, this is not always possible. Nevertheless, a reconfiguration of clinics and additional resources to allow for this service should be actively considered. During counselling a re-evaluation of the diagnosis and the need for continued antiepileptic medication

should take place. Consideration should be given to the AED and indeed the dosage of any AED that is prescribed. The risks and benefits of reducing or changing medication should be fully discussed with each individual patient. That the risk of MCMs is at least doubled to trebled (4–9%) in women receiving AEDs, compared with the general population (2–3%), must be discussed. Details of particular malformations, occurring with specific AEDs, with the levels of risk (where known) should also be mentioned. At present, while there are some growing concerns regarding the use of sodium valproate in human pregnancy, there is insufficient evidence to suggest that women contemplating pregnancy who are taking valproate should be routinely switched to an alternative medication, although this may be considered in each individual case. As well as MCMs, the risk of minor anomalies, and cognitive and developmental delay should also be mentioned. The genetics of the seizure disorder may also need to be taken into consideration. For example, for autosomal dominant conditions such as tuberous sclerosis there is a 1:2 risk of a child inheriting the condition. Most of the inheritable syndromes which include epilepsy in their phenotype are autosomal recessive and there is therefore a low risk of children developing the condition. The risk of a child developing epilepsy is dependent on the type of seizure disorder and the number of affected relatives. For primary generalised seizure disorders there is up to a 10% chance of offspring developing epilepsy, but this is increased if both parents have epilepsy or if the child’s siblings develop epilepsy. The risk seems to be lower if only the father has epilepsy compared with if only the mother has epilepsy.84

Contraception (Table 10.8) The AEDs phenobarbitone, primidone, phenytoin, carbamazepine85 and topiramate86 are inducers of the hepatic P-450 microsomal isoenzyme CYP3A4 which is responsible for the metabolism of oestrogens and progestogens. This results in an increased metabolism of the combined oral contraceptive pill (COCP) which may lead to a higher rate of breakthrough bleeding and contraceptive failure. Sodium valproate and the newer AEDs, vigabatrin, gabapentin, tiagabine and levetiracetam do not induce hepatic enzymes and hence do not react with the COCP. Oxcarbazepine is considered a weak enzyme-inducing agent.87 The situation for lamotrigine is less clear. While initially not thought to interfere with the COCP, there is one report in which lamotrigine was associated with a small decrease in the levels of the progestin used, levonorgesterol, with the area under the curve reduced by 19% and maximal concentration by 12%.88 It is recommended that women taking enzymeinducing AEDs increase their ethinyl oestradiol dose from 20–35 µg to 50 µg. If breakthrough bleeding

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Table 10.8 Effect of antiepileptic drugs (AEDs) on hormonal methods of contraception.

AEDs that may interfere with hormonal methods of contraception Enzyme inducing AEDs phenobarbital primidone phenytoin carbamazepine topiramate oxcarbazepine Non-enzyme inducing AEDs lamotrigine AEDs that do not interfere with hormonal methods of contraception Sodium valproate Ethosuximide Clobazam Clonazepam Vigabatrin Gabapentin Tiagabine Levetiracetam Pregabalin Zonisamide

occurs ethinyl oestradiol dosages may need to be increased to 75 or 100 µg or the 50 µg pill may be tricycled (three packets taken continuously, then a 4-day break). Women also need counselling that even on a higher dose COCP, efficacy may be reduced. Breakthrough bleeding occurring in the middle of a cycle of contraceptive use is generally due to a relative oestrogen deficiency and usually taken as a sign of incipient failure of contraception. However, pregnancy rates (approximately 7% per year) still appear to be lower compared with barrier methods which have a failure rate of between 15 and 20%. Levonorgestrol implants have an increased failure rate in women taking enzyme-inducing AEDs,89 and although the data are not available it can only be assumed that the efficacy of progesterone only OCPs is also reduced. Medroxyprogesterone injections may be effective in women with epilepsy, with their elimination being dependent on hepatic blood flow instead of hepatic metabolism, but data proving this are not as yet available. The dose of the morning-after pill should be increased in those on enzyme-inducing drugs, with guidelines suggesting that the dose of levonorgestrel be increased to 1.5 mg and 750 µg 12 hours apart.82 Of note, COCPs can reduce the levels of lamotrigine to a clinically significant level.90

Fertility It has been reported that women with epilepsy have reduced fertility.91,92 The potential reasons for this are

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likely to be complex, and include social and economic factors. It has also been reported that sexual arousal may be reduced in women with epilepsy.93 However, the situation is far from resolved, with other studies showing that when women with epilepsy marry they have near normal fertility.94 It is recognised that there is a high incidence of menstrual disorders among women with epilepsy.95 Over 35% of women with partial seizures of temporal lobe origin had anovulatory cycles when studied over three cycles, compared with 8% of controls.96 Treatment has been tried with progesterone suppositories in the appropriate phase of the menstrual cycle,97 as well as clomiphene98 and medroxyprogesterone,99 with some success. It has been proposed that fertility problems are drug specific, with particular emphasis on valproate. In 1993, Isojarvi et al reported that polycystic ovaries and hyperandrogenism are frequently detected in women on valproate.100 Subsequently they reported that these abnormalities were more common in women on valproate who gained weight,101 especially if this was during pubertal maturation.102 However, their initial study was retrospectively based in a selected population and did not concentrate on clinical endocrine status. More recently, Betts et al have shown that women who had taken valproate for at least 1 year were more likely to have biochemical evidence of hyperandrogenism than those who had taken carbamazepine or lamotrigine.103 However, others have not been able to replicate these results reporting that the occurrence of polycystic ovaries in women taking AEDs is not higher than in the general population.104 The occurrence of polycystic ovarian syndrome (PCOS), which is associated with menstrual disturbance, has also been shown to be similar for women with epilepsy taking either carbamazepine or valproate, and similar to women with epilepsy on no treatment.105 Furthermore, a recent study performed in monkeys did not indicate that exposure to valproate for 12–15 months induced hormonal or morphological ovarian abnormalities or characteristics of PCOS.106 In conclusion, there is no definite evidence to implicate valproate as more likely to reduce fertility than other AEDs,107 but women should be informed about weight gain and its association with PCOS.

Folic acid The prescription of folic acid before conception and at least until the end of the first trimester is recommended in patients taking antiepileptic medication, as it is for all women. This is particularly important as there seems to be good evidence of an increased risk of neural tube defect in children born to mothers taking AEDs, in particular sodium valproate and carbamazepine.36,43,44 Large community-based studies have demonstrated a reduction in the rate of neural tube defects in women taking folic acid pre-conceptually.108–110 It has been

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inferred from this that folic acid will protect women with epilepsy who are also at increased risk of this complication. It should be noted, however, that this has not been studied, never mind proven and the optimum dosage of folic acid remains undetermined. Communitybased studies have used dosages ranging from 0.5 to 4 mg daily, the higher dosage being suggested for women considered at higher risk. It is the higher dosage that is generally recommended in the UK for women with epilepsy (5 mg daily). Some concerns have been raised that folic acid may exacerbate seizures but these fears have generally been thought to be unfounded. There is as yet no direct evidence that folic acid will protect against the neural tube defects seen in association with AEDs. Furthermore, there is some evidence that the neural tube defects which occur in association with sodium valproate are somewhat different from those seen in the general population. They tend to be low lumbar or sacral in site.111 Other abnormalities are less common and the defect may be the result of altered canalisation rather than folding of the developing neural crest. It remains uncertain as to whether folic acid will protect against this form of neural tube defect,112 or other defects associated with AEDs.113

During pregnancy Ideally all pregnancies occurring in women with epilepsy will have been planned, permitting seizure control and medications to have been optimised preconceptionally. For those women presenting with unplanned pregnancies abrupt withdrawal or switching of medications cannot be advised due to the potential risks of breakthrough or uncontrolled seizures to mother and baby. Seizure freedom should be the aim throughout pregnancy. As a means of achieving this, the importance of full compliance with AEDs and the need to promote the best possible general health should be stressed.

Monitoring seizure control in pregnancy There is currently no consensus on how best to monitor AED levels during pregnancy. It has been advocated that a baseline, pre-conception, unbound (free) AED level, repeated at the beginning of each trimester and in the last 4 weeks of pregnancy should be the minimum level of monitoring.114 More frequent measurements will be necessary if seizure control deteriorates, side-effects ensue or compliance is an issue. There is currently, however, no accepted opinion on how to act on changing AED levels throughout pregnancy. While some groups support pre-emptive increases in AED dosages in the context of falling AED levels in an attempt to reduce the risk of breakthrough seizures, others do not support this approach favouring adjustment on clinical grounds only, that is if seizure control deteriorates or side-effects ensue.

Monitoring pregnancy in women with epilepsy Ideally pregnancies in women with epilepsy should be supervised in an obstetric unit, with access to high resolution ultrasound scanning and the full range of prenatal tests, which has access to a physician who has specialist expertise in epilepsy. Where the latter is not available an obstetrician who specialises in medically complicated pregnancies should be identified.

Vitamin K Since 1958 over 40 cases of neonatal bleeding associated with maternal AED treatment have been reported.115 It is felt that this is due to reduced clotting factors, consequent to alterations in vitamin K metabolism, in infants exposed to enzyme inducing AEDs, such as phenytoin, phenobarbitone and carbamazepine. There is evidence that newborn infants who have been exposed to enzyme inducing AEDs in utero may show increased levels of protein induced by vitamin K absence of factor II (PIVKA II), an indirect marker of vitamin K deficiency.116,117 While there is no evidence directly linking this biochemical marker to a clinically increased risk of bleeding in the neonate, its suppression with vitamin K1 supplementation given as 10 mg orally each day from the 36th week of gestation118 has resulted in most guidelines for best practice advocating maternal supplementation with vitamin K1, with all infants also being given 1 mg of vitamin K1 intramuscularly at birth.82,114,119 However, the results from a case–control study did not show that there was an increased risk for bleeding in infants exposed in utero to enzyme inducing AEDs (mainly carbamazepine and phenytoin),120 although it was felt that supplementation might be necessary in selected cases, such as when prematurity was anticipated or the mother-to-be had a history of alcohol abuse. Nevertheless, although the risk of haemorrhagic disease of the newborn is small, UK and other best practice guidelines recommend the prescription of 10–20 mg/ day of vitamin K, to be given orally to women with epilepsy in the last month of pregnancy,82,119 especially if an enzyme inducing AED is being taken. At birth it is also recommended, as is the case for all newborns, that infants receive vitamin K, with 1 mg of vitamin K being given intramuscularly.82,119

Management of labour and puerperium Labour Most women with epilepsy will have a normal uncomplicated vaginal delivery.7 However, in approximately 2–4% seizures do occur during labour or in the following 24 hours, possibly due to the physiological and emotional stresses associated labour.18,121 Tonic–clonic seizures may result in foetal hypoxia and it is therefore generally recommended that delivery takes place in a unit equipped with facilities for maternal and neonatal resuscitation.

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Factors that increase the risk of seizures such as sleep deprivation, pain, over-breathing and emotional distress should be reduced as much as possible and early consideration given for epidural anaesthesia. The analgesic pethidine may have a pro-convulsant effect and is best avoided if possible. AEDs should be continued throughout labour. If necessary, all AEDs can be given by nasogastric tube; phenytoin, sodium valproate, phenobarbitone, levetiracetam, diazepam and clonazepam can be given parenterally and carbamazepine rectally. Seizures in labour should be terminated as soon as possible using intravenous lorazepam or diazepam. For persisting seizures treatment should be for status epilepticus and delivery expedited by whatever means are available. Where there is doubt about whether seizures are due to eclampsia or epilepsy a slow bolus of 4 mg of magnesium sulphate over 3–5 minutes, followed by 1 mg/hour for 24 hours is recommended in addition to intravenous lorazepam or diazepam. If pre-term labour is threatened in a woman taking an enzyme inducing AED (Table 10.8), doubling the dose of corticosteroids, including betamethasone, to reduce the risk of neonatal respiratory distress, given over 48 hours, is generally recommended.122

Puerperium AED levels quickly revert to pre-pregnancy levels after birth.123 Hence, if the dose of an AED has been increased during pregnancy because of falling AED levels it may be useful to measure serum levels during the first month after delivery to predict for toxicity. The decision to reduce the AED dosage if the increase has been made solely because of worsening seizure control during pregnancy should be made on an individual basis. In particular, if the increase has resulted in a sustained improvement in seizure control with no evidence of toxicity the dose should not be changed. Breast feeding is generally to be encouraged and may even have the additional advantage that it ensures the baby is gradually withdrawn from the AED. AEDs are excreted in breast milk at a level inversely proportional to the degree of maternal serum protein binding. Hence, the amount transferred to the infant in breast milk varies substantially between AEDs. In addition, concentrations of AEDs can differ substantially between the start and end of a meal, and between the right and left breast depending on the fat and protein contents of the milk. For some AEDs, such as phenobarbitone and primidone, reduced neonatal serum protein binding and immature elimination mechanisms can also result in drug accumulation. This can result in sedation of the infant and necessitate the discontinuation of breastfeeding. However, for most AED, including phenytoin, carbamazepine and valproate, breast feeding is usually without problems as these drugs are highly protein

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bound and therefore are poorly excreted into breast milk. Information on the concentration in breast milk of the newer AEDs is rather limited as yet.124 Preliminary data indicate that lamotrigine passes into breast milk at 40–45% of the level in plasma, with levels comparable to those seen in patients.52 However, no adverse effects were found. Risk of injury to the infant from maternal seizures largely depends on seizure type and frequency. Any such risk can be minimised if time is allocated to training mothers with epilepsy on safe handling, bathing techniques, feeding, and safe practice around the home. The postnatal check in addition to providing a chance to examine the infant for any abnormalities also offers an opportunity to discuss contraception, the need for planning of future pregnancies, folate requirements and risks associated with AEDs in pregnancy.

References 1. Hauser WA, Annegers JF, Rocca WA. Descriptive epidemiology of epilepsy: contributions of population-based studies from Rochester, Minnesota. Mayo Clin Proc 1996; 71: 576–86. 2. Dansky LV, Finnell RH. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiological and experimental findings spanning three decades; 2: human studies. Reprod Toxicol 1991; 5: 301–35. 3. Olafsson E, Hallgrimsson JT, Hauser WA et al. Pregnancies of women with epilepsy: a populationbased study in Iceland. Epilepsia 1998; 39: 887–92. 4. Fairgrieve SD, Jackson M, Jonas P et al. Populationbased, prospective study of the care of women with epilepsy in pregnancy. BMJ 2000; 321: 674–5. 5. Krauss GL, Brandt J, Campbell M et al. Antiepileptic medication and oral contraceptive interactions: a national survey of obstetricians and neurologists. Neurology 1996; 46: 1534–9. 6. Russell AJ, MacPherson H, Cairnie V, Brodie MJ. The care of pregnant women with epilepsy – a survey of obstetricians in Scotland. Seizure 1996; 5: 271–7. 7. Sabers A. Complications during pregnancy and delivery. In: Tomson T, Gram L, Sillanpaa M, Johannnessen SI, eds. Epilepsy and Pregnancy. Petersfield, UK: Wrightson Biomedical Publishing Ltd, 1997: 105–11. 8. Yerby M, Koepsell T, Daling J. Pregnancy complications and outcomes in a cohort of women with epilepsy. Epilepsia 1985; 26: 631–5. 9. Hiilesmaa VK, Bardy A, Teramo K. Obstetric outcome in women with epilepsy. Am J Obstet Gynecol 1985; 152: 499–504. 10. Nelson KB, Ellenberg JH. Maternal seizure disorder, outcome of pregnancy, and neurologic abnormalities in the children. Neurology 1982; 32: 1247–54. 11. Yerby MS, Cawthorn L. Mortality rates in infants of mothers with epilepsy. Ann Neurol 1994; 36: 330. 12. Martin PJ, Millac PAH. Pregnancy, epilepsy, management and outcome: a 10 year perspective. Seizure 1993; 2: 277–80.

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13. Teramo K, Hiilesmaa V, Bardy A, Saarikoski S. Fetal heart rate during a maternal grandmal epileptic seizure. J Perinat Med 1979; 7: 3–6. 14. Devinsky O, Yerby MS. Women with epilepsy: reproduction and effects of pregnancy on epilepsy. Neurol Clin 1994; 12: 479–95. 15. Gaily E, Granstrom ML, Hiilesmaa V, Bardy A. Minor abnormalities in children of mothers with epilepsy. J Paediatr 1988; 112: 520–9. 16. Steegers-Theunissen RP, Renier WO, Borm GF et al. Factors influencing the risk of abnormal pregnancy outcome in epileptic women: a multi centre prospective study. Epilepsy Res 1994; 18: 261–9. 17. Teramo K, Hiilesmaa V. Pregnancy and fetal complications in epileptic pregnancies. In: Janz D, Dam M, Richens A, Bossi L, Helge H, Schmidt D, eds. Epilepsy, Pregnancy and the Child. New York, USA: Raven Press, 1982: 53–9. 18. The EURAP Study Group. Seizure control and treatment in pregnancy. Observations from the EURAP Epilepsy Pregnancy Registry. Neurology 2006; 66: 354–60. 19. Samren EB, Van Duijn CM, Christiaens L et al. Antiepileptic drug regimes and major congenital abnormalities in the offspring. Ann Neurol 1999; 46: 739–46. 20. Delgado-Escuta AV, Janz D. Consensus guidelines: preconception counselling, management, and care of the pregnant woman with epilepsy. Neurology 1992; 42: 149–60. 21. Janz D. Are antiepileptic drugs harmful when taken during pregnancy? J Perina Med 1994; 22: 367–77. 22. Holmes LB, Harvey EA, Coull BA et al. The teratogenicity of anti convulsant drugs. N Engl J Med 2001; 344: 1132–8. 23. Finnell RH, Dansky LV. Parental epilepsy, anticonvulsant drugs, and reproductive outcome: epidemiologic and experimental findings spanning three decades; 1: animal studies. Reprod Toxicol 1991; 5: 281–99. 24. Samren EB, Van Duijin C, Koch S et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy. Epilepsia 1997; 38: 981–90. 25. Canger R, Battino D, Canevini MP et al. Malformations in offspring of women with epilepsy: a prospective study. Epilepsia 1999; 40: 1231–6. 26. Kaneko S, Battino D, Andermann E et al. Congenital malformations due to antiepileptic drugs. Epilepsy Res 1999; 33: 145–8. 27. Kaaja E, Kaaja R, Hiilessmaa V. Major malformations in offspring of women with epilepsy. Neurology 2003; 60: 575–9. 28. Morrow J, Russell A, Guthrie E et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193–8. 29. Cunnington M, Tennis P, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee (2005) Lamotrigine and the risk of malformation in pregnancy. Neurology 2005; 64: 955–60.

30. Arpino C, Brescianini S, Robert E et al. Teratogenic effects of antiepileptic drugs: use of an international database on malformations and drug exposure (MADRE). Epilepsia 2000; 41: 1436–43. 31. Anderson RC. Cardiac defects in children of mothers receiving anticonvulsant therapy during pregnancy. J Pediatr 1976; 89: 318–19. 32. Hirschberger M, Kleinberg F. Maternal phenytoin ingestion and congenital abnormalities: report of a case. Am J Dis Child 1975; 129: 984. 33. Hanson JW, Smith DW. The fetal hydantoin syndrome. J Pediatr 1975; 87: 285–90. 34. Holmes LB, Wyszynski DF, Lieberman E, for the AED Pregnancy Registry. The AED (Antiepileptic Drug) Pregnancy Registry: a 6-year experience. Arch Neurol 2004; 61: 673–8. 35. Diav-Citron O, Shechtman S, Arnon J, Ornoy A. Is carbamazepine teratogenic? A prospective controlled study of 210 pregnancies. Neurology 2001; 57: 321–4. 36. Rosa FW. Spina bifida in infants of women treated with carbamazepine during pregnancy. N Engl J Med 1991; 324: 674–7. 37. Granstrom ML, Hiilesmaa VK. Malformations and minor anomalies in children of epileptic mothers: preliminary results of the prospective Helsinki study. In: Janz D, Dam M, Richens A et al, eds. Epilepsy, Pregnancy and the Child. New York, USA: Raven Press, 1992: 251–8. 38. Bertollini R, Kallen B, Mastroiacovo P, Robert. Anticonvulsant drugs in monotherapy. Effect on the fetus. Eur J Epidemiol 1987; 3: 164–71. 39. Hiilesmaa VK, Teramo K, Granstrom ML. Fetal head growth retardation associated with antiepileptic drugs. Lancet 1981; 2: 165–7. 40. Wyszynski D, Nambisan M, Surve T et al. for the Antiepileptic Drug Pregnancy Registry. Increased risk of major malformations in offspring exposed to valproate during pregnancy. Neurology 2005; 64: 961–5. 41. Vajda FJ, O’Brien TJ, Hitshcock A et al. Critical relationship between sodium valproate dose and human teratogenicity: results of the Australian register of anti-epileptic drugs in pregnancy. J Clin Neurosci 2004; 11: 854–8. 42. Meador KJ, Baker GA, Finnell RH et al. In utero antiepileptic drug exposure. Fetal death and malformations. Neurology 2006; 67: 407–12. 43. Omtzigt JG, Los FJ, Grobbee DE et al. The risk of spina bifida aperta after first-trimester exposure to valproate in a prenatal cohort. Neurology 1992; 42: 119–25. 44. Lindhout D, Omtzigt JGC, Cornel MC. Spectrum of neural-tube defects in 34 infants prenatally exposed to antiepileptic drugs. Neurology 1992; 42: 111–18. 45. Koch S, Losche G, Jager-Roman et al. Major birth malformations and antiepileptic drugs. Neurology 1992; 42: 83–8. 46. Diliberti JH, Farndon PA, Dennis NR, Curry CJR. The fetal valproate syndrome. Am J Med Genet 1984; 19: 473–81. 47. Duncan S, Mercho S, Lopes-Cended I et al. Repeated neural tube defects and valproate

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monotherapy suggest a pharmacogenetic abnormality. Epilepsia 2001; 42: 750–3. Malm H, Kajantie E, Kivirikko S et al. Valproate embryopathy in three sets of siblings: further proof of hereditary susceptibility. Neurology 2002; 59: 630–3. Faiella A, Wernig M, Consalez GC et al. A mouse model for valproate teratogenicity: parental effects, homeotic transformations, and altered HOX expression. Hum Mol Genet 2000; 9: 227–36. Nau H. Teratogenic valproic acid concentrations: infusion by implanted minipumps vs conventional injection regimen in the mouse. Toxicol Appl Pharmacol 1985; 80: 243–50. Quattrini A, Ortenza A, Paggi A et al. Lamotrigine and pregnancy. Ital J Neurol Sci 1996; 17: 441. Rambeck B, Kurlemann G, Stodieck SRG et al. Concentrations of lamotrigine in a mother on lamotrigine treatment and her newborn child. Eur J Clin Pharmacol 1997; 51: 481–4. Tomson T, Ohman I, Vitols S. Lamotrigine in pregnancy and lactation: a case report. Epilepsia 1997; 38: 1039–41. Tennis P, Eldridge RR, and the International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia 2002; 43: 1161–7. Meischenguiser R, D’Giano CH, Ferraro SM. Oxcarbazepine in pregnancy: clinical experience in Argentina. Epilepsy Behav 2004; 5: 163–7. Montouris G. Safety of the newer antiepileptic drug oxcarbazepine during pregnancy. Curr Med Res Opin 2005; 21: 693–702. Wilton LV, Shakir S. A post-marketing surveillance study of gabapentin as add-on therapy for 3,100 patients in England. Epilepsia 2002; 43: 951–5. Leppik I, Gram L, Deaton R, Sommerville K. Safety of tiagabine: summary of 53 trials. Epilepsy Res 1999; 33: 235–46. Ohman I, Vitols S, Luef G et al. Topiramate kinetics during delivery, lactation and in the neonate: preliminary observations. Epilepsia 2002; 43: 1157–60. Hunt S, Craig J, Russell A et al. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology 2006; 67: 1876–9. Lindhout D, Omtzigt JGC. Teratogenic effects of antiepileptic drugs: Implications for the management of epilepsy in women of the child bearing age. Epilepsia 1994; 35: 19–28. Petrere JA, Anderson JA. Developmental toxicity studies in mice, rats and rabbits with the anticonvulsant gabapentin. Fundam Appl Toxicol 1994; 23: 585–9. Nulman I, Scolnik D, Chitayat D et al. Findings in children exposed in utero to phenytoin and carbamazepine monotherapy: independent effects of epilepsy and medications. Am J Med Genet 1997; 68: 18–24. Rudd NL, Freedom RM. A possible primidone embryopathy. J Pediatr 1979; 94: 835–7.

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65. Jager-Roman E, Deichl A, Jakob S et al. Fetal growth, major malformations, and minor anomalies in infants born to women receiving valproic acid. J Pedriatr 1986; 108: 997–1004. 66. Adab N, Tudur SC, Vinten J et al. Common antiepileptic drugs in pregnancy in women with epilepsy (Cochrane review). In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, 2003. 67. Gaily E, Kantola-Scorsa E, Granstrom ML. Intelligence of children of epileptic mothers. J Pediatr 1988; 113: 677–84. 68. Scolnik D, Nulman I, Rovet J et al. Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994; 271: 767–70. 69. Adab N, Jacoby A, Smith D, Chadwick D. Additional educational needs in children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2001; 70: 15–21. 70. Adab N, Kini U, Vinten J et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 1575–83. 71. Jones KLJ, Lacro RV, Johnson KA, Adams J. Pattern of malformations in the children of women treated with carbamazepine during pregnancy. N Eng J Med 1989; 320: 1661–6. 72. Ornoy A, Cohen E. Outcome of children born to epileptic mothers treated with carbamazepine during pregnancy. Arch Dis Child 1996; 75: 517–20. 73. Dean JCS, Hailey H, Moore SJ et al. Long term health and neurodevelopment in children exposed to antiepileptic drugs before birth. J Med Genet 2002; 39: 251–9. 74. Tomson T, Lindbom U, Ekqvist B, Sundqvist A. Epilepsy and pregnancy: a prospective study of seizure control in relation to free and total plasma concentrations of carbamazepine and phenytoin. Epilepsia 1994; 35: 122–30. 75. Schmidt D, Canger R, Avanzini G et al. Change of seizure frequency in pregnant epileptic women. J Neurol Neurosurg Psychiatry 1983; 46: 751–5. 76. Williams J, Myson V, Sterard S et al. Self-discontinuation of antiepileptic medication in pregnancy: detection by hair analysis. Epilepsia 2002; 43: 824– 31. 77. Perucca E, Crema A. Plasma protein binding of drugs in pregnancy. Clin Pharmacokinet 1982; 7: 336–52. 78. Lander CM, Eadie MJ. Plasma antiepileptic drug concentrations during pregnancy. Epilepsia 1991; 32: 257–66. 79. Yerby MS, Friel PN, McCormack K. Antiepileptic drug disposition during pregnancy. Neurology 1992; 42: 12–16. 80. Pennell PB, Newport DJ, Stowe ZN et al. The impact of pregnancy and childbirth on the metabolism of lamotrigine. Neurology 2004; 62: 292–5. 81. Petrenaite V, Sabers A, Hansen-Schwartz J. Individual changes in lamotrigine plasma concentrations during pregnancy. Epilepsy Res 2005; 65: 185–8. 82. Scottish Intercollegiate Guidelines Network. Diagnosis and Management of Epilepsy in Adults.

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Textbook of Periconceptional Medicine A National Clinical Guideline, Edinburgh: Royal College of Physicians 2003. Bell GS, Nashef L, Kendall et al. Information recalled by women taking anti-epileptic drugs for epilepsy: a questionnaire study. Epilepsy Res 2002; 52: 139–46. Shorvon S. The classical genetics of the epilepsies. In: Hopkins A, Shorvon S, Cascino G, eds. Epilepsy, 2nd edn. London: Chapman & Hall, 1995: 87–92. Coulam BB, Annegers JF. Do anticonvulsants reduce the efficacy of oral contraceptives? Epilepsia 1979; 20: 519–26. Rosenfeld WE, Doose DR, Walker SA et al. Effects of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia 1997; 38: 317–23. Baruzzi A, Albani R, Riva R. Oxcarbazepine: pharmacokinetic interactions and their clinical relevance. Epilepsia 1994; 35(Suppl 3): S14–19. Sidhu J, Bulsara S, Job S et al. A bidirectional pharmacokinetic interaction study of lamotrigine and the combined oral contraceptive pill in healthy subjects. Epilepsia 2004; 45(Suppl 4): 330. Haukkamaa M. Contraception by Norplant subdermal capsules is not reliable in epileptic patients on anticonvulsant therapy. Contraception 1986; 33: 559–65. Sabers A, Bucholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res 2001; 47: 151–4. Dansky LV, Andermann E, Andermann F. Marriage and fertility in epileptic patients. Epilepsia 1980; 21: 261–71. Olafsson E, Hauser WA, Gudmundsson G. Fertility in patients with epilepsy: a population-based study. Neurology 1998; 51: 71–3. Morrell MJ, Guldner GT. Self-reported sexual function and sexual arousability in women with epilepsy. Epilepsia 1996; 37: 1204–10. Jalava M, Sillanpaa M. Reproductive activity and offspring health of young adults with childhoodonset epilepsy: a controlled study. Epilepsia 1997; 38: 532–40. Herzog AG, Seibel MM, Schomer DL et al. Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol 1986; 43: 341–5. Cummings LN, Giudice L, Morrell MJ. Ovulatory function in epilepsy. Epilepsia 1995; 36: 353–7. Herzog AG. Intermittent progesterone therapy and frequency of complex partial seizures in women with menstrual disorders. Neurology 1986; 36: 1607–10. Herzog AG. Clomiphene therapy in epileptic women with menstrual disorders. Neurology 1988; 38: 432–4. Mattson RH, Cramer JA, Caldwell BV et al. Treatment of seizures with medroxyprogesterone acetate: preliminary report. Neurology (Cleveland) 1984; 34: 1255–8. Isojarvi JI, Laatikainen TJ, Pakarinen AJ et al. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993; 329: 1383–8.

101. Isojarvi JI, Laatikainen TJ, Knip M et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol 1996; 39: 579–84. 102. Vainionpaa LK, Rattya J, Knip M et al. Valproateinduced hyperandrogenism during pubertal maturation in girls with epilepsy. Ann Neurol 1999; 45: 444–50. 103. Betts T, Yarrow H, Dutton N et al. A study of anticonvulsant medication on ovarian function in a group of women with epilepsy who have only ever taken one anticonvulsant compared with a group of women without epilepsy. Seizure 2003; 12: 323–9. 104. Murialdo G, Galimberti CA, Magri F et al. Menstrual cycle and ovary alterations in women with epilepsy on antiepileptic therapy. J Endocrinol Invest 1997; 20: 519–26. 105. Bauer J, Jarred A, Klingmuller D, Elger CE. Polycystic ovary syndrome in patients with focal epilepsy: a study in 93 women. Epilepsy Res 2000; 41: 163–7. 106. Ferin M, Morrell M, Xiao E et al. Endocrine and metabolic responses to long-term monotherapy with the antiepileptic drug valproate in the normally cycling rhesus monkey. J Clin Endocrinol Metab 2003; 88: 2908–15. 107. Genton P, Bauer J, Duncan S et al. On the association between valproate and polycystic ovary syndrome. Epilepsia 2001; 42: 295–304. 108. Medical Research Council Research Group (MRC) Vitamin Study Research Group. Prevention of neural-tube defects: results of the Medical research council vitamin study. Lancet 1991; 338: 131–7. 109. Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptual vitamin supplementation. N Engl J Med 1992; 327: 1832–5. 110. Rosenberg IH. Folic acid and neural-tube defects – time for action? N Engl J Med 1992; 327: 1875–6. 111. Van Allen MI, Kalousek DK, Chernoff GF et al. Evidence for multi-site closure of the neural tube in humans. Am J Med Genet 1993; 47: 723–43. 112. Craig J, Morrison P, Morrow J et al. Failure of periconceptual folic acid to prevent a neural tube defect in the offspring of a mother taking sodium valproate. Seizure 1999; 8: 253–4. 113. Hernandez-Diaz S, Werler MM, Walker AM, Mitchell AA. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med 2000; 343: 1608–14. 114. Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: Management issues for women with epilepsy (summary statement). Neurology 1998; 51: 944–8. 115. Laosombat V. Hemorrhagic disease of the newborn after maternal anticonvulsant therapy: a case report and literature review. J Med Assoc Thai 1988; 71: 643–8. 116. Cornelissen M, Steegers-Theunissen R, Kollee L et al. Increased incidence of neonatal vitamin K deficiency resulting from maternal anticonvulsant therapy. Am J Obstet Gynecol 1993; 168: 923–8. 117. Howe AM, Oakes DJ, Woodman PDC, Webster WS. Prothrombin and PIVKA-II levels in cord blood from newborns exposed to anticonvulsants during pregnancy. Epilepsia 1999; 40: 980–4.

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121. Bardy A. Epilepsy and Pregnancy. A Prospective Study of 154 Pregnancies in Epileptic Women. Helsinki, Finland: University of Helsinki, 1982. 122. Patsalos PN, Duncan JS. Antiepileptic drugs. A review of clinically significant drug interactions. Drug Safety 1993; 9: 156–86. 123. Ohman I, Vitols S, Tomson T. Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation. Epilepsia 2000; 41: 709–13. 124. Bar-Oz B, Nulman I, Koren G, Ito S. Anticonvulsants and breast feeding: a critical review. Paediatr Drugs 2000; 2: 113–26.

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11 The patient at risk from thrombosis and bleeding disorders Scott M Nelson, Ian A Greer

Introduction The extremes of the haemostatic response – bleeding and thrombosis – are frequently seen in conjunction with pregnancy and may also complicate assisted conception. In this chapter we discuss in turn the haemostatic changes that occur in conjunction with fertility treatment and pregnancy, the impact of acquired and genetic disorders that may predispose to bleeding or thrombosis, and the clinical impact of these conditions and their suggested management.

coagulants, decreased antithrombin and protein S levels.1–3,8 Notably in women with ovarian hyperstimulation syndrome (OHSS) the coagulation changes are usually more pronounced: higher levels of fibrinogen, von Willebrand factor, D-dimers, thrombin–antithrombin complexes and prothrombin fragment 1 + 2, low levels of prekallikrein and tissue factor inhibitor,4,5,8 with delays to normalisation even in the absence of pregnancy.

Thrombotic disorders Physiological changes in the haemostatic system

Inherited thrombophilias

In preparation for maternal blood loss at the time of delivery, pregnancy is associated with substantive changes in the haemostatic system with increased concentrations of coagulation factors, a reduction in endogenous anticoagulants and suppressed fibrinolytic activity.1 In brief, the concentrations of factors V, VII, VIII, IX, X and XII, and von Willebrand factor increase significantly in pregnancy, accompanied by a pronounced increase in fibrinogen levels which increase up to two-fold from non-pregnant levels.1 Protein C and antithrombin levels remain within the normal non-pregnant range,2,3 but protein S (which exists in plasma in two forms: the functionally active free protein S and protein S complex with C4B-binding protein, which is inactive) levels fall substantially from early in pregnancy in association with an increase in the C4B-binding protein.4,5 At term, 45% of pregnant women have an activated protein C sensitivity ratio below the 95th centile of normal non-pregnant women of similar age.6 In contrast plasma fibrinolytic activity is reduced during pregnancy, remains low during labour and delivery, but it returns to normal shortly after delivery.1 Similar changes in the haemostatic system are also observed in conjunction with controlled ovarian stimulation,7 with increases in several circulating coagulation factors, including factor V, fibrinogen and von Willebrand factor; increased coagulation activation markers, prothrombin fragment 1 + 2 and D-dimers; and impairment of endogenous anti-

Thrombophilic risk factors are common, affecting 15– 25% of Caucasian populations, and many exert their effects by disruption of the endogenous anticoagulant systems – the antithrombin and protein C/protein S system.9 Heritable thrombophilias include deficiencies of the endogenous anticoagulants, antithrombin, protein C and protein S, and genetic mutations in procoagulant factors such as factor V Leiden and prothrombin G20210A, and the thermolabile (C677T) variant of the methylene tetrahydrofolate reductase (MTHFR) gene. Other relatively common thrombophilias with a combination of both heritable and acquired components include elevated factor VIIIc concentrations, hyperhomocysteinaemia and acquired activated protein C resistance. The relative prevalence of these thrombophilias is variable (Table 11.1) and demonstrates significant ethnic variation, e.g. 2–7% of Western European populations are heterozygous for factor V Leiden and prothrombin 20210A but the percentage is only 0.2% for Taiwan Chinese.10–12 Nutritional factors may also interact with the homozygosity for methylene tetrahydrofolate reductase C677T associated with arterial and venous thrombosis only in the presence of concomitant B vitamin deficiency.13 Therefore, although 10% of individuals in Western European populations are homozygous for this genetic variant, they do not appear to be at increased risk of pregnancy-related venous thromboembolism (VTE),13,14 potentially due

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to pregnancy-related physiological reductions in homocysteine levels and/or the effects of folic acid supplementation.15

Acquired thrombophilias Antiphospholipid syndrome,16 the commonest acquired thrombophilia, is associated with an unusually high proportion of pregnancy losses17,18 and an increased risk of recurrent miscarriage.6,19 Despite an updated consensus definition,16,20 the diagnosis is difficult as it is dependent on only one clinical event and only one laboratory marker (Table 11.2) with the latter being poorly standardised, particularly if titres are weak.21,22 Lupus anticoagulant (LAC) is a much better correlate of thromboembolic events and pregnancy morbidity than anticardiolipin or anti-β2-glycoprotein-I (anti-β2-GPI) assays.9,23 This may reflect that, although

Table 11.1 Prevalence rates for thrombophilia in a European population. Thrombophilic defect Factor V Leiden heterozygous Prothrombin G20210A heterozygous Antithrombin deficiency Protein C deficiency Protein S deficiency MTHFR C677T homozygous Antiphospholipid antibodies

Table 11.2

Prevalence (%) 2–7 2 0.25–0.55 0.20–0.33 0.03–0.13 10 1–5

there is overlap of antibody subsets responsible for the LAC effect, these are not the same as those determined by the anticardiolipin assay.10 Discrimination of LAC subsets by characterisation of β2-GPI phospholipid binding11,24 has confirmed that anti-β2-GPI dependent LACs correlate better with thromboembolic events,25 consistent with β2-GPI being the predominant target in the syndrome. Although the more recent consensus definition no longer requires β2-GPI dependency,16,20 thereby reducing specificity by incorporation of nonautoimmune related anticardiolipin antibodies, antiβ2-GPI antibodies were added to the diagnostic criteria.16 Theoretically and indeed practically the direct anti-β2-GPI performs better than the standard anticardiolipin assay.12,26 However, they are not without weaknesses due to artificial cut-off limits, use of bound bovine β2-GPI, differing types of enzyme linked immunosorbent assay (ELISA) plate altering β2-GPI orientation13 and relatively widespread prevalence of low affinity anti-β2-GPI antibodies in the population.14 Despite the limitations of commercially available assays, clearly the detection of antiphospholipid antibodies identifies patient subgroups at risk of thrombosis and pregnancy complications. The relative merits of any individual antiphospholipid antibody are, however, unclear, with a meta-analysis and subsequent studies not demonstrating an association between anticardiolipin antibodies and venous thromboembolism9,15,27,28 despite a positive association with LAC9 and potentially anti-β2GPI.29,30 In contrast a pregnancy-related meta-analysis found a significant association between anticardiolipin

Inclusions criteria* for definitive antiphospholipid syndrome.16

CLINICAL CRITERIA 1.

Vascular thrombosis One or more clinical episodes of arterial, venous, or small vessel thrombosis,† in any tissue or organ. Thrombosis must be confirmed by objective validated criteria (i.e. unequivocal findings of appropriate imaging studies or histopathology). For histopathological confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall

2.

Pregnancy morbidity (a) One or more unexplained deaths of a morphologically normal foetus at or beyond the 10th week of gestation, with normal foetal morphology documented by ultrasound or by direct examination of the foetus, or (b) One or more premature births of a morphologically normal neonate before the 34th week of gestation because of (i) eclampsia or severe pre-eclampsia defined according to standard definitions,‡ or (ii) recognised features of placental insufficiency, or (c) Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded

LABORATORY CRITERIA 1.

Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Haemostasis (Scientific Subcommittee on LAs/phospholipid-dependent antibodies)

2.

Anticardiolipin (aCL) antibody of IgG and/or IgM isotype in serum or plasma, present in medium or high titre (i.e. >40 GPL units or MPL units, or >99th centile), on two or more occasions, at least 12 weeks apart, measured by a standardised ELISA

3.

Anti-β2 glycoprotein-I antibody of IgG and/or IgM isotype in serum or plasma (in titre >99th centile), present on two or more occasions, at least 12 weeks apart, measured by a standardised ELISA, according to recommended procedures.

*Antiphospholipid antibody syndrome is present if at least one of the clinical criteria and one of the laboratory criteria. † Superficial venous thrombosis is not included in the clinical criteria. ‡ Generally accepted features of placental insufficiency include: (i) abnormal or non-reassuring foetal surveillance test(s), e.g. a non-reactive non-stress test, suggestive of foetal hypoxemia, (ii) abnormal Doppler flow velocimetry waveform analysis suggestive of foetal hypoxaemia, e.g. absent end-diastolic flow in the umbilical artery, (iii) oligohydramnios, e.g. an amniotic fluid index of 5 cm or less, or (iv) a postnatal birth weight less than the 10th centile for the gestational age.

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antibodies and both early and late recurrent foetal loss,23 but this was stronger with respect to recurrent foetal loss for LAC. Presence of anti-β2-GPI antibodies is also more strongly associated with foetal loss.31–36 Additional antiphospholipid antibodies including those against Annexin A5 have been described and associated with thrombosis37 and foetal loss.28,31,38 It is clear, however, that in spite of the limited association of any specific antibody that patients testing positive for more than one antibody have a substantive increase in risk of thrombosis30,39 or pregnancy morbidity.35,40

Thrombotic disorders and clinical sequelae Maternal thrombosis Women with thrombophilia are at increased risk of recurrent thromboembolic events during in vitro fertilisation (IVF), pregnancy and the puerperium, with 50% of VTE events during IVF, pregnancy or the puerperium being associated with known thrombophilias. Deficiencies of the naturally occurring anticoagulants are rare but are associated with high recurrence risk of thrombosis: protein C (12–17%), protein S (22–26%) and antithrombin (31–51%). Factor V Leiden and PT20210A, although more prevalent in Western populations (Table 11.1), are associated with a lower risk of recurrent thrombosis (Table 11.3). Notably all thrombophilias can interact with other risk factors to precipitate thrombosis (Table 11.3) and therefore a full risk assessment is required in the context of IVF, pregnancy and the puerperium with the relative risks changing across this period. Overall the incidence of VTE consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE) has been estimated at 0.6–1.3 episodes per 1000 deliveries, that is, 5–10-fold higher than the rate reported for nonpregnant women of reproductive age,41,42 with a mortality rate for PE of 1.2 per 100 000 maternities43,44 making it the leading cause of maternal mortality in developed countries. This pregnancy-related risk can, however, predate conception with controlled ovarian stimulation for IVF associated with a VTE incidence of 0.08–0.11% of treatment cycles.45,46 Notably in the presence of ovarian hyperstimulation syndrome (OHSS), this risk is substantially increased with approximately 1 in 128 women with severe OHSS developing a thromboembolic complication.47,48 The majority of these VTE episodes during pregnancy and ovarian stimulation are DVT rather than PE, with DVT constituting approximately 85% of thrombotic events,42,49–52 as compared to 70% in non-pregnant patients with VTE.53 Although left ilio-femoral VTE is the classical DVT of pregnancy,54 in the context of ovarian stimulation, upper extremity deep venous thrombosis (UEDVT) predominates, potentially reflecting drainage of oestrogen rich abdominal fluid via the thoracic duct into the subclavian and internal

Table 11.3

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Risk factors for venous thromboembolism (VTE).

RISK FACTORS Previous venous or arterial thrombembolism Obesity (body mass index ≥30 kg/m2) Gross varicose veins Previous intravenous drug abuse Prolonged bed rest

Age over 35 years Prolonged travel Dehydration Ovarian hyperstimulation Immobility

Medical conditions such as infections, inflammatory conditions, systemic lupus erythematosus, hyperlipidaemia, sickle cell anaemia, ulcerative colitis, diabetes mellitus, cushing’s syndrome, nephrotic syndrome, malignancy, myeloproliferative disorders and liver disease Inherited thrombophilia∗

Odds ratio (95% confidence Interval) 9.32 (5.44–12.70) 34.40 (9.86–120.05) 4.69† (1.30–16.96) 4.76 (2.15–10.57) 6.80 (2.46–19.77)

Factor V Leiden heterozygous Factor V Leiden homozygous Antithrombin deficiency Protein C deficiency Prothrombin G20210A heterozygous Prothrombin G20210A 26.36 (1.24–559.29) homozygous Family history of VTE in one 2.7 (95% CI 1.8–3.8) or more first degree relatives‡ Acquired thrombophilia: Lupus anticoagulant∗∗ Five associations with odds ratio of 5.7–9.4 and all significant at 95% CI Anticardiolipin antibodies∗∗ Eight associations with deep vein thrombosis were analysed in 4 studies: one had a significant 95% CI but only for IgG anticardiolipin antibody titres exceeding the 95th centile (i.e. 33 GPL units) ∗

Data derived from pregnancy related risk of venous thromboembolism.94 ‡ Antithrombin deficiency OR is a serious underestimate of risk for venous thromboembolism (VTE) given 73% of affected individuals have a VTE (see text for full details). † Data derived from non-pregnant related risk of venous thromboembolism.95 ∗∗ Data derived from non-pregnant related risk of venous thromboembolism.9

jugular veins.55 Furthermore, despite the association with ovarian stimulation, suggesting an immediate increase in VTE risk, the frequency of VTE is equal across the three trimesters,56,57 however, the puerperium is associated with a further four-fold increase in risk with a 35% and 43–60% of DVT and PE events, respectively, occurring postnatally.49–52,56

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Infertility and assisted conception outcomes Despite being largely underpowered, two studies have demonstrated an association between factor V Leiden and unexplained infertility.58 Conversely three studies did not show any alteration in prevalence of heritable thrombophilias in association with unexplained infertility,59–61 suggesting that any potential effect is likely to be small. With respect to implantation failure after assisted reproductive technologies (ART), an increased prevalence of thrombophilias has been observed in women who fail to conceive after three or more embryo transfers.62,63 Although others have not replicated these findings for factor V Leiden,60,64 Azem et al again showed a significantly higher prevalence of heritable thrombophilias in women with four or more failed IVF cycles as compared to spontaneous conceptions (OR 3.6, 95% CI 1.25–10.6), or women who conceived after their first cycle (OR 2.9, 95% CI 1.02–8.4,64 findings replicated by Coulam et al.65 On balance heritable thrombophilia therefore does appear to contribute to repeated ART failure and, although the contribution of any single thrombophilia to implantation failure is likely to be small, it is likely that for any given individual this association will reflect the total number of mutations rather than the involvement of specific genes. The role of antiphospholipid antibodies in contributing to infertility is contentious with no effect reported,66 however, there was significant heterogeneity in the definition of the antiphospholipid antibody positivity within the meta-analysis.66 In addition to these problems with assays, power remains an issue as a single study of 1240 women would be required to definitively address the role of antiphospholipid antibodies with an agreed a priori definition of which antibodies should be tested for and what level corresponds to a positive result.67,68 Consequently, at present routine antiphospholipid antibody evaluation in the general assisted conception population, outwith a large prospective trial, still does not appear to be warranted,69 a view shared by the Practice Committee of the American Society for Reproductive Medicine.70 Although these studies have questioned the role of antiphospholipid antibodies in infertility, they do not address the outcome of assisted conception for women who experience repeated failure or consecutive foetal losses after IVF. Indeed, similar to inherited thrombophilia, it would appear that women who do not achieve pregnancy after three embryo transfers do exhibit an increased prevalence of antiphospholipid antibodies.63,71,72 With respect to pregnancy loss, thrombophilia screening after one IVF related early miscarriage is not supported.73 However, antiphospholipid seropositivity was similar in women with two IVF related early miscarriages compared to women with spontaneous recurrent miscarriage,74 a group with a high risk of recurrence (approximately 90%).75 This may be amenable to therapy,76 and therefore it would seem appropriate that screening is

undertaken after two IVF related early miscarriages, rather than waiting until the usual definition of recurrent miscarriage is achieved.

Foetal loss Hereditary thrombophilia is a relatively common finding in women with early foetal loss, with associations with homozygous factor V Leiden (OR 2.71, 95% CI 1.32–5.58), heterozygous factor V Leiden (OR 1.68, 95% CI 1.09–2.58) and prothrombin heterozygosity (OR 2.49, 95% CI 1.24–5.00).50 Similarly recurrent early foetal loss of three or more successive losses shows a positive association with hereditary thrombophilia: factor V Leiden (OR 1.91, 95% CI 1.01–3.61), prothrombin heterozygosity (OR 2.70, 95% CI 1.37–5.34), anticardiolipin antibodies (OR 5.05, 95% CI 1.82–14.01) and hyperhomocysteinaemia (OR 4.21, 95% CI 1.28– 13.87).50 Notably this association with foetal loss also extended in to the second trimester and was stronger for both factor V Leiden (OR 4.12, 95% CI 1.93–8.81) and prothrombin heterozygosity (OR 8.60, 95% CI 2.18–33.95). In addition to recurrent foetal loss there is now evidence linking thrombophilia to an unexplained first pregnancy loss after 10 weeks of gestation: factor V Leiden (OR 3.46, 95% CI 2.53–4.72) and factor II G20210A (OR 2.60, 95% CI 1.86–3.64).51 As unexplained first pregnancy loss occurred in about 10.9% of gestations, these findings have substantial clinical impact and suggest that all women who have a first unexplained pregnancy loss after 10 weeks of gestation should be screened for thrombophilia.

Pre-eclampsia The widespread vascular damage of pre-eclampsia associated with endothelial dysfunction, enhanced coagulation and fibrin deposition suggests a role for thrombophilia as a potentially modifiable risk factor. Analysis of 25 studies with 11 183 women detailing the risk of thrombophilia and pre-eclampsia, suggests that overall the increase in risk of pre-eclampsia with thrombophilia is modest. Indeed thrombophilia should not be considered an aetiological factor for pre-eclampsia but rather as a contributor to the severity of pre-eclampsia because of an exaggerated effect on the haemostatic system in women with thrombophilia.61,62

Intrauterine growth restriction The association of thrombophilia with intrauterine growth restriction (IUGR) is more controversial, with a number of case–control studies demonstrating an association, while other studies have refuted this occurrence.63–66 Overall these studies suggest a general trend of increased IUGR risk in women with thrombophilia,

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and in combination with subgroup analyses, there is a suggestion that this effect would be greatest in women with severe IUGR.

Placental abruption Placental abruption is a devastating clinical condition, affecting 0.5% of gestations and an association with thrombophilia has been suggested by a number of studies,50,69,70 with the strongest association being seen in women who are heterozygous for prothrombin (OR 7.71, 95% CI 3.01–19.76).

Agents for thromboprophylaxis Thromboprophylaxis in pregnancy centres on the use of unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) due to the foetal hazards of coumarins.77 Coumarin embryopathy is characterised by midface hypoplasia, stippled chondral calcification, scoliosis, short proximal limbs and short phalanges, and affects 5% of foetuses exposed to the drug between 6 and 9 weeks’ gestation. Furthermore, the risk of miscarriage and stillbirth are increased with prolonged exposure, with a significant risk of both retroplacental and foetal intracerebral bleeding when used in the third trimester, particularly after 36 weeks’ gestation. In addition coumarin use has been associated with an increase in delayed neurodevelopment independent of the increased risk of haemorrhage in the mother and foetus.78 Neither UFH79 nor LMWH80,81 cross the placenta, as determined by measuring anti-Xa activity in foetal blood, and thus there is no evidence of teratogenesis or risk of foetal haemorrhage. LMWH is now, however, the preferred choice for prevention and treatment of VTE in pregnancy as it has an enhanced ratio of anti-Xa (antithrombotic) to anti-IIa (anticoagulant), resulting in a reduced risk of bleeding; stable and predictable pharmacokinetics with increased bioavailability and half-life, allowing less frequent fixed or weight based dosing without the need for monitoring; subcutaneous administration; less activation of platelets, with less binding to platelet factor 4 substantially reducing the risk of heparin-induced thrombocytopenia (HIT).82 Furthermore, a major concern with the widespread use of UFH in pregnancy has been the 2% risk of symptomatic heparin-induced osteoporotic fracture in pregnancy; in contrast LMWHs have a significantly lower risk.83 With respect to individual preparations most experience is with enoxaparin and dalteparin and, given their accurate safety data, at present these should be the first choice preparations.83 During pregnancy, aspirin can be combined with anticoagulant drugs to minimise pregnancy complications as well as to reduce the risk of thrombosis in high-risk women, e.g. those with mechanical heart valves. Concerns regarding teratogenicity and bleeding in the mother, have been generally unfounded

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with no overall increase in the risk of congenital malformations after first trimester exposure, however, examination of individual anomalies demonstrated a slight increase in risk of gastroschisis.84 In contrast a meta-analysis of second and third trimester exposure of 60–150 mg per day has not reported an increased risk of anomalies, or foetal or maternal bleeding or compromise of ductus arteriosus flow.85 At present the safety of higher doses of aspirin in pregnancy is unknown. The alternative antiplatelet agent, the thienopyridine derivative Clopidogrel, has been studied in rats and rabbits suggesting no foetal toxicity, with safe use in a limited number of pregnancies. In addition to pharmacological strategies, graduated elastic compression stockings are effective for thromboprophylaxis in the non-pregnant population and are also likely to be effective in pregnancy.86 They may act by preventing overdistension of veins, so preventing endothelial damage and exposure of subendothelial collagen. They can therefore be combined safely with pharmacological thromboprophylaxis in both the antenatal period and postnatally. For women with confirmed DVT they can reduce the risk of postthrombotic syndrome if used for up to 2 years after the event.86 It is, however, important that correctly fitted class 2 graduated stockings are used with repeat fittings as pregnancy progresses.86

Management of thrombotic disorders Indications for thromboprophylaxis Since thromboprophylaxis with heparin or warfarin is not without risks and discomfort, assessment of individual risk is warranted. Opinion differs on the optimal approach and given the lack of large randomised studies the authors suggest the strategies outlined in Table 11.4 for thromboprophylaxis and acute management of VTE during IVF, pregnancy and the puerperium; however, specialist advice for individualised management of patients is advisable in many of these situations, with use of weight adjusted regimens recommended. With respect to recurrent pregnancy loss, a systematic review87 and subsequent Cochrane analysis,76 demonstrated for antiphospholipid syndrome that treatment with LMWH or UFH was associated with a 35% reduction in pregnancy loss or premature delivery (RR 0.65, 95% CI 0.49–0.86). This conclusion was despite one study showing no additional benefit of aspirin and LMWH combined, compared with aspirin alone;88 however, this study had limited power to detect a difference because of a high crossover rate with 25% of women not receiving the allocated treatment. Also, definitions of seropositivity have been questioned in two studies,88,89 with criticisms of inclusion of women with relatively low levels of IgG antiphospholipid antibodies.90 On this basis women with thrombophilia and adverse pregnancy outcome

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Table 11.4

Suggested management strategies for various clinical situations.

Clinical situation

Suggested management*

Single previous venous thromboembolism (VTE) (not pregnancy- or ‘pill’ related) associated with a transient risk factor and no additional current risk factors, such as obesity

Surveillance or prophylactic doses of low molecular weight heparin in (LMWH) (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily) ± graduated elastic compression stockings. Discuss decision regarding LMWH with the woman

Single previous idiopathic VTE or single previous VTE with underlying thrombophilia and not on long-term anticoagulant therapy, or single previous VTE and additional current risk factor(s) (e.g. body mass index (BMI) ≥35)

Prophylactic doses of low moleculor weight heporin (LMWH) (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily) commenced in conjunction with controlled ovarian stimulation or positive pregnancy test if spontaneous conception and continued throughout pregnancy ± graduated elastic compression stockings. With antithrombin deficiency there is a strong case for more intense LMWH therapy (e.g. enoxaparin 0.5–1 mg/kg 12 hourly or dalteparin 50–100 IU/kg 12 hourly)

More than one previous episode of VTE, with no thrombophilia and not on long-term anticoagulant therapy

Prophylactic doses of LMWH commenced (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily) and fitted with graduated elastic compression stockings at time of starting controlled ovarian stimulation or positive pregnancy test if spontaneous conception and continued throughout pregnancy

Previous episode(s) of VTE in women receiving long-term anticoagulants (e.g. with underlying thrombophilia)

Switch from oral anticoagulants to LMWH therapy (e.g. enoxaparin 0.5–1 mg/kg 12-hourly or dalteparin 50–100 IU/kg 12 hourly) prior to controlled ovarian stimulation or positive pregnancy test if spontaneous conception and continue throughout pregnancy and fit graduated elastic compression stockings

Thrombophilia (confirmed laboratory abnormality) but no prior VTE

Surveillance or prophylactic LMWH ± graduated elastic compression stockings. The indication for pharmacological prophylaxis in the antenatal period is stronger in antithrombin (AT)-deficient women than the other thrombophilias, in symptomatic family members compared to asymptomatic relatives and also where additional risk factors are present

Risk factors for VTE present prior to controlled ovarian stimulation but no previous VTE or thrombophilia

Carry out risk assessment for VTE. If multiple risk factors present, such as high BMI, immobility and pre-eclampsia, or if single major risk factor present, such as morbid obesity, consider LMWH thromboprophylaxis (e.g. 40 mg enoxaparin or 5000 IU dalteparin but dose may need to be increased with extreme levels of BMI) ± graduated elastic compression stockings

Ovarian hyperstimulation syndrome (OHSS)

Prophylactic doses of LMWH (e.g. 40 mg enoxaparin or 5000 IU dalteparin daily) ± graduated elastic compression stockings. In women who do not conceive, thromboprophylaxis may be discontinued with resolution of OHSS. For women who do conceive continuation until the end of the first trimester, or even longer, depending on the presence of additional risk factors and course of the OHSS

Develops VTE

Therapeutic doses of LMWH (e.g. 1 mg/kg 12 hourly or dalteparin 90 IU/kg 12 hourly) with specialist advice sought for duration of therapy, but usually for at least 6 months with therapeutic or prophylactic treatment continued until at least 6 weeks’ postpartum

†

Day of oocyte retrieval – refrain from administering LMWH for 12 hours prior to oocyte retrieval if prophylactic dose and 24 hours if on therapeutic dose. Both regimens can be restarted 3 hours after oocyte retrieval. Antenatal prophylactic and therapeutic doses of LMWH: Prophylaxis Normal body weight (50–90 kg): Enoxaparin 40 mg/daily Dalteparin 5000 IU daily Tinzaparin 4500 IU daily Body weight <50 kg: Enoxaparin 20 mg/daily Dalteparin 2500 IU daily Tinzaparin 3500 IU daily Body weight >90 kg: Enoxaparin 40 mg/12 hourly Dalteparin 5000 IU 12 hourly Tinzaparin 4500 12 hourly Therapy Therapeutic dose: Enoxaparin 1mg/kg 12 hourly Dalteparin 90 IU/kg 12 hourly Tinzaparin 90 IU/kg 12 hourly

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have been widely prescribed LMWH and low dose aspirin throughout the pregnancy with it becoming standard therapy. For women with antiphospholipid antibodies undergoing assisted conception, there are only a few studies examining the role of heparin; however, collectively these data suggest that for women with either definitive antiphospholipid syndrome8 or repeated implantation failure and antiphospholipid seropositivity, LMWH and aspirin should be commenced in conjunction with ovarian stimulation and continued throughout pregnancy. For women who are seropositive for one antiphospholipid antibody undergoing their first cycle of ART, treatment with LMWH or aspirin would not be appropriate given the current lack of evidence and wide prevalence of antiphospholipid antibodies in infertility and general populations. In contrast, if multiple antiphospholipid antibodies have been detected, given the strong association with VTE30,39 and pregnancy morbidity,35,40 pragmatic treatment with LMWH and aspirin would be appropriate, accepting the current lack of trials in this area. For women with heritable thrombophilia only two randomised trials have been published,91 with again the treatment of LMWH and aspirin being associated with an improvement in outcomes.

Prepregnancy management Women with a history of thrombosis, recurrent miscarriage, intrauterine foetal death, or severe early onset preeclampsia or IUGR should be screened for the presence of thrombophilias. Notably, however, only a limited number of thrombophilias are routinely tested for and therefore a negative thrombophilia screen means that the common thrombophilias were not detected. However, for patients experiencing thrombosis an undetected thrombophilia is still likely given the multifactorial nature of thrombosis. In addition to testing, a detailed history of the circumstances of the foetal loss is essential to exclude other causes of late miscarriage including cervical incompetence or premature labour. Consideration for the timing of the pregnancy must also be given and, although many of the described risk factors (Table 11.3) are not modifiable prepregnancy, the prothrombotic factors associated with obesity have been shown to improve with weight loss potentially reducing VTE risk.92 Similarly stabilisation of medical conditions may also potentially improve thrombotic risk prior to embarking on pregnancy. Women on long-term anticoagulant therapy (warfarin) need to be aware that they will require to be switched to LMWH before 6 weeks’ gestation to avoid the risks of coumarin embryopathy. For women undergoing IVF on long-term anticoagulation, this switch can be done prior to ovarian stimulation with a target anti-Xa of 0.7–1.0, with the last LMWH injection taken 24 hours prior to oocyte retrieval and then recommenced in the evening after completion of oocyte retrieval.

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Antenatal management For women with thrombophilias receiving long-term LMWH, unless there has been a history of UFH exposure, a platelet count 1 week after starting LMWH is not required. Similarly, unless there is a history of recurrent events monitoring of doses is not required, with weight adjusted doses being adequate. For women with a history of antiphospholipid syndrome care should be multidisciplinary, given the risk of obstetric complications and thrombosis, and must be undertaken in centres with expertise in management.

Management of anticoagulation at the time of delivery Women on thromboprophylaxis doses should be instructed to stop their LMWH on the first signs of labour as the use of regional anaesthetics is contraindicated within 12 hours of prophylactic heparin and 24 hours after the last dose if on therapeutic anticoagulation. This time period was based on a Food and Drug Administration (FDA) warning of an increased risk of epidural haematoma in a study of enoxaparin 30 mg twice a day in elderly women undergoing orthopaedic surgery; however, over 10 000 cases of LMWH with prophylactic doses with regional anaesthetics have been reported without incident. Consequently, for women on therapeutic anticoagulation, induction of labour facilitates accurate timing of events and minimisation of the risk of labour/anaesthesia on full anticoagulation, and we generally recommend induction of labour at 38–39 weeks. The dose of enoxaparin should be reduced to 40 mg once daily (thromboprophylactic single dose) on the day prior to induction of labour or, if the thrombosis was recent, a single dose of 1.5 mg/kg in the morning of the day prior to planned induction. After delivery enoxaparin should not be given for at least 3 hours after the epidural catheter has been removed and the cannula should not be removed within 6 hours of the most recent injection. The treatment dose (twice daily administration) should be recommenced immediately following delivery. For patients on concomitant aspirin, this does not require to be stopped prior to delivery. For delivery by elective Caesarean section, the woman should receive either a thromboprophylactic dose of enoxaparin (40 mg once daily) or if the thrombosis was recent a single dose of 1.5 mg/kg in the morning of the day prior to section. On the day of section the morning dose of enoxaparin should be omitted and the operation performed that morning.

Management of anticoagulation in the puerperium Neither heparin nor warfarin are excreted in breast milk and consequently breast feeding is not contraindicated. Importantly thromboprophylaxis should be commenced shortly after delivery with a delay of 3 hours postoperatively with a general anaesthetic, or more than 3 hours postremoval of the epidural

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catheter to minimise the risk of epidural haematoma. This period of risk is maintained until 6 weeks postdelivery and thromboproprophylaxis should be maintained until then. For women who have newly developed a thrombosis during pregnancy therapeutic anticoagulation should be continued for 6 months after the confirmed event, with use of graduated compression stockings for 2 years to minimise the risk of post-thrombotic syndrome.86 Postnatally either warfarin or LMWH can be used, but most women prefer to use LMWH because this is what they are accustomed to and they appreciate the convenience of not having to attend clinics or GP practices to have their international normalised ratio (INR) checked. Alternatively should a patient wish to be commenced or restarted on warfarin, they can be loaded appropriately on day 3 after delivery and the INR checked as per the British Haematology guidelines,93 with subsequent referral for anticoagulant monitoring. In women who have experienced a recurrent event during pregnancy close liaison with haematologists is required as lifelong therapy may be warranted.

Heritable bleeding disorders The most commonly encountered inherited bleeding problems are haemophilia A and B, and von Willebrand disease. Haemophilia A and B are due to deficiencies of coagulation factor VIII and factor IX. Von Willebrand disease is due to a qualitative deficiency of von Willebrand factor. Von Willebrand factor is a glycoprotein with several functions. It carries factor VIII protecting it from proteolytic breakdown in the circulation. It also plays a key role in primary haemostasis where it mediates the adhesion of platelets to the exposed subendothelium at the site of injury and also mediates platelet–platelet adhesion during aggregation.

Haemophilia A and B Haemophilia A and B are X chromosome linked recessive genetic disorders. Males are, therefore, affected by these disorders. The prevalence is of the order of 10–20 per 100 000 males for haemophilia A, which is around four times more common than haemophilia B. As women will usually be heterozygous for this condition they will usually only be carriers, however, there are a variety of situations where a woman can demonstrate a significant bleeding tendency. Rarely the women may be homozygous for a mutation or demonstrate lyonisation with low factor VIII levels or be a haemophilia carrier with Turner’s syndrome. (Lyonisation is the random inactivation of one of the X chromosomes that occurs in all female mammalian cells. If the inactivation process influences the expression of the genes on the normal X chromosome in factor VIII producing cells then low levels of factor VIII can result in the female, who will phenotypically demonstrate a bleeding tendency.) In contrast to

affected males who may have extremely low levels of factor VIII or factor IX, carriers tend to have an intermediate level and usually this is insufficiently low to be associated with spontaneous haemorrhagic problems. Thus, for such women exhibiting a bleeding tendency there is usually extreme lyonisation of the normal chromosome, Turner syndrome where no second X chromosome is present or the common inheritance of another haemorrhagic disorder, most commonly von Willebrand disease. In terms of inheritance therefore 50% of the male offspring of a woman who is a haemophilia carrier will suffer from the disease and 50% of her daughters will be carriers assuming that the woman herself is heterozygous for this condition. It should also be noted that the haemophilias are not due to a single gene disorder but rather a variety of genetic abnormalities or mutations affecting the gene coding for factor VIII or IX. Daughters of men affected by haemophilia A or B will be obligate carriers of the condition. The severity of the condition is based on the level of the particular coagulation factor, factor VIII or IX, found in the circulation and the phenotype correlates well with these levels. For haemophilia A and B, men with coagulation factors less than 0.01 IU/ml are considered severe, between 0.01 and 0.05 IU/ml moderate, and between 0.05 and 0.4 IU/ml mild.96 It is important to understand how the disease is manifest. Affected males have a lifelong haemorrhagic tendency. This is often first diagnosed when minor trauma occurs when the child begins to crawl or walk. Those classified as severe will often have spontaneous bleeding. Those with moderate disease tend to bleed only after minor trauma and those with mild haemophilia tend to have a bleeding problem only associated with major trauma or surgery. In haemophilia the joints are most commonly affected with haemarthroses. An initial bleeding event will often trigger recurrent events in that same joint. Recurrent haemarthroses result in severe arthropathy and disability. The knee is most commonly affected and where recurrent haemarthroses occur with severe arthropathy joint replacement may be required. Other bleeding problems include intramuscular bleeding and subcutaneous bleeding. Severe bleeding can also follow minor surgical procedures, in particular dental extraction. The diagnosis will be made via prolongation in the activated partial thromboplastin time (APTT) and confirmed by specific measurement of factor VIII coagulant (functional assessment) and factor VIII antigen levels to provide a qualitative and quantitative assessment of factor VIII. Haemophilia B will also result in a prolongation of the APTT and will require determination of factor IX activity in the plasma. Treatment of haemophilia requires replacement of the deficient coagulation factor with recombinant or high purity factor VIII or factor IX preparations. Prophylactic therapy with recombinant factor VIII can significantly reduce joint bleeding and damage in affected boys.98

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Management of carriers It is critical that families affected by haemophilia understand the genetic basis of the disease and the pattern of inheritance. Even though not at risk of significant bleeding problems themselves it is usual for carriers to be reviewed at regular intervals by the appropriate haemophilia unit during their reproductive life. This is to allow appropriate counselling, carrier testing when required and preparation for pregnancy including consideration of prenatal or preimplantation diagnosis. When discussing the implications of the disease with carriers it is important to know that within a specific kindred the disease severity stays relatively constant. For example, where a woman’s father has been severely affected, her son, if also affected, is likely to exhibit the severe form of the disease. Usually carrier testing will have taken place through the local haemophilia unit well in advance of any pregnancy. Where women are obligate carriers (daughters of haemophilac men) there is no requirement for specific genetic testing, although this is offered by some centres. This can raise issues such as non-paternity and should be dealt with through the expertise of a haemophilia centre. Carrier status can be more difficult to establish within the extended family. Key information for the potential carriers is to understand whether they have the genetic mutation and also the phenotype for their specific form of haemophilia, and their own level of factor VIII or factor IX. They will require access to genetic counselling services and haematology to allow appropriate testing to occur. It is important to understand that some carriers will have relatively low levels of factor VIII, as discussed above, that would place them in the mild haemophilia category and who may therefore encounter significant bleeding problems in association with trauma or surgical procedures. Clearly good liaison is required between the haemophilia centre and treating doctors in other specialties99 particularly in relation to fertility and pregnancy. For the reproductive medicine specialist and obstetrician, knowledge of carrier status is important as it allows planning for pregnancy and in particular consideration of preimplantation diagnosis or prenatal diagnosis and management of pregnancy and delivery. Clearly such considerations are best dealt with prior to pregnancy and if not already addressed should be undertaken prior to proceeding to fertility treatment or assisted conception therapy. With regard to preimplantation diagnosis it is important to note that not all genetic mutations for haemophilia are identified and it may not be possible to identify the specific mutation within a particular family. In this situation pre-implantation diagnosis would rely on the diagnosis of the embryo to be replaced being female rather than the specific genetic abnormality causing the haemophilia. This information is essential for counselling on preimplantation diagnosis.

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Issues to be addressed in the haemophilia carrier planning pregnancy or assisted reproduction As discussed above, it is important to ensure good liaison between the haemophilia unit caring for the patient and the reproductive medicine specialist or obstetrician. It is usual to ensure that the woman has been immunised against hepatitis B, including whether the specific genetic abnormality can be detected. Interestingly only a minority of carriers of haemophilia opt for invasive prenatal diagnosis.100–102 It is important to consider the woman’s own risk of bleeding in association with pregnancy. It is usual to identify the level of factor VIIIc or factor IXc prior to pregnancy or early in pregnancy and repeat this in the third trimester. Carriers who start pregnancy with a relatively low level of factor VIII or factor IX that would place them in the mild haemophilia category, may increase their levels to the normal range. It is important to note that while this is usual with factor VIII levels in haemophilia A, factor IX tends not to increase substantially in haemophilia B carriers.103 Levels of factor VIII or factor IX above 0.4 IU/ml are considered sufficient to avoid haemorrhagic problems during pregnancy or a vaginal delivery, and a level greater than 0.5 IU/ml is considered to be appropriate for diagnostic procedures such as amniocentesis or chorionic villus sampling and for delivery by Caesarean section and epidural anaesthesia. Carriers who require treatment will usually receive recombinant blood products to avoid the small risk of virus transmission including parvovirus. As an alternative, desmopressin (DDAVP) can be used. It is a synthetic analogue of vasopressin and will increase plasma levels of factor VIIIc and von Willebrand factor in patients with haemophilia and certain types of von Willebrand disease (see below). DDAVP can be given intravenously or by concentrated nasal spray. It is safe in pregnancy but can be associated with fluid retention and hyponatraemia. This agent increases the release of factor VIII and con Willebrand factor from vascular endothelial cells so improving the coagulation status. A DDAVP infusion or intranasal administration can be given before invasive procedures or indeed should a bleeding episode occur. The response to intravenous DDAVP is relatively rapid, increasing factor VIII and von Willebrand factor up to five-fold within 30 minutes. The duration of action is around 6–8 hours. Treatment can be repeated every 12–24 hours but tachyphylaxis can occur with repeated dosing. Speed of onset with intranasal administration is slower than with intravenous administration. It is usual to establish, before pregnancy or fertility treatment, with the haemophilia unit whether the woman responds to DDAVP. Clearly before embarking on procedures such as egg retrieval with ART it is important to ensure that haemostasis will be adequate in carriers of haemophilia A and B as pretreatment with DDAVP or a recombinant factor VIII or factor IX may be required.

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During pregnancy bleeding complications due to haemophilia A or B are unusual. In part this is because of the normalisation of coagulation factor levels as discussed above. The most vulnerable time would be in the first trimester before coagulation factor levels have increased and postpartum as levels may drop relatively rapidly to the prepregnancy level.102,103 It should be emphasised, however, that such problems are essentially limited to those carriers with a phenotype consistent with mild haemophilia. For labour and delivery certain precautions are also required. Prior to labour factor VIII or factor IX levels should be checked to ensure that levels of these coagulation factors are satisfactory for delivery. Discussion with the anaesthetist prior to labour will ensure an appropriate management plan is in place so that there are clear instructions as to whether the patient should receive epidural or spinal anaesthesia which is often possible.102 One of the most important factors to consider is the risk of the foetus being affected and even if female lyonisation, could be exhibited and, therefore, both male and female foetuses may be at risk of bleeding problems. Because of this efforts are made to improve the level of coagulation factors in the neonate. As neonates are vulnerable to vitamin K deficiency some units prescribe vitamin K 20 mg a day to haemophilia carriers in the weeks leading up to delivery in an attempt to maximise foetal coagulation factor production. Delivery options should be discussed and these patients will have a higher Caesarean section rate than the general population: in one recent publication describing the experiences of over 50 carriers between 1995 and 2005 the rate was close to 50%.102 The main concern is foetal intracranial bleeding in the course of delivery. Thus, it is prudent to avoid procedures that may place the foetus at increased risk of bleeding. This will include the use of a foetal scalp electrode and foetal blood sampling, both of which should be avoided. Similarly ventouse and rotational forceps delivery are best avoided. Despite these risks there is no absolute contraindication to vaginal delivery and currently it is not considered that Caesarean section in the foetal interest is mandatory for carriers of haemophilia A or B. Recent guidelines on the management of these patients during pregnancy are available, having been produced by a taskforce of the UK Haemophilia Centre Doctors’ Organisation.104 It is, however, worth noting that around 4% of boys with haemophilia born in countries where there is a good standard of maternal care for haemophilia carriers will suffer an intracranial haemorrhage in the neonatal period.99 Cord blood can be taken at the time of delivery to help assess whether the baby is affected. Vitamin K should be given orally rather than intramuscularly. Vaccines should be subcutaneous and intramuscular injections and heel stabs avoided until the coagulation status of the baby is known. It is essential to liaise with the paediatric haemophilia unit to ensure adequate follow-up occurs.

Following delivery it is usual to aim to maintain maternal factor VIII or factor IX levels above 0.04 IU/ml for at least 3–4 days following vaginal delivery and for 5 days following Caesarean section.

Von Willebrand disease Von Willebrand disease is the most common haemorrhagic disorder. As noted above von Willebrand factor plays a key role in platelet-vessel wall and platelet– platelet interaction. It also prevents the proteolytic breakdown of factor VIIIc in the circulation such that without von Willebrand factor, the half-life of factor VIII in the circulation falls to a few hours. Consequently factor VIII levels in the circulation may be 0.01–0.1 IU/ml. Von Willebrand disease is associated with bleeding consequent upon the reduction of von Willebrand factor (and indirectly the reduction in factor VIII). The frequency has been estimated to be as high as 1–2%105 but there is substantial difficulty in identifying an accurate prevalence as mild cases often remain undiagnosed because subjects are relatively asymptomatic. Von Willebrand disease is an autosomal condition which is usually autosomal dominant but occasionally may be recessive, with the gene on chromosome 12, so both men and women can be affected. Von Willebrand factor is synthesised by both megakaryocytes and endothelial cells. It is a multimeric molecule which undergoes considerable post-translational modification. The clinical manifestations of von Willebrand disease are characterised by a prolonged bleeding time, easy bruising and mucosal bleeding. Women are often affected by heavy menstrual bleeding. There are a variety of subtypes reflecting quantitative or qualitative deficiencies in von Willebrand factor, these are shown in Table 11.5.106–109 Diagnosis will require assessment of coagulation including the APTT and specific measurements of von Willebrand factor antigen and activity assessed using the ristocetin co-factor assay, and also factor VIII coagulant activity. Bleeding time is often performed, but in some forms of von Willebrand disease the bleeding time may be within normal limits. Von Willebrand factor and factor VIII increase in response to oestrogen and will therefore increase during pregnancy. Diagnosis is often problematic in women who may be receiving the oral contraceptive pill and similarly diagnosis is more difficult in pregnancy. Genetic diagnosis requires identification of the mutation directly or indirectly through linkage analysis. With regard to treatment for type 1 von Willebrand disease, infusion of DDAVP will usually provoke a significant response. Type 3 disease, however, will require treatment with von Willebrand factor. In type 2, concentrate containing both factor VIII and von Willebrand factor is usually required, and in type 2b, which is associated with a mild thrombocytopenia, the platelet count may fall in response to the DDAVP and in this situation DDAVP is usually avoided. Patients who do not respond to DDAVP will require

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Table 11.5

131

Classification of von Willebrand disease (vWD).

Type

Description

Treatment

Comment

1

Partial quantitative deficiency of vWF

DDAVP

Most common type accounts for 60–80%. Usually autosomal dominant. Mild/moderate bleeding. vWF increases in pregnancy with reduced bleeding tendency

Decreased platelet-dependent vWF function, with lack of high molecular weight multimers (HMWM) of vWF Increased vWF platelet-dependent vWF function, with lack of HMWM Decreased platelet-dependent vWF function, with normal multimeric structure Decreased vWF affinity for factor VIII

Factor VIII–vWF concentrates

Usually autosomal dominant. Most common form of type 2 vWD

Factor VIII–vWF concentrates

Autosomal dominant. Mild thrombocytopenia, often more marked during pregnancy. DDAVP treatment may worsen thrombocytopenia Autosomal dominant

2 Qualitative deficiency of vWF 2A

2B

2M

2N

3

Complete deficiency of vWF

Factor VIII–vWF concentrates Factor VIII–vWF concentrates, only transient response to DDAVP Factor VIII–vWF concentrates. Usually unresponsive to DDAVP

Autosomal dominant. Phenotype similar to haemophilia A Accounts for 5–10% of cases. Autosomal recessive. Severe bleeding problems – joint, muscle and mucocutaneous bleeding

vWF, von Willebrand factor; DDAVP, desmopression.

treatment with a plasma-derived concentrate containing both factor VIII and von Willebrand factor (see Table 11.5).109 With regard to the prepregnancy and pregnancy management, the principles are similar to haemophilia A: it is critical that appropriate prepregnancy counselling occurs and the woman is aware of the nature of the disease and its inheritance pattern. She should also be informed with regard to the problems that may be encountered during pregnancy, the management of the pregnancy and whether haemostatic treatment may be required for any assisted conception treatment. Just as with haemophilia A, some subtypes of von Willebrand disease show an improvement in von Willebrand factor and bleeding problems in pregnancy and often the times of greatest risk for maternal bleeding are in the first trimester and postpartum. It is important to assess the haemostatic response to pregnancy and check von Willebrand factor levels before pregnancy, in early pregnancy and in the early part of the third trimester to ensure that a satisfactory pregnancy response has been obtained. Where the response is insufficient the patient may need DDAVP or specific treatment with a von Willebrand factor product around the time of delivery. Specifically when levels are greater than 0.4 and 0.5 IU/ml, vaginal delivery and Caesarean section, respectively, are considered safe. An anaesthetic review is useful in the third trimester to plan anaesthesia and analgesic options, and neuraxial anaesthesia is possible where satisfactory levels of von Willebrand factor and

factor VIII are present. Similarly, if an invasive procedure such as amniocentesis or chorionic villous sampling is required a similar target for von Willebrand factor levels would be appropriate. Because of the risk of postpartum haemorrhage, monitoring of levels and where necessary treatment should continue for several days after delivery. Similar precautions to prevent foetal bleeding are required in von Willebrand disease just as in haemophilia A and B. Liaison with the paediatric haematologist is also required to ensure adequate follow-up of the baby.109

Conclusion Thrombotic and haemostatic problems have significant implications for the management of fertility treatment in pregnancy. They raise important issues which ideally must be considered prior to conception to allow adequate time for reflection, appropriate decision-making and the development of a management plan for the pregnancy. These disorders often present considerable challenges to reproductive medicine specialists and obstetricians, and often a multidisciplinary approach will be required. The issues are complex ranging from screening for thrombophilic or heritable haemorrhagic conditions prior to conception to preimplantation diagnosis and the management of thrombotic or haemorrhagic risks around the time of assisted conception through to pregnancy

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outcome and particular problems for the management of delivery and the postpartum period. An awareness of potential issues will usually allow the clinician to seek appropriate advice and so provide the patient with the bespoke information she needs and also to create the best multidisciplinary team to deliver the best care to the patient.

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12 The patient with polycystic ovary syndrome Robert J Norman, Siew Lim

Introduction Polycystic ovary syndrome (PCOS) is the commonest hormone disorder of young women and, therefore, presents frequently in couples seeking to become pregnant either as a contributory factor to infertility problems or as an incidental finding amongst other causes.1,2 PCOS has many consequences for pregnancy, whether natural or assisted and it is essential that the diagnosis is made before a woman seeks to become pregnant. Even if the condition is not present as the syndrome, it is important to determine the ovarian morphology on ultrasound prior to stimulation with gonadotrophins.

Polycystic ovary syndrome as a disease PCOS is a very heterogeneous condition with a multitude of different presentations and combinations of symptoms.2,3 While some women are severely overweight, others can be underweight, and androgenic symptoms can vary considerably between different subjects. Attempts have been made to define PCOS and its diagnosis but these have been very controversial with a strong North Atlantic divide. The so called “National Institutes of Health (NIH) definition” includes irregular anovulatory periods and either hirsutism or a raised testosterone in the peripheral blood.4 It is understood that there should be exclusion of other causes including abnormal thyroid function, high prolactin and abnormal adrenal function. This definition is flawed because measurement of androgens in the clinical setting is extremely difficult with the currently available automated assays and the cardinal characteristic is therefore unreliable.5,6 The Rotterdam definition of PCOS includes the potential role of ultrasound of the ovaries which has become extremely popular in Europe and the rest of the world over the past two decades.7 Under this definition, PCOS is diagnosed on the basis of two or three of the following: (1) Irregular or anovulatory periods; (2) Hirsutism or hyperandrogenism; (3) Polycystic ovaries on ultrasound.

The usual exclusion criteria, as for the NIH, apply. This definition widens the inclusion of subjects with PCOS as more than 20% of normal ovulating women have polycystic ovaries on ultrasound. Assessment of the ovary by ultrasound can be as unreliable and subjective as that of measuring testosterone in the blood and this definition has not received wide acceptance in North America. However, using standardised ultrasound criteria can be very useful.8 Other groups have sought to change the diagnostic criteria by including the Androgen Excess Society criteria for PCOS.9 The presentation of PCOS also varies markedly between different ethnic groups. PCOS is a condition that frequently presents in puberty and has consequences for life.10 There is a much higher prevalence of hyperlipidaemias including raised triglycerides and lower high density lipoprotein (HDL) cholesterol in patients with PCOS.11 Insulin resistance and glucose intolerance are common with a much higher presentation of early onset diabetes mellitus.12–14 Central adiposity is common as many women in the Western world with PCOS are significantly overweight or obese. Inflammatory markers such as C reactive protein and plasminogen activator inhibitor are often raised with evidence of abnormal vascular function and of early artherosclerosis in some women.15–17 From a reproductive point of view, anovulatory infertility is common and necessitates intervention with metformin, clomiphene citrate, aromatase inhibitors, injectable gonadotrophins, laparoscopic ovarian surgery or in vitro fertilisation (IVF).2,18 Accordingly, a higher proportion of women with PCOS undergo some form of infertility treatment which permits the treating doctor an opportunity to give an adequate pre-conceptional assessment. In addition, many women who need IVF for other reasons, such as male infertility, have polycystic ovaries with no other features of PCOS but still suffer some of the consequences of treatment complications, including ovarian hyperstimulation syndrome (OHSS).

Influence of polycystic ovary syndrome on pregnancy outcome Our best knowledge of pregnancy outcome comes from the meta-analysis published by Boomsma et al in

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200619 which analysed a large number of studies in which PCOS pregnancy outcome was described. Out of 525 publications, 15 studies were finally included in the meta-analysis. Conclusions as to the effect of PCOS on pregnancy are as follows:19 (1) Gestational diabetes. Women with PCOS demonstrated a significantly higher chance of developing gestational diabetes. This is an expression of the underlying risk of insulin resistance. Odds ratio 2.94 (1.70–5.08). (2) Pregnancy induced hypertension and pre-eclampsia. There was a significantly higher chance of developing pregnancy induced hypertension, again a possible consequence of hyperinsulinaemia. Odds ratio 3.67 (1.98–6.8). There was also a high chance of developing pre-eclampsia. Odds ratio 3.47 (1.95– 6.17). (3) Lengths of gestation and premature delivery rate. There was a significantly higher chance of delivering prematurely. Odds ratio 1.75 (1.16–2.62). (4) Birth weight, macrosomia and small for gestational age (SGA). Infants from women with PCOS demonstrate a significantly lower neonatal birth weight of around 38.4 g less than that of infants born to women withouot PCOS. When higher quality studies were analysed, this significant difference disappeared. There was no significant increase in the incidence of macrosomia or SGA neonates. (5) Admission to neonatal intensive care (NICU), neonatal malformations and perinatal mortality. Data from women with PCOS demonstrated a significantly higher rate of admission to an NICU. Odds ratio 2.31 (1.25–4.26). There was no evidence for increased neonatal malformations. There was a significantly increased perinatal mortality. PCOS versus controls odds ratio 3.07 (1.03– 9.2). A similar incidence of multiple pregnancies was shown between controls and PCOS. (6) Caesarean section and instrumental vaginal delivery. Women with PCOS demonstrated a higher chance of delivering by caesarean section. Odds ratio 1.56 (1.20–2.02). Higher quality studies did not show this difference. A significant difference was also demonstrated in the chance of delivering by vacuum or forceps. Odds ratio 1.37 (0.80–2.35). These studies did not really compensate for confounding factors such as co-existent obesity because many of the studies do not report body mass index. The increased prevalence for gestational diabetes is not a surprise, given the pre-existing insulin resistance and impaired glucose tolerance that exists in many non-pregnant women with PCOS. The increased prevalence of gestational hypertension may also be related to the insulin resistance that affects vascular function.

In a further meta-analysis by Heijnen et al 2006,20 outcomes of conventional IVF and women with PCOS were studied. IVF is not commonly used in this group of women because of the effective nature of oral and injectable medications for ovulation induction. However, the demand for singleton pregnancies has led to an increased use of IVF as a means of controlling the plurality of pregnancies. As part of the metaanalysis, seven out of 290 initial publications were selected as being suitable for evaluation. The following additional results were found:20 (1) Cancellation rate. PCOS women demonstrated a much higher chance of cycle cancellation (12.8% versus 4.1%). Odds ratio 0.5 (0.2–1.0). (2) Gonadotrophins used. No significant difference was shown in the amount of gonadotrophins used in PCOS versus controls. (3) Duration of stimulation. Stimulation was significantly longer in women with PCOS (1.2 days). (4) Number of oocytes obtained, number of oocytes fertilised. Significantly more oocytes per egg pick-up were obtained in PCOS patients compared with controls but the number of oocytes fertilised did not significantly differ between the two groups. (5) Number of clinical pregnancies. No significant difference was observed for the clinical pregnancy rate per started cycle, the number of live births per started cycle, the clinical pregnancy rate per oocyte retrieval, the clinical pregnancy rate per embryo transfer and the number of miscarriages. (6) Ovarian hyperstimulation after oocyte retrieval. There was inadequate information to assess these data other than to note that in some papers there was a significantly increased incidence of OHSS. Overall these studies indicate that there are significant complications with PCOS pregnancies that impact on metabolic and vascular function. Clearly, adequate assessment pre-pregnancy would alleviate some of these problems. The meta-analyses published do not deal much with multiple pregnancies but it is clearly common in clinical practice for the use of clomiphene citrate and injectable follicle stimulating hormone (FSH) to induce multiple pregnancies. This will significantly impact on perinatal mortality rate, preterm labour rate and admission to neonatal intensive care, which is not reflected in the published meta-analyses.19,20

The effect of pregnancy on the polycystic ovary syndrome disease Pregnancy is a state in which the glucose–insulin axis is significantly stressed and it is not surprising that there is a much higher prevalence of diabetes mellitus

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occurring in gestational conditions associated with PCOS.21,22 Many patients with PCOS have a pre-existing family history of impaired glucose tolerance or noninsulin dependent diabetes and, therefore, are particularly prone to gestational diabetes.23 This condition, clearly, will have an effect on the developing fetus. With respect to the vascular changes that occur in pregnancy with PCOS, gestational hypertension and pre-eclampsia are serious conditions that can lead to a serious impact on mother and baby. Inability to return to pregnancy weight occurs in most women, and in a woman who is already overweight or obese this may have a significant impact. Obesity is associated with increased risk of miscarriage, gestational diabetes, hypertension, congenital abnormalities, difficulties with delivery and postpartum complications. 24–26 The co-existence of obesity and PCOS aggravates these situations. The issue of miscarriage being increased in PCOS is a vexed one and appears to be largely connected to obesity as opposed to the condition of PCOS alone. A study by Wang et al27 on a large number of women with PCOS was unable to show the effect of the condition but did demonstrate the effect of obesity. The effect of being overweight on miscarriage has been shown in a number of studies.28,29

Prenatal advice given to women with polycystic ovary syndrome Initial assessment of PCOS should include an adequate and informed diagnosis. This will indicate to the treating clinician that complications may become more prevalent. It is mandatory that glucose tolerance is assessed. There is little doubt that the optimum test, regardless of weight, is an oral glucose tolerance test with 75 g of glucose and measuring a 2-hour glucose. It has been suggested that a fasting glucose/ insulin ratio or the homeostasis model assessment (HOMA) index is an appropriate alternative,30–33 but these are not of the same diagnostic power as an oral glucose tolerance test.34,35 There would appear to be little value in measuring insulin alone as a measure of insulin resistance. An assessment should be made on fasting cholesterol, triglycerides and HDL cholesterol as part of a pre-pregnancy review together with measurement of testosterone and sex hormone binding globulin. Some women develop fatty liver and liver function tests may become an important component of the initial assessment.36 The valuation of C reactive protein and plasminogen activator inhibitor may give some indication of the inflammatory background to the PCOS. If the woman is not ovulating adequately assessment needs to be made of reproductive hormones and, in particular, seeking to detect whether ovulation is occurring as best judged by appropriately timed serum progesterone results. Assessment of body mass index, weight circumference and blood

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pressure are essential for any woman with PCOS. Cardiac assessment may be necessary for some women. Vaginal ultrasound is often helpful and should be judged against the agreed international criteria for ultrasound diagnosis of polycystic ovaries.8 Endometrial hyperplasia should be excluded and, if present, should be assessed by tissue sampling. Women with PCOS should be advised to contemplate an earlier age of first pregnancy in case any difficulties in fertility arise that may necessitate infertility treatment. Lack of ovulation is best treated by clomiphene citrate which appears to be superior to metformin alone or metformin plus clomiphene citrate.18,37 Failure of these oral agents may necessitate the injection of FSH as gonadotrophins but there must be very close monitoring to exclude multiple oocyte ovulation and the subsequent multiple pregnancies that may occur.38 Laparoscopic ovarian drilling is associated with a normal rate of singleton pregnancy and, in some instances, may be very successful.39 The infrequent use of IVF should be with a single embryo transfer and with significant precautions to avoid OHSS by using lower doses of gonadotrophins. One of the major pre-pregnancy issues that must be addressed is weight and, in particular, obesity. Obesity has many concurrent problems in pregnancy and may interfere with infertility management. Reduction of body weight by 5% is associated with a higher rate of spontaneous ovulation and of spontaneous fertility, as well as an increased chance of becoming pregnant on treatment programs.40–42 Lifestyle modification is central to achieving adequate weight loss and fitness, and involves diet, exercise and addressing many other issues, including smoking, stress, alcohol, natural therapies and caffeine.43 A full pre-pregnancy assessment should be made and if abnormalities are found in weight or any other aspect of lifestyle, attempts should be made to remedy these situations before pregnancy is attempted. With respect to overweight, there have been a number of studies on diet suggesting that low calories are more important than macronutrient composition of the diet.44 Exercise adds substantially to the success of reducing insulin resistance and a combination of diet and exercise can be made into a program such as Fertility Fitness which has been described by Clark et al.40,41 There is a great need for pre-conception clinics to address the issue of lifestyle modification in women with PCOS so that they enter into pregnancy under optimal conditions for developing a healthy embryo and foetus. The use of metformin in early pregnancy is controversial and has not been subjected to randomised control trials.45,46 There are many studies that indicate that miscarriage might be reduced and that gestational diabetes might be less prevalent after lifestyle intervention, but these studies are yet to be confirmed by proper randomised prospective studies. There is evidence from a number of women who receive metformin in pregnancy that there is no

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increase in congenital abnormality of their offspring or indeed of any perinatal difficulties.47–49 The role of metformin needs much better clarification in the treatment of PCOS. The role of aromatase inhibitors for ovulation induction has been controversial and there have been allegations of increased congenital abnormality rates with this drug, although the overwhelming experience does not accord with this.50,51 When a woman is going to be given gonadotrophins, the dose needs to be titrated against the response and predictors of excessive response include a high pre-existing antiMüllerian hormone value, a large number of pre-antral follicles, a low body weight and a previous excessive response.52 OHSS is a highly dangerous and distressing condition for the woman and needs to be avoided at all costs. It is best prevented by prediction of PCOS or PCO, by reducing the dose of FSH that is used, by withholding human chorionic gonadotrophin (hGC) for ovulation induction if there are too many follicles, and by not using hCG in the luteal phase for support. Treatment of OHSS is not part of this chapter but is adequately covered by other authors.

Concluding remarks PCOS is a common condition and often necessitates infertility treatment. It is essential that the treating physician does the appropriate pre-pregnancy workout before starting any treatment for infertility, with the major emphasis on reducing insulin resistance through weight reduction, adequate diet and exercise. Outcomes of PCOS pregnancies where there has been adequate evaluation of the risks are usually excellent and elimination of multiple pregnancies is best achieved by adequate monitoring of cycles during infertility treatment and by cancelling those cycles where unexpected over-stimulation occurs. Babies born to women with PCOS appear to have slightly different growth rates and have early evidence of altered hormonal and physical characteristics. It is therefore important that women with PCOS understand that their daughters and sons need to be reviewed during their development as there is emerging evidence of familial predisposition of PCOS and common intergenerational metabolic sequelae.53,54 Long-term follow-up of women after pregnancy is essential given their risks for diabetes mellitus and hyperlipidaemia.

References 1. Ehrmann DA. Polycystic ovary syndrome. N Engl J Med 2005; 352: 1223–36. 2. Norman RJ, Dewailly D, Legro RS, Hickey TE. Polycystic ovary syndrome. Lancet 2007; 370: 685–97. 3. Pasquali R, Gambineri A. Polycystic ovary syndrome: a multifaceted disease from adolescence to adult age. Ann N Y Acad Sci 2006; 1092: 158–74.

4. Zawadski JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome; towards a rational approach. In: Dunaif A, Givens JR, Haseltine F, eds. Polycystic Ovary Syndrome. Boston: Blackwell Scientific, 1992, 377–84. 5. Kane J, Middle J, Cawood M. Measurement of serum testosterone in women; what should we do? Ann Clin Biochem 2007; 44: 5–15. 6. Wheeler MJ. Measurement of androgens. Methods Mol Biol 2006; 324: 197–211. 7. Group REA-SPCW. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Hum Reprod 2004; 19: 41–7. 8. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definitions. Hum Reprod Update 2003; 9: 505–14. 9. Azziz R, Carmina E, Dewailly D et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab 2006; 91: 4237–45. 10. Ibanez L, Jaramillo A, Enriquez G et al. Polycystic ovaries after precocious pubarche: relation to prenatal growth. Hum Reprod 2007; 22: 395–400. 11. Wild RA. Long-term health consequences of PCOS. Hum Reprod Update 2002; 8: 231–41. 12. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes 1989; 38: 1165–74. 13. Hoffman LK, Ehrmann DA. Cardiometabolic features of polycystic ovary syndrome. Nat Clin Pract Endocrinol Metab 2008; 4: 215–22. 14. Dabadghao P, Roberts BJ, Wang J et al. Glucose tolerance abnormalities in Australian women with polycystic ovary syndrome. Med J Aust 2007; 187: 328–31. 15. Wu Y, Zhang J, Wen Y et al. Increased acylationstimulating protein, C-reactive protein, and lipid levels in young women with polycystic ovary syndrome. Fertil Steril 2008; in press. 16. Tarkun I, Canturk Z, Arslan BC et al. The plasminogen activator system in young and lean women with polycystic ovary syndrome. Endocr J 2004; 51: 467–72. 17. Battaglia C, Mancini F, Cianciosi A et al. Vascular risk in young women with polycystic ovary and polycystic ovary syndrome. Obstet Gynecol 2008; 111: 385–95. 18. Consensus on infertility treatment related to polycystic ovary syndrome. Hum Reprod 2008; 23: 462–77. 19. Boomsma CM, Eijkemans MJ, Hughes EG et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum Reprod Update 2006; 12: 673–83. 20. Heijnen EM, Eijkemans MJ, Hughes EG et al. A metaanalysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006; 12: 13–21. 21. Homburg R. Pregnancy complications in PCOS. Best Pract Res Clin Endocrinol Metab 2006; 20: 281–92.

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The patient with polycystic ovary syndrome 22. Dahlgren J. Pregnancy and insulin resistance. Metab Syndr Relat Disord 2006; 4: 149–52. 23. Ehrmann DA, Kasza K, Azziz R et al. Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 66–71. 24. Norman RJ, Chura LR, Robker RL. Effects of obesity on assisted reproductive technology outcomes. Fertil Steril 2007; in press. 25. Callaway LK, Prins JB, Chang AM, McIntyre HD. The prevalence and impact of overweight and obesity in an Australian obstetric population. Med J Aust 2006; 184: 56–9. 26. Raatikainen K, Heiskanen N, Heinonen S. Transition from overweight to obesity worsens pregnancy outcome in a BMI-dependent manner. Obesity (Silver Spring) 2006; 14: 165–71. 27. Wang JX, Davies MJ, Norman RJ. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum Reprod 2001; 16: 2606–9. 28. Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A metaanalysis of the evidence. Fertil Steril 2007; in press. 29. Yu CK, Teoh TG, Robinson S. Obesity in pregnancy. BJOG 2006; 113: 1117–25. 30. Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008; 294: E15–26. 31. Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res Clin Endocrinol Metab 2003; 17: 305–22. 32. Legro RS, Finegood D, Dunaif A. A fasting glucose to insulin ratio is a useful measure of insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1998; 83: 2694–8. 33. Carmina E, Lobo RA. Use of fasting blood to assess the prevalence of insulin resistance in women with polycystic ovary syndrome. Fertil Steril 2004; 82: 661–5. 34. Chen X, Yang D, Li L et al. Abnormal glucose tolerance in Chinese women with polycystic ovary syndrome. Hum Reprod 2006; 21: 2027–32. 35. Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls. Obstet Gynecol Surv 2004; 59: 141–54. 36. Setji TL, Holland ND, Sanders LL et al. Nonalcoholic steatohepatitis and nonalcoholic Fatty liver disease in young women with polycystic ovary syndrome. J Clin Endocrinol Metab 2006; 91: 1741–7. 37. Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551–66. 38. Gorry A, White DM, Franks S. Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment. Endocrine 2006; 30: 27–33.

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39. Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove P. Laparoscopic ‘drilling’ by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2007; CD001122. 40. Clark AM, Ledger W, Galletly C et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995; 10: 2705–12. 41. Clark AM, Thornley B, Tomlinson L et al. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum Reprod 1998; 13: 1502–5. 42. Norman RJ, Noakes M, Wu R et al. Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 2004; 10: 267–80. 43. Norman RJ, Homan G, Moran L, Noakes M. Lifestyle choices, diet, and insulin sensitizers in polycystic ovary syndrome. Endocrine 2006; 30: 35–43. 44. Moran LJ, Noakes M, Clifton PM et al. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. J Clin Endocrinol Metab 2003; 88: 812–19. 45. Thatcher SS, Jackson EM. Pregnancy outcome in infertile patients with polycystic ovary syndrome who were treated with metformin. Fertil Steril 2006; 85: 1002–9. 46. Vanky E, Zahlsen K, Spigset O, Carlsen SM. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril 2005; 83: 1575–8. 47. Moore LE, Briery CM, Clokey D et al. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med 2007; 52: 1011–15. 48. Glueck CJ, Phillips H, Cameron D et al. Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75: 46–52. 49. Glueck CJ, Wang P, Goldenberg N, Sieve-Smith L. Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin. Hum Reprod 2002; 17: 2858–64. 50. Casper RF. Aromatase inhibitors in ovarian stimulation. J Steroid Biochem Mol Biol 2007; 106: 71–5. 51. Kafy S, Tulandi T. New advances in ovulation induction. Curr Opin Obstet Gynecol 2007; 19: 248–52. 52. van Wely M, Fauser BC, Laven JS et al. Validation of a prediction model for the follicle-stimulating hormone response dose in women with polycystic ovary syndrome. Fertil Steril 2006; 86: 1710–15. 53. Colilla S, Cox NJ, Ehrmann DA. Heritability of insulin secretion and insulin action in women with polycystic ovary syndrome and their first degree relatives. J Clin Endocrinol Metab 2001; 86: 2027–31. 54. Diamanti-Kandarakis E, Piperi C, Spina J et al. Polycystic ovary syndrome: the influence of environmental and genetic factors. Hormones (Athens) 2006; 5: 17–34.

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13 The patient with HIV Kees Boer, Mieke H Godfried

Since 1998 the risk of transmission of HIV from mother-to-child has dropped considerably in western Europe and North America by the introduction of highly active antiretroviral therapy (HAART) as prophylactic treatment of HIV-infected pregnant women. Not long before this, HAART was successfully introduced to treat HIV-infected persons with a low cellular resistance or AIDS without the high threat of viral resistance. HAART dramatically changed the lifeexpectancy of HIV-infected people and turned HIVinfection from a lethal disease into a chronic disease like insulin dependent diabetes or chronic hepatitis B. Concordant or discordant HIV-infected couples started to consider pregnancy and asked for preconceptional advice. This chapter describes the history and pathogenesis of mother-to-child transmission (MTCT) of HIV, the therapeutic developments and efficacy of prevention of MTCT (PMTCT). It then focuses on the known or suspected drawbacks of these interventions on the health of the mother and child, on risk factors with respect to some serious side-effects and on the measures that can be taken to avoid side-effects as much as possible. Finally, the processing of semen to avoid HIV-infection of the woman in a HIV-discordant couple is briefly discussed.

Epidemiology It is estimated that as of December 2007, 33.2 million people were living with HIV infection or AIDS.1 Most of these are adults (30.8 million); children <15 years constitute 2.5 million. Most of these children are infected by their mother during pregnancy, delivery or breast feeding. Women constitute 50% of the adult HIV-infected population, and their proportion is still growing. By comparison, in 1996 the percentage of women was approximately 42%. On a national scale the picture is varied. Whereas in sub-Saharan Africa, the total number of HIV-infected individuals has decreased in some countries because of preventive policies combined with a high death rate, in countries like India and China or the Russian Federation, the numbers are rising rapidly.1,2 In these countries the HIV epidemic has started much later than in sub-Saharan

Africa, the death rate is still low and preventive measures are not yet implemented or effective. HIV in adults is mainly transmitted sexually, through intravenous drug use with sharing of needles and via transfusions of blood or blood products. Heterosexual contact with a HIV-infected partner is the main mode of transmission even in the industrialised countries except for the Russian Federation, where many infections are the result of injecting drug use with contaminated needles.2 In non-industrialised countries, where screening for HIV infection is not always routine, exposure to infected blood or blood products remains a real risk.

Influence of HIV-infection on pregnancy outcome Apart from MTCT of HIV, HIV infection in itself is not a major problem with respect to the course of pregnancy and pregnancy outcome. Some studies show that the rate of miscarriage in HIV-infected women is increased.16 It is likely that the underlying reason must be related to immunological deficits of the mother, not protecting the trophoblast against cytotoxic lymphocytes, or in an increased rate of genital infections rather than HIV transmission to the foetus in early pregnancy. The much higher rate (50%) of HIV infections found in spontaneously aborted foetuses of HIV-infected women17 than the congenital MTCT rate in untreated women (15–30%; see below), strongly suggests these infections to occur in the process of miscarriage with a “leaking placenta” rather than that miscarriages are induced by early infection. Preterm delivery is another complication of pregnancy that might be increased in untreated HIVinfected women because of the concomitant risk of genital infections and low CD4+ cell counts. In the European collaborative study CD4+ cell counts were found to be related to preterm labour in HIV-seropositive women.18 In the same prospective study the percentage of preterm labour was only 5% and thus not more than in a general population.19 At the onset of the HIV epidemic lower birth weights of the offspring in HIV infected women were

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mainly due to drug addiction. From studies linking infection status of the infant to birth weight, it became clear that only a moderate decrease in birth weight is due to HIV infection of the foetus.20,21 On the one hand, this effect could be the result of bias, as HIV-infected symptomatic women are more likely than asymptomatic women both to infect their child and to have lighter children due to their physical condition.21 On the other hand, 75% of the infected infants are only infected during labour (see below), which means that the effect of intrauterine infection might be more pronounced if this were analysed separately. Such an analysis has not been performed to our knowledge. Finally, HIV-induced immunodeficiency can increase the risk of stillbirth. Decreasing CD4+ cell count, but not HIV infection in itself appeared inversely related to risk of stillbirth.22

Influence of natural course The first study in which HIV-seropositive women were followed after term pregnancy suggested an acceleration of disease progression by pregnancy.3 A selection bias existed, however, towards women with advanced disease since they were traced via their child after it developed a symptomatic HIV infection. Later studies showed indeed that disease progression of the child is related to the disease stage of the mother at delivery.4 Subsequent prospective studies on disease progression after pregnancy did not show clinical deterioration by pregnancy, at least in asymptomatic women.5 During normal pregnancy cell-mediated immune response is depressed.6 Initially, the decline in CD4+ cells seemed to be faster in HIV-seropositive pregnant women with less rebound in the last trimester of pregnancy and postpartum than in HIV-seronegative pregnant women.7 However, this phenomenon may also be explained by the natural course of HIV infection. A larger study from sub-Saharan Africa by Temmerman et al5 did not find significant differences. A systematic literature review and meta-analysis of seven prospective cohort studies including the two aforementioned studies, suggested that pregnancy in HIV-positive women may be associated with at least small increases in the risk of adverse maternal outcomes.8 Later studies largely, but not all,9,10 showed, however, that pregnancy does not negatively influence the natural course of HIV disease.10–12 Repeat pregnancies also do not appear to have significant effects on the course of HIV disease.13 Probably because women who want to be or are able to get pregnant in general have a healthier immune status than those who do not, pregnancy was associated with a lower risk of HIV disease progression in a recent study, where women had access to HAART.14 A beneficial interaction between pregnancy and HAART is also possible. It is reassuring that another recent study in pregnant women in London showed the median-term postpartum prognosis of HIVinfected pregnant women with access to HAART to be good.15 It also showed that exposure to short-course

zidovudine monotherapy or short-term HAART given during pregnancy and discontinued on delivery did not jeopardise the response to subsequent therapy. When couples come for pre-conceptional advice, fear of deterioration during pregnancy seems unfounded. Women in whom the CD4 count is less than 200 cells/µl should be advised not to get pregnant before HAART has restored their cellular resistance and to receive prophylaxis against Pneumocystis carinii (PCP). If women, nevertheless, get pregnant they should not arrest their medication including the PCP prophylaxis (usually cotrimoxazol).

Mother-to-child-transmission In non-selected populations with HIV type 1 infection, MTCT is usually between 15 and 30%, but in particular from Africa higher transmission rates of up to over 40% are reported.23–25 This is probably due to transmission by breast feeding, which accounts for 14%26 or more (see below). HIV type 2 infections, that are predominantly seen in West African people, are transmitted from mother-to-child in 0–3% of cases.27 Transmission in pregnancy varies with HIV-disease stage of the mother: a high Centers for Disease Control and Prevention (CDC) classification, a low CD4+ cell count, a low CD4+/CD8+ ratio and the presence of p24 antigenemia during pregnancy are related to a 2– 3 times increased transmission rate.23,28 All these variables are an expression of viral load in women without antiretroviral therapy. The large American– French intervention trial (ACTG-076 study) clearly showed the amount of replicated viruses (HIV-RNA load) in blood to be positively related to mother-tochild transmission: 41.7% in the highest quartile (>15 700 copies/ml) and 7.1% in the lowest quartile (<1730 copies/ml).29 Viral load is highest during acute infection and in symptomatic persons. However, HIV viral load can also be high in persons with a normal resistance and appears to be more or less steady in a given person until cellular resistance decreases (CD4+ cell counts <200 cells/mm3) and viral load increases.30 Immunological factors seem to be important in the risk of MTCT. The higher risk of girls than boys to be infected (in utero and perinatal) with HIV31,32 is explained by minor histocompatibility reactions between maternal lymphocytes and infant Y chromosome-derived antigens, that reduce the risk of HIV transmission in boys.32 Moreover, human leucocyte antigen (HLA) alleles, and in particular class I concordance between maternal and neonatal HLA, appears to be associated with the risk of perinatal HIV-1 transmission.33,34

Transmission during pregnancy Transmission of HIV before 28 weeks of gestation in an ongoing pregnancy is rare. Early transmission of HIV has been reported in well performed studies on miscarriages,17 but a carefully designed French study

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on 100 foetuses from HIV-seropositive women, in most of whom a mid-trimester termination of pregnancy (TOP) was performed (mean 22.4 weeks) showed only two infections (confidence interval (CI) 0.2–7) and none in the 92 elective TOPs.35 A subsequent study by the same group on foetal blood samples taken before mid-trimester TOP (28 women, 15–29 weeks, mean 22 weeks) also did not show intrauterine infections.36 A more recent study from Thailand on foetal heart blood obtained after 42 prostaglandin-induced mid-trimester TOPs found HIV-1 RNA in two samples.37 This is probably not proof of early infection in otherwise uncomplicated pregnancies as the induction by prostaglandins might well have induced maternal–foetal blood exchange, as has been found in the mother after medically induced abortions38 and in umbilical cord blood after parturition, related to the mode of delivery (vaginal more than elective Caesarean).39,40 Intrauterine infection beyond 28 weeks is responsible for up to 30% of all congenital infections in untreated women, as shown most clearly by the remaining percentage of infections after an elective Caesarean section in otherwise untreated women.41 The finding that in the first week of neonatal life viral markers, such as p24 antigen, anti-HIV IgM and viral DNA are detectable in about 30% of HIV-infected children supports the hypothesis of late intrauterine infection.42–44 Intrauterine infection of the foetus is probably also responsible for the rapid development of severe immunodeficiency or death in more than 15% of infected children by 1 year of age.45 HIV transmission during pregnancy is associated with maternal HIV-RNA load in untreated women. In various studies a high HIV-1 viral load appeared to be a strong risk factor for in utero transmission (adjusted odds ratio (OR) around 5).44,46 Recently it was shown that in both untreated47 and zidovudine treated women47b MTCT is also and even more strongly related to peripheral blood mononuclear cell (PBMC)-associated HIV-1 DNA independently from RNA viral load. It is clear from the MTCT rates that HIV fortunately does not cross the placenta freely. However, in the presence of a syphilitic infection of the placenta, intrauterine transmission of HIV is increased (adjusted relative risk (RR) 2.77, 95% CI 1.40–5.46).48 In syphilitic villitis, maternal lymphocytes, including CD4+ cells are found intravillous,49 where they may infect Hofbauer cells, foetal macrophages,50,51 abundantly present in villitis,52 that presumably are involved in MTCT.53 In general, (chronic) chorioamnionitis is more often met in HIV-seropositive than HIV-uninfected women and is associated with an increased transmission rate.54,55 Also, and to a greater extent, malaria infection during pregnancy can increase MTCT. In a recent study, after adjusting for maternal HIV viral load, the risk of MTCT was increased for mothers co-infected with placental malaria (RR 7.9, p=0.025).56 Furthermore, HIV-infected lymphocytes crossing the placental barrier might also induce a foetal infection.

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Transfer of maternal lymphocytes across the placenta to the foetus appears to occur in 30%.57 This could be the result of microlesions in most of the women or partial placental abruption in some. It seems prudent not to perform invasive diagnostics (amniocentesis) or version of breech infants in order to avoid maternofoetal blood contamination.58

Transmission during labour During labour HIV-contaminated fluids, such as cervical secretions and maternal blood, surround the foetus and are also found in the neonatal oropharynx or stomach.59 Genital shedding of HIV-DNA during pregnancy was found in 32% of 212 cervical and 10% of 215 vaginal specimens.60 Shedding appeared in this study to be related to low CD4+ counts and to severe vitamin A deficiency. Although vitamin A deficiency is associated with MTCT, neither vitamin A nor multivitamins improved the risk of vertical transmission of HIV in utero or during the intrapartum and early breastfeeding periods.61–63 The European collaborative study (ECS) showed that preterm delivery below 34 weeks is one of the clear risk factors for MTCT with an OR of 3.8.23 The 5% deliveries before 34 weeks was not higher than expected, arguing against intrauterine HIV infection as the cause of preterm labour. Since later analyses of the ECS showed that low maternal CD4+ counts were related to preterm delivery,18 it cannot be excluded, however, that the increased risk of HIV transmission in preterm infants occurred in utero. Another explanation for the increased risk of HIV transmission in preterm infants is that these are less protected against HIV infection by (maternal) anti-HIV-antibodies, as passive antibody transfer across the placenta largely occurs during the last two months of pregnancy.64 The most likely explanation, however, is that both preterm delivery65 and MTCT of HIV66–68 during labour are influenced by (sub)clinical co-infections in the genital tract. In many cohort studies, the duration of ruptured membranes appears to be an important determinant of HIV transmission from mother-to-child, in particular in women with a low CD4+ cell count.69 Here too subclinical infection might be the common underlying factor. Local conditions in the genital tract certainly are important for MTCT. Recently, Cowan et al70 performed a case control study in Zimbabwe and found herpes simplex virus (HSV)-2 infection to be common among HIV-1-positive women and associated with an increased risk of intrapartum MTCT. Although syphilis, at the time of delivery was not associated with intrapartum MTCT risk, maternal HSV-2 coinfection, another genital infection causing ulcers, was found to be responsible for more than 25% of intrapartum MTCT. Moreover, Montano et al found that when blood HIV-1 DNA load of untreated pregnant women was combined with HIV-1 DNA load of the cervical vaginal fluid, the association with transmission increased from OR 10.30 (95% CI 2.11–50.38)

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to 25.0 (95% CI 2.73–228.60).47 This still indicates birth canal exposure to play a role in MTCT. A multicentre study on blood taken during the first 2 days of life showed DNA to be detectable in 38% of the infected non-breastfed children and by 14 days of age in 93%.71 This indicated that (in untreated women) intrauterine infection occurs in 40% and perinatal infection in 60% of all congenitally infected infants. This has been corroborated by two meta-analyses of prospective studies, showing that Caesarean section halves the risk of infection72,73 and the subsequent mode of delivery trial.41 The mode of delivery trial was a randomised controlled trial, showing a MTCT rate of 6·8% in untreated non-breastfeeding women after an actual Caesarean section versus 18·9% following an actual vaginal delivery. In a recent study of Jourdain et al46 the following risk factors were related to intrapartum transmission of HIV: HIV-1 load, induction of labour and preterm labour with tocolysis. Maternal antenatal viral load and antiretroviral therapy were associated with risk of both in utero and intrapartum transmission. Magder et al found that after controlling for maternal antenatal viral load and antiretroviral therapy, low birth weight was significantly associated with in utero transmission, while age, antenatal CD4+ cell percentage, year, birth weight and duration of membrane rupture were associated with intrapartum transmission.74 In another recent study evidence was obtained that the amount of placental microtransfusions was associated with intrapartum MTCT,75 indicating strongly that not all infections during labour are caused by foetal exposure to the birth canal. This evidence is the reason to clamp the umbilical cord quickly after birth, a measure described in some guidelines, hitherto based upon common sense only. In summary, circumstantial evidence exists that up to about 75% of infected infants are infected during birth, possibly by ingestion of HIV-containing maternal fluids or by transplacental microtransfusions, both of which can be prevented by an elective Casearean section, if necessary.

Transmission during lactation It is estimated that extended breast feeding accounts for approximately 40% of infant HIV infections worldwide. Transmission of HIV through breast feeding has been well documented from the onset of the AIDS epidemic following acute HIV infections caused by blood transfusions in the puerperium.76,77 As opposed to what has been reported for intrauterine transmission,78 acute HIV infections during lactation have a higher risk of transmission than chronic infections, because of the related high viral load and infectivity of the mother. Transmission rates are 26% (CI 13–39%) for acute infections79 and 14% (CI 7–22%) for women who were already infected before pregnancy.26 The presence of HIV-infected cells in the milk of the mother predicts MTCT rate and seems to play a more

important role in transmission of HIV via breast feeding than does cell-free virus.80 Since colostrum and early breast milk contain many more cells than later milk, the risk of infection might be highest in the early phase of lactation. Late postnatal transmission (negative HIV-1 test ≥4 weeks postnatally, followed by a postive test) appeared roughly constant over time with a cumulative probability at 18 months of 9.3%.81 In line with the cellular transmission, the risk of infection was also shown to be high in the presence of a breast abscess even during late lactation.82 Besides important psychological benefits, breast feeding protects the infant against agents causing diarrhoea and respiratory diseases especially in developing countries, where these are responsible for most infant mortality. In addition to the immunoglobulins involved in this protection, human milk also contains immunoglobulins against HIV, of which anti-HIV secretory IgA in early milk samples appeared to be associated with absence of MTCT.83 The secretion of both anti-HIV IgA and IgM takes place in the mammary gland, probably as a local reaction to HIV, and does not reflect serum levels.84 Recently it became clear that human milk contains compounds or natural antibodies, that bind to the so-called DC-sign of the antigen presenting dendritic cells, that are present in the mucosal layer and so block infection of the breastfed infant.85,86 It seems that for this effect the integrity of the mucosal wall is important since in a South African trial exclusive breast feeding carried a significantly lower risk of HIV-1 transmission than mixed feeding (hazard ratio (HR) 0.52, CI 0.28–0.98) and a similar risk to no breast feeding (0.85, CI 0.51–1.42).87 This confirmed finding is important for the developing world as it would diminish infant mortality related to non-breast feeding without considerable risk of MTCT of HIV.

Prevention of mother-to-child transmission Fortunately, methods to reduce MTCT have proven to be very effective. At the onset of the epidemic and only in industrialised countries, abstinence from breast feeding was the only real prevention of MTCT. Today, the two measures that are effective as prophylaxes are a planned elective Caesarean section and perinatal use of antiretroviral therapy (see below). Less costly and easier to apply treatments, like vaginal cleansing with benzalkonium chloride,88 vitamin A supplementation,89 zinc supplementation90 and antibiotics against bacterial vaginosis91 have not proven to be effective to date. The first strong indication that an elective Caesarean section reduces MTCT of HIV came from a meta-analysis of prospective cohorts in 1993,92 followed by two larger ones.72,73 The inefficacy of an elective Caesarean section to lower the incidence of congenital HSV infections combined with reported increased complication rates after a Caesarean section in HIV-infected

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women93,94 probably prevented a quick implementation of the elective Caesarean section in the PMTCT until the publication of the European mode of delivery trial.41 In that trial in a non-breast feeding population in both untreated (OR 0·2, CI 95% 0–0·8) and zidovudine-treated women (OR 0·2, 0–1·7) MTCT decreased substantially in the women allocated to an elective Caesarean section. The transmission rate in the zidovudine-treated women allocated to an elective Caesarean section was 0.8%.95 In those who actually had a Caesarean section it was higher 2.1%, because this group included women who had a secondary Caesarean section. Similar results were seen in the prospective French cohort study.95 Shortly after the first meta-analysis of the efficacy of an (elective) Caesarean section, the interim report of the large PACTG076 trial on the efficacy of zidovudine (ZDV) to prevent MTCT of HIV29 became available in February 1994. This French–American multicentre placebo controlled trial showed a 67% reduction of transmission from 22.6% (95% CI 17.0– 29.0) to 7.6% (CI 4.3–12.3) in a selected group of women who did not need ZDV for themselves and who started between 14 and 34 weeks (median 26 weeks) of pregnancy. During delivery ZDV infusion was given and the bottle fed children received ZDV for 6 weeks after birth. The absolute reduction in HIVtransmission was highest in women with the highest viral RNA load before therapy. Reduction was also encountered, however, in women with low viral load. The reduction of MTCT could not be fully explained by viral RNA reduction in plasma. Viral load in cervical secretions was not measured. It has been found that plasma does not always reflect HIV load in cervical secretion,59 whereas HIV load in cervical shedding might be clinically more important for contamination and thus infection during birth. Moreover, accidents during pregnancy, like partial placental abruption and maternofoetal transfusion, may be conditions that cannot be avoided, but have a high risk of infection even in women with low viral load. Indeed, recently evidence was obtained that the amount of placental microtransfusions was associated with MTCT.75 Another possibility, for which purpose children are treated after birth, is post-exposure prophylaxis. The PErinatal TRAnsmission (PETRA) trial, studying the efficacy of three short-course regimens of zidovudine and lamivudine showed that post-exposure prophylaxis (PEP) is an essential part of perinatal protection in case of short antiretroviral therapy (ART) courses to prevent MTCT.96 Several other randomised controlled trials showed that short ART courses are effective in diminishing MTCT of HIV in developing countries, albeit that the ultimate effect is usually diminished by transmission during lactation. The study with the largest impact on treatment in the developing world was the HIVNET 012 randomised trial, in which nevirapine 200 mg orally at onset of labour and 2 mg/kg to babies within 72 hours of birth

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proved twice as effective as zidovudine 600 mg orally to the mother at onset of labour and 300 mg every 3 hours until delivery, and 4 mg/kg orally twice daily to babies for 7 days after birth.97 The disadvantage of the widely applied nevirapine prophylaxis is the resulting resistance against nevirapine containing ART regimens, amounting to 32% in one study, that also showed this to negatively influence later viral suppression by nevirapine-containing regimens.98 The justified fear for resistance against ART in case of mono- or duotherapy for the prevention of MTCT of HIV, led to the implementation of highly active antiretroviral therapy (HAART) in most developed countries without randomised controlled trials to show their efficacy. In the past years, however, cohort studies showed that HAART is much more effective than all other measures in reducing MTCT.99–101 HAART is usually started as soon as possible in those women who need medication for themselves or at 20–28 weeks depending on HIV-RNA load for those who do not. The additional benefit of an elective Caesarean section, except for conditions for which HAART is not given or effective, is very doubtful. It seems logical to recommend HAART to prevent MTCT, where possible, and to use an elective Caesarean section as a safety valve in case of HAART failure. However, it is also argued that in women with HIV RNA levels of <1000 copies/ml, a three-part zidovudine prophylaxis regimen (prenatal, intrapartum and neonatal) should be used alone.102 The main argument for this last advice is the uncertainty about long-term drug sideeffects on the offspring (see below).

Disadvantages of antiretroviral therapy in the neonate Current recommendations for the prevention of MTCT of HIV-1 include the use of HAART.102,103 Although the use of combination therapy during pregnancy and in the first weeks after birth has reduced MTCT from 25% to less than 1–2%, use of antiretroviral agents during pregnancy and for the first weeks after birth, entails in utero and neonatal exposure to drugs with possible toxicity for the neonate.99,102,104 This is of particular concern in children who are HIVexposed but are HIV-uninfected. Several large study groups (prospectively) monitor possible adverse effects of these agents on the neonate. In the US, pregnancies in HIV-infected women, pregnancy outcome and neonates are monitored by the Antiretroviral Pregnancy Registry (APR)105 and in several clinical studies such as the Women Infants Transmission Study (WITS) and the Perinatal AIDS Clinical Trails Group (PACTG) studies. In Europe, the ECS and the French Perinatal Cohort (EPF) are examples of such prospectively followed cohorts of pregnant women and their children. To date, in these studies more than 20 000 children have been born to HIV-infected

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women, many of whom have used antiretroviral agents during pregnancy. Thus, data on possible toxic effects are still limited and the risk of the use of many, if not most, antiretroviral drugs in pregnancy is still largely unknown. A summary of the carcinogenicity and teratogenicity data from animal studies (and some human studies) is given in Table 13.1. Nowadays, the first-line antiretroviral combination recommended for the prevention of MTCT contains two nucleoside analogues (NRTIs) in combination with either a protease inhibitor (PI) or the non-nucleoside nevirapine (NVP).103 Although maternal–foetal transmission of antiretroviral drugs may be beneficial in terms of the prevention of MTCT of HIV, it may also pose risks to the foetus. In general, all NRTIs and also nevirapine have good placental passage. In contrast, most PIs have only minimal placental passage (Table 13.1). Several new agents, as well as new classes of antiretroviral agents have been introduced in the last years. About these newer agents much less is known. The US Food and Drug Administration (FDA) has assigned specific pregnancy categories for each antiretroviral drug, based on the risk to the foetus (Table 13.2).

Congenital malformations ART is mainly started in the second half of pregnancy, after organogenesis is completed. However, increasing numbers of women are using ART for themselves at the time of conception. Most antiretroviral agents have been studied individually in animals and there seems to be little evidence for teratogenicity (Table 13.1).103 However, much less is known about the use of antiretroviral combination therapy. Some exceptions excluded (see below), the data about congenital malformations after exposure to antiretroviral agents are reassuring (Table 13.3).105 In three of 20 fetuses and infants from efavirenz-treated cynomolgus monkeys in a developmental toxicity study central nervous system (CNS) malformations were observed.106 In humans, there have been four retrospectively reported cases of neural tube or CNS defects in neonates with first trimester exposure to efavirenz.107–109 However, in the APR, no increased risk of congenital malformations or neural tube defects was detected in prospectively monitored pregnancies with first trimester exposure to efavirenz (Table 13.3).105 Although a causal relationship with these defects has not been proven, the FDA has classified efavirenz as a class D drug (Table 13.1).103 Retrospectively, a higher risk of congenital abnormalities was reported in one study after first trimester exposure to antiretroviral agents in combination with folate antagonists. No higher risk after exposure to antiretroviral agents or folate antagonists alone was found in this study.110 Periconceptual folic acid use may reduce the risk of birth defects in women using the combination of antiretroviral agents and folic acid antagonists and folic acid supplementation should therefore be part of pre-conception counselling.111

In the prospective observational WITS, no overall increase of birth defects after first trimester exposure to antiretrovirals was detected, but an increased risk of hypospadias after first trimester zidovudine (ZDV) exposure was found with an adjusted OR of 10.68 (95% CI 2.11–54.13, adjusted amongst others for smoking).112 An increase of hypospadias has not been detected in other cohorts or studies.105,113–115 An increased risk of hydrocephalus at high doses in rodents has been found for zalcitabine (ddC) and an increased risk of ventricular septal defects for delavirdine. Both drugs are not recommended for use in pregnancy.103 Although no increased rates of birth defects have been detected after first trimester exposure to tenofovir, limited data on its use in human pregnancy and concern about possible foetal bone effects and nephrotoxicity, make this drug less suitable for use during pregnancy.103 Nelfinavir is no longer recommended as part of antiretroviral regimens in pregnancy. In 2007, the manufacturer gave a warning that low levels of ethyl methane sulfonate (EMS), a process-related impurity, had been found in nelfinavir.115 EMS is teratogenic, mutagenic and carcinogenic in animals. No data from humans exist about exposure to EMS. In the APR no increase in birth defects has been observed.105,116 Animal teratogen studies have not demonstrated an increased rate of congenital malformations for didanosine (ddI).103 However, in 15 of 259 live born children with first trimester exposure to ddI (5.8%), birth defects were reported in the APR.105 This trend was significant. No specific clustering of defects could be ascertained, however, and the higher rate of birth defects has not been detected in other cohorts.112–115 Excepting the above-mentioned data, no increase in any particular abnormality associated with the use of antiretroviral medication or HAART during pregnancy has been demonstrated.105,112–116 Monitoring of congenital malformations and other adverse events continues and the guidelines for the use of antiretroviral drugs are being continuously updated.103,105

Mitochondrial toxicity Some of the adverse effects noted in HIV-infected children and adults, treated with antiretroviral drugs, have been ascribed to mitochondrial toxicity due to use of class drugs. Mitochondrial toxicity is Nucleoside Reverse Transcriptase Inhibitor (NRTI) class drugs. Mitochondrial toxicity is thought to result from inhibition of the enzyme DNA polymerase gamma, which is involved in the replication of the mitochondrial DNA, resulting in mitochondrial DNA depletion and dysfunction.117 Clinically, mitochondrial toxicity has been associated with neuropathy, myopathy, cardiomyopathy, pancreatitis, hepatic steatosis, lactic acidosis and loss of subcutaneous fat (lipoatrophy). A genetic predisposition to develop mitochondrial toxicity has been suggested.118 Evidence for mitochondrial toxicity has been found in the offspring of rodents and monkeys after NRTI

C C B C C C B B

B D

C B B B C C B C B

B B C

NRTIs ZDV ddC ddI d4T 3TC ABC TDF FTC

NNRTIs NVP EFV

PIs IDV SQV RTV NFV LPV FPV AZV TPV DRV

OTHERS ENF MRV RGV Unknown Unknown Yes (rats, 1.5–2.5)

Minimal (humans) Minimal (humans) Minimal (humans) Minimal (humans) Yes (humans 0.20) Unknown Minimal (humans) Unknown Unknown

Yes (humans 1.0) Yes (monkeys, rodents 1.0)

Yes (humans 0.85) Yes (monkeys 0.30–0.50) Yes (humans 0.50) Yes (monkeys 0.80) Yes (humans 1.0) Yes (rodents) Yes (humans 0.95–0.99) Yes (rodents 0.40–0.50)

Placental passage (newborn:mother ratio)

not done In progress

+ (thyroid) − + (rodents, HCC) + (rodents, thyroid) + (rodents, HCC) + (rodents, HCC) + (rodents) In progress Not completed

+ (rodents) + (mice)

+ (rodents) + (rodents) − + (rodents) − + (rodents) + (rodents) −

Carcinogenicity (long-term animal)

− − (rodents, extra ribs)

− (extra ribs, bilirubin elevation) − − (cryptorchism) − − (rodents, skeletal defects) − (abortions, skeletal defects) − (bilirubin) − (rodents, decreased ossification in rats) −

− + (humans, monkeys, neural tube defects)

+ (rodents) + (rodents, skeletal defects, hydrocephalus) − − − + (rodents, skeletal defects, anasarca) − (osteomalacia, nephrotoxicity) −

Teratogenicity (animal)

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FDA, Food and Drug Administration; NRTIs, nucleoside inhibitors or nucleotide (TDF) inhibitor; ZDV, zidovudine; ddC, zalcitibine; ddI, didanosine; d4T, stavudine; 3TC, lamivudine; ABC, abacavir; TDF, tenofovir; FTC, emtricitabine; NNRTs, non-nucleoside reverse transcriptase inhibitors; NVP, nevirapine; EFV, efavirenz; PIs, protease inhibitors; IDV, indinavir; SQV, saquinavir; RTV, ritonavir; NFV, nelfinavir; LPV, lopinavir; FPV, fosamprenavir; AZV, atazanavir; TPV, tipranavir; DRV, darunavir; Others, fusion, entry or integrase inhibitors; ENF, enfurtide; MRV, maraviroc; RGV, raltegravir; HCC, hepatocellular carcinoma.

FDA category

Antiretroviral agent

Table 13.1 Summary of animal and clinical data on individual antiretroviral data. Adapted from Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States.103

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Table 13.2

US Food and Drug Administration (FDA) pregnancy categories and antiretroviral drugs.

Category

Description

A

Adequate and well-controlled studies have failed to demonstrate a risk to the foetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters) Animal reproduction studies have failed to demonstrate a risk to the foetus and there are no adequate and well-controlled studies in pregnant women Animal reproduction studies have shown an adverse effect on the foetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks There is positive evidence of human foetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks Studies in animals or humans have demonstrated foetal abnormalities and/or there is positive evidence of human foetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in the use of the drug in pregnant women clearly outweigh potential benefits

B C

D

X

Table 13.3 Prevalence of congenital malformations after first trimester exposure to different antiretroviral drugs. From The Antiretroviral Pregnancy Registry.105 Regimen

Lamivudine Zidovudine Nelfinavir Nevirapine Stavudine Ritonavir Abacavir Efavirenz Tenofovir Didanosine Lopinavir

Defects/live births

Prevalence

95% CI

55/1888 51/1643 24/638 13/543 13/468 11/410 13/404 7/281 7/266 15/259 6/232

2.9% 3.1% 3.8% 2.4% 2.8% 2.7% 3.2% 2.5% 2.6% 5.8% 2.6%

2.2–3.8 2.3–4.1 2.4–5.6 1.3–4.1 1.5–4.7 1.3–4.8 1.7–5.4 1.0–5.1 1.1–5.4 3.3–9.4 1.0–5.5

CDC population-based birth defects surveillance (1968–2003): prevalence of birth defects 2.67 per 100 live births.

exposure during pregnancy.119–121 There are several data that suggest mitochondrial dysfunction might also occur in children after in utero exposure to NRTIs.119 Asymptomatic, elevated lactate levels in neonates have been inconsistently reported.122,123 In 1999, signs of possible mitochondrial dysfunction were first described in eight of 1754 HIV-uninfected children followed in the Enquête Périnatale Française (EPF), who had been exposed in utero to ZDV or ZDV with lamivudine (3TC).124 Two of the children died. In a subsequent analysis, the rate of mitochondrial dysfunction was estimated at 0.3% after in utero exposure to antiretroviral drugs (and 0% in unexposed children), much higher than the estimated rate of 0.01% in the general northern European population.125 The relative risk of possible or established mitochondrial dysfunction was estimated to be 2.5 times greater after in utero exposure to combination NRTI than after exposure to ZDV only.126 In contrast, no evidence of mitochondrial dysfunction could be found in several other studies. Retrospectively, mitochondrial dysfunction could not be established as

the cause of death in 30 NRTI-exposed, HIV-uninfected children out of more than 20 000 children born to HIVinfected mothers, approximately half of whom had been exposed to antiretroviral agents in utero.126 No clinical signs of mitochondrial dysfunction could be found in 1008 HIV-uninfected children, exposed to ART during pregnancy in the ECS.127 No difference in adverse neurological events was reported in children who had been exposed during gestation to NRTIs compared with placebo in the PETRA study.96 No differences in neurodevelopment could be demonstrated in 39 HAARTexposed infants compared with 24 control infants.128 Likewise, ZDV was not associated with acute or chronic abnormalities in left ventricular structure or function in 382 HIV-uninfected infants of whom 36 were exposed to ZDV in the perinatal period.129 In a recent retrospective study, no association between overall in utero exposure to antiretroviral drugs and mitochondrial dysfunction could be established. However, in HIV-uninfected children with unexplained clinical signs consistent with possible mitochondrial dysfunction higher odds of first in utero exposure to 3TC and to ZDV/3TC in the third

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trimester were observed.130 Thus, the evidence for an association between mitochondrial dysfunction and NRTI exposure remains equivocal. Mitochondrial dysfunction after NRTI exposure in the antepartum and neonatal period does occur, but the incidence of clinically relevant MD appears to be rare.

Haematological changes associated with use of antiretroviral therapy In HIV-exposed, uninfected infants with in utero and neonatal exposure to antiretroviral agents, several haematological parameters were shown to be lower than in antiretroviral-unexposed neonates.131–135 Lower haemoglobin concentrations and lower platelet, neutrophil, total lymphocyte, CD4+ and CD8+ cell counts were first reported in the EPF.131 The lower haemoglobin concentrations were transient, consistent with a shortterm effect that resolved after arrest of exposure to the antiretroviral agent(s). The differences in the other parameters, however, persisted until the age of 18 months. Several other studies have reported similar alterations and have extended these findings.132–135 The reduction of the neutrophil cell count, as well as the reduction of the lymphocyte and CD8+ cell counts was long term and in some studies persisted until at least 8 years.132,133 The effect on CD4+ cell count appeared to be of shorter duration and had dissolved in some studies after 2 months. Exposure to antiretroviral combination therapy was associated with more pronounced differences than exposure to one drug only, but the type of drug in the combination (e.g. Protease Inhibitor (PIs) or NNRTIs) was of no influence. Infant CD4+ cell counts were not only influenced by use of antiretroviral agents, but were also associated with maternal immune status, possibly through defective transplacental transfer of haematopoietic cytokines, thus affecting thympoiesis of CD4+ cells in the infant.135 The haematological effects of antiretroviral agents are possibly mediated through myelotoxic effects on the haematopoietic progenitor cells of the foetus and neonate. The clinical significance of these effects does not seem important, but long-term data are still lacking.

Carcinogenicity Animal toxicology studies have shown that many antiretroviral drugs may have carcinogenic properties (Table 13.1).116 Transplacental carcinogenicity studies have not been carried out for many drugs or combinations of drugs, however. In mice, ZDV and ZDV with 3TC administered during pregnancy caused an increase of nucleated red blood cells and mutants in the offspring.136 Mutation frequency was higher with combined exposure. Moreover, in the offspring of mice and rats treated with ZDV during pregnancy significant increases and dose-related trends were found in the incidence of haemangiosarcomas and hepatic carcinoma in male mice

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and mononuclear cell leukaemia in female rats.137 ZDV is incorporated into nuclear and mitochondrial DNA in multiple organs in mice and monkeys and in the leucocytes of infants following transplacental exposure.136,138 ZDV incorporation in DNA may lead to genotoxic damage through oxidative stress and chain termination during replication. If damage is not cleared away, this may result in deletions, point mutations and clastogenic events, micronucleus formation and other manifestations of genomic instability. In all, many animal studies as well as some isolated data in humans suggest that perinatal exposure to antiretroviral drugs may put the infant at an increased risk for malignancies later in life. To date, no increased incidence of malignancies has been reported, but follow-up of children with perinatal exposure to antiretroviral drugs is still too short and long-term data are lacking.127,139,140 Continued surveillance of these children, therefore, seems justified.

Safety of antiretroviral therapy in pregnant women Several adverse effects of the use of HAART during pregnancy have been described with sometimes inconsistent results. These adverse effects include an increased risk of prematurity and low birth weight, increased risk of pre-eclampsia and gestational diabetes mellitus, as well as enhanced toxicity of some antiretroviral agents in pregnant women. An increased rate of preterm delivery was reported in several (mostly European) studies, and contradicted in other (mostly American) studies.99,141–146 Use of PIcontaining HAART, especially when started before pregnancy or in the first trimester, seems to be associated with preterm delivery, but this association could not be confirmed in other studies. One study even showed a protective effect of HAART on pregnancy outcome possibly through improvement of maternal health.147 Likewise, very low birth weight has been reported by some, but not by others. The differences in these results may be explained by the fact that most studies were observational cohort studies with different criteria for maternal disease severity, and by the fact that most studies did not control for other factors known to affect pregnancy outcome, e.g. previous preterm delivery, smoking, substance abuse, etc. In a recent matched case–control study, a HAART-associated increase in preterm delivery was mainly seen after first trimester HAART use.99 No increase in (very) low birth weight or the rate of pre-eclampsia was noted in that study. In contrast, in a Spanish study a sharp increase in the incidence of pre-eclampsia and foetal death after the introduction of HAART in pregnancy was reported as compared with the pre-HAART era.148 No increase in hospitalisations for pre-eclampsia was noted over the years 1994–2003 in the US, but hospitalisations for preterm labour and delivery, and for liver disorders were more frequent in pregnant HIV-infected than in HIV-uninfected pregnant women.149

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Antiretroviral drugs appear to have more toxicity in pregnant women. In 186 pregnant HIV-infected women, nelfinavir-related gastrointestinal symptoms and hyperglycaemia, and nevirapine-related hepatotoxicity, but not rash, occurred more often than in 186 non-pregnant HIV-infected women.150 Severe hepatotoxicity from nevirapine-containing HAART is more common in women and is related to CD4+ counts (>250 cells/µl).151 Deaths due to hepatic failure have been reported in HIV-infected pregnant women receiving prophylactic nevirapine-containing HAART.152,153 It is unknown, however, whether pregnancy itself increases nevirapine toxicity. In a retrospective study, the frequency of nevirapine-related rash and hepatoxicity in pregnant women was even lower than usually reported.154 Even so, many guidelines strongly recommend that in pregnant women nevirapine should only be initiated with due caution and preferentially not at CD4+ counts >250 cells/µl. After initiating nevirapine-containing HAART women should be more frequently and carefully monitored, clinically as well as for hepatic transaminases.103,155,156 Both PIs and NRTIs have been shown to affect glucose metabolism.157,158 Impaired glucose tolerance, and overt diabetes mellitus have been reported in association with use of PIs by HIV-infected patients.157 Though gestational diabetes mellitus is more common in HIV-infected women, it is still unclear whether use of PI-containing HAART is an extra risk factor.150,159,160 HIV-infected women, who use ART should be considered as a highrisk group for the development of glucose intolerance and should therefore be screened accordingly. Both fatal and non-fatal cases of lactic acidosis in late gestation or postpartum have been described in women with prolonged use of d4T and ddI in combination with other antiretroviral drugs (nevirapine or a protease inhibitor).161,162 It is unclear whether pregnancy is a risk factor for the development of lactic acidosis/hepatic steatosis syndromes that have been reported for NRTIs, or whether mitochondrial toxicity caused by nucleoside analogues increases development of haemolysis, elevated liver enzymes, low platelets (HELLP) syndromes. Alertness for the possibility of these problems in pregnant women receiving NRTIs is important. Moreover, in view of the maternal mortality secondary to lactic acidosis with use of the combination of d4T and ddI, it is advised, if possible, not to prescribe this antiretroviral combination during pregnancy.103,161

Artificial reproduction In couples, where one of the partners is HIV-infected, pre-conceptional advice is warranted to consider the pros and cons of the measures that should be taken to avoid horizontal as well as vertical transmission of HIV. In case of a HIV infection of both partners, such advice is also warranted since risk may exist of a new infection with a resistant virus or another virus strain. If no fertility problem exists in a HIV-infected women with an uninfected man, information on the risk of

MTCT and the ways to avoid it should be given. If the couple chooses for pregnancy, instructions should be given to perform self-insemination at home. An ovulation test will help to reduce unnecessary inseminations. In case this does not yield pregnancy in 6–12 months, a fertility examination of the couple should follow. When a fertility problem exists, that can only be treated by in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI), a HIV-infected woman should be referred to a centre that offers such facilities. Except for the reserved equipment used for HIVinfected women, no special precautions or protocols have to be observed. This is different in case of a HIV infection of the male partner since HIV is transmitted by sperm. In 1992, Semprini et al reported on 29 women inseminated with processed semen of their HIV-seropositive partner.163 None of the inseminated women seroconverted and their ten babies remained HIV seronegative. Recently, the first multicentre retrospective study of assisted reproduction following sperm washing demonstrated this method to be effective (580 pregnancies from 3315 cycles) and to significantly reduce HIV-1 transmission risk to the uninfected female partner. The calculated probability of contamination was equal to zero (CI 95% 0–0.09%).164 In case of a HIV-infected seroconcordant couple, a decision has to be taken (on the basis of the potential risk of cross-infection with unwanted HIV strains) whether the woman should be inseminated with processed sperm or the couple should be advised to have a natural conception, preferably well timed by ovulation tests in order to minimise the number of unprotected sex acts. In summary, it looks as if reproduction in HIVinfected couples can occur nearly without risk of horizontal as well as of vertical transmission. The risks involved for the well-being of the future infant are not zero but fortunately very limited.

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uninfected infants: clinical screening in a large prospective cohort. AIDS 2003; 17: 1769–85. Nucleoside exposure in the children of HIVinfected women receiving antiretroviral drugs: absence of clear evidence for mitochondrial disease in children who died before 5 years of age in five United States cohorts. J Acquir Immune Defic Syndr 2000; 25: 261–8. European Collaborative Study. Exposure to antiretroviral therapy in utero or early life: the health of uninfected children born to HIV-infected women. J Acquir Immune Defic Syndr 2003; 32: 380–7. Alimenti A, Forbes JC, Oberlander TF et al. A prospective controlled study of neurodevelopment in HIV-uninfected children exposed to combination antiretroviral drugs in pregnancy. Pediatrics 2006; 118: e1139–45. Lipshultz SE, Easley KA, Orav EJ et al. Absence of cardiac toxicity of zidovudine in infants. Pediatric Pulmonary and Cardiac Complications of Vertically Transmitted HIV Infection Study Group. N Engl J Med 2000; 343: 759–66. Brogly SB, Ylitalo N, Mofenson LM et al. In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children. AIDS 2007; 21: 929–38. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C et al. Perinatal antiretroviral treatment and hematopoiesis in HIV-uninfected infants. AIDS 2003; 17: 2053–61. European Collaborative Study. Levels and patterns of neutrophil cell counts over the first 8 years of life in children of HIV-1-infected mothers. AIDS 2004; 18: 2009–17. Bunders M, Thorne C, Newell ML; European Collaborative Study. Maternal and infant factors and lymphocyte, CD4 and CD8 cell counts in uninfected children of HIV-1-infected mothers. AIDS 2005; 19: 1071–9. Bunders MJ, Bekker V, Scherpbier HJ et al. Haematological parameters of HIV-1-uninfected infants born to HIV-1-infected mothers. Acta Paediatr 2005; 94: 1571–7. Pacheco SE, McIntosh K, Lu M et al. Effect of perinatal antiretroviral drug exposure on hematologic values in HIV-uninfected children: An analysis of the women and infants transmission study. J Infect Dis 2006; 194: 1089–97. Wogan GN. Does perinatal antiretroviral therapy create an iatrogenic cancer risk? Environ Mol Mutagen 2007; 48: 210–14. Walker DM, Malarkey DE, Seilkop SK et al. Transplacental carcinogenicity of 3′-azido-3′deoxythymidine in B6C3F1 mice and F344 rats. Environ Mol Mutagen 2007; 48: 283–98. Witt KL, Cunningham CK, Patterson KB et al. Elevated frequencies of micronucleated erythrocytes in infants exposed to zidovudine in utero and postpartum to prevent mother-to-child transmission of HIV. Environ Mol Mutagen 2007; 48: 322–9. Culnane M, Fowler M, Lee SS et al. Lack of longterm effects of in utero exposure to zidovudine among uninfected children born to HIV-infected women. Pediatric AIDS Clinical Trials Group Protocol 219/076 Teams. JAMA 1999; 281: 151–7.

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140. Hanson IC, Antonelli TA, Sperling RS et al. Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine. J Acquir Immune Defic Syndr Hum Retrovirol 1999; 20: 463–7. 141. European Collaborative Study; Swiss Mother and Child HIV Cohort Study. Combination antiretroviral therapy and duration of pregnancy. AIDS 2000; 14: 2913–20. 142. Thorne C, Patel D and Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS 2004; 18: 2337–9. 143. Tuomala RE, Shapiro DE, Mofenson LM et al. Antiretroviral therapy during pregnancy and the risk of an adverse outcome. N Engl J Med 2002; 346: 1863–70. 144. Townsend CL, Cortina-Borja M, Peckham CS, Tookey PA. Antiretroviral therapy and premature delivery in diagnosed HIV-infected women in the United Kingdom and Ireland. AIDS 2007; 21: 1019–26. 145. 46. Kourtis AP, Schmid CH, Jamieson DJ, Lau J. Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a metaanalysis. AIDS 2007; 21: 607–15. 146. Grosch-Woerner I, Puch K, Maier RF et al. Increased rate of prematurity associated with antenatal antiretroviral therapy in a German/Austrian cohort of HIV-1-infected women. HIV Med 2008; 9: 6–13. 147. Tuomala RE, Watts DH, Li D et al. Women and Infants Transmission Study. Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy. J Acquir Immune Defic Syndr 2005; 38: 449–73. 148. Suy A, Martínez E, Coll O et al. Increased risk of pre-eclampsia and fetal death in HIV-infected pregnant women receiving highly active antiretroviral therapy. AIDS 2006; 20: 59–66. 149. Kourtis AP, Bansil P, McPheeters M et al. Hospitalizations of pregnant HIV-infected women in the USA prior to and during the era of HAART, 1994–2003. AIDS 2006; 20: 1823–31. Erratum in: AIDS 2007; 21: 2257. 150. Timmermans S, Tempelman C, Godfried MH et al. Nelfinavir and nevirapine side effects during pregnancy. AIDS 2005; 19: 795–9. 151. Stern JO, Robinson PA, Love J et al. A comprehensive hepatic safety analysis of nevirapine in different populations of HIV infected patients. J Acquir Immune Defic Syndr 2003; 34: S21–33. 152. Lyons F, Hopkins S, Kelleher B et al. Maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy. HIV Med 2006; 7: 255–60. 153. Hitti J, Frenkel LM, Stek AM et al. Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr 2004; 36: 772–6. 154. Natarajan U, Pym A, McDonald C et al. Safety of nevirapine in pregnancy. HIV Med 2007; 8: 64–9. 155. Prevention of HIV Transmission from HIV Mothers to their Infants. Clinical Protocol for the WHO European Region. WHO 2006; at: http://www. euro.who.int/pubrequests.

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156. Hawkins D, Blott M, Clayden P et al. Guidelines for the management of HIV infection in pregnant women and the prevention of mother-to-child transmission of HIV. HIV Med 2005; 6(Suppl 2): 107–48. 157. Florescu D, Kotler DP. Insulin resistance, glucose intolerance and diabetes mellitus in HIV-infected patients. Antivir Ther 2007; 12; 149–62. Review. 158. Blümer RM, van Vonderen MG, Sutinen J et al. Zidovudine/lamivudine contributes to insulin resistance within 3 months of starting combination antiretroviral therapy. AIDS 2008; 22: 227–36. 159. Hitti J, Andersen J, McComsey G et al. Protease inhibitor- based antiretroviral therapy and glucose tolerance in pregnancy: AIDS Clinical Trials Group A5084. Am J Obstet Gynecol 2007; 196: 331.e1–7. 160. Martí C, Peña JM, Bates I et al. Obstetric and perinatal complications in HIV-infected women. Analysis of a cohort of 167 pregnancies between

161. 162.

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1997 and 2003. Acta Obstet Gynecol Scand 2007; 86: 409–15. Bristol-Myers Squibb Company. Healthcare Provider Important Drug Warning Letter. January 5, 2001. Sarner L, Fakoya A. Acute onset lactic acidosis and pancreatitis in the third trimester of pregnancy in HIV-1 positive women taking antiretroviral medication. Sex Transm Infect 2002; 78: 58–9. Erratum in: Sex Transm Infect 2003; 79: 429. Semprini AE, Levi-Setti P, Bozzo M et al. Insemination of HIV-negative women with processed semen of HIV-positive partners. Lancet 1992; 340: 1317–19. Bujan L, Hollander L, Coudert M et al. Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network. AIDS 2007; 21: 1909–14.

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14 The patient with cystic fibrosis Godelieve CML Page-Christiaens, Ferdinand Teding van Berkhout

Introduction In Caucasians cystic fibrosis (CF) is the most frequent inherited life-limiting disease. It affects multiple organs. Respiratory and gastrointestinal complications are the predominant manifestations, the former being the cause of death in over 90% of affected individuals. In the past, life expectancy was very low. Improvement in treatment and care in specialised centres led to a considerable rise in survival. This has raised new questions regarding future choices not only for study and career, but also about fertility, reproduction and parenthood. In this chapter fertility, reproduction and parenthood in females with CF are discussed.

Epidemiology CF is caused by mutations on chromosome 7 in the CF transmembrane conductance regulator gene (CFTR). The mutation spectrum and frequency are highly dependent on ethnic origin. More than 1500 CFTR mutations have been identified, delta F 508 mutation (F508del) being the most common.1 In the European Union CF occurs on average in one in 2500 liveborns. In France the birth prevalence has been well defined from nationwide newborn screening and was 1/4700.2 A similar figure has been calculated for the Netherlands through case identification via the seven CF treatment centres.3 The Republic of Ireland is an outlier with one in 1353 as is Finland with one in 25 0002,4–6 (Table 14.1). In non-Caucasians the birth incidence is much lower with one in 5000 newborns affected in North American Afro-Americans and one in 31 000 in Asian Americans.7–9 In France10 and the USA11 a gradual decrease in birth incidence has been noticed during the past two decades, ascribed at least in part to the fact that preconception, prenatal and newborn screening increase the reproductive options of parents at a one in four risk of having another child with CF. Before neonatal screening was introduced, The Netherlands reported a decrease in birth incidence from 1/3600 between 1961 and 1965 to 1/4750 between 1974 and 1994. Immigration from countries with a lower carrier

Table 14.1 Number of cystic fibrosis (CF) patients according to several national registries. Country USA Canada UK France The Netherlands Norway and Sweden

Number of CF patients 24 487 3 452 7 046 4 744 1 155 700

frequency and increased use of prenatal diagnosis and termination of pregnancy in case of an affected foetus have at least in part been held responsible for this decrease.3 Through early diagnosis, early interventions, new medications and a multidisciplinary approach, survival in CF has improved tremendously during the past five decades. In the years 1943–1964 only 15% of the CF patients with meconium ileus survived beyond the age of 12 months. Of those without meconium ileus, 20% were alive at the age of 4.12 In 2006, the median survival of CF patients in the USA and Canada was 37 years. Younger birth cohorts of CF patients prosper even better (Cystic Fibrosis Foundation Patient Registry Annual Data Report 2006; page 3) and a further increase of survival is to be expected3,13,14 (Figs 14.1 and 14.2). The adult CF population in the Western world is growing (Fig 14.3). More than 40% of CF patients is older than 18 years. Several CF centres now report CF patients living into their 6th decade. CF has hence evolved from a paediatric to an adult disease, and pregnancy and parenthood have become a realistic option. Obstetricians, midwives and obstetric anaesthesiologists now have become members of the multidisciplinary CF teams.

Genetics and molecular biology Dorothy Anderson was the first to recognise the clinical picture of CF. In 1938 she gave a detailed description of the clinical and autopsy findings of children suffering from this condition.15 The autosomal recessive mode of inheritance was noted several years later16 and in 1989,

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100 90 80

Survival (%)

70 60 50 40 30 20 10 0 0

5

1950–1954 1970–1973

10

15

20

1955–1959 1974–1979

25 30 Age (years)

35

1960–1964 1980–1984

40

45

1965–1969 1985–1989

50

55

1990–1994

Fig 14.1 Survival of different cohorts of patients with cystic fibrosis (CF) born between 1950 and 1989. From reference 3, with permission.

42

Median survival age (years)

40 38 36 34 32 30 28 26 24 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 Year

finally, it was Lap-Chee Tsui who identified the CF gene on the long arm of chromosome 7.17–19 The normal CF gene encodes for a transmembrane protein, CFTR, which is expressed in sweat glands, exocrine glands, lungs and in the male and female reproductive tract. This protein provides a chloride channel in the apical membrane of exocrine epithelial cells. The occurence of two identical mutations (homozygous) or of two different mutations (compound heterozygous) in the chromosomes 7 causes CF. In CF the CFTR protein is absent, non-functional or deficient.28 The CFTR protein is a member of the adenosine triphosphate (ATP) binding cassettes (ABC) transporter proteins. It consists of two membrane spanning domains (MSD 1 and MSD 2), which form the channel, two nucleotide binding domains (NBD 1 and NBD 2) capable of ATP hydrolysis, and a regulatory domain (R) with several phosphorylation sites20 (Fig 14.4).

Fig 14.2 Median age to which half of the current population with CF would be expected to survive. Data from the USA CFF Patient Registry Annual Data Report 2006, with permission. (www.cff.org)

In epithelial exocrine cells, CFTR functions as a meticulously regulated chloride channel. The composition of airway surface fluid, bile, pancreatic secretion and sweat is determined in part by this channel. In CF, CFTR is absent or deficient in exocrine epithelial cells leading to an imbalance of water and electrolyte movement across the epithelial membrane and an alteration of the mucus produced in the affected organs. Wild type CFTR is translated in the endoplasmatic reticulum (ER) and folded. Only the adequately folded CFTR travels to the Golgi apparatus and is incorporated in the apical membrane of the epithelial cell. Misfolded CFTR is recognised by the ER quality control system, and targeted for proteosomal degradation.20,22,23 Several classes of CF mutations have been identified.22–26 They are described in Table 14.2 and Fig 14.5.

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Individuals with cystic fibrosis aged ≥18 years (%)

50

40

30

20

10

0 1970

1975

1980

1985 1990 Year

1995

2000

2005

No. of individuals with cystic 7962 fibrosis in registry

10526

11916

14117

19736

21379

23347

15671

Fig 14.3 Number of individuals with CF registered in the USA CFF Patient Registry Data between 1970 and 2005 and percentage of those above the age of 18 years. From reference 38, with permission.

MSD 2

MSD 1

Cl−

N

NBD 1

NBD 2

Table 14.2

Classification of CFTR mutations.

Class

Mutations

I II III IV V

W1282X, G542X, R553X, E822X F508del, D1507, S549I, G85E G551D, S492F, R553G, R560S R117H, R117C, R117P, L88S 3849 + 10kb CT, 1811 + 1.6kb AG, 3272–26 AG.

R Domain

Cytoplasm

C

Fig 14.4 Different components of the CFTR protein in the apical cells. MSD 1 and 2, membrane spanning domain 1 and 2; NBD 1 and 2, nucleotide binding domain 1 and 2; R, regulatory domain. From references 20 and 21, with permission.

In mutation classes I, II and III no functional CFTR is present in the apical membrane of the epithelium. These mutations lead to more severe disease in CF. In mutation classes IV and V some residual CFTR activity is present leading to milder disease with fewer respiratory symptoms and no pancreatic insufficiency. The relative frequencies of CFTR mutations in CF patients vary considerably between regions and populations.28,29 In Denmark a F508del mutation is found in 90% of Caucasian CF patients 70% of whom are homozygotic. In Turkish CF patients, the F508del frequency is 21.3%. In Turkish and North African CF patients a substantial proportion of CFTR mutations remain undetected even with the use of extended CFTR mutation panels.29 Standard kits usually identify 30–35

mutations. In the Dutch population this accounts for 88% of CF alleles. The sensitivity of carrier testing varies between 70 and 95% in different populations. By denaturating gradient gel electrophoresis (DGGE) and sequencing, almost 100% of CFTR mutations can be identified. These techniques are too cumbersome for population screening, but can be used in the individual CF patient.

Pathophysiology CF is a multisystem disease affecting organs of epithelial origin. It is characterised by chronic bronchopulmonary infection, pancreatic insufficiency, diabetes mellitus, meconium ileus, liver cirrhosis, growth failure, male infertility and female subfertility. Absent, non-functional or dysfunctional CFTR interferes with normal epithelial ion transport, leading to dysfunction of the affected organs as illustrated in Fig 14.6. Normal airways are covered by a single layer of epithelial cells, comprising ciliated cells and goblet cells. The cilia are bathed with periciliar fluid and on

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Fig 14.5 Classification of CFTR mutations. Adapted from reference 27, with permission. In class I and II mutations there is no protein, in class III mutations the chloride channel does not open well leading to absence of secretion of the protein, in class IV mutations the chloride conduction is diminished and CFTR secretion diminished, and in class V mutations the CFTR production is diminished.

A

Non-CF

CF

B

Poorer mucociliary clearance Bacteria trapped in mucus poorly hydrated mucus Decreased pO2

MEP Decreased depth of periciliary fluid

Airway epithelium

top of the cilia mucus is present. In the viscous mucus particles and bacteria are caught. The orchestrated ciliary beat moves the mucus towards the throat, where it is swallowed. This so-called mucociliary clearance is able to keep the airways clean and prevent bacterial growth. The airway surface liquid (ASL) consists of mucus, formed in submucosal glands and goblet cells, and the periciliary fluid is secreted by the epithelial monolayer. The volume and water content of the ASL is regulated by absorption and secretion of liquid, driven by active electrolyte transport of electrolytes across the epithelial cells. In CF this equilibrium is disturbed: chloride secretion is limited and hyperabsorption of sodium ions and water results in dehydrated mucus and defective mucociliary clearance favouring

Fig 14.6 Periciliar fluid in the normal situation and in cystic fibrosis (CF) patients. MEP, Mucoid exopolysaccharide produced by pseudomonas aeruginosa and added to the mucus, contributing to biofilm formation. From reference 32, with permission.

bacterial growth. Bacterial growth leads to local ongoing inflammation and damage to the airways.31–34

Cystic fibrosis: clinical aspects Cystic fibrosis is a multiorgan disorder. Most patients are troubled by respiratory problems, recurrent bronchopulmonary infections, exocrine pancreatic insufficiency, malabsorption, growth retardation and gastrointestinal complaints. Even with the same mutations, leading to the so-called classical disease, the age of onset, organ involvement, severity and progression of disease, and life expectancy vary considerably. There is no strict genotype–phenotype correlation, although some CFTR mutations result in residual

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Table 14.3

163

Frequently occurring problems in patients suffering from cystic fibrosis (CF) and their management.

Organ system

Symptoms/syndromes

Therapeutic measures

Respiratory system

Recurrent bacterial infections Bronchiectasis Haemoptysis Pneumothorax Allergic bronchopulmonary aspergillosis Respiratory insufficiency

ENT

Nasal polyps Chronic rhinosinusitis

Oral or parenteral antibiotics Nebulisation of: • Mucolytics: dornase alpha • Hypertonic saline • Antibiotics Physiotherapy Additional oxygen, non-invasive positive pressure ventilation (NIPPV), Lung transplantation Nasal saline irrigation Topical steroids Antibiotics Endoscopic sinus surgery

Gastrointestinal system

Meconium ileus Distal intestinal obstruction syndrome (DIOS) Constipation Gastroesophageal reflux Rectal prolapse

Gastrografin enema, surgery Laxatives, enemas, intestinal lavage Proton pump inhibitors (PPI)

Pancreas

Exocrine pancreatic insufficiency Pancreatitis CF related diabetes Steatosis hepatic Liver cirrhosis Gallstones

Oral replacement of pancreatic enzymes + PPI Insulin Ursodeoxycholic acid (UDCA), liver transplantation UDCA, surgery

Reproductive health

CBAVD in males Subfertility in women

MESA, PESA, TESE Intrauterine insemination

Growth, maturation

Malabsorption, poor growth Pubertal delay Osteopenia/osteoporosis

Vit D + Vit K supplementation, calcium, bisphosphonates

Other

Arthropathia/arthritis Nephrolithiasis Vasculitis Urinary incontinence in women

Hepatobiliary system

CBAVD, congenital bilateral absence of the vas deferens; MESA, microsurgical epididymal sperm aspiration; PESA, percutaneous epidydimal sperm extraction; TESE, testicular sperm extraction.

CFTR function and a different phenotype, called “non-classical cystic fibrosis”.35 Factors influencing this variability are listed below:36–38 (1) CFTR mutation class. In the severe mutations (classes I, II, III and IV) CFTR is absent or nonfunctional, and pancreatic insufficiency is unvariably present. In mutation classes IV and V, residual CFTR function is preserved. CF patients with these milder mutations are commonly pancreatic sufficient, manifest milder lung disease and have a better prognosis. (2) Modifier genes. In patients homozygous for F508del the severity of respiratory disease varies substantially. Modifier genes (non-CFTR genes), for example TGFß1 polymorphism, are associated with severity of lung disease.

(3) Environmental influences. These include nutrition, micro-organisms, tobacco, stress, socio-economic status, time of diagnosis, adherence to and access to therapy and centralisation of care.39 The main clinical manifestations and their principle therapeutic approaches are listed in Table 14.3. (1) Respiratory complications. Over 90% of morbidity and mortality is due to bronchopulmonary disorders. Haemophilus influenzae, Staphylococcus aureus and Pseudomonas aeruginosa are the main micro-organisms causing recurrent respiratory infections. Chronic inflammation damages the airways, causing bronchiectasis and progressive irreversible bronchial obstruction, eventually resulting in a respiratory insufficiency.40 The

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(3)

(4)

(5)

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cornerstone of treatment is airway clearance therapy, adequate prevention and treatment of infections and inflammation, and physiotherapy. Most bronchodilator drugs are allowed in pregnancy. The choice of antibiotics needs special attention as some are clearly contraindicated in pregnancy. Ear, nose and throat complications. Many CF patients suffer from chronic rhinosinusitis. Nasal polyposis causes nasal obstruction, anosmia and headache. The sinuses become chronically infected by organisms such as P. aeruginosa. The inflammatory burden of the upper airways contributes to the inflammation of the lower airways.41 Gastrointestinal problems. Meconium ileus is the presenting symptom in about 6–20% of CF neonates.42 Distal intestinal obstruction syndrome (DIOS) occurs in about 16% of adolescent and adult CF patients. Terminal ileum and ascending colon become obstructed by inspissated faecal material, causing pain, abdominal distension and vomiting.43 Gastroesophageal reflux disease (GER) occurs in 20–50% of CF patients. GER may compromise pulmonary function and nutritional status.44 Laxatives and proton pump inhibitors may be required and can be continued in pregnancy. Pancreatic problems. Exocrine pancreatic insufficiency (PI) is present in more than 85% of CF patients, causing steatorrhoea and malabsorption. If two severe mutations are present (homozygosity or compound heterozygosity for class I, II or III mutations), CFTR is absent or non-functional and the patient has pancreatic insufficiency. Compound heterozygosity for milder mutations (one class IV or V mutation is present, some CFTR activity remains) is associated with pancreatic sufficiency (PS).45 Pancreatic insufficiency is treated with pancreatic enzymes, which can be safely taken during pregnancy. Long lasting pancreatic insufficiency results in defective insulin secretion by the islets of Langerhans and CF related diabetes (CFRD). Due to the increased survival of CF patients the prevalence of CFRD is rising.46 Hepatobiliary disease. CF associated liver disease (CFALD) is diagnosed in approximately 20% of CF patients in their first two decades of life.47 Six per cent of CF patients have evidence of biliary cirrhosis and 2% manifest signs of liver decompensation (e.g. ascites, variceal bleeding, encephalopathy). Gall stones are frequently found.48 Although ursodeoxycholic acid is recommended for the treatment of intrahepatic cholestasis in the second and third trimesters of pregnancy, there are few data on their use in the first trimester. Reproductive health. Of male infertility 1–2% is caused by mutation(s) in the CFTR encoding gene. Males with CF have congenital bilateral absence of the vas deferens (CBAVD) and obstructive azoospermia, that cannot be surgically corrected.49 Nevertheless, spermatogenesis is preserved and

patients can father a pregnancy via assisted reproductive techniques (ART) such as percutaneous or microsurgical epidydimal sperm aspiration (PESA or MESA) or testiscular sperm extraction (TESE) followed by intracytoplasmatic sperm injection (ICSI). Hubert et al49 described 23 men with CF and azoospermia pursuing a pregnancy who elected to undergo ART including ICSI. Pregnancies occurred in 12 couples and in nine couples 11 singletons were born. Although all men were described to be azoospermic, with at least one semen sample analysed, two men became parents by natural conception. Paternity testing was not done for ethical reasons. In another study50 one out of 94 CF men fathered a child naturally. Mispaternity was not tested here either. ICSI is associated with a 1% additional risk of de novo numerical abnormalities of the sex chromosomes in the offspring. The major congenital malformation rate is similar for IVF and ICSI. A few children have diseases caused by imprinting disorders, especially Beckwith-Wiedemann syndrome and retinoblastoma.51 There has been concern that imprinting disorders may occur when sperm is obtained via surgical methods.52 The true fertility rate in women with CF is unknown, but this is likely to be high (see below).

Cystic fibrosis diagnosis and prognosis The majority of CF patients have a classical presentation of CF: chronic sinopulmonary disease, steatorrhoea, malnutrition, failure to thrive and salt loss syndrome. Meconium ileus and intestinal obstruction within 48 hours of birth is the first symptom of CF in 15–20% of newborns. These are sometimes predicted by foetal bowel densities on antenatal ultrasound. In most children the diagnosis is made later in life, in The Netherlands at an average age of 11 months with failure to thrive and repetitive pulmonary infections as presenting symptoms. Some patients have much milder disease manifestations and are diagnosed late, despite the presence of mutations on both CFTR genes (e.g. a man with mild sinopulmonary disease and CBAVD). The clinician has to consider the diagnosis CF, if a patient has presenting symptoms listed in Table 14.4.53 The Gibson and Cooke sweat test (the pilocarpine iontophoresis sweat test) is unequivocally efficient in diagnosing patients with the classical picture of CF. In a North American study an elevated sweat chloride concentration was found in 98% of CF patients.54 As a result classical CF (or typical CF) is defined as one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. Non-classical CF or atypical CF is defined as a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30–60 mmol/l) sweat chloride level. The diagnosis in non-classical CF is confirmed by detection of

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Table 14.4 Presenting symptoms of patients diagnosed with cystic fibrosis. Recurrent respiratory infections Rhinosinusitis and polyposis nasi in a patient without asthma Steatorrhoea Failure to thrive/malnutrition Meconium ileus Distal intestinal obstruction syndrome (DIOS) Rectal prolapse Electrolyte imbalance Hepatobiliary disease Digital clubbing Azoospermia/congenital bilateral absence of the vas deferens (CBAVD)

Table 14.5 Predictors of poor prognosis in cystic fibrosis (CF). Respiratory complications have the greatest impact on survival (2 year survival 50% if forced expiratory volume in 1 second (FEV1) <30% or rapidly declining). FEV1 <30% predicted or rapid decline in FEV1 Hypoxia, hypercarbia Pulmonary hypertension Poor nutritional state: hypoalbuminaemia, wasting, poor weight for height (BMI <18 kg/m2) Frequent respiratory infections Massive haemoptysis Recurrent pneumothorax Liver disease CF related diabetes Female BMI, body mass index.

mutations on both CFTR genes or by direct quantification of CFTR dysfunction by nasal potential difference measurement (NPD). Borderline sweat test results are found in about 4% of tests. Of these patients around 23% have two CFTR mutations and are diagnosed as patients suffering from non-classical CF.54–56 In the majority of patients the clinical picture is indicative. Additional tests of CFTR function (sweat test or NPD) or mutation analysis will categorise these patients in three groups: CF unlikely, non-classical CF or classical CF. The European Diagnostic Working Group on CF proposed the diagnostic work-up shown in Fig 14.7.54 Prognostically the forced expiratory volume in 1 second (FEV1) is the most useful test. This is the amount of gas which can be forcibly expired from a maximal inspiration in one second and reflects airway resistance of the lungs as well as of the bronchial tree. FEV1 does not change during pregnancy. Other prognostic factors are listed in Table 14.5.13,39,57,58

Neonatal screening Several countries and regions have introduced59 or even legally required60 neonatal screening for early detection of CF. Determination of immunoreactive trypsinogen

165

(IRT) and pancreatitis associated protein (PAP) shortly after birth in neonatal blood is most promising in detecting infants who will develop the clinical picture of classic CF.61 It is most likely that early diagnosis of CF improves the outcome for the CF patient as compared with clinically diagnosed cases.62–64

Fertility in the female patient with cystic fibrosis Although women with CF have a decreased fertility due to unfavourable cervical mucus characteristics and ovulatory disturbances,65 they have fewer fertility problems than hitherto assumed. In a recent Scandinavian study66 46 out of 61 (75%) women wishing to conceive became pregnant, 34 spontaneously, seven with intrauterine insemination and five with in vitro fertilisation (IVF). Avoiding multiple pregnancy is crucial for the CF patient who is very unlikely to be able to cope with the increased nutritional, mechanical and ventilatory demands of a multiple pregnancy. Intrauterine insemination should be done in a natural cycle and single embryo transfer in case of IVF. More than half of the women interviewed in the Scandinavian study, however, did not pursue pregnancy. Reasons for refraining from pregnancy are difficulties in finding a permanent partner, reluctance towards medical interventions in such a private matter, being physically not fit enough, lack of excess energy to raise a child, fear of complications, uncertainty about the future, reduced life expectancy and not wishing to transmit disease or carriership. In rare cases there has been an individual request for surrogate mothership. Intensive multidisciplinary discussions should precede such a decision (see Ethical considerations). In 2007 a case was presented in the Dutch press67 where the patient’s mother successfully carried her twins.

Cystic fibrosis and pregnancy: figures Since the publication of the first case of a pregnancy in a woman with CF in 196068 worldwide more than 1500 pregnancies have been described in women with CF. The largest study is a nationwide study by Goss et al69 describing 680 patients enrolled in the USA Cystic Fibrosis Foundation National Patient Registry between 1985 and 1997 and matching them to nonpregnant control women with CF. Other nationwide data come from France,70 The Netherlands,3 Israel,71 Norway and Sweden,66,72 the UK,73 Canada74 and the USA.75 Many of the other data come from smaller retrospective studies or case histories76–79 describing patients from 1960 onwards up to 2004. The number of pregnancies increases as general CF patient condition and survival improve together with a change in attitude of the medical teams. The USA Cystic Fibrosis Foundation registered 209 pregnant women in its 2006 Annual Data Report. The 2001 UK Cystic Fibrosis

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Clinical suspicion

Sweat test

30–60 mmol/l

<30 mmol/l

>60 mmol/l

CF centre

Repeat sweat test

<30 mmol/l

>60 mmol/l

30–60 mmol/l CFTR DNA test

CFTR DNA test 0 mutation

1 mutation

2 mutations 0 mutation

1–2 mutations

Clinical review other diagnosis

Yes

No

Nasal PD Consult genetic lab

Normal

Inconclusive

Abnormal

Mutatation scanning of CFTR gene

0 mutation

1 mutation

2 mutations

Consider CF heterogeneity? False + sweat test?

Inconclusive Consider FU (at CF centre)

CF unlikely

CFTR dysfunction

Classic CF

• non-classic CF • WHO diagnostic list

Consider alternative diagnosis Appropriate investigations and follow-up

Follow-up at CF centre

Fig 14.7 Algorithm for the diagnosis of cystic fibrosis (CF) starting with the sweat test. PD, potential difference; FU, follow-up. From reference 54, with permission.

Database reports on 84 pregnancies in 5.7% of women of reproductive age with CF.74 Odegaard and colleagues reported on 23 women carrying 33 pregnancies in Norway and Sweden (total number of CF patients 700) between 1977 and 1998 and on 46 women conceiving 80 pregnancies and delivering 60 babies in 2000.72 In The Netherlands the estimated number of CF patients is 1300. To date, only 20–25 Dutch women with CF have

carried a pregnancy and delivered one or more children (Elly van Es, Dutch Foundation for CF, Personal communication). Of all the Dutch CF patients (male and female) 8% have children. This is in sharp contrast with Australian data where 37% of CF patients have children. There are few data on female patients requesting reproductive assistance when natural intercourse fails to result in conception.

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Influence of the disease on pregnancy Most women with CF deliver healthy children. Premature delivery either spontaneously or via Caesarean section for maternal reasons is the most common complication. Women with poor nutritional status, diabetes, colonisation with Burkholderia cepacia, moderate to severe lung disease and/or pancreatic insufficiency have an increased rate of premature delivery. A low FEV before pregnancy and a low weight gain during pregnancy are the best predictors of premature delivery. There are no reports on chronic CF related liver disease and pregnancy. As to route of delivery, in a Scandinavian study one-quarter of the deliveries were via Caesarean section, most for maternal reasons. Eighty per cent of the babies were breastfed, although in all cases only for 3 months. The only neonatal complications were those of prematurity. All women who delivered at term had conceived spontaneously.66,72

Influence of pregnancy on disease Women in a stable pulmonary and nutritional condition receiving good medical care usually are considered at low risk for disease deterioration. Prepregnancy FEV1 and body mass index (BMI) are good predictors for both maternal and child outcome. The average weight gain of a patient with CF in a Scandinavian series72 was 10 kg (19% increase of body weight) which is within the normal range. Fifty per cent of women, all with pancreatic insufficiency, needed nutritional supplements either via a nasogastric tube or parenteral. The need for intravenous antibiotics was doubled during pregnancy as compared to the pre- or postpregnancy period. Lung function did not deteriorate during pregnancy. Four out of 23 women developed gestational diabetes, in concordance with data from other studies.74,75 The matched control study of McMullen et al, covering 216 CF patients pregnant between 1995 and 2003 from the USA Cystic Fibrosis Foundation (CFF) National Patient Registry, showed that the prevalence of diabetes more than doubled.75 Pregnancy in CF is associated with decreased insulin sensitivity and secretion and high hepatic glucose production. This predisposes pregnant CF women to gestational diabetes.80 In the past 20 years the Norwegian registry of maternal death has not mentioned a single mother with CF dying during pregnancy or within 1 year of delivery. There are literature reports on one maternal death during pregnancy and three in the year following the pregnancy in France between 1980 and 1999.70 Goss et al studied the effect of pregnancy in CF patients on survival, using the CFF database and matched pregnant CF women to non-pregnant CF women. Matching was done for FEV1, BMI, age and pulmonary exacerbation rate per year. Pregnancy did not have a negative influence on survival, not even in women with a FEV1 below 40% of expected or with diabetes mellitus. There are

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no data on the effect of parenthood on morbidity and survival of CF patients. In general, one in five children will be raised without a mother at the age of 10 years. In patients with unfavourable parameters (FEV1 below 40% or diabetes) this will be the case for two in five children.69

Pregnancy after transplantation CF patients with deteriorating respiratory status, severely restricted physical activity and poor quality of life, are selected for lung transplantation. After lung transplantation CF patients have a median survival of more than 7 years in some transplantation centres (unpublished data). There are very few data on pregnancies after lung transplantation in CF patients. Gyi et al81 described ten cases from the UK. Four mothers showed rejection during pregnancy of whom one already showed signs before pregnancy. All four died of chronic rejection within 38 months after delivery. The other six women were stable 1–6 years after delivery. As to the foetal outcome, one pregnancy was terminated, the other nine ended with livebirth and, although some infants were premature, all were doing well at follow-up. Lung transplantation is generally considered to be a contraindication for pregnancy in CF patients, and this is certainly the case in patients showing episodes of rejection, and in patients with obliterative bronchiolitis. Comorbidity and medication also have to be taken into account.

Pre-conceptional assessment A thorough prepregnancy assessment and multidisciplinary consultation (pulmonologist, gynaecologist, clinical geneticist, nurse practitioner, dietician) should precede any pregnancy in a woman with CF. The assessment should include pulmonary function, sputum cultures, BMI, haemoglobin A1c, adaptation of medication if pregnancy is to be pursued, and carrier testing of the partner if so wished. Pregnancy should be discouraged or strongly advised against because of maternal risks in cases with pulmonary hypertension, significant liver disease and status after lung transplantation. A BMI below 18 kg/m2 and a FEV1 below 50% of predicted are relative contraindications because they are associated with a significant increase of the risk for (iatrogenic) preterm delivery. In severe pancreatic dysfunction, reaching an adequate weight gain during pregnancy will be difficult.

Contraception Pharmacokinetic studies have shown adequate concentrations of oestradiol in three CF patients receiving 50 µg ethinyl oestradiol orally and no systemic antibiotics.82

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However, multiple drug interactions, malabsorption, diarrhoea and liver disease with disturbed enterohepatic circulation may diminish the bioavailability of oral contraceptives. This is sometimes, but not always, heralded by breakthrough bleeding.

Ethical issues Parenthood is a full-time job and the decision to have a family is never a simple one. CF patients usually need 2–4 hours a day for airway cleaning, nebulisation, administration of medication (local and systemic) and physiotherapy. On the one hand, having a child may give a new purpose to life and enhance motivation to do these daily chores, while on the other, the care for the newborn may entail a time constraint prohibiting adequate self care. Also, young children increase the infectious load within a family unit. Another issue is the health and happiness of the child itself. The child will have one parent with a progressive chronic disease and experience the restrictions this entails for family life and activities. The child might become a caregiver at a young age. He or she eventually will lose a parent at a young age. The median maternal survival in a study from the UK covering 72 pregnancies was 11.9 years after the birth of the first child. In women delivering preterm this median survival was 7.6 years.79 However, the child will realise that not everyone is healthy and that health is not a given. Finally, the child will be by definition a carrier of one CF mutation and in due time have to inform a potential partner.

Special considerations when the partner is a cystic fibrosis carrier Reproductive choices when the partner is a carrier too consist of undergoing prenatal diagnosis followed by eventual termination of pregnancy in case of an affected foetus, to refrain from having children, to use donor gametes, or to use IVF in combination with preimplantation genetic diagnosis (PGD). Couples are more likely to consider PGD when there is a need for ART because of reduced fertility, when they have moral objections against pregnancy termination or negative experience with a previous termination, and when there is a strong wish to have children that are biologically their own. Worldwide, CF was the first autosomal monogenic disorder for which PGD became available. The first cases of PGD for CF were published by Alan Handyside from London and his coworkers,83 following the first report on sexing for medical reasons in preimplantation embryos and successful pregnancy thereafter.84 The European Society of Human Reproduction and Embryology (ESHRE) PGD consortium, established in 1997, reported on PGD data from 45 European centres up to and including 2004.85 In all, 403 cycles have been started with the aim of performing PGD for CF (not only in CF

patients, but also in CF carriers). Of these 333 resulted in an embryo transfer, and 87 in a clinical pregnancy with positive heartbeat. This is a pregnancy rate of 21% of oocyte retrievals and 26% of embryo transfers, which is fully comparable to the overall results of PGD in Europe. One “adverse” (unaffected embryo predicted, affected child born) misdiagnosis has been reported. This can be due to failure of amplification of one of the alleles (the so called allele drop out) or contamination, two problems related to single cell polymerase chain reaction (PCR). Alternatively, unprotected intercourse against advice, during the treatment cycle may also be responsible for the so called “misdiagnosis”. The Brussels group, one of the largest centres in Europe, reported on the clinical outcome of 47 couples having PGD for CF (four were male CF patients with CBAVD) from 1992 up to and including 2002.86 Half of the couples chose PGD because of concurrent fertility problems and hence not primarily for avoiding a child with CF. The results in terms of live births were in line with those reported in the larger ESHRE series: 20 women became pregnant, amongst whom five were pregnant with twins. The average number of cycles per patient was 1.9 (range 1–6). There were no misdiagnoses. Most centres use direct mutation testing for the delta F 508 mutation (the most frequent mutation in Western countries) and eventually for other current mutations. For other more rare mutations PCR based analysis with closely linked markers can be set up.87 We are not aware of any published cases of PGD in female CF patients.

Management of pregnancy Special considerations in case the male partner is a carrier If both mutations are known prenatal diagnosis via direct mutation analysis is possible in the first trimester in chorionic villi and in the second trimester in amniotic fluid. In view of the 50% risk of an affected child, early diagnosis will be preferred by most couples. In case not all three relevant mutations are known, linkage studies in chorionic villi can enable prenatal diagnosis provided the diagnosis of CF and paternity are certain and provided living affected and non-affected family members are available and willing to cooperate in giving blood samples. It is strongly recommended to set up such a linkage study before an actual pregnancy. In case the paternal mutation differs from the maternal mutations, the paternal mutation can be identified in maternal plasma, hence avoiding invasive prenatal diagnosis.88,89 This technology is, however, not readily available in most countries.

Care of the pregnant woman Any physician caring for a woman with CF, who wishes to become pregnant or is already pregnant,

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will tremendously benefit from reading the recently published guidelines for the management of pregnancy in women with CF, based on expert consensus.90 Pregnancy care for the patient with CF centres around adapting medication if necessary, optimising lung function and nutritional status, good diabetes care and adapting physiotherapy according to the stage and the requirements of pregnancy. The CF nurse acts as the liaison officer, coordinating the care in such a way that it is maximally time-effective for the patient. The number of physicians involved in the care will increase during pregnancy and now also include an obstetrician, an obstetric anaesthesiologist and a clinical geneticist. Most medications used to treat CF are safe for use in pregnancy but multidrug resistant organisms may force the use of agents with less extensive pregnancy data. Pulmonary exacerbations and infections should be treated aggressively because of the associated risk of premature delivery. Pulmonary function, oxygen saturation, sputum cultures and measurement of weight should be done at intervals of at most 4 weeks. A regular assessment of lung function and nutrition is essential. Pregnancy requires an additional 300 kcal per day. Failure to gain weight is associated with an increased rate of premature delivery, and therefore it is important to install a nasogastric tube or gastrostomy feeding or rarely parenteral feeding when nutritional problems become apparent. Additional essential fatty acids, minerals, fat soluble vitamins (A, D and K), iron and folic acid may be required because of resorption disturbances. Iron resorption can be optimised by increasing the intake of vitamin C. Common CF gastrointestinal problems such as reflux, dyspepsia, vomiting and obstipation may be aggravated during pregnancy and should be tackled preventively. Some women have problems of cholestasis and the associated pruritus that can be excruciating. Ursodeoxycholic acid can be beneficial here. Patients with diabetes should be monitored according to a diabetes protocol. Those patients who have not developed diabetes should undergo screening for gestational diabetes at 24 weeks. Glucose levels should be monitored during episodes of infection and during delivery.

Foetal monitoring Pregnancies of women with CF are at increased risk of premature (spontaneous and iatrogenic) delivery and foetal growth retardation. From 24 weeks onwards antenatal assessment should be undertaken once every 2 weeks with ultrasonographic assessment of foetal growth and, eventually, Doppler flow measurements in the umbilical arteries are to be recommended to identify risk factors sufficiently early to allow time for complex multidisciplinary decisions. Corticosteroids to promote lung maturity should be considered whenever iatrogenic premature delivery before 34 weeks is foreseen.

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Management of delivery Consultation with an obstetric anaesthesiologist is mandatory at the onset of pregnancy as well as a couple of weeks before expected delivery. Early delivery for maternal reasons should be considered when maternal weight decreases and/or respiratory function declines. This will very often have to be via Caesarean section because of an unripe cervix. General anaesthesia is to be avoided because of potential worsening of pulmonary function, difficulties with postoperative weaning from the respirator and inadequate postoperative pain relief. Good outcomes have been achieved with combined spinal/epidural anaesthesia.91 If necessary, inhalation therapy and airway cleaning should be carried out before anaesthesia. In all other situations vaginal delivery with optimal pain relief is the preferred route. Caesarean section is only recommended for obstetric reasons. During delivery bronchodilators can be used, if necessary, and glucose levels should be monitored. Adequate pain relief and good oxygenation are paramount. Maternal exhaustion during the second stage of labour may necessitate a vacuum or forceps delivery.

Management of puerperium Postoperatively or postdelivery rapid mobilisation and physiotherapy are to be installed. Abdominal surgery goes hand in hand with an increased risk of postoperative pneumonia. Patients who are well enough should be encouraged to breastfeed. The breast milk of women with CF contains sufficient nutrients, although the fat content is somewhat lower than normal. Compatibility of medication with breast feeding should be checked. Drugs that are safe during pregnancy are not by definition safe during breast feeding.

Reflection Care for women with CF wishing to conceive benefits from a multidisciplinary approach where the team members have interest in and knowledge about CF, and interact well. In view of the rarity of the condition one or two members of each discipline of a perinatal team should care for these patients and the care should be done in a CF centre or a centre closely collaborating with a CF centre. With earlier diagnosis and better treatment of CF from childhood onwards more women will receive a positive answer to their question as to whether pregnancy is safe for themselves and for their future children. www.cfww.org www.cysticfibrosismedicine.com genes-r-us.uthsca.edu/nbsdisorders.pdf

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Acknowledgement The authors are grateful to Mrs E van Es for so openly sharing experiences and knowledge and to Professor Dr CK van der Ent, paediatric pulmonologist and Dr KD Lichtenbelt, clinical geneticist, for reviewing an earlier version of the manuscript.

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18. Riordan JR, Rommens JM, Kerem B et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066–73. 19. Rommens JM, Iannuzzi MC, Kerem B et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059–65. 20. Vankeerberghen A, Cuppens H, Cassiman JJ. The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions. J Cyst Fibros 2002; 1: 13–29. 21. http://www.ornl.gov/sci/techresources/Human_ Genome/posters/chromosome/Gifs/CFTRmodel2.gif 22. Amaral MD, Kunzelmann K. Molecular targeting of CFTR as a therapeutic approach to cystic fibrosis. Trends Pharmacol Sci 2007; 28: 334–41. 23. Kerem E. Pharmacological induction of CFTR function in patients with cystic fibrosis: mutation-specific therapy. Pediatr Pulmonol 2005; 40: 183–96. 24. Ameen N, Silvis M, Bradbury NA. Endocytic trafficking of CFTR in health and disease. J Cyst Fibros 2007; 6: 1–14. 25. Zeitlin PL. Novel pharmacologic therapies for cystic fibrosis. J Clin Invest 1999; 103: 447–52. 26. Ratjen F. New pulmonary therapies for cystic fibrosis. Curr Opin Pulm Med 2007; 13: 541–6. 27. Heijerman, HGM and De Jonge HR. Expressie van het cystische-fibrose-gen in de longen. Ned Tijdschr Geneeskd 2004; 148: 816–19. 28. Hodson M, Geddes D, Bush A, eds. Cystic Fibrosis, 3rd edn. London: Hodder Arnold, 2007. 29. Lakeman P, Gille JJ, Dankert-Roelse JE et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: Implications for screening. Genet Test 2008; 12: 25–35. 30. http://respiratory-research.com/content/figures/ 1465–9921–4–8–2.jpg 31. Knowles MR, Robinson JM, Wood RE et al. Ion composition of airway surface liquid of patients with cystic fibrosis as compared with normal and disease-control subjects. J Clin Invest 1997; 100: 2588–95. 32. Caldwell RA, Grubb BR, Tarran R et al. In vivo airway surface liquid Cl- analysis with solid-state electrodes. J Gen Physiol 2002; 119: 3–14. 33. Matsui H, Grubb BR, Tarran R et al. Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease. Cell 1998; 95: 1005–15. 34. Jayaraman S, Song Y, Vetrivel L, Shankar L, Verkman AS. Noninvasive in vivo fluorescence measurement of airway-surface liquid depth, salt concentration, and pH. J Clin Invest 2001; 107: 317–24. 35. Knowles MR, Durie PR. What is cystic fibrosis? [Editorial]. N Engl J Med 2002; 347: 439–42. 36. Drumm ML, Konstan MW, Schluchter MD et al. Genetic modifiers of lung disease in cystic fibrosis. N Engl J Med 2005; 353: 1443–53. 37. Knowles MR. Gene modifiers of lung disease. Curr Opin Pulm Med 2006; 12: 416–21. 38. Boyle MP. Adult cystic fibrosis. JAMA 2007; 298: 1787–93. 39. Courtney JM, Bradley J, McCaughan J et al. Predictors of mortality in adults with cystic fibrosis. Pediatr Pulmonol 2007; 42: 525–32.

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The patient with cystic fibrosis 40. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med 2003; 168: 918–51. 41. Brihaye P, Jorissen M, Clement PA. Chronic rhinosinusitis in cystic fibrosis (mucoviscidosis). Acta Otorhinolaryngol Belg 1997; 51: 323–37. 42. Coutts JA, Docherty JG, Carachi R, Evans TJ. Clinical course of patients with cystic fibrosis presenting with meconium ileus. Br J Surg 1997; 84: 555. 43. Dray X, Bienvenu T, Desmazes-Dufeu N et al. Distal intestinal obstruction syndrome in adults with cystic fibrosis. Clin Gastroenterol Hepatol 2004; 2: 498–503. 44. Button BM, Roberts S, Kotsimbos TC et al. Gastroesophageal reflux (symptomatic and silent): a potentially significant problem in patients with cystic fibrosis before and after lung transplantation. J Heart Lung Transplant. 2005; 24: 1522–9. 45. Ahmed N, Corey M, Forstner G et al. Molecular consequences of cystic fibrosis transmembrane regulator (CFTR) gene mutations in the exocrine pancreas. Gut 2003; 52: 1159–64. 46. Marshall BC, Butler SM, Stoddard M et al. Epidemiology of cystic fibrosis-related diabetes. J Pediatr 2005; 146: 681–7. 47. Lamireau T, Monnereau S, Martin S et al. Epidemiology of liver disease in cystic fibrosis: a longitudinal study. J Hepatol 2004; 41: 920–5. 48. Stern RC, Rothstein FC, Doershuk CF. Treatment and prognosis of symptomatic gallbladder disease in patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 1986; 5: 35–40. 49. Hubert D, Patrat C, Guibert J et al. Results of assisted reproductive technique in men with cystic fibrosis. Hum Reprod 2006; 21: 1232–6. 50. Sawyer SM, Farrant B, Cerritelli B, Wilson J. A survey of sexual and reproductive health in men with cystic fibrosis: new challenges for adolescent and adult services. Thorax 2005; 60: 326–30. 51. Neri QV, Takeuchi T, Palermo GD. An update of assisted reproductive technologies results in the United States. Ann N Y Acad Sci 2008; 1127: 41–8. 52. Devroey P, Van Steirteghem A. A review of ten years experience of ICSI. Hum Reprod Update 2004; 10: 19–28. 53. Rosenstein BJ. What is a cystic fibrosis diagnosis? Clin Chest Med 1998; 19: 423–41, v. 54. De Boeck K, Wilschanski M, Castellani C et al. Cystic fibrosis: terminology and diagnostic algorithms. Thorax 2006; 61: 627–35. 55. Desmarquest P, Feldmann D, Tamalat A et al. Genotype analysis and phenotypic manifestations of children with intermediate sweat chloride test results. Chest 2000; 118: 1591–7. 56. Gilljam M, Ellis L, Corey M et al. Clinical manifestations of cystic fibrosis among patients with diagnosis in adulthood. Chest 2004; 126: 1215–24. 57. Kerem E, Reisman J, Corey M, Canny GJ, Levison H. Prediction of mortality in patients with cystic fibrosis. N Engl J Med 1992; 326: 1187–91. 58. Mayer-Hamblett N, Rosenfeld M, Emerson J, Goss CH, Aitken ML. Developing cystic fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir Crit Care Med 2002; 166: 1550–5. 59. Loeber JG. Neonatal screening in Europe; the situation in 2004. J Inherit Metab Dis 2007; 30: 430–8.

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60. (http://genes-r-us.uthsca.edu/nbsdisorders.pdf) 61. Sarles J, Berthezene P, Le Louarn C et al. Combining immunoreactive trypsinogen and pancreatitis-associated protein assays, a method of newborn screening for cystic fibrosis that avoids DNA analysis. J Pediatr 2005; 147: 302–5. 62. Dankert-Roelse JE, Merelle ME. Review of outcomes of neonatal screening for cystic fibrosis versus nonscreening in Europe. J Pediatr 2005; 147(3 Suppl): S15–20. 63. Farrell PM, Lai HJ, Li Z et al. Evidence on improved outcomes with early diagnosis of cystic fibrosis through neonatal screening: enough is enough! J Pediatr 2005; 147(3 Suppl): S30–6. 64. Lai HJ, Cheng Y, Farrell PM. The survival advantage of patients with cystic fibrosis diagnosed through neonatal screening: evidence from the United States Cystic Fibrosis Foundation registry data. J Pediatr 2005; 147(3 Suppl): S57–63. 65. Johannesson M, Landgren BM, Csemiczky G, Hjelte L, Gottlieb C. Female patients with cystic fibrosis suffer from reproductive endocrinological disorders despite good clinical status. Hum Reprod 1998; 13: 2092–7. 66. Odegaard I, Stray-Pedersen B, Hallberg K et al. Prevalence and outcome of pregnancies in Norwegian and Swedish women with cystic fibrosis. Acta Obstet Gynecol Scand 2002; 81: 693–7. 67. www.cfenkinderen.nl 68. Siegel B, Siegel S. Pregnancy and delivery in a patient with cystic fibrosis of the pancreas. Obstet Gynecol 1960; 16: 438–40. 69. Goss CH, Rubenfeld GD, Otto K, Aitken ML. The effect of pregnancy on survival in women with cystic fibrosis. Chest 2003; 124: 1460–8. 70. Gillet D, de Braekeleer M, Bellis G, Durieu I. Cystic fibrosis and pregnancy. Report from French data (1980–1999). BJOG 2002; 109: 912–18. 71. Barak A, Dulitzki M, Efrati O et al. Pregnancies and outcome in women with cystic fibrosis. Isr Med Assoc J 2005; 7: 95–8. 72. Odegaard I, Stray-Pedersen B, Hallberg K et al. Maternal and fetal morbidity in pregnancies of Norwegian and Swedish women with cystic fibrosis. Acta Obstet Gynecol Scand 2002; 81: 698–705. 73. Boyd JM, Mehta A, Murphy DJ. Fertility and pregnancy outcomes in men and women with cystic fibrosis in the United Kingdom. Hum Reprod 2004; 19: 2238–43. 74. Gilljam M, Antoniou M, Shin J et al. Pregnancy in cystic fibrosis. Fetal and maternal outcome. Chest 2000; 118: 85–91. 75. McMullen AH, Pasta DJ, Frederick PD et al. Impact of pregnancy on women with cystic fibrosis. Chest 2006; 129: 706–11. 76. Canny GJ, Corey M, Livingstone RA et al. Pregnancy and cystic fibrosis. Obstet Gynecol 1991; 77: 850–3. 77. Kent NE, Farquharson DF. Cystic fibrosis in pregnancy. CMAJ 1993; 149: 809–13. 78. Cheng EY, Goss CH, McKone EF et al. Aggressive prenatal care results in successful fetal outcomes in CF women. J Cyst Fibros 2006; 5: 85–91. 79. Edenborough FP, Mackenzie WE, Stableforth DE. The outcome of 72 pregnancies in 55 women with cystic fibrosis in the United Kingdom 1977–1996. BJOG 2000; 107: 254–61.

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80 Hardin DS, Rice J, Cohen RC, Ellis KJ, Nick JA. The metabolic effects of pregnancy in cystic fibrosis. Obstet Gynecol 2005; 106: 367–75. 81. Gyi KM, Hodson ME, Yacoub MY. Pregnancy in cystic fibrosis lung transplant recipients: case series and review. J Cyst Fibros 2006; 5: 171–5. 82. Stead RJ, Grimmer SF, Rogers SM et al. Pharmacokinetics of contraceptive steroids in patients with cystic fibrosis. Thorax 1987; 42: 59–64. 83. Handyside AH, Lesko JG, Tarin JJ, Winston RM, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med 1992; 327: 905–9. 84. Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature 1990; 344: 768–70. 85. Harper JC, de Die-Smulders C, Goossens V et al. ESHRE PGD consortium data collection VII: cycles from January to December 2004 with pregnancy follow-up to October 2005. Hum Reprod 2008; 23: 741–55.

86. Keymolen K, Goossens V, De Rycke M et al. Clinical outcome of preimplantation genetic diagnosis for cystic fibrosis: the Brussels’ experience. Eur J Hum Genet 2007; 15: 752–8. 87. Dreesen JC, Jacobs LJ, Bras M et al. Multiplex PCR of polymorphic markers flanking the CFTR gene; a general approach for preimplantation genetic diagnosis of cystic fibrosis. Mol Hum Reprod 2000; 6: 391–6. 88. Gonzalez-Gonzalez MC, Garcia-Hoyos M, Trujillo MJ et al. Prenatal detection of a cystic fibrosis mutation in fetal DNA from maternal plasma. Prenat Diagn 2002; 22: 946–8. 89. Norbury G, Norbury CJ. Non-invasive prenatal diagnosis of single gene disorders: how close are we? Semin Fetal Neonatal Med 2008; 13: 76–83. 90. Edenborough FP, Borgo G, Knoop C et al. Guidelines for the management of pregnancy in women with cystic fibrosis. Cystic Fibrosis 2008; 7: S2–S32. 91. Muammar M, Marshall P, Wyatt H, Skelton V. Caesarean section in a patient with cystic fibrosis. Int J Obstet Anesth 2005; 14: 70–3. 92. www.cff.org: Annual Data Report 2006 of the Cystic Fibrosis Foundation Patient Registry.

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15 The patient with inflammatory bowel disease Sunanda Kane, Rebecca Kowalczyk

Background The incidence of Crohn’s disease (CD) in women has been increasing over the past few decades.1 It is not clear whether this is due to improved diagnostic techniques, an increase in smoking habits in young women (patients with CD tend to be smokers compared with people without CD2) or other factors not yet identified. Because the diagnosis of CD or ulcerative colitis (UC) is often made in the childbearing years, fertility and pregnancy are important issues. Physicians involved in the care of these patients need to be prepared to offer effective pre-conception counselling to improve pregnancy outcomes in patients with inflammatory bowel disease (IBD). The aim of this chapter is to review some clinically relevant preconception issues in IBD.

Effect of inflammatory bowel disease on pregnancy Women with inactive IBD appear to be no more likely to experience spontaneous abortion, stillbirth, or children born with a congenital abnormality than those without IBD. Some work has suggested that babies born to women with IBD, regardless of disease activity, are of smaller birth weight.3 This appears to be particularly the case in women with CD. Women with active disease run a greater risk for premature birth, especially those with high disease activity.4 In a recently published community-based study 461 pregnant women with IBD were matched to 493 unexposed pregnant women.5 Women with IBD were more likely to have an adverse conception outcome (odds ratio (OR) 1.65, 95% confidence interval (CI) 1.09– 2.48), an adverse pregnancy outcome (OR 1.54, 95% CI 1.00–2.38), or a pregnancy complication (OR 1.78, 95% CI 1.13–2.81); however, the difference between the two groups in adverse newborn outcomes was not statistically significant (OR 1.89, 95% CI 0.98–3.69). These increased odds must be put into perspective, as only 4% of patients in this study were on immunomodulators to control their disease activity, and the vast majority did not have disease activity during their pregnancy.

The presence of IBD does not appear to have an impact on maternal complications related to pregnancy, including hypertension or proteinuria.6 However, perianal disease may worsen or develop after a vaginal delivery. One retrospective study of women with CD demonstrated 18% of those without previous perianal disease developed such disease after delivery, usually involving an extensive episiotomy.7 Most gastroenterologists agree, however, that unless perianal disease is present the decision to perform Caesarean section should be based on obstetric need.

Effect of pregnancy on inflammatory bowel disease For women with quiescent IBD, the rate of relapse is approximately the same in pregnant versus non-pregnant patients.8 This is in contrast to the presence of active disease at the time of conception, which is associated with continued or worsening disease activity in approximately 70% of women. Older literature suggested a trend for disease to flare in the first trimester, but these observations were made prior to the accepted practice of maintenance therapy, continued even during pregnancy. It is important to remember that haemoglobin and albumin levels normally decrease and the erythrocyte sedimentation rate (ESR) increases during pregnancy. Because of these normal physiological changes, disease assessment during pregnancy should rely more on clinical symptoms than laboratory parameters. Ultrasound exams are clearly safe, and there is no evidence that, if indicated, a sigmoidoscopy will induce premature labour.9 Full colonoscopy should only be performed when the extent and severity of disease specifically need to be ascertained. There are data that suggest that a history of child bearing changes the natural history of CD.10 Women who had been pregnant had fewer resections or longer intervals between resections as compared with women who had not had children but had otherwise similar disease. One theory proposed by the authors is the inhibition of macrophage function by relaxin. Relaxin is a hormone produced exclusively during pregnancy which may result in less fibrosis

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and stricture formation by this inhibition of macrophages. A more recent study found that patients with IBD who became pregnant during their disease course did not have changes in surgery rates, stenosis formation, or disease phenotype but did have decreased relapse rates in the years following pregnancy.11

Pre-conceptional counselling Fertility Overall, the fertility rates for women with IBD are essentially the same as those of the normal population.12 Early studies suggesting lower fertility rates had not taken into account an increased voluntary childlessness rate in women with IBD. Active CD however, can reduce fertility in several ways, depending upon the location of inflammation. Active inflammation in the colon13 and terminal ileal disease14 can decrease fertility. Active ileal inflammation can cause inflammation or scarring of the fallopian tubes or ovaries. Women who have had any surgical resection are at risk for adhesions, which can also impair tubal function. One retrospective study from Scotland revealed that women who had had surgery for IBD had infertility rates of 25% compared with 7% in the general population.15 A limitation to this study, however, was that there was no control for voluntary childlessness. Another reason for an increased rate of infertility is having undergone an ileoanal anastomosis procedure. A recent meta-analysis demonstrated a 3-fold increased risk for infertility resulting from this procedure.16 Alternative surgeries include a sub-total colectomy with temporary ileostomy or an ileorectal anastomosis to preserve fertility.17 None of the medications used to treat IBD has an effect on female fertility, but it is important to remember that sulfasalazine therapy reduces sperm count and motility in males taking this medication.18 There is no minimum required time period for quiescent disease prior to a planned conception, but at least 3 months without active symptoms has been recommended. Open discussions between patient and physician about the timing of a pregnancy are the best way to ensure the best outcome. If a woman is doing well and in remission, there is every reason to expect the pregnancy to proceed smoothly. If active disease is present, it is likely to continue during pregnancy and will place the pregnancy at greater risk for complications.8 This risk appears to be higher in CD than in UC. The main priority is to establish and maintain remission before the patient conceives.

Inheritance Some women remain childless for fear of disease transmission to their offspring. Current data suggest that this risk is low: 7% if one parent has CD and less if one parent has UC.19 However, the risk of IBD

increases to as high as 37% if both parents have the disease. The risk of inheriting IBD is higher in Jewish (7.8%) than in non-Jewish (5.8%) parents.20 Even though the NOD2 gene has been identified and associated with CD, it is important to remember that IBD is not a genetic disorder in a true Mendelian fashion. Even with genetic predisposition, other factors are necessary to produce expression of either disease.

Treatment of inflammatory bowel disease during pregnancy The key principle to management is to remember that the greatest risk to pregnancy is active disease, not active therapy.21 Since there are limited definitive data available on the safety of IBD medications in pregnancy, the focus should be on establishing remission before conception and maintaining remission during pregnancy. Sulfasalazine readily crosses the placenta but has not been associated with any foetal abnormalities. However, patients taking sulfasalazine should also be supplemented with folic acid before conceiving to decrease the risk of neural tube defects. A dose of 1 mg twice daily would be appropriate. The safety of mesalamine during pregnancy has been demonstrated in a number of trials despite the fact that it and its metabolite acetyl-5-aminosalicylic acid are found in foetal plasma.22,23 In two separate studies, women taking 2–3 g/day had no increased incidence of foetal abnormalities compared with normal healthy women. The data regarding immunomodulator therapy (azathioprine, 6-mercaptopurine (6-MP)) are more conflicting. There are no large prospective studies on the use of these medications during pregnancy in women with IBD. To date, the largest amount of information comes from the transplantation literature,24 and more recently from retrospective series in IBD.25,26 Azathioprine metabolites have been found to cross the placenta but with careful dosing this can be minimised.27 It is generally believed, by most experienced IBD clinicians, that immunosuppressives such as 6MP, azathioprine and cyclosporine can be used safely during pregnancy if the mother’s health mandates therapy. There is evidence from a recent Danish study that women taking these medications have an increased risk of preterm birth after adjusting for cofounders, so it is important to weigh the risks and benefits of the medication.28 Methotrexate, another immunomodulatory medication, is contraindicated in pregnancy due to its abortogenic effect. It is also advisable to avoid its use in men who wish to father children as it is toxic to sperm. Biological agents are now commonly used for more aggressive disease. Mahadevan et al examined the pregnancy outcomes of ten women intentionally treated with infliximab for active disease CD during pregnancy.29 All ten pregnancies resulted in live births, with no congenital malformations. Infliximab is

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Table 15.1 Safety of inflammatory bowel disease medications during pregnancy.

Table 15.2 Safety of inflammatory bowel disease medications during breastfeeding.

Safe to use when indicated Oral, topical mesalamine Balsalazide Sulfasalazine Corticosteroids Infliximab, adalimumab

Safe to use when indicated Oral, topical mesalamine Balsalazide Sulfasalazine Corticosteroids No data Olsalazine Azathioprine 6-mercaptopurine (6-MP) Infliximab, adalimumab

Limited data but benefit outweighs risk Olsalazine Azathioprine 6-mercaptopurine (6-MP) Cyclosporine Metronidazole

Contraindicated Methotrexate Thalidomide Cyclosporine Ciprofloxacin Metronidazole Loperamide Diphenoxylate

Contraindicated Methotrexate Thalidomide Diphenoxylate

detected in the offspring of women treated with infliximab throughout pregnancy but to date the long-term effect of this placental transfer is unknown.30 It is important, therefore, for the physician to discuss with each patient the risk to benefit ratio of biological therapy to control disease. Similar case reports with adalimumab demonstrate its relative safety during pregnancy.31,32 Corticosteroids have not been associated with teratogenicity in humans and can be used as required to control disease activity. Prednisolone crosses the placenta less efficiently than other steroid formulations such as betamethasone or dexamethasone. Only limited data are available regarding the safety of antibiotics as treatment for CD. Currently, ampicillin, cephalosporins and erythromycin are believed safe, as well as ciprofloxacin. Metronidazole has been used to treat vaginitis in women during the first trimester of pregnancy but no controlled trials have definitively shown its safety long term, as used in CD.33 Table 15.1 summarizes the safety of commonly used medications in IBD.

Surgery during pregnancy The indications for surgery during pregnancy are identical to those of non-pregnant patients. These include obstruction, perforation, abscess and haemorrhage. Pregnancy has not been shown to complicate stoma function. Women may experience some prolapse due to abdominal pressure, but no increased risk to the pregnancy is encountered. For those women who have had ileoanal pull through procedures, an increase in the number of bowel movements during pregnancy has been reported, but no increased risk for pouchitis or delivery complications.34

Method of delivery In the absence of perianal disease, the diagnosis of IBD alone does not have a significant impact on the

method of delivery, nor is it an indication for Caesarean section. Despite this fact women with IBD are 1.5 times more likely to undergo Caesarean section.35 It is important to note that in one study, even patients with a history of perianal CD had no relapse of perianal disease in 1 year of follow-up after vaginal delivery.7 Several studies have found that there is an increased rate of Caesarean section after restorative proctocolectomy despite the fact that there have been no significant differences in pouch function following vaginal delivery.36,37 Mode of delivery should be determined by obstetric need not presence or absence of IBD or ilealanal pouch. One exception is for women with extensive fibrosis of the perineum for whom Caesarean section is the preferred method of delivery.

Breast feeding Medications known to be safe for breast feeding include sulfasalazine, mesalamine and steroids. Mothers planning on nursing should discontinue the use of cyclosporine, metronidazole and ciprofloxacin. The antidiarrhoeals loperamide and diphenoxylate should also be discontinued. Preliminary data regarding the thiopurines suggest minimal secretion into breast milk and continued use should be discussed on a case by case basis. Biological agents have not been detected in milk.30 Table 15.2 summarises the safety data regarding medications and their use during breast feeding.

Summary • •

Fertility is not affected in UC, but can be in active CD There is no increase in adverse pregnancy outcomes in quiescent IBD

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Active disease at conception increases the risk for adverse outcomes during pregnancy The majority of medications for IBD are safe in pregnancy and breast feeding – active disease is more deleterious than active therapy.

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References 1. Kappelman MD, Rifas-Shiman SL, Klkeinman K et al. The prevalence and geographic distribution of Crohn’s disease and ulcerative colitis in the United States. Clin Gastroenterol Hepatol 2007; 5: 1424–9. 2. Silverstein MD, Lashner BA, Hanauer SB et al. Cigarette smoking in Crohn’s disease. Am J Gastroenterol 1989; 84: 31–3. 3. Moser MA, Okun NB, Mayes DC, Bailey RJ. Crohn’s disease, pregnancy, and birth weight. Am J Gastroenterol 2000; 95: 1021–6. 4. Norgard B, Hundborg HH, Jacobsen BA et al. Disease activity in pregnant women with Crohn’s disease and birth outcomes: a regional Danish cohort study. Am J Gastroenterol 2007; 102: 1947–54. 5. Mahadevan U, Sandborn WJ, Li DK et al. Pregnancy outcomes in women with inflammatory bowel disease: a large community-based study from Northern California. Gastroenterology 2007; 133: 1106–12. 6. Porter RJ, Stirrat GM. The effects of inflammatory bowel disease on pregnancy: a case-controlled retrospective analysis. Br J Obstet Gynaecol 1986; 93: 1124–31. 7. Ilnyckyj A, Blanchard JF, Rawsthorne P, Bernstein CN. Perianal Crohn’s disease and pregnancy: role of the mode of delivery. Am J Gastroenterol 1999; 94: 3274–78. 8. Miller JP. Inflammatory bowel disease in pregnancy: a review. J R Soc Med 1986; 79: 221–5. 9. Cappell MS, Colon VJ, Sidhom OA. A study at 10 medical centers of the safety and efficacy of 48 flexible sigmoidoscopies and 8 colonoscopies during pregnancy with follow-up of fetal outcome and with comparison to control groups. Dig Dis Sci 1996; 41: 2353–61. 10. Nwokolo C, Tan WC, Andrews HA, Allan RN. Surgical resections in parous patients with distal ileal and colonic Crohn’s disease. Gut 1994; 35: 220– 3. 11. Riis L, Vind I, Politi P et al. Does pregnancy change the disease course? A study in a European cohort of patients with inflammatory bowel disease. Am J Gastroenterol 2006; 101: 1539–45. 12. Willoughby, CP, Truelove SC. Ulcerative colitis and pregnancy. Gut 1980; 21: 469–74. 13. Mayberry JF, Weterman IT. European survey of fertility and pregnancy in women with Crohn’s disease: a case control study by European collaborative group. Gut 1986; 27: 821–5. 14. Fonager K, Sorensen HT, Olsen J et al. Pregnancy outcome for women with Crohn’s disease: a followup study based on linkage between national registries. Am J Gastroenterol 1998; 93: 2426–30. 15. Alstead E. Fertility and pregnancy in inflammatory bowel disease. World J Gastroenterol 2007; 7: 455–9. 16. Waljee A, Waljee J, Morris A, Higgin PD. Threefold increased risk of infertility: a meta-analysis of infertil-

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ity after ileal pouch anal anastomosis in ulcerative colitis. Gut 2006; 55: 1575–80. Mortier PE, Gambiez L, Karoui M et al. Colectomy with ileorectal anastomosis presevers female fertility in ulcerative colitis. Gastroenterol Clin Biol 2006; 30: 594–7. O’Morian C, Smethurst P, Dore CJ, Levi AJ. Reversible male infertility due to sulphasalazine: studies in man and rat. Gut 1984; 25: 1078–84. Orholm M, Fonager K, Sorensen HT. Risk of ulcerative colitis and Crohn’s disease among offspring of patients with chronic inflammatory bowel disease. Am J Gastroenterol 1999; 94: 3236–8. Yang H, McElree C, Roth MP et al. Familial empirical risks for inflammatory bowel disease: differences between Jews and non-Jews. Gut 1993; 34: 517–24. Sachar D. Exposure to mesalamine during pregnancy increased preterm deliveries (but not birth defects) and decreased birth weight. Gut 1998; 43: 316. Diav-Citrin O, Park YH, Veerasuntharam G et al. The safety of mesalamine in human pregnancy: a prospective controlled cohort study. Gastroenterology 1998; 114: 23–8. Marteau P, Tennenbaum R, Elefant E et al. Fetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules. Aliment Pharmacol Ther 1998; 12: 1101–8. McKay DB, Josephson AM. Pregnancy in recipients of solid organs—effects on mother and child. N Engl J Med 2006; 354: 1281–93. Alstead EM, Ritchie JK, Lennard-Jones JE et al. Safety of azathioprine in pregnancy in inflammatory bowel disease. Gastroenterology 1990; 99: 443–6. Francella A, Dayan A, Bodian C et al. The safety of 6mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology 2003; 124: 9–17. De Boer NK, Jarbandhan SV, Peer de Graff MS et al. Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol 2006; 101: 1390–2. Norgard B, Pedersen L, Christensen LA, Sorensen HT. Therapeutic drug use in women with Crohn’s disease and birth outcomes: A Danish nationwide cohort study. Am J Gastroenterol 2007; 102: 1406–13. Mahadevan U, Kane S, Sandborn WJ et al. Intentional infliximab use during pregnancy for induction or maintenance of remission in Crohn’s disease. Aliment Pharmacol Ther 2005; 21: 733–8. Vasiliauskas EA, Chruch JA, Silverman N et al. Case report: evidence for transplacental transfer of maternally administered infliximab to the newborn. Clin Gastroenterol Hepatol 2006; 4: 1255–8. Mishkin D, van Deinse W, Becker J, Farraye FA. Successful use of adalimumab for Crohn’s disease in pregnancy. Inflamm Bowel Dis 2006; 12: 827–8. Vesga L, Terdiman JP, Mahadevan U. Adalimumab use in pregnancy. Gut 2005; 54: 890. Rosa FW, Baum C, and Shaw M. Pregnancy outcomes after first-trimester vaginitis drug therapy. Obstet Gynecol 1987; 69: 751–5. Juhasz ES, Fozard B, Dozois RR et al. Ileal pouchanal anastomosis function following childbirth. An extended evaluation. Dis Colon Rectum 1995; 38: 159–65.

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function, fertility, pregnancy, and delivery: a systematic review. Dis Colon Rectum 2007; 50: 1128–38. 37. Lepisto A, Sarna S, Tiitinen A, Jarvinen HJ. Female fertility and childbirth after ileal pouch-anal anastomosis for ulcerative colitis. Br J Surg 2007; 94: 478–82.

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16 The Patient with prolactinoma Mark E Molitch

Epidemiology and pathogenesis Prolactinomas are the most frequent of the hormonesecreting pituitary tumours. Earlier studies reported the prevalence of prolactinomas at 100 cases per million adults,1 but a recent study determined that the prevalence may be up to 7-fold higher.2 Prior to menopause, the incidence of prolactinomas is 10-fold greater in women than in men, but after menopause and in autopsy series sex-related differences in the prevalence of these tumours disappear. Microprolactinomas (tumours <1 cm in diameter) occur more commonly in women, whereas macroprolactinomas (tumours >1 cm in diameter) occur in equal numbers of women and men. The greater prevalence of microprolactinomas in younger women may reflect the fact that mild hyperprolactinaemia results in more symptoms in women than in men thus bringing them to clinical attention. However, there may also be gender-specific biological differences in the behaviour of these tumours. Fewer than 100 cases of malignant prolactinomas have been reported.3 Virtually all prolactinomas are sporadic, but familial cases of prolactinomas may occur, usually in association with multiple endocrine neoplasia type 1.1 Similar to other types of pituitary adenomas, prolactinomas arise from a single transformed cell (lactotroph) with monoclonal proliferation. A number of candidate genetic alterations involved in the genesis and progression of prolactinomas have been sought, but, to date, no specific mutations have been found that account for more than a handful of cases.4

Clinical manifestations of prolactinomas The most typical symptoms of hyperprolactinaemia are amenorrhoea (94% of women) and galactorrhoea (up to 85% of women).5 Non-puerperal galctorrhoea may occur in 5–10% of normally menstruating, normoprolactinaemic women, and therefore is suggestive, but not definitive of hyperprolactinaemia. However, when oligo/amenorrhoea is associated with galactorrhoea about 75% of women will be found to have hyperprolactinaemia.5 Galactorrhoea is reported in about 10% of cases in men, and is virtually pathognomonic of a prolactinoma.5

Hyperprolactinaemia inhibits the pulsatile secretion of gonadotrophin releasing hormone (GnRH), alters the pattern of release of luteinising hormone (LH) and follicle stimulating hormone (FSH), and suppresses gonadal steroidogenesis.6 In women, hyperprolactinaemia impairs the positive oestrogen feedback effect on gonadotrophin secretion and abolishes the ovulatory surge of LH. High concentrations of prolactin (PRL) also directly inhibit ovarian production of progesterone and oestrogen.7 Collectively, these hormonal changes result in hypogonadism. In women, hyperprolactinaemia usually causes secondary amenorrhoea, but it may be associated with primary amenorrhoea, if the disorder begins before the usual age of puberty. Adolescents with primary amenorrhoea due to hyperprolactinaemia may present with oestrogen deficiency and failure to develop normal secondary sexual characteristics.8 For unknown reasons, adolescents have a disproportionately high frequency of macroadenomas. Infertility, which occurs when gonadotrophin levels are suppressed with anovulation, may be a presenting feature of some women with prolactinomas. Reduced libido and orgasmic dysfunction are found in most hyperprolactinaemic/amenorrhoeic women; treatment that normalises PRL levels generally restores normal libido and sexual function. In men, hypogonadism generally manifests as decreased libido, erectile dysfunction and infertility. Testosterone levels generally fall below or into the lower part of the normal reference range, and spermatogenesis is impaired with decreased sperm counts, impaired sperm motility and an increased percentage of abnormal forms.9,10 If there is sufficient normal pituitary tissue, normalisation of hyperprolactinaemia usually results in a return of normal testosterone levels.9 In approximately 80% of men who achieve normal prolactin and testosterone levels with cabergoline therapy, sperm count, volume and motility return to normal.10 Hyperprolactinaemia has been found in 2–25% of males with impotence in various series, but in only 1–5% of men with infertility.11 Testosterone therapy for the treatment of impotence may only become effective once PRL levels are normalised. Hyperprolactinaemia is associated with reduced bone mineral density.12 Correction of the hyperprolactinaemia

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increases bone mass but does not necessarily normalise bone mineral density. Hyperprolactinaemic women who are not amenorrhoeic have normal bone mineral density, supporting the premise that it is the oestrogen deficiency that mediates the reduction in bone density.12 Large macroadenomas can also cause mass effects. Visual field defects may occur with compression of the optic chiasm. Ophthalmoplegias are relatively uncommon, being due to invasion of the cavernous sinus with entrapment of cranial nerves III, IV, V1, V2 and VI. Hypopituitarism may occur because of direct compression of other pituitary cell types or as a result of hypothalamic dysfunction or stalk compression. These large, invasive tumours should be differentiated from true carcinomas, which diagnostically must have evidence of distant metastases. Rarely, large macroadenomas function as a “cork” at the base of the skull; substantial tumour shrinkage from dopamine agonist therapy can lead to cerebrospinal fluid (CSF) leaks that must be surgically repaired to prevent meningitis.

Diagnostic evaluation Differential diagnosis Many other conditions can cause hyperprolactinaemia and must be considered in evaluating the patient with hyperprolactinaemia (Table 16.1). Most are due to decreases in dopamine (the PRL inhibitory factor) resulting in modestly elevated PRL levels (25–150 ng/ml). Medications represent the most frequent cause of nontumoural hyperprolactinaemia, the most common being antipsychotic agents, verapamil and the antiemetics domperidone and metoclopramide. Tricyclic antidepressants, monoamine oxidase inhibitors and serotonin reuptake inhibitors rarely cause hyperprolactinaemia.13 Hyperprolactinaemia occurs in many patients with renal insufficiency; concomitant use of medications known to alter hypothalamic dopamine may further increase PRL levels. Primary hypothyroidism is associated with hyperprolactinaemia in about 10% of cases. Rare cases of hyperprolactinaemia have been reported in patients with adrenal insufficiency due to the loss of glucocorticoid-mediated repression of PRL gene transcription. Stimulation of afferent neural pathways by breast, chest wall and cervical cord lesions can rarely cause hyperprolactinaemia. Hyperprolactinaemia caused by lesions of the hypothalamus and of the pituitary stalk results from interference with dopamine inhibition and PRL levels are typically less than 150 ng/ml.14 The recognition of this effect is critical for instituting appropriate therapy, as the treatment for large non-secreting tumours is surgery, whereas primary treatment of such a large prolactinoma would be a dopamine agonist. Two laboratory artefacts can confound the interpretation of PRL levels. Monomeric PRL has a molecular weight of 23 kDa and constitutes up to 95% of

Table 16.1

Differential diagnosis of hyperprolactinaemia.

Pituitary disease Prolactinoma Somatomammotropinoma Plurihormonal adenomas Empty sella syndrome Lymphocytic hypophysitis Non-secreting pituitary adenomas Hypothalamic disease Craniopharyngioma, Rathke’s cleft cysts Meningioma Dysgerminoma Infiltrative disorders (sarcoidosis, histiocytosis X) Neuraxis irradiation Pituitary stalk section Medications Phenothiazines Haloperidol Risperdal Molinidone Monoamine oxidase inhibitors Tricyclic antidepressants Serotonin reuptake inhibitors Reserpine Methyldopa Metoclopramide Cocaine Verapamil Neurogenic Chest wall lesions Spinal cord lesions Breast stimulation Other Pregnancy Hypothyroidism Chronic renal failure Cirrhosis Pseudocyesis Adrenal insufficiency Idiopathic

adult serum PRL. Macroprolactin is a large complex of PRL and IgG and has reduced bioactivity.15–17 The frequency of this artefact has probably been underestimated in the past.15 The presence of macroprolactinaemia should be suspected when a patient’s clinical history and/or radiological imaging are incompatible with the reported PRL level. Gel filtration chromatography is the gold standard method for excluding this condition, but polyethylene glycol precipitation yields results that correlate reasonably well and is the most practical method available.15 Whether the presence of macroprolactin should be ascertained in all patients with hyperprolactinaemia is controversial. Recent guidelines published by the Pituitary Society recommend assessment for macroprolactin in patients with moderately elevated PRL

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levels and less typical symptoms, such as headaches or diminished libido.5 The “hook effect” occurs less frequently but is important to consider, as a misdiagnosis can potentially lead to unnecessary surgery. The “hook effect” can occur when serum PRL levels are extraordinarily high, as found in patients with giant prolactinomas18 and two-site immunoradiometric or chemiluminometric assays are used. In this circumstance, falsely normal or minimally elevated PRL levels may be reported due to saturation of the antibody with the very high amounts of PRL. PRL levels should always be re-measured at 1:100 dilution in patients with macroadenomas who have normal to modestly elevated basal PRL levels; if a “hook effect” is present, then PRL levels in the diluted samples will increase dramatically.

Evaluation Patient evaluation consists of a careful history and physical examination, serum blood chemistries, a thyroid stimulating hormone assay and a pregnancy test.5 If these are normal, magnetic resonance imaging (MRI) of the hypothalamic–pituitary area is mandatory to evaluate for a mass lesion.5 This includes patients with even mild PRL elevations. Because MRI studies may detect incidental lesions (including non-secreting tumours, cysts, infarcts), the finding of a “microprolactinoma” on a scan in a patient with elevated PRL levels may not always be a true positive finding.5 All patients with macroadenomas should undergo an appropriate evaluation for hypopituitarism. Formal visual field testing should be performed in patients whose tumours are found to abut the optic chiasm on MRI.5 When no specific cause is found, and macroprolactinaemia has been excluded, the hyperprolactinaemia is designated to be idiopathic. In some cases, prolactinomas may be present that are too small to be detected by MRI. In other cases, the hyperprolactinaemia presumably results from hypothalamic regulatory dysfunction. In such patients who are followed long term, PRL levels normalise in about one-third, rise in 10–15%, and remain stable in the remainder. Only about 10% are found to have microadenomas on repeat imaging.19,20

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of untreated microprolactinomas occurs in only about 7% of patients. 21–25 Thus, the treatment of microadenomas should not be instituted merely to prevent further growth. On the other hand, an untreated prolactinoma should be followed with periodic PRL levels to determine whether it is among the minority that will enlarge. It is very unlikely for a prolactinoma to grow significantly without an increase in serum PRL levels, although some clinicians opt to monitor patients with pituitary MRI every few years to verify the absence of tumour growth. If PRL levels rise or symptoms of mass effects develop (such as headaches), then repeat scanning is indicated. A microadenoma with documented evidence of growth demands therapy for the size change alone, as it may be one of the few that will become a macroadenoma. The presence of a macroadenoma already implies a propensity for growth. Moreover, most macroprolactinomas are associated with PRL elevations significant enough to elicit symptoms that normally warrant treatment. Therefore, unless there are specific contraindications, therapy is usually advisable for these tumours. Local or diffuse invasion and compression of adjacent structures, such as the stalk or optic chiasm, are additional indications for therapy. Other indications for therapy are relative, being due to gonadal dysfunction and/or galactorrhoea. Oestrogen replacement may be an appropriate option for women to prevent osteoporosis. Women with microadenomas treated with oral oestrogens do not appear to be at increased risk for tumour enlargement.26–28 Individual case reports of tumour enlargement during oestrogen therapy have been documented, but whether tumour enlargement in these cases was related to use of oestrogen or reflected the natural progression of these particular tumours is not known. Because of this uncertainty, it is advisable to monitor patients who use oral oestrogens carefully with periodic measurement of PRL levels. The ability to follow patients closely with PRL levels, MRI scans and bone mineral density studies, and the knowledge of the efficacy of various modes of therapy permit a highly individualised approach to managing patients and choosing an ideal form of therapy. For almost all patients, the preferred treatment modality is a dopamine agonist.

Treatment The major objectives of treating patients with prolactinomas are (1) to suppress excessive PRL secretion so as to ameliorate its clinical consequences such as infertility, sexual dysfunction and osteoporosis; (2) to decrease or at least control tumour mass, thereby relieving visual field defects, cranial nerve dysfunction and (where applicable) hypopituitarism; and (3) to prevent disease recurrence or progression. Asymptomatic patients with idiopathic hyperprolactinaemia or microprolactinomas do not have an absolute indication for treatment. Significant growth

Medical therapy The compounds used in clinical practice to treat prolactinomas are all dopamine agonists. Bromocriptine, pergolide and cabergoline are all ergot derivatives but quinagolide is not. Dopamine agonists inhibit prolactin synthesis and secretion by binding to and activating dopamine D2 receptors on pituitary lactotrophs. Dopamine agonist treatment causes an involution of the endoplasmic reticulum and Golgi apparatus, leading to reduction in the size of individual lactotrophs; perivascular fibrosis and cell necrosis may also occur.29

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Responsiveness to dopamine agonists varies widely.29,30 In addition, individual prolactinomas may respond variably, such that tumours that respond poorly or incompletely to one dopamine agonist may respond well to another. Dopamine agonist resistance must be distinguished from dopamine agonist intolerance, in which adverse effects of the medication prevent the achievement of an effective response.30 The molecular mechanisms underlying dopamine agonist resistance are genetically heterogeneous and complex; in some cases, resistance is associated with a reduction in D2 receptor density on tumourous cells.30,31

Bromocriptine Bromocriptine was the first dopamine agonist introduced into clinical practice. It has a relatively short halflife, so that it is usually taken two or three times daily. The usual therapeutic dose range is 2.5–7.5 mg/day. Bromocriptine normalises serum PRL levels, restores gonadal function and reduces tumour volume in 80– 90% of patients with microadenomas.29,31 Substantial macroadenoma size reduction occurs in about twothirds of patients.29,31,32 The major adverse effects of bromocriptine are nausea and vomiting, which tend to occur after the initial dose and with dosage increases; introducing the drug at a low dosage (0.625 or 1.25 mg/day) at bedtime with food and gradual dose escalation will reduce these adverse effects.29,31 Intravaginal rather than oral administration often causes less gastrointestinal symptoms.33 Other less common side-effects include orthostatic hypotension, vasospasm, cramps, flushing and nasal congestion. Headache, drowsiness and psychiatric adverse effects are infrequent. Rare patients with Parkinson’s disease treated with very high doses of bromocriptine have been reported with pulmonary infiltrates, fibrosis, pleural effusions, pleural thickening and retroperitoneal fibrosis;29,31 however, these adverse effects are unlikely to occur at the low doses used for treatment of prolactinomas.

Cabergoline Cabergoline has a long duration of action permitting once or twice weekly administration. The long duration of action is due to slow elimination from pituitary tissue, high affinity binding to pituitary dopamine receptors, and extensive enterohepatic recycling.29 PRL lowering effects begin within 3 hours and plateau between 48 and 120 hours.31 A multicentre, randomised, prospective, 24-week trial conducted in 459 hyperprolactinaemic women, demonstrated that cabergoline induced normal PRL levels in 83% of woman compared with 59% with bromocriptine; ovulatory cycles or pregnancies were recorded in 72% with cabergoline compared with 52% with bromocriptine, and side-effects with cabergoline were less frequent, less severe and shorter

lived.34 After 1–2 years of treatment with cabergoline, a greater than 20% decrease of baseline tumour size in more than 80% of cases with complete disappearance of tumour mass in 26–36% of cases has been reported.35 Colao et al showed that 85% of 20 patients resistant to both bromocriptine and quinagolide treated with cabergoline responded with a normalisation of PRL levels and 70% responded with some change in tumour size.36 Cabergoline treatment is also effective and safe in patients with prolactinomas with onset in childhood or adolescence.37 About 80–90% of patients who respond to dopamine agonists will do so rapidly and with low doses. However, about 10–15% of patients respond with a step-wise reduction in PRL levels with each increase in dose.30,38 Increasing the weekly dose of cabergoline to 7 mg/week permitted recovery of gonadal and sexual function in 30% of those with macroadenomas and all of those with microadenomas.38 In general, large doses of cabergoline are very well tolerated, as demonstrated by the many studies in which this drug has been used to treat Parkinson’s disease.30 As long as adverse effects from higher doses do not develop, dose escalations are reasonable, with the awareness that doses of cabergoline greater than 2.0 mg/week are beyond those recommended in the package insert. Side-effects associated with the use of cabergoline are similar to those reported for the other dopamine agonists, but are generally less frequent, less severe and of shorter duration.29,31 The long half-life of cabergoline, which results in a relatively flat plasma drug concentration, may be advantageous with respect to the induction of side-effects. Pleuropulmonary inflammatory-fibrotic syndrome has been described in a few patients. Constrictive pericarditis was diagnosed in a patient with Parkinson’s disease receiving cabergoline therapy at the dose of 10 mg/day.31 Cardiac valvular lesions have been found in Parkinson’s disease patients treated with very high doses (>3 mg/day) of cabergoline.39,40 In these cases, the echocardiographic and/or microscopic features resembled those found in valvular disorders associated with ergot alkaloid agents and appetite suppressants. An excessive number of cardiac valvular lesions has not been reported in patients treated with the lower doses generally used for treatment of prolactinomas. However, in resistant patients who are receiving much greater than usual doses, it may be prudent to monitor them with echocardiograms.

Pergolide Pergolide is approximately 100 times more potent than bromocriptine and suppresses PRL secretion for up to 24 hours after a single dose,29,31,41 allowing effective control of hyperprolactinaemia with once daily dosing at rates similar to those found with bromocriptine. In a series of 22 patients with macroprolactinomas treated with pergolide reported by Freda et al,42

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PRL levels normalised in 15 patients and approached normal in two others with substantial tumour size reduction also being noted. In general, the nature and incidence of most sideeffects reported with pergolide are similar to those of bromocriptine.29,31 Daytime somnolence has been reported at very high doses. Similar to cabergoline, cases of pergolide-associated valvular heart disease have been reported in adults with Parkinson’s disease treated with doses much higher than those used for the treatment of hyperprolactinaemia.39,40 In the US, pergolide has been removed from the market by the US Food and Drug Administration.

Quinagolide Quinagolide (CV 205-502) is a non-ergot dopamine agonist with similar tolerance and efficacy to bromocriptine and pergolide, and can be given once daily. Approximately 50% of patients who are resistant to bromocriptine respond to quinagolide. Its efficacy in reducing tumour size and normalising PRL levels is similar to that of bromocriptine and pergolide.29,31 In a randomised, cross-over study of 20 patients with hyperprolactinaemia receiving once-daily quinagolide or twice-weekly cabergoline for 12 weeks, a higher percentage of patients achieved normal PRL levels with cabergoline compared with quinagolide but clinical efficacy in ameliorating amenorrhoea, oligomenorrhoea, galactorrhoea and impotence was similar, as was the occurrence of sideeffects.43 Adverse effects are consistent with those reported for other dopamine agonists, although they occur less frequently than with bromocriptine.31 Quinagolide is not available in the US.

Dopamine agonist withdrawal A significant number of patients may achieve remission following withdrawal of cabergoline or bromocriptine. After withdrawal of bromocriptine, remission rates have been reported as high as 20–44%. Importantly, an increase of tumour volume has been found in less than 10% of cases after bromocriptine discontinuation. A retrospective analysis of 131 patients with prolactinomas treated with bromocriptine demonstrated that 26% of patients with microprolactinomas and 16% of patients with macroprolactinomas sustained a normal PRL level 44 months after drug withdrawal.44 Following withdrawal of cabergoline, persistent normoprolactinaemia has been reported in about onethird of patients in several small studies. A prospective analysis of 200 patients treated with cabergoline for 42 months showed that remission of hyperprolactinaemia was sustained in 69% of patients with microprolactinomas and 64% of patients with macroprolactinomas 2–5 years after drug withdrawal.45 In those patients for whom hyperprolactinaemia

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recurred, only ten women (22.2%) and seven men (38.9%) experienced recurrence of gonadal dysfunction. The patients showing small remnant tumours on MRI at the onset of drug withdrawal had a higher estimated recurrence rate after 5 years compared with those without evident tumour (macroprolactinomas 77.5 vs 32.6%; microprolactinomas 41.5 vs 26.2%).45 Another retrospective study of 89 patients with microprolactinomas treated with bromocriptine or cabergoline showed that 36% maintained normal prolactin levels 1 year following drug withdrawal.46 In neither of these latter studies was recurrence of hyperprolactinaemia associated with regrowth of the tumours. Therefore, it is reasonable to attempt periodic treatment withdrawal, especially for patients without demonstrable tumour on MRI during treatment. Following withdrawal, patients should be closely monitored for recurrent hyperprolactinaemia and tumour regrowth.

Medical therapy – conclusions By far, the greatest experience in treating patients with prolactinomas has been with bromocriptine and cabergoline. In head-to-head randomised, prospective comparison studies,34 retrospective analyses36 and general clinical experience, cabergoline has been shown to be more effective in normalising PRL levels and more successful in reducing tumour size, while maintaining a more favourable side-effect profile. Patients are less likely to be resistant to the therapeutic effects of cabergoline; furthermore, most patients found to be resistant to bromocriptine subsequently respond to cabergoline. Finally, treatment with cabergoline affords a greater chance of obtaining permanent remission and successful withdrawal of medication, compared with treatment with bromocriptine. Thus, in general, cabergoline is preferable to bromocriptine as an initial therapeutic agent. The single exception to a preference for cabergoline may be for the treatment of women who wish to become pregnant (see below). In patients who do not achieve acceptable biochemical or tumour size changes in response to dopamine agonists, transsphenoidal surgery remains an option if the tumour is potentially resectable and an experienced neurosurgeon is available. Radiotherapy may be effective in controlling tumour growth, although its efficacy in restoring PRL levels to normal is limited. If fertility is a major concern, induction of ovulation is possible in hyperprolactinaemic patients even without lowering PRL levels, using clomiphene citrate, gonadotrophins and pulsatile GnRH.47

Surgery The primary indications for surgery are failure of medical therapy, defined as inadequate PRL reduction on high doses of dopamine agonists, tumour enlargement despite the use of a dopamine agonist and a

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growing macroadenoma in pregnant women associated with unstable visual field deficits that does not respond to dopamine agonists. The transsphenoidal approach is used for microprolactinomas and the overwhelming majority of macroprolactinomas. Craniotomy is reserved for tumours which are inaccessible via the transsphenoidal approach. Giant and invasive prolactinomas cannot be cured by surgery, regardless of the surgical technique employed or experience of the neurosurgeon; therefore, if undertaken, the goal of surgery under these circumstances is to debulk with the prospect of improving symptoms related to mass effects.48 Compared with the standard transsphenoidal approach, the complication rates of the endonasal, endoscopic approach are similar, or perhaps slightly lower, but cure rates are no different.49 Surgical outcomes are highly dependent upon the expertise and experience of the neurosurgeon, as well as the size of the tumour. Combining data from 50 surgical series, 1596/2137 (75%) microadenomas and 755/2226 (34%) macroadenomas were classified as achieving initial surgical remission, i.e. having PRL levels normalised within 1–12 weeks following surgery.29 Among these series the surgical success rates were highly variable. For macroadenomas, the success rate in large part was dependent on the size of tumours chosen for surgery. In many series, the objective was, appropriately, debulking of a very large tumour rather than cure and in other series very large tumours were not operated upon. Data available from the 50 series referred to above show that recurrence rates for microadenomas (147/809=18%) and macroadenomas (106/465=23%) are similar.29 Recurrence is usually detected by finding hyperprolactinaemia again and not necessarily with radiographic documentation of tumour regrowth. Recurrence of the hyperprolactinaemia is usually accompanied by sexual/reproductive dysfunction, which thereby serves as an indication for medical therapy to reduce PRL hypersecretion. Overall, long-term surgical cure rates, based on the initial remission and recurrence rates cited above, are 61% for those with microadenomas and 26% for macroadenomas. For patients with giant prolactinomas and those with considerable cavernous sinus invasion, the chance for surgical cure is essentially zero. Complications from transsphenoidal surgery for microadenomas are infrequent, the mortality rate being at most 0.6%, the major morbidity rate being about 3.4% (visual loss 0.1%, stroke/vascular injury 0.2%, meningitis/abscess 0.1% and oculomotor palsy 0.1%) and CSF rhinorrhoea occurring in 1.9%. The mortality rate for transsphenoidal surgery for all types of secreting and non-secreting macroadenomas is 0.9%, the major morbidity rate is 6.5% (visual loss 1.5%, stroke/vascular injury 0.6%, meningitis/abscess 0.5% and oculomotor palsy 0.6%) and the rate of CSF rhinorrhoea is 3.3%.50,51 Transient diabetes insipidus

is quite common with transsphenoidal surgery for both micro- and macroadenomas and permanent diabetes insipidus occurs in about 1% of surgeries on macroadenomas. More than 50% of patients with macroadenomas have hypopituitarism prior to surgery as a result of mass effects.32 Following surgery, both further worsening or improvement may occur. Surgery involving craniotomy is much more hazardous. Visual field defects and reduction in visual acuity can be improved in 74% of patients with surgery. Visual field defects rarely may occur due to herniation of the chiasm into an empty sella, direct injury or devascularisation of the optic apparatus, fracture of the orbit, postoperative haematoma, or cerebral vasospasm.

Radiotherapy Radiotherapy is generally used after failed transsphenoidal surgery and medical therapy. Approximately 250 patients have been reported who have undergone treatment with conventional radiotherapy alone or after failure of medical and/or surgical therapy, with an overall normalisation rate for the entire series of 34% over many years.29 Almost 300 patients have been reported who have received single dose stereotactic radiotherapy alone, or after failure of medical and/or surgical therapy, with an overall normalisation rate for the entire series of 31.4%.29 With single dose stereotactic radiotherapy using the gamma knife or linear accelerator as primary therapy for prolactinomas, the rate of PRL normalisation rate was 21% after a median of 2 years.52 Pituitary adenomas with less than 5 mm clearance between the tumour margin and the radiosensitive optic apparatus are poor candidates for single dose radiotherapy. On the other hand, tumours with residual tumour in the cavernous sinus may be good candidates for single dose radiotherapy, as the cranial nerves in the cavernous sinus are relatively radioresistant. Fractionated radiotherapy is also preferable to single dose radiotherapy when the tumour volume is so large (>3 cm) that an effective radiation dose cannot be safely delivered in a single session. The most frequent long-term morbidity of conventional radiotherapy is radiation induced hypopituitarism, with a cumulative actuarial risk of approximately 50% at 10–20 years.29 Hypopituitarism is likely secondary to hypothalamic and pituitary damage, although the former is considered of primary importance. In addition, the standardised mortality rate is higher in patients with hypopituitarism who had received radiotherapy for pituitary tumours compared with those who had not received radiotherapy, due primarily to cerebrovascular disease.53 Additional late complications include cerebrovascular accidents, optic nerve damage, neurological dysfunction and secondary radiation-induced intracranial malignancies. Following single dose radiotherapy, hypopituitarism appears to occur at rates similar to those for

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Fig 16.1 Coronal and sagittal magnetic resonance imaging (MRI) scans of an intrasellar prolactin-secreting macroadenoma in a woman prior to conception (upper) and at 7 months of gestation (lower). Note the marked tumour enlargement on the later MRI scans, at which time the patient was complaining of headaches. Reproduced from reference 55, with permission.

conventional radiotherapy.54 Cranial neuropathies may occur but are usually transient and radiation necrosis of surrounding brain tissue is very rare. With limited follow-up, there have been no cases of secondary intracranial malignancies reported yet.

Pregnancy Effect of pregnancy on prolactinoma growth During pregnancy, oestrogen stimulates PRL synthesis and secretion, and lactotroph cell hyperplasia. Tumour enlargement during pregnancy has been reported (Fig 16.1). This enlargement results from both the discontinuation of the dopamine agonist that was responsible for tumour shrinkage and the stimulatory effect of high oestrogen levels produced by the placenta.47 Data analysing the risk of symptomatic tumour enlargement in pregnant women with prolactinomas, divided according to their status as micro- or macroprolactinomas have been analysed29,47,56 (Table 16.2).

Table 16.2

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The risk of symptomatic tumour enlargement for microadenomas is only 2.6% (13/528 pregnancies). Surgical intervention was not required in any of the patients and therapy with bromocriptine in six individuals was followed by the resolution of their symptoms. Fifty-six of 172 pregnancies (32.6%) in patients with macroadenomas were complicated by symptomatic tumour enlargement; surgical intervention was carried out in 12 of these cases and bromocriptine therapy in 17, leading to resolution of their symptoms. A total of 161 women with macroadenomas had undergone surgery or radiation prior to pregnancy; for these, the risk for tumour enlargement was only 4.3%.29,47 Therefore, a patient with a microadenoma treated only with a dopamine agonist pre-gestationally should be carefully followed throughout pregnancy. PRL levels do not always rise during pregnancy in women with prolactinomas, as they do in normal women. Usually PRL levels rise over the first 6–10 weeks after discontinuing bromocriptine and then do not increase further. Prolactin levels may also not rise with tumour enlargement. For these reasons, periodic assessment of PRL levels is not helpful and may even be misleading. Because of the low incidence of tumour enlargement in microprolactinomas, routine periodic visual field testing is not cost effective. Visual field testing and MRI scans should be performed, however, in patients who develop visual changes or symptoms of mass effects.29,47 For a woman with a larger macroadenoma that may have suprasellar extension, there is no definitive answer as to the best therapeutic approach, and the patient should be informed of the risks and benefits of the various therapeutic alternatives, and permitted to make a highly individualised decision. Transsphenoidal surgical debulking of the tumour prior to conception should greatly reduce the risk of serious tumour enlargement, but cases with massive tumour expansion during pregnancy even after such surgery have been reported. After surgical debulking, a dopamine agonist will still be required to restore normal PRL levels in most cases to allow ovulation. Alternatively, the dopamine agonist could be administered continuously throughout gestation but the safety of this approach has not been established. The most common approach is to discontinue the dopamine agonist after pregnancy is confirmed, as done in patients with microadenomas. Careful follow-up with 1–3 monthly visual field testing is

Effect of pregnancy on prolactinomas.47,56

Microadenomas Macroadenomas Macroadenomas prior surgery or radiation

Total Patients (N)

Symptomatic enlargement

Symptomatic enlargement (%)

528 172 161

13 56 7

2.5 32.6 4.3

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Table 16.3

Effect of bromocriptine and cabergoline on pregnancies. Bromocriptine57,58

Pregnancies spontaneous abortions terminations ectopic hydatidiform moles Deliveries (known duration) at term (> 37 weeks) preterm (< 37 weeks) Deliveries (known outcome) single births multiple births Babies (known details) normal with malformations *

--

Cabergoline34,56,61–66

N

%

N

%

Normal67–69 (%)

6239 620 75 31 11 4139 3620 519 5120 5031 89 5213 5030 93

100 9.9 1.2 0.5 0.2 100 87.5 12.5 100 98.3 1.7 100 98.2 1.8

478 41 52* 0 1 291 242† 49 262 254 8 375 363 12

100 8.6 10.9 0 0.2 100 83.2 16.8 100 96.9 3.1 100 96.8 3.2

100 10–15 20 1.0–1.5 0.1–0.15 100 87.3 12.8 100 96.8 3.2 100 96.2 3.0

8 of these terminations were for malformations. 4 of these births were stillbirths.

†

warranted. Repeat scanning is reserved for patients with symptoms of tumour enlargement and/or evidence of a developing visual field defect.47 Should symptomatic tumour enlargement occur with any of these approaches, reinstitution of a dopamine agonist usually causes rapid tumour size reduction with no adverse effects on the infant. Any type of surgery during pregnancy results in a 1.5-fold increase in foetal loss in the first trimester and a 5-fold increase in foetal loss in the second trimester, although there is no risk of congenital malformations from such surgery.47 Thus, dopamine agonist reinstitution would appear to be preferable to surgical decompression. However, such medical therapy must be very closely monitored, and transsphenoidal surgery or delivery (if the pregnancy is far enough advanced) should be performed if there is no response to the dopamine agonist and vision is progressively worsening.47

Effects of dopamine agonists on the foetus Most patients with prolactinomas that come to clinical attention will require treatment of hyperprolactinaemia to ovulate and conceive. Therefore, the foetus is likely to be exposed to these drugs for at least 3–4 weeks of gestation, until a pregnancy test can verify conception and allow discontinuation of the medication. The use of bromocriptine, when it is taken for only the first few weeks of gestation, has not been associated with an increase in the rates of spontaneous abortions, ectopic pregnancies, trophoblastic disease, multiple pregnancies, or congenital malformations in a very large number of pregnancies (Table 16.3).57,58 Long-term follow-up studies of 64 children, between the ages of 6 months and 9 years, who were born to

mothers who took bromocriptine for a limited duration in early pregnancy have shown no adverse effects on childhood development.59 Data available on the effects of continuous bromocriptine on foetal/infant development in only about 100 women revealed minor abnormalities in only two infants.60 Experience with the use of cabergoline in pregnancy is accumulating. Data on exposure of the foetus or embryo during the first several weeks of pregnancy have been reported in nearly 500 cases and such use has not shown an increased percentage of spontaneous abortion, premature delivery, or multiple births (Table 16.3).34,56,61–66 Outcome data with respect to malformations were available for 375 pregnancies.34,56,61–66 Major malformations were found in only two of these series. Ricci et al found one major malformation in 49 live births but in their series one woman terminated her pregnancy because of a major malformation found on ultrasound.65 In the series of Colao et al there were 258 deliveries, with four stillbirths and 11 babies having major malformations.56 Thus, the total frequency of malformations in pregnancies that went to term was 3.2% (12/375). However, in addition there were six pregnancy terminations because of malformations in the series of Colao et al.66 There was also one termination for a foetal malformation in the series of 23 pregnancies reported by Webster et al.34 If the 52 elective terminations and the eight malformations in the termination group are added to the above numbers for pregnancy outcomes, then there were 20 malformations out of 427 pregnancies, or 4.7%. Short-term follow-up studies of 107 infants born to mothers who used cabergoline during pregnancy indicate normal neonatal physical and mental development.70

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Few data are available on the safety of pergolide in pregnancy. In one report, two major and three minor congenital abnormalities were described among 38 pregnancies in women receiving pergolide in pre-marketing studies, but a causal relationship was not definitively established.71 The manufacturer of pergolide, Eli Lilly & Co., reports limited data on pregnancies in which the foetus was exposed to pergolide, but did find that 7.2% of pregnancies resulted in spontaneous abortions, 7.2% in minor malformations, 14.3% in intentional abortions, 28.6% in healthy infants, and 43.4% with no information available.72 This limited information seems sufficient to recommend against the use of pergolide for a woman desiring pregnancy. Quinagolide does not appear to be safe during pregnancy. A review of 176 pregnancies, in which quinagolide was maintained for a median duration of 37 days, reported 24 spontaneous abortions, one ectopic pregnancy and one stillbirth at 31 weeks of gestation.73 Furthermore, nine foetal malformations were reported in this group, including spina bifida, trisomy 13, Down syndrome, talipes, cleft lip, arrhinencephaly and Zellweger syndrome.73 Thus, bromocriptine has the largest safety database and has a proven safety record for pregnancy. The database for the use of cabergoline in pregnancy is much smaller, but there is no evidence at present indicating that it exerts deleterious effects on pregnant women. The incidence of malformation in their offspring is not greater than that found in the general population. For the woman who is intolerant to bromocriptine and who is doing well with cabergoline, continuation of cabergoline to facilitate conception is reasonable. The numbers of abortions and malformations associated with the use of pergolide and quinagolide during pregnancy raise serious concern. Therefore, quinagolide and pergolide should not be used when fertility is desired. If reinstitution of a dopamine agonist is needed later in gestation to control tumour growth, bromocriptine is favoured over the other dopamine agonists due to greater experience with this drug in this setting.

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23. Koppelman MCS, Jaffe MJ, Rieth KG et al. Hyperprolactinaemia, amenorrhea, and galactorrhea. Ann Intern Med 1984; 100: 115–21. 24. Sisam DA, Sheehan JP, Sheeler LR. The natural history of untreated microprolactinomas. Fertil Steril 1987; 48: 67–71. 25. Schlechte J, Dolan K, Sherman B et al. The natural history of untreated hyperprolactinaemia: a prospective analysis. J Clin Endocrinol Metab 1989; 68: 412–18. 26. Corenblum B, Donovan L. The safety of physiological oestrogen plus progestin replacement therapy and with oral contraceptive therapy in women with pathological hyperprolactinaemia. Fertil Steril 1993; 59: 671–4. 27. Testa G, Vegetti W, Motta T et al: Two-year treatment with oral contraceptives in hyperprolactinemic patients. Contraception 1998; 58: 69–73. 28. Fahey UM, Foster PA, Torode HW et al. The effect of combined oestrogen/progestogen treatment in women with hyperprolactinemic amenorrhea. Gynecol Endocrinol 1992; 6: 183–8. 29. Gillam MP, Molitch ME, Lombardi G, Colao A. Advances in the treatment of prolactinomas. Endocr Rev 2006; 27: 485–534. 30. Molitch ME. Pharmacologic resistance in prolactinoma patients. Pituitary 2005; 8: 43–52. 31. Colao A, di Sarno A, Pivonello R et al. Dopamine receptor agonists for treating prolactinomas. Expert Opin Investig Drugs 2002; 11: 787–800. 32. Molitch ME, Elton RL, Blackwell RE et al. Bromocriptine as primary therapy for prolactinsecreting macroadenomas: results of a prospective multicenter study. J Clin Endocrinol Metab 1985; 60: 698–705. 33. Katz E, Schran HF, Adashi EY. Successful treatment of a prolactin-producing pituitary macroadenoma with intravaginal bromocriptine mesylate: a novel approach to intolerance of oral therapy. Obstet Gynecol 1989; 73: 517–20. 34. Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 1994; 331: 904–9. 35. Colao A, Di Sarno A, Landi ML et al. Long-term and low-dose treatment with cabergoline induces macroprolactinoma shrinkage. J Clin Endocrinol Metab 1997; 82: 3574–9. 36. Colao A, Di Sarno A, Sarnacchiaro F et al. Prolactinomas resistant to standard dopamine agonists respond to chronic cabergoline treatment. J Clin Endocrinol Metab 1997; 82: 876–83. 37. Gillam MP, Fideleff H, Boquete HR, Molitch ME. Prolactin excess: treatment and toxicity. Pediatr Endocrinol Rev 2004; 2: 108–14. 38. Di Sarno A, Landi ML, Cappabianca P et al. Resistance to cabergoline as compared with bromocriptine in hyperprolactinaemia: prevalence, clinical definition, and therapeutic strategy. J Clin Endocrinol Metab 2001; 86: 5256–61. 39. Schade R, Andersohn F, Suissa S et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007; 356: 29–38.

40. Zanettini R, Antonini A, Gatto G et al. Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. N Engl J Med 2007; 356: 39–46. 41. Perryman RL, Rogol AD, Kaiser DL et al. Pergolide mesylate: its effects on circulating anterior pituitary hormones in man. J Clin Endocrinol Metab 1981; 53: 772–8. 42. Freda PU, Andreadis CI, Khandji AG et al. Longterm treatment of prolactin-secreting macroadenomas with pergolide. J Clin Endocrinol Metab 2000; 85: 8–13. 43. De Luis DA, Becerra A, Lahera M et al. A randomized cross-over study comparing cabergoline and quinagolide in the treatment of hyperprolactinemic patients. J Endocrinol Invest 2000; 23: 428–34. 44. Passos VQ, Souza JJ, Musolino NR, Bronstein MD. Long-term follow-up of prolactinomas: normoprolactinaemia after bromocriptine withdrawal. J Clin Endocrinol Metab 2002; 87: 3578–82. 45. Colao A, Di Sarno A, Cappabianca P et al. Withdrawal of long-term cabergoline therapy for tumoural and nontumoural hyperprolactinaemia. N Engl J Med 2003; 349: 2023–33. 46. Biswas M, Smith J, Jadon D et al. Long-term remission following withdrawal of dopamine agonist therapy in subjects with microprolactinomas. Clin Endocrinol 2005; 63: 26–31. 47. Molitch ME. Pituitary disorders during pregnancy. Endocrinol Metab Clin North Am 2006; 35: 99–116. 48. Shrivastava RK, Arginteanu MS, King WA et al. Giant prolactinomas: clinical management and longterm follow up. J Neurosurg 2002; 97: 299–306. 49. Cho DY, Liau WR. Comparison of endonasal surgery and sublabial microsurgery for prolactinomas. Surg Neurol 2002; 58: 371–5. 50. Barker FG, Klibanski A, Swearingen B. Transsphenoidal surgery for pituitary tumours in the United States, 1996–2000: mortality, morbidity, and the effects of hospital and surgeon volume. J Clin Endocrinol Metab 2003; 88: 4709–19. 51. Laws ER, Jane JA Jr. Neurosurgical approach to treating pituitary adenomas. Growth Horm IGF Res 2005; 15: S36–S41. 52. Pan L, Zhang N, Wang EM et al. Gamma knife radiosurgery as a primary treatment for prolactinomas. J Neurosurg 2000; 93: 10–13. 53. Tomlinson JW, Holden N, Hills RK et al. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Lancet 2001; 357: 425–31. 54. Feigl GC, Bonelli CM, Berghold A et al. Effects of gamma knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 2000; 97: 415–21. 55. Molitch ME. Medical treatment of prolactinomas. Endocrinol Metab Clin North Am 1999; 28: 143–70. 56. Bronstein MD. Prolactinomas and pregnancy. Pituitary 2005; 8: 31–8. 57. Krupp P, Monka C, Richter K. The safety aspects of infertility treatments. In: Program of the Second World Congress of Gynecology and Obstetrics, Rio de Janeiro, Brazil, 1988: 9. 58. Krupp P, Monka C. Bromocriptine in pregnancy: safety aspects. Klin Wochenschr 1987; 65: 823–7.

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The Patient with prolactinoma 59. Raymond JP, Goldstein E, Konopka P et al. Followup of children born of bromocriptine-treated mothers. Horm Res 1985; 22: 239–46. 60. Konopka P, Raymond JP, Merceron RE, Seneze J. Continuous administration of bromocriptine in the prevention of neurological complications in pregnant women with prolactinomas. Am J Obstet Gynecol 1983; 146: 935–8. 61. Ferrari C, Paracchi A, Mattei AM et al. Cabergoline in the long-term therapy of hyperprolactinemic disorders. Acta Endocrinol 1992; 126: 489–94. 62. Ciccarelli E, Grottoli S, Razzzore P et al. Long-term treatment with cabergoline, a new long-lasting ergolne derivate, in idiopathic or tumourous hyperprolactinaemia and outcome of drug-induced pregnancy. J Endocrinol Invest 1997; 20: 547–51. 63. Cannavò S, Curtò L, Squadrito S et al. Cabegoline: a first-choice treatment in patients with previously untreatd prolactin-secreting pituitary adenoma. J Endocrinol Invest 1999; 22: 354–9. 64 Verhelst J, Abs R, Maiter D et al. Cabergoline in the treatment of hyperprolactinaemia: a study in 455 patients. J Clin Endocrinol Metab 1999; 84: 2518–22. 65. Ricci E, Parazzini F, Motta T et al. Pregnancy outcome after cabergoline treatment in early weeks of gestation. Reprod Toxicol 2002; 16: 791–3.

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66. Colao A, Abs R, Bárcena DG et al. Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study. Clin Endocrinol 2008; 68: 66–71. 67. Martin JA, Kung H-C, Mathews TJ et al. Annual summary of vital statistics: 2006. Pediatrics 2008; 121: 788–801. 68. American Pregnancy Association. Statistics. http:// www.americanpregnancy.org/main/statistics/. Accessed 30/3/08 69. Canfield MA, Honein MA, Yuskiv N et al. National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999–2001. Birth Defects Res A Clin Mol Teratol. 2006; 76: 747–56. 70. Robert E, Musatti L, Piscitelli G, Ferrari CI. Pregnancy outcome after treatment with the ergot derivative, cabergoline. Reprod Toxicol 1996; 10: 333–7. 71. De Mari M, Zenzola A, Lamberti P. Antiparkinsonian treatment in pregnancy. Mov Disord 2002; 17: 428–9. 72. Acharya V. Review of pregnancy reports in patients on pergolide treatment. Data on file. Indianapolis: Eli Lilly & Co, 2004. 73. Webster J. A comparative review of the tolerability profiles of dopamine agonists in the treatment of hyperprolactinaemia and inhibition of lactation. Drug Safety 1996; 14: 228–38.

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17 Periconceptional issues in neuromuscular disorders Willem Verpoest, Michel De Vos

Introduction Neuromuscular disorders are common in women of childbearing age. Apart from acquired autoimmune neuromuscular diseases, such as multiple sclerosis and myasthenia gravis, which may be either suppressed or aggravated by pregnancy itself, and acquired compression neuropathies that can occur as a complication of pregnancy, a large number of inherited congenital neuromuscular disorders present specific problems during pregnancy. Although some of these disorders display mitochondrial inheritance, such as carnitine palmitoyltransferase defciency and cytochrome oxidase deficiency mitochondrial myopathy, the majority are transmitted according to a Mendelian inheritance pattern. This chapter reviews female-specific issues of the most common heritable neuromuscular disorders and considers aspects related to fertility and pregnancy.

Inherited myopathies Congenital myopathies represent a distinct but markedly heterogeneous group of muscle disorders that are characterised by muscle weakness and wasting of variable distribution.1 These disorders typically manifest at birth or in infancy, but can appear at any age up until the middle years. The congenital myopathies have characteristic histopathological abnormalities on muscle biopsy, allowing a morphological classification. Advances in molecular genetics have led to a more rational definition and have rearranged the taxonomy for some of these conditions. Generally, the group of myopathies can be subdivided into muscular dystrophies and non-dystrophic congenital myopathies. Disrupted structural proteins, signalling molecules, enzymes and proteins involved in post-translational modifications as well as dysregulated microRNAs have been shown to underlie an increasing number of myopathies.2 Literature reports on pregnancy-related issues in patients with a congenital myopathy are spurious, either because many myopathies have a low incidence, or because many disorders display a wide

range of severity, from very mild to severe, with severely affected women not reaching childbearing age. Furthermore, abnormalities of dystrophin, resulting in Duchenne and Becker muscular dystrophy and accounting for the largest subset of patients with congenital myopathy, show X-linked recessive inheritance; women are only rarely affected, as a result of a process of skewed X-chromosome inactivation.3 For these reasons, we restrict this review to the most common autosomal dominant or recessive neuromuscular disorders; the management of pregnancy-related complications in rare non-dystrophic myopathies has previously been reviewed.4

Myotonic dystrophy General characteristics of myotonic dystrophy type 1 Myotonic dystrophy type 1 (also known as dystrophia myotonica type 1; DM1; Steinert’s disease; OMIM #160900) is an autosomal dominant disorder, with an incidence of one in 8000. The genetic defect is an unstable expansion of a CTG trinucleotide repeat at the 3′ end of the DMPK gene located on chromosome 19q13.3 (see Human Gene Organisation), which was cloned in 1992.5,6 Expansion of the trinucleotide repeat is frequently observed after parent-to-child transmission, but extreme amplifications are not transmitted through the male line. This explains anticipation, that is an increase in severity in successive generations and the occurrence of the severe, often lethal, congenital form almost exclusively in the offspring of affected women7 (Tables 17.1 and 17.2). DM1 patients are progressively affected to various degrees by myotonic dysfunction, muscle wasting, ophthalmological (cataracts) and cardiorespiratory (arrhythmia, electrocardiogram (ECG) abnormalities, reduced functional residual capacity, reduced functional vital capacity, reduced maximum peak inspiratory pressure, reduced lower oesophageal sphincter competence, laryngeal muscle weakness) problems, and more severely affected patients may suffer with chronic hypercapnia. In addition to respiratory muscle involvement, central drive is reduced. Respiratory

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Table 17.1 Type

Mild Adult Childhood Congenital

Clinical classification of myotonic dystrophy.8 Age at onset (years)

>50 10–50 1–10 Prenatal–birth

Main features

CTG repeats

Cataracts, mild weakness Myotonia, muscle weakness, cataracts, fatigue Hypotonia, learning difficulties, limited motor skills Respiratory distress, sucking difficulties, hypotonia, joint contractures, psychomotor retardation

50–100 100–1000 500–>2000 1000–>5000

Table 17.2 Classification of myotonic dystrophy based on the number of repeats.9 Type

Number of CTG repeats

Normal Mild Moderate Severe Neonatal

5–30 repeats 50–80 repeats 80–200 repeats >200 repeats Up to 2000 repeats and more

failure may occur, sometimes precipitated by anaesthesia or chest infection.10 Furthermore, there is a risk of developing respiratory insufficiency and aspiration as a result of laryngeal muscle weakness and incompetence of the lower oesophageal sphincter, which is related to the degree of myotonic dystrophy, with mild and adult types expected to have a lower risk than childhood and congenital types.11,12 The overall risk of respiratory complications including ventilatory failure requiring ventilatory support, atelectasis and pneumonia is 8.2%.13 Patients can also show an exaggerated response to induction agents, especially propofol.14 Patients with DM1 should therefore be assessed carefully prior to proceeding to any surgical procedure15 and should be counselled about the risks involved, including that of delayed recovery and prolonged postoperative ventilation, and should be kept in post-procedure observation for at least 24 hours. Cardiac features include conduction abnormalities, mitral valve prolapse and wall motion abnormality, again related to the number of CTG repeats.16 Echocardiography has been proven to be a useful adjunct in monitoring patients with congenital myotonic dystrophy, but it is unclear as yet whether subclinical or mildly affected cases benefit from this test in conjunction with electro-cardiographic follow-up. The discussion remains whether affected females need to undergo echocardiography before embarking upon reproductive treatment and pregnancy, and what may be the value of this test.17 The involvement of smooth muscle in DM affects gastrointestinal (GI) and genitourinary function, leading to a high incidence of GI symptoms including diarrhoea, and dysfunctional labour, often in association with suspected foetal distress, an increased risk of Caesarean section, and almost always associated with

Fig 17.1

Typical facial appearence of a DM1 patient.

an affected foetus. Abnormal placentation may lead to massive obstetric haemorrhage and preterm labour. Uterine inertia may lead to an increased incidence of postpartum haemorrhage,18–20 but this was not documented in the series by Rudnik-Schöneborn et al.21 Other features of myotonic dystrophy include frontal balding, and a characteristic facial appearance due to atrophy of masseter, sternocleidomastoid and temporalis muscles (Fig 17.1). Neurological features include a higher incidence of motor and sensory neuropathy, white matter lesions and cortical atrophy, dependent on age of onset and size of the CTG expansion. Mental deficiency may feature to some degree.8 A feature of potential relevance to affected females, especially those considering becoming pregnant, is the higher incidence of impaired glucose tolerance of different severity (44%), frequently with hypersecretion of insulin.22 More recently a second form of multisystem myotonic disorder has been recognised and variously designated as proximal myotonic myopathy (PROMM), proximal myotonic dystrophy (PDM), or DM2.10

Periconceptional and obstetric risks Affected males have an increased risk of fertility problems, with an increased incidence of hypogonadism, raised follicle stimulating hormone (FSH) levels and lower testosterone levels, and sperm quality is on average

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worse than in non-affected men. The major lesion in men is believed to be that of seminiferous tubular destruction. Secondary sexual development is usually normal. Ovarian function in affected women has generally been accepted to be normal, but oligomenorrhoea, abortions and early menopause have been reported.23 Contrary to Sagel et al,23 who reported normal function of the pituitary–ovarian axis, Feyereisen et al24 suggested, in a recent small series of patients, that ovarian response is lower than in controls. They based their findings on an observed significant delay in day of human chorionic gonadotrophin (hCG) and a higher prevalence of poor quality embryos in the DM1 group. The high cancellation rate (38%) per started cycle in this study is remarkable, leading to a small study population, and the poor reproductive outcome (no pregnancies in affected). Another small study by Sahu et al25 suggested a similarly reduced ovarian reserve and ovarian response. A larger study by Verpoest et al26 could not demonstrate any evidence of gonadal dysfunction in affected female DM1 patients undergoing ovarian stimulation, intracytoplasmic sperm injection (ICSI) and preimplantation genetic diagnosis (PGD). The observed and expected cumulative delivery rate in this group of DM1 patients was 42% and 72%, respectively, which is comparable to an unselected population of patients undergoing ICSI at the same centre (39% and 79%, respectively). Studies looking into reproductive function of DM1 patients outside artificial reproductive treatment (ART) are lacking. As smooth muscle organs are affected to various degrees, the uterus may show functional abnormalities, particularly in pregnancy. A higher pregnancy loss in a later stage of the pregnancy as a result of involvement of the uterine muscle was reported.27,28 Rudnik-Schöneborn et al8 reported a higher incidence of complications in a group 31 women with classic myotonic dystrophy, who delivered a total of 66 children. The first indication of maternal disease was a severely affected child in 39% of cases. In this study, the incidence of placenta previa (9%) was higher than in the general population. Postpartum haemorrhage occurred in 3% of patients, as a result of uterine inertia. Polyhydramnios was seen in 17% of pregnancies, and was exclusively seen in congenitally affected foetuses. The number of instrumental deliveries was significantly increased in labouring patients with DM1. A significantly increased risk of urinary tract infections in pregnancy was also found, indicating involvement of this organ system as well. The authors also demonstrated that the postpartum recovery period can be delayed after operative interventions but is uneventful in the majority of cases.8 Pregnancies in which the foetus is affected by congenital DM1, present with non-immune hydrops foetalis,29 reduced foetal movements, and joint contractures may be visible at prenatal ultrasound. Muscle hypotonia may lead to severe respiratory distress after birth, and may result in neonatal death. There is a marked increase of preterm labour in gestations with affected foetuses, predominantly as a result of polyhydramnios,

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whereas other complications (placenta previa, preeclampsia, emergency Caesarean section, cervical incompetence) are not more common compared with a non-affected control population.8 The complication rate is thought to be lower in women pregnant with non-affected offspring.27 There is no clinical category that allows prediction of specific obstetric risks, as similar complications can occur in early and late onset mothers. In this respect molecular genetic analysis is not of great value.21 General anaesthesia is contraindicated in these patients, in view of potential serious complications including respiratory insufficiency and cardiac arrhythmia. General anaesthesia for oocyte retrieval is avoided whenever possible. If and when general anaesthesia is necessary, preoperative measures should include multidisciplinary care, including cardiological and anaesthetic assessment. In anaesthesia, the use of opiates should be minimised, thiopentone and suxamethonium should be avoided and short-acting products should be used. Postoperative monitoring should be directed at assessing respiratory function and cardiac rhythmicity. Detubation should only be carried out when respiration has fully recovered. Physiotherapy is advised after detubation. Obstetric care of a DM1 patient should be rigorous and multidisciplinary, involving geneticists, cardiologists, neurologists, ophtalmologists and anaesthesiologists. The patient presenting with DM1, and applying for reproductive treatment and PGD, should therefore be counselled very carefully about the potential complications in pregnancy and labour.

Molecular basis of myotonic dystrophy types 1 and 2 For both DM1 and DM2 the molecular basis is expansion of an unstable repeat sequence in a non-coding part of a gene (DMPK in DM1 and ZNF9 in DM2). There is accumulating evidence that the basic molecular mechanism is disruption of mRNA metabolism, which has far-reaching effects on many other genes, in part through the induction of aberrant splicing, explaining the multisystemic nature of the disease. The unstable nature of the expansion provides a molecular explanation for anticipation.10 The CTG expansion associated with DM1 causes transcriptional silencing of the flanking Six5 gene. A decrease in Six5 gene expression has been associated with deficient spermatogenesis and a progressive decrease in testicular mass with age.30 There is insufficient evidence suggesting any effect of deficient Six5 expression on female gametogenesis.

Fascioscapulohumeral dystrophy and limb-girdle dystrophy Facioscapulohumeral muscular dystrophy (FSHD) is the third most common adult muscular dystrophy after Duchenne and myotonic dystrophy, with an estimated prevalence of one in 20 000.31 Muscular wasting

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progressively affects the facial, shoulder and upperarm muscles. The dominantly inherited disorder is linked to a contraction of variable size of the D4Z4 macrosatellite repeat on chromosome 4q35.32 This repeat consists of single units of 3.3 kb and is highly polymorphic as a result of gene conversion.33 Although DUX4, an intron-less open reading frame containing two predicted homeobox sequences, has been considered a strong candidate for the FSHD gene, there is as yet no evidence indicating transcription of D4Z4 sequences.34 The pathophysiology of the disease remains unclear. It occurs equally in males and females, but women tend to be less severely affected than men. Disease progression is usually slow, and life expectancy is normal, although about 20% of patients become wheelchair-bound. Sensorineural hearing loss35 and peripheral retinal capillary abnormalities36 are an integral part of FSHD. Limited information is currently available to guide obstetricians and neurologists in counselling women with FSHD who are planning to become pregnant. In two separate retrospective questionnaire-based studies in 58 and 105 patients respectively with FSHD, pregnancy outcomes were generally good, although exacerbation of muscle weakness and pain were reported by a quarter of patients and the incidence of operative vaginal delivery was significantly increased in comparison with national data, as a result of insufficient skeletal muscular effort in the second stage of labour.37,38 Contrary to the patients reported in the study of Rudnik-Schöneborn et al, who generally coped well with their muscle disease after delivery, the patients in the study of Ciafaloni et al denied resolution of their symptoms after childbirth, suggesting a possible irreversible effect of pregnancy on the progression of the disease. At an incidence of approximately one in 100 000,39 the limb-girdle muscular dystrophies (LGMD) encompass a broad group of rare proximal myopathies, characterised by presentation in both genders, clinical onset in the first or second decade of life, and weakness of the shoulder and pelvic girdle muscles with variable rates of progression. With the advent of molecular studies, the historical classification based on inheritance pattern (90% autosomal recessive types, 10% autosomal dominant40) has been replaced by a genotype-based classification. These studies have unravelled the aetiology of several LGMDs and have detected deleterious mutations in a collection of genes encoding proteins involved in all aspects of muscle cell biology.41 So far, mutations in 15 genes underlying LGMD have been identified.42 Because of the low incidence of LGMD, reports that illustrate the reproductive fitness and obstetric issues with regard to the disorder are scarce. In contrast with the obstetric outcome of patients with FSHD, the majority of women with LGMD experience worsening of muscle weakness in pregnancy and require assistance after delivery.37 Significant deterioration of the muscle disease is more likely to occur in LGMD patients with

early onset and the ensuing more rapid progression of the muscle disease. General anaesthesia intrapartum is best avoided, since suxamethonium and to a lesser extent volatile anaesthetics could lead to rhabdomyolysis and malignant hyperthermia.43

Inherited neuropathies Charcot-Marie-Tooth disease General characteristics Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neurological disorders, with a prevalence of nearly 40 in 100 000 worldwide.44 The disorder is highly heterogeneous and can be divided into a group that is characterised by dysfunction of the axon (CMT2), with little or no influence on nerve conduction velocity (NCV) and a group that shows disruption of the myelin sheath, resulting in decreased NCV (CMT1 and the rare subclasses CMT3 and CMT4). CMT1 and 2, which are the two most common subclasses, share an autosomal dominant inheritance pattern. CMT type IA (OMIM #118220) is the most common form. The average age of onset is 12.2 ± 7.3 years. Most affected female patients reach childbearing age, and may develop exacerbation of symptoms in pregnancy depending on the type of the disorder. Type I is characterised by earlier onset in late childhood or early adulthood, characteristic ‘glove and stocking’ sensory deficit, moderately to severely reduced motor nerve conduction velocities, bilaterally symmetric lower extremity wasting and decreased tendon reflexes. Up to 50% of patients experience exacerbations during pregnancy, potentially secondary to endoneural oedema.45 Very little is known about periconceptional issues in CMT, whereas obstetric complications have been documented well. Women with CMT have a significantly increased risk of malpresentation of the foetus, postpartum haemorrhage and operative delivery.46 Patients with significant pre-existing musculoskeletal and respiratory morbidity are at increased risk of ventilation problems, potentially leading to foetal hypoxia and intrauterine growth restriction.45,47 Type II (also known as dystrophia myotonica type 1; DM1; Steinert’s disease; OMIM #160900) patients develop similar symptoms albeit with a slower disease progression, and are less affected by pregnancy. In CMT2, which affects approximately 20–40% of CMT patients, symptoms usually start later in adult life and show a slower progression. The majority of females affected with CMT2 have a normal life expectancy reaching childbearing age with only mild symptoms. The disease is affected little by pregnancy.48

Molecular basis In accordance with its wide phenotypic range, CMT shows marked genetic heterogeneity. The majority of

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familial cases with CMT1 are linked to a locus on the short arm of chromosome 17.49–51 An estimated 70% of patients with CMT1 have a 1.5 Mb duplication on the short arm of chromosome 17,52 harbouring the PMP22 (peripheral myelin protein 22) gene,53,54 although in a subset of patients a point mutation, not a tandem duplication, is detected. This type of CMT1 is called CMT1A. Less commonly, CMT1 is linked to a locus on chromosome 154 and caused by mutations in the myelin protein Z (MPZ) gene. This type is referred to as CMT1B.

Motor neurone disease Spinal Muscular Atrophy Spinal muscular atrophy type I (SMA I) is an autosomal recessive disorder caused by a mutation or deletion in the telomeric copy of the SMN gene, known as SMN1 on the long arm of chromosome 5. The disorder is characterised by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. SMA is subdivided into four types, depending on the age of onset, the maximum muscular activity achieved, and the age of death: type I, severe infantile acute SMA, or Werdnig-Hoffman disease; type II, infantile chronic SMA; type III, juvenile SMA, or Wohlfart-Kugelberg-Welander disease; and type IV, or adult-onset SMA. Although pregnancy may be contraindicated in a large subset of women with advanced stage SMA, there are a few reported cases of women who successfully completed delivery in spite of significant respiratory dysfunction. Caesarean section may be indicated depending on the level of respiratory function restriction.55–57

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS) presenting in pregnancy is a rare event and may simply be a chance occurrence. One single patient has been reported who had a family history of ALS and developed weakness during pregnancy.58 She developed respiratory failure during pregnancy not improving after delivery.

Conclusion In spite of the availability of case reports and reviews highlighting the need for patient-tailored obstetrical management in women with neuromuscular disorders, little is known about the reproductive fitness of affected individuals. So far, there is no published evidence that fecundity is impaired in either males or females with a neuromuscular disorder apart from DM1, nor has a pathophysiological defect of the reproductive system been demonstrated. This is in contrast to the observed reduced reproduction rates in these patients as a result of psychosocial or ethical considerations, and secondary to a perceived reduction of

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general health and respiratory and muscular fitness in particular by the patient themselves. Recent years have seen an increasing availability of preimplantation diagnostic tests to patients affected with a neuromuscular disorder to prevent the transmission of the disease. The fertility- and pregnancy-related information yielded by these assisted reproductive treatments, such as ovarian and testicular function, will allow researchers to scrutinise periconceptional issues in these patients.

References 1. Davies K, Nowak K. Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev 2006; 7: 762–73. 2. Eisenberg I, Eran A, Nishino I et al. Distinctive patterns of microRNA expression in primary muscular disorders. Proc Natl Acad Sci USA. 2007; 104: 17016–21. Erratum in: Proc Natl Acad Sci USA. 2008; 105: 399. 3. Richards CS, Watkins SC, Hoffman EP et al. Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy. Am J Hum Genet 1990; 46: 672–81. 4. Sax TW, Rosenbaum RB. Neuromuscular disorders in pregnancy. Muscle Nerve 2006; 34: 559–71. 5. Brook JD, McCurragh ME, Harley HG et al. Molecular basis of myotonic dystrophy: expansion of the trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member. Cell 1992; 69: 385. 6. Mahadevan M, Tsilfidis C, Sabourin L et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3′ untranslated region of the gene. Science 1992; 255: 1253–5. 7. Harper PS, Harley HG, Reardon W, Shaw DJ. Review article: anticipation in myotonic dystrophy: new light on an old problem. Am J Hum Genet 1992; 51: 10–16. 8. Rudnik-Schöneborn S, Zerres K. Outcome in pregnancies complicated by myotonic dystrophy, a study of 31 patients and review of the literature. Eur J Obstet Gynecol and Reprod Biol 2004; 114: 44–53. 9. Sermon K, Lissens W, Joris H et al. Clinical application of preimplanation diagnosi for myotonic dystrophy. Prenatal Diagnosis 1997; 17: 925–32. 10. Machuca-Tzili L, Brook D, Hilton-Jones D. Clinical and molecular aspects of the myotonic dystrophies: a review. Muscle Nerve 2005; 32: 1–18. 11. White RJ. Case report. Anaesthetic management of a patient with myotonic dystrophy. Paediatr Anaesth 2001; 11: 494–7. 12. White RJ, Bass SP. Review article. Myotonic dystrophy and paediatric anaesthesia. Paediatr Anaesth 2003; 13: 94–102. 13. Mathieu J, Allard P, Gobeil G et al. Anesthetic and surgical complications in 219 cases of myotonic dystrophy. Neurology 1997; 49: 1646–50. 14. Aquilina A, Groves J. Case report: a combined technique utilizing regional anaesthesia and targetcontrolled sedation in a patient with myotonic dystrophy. Anaesthesia 2002; 57: 385–6.

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15. Rosenbaum HK, Miller JD. Malignant hyperthermia and myotonic disorders. Anesthiol Clin North Am 2002; 20: 623–64. 16. Tokgozoglu LS, Ashizawa T, Pacifico A et al. Cardiac involvement in a large kindred with myotonic dystrophy. Quantitative assessment and relation to size of CTG repeat expansion. JAMA 1995; 274: 813–19. 17. Bundey S, Carter CO, Soothill JF. Early recognition of heterozygote for the gene for dystrofie myotonica. J Neurol Neurosurg Psychiatry 1970; 33: 279–93. 18. Webb D, Muir I, Faulkner J, Johnson G. Myotonica dystrophica: obstetric complications. Am J Obstet Gynecol 1978; 132: 265–70. 19. Jaffe R, Mock M, Abramowicz J, Ben-Aderet N. Myotonic dystrophy and pregnancy: a review. Obstet Gynecol Surv 1986; 41: 272–8. 20. Hopkins A, Wray S. The effect of pregnancy on dystrophia myotonica. Neurology 1967; 17: 166–8. 21. Rudnik-Schöneborn S, Nicholson GA, Moragn G, Röhrig D, Zerres K. Different patterns of obstetric complications in motonic dystrophy in relation to the disease status of the fetus. Am J Med Genet 1998; 80: 314–21. 22. Barbosa J, Nuttall FQ, Kennedy W, Goetz F. Plasma insulin in patients with myotonic dystrophy and their relatives. Medicine 1974; 53: 307–23. 23. Sagel J, Distiller LA, Morley JE et al. Myotonia dystrophica: studies on gonadal function using luteinizing hormone-releasing hormone (LRH). J Clin Endocrinol Metab 1975; 40: 1110–13. 24. Feyereisen E, Amar A, Kerbrat V et al. Myotonic dystrophy: does it affect ovarian follicular status and responsiveness to controlled ovarian stimulation? Hum Reprod 2005; 21: 175–82. 25. Sahu B, Ozturk O, Deo N et al. Response to controlled ovarian stimulation and oocyte quality in women with myotonic dystrophy type I. J Assist Reprod Genet 2008; 25: 1–5. 26. Verpoest W, De Rademaeker M, Sermon K et al. Real and expected delivery rates of patients with myotonic dystrophy undergoing intracytoplasmic sperm injection and preimplanation genetic diagnosis. Hum Reprod 2008; 23: 1654–60. 27. O’Brien T, Harper PS. Reproductive problems and neonatal loss in women with myotonic dystrophy. J Obstet Gynecol 1984; 4: 170–3. 28. Dao TD, Mathieu J, Bouchard J-P, De Braekeleer M. Fertility in myotonic dystrophy in Saguenay-Lac-StJean: a historical perspective. Clin Genet 1992; 42: 234–9. 29. Stratton RF, Patterson RM. DNA confirmation of congenital myotonic dystrophy in non-immune hydrops fetalis. Prenat Diagn 1993; 13: 1027–30. 30. Sarkar PS, Paul S, Han J, Reddy S. Six5 is required for spermatogenic cell survival and spermiogenesis. Hum Mol Genet 2004; 13: 1421–31. 31. Padberg GW. Fascioscapulohumeral disease [thesis], 1982 Leiden University, Leiden. 32. Lemmers RJ, Wohlgemuth M, van der Gaag KJ et al. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet 2007; 81: 884–94. 33. Lemmers RJ, Van Overveld PG, Sandkuijl LA et al. Mechanism and timing of mitotic rearrangements in the subtelomeric D4Z4 repeat involved in

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facioscapulohumeral muscular dystrophy. Am J Hum Genet 2004; 75: 44–53. Alexiadis V, Ballestas ME, Sanchez C et al. RNAPolChIP analysis of transcription from FSHD-linked tandem repeats and satellite DNA. Biochim Biophys Acta 2007; 1769: 29–40. Brouwer OF, Padberg, GW, Ruys CJM et al. Hearing loss in facioscapulohumeral muscular dystrophy. Neurology 1991; 41: 1878–81. Fitzsimons RB, Gurwin EB, Bird AC. Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy: a general association with genetic and therapeutic implications. Brain 1987; 110: 631–48. Rudnik-Schöneborn S, Glauner B, Röhrig D, Zerres K. Obstetric aspects in women with facioscapulohumeral muscular dystrophy, limb-girdle muscular dystrophy, and congenital myopathies. Arch Neurol 1997; 54: 888–94. Ciafaloni E, Pressman EK, Loi AM et al. Pregnancy and birth outcomes in women with facioscapulohumeral muscular dystrophy. Neurology 2006; 67: 887–9. Yates JR, Emery AE. A population study of adult onset limb-girdle muscular dystrophy. J Med Genet 1985; 22: 250–7. Zatz M, de Paula F, Starling A, Vainzof M. The 10 autosomal recessive limb-girdle muscular dystrophies. Neuromuscul Disord 2003; 13: 532–44. Laval S, Bushby K. Limb-girdle muscular dystrophies – from genetics to molecular pathology. Neuropathol Appl Neurobiol 2004; 30: 91–105. Allen T, Maguire S. Anaesthetic management of a woman with autosomal recessive limb-girdle muscular dystrophy for emergency Caesarean section. Int J Obstet Anesth 2007; 16: 370–4. Yemen TA, McClain C. Muscular dystrophy, anesthesia and the safety of inhalational agents revisited; again. Pediatr Anaesth 2006; 16: 105–8. Krajewski KM, Lewis RA, Fuerst DR et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain 2000; 123: 1516–27. Greenwood JJ, Scott WE. Charcot-Marie-Tooth disease: peripartum management of two contrasting clinical cases. Int J Obstet Anesth 2007; 16: 149–54. Hoff JM, Gilhus NE, Daltveit AK. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease. Neurology 2005; 64: 459–62. Pollock M, Nukada H, Kritchevsky M. Exacerbation of Charcot-Marie-Tooth Disease in pregnancy. Neurology 1982; 32: 1311–14. Brian JE, Boyles GD, Quirk JG, Clark RB. Anesthetic management for cesarean section of a patient with Charcot-Marie-Tooth Disease. Anesthesiology, 1987; 60: 410–12. Raeymaekers P, Timmerman V, De Jonghe P et al. Localization of the mutation in an extended family with Charcot-Marie-Tooth neuropathy (HMSN I). Am J Hum Genet 1989; 45: 953–8. Vance JM, Nicholson GA, Yamaoka LH et al. Linkage of Charcot-Marie-Tooth neuropathy type 1a to chromosome 17. Exp Neurol 1989; 104: 186–9. Middleton-Price HR, Harding AE, Monteiro C, Berciano J, Malcolm S. Linkage of hereditary motor and sensory neuropathy type I to the pericentromeric

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Periconceptional issues in neuromuscular disorders region of chromosome 17. Am J Hum Genet 1990; 46: 92–4. 52. Reilly M. Axonal Charcot-Marie-Tooth disease: the fog is slowly lifting! Neurology 2005; 65: 186–7. 53. Wise CA, Garcia CA, Davis SN et al. Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication. Am J Hum Genet 1993; 53: 853– 63. 54. Nelis E, Van Broeckhoven C, De Jonghe P et al. Estimation of the mutation frequencies in CharcotMarie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet 1996; 4: 25–33.

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55. Yim R, Kirschner K, Murphy E, Parson J, Winslow C. Successful pregnancy in a patient with spinal muscular atrophy and severe kyphoscoliosis. Am J Phys Med Rehabil 2003; 82: 222–5. 56. Pugh CP, Healey SK, Crane JM, Young D. Successful pregnancy and spinal muscular atrophy. Obstet Gynecol 2000; 95: 1034. 57. Carter GT, Boneket HW, Milio L. Successful pregnancies in the presence of spinal muscular atrophy: two case reports. Arch Phys Med Rehabil 1994; 75: 229– 31. 58. Jacka MJ, Sanderson F. Amyotrophic lateral sclerosis presenting during pregnancy. Anesth Analg 1998; 86: 542–3.

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18 The patient with, or at risk of, severe mental illness R. Cantwell

Introduction Women are at greatest risk of suffering from mental illness during their reproductive years, and at very particular risk in relation to childbirth. Psychological adjustment, social challenges and neurohormonal changes in pregnancy and parturition may all contribute to this risk. The consequences of maternal mental illness may be severe. Suicide is among the leading causes of maternal death in the UK1 and psychiatric factors are implicated in a further significant number of deaths in pregnancy and during the first postnatal year. Increasing evidence points to the detrimental effect of untreated maternal anxiety and depression on infant development. Women with severe mental illness are also more likely to have unplanned pregnancies. Maternal health professionals have an important role in identifying women at risk, reducing progression to future morbidity and mortality.

Epidemiology of mental illness in relation to pregnancy and childbirth Mental illness is common. In women, major depression has a lifetime prevalence of between 5% and 8%,2 approximately twice that of men. Bipolar disorder and schizophrenia each affect approximately 1% of the population. Pregnancy offers little protection against the continuation or development of mental illness. Indeed, minor mental illness may be more common in early pregnancy and nearer to delivery. However, women with a personal or family history of certain mental disorders are at particularly high risk of developing severe disorders in the early postpartum. Identifying this risk pre-conceptually or in early pregnancy allows for preventative interventions to be offered to the woman.

Normal emotional changes in early pregnancy For most women, childbirth is an eagerly awaited event. However, some 50% of pregnancies are unplanned, and

a proportion unwanted. Even in much wanted pregnancies, ambivalence about the pregnancy, health-related anxieties and fears about inability to cope (especially in first-time mothers) are typical and normal. Increased emotional lability is common in the first trimester, and may be exacerbated by the physical changes typical of early pregnancy. Such emotional changes are largely bound up with the psychological adjustments necessary in pregnancy but may be contributed to by hormonal alterations. It is important to be able to distinguish these changes from those more clearly associated with mental illness. Oates3 described certain groups as having particular needs for increased support in relation to childbearing: • Very young, single and unsupported mothers, and women who themselves have poor experiences of mothering, may be especially vulnerable. Their own needs may conflict with those of their babies and early planning to provide appropriate support is essential to help develop the woman’s ability to care for her baby • Older mothers who may have over-idealised expectations of pregnancy and delivery, and have problems adjusting to life changes after the birth • Women who have complicated pregnancies, including those with previous pregnancy loss, those who have undergone assisted conception and those who require an emergency Caesarean section. Women also face an increased risk of domestic abuse in pregnancy. Around 30% of domestic abuse begins during pregnancy and women experiencing abuse are more likely to miscarry. In one UK study, one in six pregnant women had experienced domestic abuse.4 In light of this, it has been recommended that women should be seen alone on at least one occasion during their antenatal care, enquiries about violence should be routinely included in the antenatal history, and information should be provided to all women on legal rights and available supports.5 Indicators of abuse may include late booking or non-attendance, repeated attendance at antenatal clinics or primary care with

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minor injuries or psychological symptoms, substance misuse, sexually transmitted diseases and poor obstetric history. Reluctance or evasiveness to speak or the constant presence of a domineering partner should also raise suspicions.1

Pre-existing mental illness Bipolar affective disorder Bipolar disorder (previously known as manic depressive disorder) affects around 1% of women during reproductive years. Women with bipolar affective disorder are likely to be on maintenance therapy. There are teratogenic risks associated with most mood stabilisers, but high risk too with regard to relapse of illness on discontinuation. Viguera et al6 found that almost 60% of bipolar women who discontinued prophylactic lithium treatment at onset of pregnancy relapsed at some point during that pregnancy, a relapse rate almost identical to that among non-pregnant women who discontinue prophylaxis. Decisions regarding continuation, stopping or alteration of treatment (for part, or all, of the pregnancy) should be made on an individual basis and with the woman’s fully informed involvement. This should be done as part of pregnancy planning. Factors to be taken into account include the previous natural history of the disorder (number, severity and time interval between episodes of illness) and response to previous treatment discontinuations. Pre-existing bipolar disorder is one of the greatest risk factors for puerperal psychosis – recent studies estimate that over 60% of women with bipolar disorder will experience relapse in the first 6 postnatal months if not taking mood stabilising agents.6 Irrespective of decisions about medication during pregnancy, all women should be offered prophylactic medication (usually lithium) immediately following delivery. Finally, it is important to remember that, unlike with schizophrenia, there is little evidence that bipolar women are any less able to care appropriately for their children, except during the acute phase of their illness.

Schizophrenia There is good evidence to suggest that the fertility of women with enduring severe mental illnesses such as schizophrenia is now similar to that of the general population.7 One important reason for this is the move to novel antipsychotic medications, which have a much lower propensity to raise prolactin levels and suppress ovulation. Women who switch from older drugs may not be aware of this and may place themselves inadvertently at risk of unwanted pregnancy. Although not universally poor, the outcome in terms of the mother remaining the primary carer for her child is often unfavourable,8 leading to great distress for the mother and for those (including health professionals)

who support her. Better outcomes are seen for women with supportive social networks and absence of mental illness in the partner. Appropriate supports, including social services, should be engaged at an early stage in pregnancy to ensure sufficient help is available to the mother and her family. It is often difficult for women with schizophrenia to cope with frequent contact with health professionals during pregnancy and there is a risk that they receive suboptimal care. Advance planning will also help reduce this risk. Most women with schizophrenia will be on maintenance antipsychotic medication. The implications of relapse during pregnancy are severe for both mother and child, and, unless there are strong reasons to the contrary, treatment should continue, with appropriate monitoring, throughout pregnancy. Difficult decisions may have to be made regarding the relative advantages and problems associated with continuing a wellestablished regimen involving newer antipsychotics or switching to older medication, where the risks associated with pregnancy are better known.

Depressive and anxiety disorders These are among the commonest mental disorders experienced by women. Studies suggest that 4–6% of women are taking prescribed antidepressant treatment at the time of conception. Women are most likely to discontinue treatment, without consultation, on discovering a pregnancy.9 This may place them at greater risk of relapse of illness. A past history of depressive illness is one of the strongest risk factors for antenatal depression, which in turn is predictive of postnatal depression. Although depressive symptoms are probably as common in pregnancy as in the postnatal period10 they often remain undetected. For anxiety disorders, course in pregnancy is likely to be related to the severity of illness pre-conceptually. Physiological changes in respiratory function during pregnancy may lead to an increased propensity to panic and anxiety, and panic may worsen in the postnatal period. Non-pharmacological treatments include cognitive and behavioural therapies. Drug treatments include selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants. Beta-blockers should be avoided given the association with intrauterine growth retardation and adverse neonatal cardiorespiratory effects.

Eating disorders Research suggests that eating disorder symptoms tend to improve in pregnancy but return to baseline levels or worsen in the postpartum period.11 Fertility is reduced in anorexia nervosa, and may be reduced in bulimia, where there is associated polycystic ovarian syndrome. The use of appetite suppressants, laxatives or diuretics in early pregnancy may also have adverse effects on foetal development. With regard to the impact of a

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pre-existing eating disorder on the pregnancy, the limited literature available suggests that women with active eating disorders are at increased risk of miscarriage and intrauterine growth retardation. Guidance on effective management includes treating the disorder before pregnancy, education on nutrition, foetal development and body shape/weight changes in pregnancy, and referral to specialist services early in the pregnancy.12

Substance use disorders There has been increasing concern at the rise in drug and alcohol use among women of childbearing age. In particular, there has been a sharp increase in the number of young women drinking at harmful or hazardous levels. Evidence from the Confidential Enquiries suggests that substance misuse makes a significant contribution to maternal mortality among both the general and psychiatric cases.1 Characteristically, these women are late bookers or non-attenders at antenatal care and their impaired physical health, which may include exposure to HIV and hepatitis, places them and their pregnancy at risk. Alcohol use tends to decrease during the antenatal period, but continuing misuse may give rise to a number of physical complications, which may threaten or complicate pregnancy. These include nutritional deficiencies and cardiovascular, liver and pancreatic disease. Withdrawal complications such as delirium tremens and seizures may also have adverse consequences. Excessive alcohol use is associated with disturbed organogenesis in early pregnancy. Other teratogenic effects include abnormalities of the cardiac and urogenital systems, as well as eye, ear and limb anomalies. Foetal alcohol spectrum disorder is one term used to encompass the range of teratogenic and neurobehavioural effects of alcohol on the foetus and developing child.13 These include the original triad of growth retardation, facial dysmorphia and central nervous system dysfunction, described as foetal alcohol syndrome. Additional features include cognitive and behavioural dysfunction. Other drug use effects vary depending on the properties of the specific drug, but polysubstance use is most common, and research is very limited on its consequent effects. There is a possible link between exposure to benzodiazepines in early pregnancy and oral cleft anomalies, though research is conflicting with differing results from case–control and cohort data.14 Cocaine use is associated with growth restriction, prematurity and cardiovascular risks for mother and foetus. Opiate use is associated with neonatal withdrawal and risk of unintentional overdose postnatally, when women may return to uncontrolled use. Pregnant women who misuse drugs should be cared for jointly with specialist addiction services.1 Abrupt discontinuation of drug use is not recommended. There is accepted evidence for overall advantage to

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the foetus of methadone substitution, despite the potential for more prolonged withdrawal states, but continued use of heroin suggests a bad prognosis. For women addicted to opiates, stability in the first and third trimester is usually desirable, with any attempts at reduction confined to the second trimester. However, any decisions must take into account the woman’s wishes and risks of returning to uncontrolled/illicit use. Motivation to change is often increased in pregnancy, which, combined with increased health care input and support, may allow significant change at a crucial time. Early, proactive involvement of social work services is essential.

Personality disorder Personality disorders are deeply ingrained and enduring patterns of behaviour, resulting in inflexible responses to a broad range of personal and social situations. They are stable and unchanging, usually present from adolescence, and often cause the person, or those around them, to suffer.15 There are often difficulties in forming and/or sustaining relationships, and this may extend to health professionals involved in the person’s care. In one epidemiological study, the prevalence of personality disorder in pregnancy was 6.4%.16 Of the group of personality disorders, the emotionally unstable type is perhaps the most commonly diagnosed in young women. It is characterised by emotional instability, impulsivity, dysphoric mood, disturbances in self-image, chronic feelings of emptiness, and self-destructive behaviour, including recurrent self-harm, and drug or alcohol misuse. Such difficulties cause high levels of anxiety among health and social care professionals, and may interfere with effective antenatal care. Impaired forward planning and tolerance of distress may increase anxieties regarding child welfare. Effective management is usually provided through good joint working and communication between professionals, and a clear and consistent treatment plan to which the patient agrees. There may be a role for specific psychological and drug therapies.

Psychological aspects of miscarriage Around one in five pregnancies will end in spontaneous loss before 20 weeks. Early loss is often not associated with the same acknowledgement and support attending stillbirth or neonatal death. In the absence of an obvious cause, miscarriage may also lead to a greater sense of self-blame and guilt. Around 40% of women will go through a typical bereavement process, similar to that following stillbirth or neonatal death, with emotional reactions that may include numbness, disbelief, social withdrawal, anger, guilt, sadness and anxiety, leading eventually to acceptance and resolution. Depressive symptoms are present, at a rate two to four times that of the general population in the first 6 months,17 and anxiety symptoms are similarly elevated.

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In most cases, symptoms have returned to background levels by 1 year. However, some women may experience an abnormal or prolonged grief reaction, depressive or anxiety disorder. In early studies, depressive disorders were found in around 50% of women. However, these were often conducted in the early stages following pregnancy loss, and lacked a comparison group. More recent research suggests a rate of around 10% in the first 6 months, giving a relative risk of 2.5.18 For anxiety disorders, the literature is less clear. Some work suggests an increase in obsessive-compulsive and post-traumatic stress disorders, but more research is required. Risk factors most clearly associated with development of psychological morbidity post-miscarriage include previous psychiatric disorder, poor social or partner support, childlessness and ambivalence toward the pregnancy.19 There is no consistent evidence of association with sociodemographic variables, duration of pregnancy or other obstetric factors. Interventions to reduce the risk of psychological morbidity are poorly researched. Women consistently say they wish for greater access to psychological support, and there is some evidence for the benefit of psychological interventions. Where benefit has been demonstrated, it has mostly been for interventions targeted at those displaying early difficulties, rather than for general approaches to all women who miscarry. However, an empathic approach, and acknowledgement of the significance of the loss, is important for all women.

Medication issues The research base for psychotropic medication effects in pregnancy is limited but ever changing. For this reason, it is not possible to give definitive advice. The National Institute for Clinical and Health Excellence (NICE)20 provides some general principles which shoud govern prescribing in pregnancy: • The lowest effective dose should be used • Monotherapy should be used in preference to combination treatments • Drugs with the greatest evidence of safety for mother/foetus should be considered first • The woman’s history of previous treatment response should guide future treatment • Changes in treatment to reduce risk of harm must be balanced against risks of switching • The individual woman’s views, wishes, fears and priorities are key factors in decisions about treatment. NICE also recommends that access to psychological therapies, where appropriate, should be promptly available.

Antidepressants Antidepressants are among those psychotropics most likely to be prescribed co-incidentally at conception.

Older drugs, such as the tricyclics, have the lowest known risks to foetal development in pregnancy, but SSRI antidepressants are much more commonly prescribed. Of these, fluoxetine is regarded as the safest,20 predominantly because of its longer and more widespread use, while paroxetine has been associated with a doubling of ventricular septal defects. There remains uncertainty whether SSRIs are associated with an increased risk of persistent pulmonary hypertension in the neonate, if given after 20 weeks.21 All antidepressants may cause withdrawal effects or toxicity in the neonate, although these are largely self-limiting.22 Typical symptoms of neonatal withdrawal may include irritability, constant crying, shivering, increased tone and tremor, poor feeding and, rarely, seizures. In a well-controlled study of children exposed to fluoxetine or tricyclic antidepressants in pregnancy there was no evidence of impaired intelligence, growth, language or behavioural development over a 4-year follow-up period.23

Antipsychotics Many antipsychotics raise prolactin levels and reduce fertility. Second generation antipsychotics may be associated with being large for gestational age and, for the mother, impaired glucose tolerance and risk of gestational diabetes. Older drugs are linked with intrauterine growth retardation.24 The evidence of any association with foetal malformation is very limited. Where these drugs are prescribed for the management of severe and enduring mental illness (i.e. schizophrenia and related disorders), the risks of discontinuing will usually outweigh any risks of medication to the developing foetus. In the majority of cases, usual practice would be to continue medication throughout pregnancy. For novel antipsychotics, where risks in pregnancy are less well evaluated, the option may exist to switch to a more established, older preparation. For women on depot medication, which may persist in the neonate for considerable periods, it may be possible to change to an oral preparation during the pregnancy. Such decisions need to take individual circumstances into account, particularly the significant risk of relapse of illness.

Mood stabilisers These drugs, most commonly prescribed for prophylaxis of bipolar disorder, include lithium and the antiepileptics valproate, carbamazepine and lamotrigine. In early pregnancy, lithium is associated with an increased risk of cardiac malformation, including Ebstein’s anomaly. Overall, the risk of cardiac malformations is 6–10% that of the general population. Sudden discontinuation is associated with greatly increased risk of relapse in bipolar disorder and specialist advice should be sought urgently if a woman presents, on lithium, in early pregnancy.

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The antiepileptic mood stabilisers carbamazepine and valproate are associated with risk of neural tube defects (0.5% for carbamazepine, 1–2% for valproate), including spina bifida. They are also associated with cardiac, gastrointestinal and facial anomalies, along with a range of other minor malformations. Given that many pregnancies will not be confirmed until after the neural tube closes (day 28), reducing this risk is dependent on pre-conceptual advice and management. This may include high dose folate (5 mg/day) from at least 12 weeks prior to conception, although its prescription has not been shown directly to reduce the rate of neural tube defects in women on antiepileptics. For valproate, there is evidence of a dose relationship, with greater risk at doses above 1000 mg/day. Valproate has also been linked to a significant impairment in cognitive function, with 22% of children noted to have exceptionally low verbal IQ, compared with an expected rate of 2% in the general population.25 Given these concerns, it is recommended that valproate is not prescribed to bipolar women of childbearing potential unless there are no effective alternatives. Lamotrigine in pregnancy is associated with an increased rate of cleft palate.

Managing risk Pre-pregnancy Women who are planning a pregnancy should be asked about a history of significant mental illness. Those at greatest risk of adverse consequences include women with bipolar disorder or schizophrenia (risk of relapse of illness postnatally), and women with schizophrenia, substance misuse or personality disorder (who may struggle to cope with the challenges of pregnancy and childcare, without appropriate support). If a woman is taking psychotropic medication, she should have advice regarding any known teratogenicity, and should have a specialist review to establish the safest and most effective treatment in advance of pregnancy.

Early pregnancy First contact with maternity services provides an important opportunity to identify women with preexisting mental illness, or those with a raised risk of postnatal mental illness. NICE20 recommends that all women are asked about: • Past or present severe mental illness, including schizophrenia, bipolar disorder, psychosis in the postnatal period and severe depression • Previous treatment by a psychiatrist/specialist mental health team, including inpatient care • A family history of perinatal mental illness. In addition, women should be asked about a family history of bipolar disorder. Women confirming any of

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these risk factors should be referred for assessment and management of risk, which may include prophylactic medication in the immediate postpartum period. Where available, specialist perinatal mental health services should provide this role. NICE20 also makes recommendations regarding detection of depression in pregnancy. Two questions are suggested for all women at booking and subsequent contacts: • During the past month, have you often been bothered by feeling down, depressed or hopeless? • During the past month, have you often been bothered by having little interest or pleasure in doing things? If either is answered ‘yes’ these should be followed up by a third question: • Is this something you feel you need or want help with? There is, however, little evidence that identifying risk factors such as poor social support can reliably identify women who may go on to develop depression in the postnatal period. Finally, the Confidential Enquiry into Maternal and Child Health1 also provides guidance on reducing risk in pregnancy. In its ‘top ten’ recommendations, emphasis is placed on pre-conception counselling and support for women with pre-existing severe mental illness which may be aggravated by pregnancy. This, and the preceding two reports, repeatedly comment on the need for good communication and sharing of information between maternity, primary care and mental health professionals. Poor communication has remained a contributory factor in a number of deaths by suicide.

References 1. Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: the Seventh Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH, 2007. 2. Regier DA, Boyd JH, Burke Jr JD et al. One month prevalence of mental disorders in the United States, based on five epidemiological catchment area sites. Arch Gen Psychiatry 1988; 45: 977–86. 3. Oates M. Normal emotional changes in pregnancy and the puerperium. Ballieres Clin Obstet Gynaecol 1989; 3: 791–804. 4. Johnson JK, Haider K, Ellis DM et al. The prevalence of domestic violence in women. BJOG 2003; 110: 272–5. 5. Department of Health. Responding to Domestic Abuse: A Handbook for Health Professionals. London: Department of Health, 2006. 6. Viguera AC, Nonacs R, Cohen LS et al. Risk of recurrence of bipolar disorder in pregnant and non-pregnant

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Textbook of Periconceptional Medicine women after discontinuing lithium maintenance. Am J Psychiatry 2000; 157: 179–84. Lane A, Byrne M, Mulvany F et al. Reproductive behaviour in schizophrenia related to other mental disorders: evidence for increased fertility in men despite decreased marital rate. Acta Psychiatr Scand 1995; 91: 222–8. Abel KM, Webb RT, Salmon MP et al. Prevalence and predictors of parenting outcome in a cohort of mothers with schizophrenia admitted for joint mother and baby psychiatric care in England. J Clin Psychiatry 2005; 66: 781–9. Imrie W, Math V, Cantwell R. A pilot study of the extent of and expectant mothers’ attitudes to the use of medication for mental health problems during pregnancy and breastfeeding. Arch Womens Ment Health 2005; 8: 125. Heron J, O’Connor TG, Evans J et al. The course of anxiety and depression through pregnancy and the postpartum in a community sample. J Affect Disord 2004; 80: 65–73. Crow SJ, Agras WS, Crosby R et al. Eating disorder symptoms in pregnancy: a prospective study. Int J Eating Disord 2008; 41: 277–9. Ward VB. Eating disorders in pregnancy. BMJ 2008; 336: 93–6. Riley EP, McGee CL. Fetal alcohol spectrum disorders: an overview with emphasis on changes in brain and behaviour. Exp Biol Med 2005; 230: 357–65. Dolovich L, Addis A, Vaillantcourt J et al. Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies. BMJ 1998; 317: 839–43. World Health Organisation. International Classification of Diseases, 10th Revision. 2007. Accessed at http:// www.who.int/classifications/apps/icd/icd10online/

16. Borjesson K, Ruppert S, Bagedahl-Strindlund M. A longitudinal study of psychiatric symptoms in primiparous women: relation to personality disorders and sociodemographic factors. Arch Womens Ment Health 2005; 8: 232–42. 17. Neugebauer R, Kline J, O’Connor P et al. Depressive symptoms in the six months after miscarriage. Am J Obstet Gynecol 1992; 166: 104–9. 18. Neugebauer R, Kline J, Shrout P et al. Major depressive disorder in the six months after miscarriage. JAMA 1997; 277: 383–8. 19. Lok IH, Neugebauer R. Psychological morbidity following miscarriage. Best Pract Res Clin Obstet Gynaecol 2007; 21: 229–47. 20. National Institute for Clinical and Health Excellence. Antenal and Postnatal Mental Health: The National Guideline on Clinical Mangement and Service Guidance. London: NICE, 2007. 21. Oberlander TF, Warburton W, Misri S et al. Effects of timing and duration of gestational exposure to serotonin reuptake inhibitor antidepressants: population-based study. Br J Psychiatry 2008; 192: 338–43. 22. Sanz EJ, De Las Cuevas C, Kiuru A et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet 2005; 365: 482–7. 23. Nulman I, Rovet J, Stewart D et al. Neurodevelopment of children exposed in utero to antidepressant drugs. N Engl J Med 1997; 336: 258–62. 24. Newham JJ, Thomas SH, MacRitchie K et al. Birth weight of infants after maternal exposure to typical and atypical antipsychotics: prospective comparison study. Br J Psychiatry 2008; 192; 333–7. 25. Adab N, Kini U, Vinten J et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry 2004; 75: 1575–83.

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19 How to conceive: evidence-based fertility investigation BW Mol, JW van der Steeg, HR Verhoeve, F van der Veen

Introduction Subfertility is defined as an inability to conceive after 1 year of regular unprotected sexual intercourse. One in six couples seek specialist care for this problem.1–4 In most clinics the fertility work-up consists of medical history taking and clinical examination, followed by diagnostic tests aimed at excluding recognised causes of infertility such as azoospermia, anovulation and bilateral tubal blockage. As a consequence, the initial diagnostic tests for infertility include evaluation of ovulation, a semen analysis and tests for tubal patency and function. In this chapter we focus on existing data on diagnostic tests.

androgen assays and ultrasound of the ovaries are required for the diagnosis of polycystic ovary syndrome (PCOS).7

Assessment of ovarian reserve Natural fecundity and pregnancy rates decline with increasing age.8 This decrease in fecundability is related to a reduction in both quality and quantity of the primordial follicle pool (referred to as ovarian reserve).9 Several tests have been studied to screen for diminished ovarian reserve, mostly in relation to assisted reproductive technologies (ART).

Follicle stimulating hormone

Assessment of ovulation A history of a regular menstrual cycle indicates ovulation in more than 95% of women. Direct observation of ovulation is possible by monitoring follicular development sonographically until collapse is observed and fluid appears in the pouch of Douglas.5 This method, however, requires regular visits to the clinic and is costly. Ovulation can be predicted by measuring oestrogen or luteinising hormone (LH) in the blood. Self-testing kits of LH in the urine are frequently used and easy to perform, but give a higher incidence of false negative results than blood tests.6 Confirmation of whether ovulation has occurred can be obtained by basal body temperature (BBT), measurement of midluteal phase progesterone or endometrial dating through biopsy of the endometrium. A diagnosis should be made in cases of anovulation or oligo-ovulation. Thyroid stimulating hormone levels can point to a thyroid disorder and prolactin levels should exclude hyperprolactinaemia. These disorders can easily be corrected by treatment. Gonadotrophin levels in conjunction with oestrogen levels should be measured to assess whether one is dealing with hypogonadotrophic gonadism, normogonadotrophic normogonadism or hypergonadotrophic hypogonadism. In case of normogonadotrophic normogonadism (WHO type II),

Cycle day 3 serum (so called basal) follicle stimulating hormone (FSH) levels are widely used in many fertility centres. The FSH value is an indirect measure of serum inhibin B and oestradiol being produced by a cohort of follicles, the concentrations of which result in feedback at the pituitary level. In an indexed cohort study10 the fecundity in subfertile patients below the age of 40 years, with elevated FSH levels (>10 IU/l) and regular ovulatory cycles, was not different from the fecundity in controls and both groups had comparable cumulative delivery rates. Another study showed that FSH did not have an independent predictive effect on pregnancy rates in a general subfertility population but should be interpreted in the light of other clinical variables such as age.11 In a study of patients ≤41 years with elevated basal FSH levels it was shown that these patients had reasonable ongoing pregnancy rates, despite a considerable probability of cycle cancellation due to poor ovarian response, indicating that the quantity but not necessarily the quality of oocytes is diminished.12 A meta-analysis on the performance of basal FSH level in the prediction of poor ovarian response and failure to become pregnant after IVF showed that a possible clinical application of basal FSH refers to only a minority of patients with extremely high basal FSH levels (>20 IU/l) but should not be regarded as a

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useful routine test for the prediction of in vitro fertilisation (IVF) outcome.13 In short, basal FSH is not a good screening test for ovarian reserve and pregnancy outcome in a general subfertility population or as a predictor for fertility outcome in patients undergoing assisted reproductive technology (ART). Inhibin B, like basal FSH, is not a useful screening test to predict diminished ovarian reserve. 14

Antral follicle count Antral follicle count (AFC), defined as the number of follicles smaller than 10 mm in diameter in the early follicular phase, can be easily assessed by transvaginal ultrasound and was introduced to predict ovarian responsiveness in IVF treatment.15 In a recent metaanalysis the performance of AFC in the prediction of poor ovarian response and pregnancy after IVF was assessed and compared with the performance of basal FSH. 16 The AFC showed a significantly better performance than basal FSH in the prediction of poor ovarian response. In predicting non-pregnancy the predictive capacity of both tests was poor. In this study the performance of AFC was analysed independent of female age because of the lack of homogeneity between the available studies. In a study of patients aged >38 years multivariate logistic regression analysis showed the AFC to be a valuable test to assess the individual chance of pregnancy in IVF. The AFC was significantly associated with the occurrence of an ongoing pregnancy after IVF treatment, whereas age and basal FSH were not. However, pregnancy could not be excluded amongst those younger than 43 years of age.17

Anti-Mullerian hormone Anti-Mullerian hormone (AMH) is produced by the granulosa cells of preantral and small antral follicles. In a longitudinal study of normal fertile women decline of serum AMH levels was associated with increasing age and as such expressed a decline in reproductive function.14 In two studies decreased AMH levels were associated with poor ovarian response in IVF treatment but pregnancy outcome was not evaluated.18,19 Like the AFC, AMH cannot identify poor IVF outcome with a certainty high enough to justify its use.

Clomiphene citrate challenge test Another ovarian reserve test that has been assessed is the clomiphene citrate challenge test (CCCT). This test evaluates the basal FSH level on cycle day 3 and the FSH response to clomiphene citrate administration from cycle day 5 to 9.20 In comparison to basal FSH combined with AFC the predictive accuracy and clinical value in outcome of IVF of this test was not shown to be better and should not be used.21

Summary In general, it can be concluded that AFC is a good predictor of ovarian response to gonadotrophins but not of pregnancy in young patients, whereas in older patients low AFC predicts poor response and poor pregnancy outcome in IVF treatment. It should therefore not be used as a routine test in the fertility workup, but is useful in the older patient. Basal FSH and serum inhibin B levels should not be routinely used as a screening test for predicting ovarian response and pregnancy outcome. Anti-Mullerian factor, like the AFC could prove useful as a screening test in the older patient but this needs to be confirmed in further studies. The CCCT should not be used as a screening test for ovarian reserve.

Semen analysis Azoospermia, repeatedly confirmed, implicates absolute infertility. When semen analysis adheres to the WHO reference values, i.e. a sperm concentration of 20 x 106/ml, 50% progressive motility (grades a and b) and 15% normal morphology according to strict criteria,22 the male is considered to be normal fertile. Despite the standardisation of semen analysis, the relationship between semen quality and biological fertility remains controversial.23 The definition of normality is hampered by two problems. First, impaired male fertility can be compensated for by the female partner. Second, semen parameters are of predictive value in treatment independent pregnancy where the female has no reproductive dysfunction. This issue has been assessed in two case–control studies that recommend values of 14.3–13.5 × 106/ml for concentration, 28–32% for progressive motility and 5–9% for normal morphology (using strict criteria), respectively. Both studies thus showed comparable parameters in discriminating between fertile and subfertile men. Morphology appeared to be the best discriminator between fertile and subfertile men.24,25 A disadvantage of these case–control studies is that they contrast subfertile men with fertile men, whereas the purpose of the fertility work-up is to distinguish those who have good spontaneous pregnancy prospects from those who have poor prospects. Bonde et al performed such a study amongst firstpregnancy planners and found that use of WHO values might be inappropriate, as many men with subfertility would be inside the range of normality according to the values.26 In the presence of male subfertility the couple should be counselled as to which ART is most appropriate (intrauterine insemination (IUI) IVF or ICSI), taking into account expected pregnancy rates, costs, patient discomfort and possible complications. The question is how this should be done and which sperm parameters can select men for the best treatment option? Individual semen parameters like volume,

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concentration and motility can be combined into the parameter of total motile sperm count (TMC), i.e. the total number of progressively motile spermatozoa present in the ejaculate. The TMC can be assessed directly from the ejaculate (prewash TMC) or after semen preparation (postwash TMC). The value of the postwash TMC in the fertility work-up could be in its prediction of patients who are unlikely to become pregnant after IUI and should therefore be advised to undergo IVF or ICSI. However, the TMC has only been assessed during the IUI cycles and not during the fertility work-up.27

Postcoital test The postcoital test (PCT) assesses the interaction between sperm and cervical mucus. A specimen of cervical mucus is obtained shortly before the expected ovulation and 8–16 hours after intercourse. The sample is examined under the microscope at 400× magnification and considered normal if at least one progressive motile spermatozoa is present in six high power fields.22 Controversies exist regarding technique, timing and interpretation of a normal test. In a systematic review of 11 observational studies the PCT showed a relative risk of pregnancy of 2, qualified as poor by the researchers, but potentially useful in clinical practice.28 The same group published a randomised controlled trial which compared cumulative pregnancy rates between couples offered a PCT versus couples who were not offered this test as part of their fertility work-up.29 No significant differences were shown in their respective cumulative pregnancy rates (49%, 95% confidence interval (CI) 42–55% in the PCT group versus 48%, 95% CI 42–55% in the control group). In this study no clear definition was given of a positive PCT result. The result did not alter the management of the patients and treatments were applied non-specifically and inconsistently. Anovulatory patients were included and treatment consisted of IUI with controlled ovarian hyperstimulation, not in a natural cycle. It is therefore not surprising that performing a PCT as part of the fertility work-up had no effect on outcome. If a well timed postcoital test is negative and no defined causes for infertility are found, cervical hostility is considered to be the cause of subfertility. Whether IUI is an effective treatment for cervical factor subfertility is not clear. Of five identified randomised trials the results were conflicting, but IUI can give reasonable pregnancy rates in a natural cycle as well as in cycles with controlled ovarian hyperstimulation.30 The test can also be negative because of poor semen quality. In these cases, IUI offers a benefit over timed intercourse both in natural and in controlled ovarian hyperstimulation cycles.31 A retrospective study which examined the relation between test outcome and duration of subfertility

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showed that the PCT is an effective predictor of treatment-independent conception in the absence of defined female causes of infertility and provided that the duration of subfertility was short. 32 In couples with less than 3 years of subfertility and a positive PCT, 68% conceived within 2 years compared with 17% of the couples with a negative test result. In couples with a duration of subfertility of more than 3 years the PCT result did not have any additional prognostic value. More recently, a prospective study33 assessed the validity of a prediction model for treatment-independent fertility outcome in couples34 and showed that the result of the PCT discriminated better between women who became pregnant and women who did not become pregnant than if the model was applied ignoring the result of the PCT. However, although the PCT is not recommended as a routine diagnostic test,35 this recent evidence of the prognostic value of the PCT in the subfertile couple suggests that the PCT should be part of the fertility work-up. In order to reduce cost and burden for couples another recent study has shown that the outcome of the PCT can be predicted in about 50% of the patients without compromising the prediction of fertility prospects, by using information from the medical history and semen analysis.36 Although in this study the PCT was performed by one gynaecologist, the level of experience in performing a PCT does not appear to have an effect on the predictive value of the PCT.33

Tubal assessment Tubal obstruction is thought to be the cause of subfertility in 12–33% of subfertile couples.37 The prevalence depends on the reference population and has a tendency to increase from a primary to a tertiary care level.3 Tubal patency tests usually are descriptive tests that visualise the cervical, uterine and Fallopian morphology, and in the case of laparoscopy or transvaginal hydrolaparoscopy, assess the pelvic cavity. They are not capable of assessing the tubal physiology and function that are necessary for successful conception.38 The medical history can be an indication of the presence of tuboperitoneal pathology (pelvic inflammatory disease (PID), septic abortion, endometriosis, pelvic surgery, chronic pelvic pain, dyspareunia) as can the clinical examination (pelvic tenderness, palpable mass).

Chlamydia antibody titre Chlamydia trachomatis is a major cause of PID, leading to chronic abdominal pain, ectopic pregnancy and tubal factor infertility.39,40 The infection is asymptomatic in the majority of cases. The chlamydia antibody titre (CAT) can be tested in the serum of women. CAT is based on the detection of a previous infection. Different serological methods are available,

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but in a meta-analysis it was shown that enzyme immunoassay or (micro)-immunofluorescence (MIF/ IF) perform best with a point estimate of 75% for both sensitivity and specificity.41 In a recent study, in a tertiary centre, the tubal status of 1006 women was examined by laparoscopy and related to the serum CAT.42 This study showed a linear trend between serum CAT and the likelihood of tubal damage. Increasing antibody titres were quantatively related to both presence of tubal damage and the severity of tubal damage. CAT performs equally well in the diagnosis of tubal pathology as a hysterosalpingogram (HSG) and can therefore be used as a triage before laparoscopy.41 If the CAT is negative (<1:64), tubal pathology at laparoscopy can be found in 7–12% of the patients,43 severe damage is more likely if higher titres are found.42

Hysterosalpingogram HSG is a widely used test in the assessment of tubal patency. Interpretation of the results can be hampered by technical difficulties or tubal spasm. The diagnostic performance of HSG was compared with laparoscopy and dye for tubal occlusion and peritubal adhesions in a meta-analysis.44 The metaanalysis showed a sensitivity of 65% (95% CI 50– 78%) and specificity of 83% (95% CI 77–88%) for the diagnosis of tubal occlusion. The HSG is reasonably accurate for detecting proximal tubal occlusion, but not for distal tubal disease or peritubal adhesions. 44,45 An abnormal result should be confirmed by laparoscopy, but with a normal result laparoscopy is likely to show tubal patency in 95% of cases. 45 More importantly, one-sided occlusion detected using HSG was found to decrease the fecundity rate ratio slightly (FRR 0.80), whereas more importantly bilateral occlusion reduced fertility prospects (FRR 0.49).46 Centres performing HSG tend to use water-soluble contrast media (WSCM) rather than oil-soluble contrast media (OSCM) because of the potential sideeffects of oil-soluble contrast media. A recently updated Cochrane review47 found evidence of the effectiveness of tubal flushing with OSCM if used therapeutically. OSCM increased the odds of pregnancy (odds ratio (OR) 3.5, 95% CI 1.8– 6.8) and live birth rate (OR 3.0, 95% CI 1.4–6.4) versus no intervention. Limited evidence exists of an increase in the odds of live birth following tubal flushing with OSCM versus WSCM (OR 1.49, 95% CI 1.05–2.1) and must be interpreted cautiously, since this was based on two trials of which the higher quality trial showed no significant difference, justifying a further randomised trial comparing oil-soluble and water-soluble media, where live birth is considered as the primary outcome.47

Laparoscopy and dye test The laparoscopy and dye test allows the clinician to assess the pelvic cavity for the presence of adhesions and endometriosis directly. Usually, this procedure is performed at the end of the fertility work-up, when a HSG or CAT has been assessed as being abnormal or sooner if the patient has comorbidity such as a medical history of PID, ectopic pregnancy or previous pelvic surgery. Laparoscopy cannot be considered the gold standard for assessing tubal patency as presumed tubal obstruction may be due to differences in resistance between the tubes, spasm or technical failure. This was illustrated in a cohort study comparing results of HSG and laparoscopy which implicated that 35% of the tubes that were found to be occluded at laparoscopy showed patency at HSG.46 In this study laparoscopy was shown to be a better predictor for infertility than a HSG with a FRR of 0.51 for one-sided occlusion and FRR of 0.15 for two-sided occlusion. Findings of phimosis and/or adhesions of the tubes showed a FRR of 0.60, endometriosis grade I/II of 0.52, whereas no spontaneous pregnancies occurred in patients with endometriosis grade III/IV.46 Compared with HSG, laparoscopy has the advantage of assessing whether microsurgery is feasible in the presence of tubal pathology. If mild to moderate endometriosis is found, direct treatment appears to improve fertility prospects by 13%.48 This improvement could, however, be the result of adhesiolysis that was performed in the same setting, since the results of another randomised trial did not show a benefit from treating mild to moderate endometriosis on fertility outcome.49

Selective salpingography and tubal catheterisation If proximal tubal occlusion is suspected at HSG or laparoscopy, selective salpingography and tubal catheterisation can be performed under fluoroscopic guidance to assess whether proximal tubal blockage is caused by cornual spasm. In this procedure the tubes are cannulated and flushed with contrast media. Tubal perfusion pressure, which can be measured using this test, appears to have a prognostic value in predicting pregnancy,50 but no randomised controlled trials have been published that assess the prognostic value.

Transvaginal hydrolaparoscopy Transvaginal hydrolaparoscopy (THL) is a technique that makes use of micro-endoscopic instruments. A scope is entered through the posterior fornix of the vagina into the pelvic cavity. By means of aquaflotation, using instillation of warm saline, the tuboovarian structures are assessed. The procedure is usually combined with hysteroscopy and chromopertubation and can be combined with falloposcopy. The procedure can be performed using local anaesthesia or

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sedation and could be done in an outpatient setting. Findings at THL appear to be in agreement with laparoscopic findings.51 However, no studies have been published that assess the performance of THL as a predictor of treatment-independent fertility.

Hystero-contrast sonography Transvaginal hysterosalpingo contrast sonography (HyCoSy) combines the instillation of contrast agents into the uterine cavity with a transvaginal ultrasound and through this allows assessment of the uterine cavity, tubal patency as well as ovarian morphology. The procedure can be performed in an outpatient clinic and requires a similar time to perform as the HSG. The performance of HyCoSy as a screening test for tubal infertility compares well with HSG with a high concordance rate. A diagnosis of occlusion requires additional laparoscopy for confirmation.52,53

Summary In summary, to assess tubal patency, it is reasonable to start with screening for chlamydia antibodies. If negative, visual tests of tubal patency can be delayed for several months. If pregnancy has not occurred in these months a visual test for tubal patency can be performed such as HSG or hystero-contrast – sonography. If these show tubal abnormalities a laparoscopy and dye test is indicated. In patients with co-morbidity for tubal pathology or high chlamydia antibody titres, it is reasonable to proceed to laparoscopy as the initial investigation.23,35 However, a rational approach to the assessment of tubal pathology can, at present, not be based on indisputable evidence.

Prediction models in reproductive medicine Until recently, emphasis in reproductive medicine has mainly been on finding causal diagnoses of subfertility and fertility treatment in order to bypass the identified pathology. Examples of this are ovulation induction in women diagnosed with anovulation, tubal surgery or IVF and embryo transfer in women with bilateral tubal disease, or IVF with or without ICSI, with or without surgical sperm retrieval in couples with reduced semen quality or even azoospermia. However, in many couples such a causal diagnosis cannot be found, and such couples are then classified as having unexplained subfertility, mild male subfertility, cervical factor subfertility, mild endometriosis or one-sided tubal pathology. In these couples ART like IUI or IVF can be considered. However, as these interventions are expensive and not without side-effects, they should only be offered if their success rates clearly exceed the probability of a spontaneous

209

pregnancy.54,55 This means that in these couples the fertility work-up also has to include a prognostic dimension.56 Because many factors affect pregnancy chances, it is impossible to make reliable predictions based on clinical evaluation of the data generated by the fertility work-up alone. Formal prediction models, in which the contribution of each factor is quantified, may be useful tools for adequate and reliable predictions. The first prediction model for spontaneous pregnancy was developed in 1993.57 This model was based on a Danish cohort and included three variables: duration of subfertility; the sperm penetration test, defined as the ability of sperm to move through fresh hen egg white; and the female subfertility factor, categorised as no disorder, having an ovulation or cervical disorder, an anatomical disorder, or a combination of the disorders. Since then, eight other prediction models have been published.37,58–63 They are presented in Tables 19.1 and 19.2. The most recently developed model is the so-called synthesis model, designed in The Netherlands.34 This model was based on the patient data of the three previous cohorts of Eimers, Collins and Snick, combined into one.37,58,61 It includes the variables female age, duration of subfertility, subfertility being primary or secondary, referral status (being referred by the general practitioner or another gynaecologist), percentage motile sperm and result of the PCT. Recently, the synthesis prediction model for spontaneous pregnancy (model of Hunault) was validated in a large prospective validation study.34 This prediction model accurately predicts the chance of a spontaneous pregnancy among subfertile ovulatory couples. 62 Such prediction models can be used to classify subfertile couples accordingly, and we have shown that such an approach can prevent overtreatment.63 Because of this, such a prediction model should be used as the final step of the fertility work-up, as an additional and essential tool in the counselling of patients.

Summary The presence of ovulatory cycles can be easily assessed. Basal FSH level is neither a good diagnostic test for ovarian reserve and pregnancy outcome in a general subfertility population nor a predictor of fertility outcome in patients with regular menstrual cycles undergoing ART. In the older patient, a low antral follicle count is a good predictor of poor ovarian response and poor pregnancy outcome in IVF treatment. More research is required into the predictive value of total motile sperm count and other semen parameters in the presence of suboptimal semen quality. The PCT does have a predictive value in pregnancy outcome and should be part of the fertility work-up, especially in couples with a duration of subfertility shorter than 3 years and normal semen parameters. More research into a rational approach for the assessment of tubal patency is needed.

1993 Denmark

1994 Argentina

1994 Finland

1994 The Netherlands

1995 Canada

1997 The Netherlands

1997 The Netherlands

Bahamondes et al58

Wichmann et al60

Eimers et al59

Collins37

Snick I61

Snick II61 724

Duration of subfertility (per year) Sperm penetration test (normal) Ovulation or cervical factor Anatomical disorder Ovulation and anatomical disorder Female age (per year) Duration of subfertility (per year) Secondary infertility of the couple Sperm morphology Normal cycle Pelvic surgery Female age (per year) Duration of subfertility (per year) Urethritis of men in history Sperm motility <20% and Quality of motility <2 Sperm morphology <70% Female age (per year) Duration of subfertility (per year) Female secondary infertility Family history man Semen motility (per %) PCT non-progressive PCT progressive Female age (<30/>30) Duration of subfertility (<36/>36 months) Secondary infertility of the couple Male defect Endometriosis Tubal defect Duration of subfertility <24 months Abnormal PCT Ovulation defect Tubal defect Female age (<30 years) Duration (<24 months) Secondary infertility of the couple WHO semen defect Ovulation defect Tubal defect

Predictive factors 0.76–0.95 1.2–2.0 0.41–1.1 0.29–0.71 0.12–0.76 — — — — — — 0.95–1.0 0.79–0.90 0.33–0.97 0.06–0.43 0.58–0.96 0.93–1.01 0.82–0.96 1.3–2.4 0.43–1.1 1.02–1.02 1.2–3.7 2.5–7.4 1.05–2.2 1.1–2.5 1.2–2.7 0.30–0.80 0.18–0.85 0.40–0.60 1.1–2.1 0.17–0.40 0.21–0.58 0.06–0.33 1.00–1.9 1.06–2.1 1.13–2.1 0.44–0.78 0.21–0.59 0.05–0.30

0.78 0.97 0.89 1.74 0.69 1.013 2.1 4.3 1.5 1.7 1.8 0.47 0.39 0.50 1.49 0.26 0.35 0.14 1.35 1.50 1.53 0.59 0.35 0.13

95% CI

0.85 1.51 0.68 0.45 0.30 0.90 0.85 2.45 1.09 2.35 0.38 0.97 0.84 0.57 0.16

HR

0.76

0.79

0.59

—

—

—

—

AUC

0.72–0.80

0.75–0.83

0.56–0.63

—

—

—

—

95% CI

Internal validation

0.59*

0.59*

0.64*

0.60∗

—

—

—

AUC

0.57–0.62

0.57–0.62

0.61–0.66

0.58–0.63

—

—

—

95% CI

External validation

(continued)

Poor∗

Poor∗

Poor∗

Poor*

—

—

—

Calibration

--

724

2198

914

907

559

321

No

Prediction models for spontaneous pregnancy.

210

Bostofte et al57

Table 19.1

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2459

Female age <31 years (per year) Female age >31 years (per year) Duration of subfertility (per year) Female primary subfertility Semen motility (per %) Referral status (tertiary care) Abnormal PCT

Female age <31 years (per year) Female age >31 years (per year) Duration of subfertility (per year) Female primary subfertility Semen motility (per %) Referral status (tertiary care)

Predictive factors

†

As reported by van der Steeg et al63 As reported by Hunault et al33 HR, hazard ratio; AUC, area under the curve; CI, confidence interval; PCT, postcoital test.

2004 The Netherlands

Hunault II33

2459

No

0.97 0.94 0.88 0.64 1.008 0.79 0.39

0.97 0.92 0.83 0.56 1.008 0.78

HR

— — — — — — —

— — — — — —

95% CI

0.64

0.62

AUC

—

—

95% CI

Internal validation

0.59∗ 0.59

0.63*

AUC

(0.46–0.73)†

Good*

95% CI

External validation

Moderate∗

Calibration

--

*

2004 The Netherlands

(continued)

Hunault I33

Table 19.1

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212

1 2 3 4 5 6

7

8 9 10 11 12 13 14

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Table 19.2

No

--

Prognostic variables for the prediction of treatment-independent pregnancy.

Variables

Female age Duration of subfertility Secondary subfertility Referral status Family history of man Urethritis of male partner in history Semen Sperm morphology Sperm motility Male defect (WHO) Sperm penetration test Cervical factor Cycle length Endometriosis Anovulation Tubal pathology Pelvic surgery

Bostofte et al57

Bahamondes et al58

Wichmann et al60

Eimers et al59

+

+ +

+ +

+ +

+ +

+

+

+

Collins37 Snick I61 Snick II61 Hunault I33 Hunault II33 Total

+

+ +

+ +

+ +

7 9

+

+

+

6

+

+

2 1

+

+

+

1

+

8 2

+

+

+ +

+

4 2

+

1

+ +

+

+

+

+ + + +

+ +

References 1. Hull MG, Glazener CM, Kelly NJ et al. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed) 1985; 291: 1693–7. 2. Snick HK, Snick TS, Evers JL, Collins JA. The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Hum Reprod 1997; 12: 1582–8. 3. Evers JL. Female subfertility. Lancet 2002; 360: 151–9. 4. de Kretser DM. Male infertility. Lancet 1997; 349: 787–90. 5. Collins W, Jurkovic D, Bourne T, Kurjak A, Campbell S. Ovarian morphology, endocrine function and intra-follicular blood flow during the periovulatory period. Hum Reprod 1991; 6: 319–24. 6. Crosignani PG, Rubin BL. Optimal use of infertility diagnostic tests and treatments. The ESHRE Capri Workshop Group. Hum Reprod 2000; 15: 723–32. 7. The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004; 19: 41–7. 8. Te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002; 8: 141–54. 9. Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod 1996; 11: 1484–6.

+ +

+ +

4 1 1 3 4 1

10. van Montfrans JM, Hoek A, van Hooff MH et al. Predictive value of basal follicle-stimulating hormone concentrations in a general subfertility population. Fertil Steril 2000; 74: 97–103. 11. van Rooij IA, de Jong E, Broekmans FJ et al. High follicle-stimulating hormone levels should not necessarily lead to the exclusion of subfertile patients from treatment. Fertil Steril 2004; 81: 1478–85. 12. van Rooij IA, Bancsi LF, Broekmans FJ et al. Women older than 40 years of age and those with elevated follicle-stimulating hormone levels differ in poor response rate and embryo quality in in vitro fertilization. Fertil Steril 2003; 79: 482–8. 13. Bancsi LF, Broekmans FJ, Mol BW, Habbema JD, te Velde ER. Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis. Fertil Steril 2003; 79: 1091–100. 14. van Rooij IA, Broekmans FJ, Scheffer GJ et al. Serum antimullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005; 83: 979–87. 15. Tomas C, Nuojua-Huttunen S, Martikainen H. Pretreatment transvaginal ultrasound examination predicts ovarian responsiveness to gonadotrophins in in-vitro fertilization. Hum Reprod 1997; 12: 220–3. 16. Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in

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17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005; 83: 291–301. Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Fertil Steril. The antral follicle count is a better marker than basal follicle-stimulating hormone for the selection of older patients with acceptable pregnancy prospects after in vitro fertilization. Fertil Steril 2005; 83: 811–14. Seifer DB, MacLaughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum Mullerianinhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002; 77: 468–71. van Rooij IA, Broekmans FJ, te Velde ER et al. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17: 3065–71. Navot D, Rosenwaks Z, Margalioth EJ. Prognostic assessment of female fecundity. Lancet 1987; 2: 645–7. Hendriks DJ, Broekmans FJ, Bancsi LF et al. Repeated clomiphene citrate challenge testing in the prediction of outcome in IVF: a comparison with basal markers for ovarian reserve. Hum Reprod 2005; 20: 163–9. World Health Organisation. WHO Laboratory Manual for the Examination of Human Semen and Sperm–Cervical Mucus Interaction, 4th edn. Cambridge: Cambridge University Press, 1999. ESHRE Capri Workshop Group. Diagnosis and management of the infertile couple: missing information. Hum Reprod Update 2004; 10: 295–307. Ombelet W, Bosmans E, Jansen M et al. Semen parameters in a fertile versus subfertile population: a need for change in the interpretation of semen testing. Hum Reprod 1997; 12: 987–93. Guzick DS, Overstreet JW, Factor-Litvak P et al. National Cooperative Reproductive Medicine Network. Sperm morphology, motility, and concentration in fertile and infertile men. N Engl J Med 2001; 345: 1388–93. Bonde JP, Ernst E, Jensen TK et al. Relation between semen quality and fertility: a population-based study of 430 first-pregnancy planners. Lancet 1998; 352: 1172–7. van Weert JM, Repping S, Van Voorhis BJ et al. Performance of the postwash total motile sperm count as a predictor of pregnancy at the time of intrauterine insemination: a meta-analysis. Fertil Steril 2004; 82: 612–20. Oei SG, Helmerhorst FM, Keirse MJ. When is the post-coital test normal? A critical appraisal. Hum Reprod 1995; 10: 1711–14. Oei SG, Helmerhorst FM, Bloemenkamp KW et al. Effectiveness of the postcoital test: randomised controlled trial. BMJ 1998; 317: 502–5. Steures P, van der Steeg JW, Verhoeve HR et al. Does ovarian hyperstimulation in intrauterine insemination for cervical factor subfertility improve pregnancy rates? Hum Reprod 2004; 19: 2263–6. Epub 2004 Aug 27. Cohlen BJ, Vandekerckhove P, te Velde ER, Habbema JD. Timed intercourse versus intra-uterine insemination with or without ovarian hyperstimulation for

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subfertility in men. Cochrane Database Syst Rev 2000: CD000360. Glazener CM, Ford WC, Hull MG. The prognostic power of the postcoital test for natural conception depends on the duration of infertility. Hum Reprod 2000; 15: 1953–7. Hunault CC, Laven JS, van Rooij IA et al. Prospective validation of two models predicting pregnancy leading to live birth among untreated subfertile couples. Hum Reprod 2005; 20: 1636–41. Hunault CC, Habbema JD, Eijkemans MJ et al. Two new prediction rules for spontaneous pregnancy leading to live birth among subfertile couples, based on the synthesis of three previous models. Hum Reprod 2004; 19: 2019–26. National Institute for Clinical Excellence, NHS. Fertility: Assessment and Treatment for People with Fertility Problems – Full Guideline. London: RCOG Press, 2004. van der Steeg JW, Steures P, Eijkemans MJ et al. Should the post-coital test (PCT) be part of the routine fertility work-up? Hum Reprod 2004; 19: 1373–9. Collins JA, Burrows EA, Wilan AR. The prognosis for live birth among untreated infertile couples. Fertil Steril 1995; 64: 22–8. Croxatto HB. Physiology of gamete and embryo transport through the fallopian tube. Reprod Biomed Online 2002; 4: 160–9. Westrom L, Wolner-Hanssen P. Pathogenesis of pelvic inflammatory disease. Genitourin Med 1993; 69: 9–17. Paavonen J, Eggert-Kruse W. Chlamydia trachomatis: impact on human reproduction. Hum Reprod Update 1999; 5: 433–47. Mol BW, Dijkman B, Wertheim P et al. The accuracy of serum chlamydial antibodies in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1997; 67: 1031–7. Akande VA, Hunt LP, Cahill DJ et al. Tubal damage in infertile women: prediction using chlamydia serology. Hum Reprod 2003; 18: 1841–7. Land JA, Gijsen AP, Kessels AG, Slobbe ME, Bruggeman CA. Performance of five serological chlamydia antibody tests in subfertile women. Hum Reprod 2003; 18: 2621–7. Swart P, Mol BW, van der Veen F et al. The accuracy of hysterosalpingography in the diagnosis of tubal pathology: a meta-analysis. Fertil Steril 1995; 64: 486–91. Mol BW, Swart P, Bossuyt PM, van Beurden M, van der Veen F. Reproducibility of the interpretation of hysterosalpingography in the diagnosis of tubal pathology. Hum Reprod 1996; 11: 1204–8. Mol BW, Collins JA, Burrows EA, van der Veen F, Bossuyt PM. Comparison of hysterosalpingography and laparoscopy in predicting fertility outcome. Hum Reprod 1999; 14: 1237–42. Johnson N, Vandekerckhove P, Watson A et al. Tubal flushing for subfertility. Cochrane Database Syst Rev 2005: CD003718. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997; 337: 217–22.

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49. Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell’Endometriosi. Hum Reprod 1999; 14: 1332–4. 50. Papaioannou S, Bourdrez P, Varma R et al. Tubal evaluation in the investigation of subfertility: a structured comparison of tests. BJOG 2004; 111: 1313–21. 51. Watrelot A, Nisolle M, Chelli H et al. International Group for Fertiloscopy Evaluation. Is laparoscopy still the gold standard in infertility assessment? A comparison of fertiloscopy versus laparoscopy in infertility. Results of an international multicentre prospective trial: the ‘FLY’ (Fertiloscopy-Laparoscopy) study. Hum Reprod 2003; 18: 834–9. 52. Helpman L, Wolman I. Hysterosalpingo contrast sonography for the evaluation of the tubal factor infertility investigation: review of the literature. Rev Gynaecol Pract 2003: 171–6. 53. Dijkman AB, Mol BW, van der Veen F, Bossuyt PM, Hogerzeil HV. Can hysterosalpingocontrast-sonography replace hysterosalpingography in the assessment of tubal subfertility? Eur J Radiol 2000; 35: 44–8. 54. te Velde ER and Cohlen BJ. The management of infertility. N Engl J Med 1999; 340: 224–6. 55. Wasson JH, Sox HC, Neff RK, Goldman L. Clinical prediction rules. Applications and methodological standards. N Engl J Med 1985; 313: 793–9. 56. Habbema JDF, Collins J, Leridon H et al. Towards less confusing terminology in reproductive medicine: a proposal. Fertil Steril 2004; 82: 36–40.

57. Bostofte E, Bagger P, Michael A, Stakemann G. Fertility prognosis for infertile couples. Fertil Steril 1993; 59: 102–7. 58. Bahamondes L, Alma FA, Faundes A, Vera S. Score prognosis for the infertile couple based on historical factors and sperm analysis. Int J Gynaecol Obstet 1994; 46: 311–15. 59. Eimers JM, te Velde ER, Gerritse R et al. The prediction of the chance to conceive in subfertile couples. Fertil Steril 1994; 61: 44–52. 60. Wichmann L, Isola J, Tuohimaa P. Prognostic variables in predicting pregnancy. A prospective follow up study of 907 couples with an infertility problem. Hum Reprod 1994; 9: 1102–8. 61. Snick HK, Snick TS, Evers JL, Collins JA. The spontaneous pregnancy prognosis in untreated subfertile couples: the Walcheren primary care study. Hum Reprod 1997; 12: 1582–8. 62. Steures P, van der Steeg JW, Hompes PG et al. Collaborative Effort on the Clinical Evaluation in Reproductive Medicine. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368: 216–21. 63. van der Steeg JW, Steures P, Eijkemans MJ et al. Pregnancy is predictable: a large-scale prospective external validation of the prediction of spontaneous pregnancy in subfertile couples. Hum Reprod 2007; 22: 536–42.

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20 Achieving pregnancy in the anovulatory woman Richard S Legro, Anuja Dokras

Introduction Anovulation is a common cause of infertility. Most women with anovulation present with irregular menses, repeated failure to detect positive luteinising hormone (LH) surge by ovulation kits or low midluteal serum progesterone levels. The typical work-up of anovulation includes blood tests for thyroid disorders, impaired gonadotrophin secretion and increased prolactin and androgen secretion. The most frequent cause of anovulation is polycystic ovary syndrome (PCOS). Treatment of women with anovulation should be directed at correcting the underlying pathology, if possible; helping the woman achieve fertility, if desired; and medical treatment to prevent complications of the disease process.

Polycystic ovary syndrome The epidemic of obesity has been associated with an epidemic of PCOS, and this greater influx of affected patients presenting with infertility has led to increased interest in the best treatments to guide infertility. Recognition of the poor fertility and pregnancy outcomes in these patients has led to greater scrutiny of treatments that may be associated with increased morbidity (due to multiple pregnancy and later pregnancy complications), both maternal and foetal. Ovulation, therefore, can no longer be the endpoint to guide infertility therapy. This section reviews front line therapies to treat infertility in women with PCOS, based largely on a recent American Society for Reproductive Medicine (ASRM)/European Society of Human Reproduction and Embryology (ESHRE) guided conference.1

Lifestyle modifications Pre-conception counselling in women with PCOS should identify risk factors for reproductive failure and correct them prior to treatment initiation. Obesity is associated with anovulation, pregnancy loss and late pregnancy complications (pre-eclampsia, gestational

diabetes, etc). Obesity is common in women with PCOS and is linked to failure or delayed response to all infertility treatments. Weight loss is recommended as first line therapy in obese women with PCOS seeking pregnancy. This recommendation is based on the benefits of weight loss seen in multiple other conditions, such as diabetes and cardiovascular disease, as well as recognition of obesity’s association with poor reproductive outcome. There is a paucity of studies suggesting that weight loss prior to conception improves the live birth rate in obese women with or without PCOS.

Diet and exercise It is generally agreed that energy restriction is required for weight loss, and therefore hypocaloric diets are a mainstay of treatment. In fact, early improvements in reproductive function, in the absence of apparent weight loss, were probably due to energy restriction per se. However, there is little agreement on what constitutes the optimal diet for women with PCOS. Increasing evidence in women without PCOS suggests that diets with reduced glycaemic load may be beneficial in alleviating hyperinsulinaemia and its metabolic consequences.2 It is clear that regular physical activity is an important component of weight loss programmes, because it is associated with better long-term weight loss maintenance. However, its independent role in achieving weight reduction and improved reproductive outcome is less obvious. Increased physical activity is recommended for obese women with PCOS, but always while considering the possible orthopaedic and cardiovascular limitations.

Pharmacological treatment and bariatric surgery for obesity The available literature supports the adjuvant use of bariatric surgery and pharmacological weight loss for the treatment of obesity in PCOS, although large clinical trials are needed to support their use for associated infertility. In morbidly obese women, the PCOS phenotype appears to be very frequent.3 Most importantly,

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Table 20.1

Summary of large randomised, blinded trials that have reported pregnancy and or live birth results. Cumulative 6-month pregnancy rates

Study

N

Treatments

Palumba et al, 20056

100

Metformin/placebo vs clomiphene/placebo

Live birth: metformin 52% clomiphene 18%

Metformin superior to clomiphene

Moll et al, 20067

225

Clomiphene/placebo vs clomiphene/metformin

Ongoing pregnancy: clomiphene 46% metformin + clomiphene: 40%

No benefit of combined therapy with metformin/clomiphene

Legro et al, 20078

626

Clomiphene/ placebo vs metformin/placebo vs clomiphene/metformin

Live birth: metformin 7% clomiphene 23% metformin + clomiphene 28%

Clomiphene superior to metformin No benefit of combined therapy with metformin/clomiphene

Palomba et al, 20079

80

Metformin/ placebo vs clomiphene/ placebo

Cumulative pregnancy rate: metformin 63% clomiphene 49%

No benefit of metformin over clomiphene

this disorder has been found to improve markedly after sustained weight loss following bariatric surgery.3 Antiobesity pharmacological agents have been used in obese women with PCOS, although few quality studies have been published. Both orlistat, which blocks intestinal absorption of fat, and sibutramine, an appetite suppressant, have displayed a weight loss-independent effect on androgens and insulin resistance.4,5

Ovulation induction with pharmacological agents Clomiphene citrate, an antioestrogen, is the front line agent to induce ovulation and achieve pregnancy in women with PCOS. The starting dose is usually 50 mg a day for 5 days begun during the early follicular phase. The dose may be increased in subsequent cycles up to 150 mg/day. Insulin sensitising agents, specifically metformin have been disappointing in properly designed trials. The four trials summarised in Table 20.1 are all large randomised double blind multicentre trials that used metformin and clomiphene or the combination for the treatment of infertility in women with PCOS. All trials studied participants up to six cycles, there were no adjuvant medications such as human chorionic gonadotrophin (hCG) to trigger ovulation, and conception was by timed intercourse without inseminations. Only one trial, Pregnancy in Polycystic Ovary Syndrome or PPCOS8 was designed and powered to detect a difference in live birth rates between the treatment groups.10 This and the other large Dutch trial,7 both found no benefit of the combination of metformin and clomiphene on live birth. The trials most at odds with one another are the trials of Palomba et al6,9 which found that metformin was significantly better or equal to clomiphene in achieving live birth and the PPCOS trial8 which found the opposite. Potential reasons for the discrepant results include population differences, including genetic and

Conclusion

environmental differences, selection criteria for the trial, and possible bias in the study design. The populations varied in terms of obesity. The Dutch and Palomba trials excluded women with PCOS with a body mass index (BMI) >30, whereas the PPCOS trial included them. One of the key findings of this trial is the role of BMI in predicting overall treatment success (Fig 20.1). Increasing obesity is clearly associated with decreasing success. However, when the primary outcome, live birth, is divided by BMI group and the highest BMI group is compared with the lowest BMI group (Table 20.2), it is obvious that the trend of each medication found in the overall study group holds regardless of weight category. The combined treatment group outcome is still better than that after single agent therapy, and clomiphene is significantly better than metformin (Table 20.2). This is a post hoc analysis and subject to the error that multiple looks at the same data set can yield, however, the size of the normal and overweight BMI group in the PPCOS trial (n=179) is still substantially larger than the trial of Palomba et al (n=100).6 Perhaps the most relevant clinical implication is that there was a trend towards increased live birth with metformin and clomiphene in combination compared with clomiphene in the most obese subgroup, suggesting the combination may be the better choice for women with PCOS and BMI >35 and this conclusion was supported by a recent meta-analysis.11 Also, the multiple pregnancy rates in the clomiphene arms in the PPCOS trial ranged from 4 to 6%, and miscarriage rates with clomiphene approximated those of a normal fertile population (~25%). Similar findings were noted in the Dutch trial. Finally, fecundity rates are fairly constant for up to six cycles with clomiphene therapy suggesting that this or longer trials may still yield acceptable pregnancy rates (Figure 20.2). Thus, clomiphene as first line therapy can be justified for use for up to six cycles.

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0.5 P value <0.001 0.4

0.3

0.2

0.1

0.0 150

200

250 300 350 400 Days from randomisation to live birth BMI <30

BMI 30–34

450

500

Fig 20.1 Kaplan–Meier curve of live births by body mass index (BMI) group independent of treatment. Adapted from reference 8.

BMI ≥35

Table 20.2 Results of the Legro et al Pregnancy in Polycystic Ovary Syndrome (PPCOS) trial stratified by body mass index (BMI) group, lowest BMI group (<30) compared with the highest group (BMI ≥35). Adapted from reference 8. BMI <30

Ovulation Live births

Clomiphene (n=57)

MET (n=57)

272/538 (50.6%) 21/57 (36.8%)

151/554 (27.3%) 5/57 (8.8%)

(n=179) COMB (n=65) 334/559 (59.7%) 24/65 (36.9%)

Clomiphene (n=110) 190/404 (47.0%) 18/110 (16.4%)

BMI ≥35

(n=311)

MET (n=105)

COMB (n=96)

145/465 (31.2%) 4/105 (3.8%)

248/405 (61.2%) 22/96 (22.9%)

MET, metformin; COMB, combination of clomiphene citrate and metformin.

0.25 0.2 0.15 0.1 0.05 0 Visit 1

Visit 2 Clomiphene

Visit 3

Visit 4 Metformin

Visit 5 Combined

What did emerge from the PPCOS trial that is relevant both to clinical practice and to the Food and Drug Administration (FDA) approval of ovulation inducing agents is that the fecundity per ovulation was twice as good for clomiphene than for metformin on a cycle basis (10.2% versus 5.1%) and even better on a per ovulated patient basis (29.9% versus 13.0%). This may

Visit 6

Fig 20.2 Live birth per ovulation (as a fraction) in Pregnancy in Polycystic Ovary Syndrome (PPCOS) trial by monthly visit. There was a significant time trend (towards improvement) in the combined arm, with constant rates noted with clomiphene and metformin alone. Adapted from reference 8.

have been due to the presumed multiple follicular recruitment of clomiphene over metformin (ultrasonography was not part of the PPCOS study), or by the improved reduction in hyperandrogenism (on the basis of reduction in the free androgen index with clomiphene compared with metformin). Some have argued that meformin’s benefit requires a longer

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period of exposure prior to ovulation, and while no time effect was noted in the metformin only arm, a time related improvement in pregnancy rates was noted in the combination arm of metformin and clomiphene in the PPCOS trial. However, these results are relevant to any ovulation induction agent and suggest that looking at ovulation rates alone does not answer the critical question of whether that ovulation led to a pregnancy.

Gonadotrophins and gonadotrophin releasing hormone analogues The aim of ovulation induction for women with anovulatory PCOS is to restore fertility, achieve a singleton live birth, and avoid complications such as ovarian hyperstimulation syndrome (OHSS). The method of ovulation induction using gonadotrophin therapy theorises that initiation and maintenance of follicle growth may be achieved by a transient increase in follicle stimulating hormone (FSH) above a threshold dose for sufficient duration to generate a limited number of developing follicles.12 Given the greater risk for complications in women with PCOS, it is generally recommended to begin with a low dose (25–75 U of gonadotrophins) protocol and to increase carefully and slowly (every 7–14 days). Overall, low dose regimens result in a monofollicular ovulation rate of approximately 70%, a pregnancy rate of 20% and a multiple live birth rate of 5.7%.13 Correspondingly, there is a low incidence of multiple pregnancies (<6%) and OHSS (<1%).

Laparoscopic ovarian surgery Surgery to treat PCOS is often used when other modalities are unsuccessful. Surgical approaches to ovulation induction have developed from the traditional wedge resection to modern day minimal access techniques, usually employing laparoscopic ovarian diathermy or laser. Multiple ovarian puncture performed either by diathermy or by laser is known as “ovarian drilling”. There is no evidence that any surgical technique is superior but as few as four punctures have been shown to be effective. In approximately 50% of laparoscopic ovarian surgery (LOS)-treated women, adjuvant therapy will be required. Five randomised controlled trials compared the effectiveness of LOS with that of gonadotrophins for women with clomiphene citrate-resistant PCOS showed similar ongoing pregnancy rates and live birth rates.14

Assisted reproduction: in vitro fertilisation In vitro fertilisation (IVF) is usually not one of the first choices for treatment, as there are simpler, less invasive, less costly methods to treat infertility. However, frequently it is used in the recalcitrant patient or for

couples who have multiple other infertility factors. Several stimulation protocols have been utilised for the treatment of patients with PCOS undergoing IVF, but currently the most standard protocol is a long desensitisation protocol associated with FSH administration. A recent meta-analysis15 demonstrated that the cycle cancellation rate is significantly increased in patients with PCOS (12.8% versus 4.1%; odds ratio (OR) 0.5, 95% confidence interval (CI) 0.2–1.0). Duration of stimulation is significantly longer in patients with PCOS (1.2 days, 95% CI 0.9–1.5), Significantly more cumulus–oocyte complexes (2.9, 95% CI 2.2–3.6) were retrieved in women with PCOS but fertilisation rates were similar as compared with women without PCOS. Regarding the probability of pregnancy, the clinical pregnancy rate per started cycle was similar (about 35%) between PCOS and non-PCOS patients. There is some evidence that the adjuvant use of metformin may enhance ongoing pregnancy rates and reduce the incidence of OHSS when used during IVF.16

Later pregnancy complications While the focus of treating pregnancy in women with PCOS has been to achieve pregnancy, it remains just one step on the way to a healthy live birth. While, as noted earlier, prospective trials do not necessarily indicate an increased first trimester loss rate in women with PCOS, there is emerging evidence of an increased chance for later major pregnancy complications. Close to 50% of women who conceived in the PPCOS trial experienced a major antepartum or postpartum complication.8 Women with PCOS appear to be at greater risk for developing complications of pregnancy including gestational hypertension, gestation diabetes and preterm labour. Infertile women with PCOS should be counselled about these risks followed by heightened surveillance during pregnancy.

Hyperprolactinaemia Hyperprolactinaemia appears to cause anovulation by suppressing pulsatile hypothalamic gonadotrophin releasing hormone (GnRH) secretion, leading to low gonadotrophin and oestradiol concentrations.17 Mild degrees of hyperprolactinaemia (20–50 ng/ml) are a common finding in the evaluation of anovulation and may contribute to infertility without causing irregularities in the menstrual cycle. It has been proposed that mildly elevated prolactin levels may be associated with insufficient progesterone secretion, and possibly a short luteal phase of the menstrual cycle.18 Moderate degrees of hyperprolactinaemia (50– 100 ng/ml) are more likely to be associated with amenorrhoea or oligomenorrhoea. Dopamine agonists are the first line of treatment for patients with idiopathic hyperprolactinaemia or with pituitary prolactinomas. The initial dose of the long tested drug bromocriptine is 2.5 mg at bedtime and

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120

Serum prolactin (µg/l)

100 80 60 40 20 0 0

6

12

18

Weeks of therapy Bromocriptine

Cabergoline

this can be increased to 5 mg twice daily. Prolactin levels should be checked 6 weeks after the initiation of treatment or change in dose. Once the serum prolactin levels normalise, ovarian function returns within a few months. Cabergoline is a long-acting ergot dopamine agonist that is administered once or twice a week (0.25–0.5 mg), and has much less tendency to cause nausea than bromocriptine.19 Both bromocriptine and cabergoline effectively decrease prolactin secretion (Fig 20.3) and reduce the size of the lactotroph adenoma in more than 90% of patients. Cabergoline has been shown to be superior to bromocriptine in decreasing the serum prolactin concentrations in women with hyperprolactinaemia and amenorrhoea who had microadenomas or no obvious cause (n=459); 87% of patients randomised to cabergoline achieved normal levels compared with 52% treated with bromocriptine. Moreover, menses resumed in 96% of those taking cabergoline compared with 87% of those taking bromocriptine. Based on serum progesterone levels, 82% of the cabergoline group and 66% of the bromocriptine group had at least one ovulatory cycle. Overall, 72% of women treated with cabergoline and 52% of those treated with bromocriptine had ovulatory cycles or became pregnant during treatment (p<0.001).19 Cabergoline has also been shown to be effective in patients with bromocriptine intolerance with normalisation of prolactin in 70% of bromocryptine-resistant subjects.20 Data to date suggest that both drugs are safe in early pregnancy.21–23 If used for the treatment of anovulation alone, it is recommended that these drugs be discontinued once pregnancy is detected.

Hypothyroidism Thyroid dysfunction is a prevalent endocrine disorder that interferes with reproductive physiology

24

Fig 20.3 Serum prolactin concentrations in women with hyperprolactinaemic amenorrhoea treated with bromocriptine and cabergoline. Both drugs lowered serum prolactin concentrations into the normal range (upper limit of normal equals 20 µg/l). Data from reference 19.

(anovulation and menstrual irregularity), reduces the likelihood of pregnancy and adversely affects pregnancy outcome, thus becoming relevant in the algorithm of reproductive dysfunction. The prevalence of hypothyroidism in the reproductive age group is approximately 2%.24 Thyroid autoimmunity is by far the most frequent cause of hypothyroidism in women of reproductive age. In women with subclinical hypothyroidism, ovulation and conception can occur, but the resulting pregnancies are often associated with miscarriage, stillbirth or prematurity.25,26 Severe hypothyroidism is commonly associated with ovulatory dysfunction and infertility with an increased risk of miscarriage and preterm delivery. Arojoki et al investigated the prevalence of hypothyroidism in 299 women with various causes of infertility.27 Overall, 4% women had increased thyroid stimulating hormone (TSH) levels, with the majority presenting with overt hypothyroidism. The highest frequency of increased serum TSH was observed among the women with ovulatory dysfunction (6.3%), but there was no statistical difference when elevated serum TSH levels were compared among the different causes of infertility. The goal of therapy in hypothyroidism is restoration of the euthyroid state, which can be achieved by oral administration of synthetic thyroxine (T4). The prohormone T4 has an advantage over other preparations, because the patient’s own physiological mechanisms control the production of active hormone. The average replacement dose of T4 in adults is approximately 1.6 µg/kg body weight per day but the range of required doses is from 50 to 200 µg/day. Given the 1week plasma half-life of T4, it takes about 6 weeks before a steady state is attained after therapy is initiated or the dose is changed. Hypothyroidism should be corrected before initiation of fertility treatment and pregnancy. Serum TSH

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concentrations rise in early pregnancy in most hypothyroid women treated with T4. The increase in T4 requirements begins at about 8 weeks and plateaus by week 16.28 On average, these women need 45% more T4 during pregnancy to maintain normal TSH secretion. Women with hypothyroidism contemplating pregnancy should be advised of the need for more T4 should they become pregnant. The clinical practice guidelines of the Endocrine Society recommend that if hypothyroidism has been diagnosed before pregnancy, the pre-conception T4 dose be adjusted to reach a TSH level ≤2.5 µU/ml before pregnancy.29 The T4 dose should be increased by about 30% (by taking an extra pill 2 days each week as soon as pregnancy is confirmed). Further dose changes should be made based upon serum TSH levels measured every 4 weeks until the TSH becomes normal. Thereafter, serum TSH should be measured once each trimester.

Hypothalamic anovulation Amenorrhoea or oligomenorrhoea occur in patients affected by hypothalamic amenorrhoea and represent the adaptive mechanism to stress, so that the reproductive axis activity is reduced. Unexplained or functional/hypothalamic anovulation can occur at any age in a woman’s reproductive life span. It generally occurs after severe stress-inducing conditions such as excessive dieting, heavy exercise training, or intense emotional events – all situations that can induce amenorrhoea with or without body weight loss.30 It is critical to understand that such a blockade of reproductive function is reversible and hence correction of the underlying pathophysiology should be the main stay of therapy. Typically, women with hypothalamic anovulation have reduced LH levels, in part activated by stress-induced endogenous opioid hypertone, and normal FSH plasma levels. For many athletic women, the first line of therapy should be to recommend increased caloric intake or reduced exercise in order to match adequate caloric intake to energy expenditure. The treatment of anorexia nervosa, however, is more complex and generally involves nutritional rehabilitation, medical monitoring and psychological treatment such as cognitive behavioural therapy (CBT), family therapy, or other psychological modalities. CBT emphasises the relationship of thoughts and feelings to behaviour and helps patients to learn to recognise the thoughts and feelings that lead to disordered eating. CBT has been shown to be effective in women with hypothalamic amenorrhoea. In one study, 16 women with functional hypothalamic amenorrhoea were randomly assigned to receive CBT (16 individual sessions with a clinician over the 20 weeks, focusing on healthy eating patterns and modifying maladaptive attitudes towards eating and weight) or observation.31 Six of eight women in the CBT arm resumed ovulatory cycles compared with two of eight in the observation group. Although this

study was small, it suggests that CBT may be a reasonable first line intervention for women with functional hypothalamic amenorrhoea. It is estimated that pulsatile LH secretion is disrupted at energy intakes below 30 kcal/kg lean body mass/day.32 Long-term follow-up of women with hypothalamic amenorrhoea (range 7–9 years) shows 70% recovery which was found to be related to increases in BMI.33 This study underscores the importance of counselling these patients aggressively using nutritional and psychological counselling. Infertility associated with hypothalamic amenorrhoea can be overcome with exogenous gonadotrophin administration or pulsatile administration of GnRH. However, neither should be recommended as a firstline treatment for these women, since increased caloric intake (a much simpler therapy) is highly effective. Furthermore, if a woman does not eat enough to have regular cycles and normal fertility, her nutrient intake during pregnancy is likely to be inadequate for normal foetal growth and development, and in those with low weight the spontaneous abortion rate is also elevated. As described in women with PCOS, the aim of ovulation induction for women with hypothalamic anovulation is to restore fertility, achieve a singleton live birth, and avoid complications such as OHSS. Treatment with FSH alone may result in multifollicular growth associated with low oestradiol levels.34 Addition of LH to the stimulation regimen in these patients has been shown to increase oestradiol and androsteindione levels, increase ovarian sensitivity to FSH, and improve the ability of the follicles to luteinise on exposure to hCG.35 Low doses of gonadotrophins are recommended to decrease the risk of multiple pregnancy and ovarian hyperstimulation syndrome. Previously GnRH pulsatile therapy has been used effectively in women with hypothalamic amenorrhoea to achieve monofollicular development. The method did not require extensive monitoring and had a low risk of OHSS. The main disadvantage was that GnRH was administered (SQ/IV) through a portable mini pump that had to be worn at all times during the stimulation period which could extend up to 2–3 weeks. The cumulative conception and live birth rates in the first course of therapy and after 12 cycles of treatment were 82.1 and 65.4% respectively.36

Summary The treatment of infertile women with PCOS has just begun to gather sufficient evidence from properly designed trials to guide treatment. Common sense recommends pre-conceptional counselling to stress the importance of life style, especially weight reduction and exercise in overweight women, and cessation of smoking and alcohol consumption. The recommended first-line treatment for ovulation induction remains clomiphene citrate. Metformin alone is probably relatively ineffective, but may offer some benefit

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to obese women in conjunction with clomiphene citrate. Second-line therapies include exogenous gonadotrophins or LOS. Recommended third-line treatment is IVF. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the foetus. Other factors associated with anovulation such as hyperprolactinaemia and hypothyroidism should be treated adequately prior to attempting or assisting conception. Women with hypothalamic amenorrhoea should be counselled regarding the underlying pathophysiology and offered CBT prior to the use of gonadotrophins to induce ovulation.

11.

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References 1. Thessaloniki ESHRE/ASRM Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Fertil Steril 2008; 89: 505–22. 2. Moran LJ, Brinkworth G, Noakes M, Norman RJ. Effects of lifestyle modification in polycystic ovarian syndrome. Reprod Biomed Online 2006; 12: 569–78. 3. Escobar-Morreale HF, Botella-Carretero JI, AlvarezBlasco F, Sancho J, San Millan JL. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J Clin Endocrinol Metab 2005; 90: 6364–9. 4. Jayagopal V, Kilpatrick ES, Holding S, Jennings PE, Atkin SL. Orlistat is as beneficial as metformin in the treatment of polycystic ovarian syndrome. J Clin Endocrinol Metab 2005; 90: 729–33. 5. Sabuncu T, Harma M, Nazligul Y, Kilic F. Sibutramine has a positive effect on clinical and metabolic parameters in obese patients with polycystic ovary syndrome. Fertil Steril 2003; 80: 1199–204. 6. Palomba S, Orio F Jr, Falbo A et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab 2005; 90: 4068–74. 7. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006; 332: 1485. 8. Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551–66. 9. Palomba S, Orio F Jr, Falbo A et al. Clomiphene citrate versus metformin as first-line approach for the treatment of anovulation in infertile patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2007; 92: 3498–503. 10. Myers ER, Silva SG, Hafley G et al. Estimating live birth rates after ovulation induction in polycystic

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ovary syndrome: Sample size calculations for the pregnancy in polycystic ovary syndrome trial. Contemp Clin Trials 2005; 26: 271–80. Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril 2006; 86: 1432–17. van der Meer M, Hompes PG, Scheele F et al. Follicle stimulating hormone (FSH) dynamics of low dose step-up ovulation induction with FSH in patients with polycystic ovary syndrome. Hum Reprod 1994; 9: 1612–17. Homburg R, Howles CM. Low-dose FSH therapy for anovulatory infertility associated with polycystic ovary syndrome: rationale, results, reflections and refinements. Hum Reprod Update 1999; 5: 493–9. Farquhar C, Lilford RJ, Marjoribanks J, Vandekerckhove P. Laparoscopic “drilling” by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database Syst Rev 2005; CD001122. Heijnen EM, Eijkemans MJ, Hughes EG et al. A metaanalysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update 2006; 12: 13–21. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod 2006; 21: 1416–25. Kooy A, de Greef WJ, Vreeburg JT et al. Evidence for the involvement of corticotropin-releasing factor in the inhibition of gonadotropin release induced by hyperprolactinemia. Neuroendocrinology 1990; 51: 261–6. Seppala M, Ranta T, Hirvonen E. Hyperprolactinaemia and luteal insufficiency. Lancet 1976; 1: 229–30. Webster J, Piscitelli G, Polli A et al. A comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. Cabergoline Comparative Study Group. N Engl J Med 1994; 331: 904–9. Verhelst J, Abs R, Maiter D et al. Cabergoline in the treatment of hyperprolactinemia: a study in 455 patients. J Clin Endocrinol Metab 1999; 84: 2518–22. Turkalj I, Braun P, Krupp P. Surveillance of bromocriptine in pregnancy. JAMA 1982; 247: 1589–91. Ricci E, Parazzini F, Motta T; Ferrari CI et al. Pregnancy outcome after cabergoline treatment in early weeks of gestation. Reprod Toxicol 2002; 16: 791–3. Colao A, Abs R, Bárcena DG et al. Pregnancy outcomes following cabergoline treatment: extended results from a 12-year observational study. Clin Endocrinol (Oxf) 2008; 68: 66–71. Bjoro T, Holmen J, Kruger O et al. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large, unselected population. The Health Study of Nord-Trondelag (HUNT). Eur J Endocrinol 2000; 143: 639–47. Abalovich M, Gutierrez S, Alcaraz G et al. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002; 12: 63–8. Davis LE, Leveno KJ, Cunningham FG. Hypothyroidism complicating pregnancy. Obstet Gynecol 1988; 72: 108–12.

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27. Arojoki M, Jokimaa V, Juuti A et al. Hypothyroidism among infertile women in Finland. Gynecol Endocrinol 2000; 14: 127–31. 28. Alexander EK, Marqusee E, Lawrence J et al. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004; 351: 241–9. 29. Abalovich M, Amino N, Barbour LA et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007; 92 (8 Suppl): s1–47. 30. Frisch RE, Mcarthur JW. Menstrual cycles: fatness as a determinant of minumum weight for height necessary for their maintenance or onset. Science 1974; 185: 949–51. 31. Berga SL, Marcus MD, Loucks TL et al. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril 2003; 80: 976–81. 32. Loucks AB, Thuma JR. Luteinizing hormone pulsatility is disrupted at a threshold of energy availability

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in regularly menstruating women. J Clin Endocrinol Metab 2003; 88: 297–311. Falsetti L, Gambera A, Barbetti L, Specchia C. Longterm follow-up of functional hypothalamic amenorrhea and prognostic factors. J Clin Endocrinol Metab 2002; 87: 500–5. Schoot DC, Harlin J, Shoham Z et al. Recombinant human follicle-stimulating hormone and ovarian response in gonadotrophin-deficient women. Hum Reprod 1994; 9: 1237–42. Recombinant human luteinizing hormone (LH) to support recombinant human follicle-stimulating hormone (FSH)-induced follicular development in LH- and FSH-deficient anovulatory women: a dosefinding study. The European Recombinant Human LH Study Group. J Clin Endocrinol Metab 1998; 83: 1507–14. Balen AH, Braat DD, West C, Patel A, Jacobs HS. Cumulative conception and live birth rates after the treatment of anovulatory infertility: safety and efficacy of ovulation induction in 200 patients. Hum Reprod 1994; 9: 1563–70.

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21 The patient with endometriosis: achieving pregnancy A Vodolazkaia, TM D’ Hooghe

Introduction The aim of this chapter is to clarify the state of the art regarding the impact of endometriosis on fertility and to discuss the management of endometriosis associated with infertility.

Background of endometriosis Endometriosis is an oestrogen-dependent, gynaecological disease, defined as the presence of endometrial-like cells outside the uterus.1 The condition is predominantly found in women of reproductive age, from all ethnic and social groups.1 The associated symptoms can impact on general physical, mental and social well-being.1 Endometriosis is associated with severe dysmenorrhoea, deep dyspareunia, chronic pelvic pain, ovulation pain, cyclical or perimenstrual symptoms (e.g. bowel or bladder associated) with or without abnormal bleeding, infertility and chronic fatigue. Some affected women, however, remain asymptomatic.1,2 The prevalence of endometriosis in women with infertility and pelvic pain is about 30% and up to 50–60%, respectively.3 Endometriosis is a painful, chronic disease affecting 5.5 million women and girls in the US and Canada4 and more than 70 million adult and adolescent females worldwide.5,6 The estimated prevalence of endometriosis is 10% among women of reproductive age4,7 making it more common than diabetes in this population.4,8 Despite significant improvement in recent years regarding our understanding of the disease, the pathogenesis of endometriosis is still unclear.9 Retrograde menstruation followed by implantation of viable endometrial cells into the peritoneum and the pelvic organs, seems to be a key step.9 However, retrograde menstruation is a universal phenomenon, occurring in at least 76–90% of women undergoing peritoneal dialysis and laparoscopy,9–11 but not all of them develop endometriosis, suggesting that other factors including the quantity and quality of endometrial cells in peritoneal fluid (PF), increased inflammatory

activity in PF, increased endometrial–peritoneal adhesion and angiogenesis, reduced immune surveillance and clearance of endometrial cells12 must be involved in determining susceptibility to the disease.9 The incidence of endometriosis appears to be increasing in industrialised countries, which is hypothesised to be related to chronic exposure to environmental pollutants, such as dioxins.9,13 There is increasing evidence to suggest that endometriosis is at least partially a genetic disease.14 Recent findings that support this association include evidence of familial clustering in humans and in rhesus monkeys, a founder effect detected in the Icelandic population, concordance in monozygotic twins, a similar age at onset of symptoms in affected non-twin sisters, a 6- to 9-times increased prevalence of endometriosis among first-degree relatives of women compared with the general population, and a 15% prevalence of magnetic resonance imaging (MRI) findings suggestive of endometriosis in the first-degree relatives of women with stage III–IV disease based on the classification of the American Society of Reproductive Medicine (ASRM).14,15 The induction of human-like endometriosis by genetic activation of an oncogenic K-ras allele lends further support to the genetic basis of this disorder.14,16 The diagnosis of endometriosis may be suspected based on pain symptoms. 1,9 However, frequently these symptoms are similar or identical to those of other gynaecological or gastrointestinal disorders.9 As yet, diagnostic approaches such as ultrasound, MRI or blood test have not been able to deliver satisfactory diagnostic power.1,9 Thus, laparoscopy is the standard technique for visual inspection of the pelvis and establishment of a definitive diagnosis.1,14 The appearance of endometriosis ranges from small peritoneal lesions to large ovarian endometriotic cysts (endometriomas) and extensive fibrosis and adhesions leading to significant distortion of pelvic anatomy.9 Peritoneal lesions mainly result in pain symptoms but are also associated with subfertility, whereas the more severe forms may cause pain, impair fertility and lead to pelvic organ dysfunction,

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often requiring extensive surgery.9 Disease severity is usually classified into four stages (I–IV or minimal– severe), using the revised American Fertility Society (rAFS) System,17,18 based on the observations acquired during laparoscopy.9 However, there is no correlation between the classification system and the type or severity of pain symptom, but a negative correlation has been reported between the degree of endometriosis and the occurrence of pregnancy following surgery.9,19

with subfertility.14,17 This effect has also been shown in primates, including cynomolgus monkeys and baboons.22,23 Although numerous mechanisms (ovulatory dysfunction, luteal insufficiency, luteinised unruptured follicle syndrome, recurrent abortion, altered immunity and intraperitoneal inflammation have been proposed,24 the association between fertility and minimal or mild endometriosis remains controversial.3,14,17

Infertility

Endometriosis and subfertility An association between endometriosis and subfertility is generally accepted, but most of the studies suggesting this link have been based on retrospective or cross-sectional analysis.19 It has been suggested that endometriosis may affect almost every step of reproduction.20 The Practice Committee of the ASRM have, in their review on endometriosis and infertility,21 summarised some possible biological mechanisms that may link endometriosis and infertility.20 (1) Distorted pelvic anatomy can impair oocyte release from the ovary and inhibit ovum pick-up or transport. (2) The peritoneal fluid alterations in women with endometriosis (increased volume of peritoneal fluid, increased concentration of activated macrophages and increased peritoneal fluid concentrations of prostaglandins, interleukin-1, tumour necrosis factor and proteases) may have adverse effects on the oocyte, sperm, embryo or Fallopian tube function. (3) Altered hormonal and cell-mediated function in the endometrium (increased IgG and IgA antibodies as well as lymphocytes) may alter endometrial receptivity and embryo implantation. (4) Endocrine and ovulatory abnormalities such as the luteinising unruptured follicle syndrome, luteal phase dysfunction, abnormal follicular growth and premature as well as multiple luteinising surges have been proposed to play a role in endometriosis related subfertility. (5) Impaired implantation, due to disorders of the endometrial function, has been observed in women with endometriosis: reduced endometrial expression of integrins during the time of implantation, as well as very low levels of an enzyme involved in the synthesis of the endometrial ligand for L-selectin (a protein that coats the trophoblast on the surface of the blastocyst). (6) None of these mechanisms, however, has actually been proven to decrease fecundity in women. When endometriosis is moderate or severe, involving the ovaries and causing adhesions that block tuboovarian motility and ovum pick-up, it is associated

There are many arguments to support the hypothesis that there is a causal relationship between the presence of endometriosis and subfertility. These arguments have been reviewed before19 and include: (1) An increased prevalence of endometriosis in subfertile women when compared with women of proven fertility; (2) An increased proportion of moderate to severe endometriosis in subfertile women with endometriosis when compared with women of proven fertility with endometriosis;25–30 (3) A reduced monthly fecundity rate in baboons with mild to severe (spontaneous or induced) endometriosis when compared with those with minimal endometriosis or a normal pelvis; (4) A trend towards a reduced monthly fecundity rate in infertile women with minimal to mild endometriosis when compared with women with unexplained infertility;24,36 (5) A dose-effect relationship demonstrated by a negative correlation between the r-AFS stage of endometriosis and the monthly fecundity rate and crude pregnancy rate; (6) A reduced monthly fecundity rate and cumulative pregnancy rate after donor sperm insemination in women with minimal–mild endometriosis when compared with those with a normal pelvis;31–34 (7) A reduced monthly fecundity rate after husband sperm insemination in women with minimal– mild endometriosis when compared with those with a normal pelvis; (8) A reduced implantation rate per embryo after in vitro fertilisation (IVF) in women with moderate to severe endometriosis when compared with women with a normal pelvis; (9) An increased monthly fecundity rate and cumulative pregnancy rate after surgical removal of minimal– mild endometriosis.

Spontaneous abortion A possible association between endometriosis and spontaneous abortion has been suggested in mostly uncontrolled or retrospective studies.14 Some controlled studies evaluating the association between endometriosis and spontaneous abortion have important

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methodological shortcomings: heterogeneity between cases and controls, analysis of the abortion rate before the diagnosis of endometriosis, and selection bias of study and control groups.14,37–39 Based on controlled prospective studies, there is no evidence that endometriosis is associated with (recurrent) pregnancy loss,40 or that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate.14,41,42

Surgical treatment and subfertility Advanced endometriosis and fertility after surgery The success of surgery in relieving infertility is probably related to the severity of endometriosis.14 In more advanced stages of endometriosis, anatomical disruption and adhesions may isolate the tube from the ovary, making it impossible for the oocyte to be picked up by the fimbriae, resulting in infertility.43 Thus, when endometriosis causes mechanical distortion of the pelvis, surgery should be performed to achieve reconstruction of normal pelvic anatomy.14 Laparoscopic cystectomy for ovarian endometriomas greater than 4 cm in diameter improves fertility compared with drainage and coagulation.14,44,45 Case series in women with surgically untreated moderate to severe endometriosis report a near zero pregnancy rate46 and a benefit with surgical restoration of the pelvic anatomy.43 Surgical treatment of moderate and severe endometriosis improves the monthly fecundity rate (reviewed).43 A retrospective multicentre analysis47 reported cumulative pregnancy rates of 39%, 31%, 30% and 25% in patients with endometriosis stages I, II, III and IV, respectively, 12 months after surgical treatment.14 Although there appeared to be a negative correlation between stage of endometriosis and fertility outcome, no significant difference was found between the four groups in this study.14 However, the study had many limitations, including retrospective design, lack of well-defined definition of male factor infertility as potential bias, multicentre data with significant interobserver variability, inclusion of only a limited number of patients with substantial adhesive disease, variable infertility treatment after 6 months of followup and absence of a control group.14 A somewhat higher cumulative intrauterine pregnancy rate has been reported in 30 women with deep uterosacral endometriosis after surgery: 48% after 12 months (47% for AFS stages I–II and 46% for AFS stages III–IV).48 A cumulative pregnancy rate of 24% was reported in patients 9 months after undergoing reoperation for stage III–IV endometriosis.14,49 Other investigators reported a negative correlation between stage of endometriosis and fertility after surgical treatment.14 In an older study, using an older classification system, a significant decrease in fecundability was seen in women with severe or extensive endometriosis compared with women with mild or

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moderate disease.14,50,51 In a more recent study,52 the negative correlation between the stage of endometriosis and the spontaneous cumulative pregnancy rate after surgical removal of endometriosis was statistically significant.14 Other studies have reported a significant negative correlation between endometriosis stage and pregnancy rate, with decreased pregnancy rates when the revised ASRM classification scores exceeded 70.14,53,54

Preoperative and postoperative medical treatment Preoperative medical treatment with danazol, gonadotrophin-releasing hormone (GnRH) agonists, or progestins may be useful to reduce the extent of endometriosis in patients with advanced disease.14 Postoperative medical treatment is rarely indicated because it does not work based on randomised trials; it prevents pregnancy, and the highest pregnancy rates occur during the first 6–12 months after conservative surgery.14,55,56 If pregnancy does not occur within 2 years of surgery, there is little chance of subsequent fertility.14,57

Endometriosis and fertility after surgery Surgical management of infertile women with minimal to mild endometriosis is controversial.14 The cumulative pregnancy rate after 5 years without therapy has been reported to be as high as 90% in women with minimal or mild endometriosis.14,58 This is comparable with the 93% rate reported in women who do not have endometriosis. Laparoscopic destruction of endometriosis has been reported to improve fertility in patients with minimal to mild disease,59–61 but not all investigators share this conclusion.14,62–64 It has been hypothesised that the monthly fecundity rate (MFR) is higher during the first 6–12 months after laparoscopic surgery than with expectant management.14,65,66 Two randomised controlled studies have evaluated the effect of surgical treatment of endometriosis on fertility parameters.14,41,42 One study41 reported that laparoscopic surgery enhanced fecundity in infertile women with minimal or mild endometriosis.14 They studied 341 infertile women, 20–39 years of age, with minimal or mild endometriosis. During diagnostic laparoscopy, the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only.14 They were followed for 36 weeks after the laparoscopy or, for those who became pregnant during that interval, for up to 20 weeks of pregnancy.14 The study subjects were recruited from among infertile women scheduled for diagnostic laparoscopy with strict eligibility criteria.14,41 The women in the study had no previous surgical treatment for endometriosis and no medical treatment for endometriosis in the previous 9 months and no other medical or surgical treatment for infertility in the previous 3 months.14 They had no history of pelvic inflammatory

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disease and no severe pelvic pain precluding expectant management.14 The diagnosis of endometriosis required the presence of one or more typical bluish or black lesions.14 The stage of endometriosis was determined according to the revised ASRM classification. During diagnostic laparoscopy, the women were randomly assigned to undergo resection or ablation of visible endometriosis or diagnostic laparoscopy only.14 Resection or ablation of minimal and mild endometriosis increased the likelihood of pregnancy in infertile women. In the treated group, 31% of the patients became pregnant, compared with 18% in the nontreated group (p=0.006).14,41 In a multicentre study in Italy,42 a similar study design was used to compare the effect of diagnostic laparoscopy with surgical resection and ablation of visible endometriosis (on fertility parameters) in infertile women with minimal to mild endometriosis.14 Eligible patients were women aged less than 36 years who were trying to conceive and had a laparoscopically confirmed diagnosis of minimal or mild endometriosis.14 None of the women had had therapy for endometriosis or infertility.14 Treatment was randomly allocated during laparoscopy. There was a follow-up period of 1 year after the laparoscopy.14 The results of this study did not show a beneficial effect of surgery regarding fertility. During the follow-up period after laparoscopy, no statistically significant differences in conception and live-birth rates were observed between the treated group (24% and 20%, respectively) and the control group (29% and 22%, respectively).14 Based on the aforementioned studies, and taking into account the larger patient population in the Canadian multicentre study, surgical treatment of minimal to mild endometriosis appears to offer a small but significant benefit with regard to fertility outcome.1,14,19,67 Furthermore, the surgical removal of peritoneal endometriosis may also be important to prevent progression of endometriosis.14 However, care is needed to prevent adhesion formation that could result as a consequence of over enthusiastic excision of minimal to mild endometriosis.14

intrauterine insemination (IUI), IVF and gamete intrafallopian transfer (GIFT) – may be an option for infertility treatment in addition to surgical reconstruction and expectant management.14 IVF is the method of choice when distortion of the tubo-ovarian anatomy contraindicates the use of superovulation with IUI or GIFT.14

Intrauterine insemination Endometriosis-associated infertility can be successfully treated with IUI, but only if it is done in combination with ovarian stimulation.14,68 The effectiveness of COH and IUI can be explained by the fact that ovulation is ensured and has become predictable or that more than one oocyte may be available for fertilisation.20 It is also possible that, in women with endometriosis, the direct ovarian stimulation effect may correct deficient granulosa cell function and improve oocyte maturation and embryo quality compared with non-stimulated cycles.19,20 A randomised study68 compared COH and IUI with no treatment during 311 cycles in 103 couples with minimal to mild endometriosis as the only infertility factor.14 In this study,68 a significantly higher live birth rate per cycle was reported in the treated group (11%) than in the control group (2%) (odds ratio (OR) 5.6, 95% confidence interval (CI) 1.8–17.4).14 However, there is clear evidence that the pregnancy rate in an insemination programme is lower in women with endometriosis than in women with unexplained infertility.14,69,70 A meta-analysis of 5214 cycles by stepwise logistic regression71 evaluated the effectiveness of ovulation induction and IUI in the treatment of persistent infertility.14 The odds ratio for pregnancy associated with endometriosis was 0.45 (95% CI 0.27–0.76) and for male factor was 0.48 (95% CI 0.37–0.61).14,71 However, recent data suggest that COH and IUI shortly after laparoscopic excision of endometriosis is as effective as COH and IUI in patients with unexplained subfertility.72

In vitro fertilisation

The treatment of endometriosis-related infertility Assisted reproduction and endometriosis Since many women with endometriosis are subfertile, they often become patients in a programme of assisted reproduction.20 The treatment of endometriosisrelated infertility is dependent on the age of the woman, the duration of infertility, the stage of endometriosis, the involvement of ovaries, tubes, or both in the endometriosis process, previous therapy, associated pain symptoms and the priorities of the patient, taking into account her attitude toward the disease, the cost of treatment, her financial means and the expected results.14 Assisted reproduction – including controlled ovarian hyperstimulation (COH) with

According to the European Society of Human Reproduction and Embryology (ESHRE) guidelines for the clinical management of endometriosis1 IVF is an appropriate treatment for subfertility in the endometriotic patient, especially when tubal function is compromised, there is also a male factor for infertility and/or other treatments have failed.20 The effect of endometriosis on IVF outcome is still unclear, as has been previously reviewed.14,43 Based on several retrospective studies,38,73 investigators have suggested that the pregnancy rate after IVF may be lower in women with endometriosis than in women without the disease.14 In earlier studies, this finding had been attributed to lower oocyte quality and decreased fertilisation rate in women with endometriosis.14 However, these findings were not confirmed in more recent studies that reported a

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normal fertilisation rate but a reduced implantation rate per embryo transferred in women obtaining oocytes from donors with endometriosis.14,74,75 This reduced implantation rate could be related to increased interleukin-6 levels in follicular fluid of women with endometriosis when compared with controls.14,76 A more recent case–control study77 in an IVF egg donation programme compared oocyte receptors in patients with endometriosis stage III or IV (cases) with oocyte receptors in patients without endometriosis (controls).14 Similar rates of implantation, miscarriage and pregnancy were observed in cases and controls, suggesting that there is no endometrial implantation problem in women with endometriosis stage III or IV treated with IVF.14,77 In another case–control study, the cumulative pregnancy rate and live-birth rates were comparable after five cycles of IVF in women with ovarian endometriosis and those with tubal infertility.14 The cumulative pregnancy rates were 63% and 63%, respectively, and the cumulative live-birth rates were 47% and 51%, respectively, but women with ovarian endometriosis had poorer responses and needed higher doses of gonadotrophin therapy.14,78 When endometriosis was assigned a stage, the pregnancy rate after IVF was decreased in patients with stage IV endometriosis but normal in women with less advanced disease.14,79–85 However, some studies have been unable to demonstrate a significant negative correlation between either the presence or stage of endometriosis and the pregnancy rate per cycle.14,86,87 The best evidence probably is provided by a recently published meta-analysis88 showing that IVF pregnancy rates are lower in patients with endometriosis than in those with tubal infertility, even when women with minimal to mild endometriosis were analysed separately.14 The use of danazol, gestrinone or GnRH agonists in women with endometriosis before IVF has been reported to improve the pregnancy rate by some85,89,90 but not all investigators.14,87 Prolonged treatment with a GnRH agonist before IVF in moderate to severe endometriosis can be considered and discussed with patients; although improved pregnancy rates have been reported,91,92 the long duration may limit the practical application of this treatment.14 Laparoscopic ovarian cystectomy is recommended if an ovarian endometrioma of 4 cm or more in diameter is present to confirm the diagnosis histologically.1,14 This procedure may rule out malignancy, reduce the risk of infection, improve access to follicles and possibly improve ovarian response.1,14 The woman should be counselled regarding the risks of reduced ovarian function after surgery.93

Intracytoplasmic sperm injection According to a large retrospective study of 980 intracytoplasmic sperm injection (ICSI) cycles90 the presence of endometriosis in patients undergoing ICSI

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because of severe male infertility did not affect fertilisation, pregnancy and implantation rates, although significantly fewer oocytes were retrieved from patients with endometriosis.20 Normal fertilisation, implantation and pregnancy rates also were reported in another recent study of ICSI.14,94 In conclusion, there is no evidence that the presence and extent of endometriosis affect implantation and clinical pregnancy rates in patients undergoing ICSI, but this evidence is derived from only two retrospective studies.20

Gamete intrafallopian transfer GIFT results in a higher monthly fecundity rate (25%) than with IVF (14%).14 This difference may be related to selection bias because less severe forms of endometriosis may have been more likely to be treated with GIFT, reserving IVF for more advanced stages of disease.14,66 In one study, the GIFT pregnancy rate in patients with a primary diagnosis of endometriosis (32.5%) was lower than in matched controls.14,95

Influence of reproduction techniques on the recurrence of endometriosis Endometriosis is considered to be an oestrogen related disease because it is rarely observed before menarche and usually disappears after menopause.96 It is well known that moderate to severe endometriosis can be a recurrent disease, both after cessation of medical suppressive treatment and after surgical treatment.96–98 Since in assisted reproductive techniques (ART) higher blood serum levels of oestrogen are reached than during a normal menstrual cycle, the assumption can be made that ART will augment the cumulative risk for recurrence of endometriosis after surgery.20 Some case reports suggest that ovarian hyperstimulation (OH) may lead to a higher recurrence rate of endometriosis.96 A rare coincidence of ureteral endometriosis and ovarian stimulation was described in a patient with a history of a surgically removed endometriotic cyst.96,99 Symptoms occurred 10 days after her first IVF attempt. Furthermore, four cases of severe digestive complications due to the rapid growth of sigmoid endometriosis were reported under OH with human menopausal gonadotrophin (hMG).96,100 In that study, all four patients underwent a laparoscopy when endometriosis of stage IV was found and treated before the onset of COH.96 D’Hooghe et al96evaluated the postoperative endometriosis recurrence rate after surgical treatment for moderate to severe endometriosis in patients who received OH for IUI or IVF. The results from this study showed that the cumulative endometriosis recurrence rate is lower after OH for IVF than after lower-dose ovarian stimulation for IUI, suggesting that temporary exposure to very high oestradiol levels in women during OH for IVF is not a major risk factor for endometriosis recurrence in

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women treated with ART.96 Although high rates of recurrence were measured in this study, no other studies are available measuring the recurrence rate after surgery for moderate to severe endometriosis in this patient group.20 Although there is a logical connection between oestrogen levels (and thus ART) and endometriosis, there clearly is a lack of research describing the risk of endometriosis recurrence after ART, and it is hard to counsel patients regarding this risk.20

Future directions in assisted reproduction research In conclusion, there is evidence that every fertility treatment is to some extent less effective in the endometriosis patient than in the patient with a normal pelvis or tubal factor, and some studies suggest that this correlation gets stronger as the stage of endometriosis progresses.20 The current evidence suggests that patients with endometriosis have a poorer ovarian response and need a higher dose of gonadotrophin therapy in IVF or ICSI programmes, but endometrial implantation is not reduced.14 It remains unclear whether the presence or degree of endometriosis is associated with impaired oocyte quality, fertilisation rate and implantation rate.14 Future studies evaluating the association between endometriosis and reproductive outcome after assisted reproduction should be prospective and should include the following components: 14,39 (1) Accurate and recent laparoscopic description of the stage of endometriosis; (2) Date, number of procedures and interval between surgical procedures; (3) Ultrasonographic evidence of endometriosis, confirmed by cytology or histology when endometriotic cysts are aspirated during oocyte aspiration; (4) Effectiveness of interim suppressive therapy between diagnosis and treatment with assisted reproduction; (5) Reliability and date of negative diagnosis; (6) Clear definition of implantation rate, pregnancy rate, abortion rate and live-birth rate per started cycle, per oocyte aspiration and per embryo transfer.

References 1. Kennedy S, Bergqvist A, Chapron C et al on behalf of the ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod 2005; 20: 2698–704. 2. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update 2007; 13: 395–404. 3. D’Hooghe TM, Debrock S, Meuleman C et al. Future directions in endometriosis research. Obstet Gynecol Clin North Am 2003; 30: 221–44.

4. Mirkin D, Murphy-Barron C, Iwasaki K. Actuarial Analysis of Private Payer Administrative Claims Data for Women With Endometriosis. J Manag Care Pharm 2007; 13: 262–72. 5. Endometriosis Research Center. Understanding endometriosis: past, present and future. The National Women’s Health Information Council 2005 Available from: http:/www.4woman.gov/ HealthPro/healtharticle/march.htm. 6. Gao X, Outley JK, Botteman M et al. The economic burden of endometriosis. Fertil Steril 2006; 86: 1561–72. 7. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am 1997; 24: 235–58. 8. Misra D. Women’s Health Data Book: A Profile of Women’s Health in the United States, 3rd edn. Washington, DC: Jacob’s Institute of Women’s Health and the Henry J Kaiser Family Foundation, 2001. 9. Mihalyi A, Simsa P, Kyama C et al. Emerging drugs in endometriosis. Expert Opin Emerg Drugs 2006; 11: 503–24. 10. Blumenkrantz MJ, Gallagher N, Bashore RA, Tenckhoff H. Retrograde menstruation in women undergoing chronic peritoneal-dialysis. Obstet Gynecol 1981; 57: 667–70. 11. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 1984; 64: 151–4. 12. Kyama CM, Debrock S, Mwenda JM, D’Hooghe TM. Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol 2003; 1: 123–32. 13. Heilier JF, Nackers F, Verougstraete V et al. Increased dioxin-like compounds in the serum of women with peritoneal endometriosis and deep endometriotic (adenomyotic) nodules. Fertil Steril 2005; 84: 305–12. 14. D’Hooghe TM, Hill JA. Endometriosis. In: Bereck JS (ed) Novak’s Gynecology, 13th edn. Philadelphia, USA: Williams and Wilkins, 2006: 1137–85. 15. Kennedy SH. Genetics of endometriosis. In: Tulandi T, Redwine D, eds. Endometriosis: Advances and Controversies. New York, NY: Marcel Dekker Publishing, 2004: 55–68. 16. Dinulescu DM, Ince TA, Quade BJ et al. Role of K-ras and Pten in the development of mouse models of endometriosis and endometrioid ovarian cancer. Nat Med 2005; 11: 63–70. 17. Revised American Fertility Society classification of endometriosis. Fertil Steril 1985; 43: 351–2. 18. Revised American Fertility Society classification of endometriosis. Fertil Steril 1997; 67: 817–21. 19. D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: Is the relationship resolved? Semin Reprod Med 2003; 21: 243–54. 20. De Hondt A, Peeraer K, Meuleman C et al. Endometriosis and subfertility treatment: a review. Minerva Ginecol 2005; 57: 257–67. 21. The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and Fertility. Fertil Steril 2004; 81: 1441–6. 22. Schenken RS, Asch RH, Williams RF, Hodgen GD. Etiology of infertility in monkeys with endometriosis – luteinized unruptured follicles, luteal phase defects,

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pelvic adhesions, and spontaneous-abortions. Fertil Steril 1984; 41: 122–30. D’Hooghe TM, Bambra CS, Raeymaekers BM et al. A prospective controlled study over 2 years shows a normal monthly fertility rate (MFR) in baboons with stage I endometriosis and a decreased MFR in primates with stage II–IV disease. Fertil Steril 1994; 5 (Suppl): 1–113. Haney AF. Endometriosis-associated infertility. Baillieres Clin Obstet Gynaecol 1993; 7: 791–812. Liu DTY, Hitchcock A, Endometriosis – its association with retrograde menstruation, dysmenorrhea and tubal pathology. BJOG 1986; 93: 856–62. Moen MH. Endometriosis in women at interval sterilization. Acta Obstet Gynecol Scand 1987; 66: 451–4. Kirshon B, Poindexter AN, Fast J. Endometriosis in multiparous women. J Reprod Med 1989: 215–17. Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Hum Reprod 1991; 6: 544–9. Moen MH, Muus KM. Endometriosis in pregnant and non-pregnant women at tubal sterilization. Hum Reprod 1991; 6: 699–702. Waller KG, Lindsay P, Curtis P et al. The prevalence of endometriosis in women with infertile partners. Eur J Obstet Gynecol Reprod Biol 1993; 48: 135–9. Jansen RPS. Minimal endometriosis and reduced fecundability: prospective evidence from an artificial insemination by donor program. Fertil Steril 1986; 46: 141–3. Hammond MG, Jordan S, Sloan CS. Factors affecting pregnancy rates in a donor insemination program using frozen semen. Am J Obstet Gynecol 1986; 155: 480–5. Portuondo JA, Echanojauregui AD, Herran C, Alijarte I. Early conception in patients with untreated mild endometriosis. Fertil Steril 1983; 39: 22–5. Rodriguez-Escudero FJ, Negro JL, Corcosstegui B et al. Does minimal endometriosis reduce fecundity? Fertil Steril 1988; 50: 522–4. D’Hooghe TM, Bambra CS, Koninckx PR. Cycle fecundity in baboons of proven fertility with minimal endometriosis. Gynecol Obstet Invest 1994; 37: 63–5. Berube S, Marcoux S, Langevin M, Maheux R. Fecundity of infertile women with minimal or mild endometriosis and women with unexplained infertility. Fertil Steril 1998; 69: 1034–41. Metzger DA, Olive DL, Stohs GF et al. Association of endometriosis and spontaneous abortion: effect of control group selection. Fertil Steril 1986; 45: 18–22. D’Hooghe TM, Hill JA. Immunobiology of endometriosis. In: Bronson RA, Alexander NJ, Anderson DJ et al eds. Immunology of Reproduction. (Blackwell Science), 1996: 322–58. Vercammen E, D’Hooghe TM, Hill JA. Endometriosis and recurrent miscarriage. Semin Reprod Med 2000; 18: 363–8. Matorras R, Rodriguez F, Gutierrez de Teran G et al. Endometriosis and spontaneous abortion rate: a cohort study in infertile women. Eur J Obstet Gynecol Reprod Biol 1998; 77: 101–5.

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41. Marcoux S, Maheux R, Bérubé S and the Canadian Collaborative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med 1997; 337: 217–22. 42. Gruppo Italiano per lo Studio dell’ Endometriosi. Ablation of lesions or no treatment in minimalmild endometriosis in infertile women: a randomized trial. Hum Reprod 1999; 14: 1332–4. 43. Allaire C. Endometriosis and infertility: a review. J Reprod Med 2006; 51: 164–8. 44. Beretta P, Franchi M, Ghezzi F et al. Randomized clinical trial of two laparoscopic treatments of endometriomas: cystectomy versus drainage and coagulation. Fertil Steril 1998; 70: 1176–80. 45. Chapron C, Vercellini P, Barakat H et al. Management of ovarian endometriomas. Hum Reprod Update 2002; 8: 6–7. 46. Olive DL, Stohs GF, Metzger DA, Franklin RR. Expectant management and hydrotubations in the treatment of endometriosis-associated infertility. Fertil Steril 1985; 44: 35–40. 47. Guzick DS, Canis M, Silliman NP et al. Prediction of pregnancy in infertile women based on the ASRM’s revised classification for endometriosis. Fertil Steril 1997; 67: 822–36. 48. Chapron C, Fritel X, Dubuisson JB. Fertility after laparoscopic management of deep endometriosis infiltrating the uterosacral ligaments. Hum Reprod 1999; 14: 329–32. 49. Pagidas K, Falcone T, Hemmings R et al. Comparison of reoperation for moderate (stage III) and severe (stage IV) endometriosis-related infertility. Fertil Steril 1996; 65: 791–5. 50. Rock JA, Guzick DS, Dengos C et al. The conservative surgical treatment of endometriosis: evaluation of pregnancy success with respect to the extent of disease as categorized using contemporary classification systems. Fertil Steril 1981; 35: 131–7. 51. American Fertility Society. Classification of endometriosis. Fertil Steril 1979; 32: 633–4. 52. Osuga Y, Koga K, Tsutsumi O et al. Role of laparoscopy in the treatment of endometriosisassociated infertility. Gynecol Obstet Invest 2002; 53: 33–9. 53. Adamson GD, Hurd SJ, Pasta DJ et al. Laparoscopic endometriosis treatment: is it better? Fertil Steril 1993; 59: 35–44. 54. Canis M, Pouly JL, Wattiez A et al. Incidence of bilateral adnexal disease in severe endometriosis (revised American Fertility Society [AFS] stage IV): should a stage V be included in the AFS classification? Fertil Steril 1992; 57: 691–2. 55. Vercellini P, Crosignani PG, Fadini R et al. A gonadotropin-releasing hormone agonist compared with expectant management after conservative surgery for symptomatic endometriosis. BJOG 1999; 106: 672–7. 56. Parazzini F, Fedele L, Busacca M et al. Postsurgical treatment of advanced endometriosis: results of a randomized clinical trial. Am J Obstet Gynecol 1994; 171: 1205–7. 57. Olive DL, Lee KL. Analysis of sequential treatment protocols for endometriosis-associated infertility. Am J Obstet Gynecol 1986; 154: 613–19.

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58. Badawy SZA, El Bakry MM, Samuel D et al. Cumulative pregnancy rates in infertile women with endometriosis. J Reprod Med 1988; 33: 757–60. 59. Nowroozi K, Chase JS, Check JH et al. The importance of laparoscopic coagulation of mild endometriosis in infertile women. Int J Fertil 1987; 32: 442–4. 60. Paulson JD, Asmar P, Saffan DS. Mild and moderate endometriosis: comparison of treatment modalities for infertile couples. J Reprod Med 1991; 36: 151–5. 61. Tulandi T, Mouchawar M. Treatment-dependent and treatment-independent pregnancy in women with minimal and mild endometriosis. Fertil Steril 1991; 56: 790–1. 62. Schenken RS, Malinak LR. Conservative versus expectant management for the infertile patient with mild endometriosis. Fertil Steril 1982; 37: 183–6. 63. Arumugam K, Urquhart R. Efficacy of laparoscopic electrocoagulation in infertile patients with minimal or mild endometriosis. Acta Obstet Gynecol Scand 1991; 70: 125–7. 64. Adamson S, Edwin SS, LaMarche S et al. Actions of interleukin-4 on prostaglandin biosynthesis at the chorion-decidual interface. Am J Obstet Gynecol 1993; 169: 1442–7. 65. Olive DL, Martin DC. Treatment of endometriosisassociated infertility with CO2 laser laparoscopy: the use of one- and two-parameter exponential models. Fertil Steril 1987; 48: 18–23. 66. Rosen GF. Treatment of endometriosis-associated infertility. Infert Reprod Med Clin North Am 1992; 3: 721–30. 67. Jacobson TZ, Barlow DH, Koninckx PR et al. Laparoscopic surgery for subfertility associated with endometriosis (Cochrane Review). In: The Cochrane Library, Issue 3. Chichester, UK: John Wiley & Sons, 2004. 68. Tummon IS, Asher LS, Martin JRB et al. Randomized controlled trial of superovulation and insemination for infertility associated with minimal or mild endometriosis. Fertil Steril 1997; 68: 8–12. 69. Nuojua HS, Tomas C, Bloigu R et al. Intrauterine insemination treatment in subfertility: an analysis of factors affecting outcome. Hum Reprod 1999; 14: 698–703. 70. Omland AK, Tanbo T, Dale PO et al. Artificial insemination by husband in unexplained infertility compared with infertility associated with peritoneal endometriosis. Hum Reprod 1998; 13: 2602–5. 71. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod 1997; 12: 1865–72. 72. Werbrouck E, Spiessens C, Meuleman C, D’Hooghe TM. No difference in cycle pregnancy rate and in cumulative live birth rate between women with surgically treated minimal – mild endometriosis and women with unexplained infertility after controlled ovarian hyperstimulation (COH) and intrauterine insemination (IUI). Fertil Steril 2006; 86: 566–71.

73. Cahill DJ, Hull MGR. Pituitary-ovarian dysfunction and endometriosis. Hum Reprod Update 2000; 6: 56–66. 74. Simon C, Guttierez A, Vidal A et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod 1994; 9: 725–9. 75. Arici A, Oral E, Bukulmez O et al. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertil Steril 1996; 65: 603–7. 76. Pellicer A, Valbuena D, Bauset C et al. The follicular endocrine environment in stimulated cycles of women with endometriosis: steroid levels and embryo quality. Fertil Steril 1998; 69: 1135–41. 77. Diaz I, Navarro J, Blasco L et al. Impact of stage III– IV endometriosis on recipients of sibling oocytes: matched case-control study. Fertil Steril 2000; 74: 31–4. 78. Al Azemi M, Lopez BA, Steele J et al. Ovarian response to repeated controlled stimulation in IVF cycles in patients with ovarian endometriosis. Hum Reprod 2000; 15: 72–5. 79. Chillik CF, Acosta AA, Garcia JE et al. The role of in vitro fertilization in infertile patients with endometriosis. Fertil Steril 1985; 44: 56–9. 80. Matson PL, Yovich JL. The treatment of infertility associated with endometriosis by in vitro fertilization. Fertil Steril 1986; 46: 432–4. 81. Molloy D, Martin M, Speirs A et al. Performance of patients with a “frozen pelvis” in an in vitro fertilization program. Fertil Steril 1987; 47: 450–5. 82. Yovich JL, Matson PL, Richardson PA et al. Hormone profiles and embryo quality in women with severe endometriosis treated by in vitro fertilization and embryo transfer. Fertil Steril 1988; 50: 249–56. 83. Oehninger S, Acosta AA, Kreiner D et al. In vitro fertilization and embryo transfer (IVF/ET): an established and successful therapy for endometriosis. J In Vitro Fertil Embryo Transf 1988; 5: 248–56. 84. Redwine DB. Conservative laparoscopic excision of endometriosis by sharp dissection: life table analysis of reoperation and persistent of recurrent disease. Fertil Steril 1991; 56: 628–34. 85. Dicker D, Goldman JA, Levy T et al. The impact of long-term gonadotrophin-releasing hormone analogue treatment on preclinical abortions in patients with severe endometriosis undergoing in vitro fertilization- embryo transfer. Fertil Steril 1992; 57: 597–600. 86. Inoue M, Kobayashi Y, Honda I et al. The impact of endometriosis on the reproductive outcome of infertile patients. Am J Obstet Gynecol 1992; 167: 278–82. 87. Tummon IS, Colwell KA, Mackinnon CJ et al. Abbreviated endometriosis-associated infertility correlates with in vitro fertilization success. J In Vitro Fertil Embryo Transf 1991; 8: 149–53. 88. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77: 1148–55. 89. Wardle PG, Foster PA, Mitchell JD et al. Endometriosis and IVF: effect of prior therapy. Lancet 1986: 276–7.

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The patient with endometriosis 90. Minguez Y, Rubio C, Bernal A et al. The impact of endometriosis in couples undergoing intracytoplasmic sperm injection. Hum Reprod 1997; 12: 2282–5. 91. Rickes D, Nickel I, Kropf S et al. Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis. Fertil Steril 2002; 78: 757–62. 92. Surrey ES, Silverberg KM, Surrey MW et al. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization-embryo transfer in patients with endometriosis. Fertil Steril 2002; 78: 699–704. 93. Geber S, Ferreira DP, Spyer-Prates LF et al. Effects of previous ovarian surgery for endometriosis on the outcome of assisted reproduction treatment. Reprod Biomed Online 2002; 5: 2–6. 94. Bukulmez O,Yarali H, Gurgan T. The presence and extent of endometriosis do not effect clinical pregnancy rate and implantation rates in patients undergoing ICSI. Eur J Obstet Gynecol Reprod Biol 2001; 96: 102–7.

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95. Guzick DS, Yao YAS, Berga SL et al. Endometriosis impairs the efficacy of gamete intrafallopian transfer: results of a case-control study. Fertil Steril 1994; 62: 1186–91. 96. D’Hooghe TM, Denys B, Spiessens C, Meuleman C, Debrock S. Is the endometriosis recurrence rate increased after ovarian hyperstimulation? Fertil Steril 2006a; 86: 283–90. 97. Punnonen R, Klemi P, Nikkanen V. Recurrent Endometriosis. Gynecol Obstet Invest 1980; 11: 307–12. 98. Wheeler JM, Malinak LR. Recurrent endometriosis – incidence, management, and prognosis. Am J Obstet Gynecol 1983; 146: 247–53. 99. Renier M, Verheyden B, Termote L. An unusual coincidence of endometriosis and ovarian hyperstimulation. Eur J Obstet Gynecol Reprod Biol 1995; 63: 187–9. 100. Anaf V, El Nakadi I, Simod P et al. Sigmoid endometriosis and ovarian stimulation. Hum Reprod 2000; 15: 790–4.

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22 The patient with poor sperm quality Bernard J Cohlen, Herman Tournaye

Defining poor sperm quality Male fertility is defined as the ability of men to produce and deliver by normal intercourse spermatozoa that can cause conception in the partner at the normal rate of 20% per month. In couples not achieving pregnancy within 1 year, poor sperm quality is often found (up to 50% of cases). But how is sperm quality defined and tested? And is this poor sperm quality related to the decreased probability of conception? The latest WHO Manual for Standardized Investigation and Diagnosis of the Infertile Couple1 defines normal sperm quality as follows: • • • •

seminal plasma volume ≥2 ml sperm concentration ≥20.0 million/ml sperm motility grade A + B ≥50% normal sperm morphology ≥30% (Kruger criteria ≥14%).

However, these criteria will be changed in the near future. Unfortunately these criteria are not evidence based and poorly correlated to the probability of conception. There are three main reasons for this. First, conceiving is a matter of fecundity of both the man and woman and one should therefore be extremely cautious in categorising the man as the single cause for the subfertility of the couple without examining the woman. Second, sperm quality changes dramatically over time (biological variability). Even in proven fertile men, sperm parameters vary largely within and between individuals.2 Third, the quality of the test performed (a semen analysis), even in a standardised setting, is low. The inter- and intraobserver variation of performing semen analysis is large, although standardisation (with internal and external quality control and assessment) between laboratories might improve the accuracy. When a semen sample is normal according to the WHO criteria a second test is not necessary. In case of abnormal results the test should be repeated after 2–3 months. When two samples are abnormal further investigation of the man is mandatory. Currently sperm function tests (e.g. zona binding test, acrosome reaction) do not add to the accuracy of

predicting the fertilising potential of sperm. Whether or not sperm proteomics are a useful tool in predicting the fertilising capacity of sperm needs to be proven in the near future.

Investigating the man The WHO has produced a monograph on the standardised investigation and treatment of male infertility.1 These authority-based guidelines recommend physically examining the male partner in every couple unable to conceive within 1 year of unprotected intercourse. However, routinely examining all male partners in subfertile couples will not alter their fertility outcome and has no prognostic value according to a study conducted in men who did not suffer from azoospermia, sexual or ejaculatory dysfunction (level of evidence (LOE) III).3 In another study from a male infertility referral centre, 13 out of 1236 men (1.1%) presented a significant medical pathology, mainly testicular tumours (n=6).4 Only one of these 13 patients had normal semen parameters. History-taking and physical examination revealed a medical problem in four men (31%) and eight men (61%), respectively. These two studies show that, rather than evaluating all male partners of subfertile couples as proposed by the WHO, patients who need further investigation can be selected on the basis of their semen analysis. It is thus sensible to start evaluating the male partner by examining his semen. Whenever abnormal values are encountered, further investigation is indicated including a comprehensive history and physical examination. Whether every patient with abnormal semen parameters needs a scrotal ultrasonography as suggested by the WHO is another area of debate. One study evaluated the role of a routine scrotal ultrasonography in men with abnormal semen parameters5 and reported abnormalities in 38% of 1372 men, 67% of which were not detected by physical examination (LOE III). Thus, scrotal ultrasonography was helpful in diagnosing additional pathology in 25% of men. But would a scrotal ultrasonography eventually change the treatment of these patients? Ultrasonographic examination detected a varicocele in 28%, an epidydimal cyst in 7% and a hydrocele in 3%. In 1% microlithiasis was present, and in 1.2% testicular cysts or tumours were observed.

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Given the lack of evidence that varicocele correction may benefit a patient’s fecundity (LOE I),6 and given that any impact of hydroceles and epidydimal cysts on a man’s fecundity remains to be proven, routine ultrasonographic scrotal evaluation does not seem to be useful for the majority of oligozoospermic subfertile men. Yet, the detection of microlithiasis and testicular tumours is significant7 and, thus, it would be interesting to evaluate whether ultrasonographic scrotal evaluation in a selected subpopulation of subfertile men, e.g. with a history of cryptorchidism, may be a more cost-beneficial alternative than routine ultrasonographic scrotal screening. Although evidence in the literature is scarce, a systematic evaluation of every man in any couple with unresolved subfertility seems not to be indicated. Thorough history-taking and physical examination must, however, be performed in every man with abnormal semen parameters. Additional tests can be indicated in selected patients.

Treating poor sperm quality Good medical practice implies that once the causative factor for a condition or inability has been identified, an efficient, safe and specific treatment should be applied. For the treatment of male subfertility, however, the causative factor remains unknown in 40% of men presenting with a “male factor” and, apart from this 40%, in another 50% no specific treatment with a proven efficiency is available. Few subfertile men can benefit from an evidence-based treatment.8,9 Empirical treatments have been very popular. However, there is now a broad consensus that most of these treatments have no proven benefit for treating male subfertility (for review see reference 10). The use of once popular drugs such as androgens, gonadotrophins, bromocriptine, kinin enhancers and corticoids is not recommended. Although more clinical evidence is needed, the administration of tamoxifen alone or in combination with androgens appears promising (LOE I).11 When specific evidence-based treatments have failed or were not indicated, improving the female partner’s fertility status is the first-line approach to improve a couple’s fecundity. This implies adequate work-up of “the female factor”. Because, in prognostic models the predictive power of “female factors” outweighs the “male factor” as long as more than 2 million sperm/ml are available,12 any attempt should be made to correct or improve the woman’s fecundity. When this first-line approach is unsuccessful, assisted reproductive techniques (ART) are the next treatment option.

Dealing with poor sperm quality In most cases of male subfertility no cause is found and idiopathic oligoasthenoteratozoospermia (OAT) is diagnosed. In extreme cases of OAT an increased incidence of obstruction and genetic abnormalities

can be found. When causal treatment is absent one has to deal with the (low) number of motile sperm available and treatment is empiric. The following options are available: • intrauterine insemination (IUI) • in vitro fertilisation (IVF) • intracytoplasmic sperm injection (ICSI) and in extreme cases of (obstructive or non-obstructive) azoospermia: • percutaneous epididymal sperm aspiration (PESA) or micro epididymal sperm aspiration (MESA) followed by ICSI • testicular sperm aspiration (TESE) followed by ICSI. To distinguish between these various treatment options it is advised to perform a semen analysis twice within 2–3 months and to perform a trial of semen preparation to obtain an impression of the number of motile sperm available for treatment.

Intrauterine insemination IUI is a simple technique that improves the number of motile sperm with normal forms at the site of fertilisation. Semen preparation and timing of the insemination are crucial.13 However, other confounders such as the age of the woman, duration of subfertility, total motile sperm count of the inseminate, etc. influence treatment outcome as well, thus making it difficult to predict success or failure before hand.14 It is therefore crucial that each individual centre collects its data prospectively and analyses these data regularly to determine its own threshold levels and adjust the protocols accordingly. Fig 22.1 shows the four comparisons to be made in randomised trials to prove/disprove the efficacy of IUI with or without mild ovarian hyperstimulation (MOH). Following evidence-based guidelines the following statements can be made: (1) At least 1–2 million motile sperm are mandatory after semen preparation to obtain reasonable chances of conception with IUI in case of a male factor. However, optimal threshold levels might differ largely between centres and might even be somewhat higher (LOE I).15 (2) Evidence based upon older randomised trials shows a significant increase in pregnancy rates per natural cycle when IUI is compared with timed intercourse in case of a semen defect (six trials, common odds ratio (OR) with 95% confidence interval CI 3.1, 1.5–6.3) (LOE I).16 However, with modern Cochrane inclusion criteria (being much more strict) and expressing results as live birth rates per couple, no high quality randomised trials could be included.17 Therefore the question remains whether IUI in natural cycles improves the probability of a live birth in cases of male subfertility (LOE I).

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Intercourse in natural cycle

IUI in natural cycle

Intercourse in stimulated cycle

IUI in stimulated cycle

(6)

Fig 22.1 Four comparisons to be performed in randomised trials to (dis-)prove the efficacy of intrauterine insemination (IUI) with or without mild ovarian hyperstimulation.

(7)

(3) In case of a moderate semen defect with on average less than 10 million motile sperm in the fresh ejaculate, IUI in the natural cycle is advised (LOE I).18 In these couples, MOH does not increase the probability of conception significantly (four trials; OR with 95% CI 1.5, 0.9–2.4) (LOE I).17 (4) In natural cycles the insemination can be timed with either detection of the onset of the luteinising hormone (LH) surge (and inseminated 24 hours later) or with the administration of 5000 IU human chorionic gonadotrophin (hCG) when the dominant follicle(s) reaches a mean diameter of 16–18 mm and inseminated 38–42 h later. Neither of these two techniques has been proven superior (LOE I).19 (5) In case of a mild semen defect almost resembling unexplained subfertility MOH might further increase the probability of conception expressed as pregnancy rate per cycle (LOE I).18 There are, however, insufficient data to conclude that the addition of MOH increases the probability of a

Study

Balasch 1994 Dankert 2005 Ecochard 2000 Kamel 1995 Karlstrom 1993 Karstrom 1998 Matorras 2002 Total

Gonadotrophins n/n 12/50 17/67 3/29 4/28 3/15 8/40 30/49 77/278

(8) (9)

(10)

Anti-oestrogens n/n

live birth in the case of a mild semen defect (LOE I) (two trials; OR with 95% CI 0.87, 0.28–2.7).17 In cycles with MOH the insemination is often timed using hCG administration when the dominant follicle(s) reaches a mean diameter of 16– 18 mm and inseminated 38–42 h later. However, in over 30% of the stimulated cycles spontaneous LH surges occur, influencing the probability of conception negatively (LOE I).20 Whether gonadotrophin releasing hormone (GnRH) antagonists should be applied to suppress these LH surges needs to be determined in a large randomised cost-effectiveness trial. There is, however, no role for GnRH agonists in IUI programmes (LOE I).21 When MOH is applied gonadotrophins should be the drug of first choice being more effective compared with clomiphene citrate (four trials; common OR with 95% CI 2.2, 1.2–3.9) (Fig 22.2), while the probability of achieving a multiple pregnancy does not differ significantly between both drugs (LOE I).21 Aggressive stimulation protocols result in unacceptable high multiple pregnancy rates. It is therefore advised to apply a low-dose step-up protocol starting with 50–75 IU FSH per day and to strive for a maximum of two to three follicles >15 mm.22 Most pregnancies achieved with IUI occur during the first three to four treatment cycles (LOE III).23 Compared with IVF and/or ICSI, IUI is a costeffective treatment option and should therefore be offered before more invasive and expensive treatment options are applied (LOE I).24,25 Recently it has been shown that a second insemination per cycle might increase the probability of conception, especially in case of a semen defect (six trials, common OR with 95% CI 1.8, 1.4–2.4) (Fig 22.3) (LOE I).26 This conclusion, however, is largely based upon one large randomised controlled trial with very high pregnancy rates per

OR (95% CI fixed)

Weight OR (95% CI fixed)

%

4/50 19/71 19/71 6/29 2/26 1/17 4/34 16/51 52/278

8.9 40.2 15.7 5.2 2.2 10.1 17.7

3.6 (1.1–12) 0.9 (0.4–2.0) 0.4 (0.1–2.0) 2.0 (0.3–12) 4.0 (0.3–43) 1.9 (0.5–6.9) 3.4 (1.5–7.9)

100.0

1.8 (1.2–2.7)

Test for heterogeneity χ2 = 10.4 df = 6 p = 0.11 Test for overall effect z = 2.7 p = 0.007

0.1

0.2

Favours anti-oestrogens

Fig 22.2

235

1

5

10

Favours gonadotrophins

Anti-oestrogens versus gonadotrophins combined with intrauterine insemination outcome: pregnancy rate per couple.

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Double IUI n/n

Single IUI n/n

OR (95% CI fixed)

Weight OR (95% CI random)

%

Ragni 1999 12–34 hour 28/92 Ragni 1999 34–60 hour 10/91 Zeyneloglu 2002 4/40 Ng 2003 11/30 Casadei 2006 9/39 Liu 2006 124/634 124/634

6/45 7/45 4/42 11/30 5/43 70/633

6.7 10.0 4.2 8.3 4.4 66.5

Total (95%CI)

103/838

100.0

186/916

2.8 (1.1–7.5) 0.67 (0.24–1.9) 1.1 (0.25–4.5) 1.0 (0.35–2.9) 2.3 (0.69–7.5) 2.0 (1.5–2.7) 1.8 (1.4–2.4)

Test for heterogeneity χ2 = 6.6 df = 5 p = 0.25 Test for overall effect z = 4.4 p<0.001

0.1

0.2

Favours single IUI

Fig 22.3

1

5

10

Favours double IUI

One intrauterine insemination (IUI) versus double IUI in stimulated cycles. Outcome: pregnancy rate per couple.

cycle even in case of a male factor. Therefore, these results should be carefully interpreted. (11) There is no evidence that one semen preparation technique is superior to another (LOE I).27 Gradient techniques yield the highest recovery rates.

In vitro fertilisation Originally IVF was developed as a treatment of infertility for couples in whom the woman had bilateral tubal occlusion. During laparoscopy in a natural cycle the dominant follicle was aspirated and fertilisation of this single oocyte was performed in the laboratory. It was not until 1982 that Fishel and Edwards reported for the first time the use of IVF for male subfertility (for review see reference 28). Increasing the number of available oocytes using ovarian hyperstimulation increased the chances for fertilisation in the laboratory even when a male factor was present. Unfortunately IVF was introduced as a treatment option for male subfertility without proper large randomised controlled trials comparing it with no treatment or more conventional treatment options. To date, there has been no convincing evidence regarding the cost-effectiveness of IVF for male subfertility. Small randomised controlled trials indicated that IVF should not be started too soon in cases of unexplained or male subfertility as it does not increase the probability of conception compared with waiting or conventional treatment, while being much more expensive (LOE I).25,29,30 It was not until 2000 that Goverde et al showed IVF to be less cost-effective compared with IUI with or without MOH in both couples with unexplained and those with male subfertility (LOE I).24 It is therefore advised that in these couples IUI should precede IVF treatment. Thus, it can be concluded that, in couples with moderate male subfertility with at least 1–2 million motile sperm after semen preparation, IUI (with or without MOH) should precede IVF therapy (LOE I). It is more difficult to determine an optimal threshold level of motile sperm after semen preparation below

which IVF should not be applied. Most clinics use 1 million motile sperm as the cut-off level but this is not based upon proper randomised trials. In general, IVF is advised when the total motile sperm concentration exceeds 1 million after semen preparation, below this level ICSI is advised. When IVF for male subfertility results in a total fertilisation failure of all oocytes, ICSI is advised. Some centres use ICSI as primary treatment option even when semen quality is only moderately to mildly impaired, but an advantage over IVF has never been proven in these cases (LOE I).31 In couples with male subfertility the woman might in most cases be fertile. One should be cautious in these healthy women as serious complications like (high order) multiple pregnancies and ovarian hyperstimulation syndrome (OHSS) can be obtained. Following evidence-based guidelines the following statements can be made regarding prevention of complications: (1) There is insufficient evidence to recommend a favourable starting dose of gonadotrophins in IVF (LEO I). Nevertheless, more and more evidence has been collected to support mild IVF stimulation protocols using GnRH antagonists and 150 IU gonadotrophins starting dose (LOE I).32 Future research comparing long GnRH agonist protocols with antagonist protocols should focus on cumulative live birth rates including cryopreserved embryo transfers, time-to-pregnancy, side-effects and costs. (2) It is generally accepted that the number of embryos to be transferred should be reduced to prevent multiple pregnancies. In favourable groups single embryo transfer should be the option of first choice (LOE I).33

Intracytoplasmic sperm injection With ICSI only one sperm is needed per oocyte and injected into the cytoplasma of the oocyte. After several years of studying this technique in animals,34,35 it

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was in 1992 that the first child born after ICSI was reported.36 Suddenly it was possible to obtain a pregnancy in couples with severe male factor or even azoospermia by aspirating or retracting sperm from the epididymis or testicles (see below). Nowadays ICSI is applied in couples with: • • • •

severe male factor (in general a total motile sperm count after semen preparation below 1 million) total fertilisation failure with IVF cryopreservation of sperm of men with cancer (treatment) (non-)obstructive azoospermia where sperm can be found in epididymis or testicles.

Again there is a lack of large randomised trials with live birth rates as outcome. Older trials randomised oocytes to either regular IVF or ICSI in couples with moderate male subfertility. ICSI resulted in a significantly higher chance of fertilising the oocyte (OR with 95% CI 4.2, 2.8–6.4) (LOE I).37 Chances of obtaining total fertilisation failure were six times lower with ICSI compared with IVF (LOE I). Although it can be concluded that ICSI is a significant new technique giving opportunities to couples without perspectives before the era of ICSI, there is still a need for proper randomised trials to establish its place in modern fertility treatment. Furthermore, its safety in respect to congenital malformations and neonatal outcome of the newborns needs a longer period of follow-up. To date results of follow-up studies seem reassuring although malformation rates are reported to be 20–30% higher after ICSI compared with the general population.38,39 Particularly the use of sperm from non-obstructive azoospermia might result in higher risk of chromosomal anomalies and needs to be further studied.

Percutaneous epididymal sperm aspiration and microsurgical sperm aspiration followed by intracytoplasmic sperm injection Epididymal sperm can be obtained from men with an otherwise irreparable obstructive azoospermia by PESA. This procedure is less invasive than MESA and can be repeatedly performed under local anaesthesia. MESA is only indicated during reconstructive surgery whenever reconstruction is impossible. For both PESA and MESA the aim is to obtain motile epididymal spermatozoa, i.e. spermatozoa with very low levels of DNA damage. Results after ICSI using epididymal sperm are comparable with those after ICSI using ejaculated sperm.40 Furthermore, the outcome after ICSI using frozen-thawed epididymal spermatozoa is comparable with that using fresh epididymal spermatozoa.41,42

Testicular sperm extraction followed by intracytoplasmic sperm injection While results after ICSI using testicular spermatozoa obtained by TESE from men with obstructive

237

azoospermia are comparable with those using epididymal spermatozoa,42 results reported on TESE-ICSI in azoospermic men with primary testicular failure are contradictory for both fertilisation and pregnancy. Larger comparative studies and a meta-analysis report a significantly lower fertilisation and clinical pregnancy rate in such men compared with azoospermic men with normal sperm production (LOE I).42,43 Differences between publications result from differences in patient selection, e.g. inclusion of a large group of men showing hypospermatogenesis at testicular histology. Life-table analysis in couples undergoing TESE-ICSI with testicular sperm from azoospermic men showed that after three cycles the chance of fathering a child was 31% in the group with primary testicular failure compared with 48% in the group with normal spermatogenesis.44 To date few publications have focused on the outcome of children born after ICSI using either epididymal or testicular sperm. From the few non-registry reports it appears that no significant differences are observed between ICSI using ejaculated spermatozoa or ICSI using surgically retrieved spermatozoa in terms of birth weight, perinatal mortality and major malformation rate.45–48 Although from these limited data, we may conclude that the results in terms of pregnancy and child outcome are reassuring, further study is certainly needed because these published studies comprise only a small number of patients.

Conclusion Poor sperm quality is often found in subfertile couples seeking help. The definition of poor sperm by the WHO will be altered soon, but regretfully, to date these definitions have not been based upon solid evidence. In all subfertile couples a semen analysis should be performed. When abnormal, a history of the man should be taken and a physical examination is advised. The role of ultrasonography of the testis is a matter of debate. In certain subgroups serious pathology might be revealed. It should be emphasised that a thorough fertility check-up of the woman is mandatory, especially when the motile count of a sperm sample exceeds 2 million. Unfortunately no effective drug is available to improve semen quality resulting in significant higher live birth rates. IUI should be offered as a cost-effective first-line treatment option when at least 1–2 million motile sperm are available after semen preparation. In couples with a mild semen defect only a mild ovarian hyperstimulation can be added. IVF and ICSI seem to be effective second-line treatment options, although their effectiveness has never been proven in large randomised trials. Epididymal sperm can be obtained from men with an otherwise irreparable obstructive azoospermia by PESA or, during reconstructive surgery by MESA. In men with non-obstructive azoospermia TESE might be the only option to father a child. Follow-up of

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these children in large prospective cohort studies is still mandatory, although to date results of follow-up studies seem reassuring.

References 1. Rowe PL, Comhaire FH, Hargreave TB, Mellows HJ. WHO Manual for the Standardized Investigation, Diagnosis and Management of the Infertile Male. Cambridge: Cambridge University Press, 2000. 2. Mallidis C, Howard EJ, Baker HW. Variation of semen quality in normal men. Int J Androl 1991; 14: 99–107. 3. Dunphy BC, Kay R, Barratt CL, Cooke ID. Is routine examination of the male partner of any prognostic value in the routine assessment of couples who complain of involuntary infertility? Fertil Steril 1989; 52: 454–6. 4. Honig SC, Lipshultz LI, Jarow J. Significant medical pathology uncovered by a comprehensive male infertility evaluation. Fertil Steril 1994; 62: 1028–34. 5. Pierik FH, Dohle GR, van Muiswinkel JM, Vreeburg JT, Weber RF. Is routine scrotal ultrasound advantageous in infertile men? J Urol 1999; 162: 1618–20. 6. Evers JL, Collins JA. Surgery or embolisation for varicocele in subfertile men. Cochrane. Database Syst Rev 2004; 3: CD000479. 7. Gouveia Brazao CA, Pierik FH, Oosterhuis JW et al. Bilateral testicular microlithiasis predicts the presence of the precursor of testicular germ cell tumors in subfertile men. J Urol 2004; 171: 158–60. 8. O’Donovan PA, Vandekerckhove P, Lilford RJ, Hughes E. Treatment of male infertility: is it effective? Review and meta-analyses of published randomized controlled trials. Hum Reprod 1993; 8: 1209–22. 9. Kamischke A, Nieschlag E. Analysis of medical treatment of male infertility. Hum Reprod 1999; 14(Suppl 1): 1–23. 10. Tournaye H. Evidence-based management of male subfertility. Curr Opin Obstet Gynecol 2006; 18: 253–9. 11. Adamopoulos DA, Pappa A, Billa E et al. Effectiveness of combined tamoxifen citrate and testosterone undecanoate treatment in men with idiopathic oligozoospermia. Fertil Steril 2003; 80: 914–20. 12. Comhaire FH. Simple model and empirical method for the estimation of spontaneous pregnancies in couples consulting for infertility. Int J Androl 1987; 10: 671–80. 13. Cohlen BJ. Should we continue performing intrauterine inseminations in the year 2004? Gynecol Obstet Invest 2004; 59: 3–13. 14. van Weert JM, Repping S, van der Steeg JW et al. IUI in male subfertility: are we able to select the proper patients? Reprod Biomed Online 2005; 11: 624–31. 15. van Weert JM, Repping S, Van Voorhis BJ et al. Performance of the postwash total motile sperm count as a predictor of pregnancy at the time of intrauterine insemination: a meta-analysis. Fertil Steril 2004; 82: 612–20. 16. Cohlen BJ, te Velde ER. Intrauterine insemination for male subfertility. In: Ombelet W, Bopmans E, eds. Modern ART in the 2000s. London: Pathenon Publishing, 1999: 9–16.

17. Bensdorp AJ, Cohlen BJ, Heineman MJ, Vandekerckhove P. Intra-uterine insemination for male subfertility. Cochrane Database Syst Rev 2007; 4: CD000360. 18. Cohlen BJ, te Velde ER, van Kooij RJ, Looman CW, Habbema JD. Controlled ovarian hyperstimulation and intrauterine insemination for treating male subfertility: a controlled study. Hum Reprod 1998; 13: 1553–8. 19. Zreik TG, Garcia-Velasco JA, Habboosh MS, Olive DL, Arici A. Prospective, randomized, crossover study to evaluate the benefit of human chorionic gonadotropintimed versus urinary luteinizing hormone-timed intrauterine inseminations in clomiphene citrate-stimulated treatment cycles. Fertil Steril 1999; 71: 1070–4. 20. Cantineau AE, Cohlen BJ. The prevalence and influence of luteinizing hormone surges in stimulated cycles combined with intrauterine insemination during a prospective cohort study. Fertil Steril 2007; 88: 107–12. 21. Cantineau AE, Cohlen BJ, Heineman MJ. Ovarian stimulation protocols (anti-oestrogens, gonadotrophins with and without GnRH agonists/antagonists) for intrauterine insemination (IUI) in women with subfertility. Cochrane Database Syst Rev 2007; (2): CD005356. 22. Cohlen BJ, van Dop P. Prevention of multiple pregnancies after non-in vitro fertilization treatment. In: Gerris J, Olivennes F, de Sutter P, eds. Assisted Reproductive Technologies. Quality and Safety. London: Parthenon Publishing, 2004: 39–48. 23. Aboulghar M, Mansour R, Serour G et al. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril 2001; 75: 88–91. 24. Goverde AJ, McDonnell J, Vermeiden JP et al. Intrauterine insemination or in-vitro fertilisation in idiopathic subfertility and male subfertility: a randomised trial and cost-effectiveness analysis. Lancet 2000; 355: 13–8. 25. Karande VC, Korn A, Morris R et al. Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril 1999; 71: 468–75. 26. Cantineau AE, Heineman MJ, Cohlen BJ. Single versus double intrauterine insemination (IUI) in stimulated cycles for subfertile couples. Cochrane Database Syst Rev 2003; 1: CD003854. 27. Boomsma CM, Heineman MJ, Cohlen BJ, Farquhar C. Semen preparation techniques for intrauterine insemination. Cochrane Database Syst Rev 2007: CD004507. 28. Hall J, Fishel S. In vitro fertilization for male infertility: when and how? Baillieres Clin Obstet Gynaecol 1997; 11: 711–24. 29. Peterson CM, Hatasaka HH, Jones KP et al. Ovulation induction with gonadotropins and intrauterine insemination compared with in vitro fertilization and no therapy: a prospective, nonrandomized, cohort study and meta-analysis. Fertil Steril 1994; 62: 535–44. 30. Soliman S, Daya S, Collins J, Jarrell J. A randomized trial of in vitro fertilization versus conventional treatment for infertility. Fertil Steril 1993; 59: 1239–44.

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The patient with poor sperm quality 31. van Rumste MM, Evers JL, Farquhar CM. ICSI versus conventional techniques for oocyte insemination during IVF in patients with non-male factor subfertility: a Cochrane review. Hum Reprod 2004; 19: 223–7. 32. Heijnen EM, Eijkemans MJ, De Klerk C et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet 2007; 369: 743–9. 33. Gerris J, De Neubourg D, Mangelschots K et al. Prevention of twin pregnancy after in-vitro fertilization or intracytoplasmic sperm injection based on strict embryo criteria: a prospective randomized clinical trial. Hum Reprod 1999; 14: 2581–7. 34. Hiramoto Y. Microinjection of the live spermatozoa into sea urchin eggs. Exp Cell Res 1962; 27: 416–26. 35. Iritani A. Current status of biotechnological studies in mammalian reproduction. Fertil Steril 1988; 50: 543–51. 36. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992; 340: 17–18. 37. Tournaye H, Devroey P, Liebaers I, Van Steirteghem AC. Intracytoplasmatische sperma-injectie. In: Evers JLH, Heineman MJ, eds. Fertiliteitsstoornissen. Utrecht: Bunge, 1997: 145–54. 38. Bonduelle M, Camus M, De Vos A et al. Seven years of intracytoplasmic sperm injection and follow-up of 1987 subsequent children. Hum Reprod 1999; 14 (Suppl 1): 243–64. 39. Bonduelle M, Legein J, Buysse A et al. Prospective follow-up study of 423 children born after intracytoplasmic sperm injection. Hum Reprod 1996; 11: 1558–64. 40. Meniru GI, Gorgy A, Batha S et al. Studies of percutaneous epididymal sperm aspiration (PESA) and

41.

42.

43.

44.

45.

46.

47.

48.

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intracytoplasmic sperm injection. Hum Reprod Update 1998; 4: 57–71. Tournaye H, Merdad T, Silber S et al. No differences in outcome after intracytoplasmic sperm injection with fresh or with frozen-thawed epididymal spermatozoa. Hum Reprod 1999; 14: 90–5. Nicopoullos JD, Gilling-Smith C, Almeida PA et al. Use of surgical sperm retrieval in azoospermic men: a meta-analysis. Fertil Steril 2004; 82: 691–701. Vernaeve V, Tournaye H, Osmanagaoglu K et al. Intracytoplasmic sperm injection with testicular spermatozoa is less successful in men with nonobstructive azoospermia than in men with obstructive azoospermia. Fertil Steril 2003; 79: 529–33. Osmanagaoglu K, Vernaeve V, Kolibianakis E et al. Cumulative delivery rates after ICSI treatment cycles with freshly retrieved testicular sperm: a 7-year follow-up study. Hum Reprod 2003; 18: 1836–40. Vernaeve V, Bonduelle M, Tournaye H, et al. Pregnancy outcome and neonatal data of children born after ICSI using testicular sperm in obstructive and non-obstructive azoospermia. Hum Reprod 2003; 18: 2093–7. Palermo GD, Schlegel PN, Hariprashad JJ et al. Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Hum Reprod 1999; 14: 741–8. Wennerholm UB, Bergh C, Hamberger L et al. Obstetric outcome of pregnancies following ICSI, classified according to sperm origin and quality. Hum Reprod 2000; 15: 1189–94. Ludwig M, Katalinic A. Malformation rate in fetuses and children conceived after ICSI: results of a prospective cohort study. Reprod Biomed Online 2002; 5: 171–8.

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23 The patient with tubal disease Annika Strandell

Does the patient with tubal disease need special consideration? Tubal disease is an indication per se for in vitro fertilisation (IVF), but several IVF centres have demonstrated results of impaired outcome in patients with tubal factor infertility, compared with other infertility diagnoses. This is partly explained by the presence of hydrosalpinx, which is a condition associated with reduced pregnancy and birth rates compared with other types of tubal infertility.1 This chapter focuses on the management of the patient with tubal disease in general and hydrosalpinx in particular.

Diagnostic methods The diagnosis of tubal disease is mainly based on the failure to detect tubal patency with laparoscopy, hysterosalpingography or hysterosalpingo contrast sonography. Chlamydia antibody testing contributes to the evaluation of risk for tubal disease, although without giving any information on the structural appearance of the tubes. The routine use of transvaginal ultrasound in the infertility investigation gives an immediate diagnosis of hydrosalpinx when the tube is fluid filled (Fig 23.1), which has direct implications on treatment choices.

Distal tubal occlusion In cases of unilateral occlusion, expectant management might still be an option, although female age and duration of infertility has to be considered. However, a unilateral hydrosalpinx in conjunction with a contralateral patent tube should be treated, due to the negative influence of the hydrosalpinx fluid. This phenomenon is further explored later in this chapter. If bilateral distal tubal occlusion is detected, treatment is necessary in order to conceive. Historically, these patients have been treated with surgery. Reports on case series of laparotomy and microsurgical techniques have well demonstrated that the status of the tubal mucosa is the most important factor for subsequent spontaneous intrauterine pregnancy and only cases with a mild to moderate degree of tubal damage should be considered for surgery. The same rule can be applied to laparoscopy, which is the most common

Fig 23.1 Hydrosalpinx in two patients examined by transvaginal ultrasound.

surgical technique used today. This is old knowledge and we can surely state that patients with mild to moderate tubal damage can be treated by either reconstructive surgery or IVF. Also, IVF results seem to be dependent on the degree of tubal damage.2 There are no randomised controlled trials to indicate which is the better of the two treatments. Instead, other factors such as treatment availability, patient’s age, patient’s preferences and economic reimbursement systems govern which treatment is proposed. As IVF results have improved over the years, the role of surgery in the treatment of tubal infertility has diminished. Indeed, patients with severe tubal damage should not undergo any tubal reconstruction but instead have IVF.

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However, patients with hydrosalpinges have been identified as a subgroup with significantly impaired pregnancy outcome after IVF compared with patients suffering from other types of tubal damage3 and this patient group has to be considered for complementary treatment prior to IVF.

Hydrosalpinx Hydrosalpinx is a commonly used term to describe a heterogeneous spectrum of pathology of distal tubal occlusion. A strict definition is a collection of watery fluid in the uterine tube, occurring as the end-stage of pyosalpinx. However, hydrosalpinx is used for any distal tubal occlusion regardless of the cause, implying that a non-tubal infection such as an adjacent appendicitis can also cause hydrosalpinx. The poor prognosis in hydrosalpinx patients undergoing IVF, has been demonstrated in several retrospective studies, summarised in meta-analyses showing a reduction by half in clinical pregnancy and delivery rates, and a doubled rate of spontaneous abortion in women with hydrosalpinx.1,4 The main theory regarding its mechanism suggests that the hydrosalpingeal fluid plays a causative role, and any surgical intervention interrupting the communication to the uterus would thus remove the leakage of the hydrosalpingeal fluid and restore pregnancy rates.

Theories of hydrosalpinx action It is not completely understood how the hydrosalpinx exerts its negative effects. The main theories have focused on the hydrosalpingeal fluid and its action through possible embryotoxic properties, mechanical leakage into the uterine cavity causing endometrial alterations hostile to embryo implantation and development, or simply mechanical washout of embryos.5,6 The expression of genes and proteins that have a putative role in the implantation process may be altered in the presence of hydrosalpinx. Several research groups have focused on the expression of cytokines and growth factors in the endometrium during the window of implantation. The expression of endometrial receptivity markers like αvβ3 integrin and leukaemia inhibitory factor (LIF) is suppressed in hydrosalpinx patients but restored after salpingectomy, compared with control patients.7,8 Also, the transcription factor HOXA10, necessary for embryo implantation, showed diminished endometrial expression in hydrosalpinx patients and its suppression was reversed after salpingectomy.9 Another theory, that hydrosalpinx fluid prevents implantation of the embryo by inhibiting the secretion of the enzymes responsible for the invasive behaviour of the blastocyst was explored by measuring proteolytic enzymes.10 Matrix metalloproteinases (MMPs), secreted by cytotrophoblastic cells, are the only enzymes capable of digesting the components of extracellular matrix. The presence of

hydrosalpinx fluid increased the MMP levels and the net result was a significant stimulation of the total gelatinolytic activity in comparison with peritoneal fluid. Other theories have included simultaneous damage to the endometrium at the time of the original tubal infection, influence of inflammatory substances transported through the blood or lymphatic system and impairment of ovarian function and oocyte quality by the original infection or by influence of toxic substances. One study has demonstrated impaired endometrial and subendometrial blood flow among hydrosalpinx patients, supporting the theory of simultaneous damage to the endometrium as the original infection.11 Several studies have shown negative bacterial cultures from hydrosalpinx fluid,12–14 indicating that a persistent infection is of rare occurrence. The mechanisms of hydrosalpinx fluid formation remain unclear. Vascular endothelial growth factor may play an important role, possibly by promoting vascular and epithelial permeability and therefore serum transudation.15

Treatment for hydrosalpinx Treatment with salpingectomy prior to IVF is the only surgical method that has been evaluated in a sufficiently large randomised controlled trial. Proximal ligation has been investigated in a smaller randomised controlled trial. Transvaginal aspiration may also be considered, but this method has only been evaluated in small retrospective studies and thus the results are of less validity.

Salpingectomy A multicentre study in Scandinavia compared laparoscopic salpingectomy with no intervention prior to the first IVF cycle and demonstrated a significant improvement in pregnancy and birth rates after salpingectomy in patients with hydrosalpinges that were large enough to be visible on ultrasound.16 Clinical pregnancy rates were 46% vs 22% (p=0.049) and birth rates were 40% vs 17% (p=0.040) in salpingectomised patients vs patients without any surgical intervention. The difference in outcome was not statistically significant in the total study population of 204 patients which included patients with hydrosalpinges that were not visible on ultrasound, demonstrating that the benefit of salpingectomy is only evident if the hydrosalpinx is fluid-filled. The psychological aspect of removing the tubes in an infertile patient is very important and has to be considered. Even if it is obvious that the patient would benefit from salpingectomy, it is crucial that she is psychologically prepared to undergo the procedure. In some cases it takes one or several failed cycles before the patient is ready to give her consent. Within the group of hydrosalpinges visible on ultrasound, there can still be tubes which are suitable for

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Author

Surgery (birth or ongoing pregnancy/patients)

No surgery (birth or ongoing pregnancy/patients)

Relative risk (95% CI)

243

Weight

Relative risk (95% CI)

Déchaud et al, 199817

13/30

6/30

20%

2.17 (0.95–4.94)

Strandell et al, 199916

31/116

15/88

49%

1.57 (0.90–2.72)

Goldstein et al, 199818

4/15

1/16

5%

4.27 (0.54–33.98)

Kontoravdis et al, 200620 23/47

1/14

26%

6.85 (1.01–46.32)

23/148

100%

2.13 (1.24–3.65)

Total

71/208

0.1

0.2

1

5

10

Favours control Favours surgery

Fig 23.2

Meta-analysis of four randomised trials on salpingectomy vs no surgical intervention prior to IVF.

reconstructive surgery. If the surgical competence is available, tubes with healthy looking mucosa should be considered for salpingostomy. There are two additional randominsed controlled trials on salpingectomy prior to IVF,17,18 both of smaller sample size than the Scandinavian study, resulting in no statistically significant difference in outcome. These three studies have been included in a systematic review in the Cochrane library19 and summary estimates from the meta-analysis demonstrated a doubled pregnancy (odds ratio (OR) 1.8, 95% confidence interval (CI) 1.1–2.9) and live birth rate (OR 2.1, 95% CI 1.2–3.7) after IVF if salpingectomy was performed compared with no surgical intervention. A meta-analysis including the fourth and most recent study on salpingectomy vs no surgical intervention demonstrated similar results (Fig 23.2).20 In the Scandinavian study, the cumulative results including all subsequent cycles were evaluated.21 Patients were offered up to three stimulated cycles, and those who were randomised to undergo salpingectomy achieved a cumulative birth rate of 55%. When all subsequent cycles were considered, including all patients regardless of the size of the hydrosalpinx and whether it was fluid-filled, salpingectomy patients had a doubled birth rate as compared with patients with persistent hydrosalpinges (hazard ratio 2.1, 95% CI 1.6–3.6, p=0.014). This result, as well as the compiled data from the Cochrane review, suggests that all patients with hydrosalpinx, regardless of size or fluid accumulation, should undergo salpingectomy. However, the cumulative data from the Scandinavian study revealed that the benefit of salpingectomy mainly affected patients with hydrosalpinges visible on ultrasound,

and, consequently, those are the only patients to be recommended prophylactic salpingectomy prior to IVF. The recommendation of salpingectomy has raised concern about unnecessary removal of tubes that might be suitable for salpingostomy and spontaneous conception. The optimal management is of course that the fallopian tube and its mucosal status should be evaluated at the time of laparoscopy and an immediate decision taken, whether the tube should be removed or reconstructed. The prerequisite for the latter scenario is surgical/laparoscopic competence for distal tubal repair and, also, postoperative time to allow for spontaneous conception. Also, in cases of salpingectomy for unilateral hydrosalpinx, time for spontaneous conception should be considered, since several case series have demonstrated high spontaneous intrauterine pregnancy rates after surgery.22–24 Ovarian function after salpingectomy The effect of salpingectomy on ovarian function has been debated and the results of hitherto published studies do not show any significant reduction in the overall number of oocytes retrieved after surgery.16,20,25–33 A summary of the published studies is presented in Table 23.1. The close anatomical association of the vascular and nervous supply to the tube and ovary constitute the theoretical rationale for the risk of impaired ovarian function after surgery. Ectopic pregnancy was the reason for salpingectomy in some of the studies. None of the studies demonstrated an effect on the overall performance measuring number of retrieved oocytes, although one study has shown a decreased response in the ovary, ipsilateral to the

29 vs 73 108 vs 79 139 vs 139 26 15 vs 34 26 32 vs 35 26 vs 52 40 vs 103 50 vs 15

Lass et al, 199826 Strandell et al, 199916 Bredkjaer et al, 199927 Dar et al, 200028 Stadtmauer et al, 200029 Strandell et al, 200130 Surrey and Schoolcraft, 200131 Tal et al, 200232 Gelbaya et al, 200633 Kontoravdis, 200620

Ectopic pregnancy, hydrosalpinx,sterilisation Ectopic pregnancy Hydrosalpinx Hydrosalpinx Ectopic pregnancy after IVF Hydrosalpinx Hydrosalpinx Hydrosalpinx Ectopic pregnancy Hydrosalpinx Hydrosalpinx

Reason for surgery

3.8 vs 6.0 p<0.01 Not studied Not studied 6.1 vs 5.3 NS Not studied Not studied Not studied 6.3 vs 6.2 NS Not studied Not studied

Not studied

Ipsilateral vs contralateral

9.9 vs 9.1 NS 10.6 vs 10.6 NS 9.5.vs 9.3 NS 11.1 vs 9.7 NS 14.0 vs 12.9 NS 9.4 vs 8.7 NS 16.2 vs 17.5 NS 8.6 vs 8.4 NS 10.2 vs 12.9 NS 12.1 vs 10.9 NS

11.2 vs 11.2 NS

Overall (two ovaries)

Prospective comparison with controls Randomised controlled trial Retrospective comparison with controls Analysis before and after surgery Retrospective cohort Analysis before and after surgery Retrospective cohort Comparison with matched controls Retrospective cohort Randomised controlled trial

Retrospective comparison with controls

Study design

--

NS, not significant.

26 vs 134

Verhulst et al,199425

No. of patients

No. of oocytes

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Table 23.1 Summary of 11 studies examining the effect of salpingectomy on ovarian function by measuring the number of retrieved oocytes after controlled ovarian hyperstimulation. Controls are the same patient before surgery, the contralateral ovary or patients without previous tubal surgery.

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Table 23.2 Clinical pregnancy rates per embryo transfer in five studies comparing tubal ligation with salpingectomy and no surgery in hydrosalpinx patients, prior to IVF.

Kontoravdis et al, 200620 Gelbaya et al, 200633 Surrey and Schoolcraft, 200131 Stadtmauer et al, 200029 Murray et al, 199834

Salpingectomy

Tubal ligation

No surgery

N/N

%

N/N

%

N/N

26/50 6/40 16/28 7/15 9/23

52 15 57 47 39

20/50 5/25 7/15 22/30 9/15

40 20 47 73 60

2/15 14/103 — 2/15 4/47

%

Study design

13* 14

Randomised controlled trial Retrospective cohort Retrospective cohort Retrospective cohort Retrospective cohort

13** 8.5**

* p<0.05 vs salpingectomy, ** p<0.05 vs both surgical procedures, all other comparisons show no significant differences.

salpingectomy.26 In the Scandinavian randomised controlled trial on salpingectomy prior to IVF, a subset of patients who underwent a stimulated cycle both before and after the salpingectomy were included in an analysis of the effect of salpingectomy on the ovarian performance by measuring the need for follicle stimulating hormone (FSH) and number of retrieved oocytes.30 There were no significant differences in either the amount of FSH used or the number of retrieved oocytes. In the cycle after salpingectomy, a mean of 0.7 fewer oocytes were retrieved compared with the cycle before surgery. However, the largest randomised trial did not show any difference at all in number of oocytes, implying that salpingectomy does not impair ovarian function.16 From the results we cannot conclude that patients with a low ovarian reserve are at greater risk to suffer from poor response after salpingectomy. However, one cannot preclude that patients already having an impaired ovarian function might experience a subsequent poor response to gonadotrophins if too a radical salpingectomy has been performed. Theoretically, it seems important to be very cautious not to damage the vascular and nervous supply when performing a salpingectomy. A laparoscopic salpingectomy should be performed with cautious use of electrocautery, no unnecessary excision of the mesosalpinx but resection very close to the actual tube to avoid damage to the medial tubal artery and rather leave a portion of an adherent tube on the ovary than to perform an unnecessarily large salpingectomy.

Tubal ligation Proximal occlusion of the fallopian tube has been suggested as an alternative to salpingectomy prior to IVF, in particular when dense adhesions complicate an intended salpingectomy. Occlusion of the tube serves the purpose of interrupting the passage of fluid to the endometrial cavity, but leaves the hydrosalpinx in place, where it might interfere with the aspiration of oocytes. The procedure can be combined with distal

fenestration of the hydrosalpinx, but the opening frequently re-occludes. In a randomised trial, 115 patients with hydrosalpinx were allocated to proximal tubal occlusion, salpingectomy, or no surgery prior to IVF.20 Both surgical methods demonstrated significantly higher ongoing pregnancy rates (34% and 46%) compared with women having no surgery (6.6%), analysed on an intention-to-treat basis (p=0.049). Although this study was underpowered, the result supports the findings of previous retrospective studies, suggesting that proximal occlusion is effective. The method, used in four small retrospective studies, has yielded comparative results as after salpingectomy but improved outcome as compared with no intervention was demonstrated in only three out of the four studies.29,31,33,34 A summary of the published literature is presented in Table 23.2. There are not sufficient data to conclude that proximal occlusion prior to IVF is as effective as salpingectomy in increasing pregnancy rates. Taking into account the technical aspects of surgery in cases complicated by severe adhesions and the potential risk of damaging the vascular supply, proximal ligation can be recommended as an alternative. The hysteroscopic route for tubal ligation has been tried in cases where laparosopy was contraindicated. One case report described the possibility of proximal tubal occlusion by hysteroscopic placement of microinsert in obese patients with favourable pregnancy outcome.35 The efficacy of hysteroscopic tubal occlusion compared with laparoscopic route was examined in a pilot randomised study in which 13 women were subjected to roller ball coagulation of the peritubal bulge prior to hysterectomy.36 Tubal occlusions were successfully achieved in 64% of patients. The different hysteroscopic methods need further clinical evaluation.

Transvaginal aspiration of fluid Ultrasound guided transvaginal aspiration has been advocated as a treatment option to remove the

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Table 23.3 Summary of two retrospective studies on transvaginal aspiration of hydrosalpingeal fluid at the time of oocyte retrieval, including only first cycle. Treatment group Aspiration

Sowter et al, 199737 Van Voorhis et al, 199838

No aspiration

Outcome

N/N

(%)

N/N

(%)

Significance (p value)

Pregnancy Birth Pregnancy Birth

6/30 5/30 5/16 5/16

20.0 16.7 31.3 31.3

3/18 3/18 1/18 0

16.7 16.7 5.6

1.0 1.0 0.078 0.015

hydrosalpingeal fluid. If the procedure is performed prior to stimulation, the fluid always re-accumulates. Even if it is done at the time of oocyte retrieval, the risk of re-occurrence is already high at the time of transfer. Until recently, there were only two small retrospective inconclusive studies (Table 23.3).37,38 A new randomised trial demonstrated clinical pregnancy rates of 31.3% (10/32) after aspiration and 17.6% (6/34) after no aspiration; a non-significant result due to the small sample.39 The result certainly suggests a benefit from aspiration although additional studies are required to draw that conclusion. In the clinical situation where a patient develops tubal fluid during stimulation, transvaginal aspiration at the time of oocyte retrieval can be considered, but freezing of embryos and subsequent surgery prior to transfer of thawed embryos, might be a better option. Further studies are certainly required. Another phenomenon sometimes associated with hydrosalpinx, is the occurrence of hydrometra. A few retrospective studies have demonstrated hydrometra at the time of transfer, to be a sign of poor prognosis.40–42 Aspiration of uterine fluid is unlikely to be beneficial, since there is a rapid re-accumulation of hydrometra.43

Antibiotic treatment The use of antibiotics has been presented as a simple treatment to overcome the negative effects of hydrosalpinx, based on a theory of persistent tubal infection. However, antibiotic treatment has never been prospectively evaluated and, to date, there is only one small retrospective study which has suggested that extended doxycycline treatment during an IVF cycle would minimise the detrimental effect of hydrosalpinx.44

Proximal tubal occlusion Proximal tubal occlusion accounts for approximately 20% of tubal factor cases. The classification into nodular (salpingitis isthmica nodosa or endometriosis), nonnodular (true fibrotic occlusion) and so-called pseudoocclusion (detritus, polyps, hypoplastic tubes) is essential for the choice of treatment. The nodular and true

fibrotic occlusions have for a long time been treated by tubocornual anastomosis by microsurgery and as opposed to microsurgery of the distal tube; laparoscopy has never become an option. Instead IVF has become the method of choice and also fluoroscopic transcervical recanalisation has been attempted. There is a total lack of randomised studies comparing the different treatments in this area, so recommendations rely solely on retrospective studies, mainly of case series character. Nowadays, the skills necessary to perform this type of surgical procedure are no longer commonly available, even in large fertility centres, since the use of microsurgery in general has declined. Besides the availability of the surgical experience, another prerequisite for this type of procedure is that there is no bifocal disease. IVF is thus the only recommended treatment for patients with both proximal and distal tubal disease. Also, selective salpingography and transcervical recanalisation should only be performed if the tube distal to the proximal occlusion is healthy, due to the poor pregnancy prognosis in patients with bifocal disease. Otherwise the method can be considered as relatively inexpensive and with a low risk of complications. One of the largest series of transcervical recanalisation demonstrated a restoration of tubal patency in 52% of tubes and in 75% patients.45 The subsequent live birth rate was 22% among 176 patients with successful recanalisation and patients with endometriosis formed the most favourable group. Previous sterilisation is a special type of proximal occlusion, considering the good prognosis after both IVF and reversal of sterilisation. The surgical procedure can nowadays be performed laparoscopically with the so called “one stitch technique”, demonstrating subsequent intrauterine pregnancy rates of 53–83%.46,47 However, the experience from the laparoscopic procedure is sufficient only in a limited number of centres. Instead, these patients are commonly recommended IVF.

Peritoneal adhesions The result of previous pelvic infections can be seen as tubal disease, peritoneal adhesions or both. Laparoscopy

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is the superior method to diagnose adhesions and to treat them at the same time. The laparoscopic route is recommended before laparotomy, mainly due to the general advantages of endoscopy, but also considering pregnancy results. There was a non-significant increase in term and intrauterine pregnancy rates, and a non-significant reduction in ectopic pregnancy rates after laparoscopic adhesiolysis according to a Cochrane review on pelvic surgery for subfertility.48 Patients with mild to moderate adhesions experience good fertility prognosis, while patients with severe adhesions are best treated with IVF. Infections after non-genital causes, such as after appendicitis are often advantageously treated by surgery, since the fallopian tubes are internally healthy and the postoperative fertility prognosis is thus good. In contrast, after surgery for inflammatory bowel disease, any attempt of fertility surgery should be avoided and patients instead referred to IVF.

Risks in early pregnancy All patients with tubal disease carry an increased risk of ectopic pregnancy subsequent to both spontaneous and assisted conception. A transvaginal ultrasound examination in early gestation is important to rule out an ectopic placentation. If more than one embryo has been transferred in IVF treatment, the risk of a heterotopic pregnancy should be remembered. The detection of an intrauterine pregnancy is not sufficient, the tubes and adnexae need to be carefully examined as well. The previously described incidence of one heterotopic pregnancy in every 250 IVF pregnancies is dependent on the number of embryos transferred and the presence of tubal disease. This high incidence has declined with the reduction in the number of embryos transferred and with the routine use of single embryo transfer this condition would probably be as rare as after spontaneous conception (1/10 000). After salpingectomy, the risk of dehiscence in the uterine wall and cornual fistulae has been described.49,50 A recommendation of resection not too close to the uterus is appropriate and a close sonographic surveillance of the early pregnancy can be considered. Patients with a persistent hydrosalpinx have an increased risk of miscarriage. Counselling and additional ultrasound in early pregnancy are supportive for the patient. If miscarriage occurs, advice on salpingectomy can be proposed.51

Summary Tubal disease is a common cause of infertility and was also the first indication for IVF treatment. Today, IVF is the major treatment for this patient group. A subset of patients with hydrosalpinx have demonstrated poor outcome after IVF, possibly due to the negative influence of the hydrosalpingeal fluid. Treatment with laparoscopic salpingectomy prior to IVF has

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resulted in doubled rates of pregnancy and live birth, and should be suggested to patients intended to undergo IVF, if the tubes are fluid-filled and visible on transvaginal ultrasound. If the laparoscopy is complicated due to adnexal adhesions, proximal ligation of the tubes can be recommended. Reconstructive surgery should only be considered in cases with mild or moderate tubal disease and if the surgical competence is available. The risk of ectopic pregnancy is increased in patients with tubal disease after both spontaneous and assisted conception. These patients should be carefully examined with transvaginal ultrasound in early pregnancy.

References 1. Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization-embryo transfer. Fertil Steril 1998; 70: 492–9. 2. Csemiczky G, Landgren BM, Fried G, Wramsby H. High tubal damage grade is associated with low pregnancy rate in women undergoing in-vitro fertilization treatment. Hum Reprod 1996; 11: 2438–40. 3. Strandell A, Waldenström U, Nilsson L, Hamberger L. Hydrosalpinx reduces in-vitro fertilization/ embryo transfer rates. Hum Reprod 1994; 9: 861–3. 4. Camus E, Poncelet C, Goffinet F et al. Pregnancy rates after IVF in cases of tubal infertility with and without hydrosalpinx: meta-analysis of published comparative studies. Hum Reprod 1999; 14: 1243–9. 5. Andersen AN, Yue Z, Meng FJ et al. Low implantation rate after in-vitro fertilization in patients with hydrosalpinges diagnosed by ultrasonography. Hum Reprod 1994; 9: 1935–8. 6. Fleming C, Hull MGR. Impaired implantation after in vitro fertilization treatment associated with hydrosalpinx. Br J Obstet Gynaecol 1996; 103: 268–72. 7. Meyer WR, Castelbaum AJ, Somkuti S et al. Hydrosalpinges adversely affect markers of endometrial receptivity. Hum Reprod 1997; 12: 1393–98. 8. Seli E, Kayisli UA, Cakmak H et al. Removal of hydrosalpinges increases endometrial leukaemia inhibitory factor (LIF) expression at the time of the implantation window. Hum Reprod 2005; 20: 3012–17. 9. Daftary GS, Kayisli U, Seli E et al. Salpingectomy increases peri-implantation endometrial HOXA10 expression in women with hydrosalpinx. Fertil Steril 2007; 87: 367–72. 10. Jastrow N, Chardonnens D, Araman M et al. Effect of hydrosalpinx fluid on secretion of trophoblastic matrix metalloproteinases. Fertil Steril 2002; 77: 588–94. 11. Ng EH, Chan CC, Tang OS, Chung PC. Comparison of endometrial and subendometrial blood flows among patients with and without hydrosalpinx shown on scanning during in vitro fertilization treatment. Fertil Steril 2006; 85: 333–8. 12. Murray CA, Clarke HJ, Tulandi T et al. Inhibitory effect of human hydrosalpingeal fluid on mouse preimplantation embryonic development is significantly reduced by the addition of lactate. Hum Reprod 1997; 12: 2504–7. 13. Granot I, Dekel N, Segal I et al. Is hydrosalpinx fluid cytotoxic? Hum Reprod 1998; 13: 1620–24.

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14. Strandell A, Sjögren A, Bentin-Ley U et al. Hydrosalpinx fluid does not adversely affect the normal development of human embryos and implantation in vitro. Hum Reprod 1998; 13: 2921–5. 15. Lam PM, Briton-Jones C, Cheung CK et al. Increased mRN expression of vascular endothelial growth factor and its receptor (FLT-1) in the hydrosalpinx. Hum Reprod 2003; 18: 2264–9. 16. Strandell A, Lindhard A, Waldenström U et al. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999; 14: 2762–9. 17. Déchaud H, Daures JP, Arnal F et al. Does previous salpingectomy improve implantation and pregnancy rates in patients with severe tubal factor infertility who are undergoing in vitro fertilization? A pilot prospective randomized study. Fertil Steril 1998; 69: 1020–5. 18. Goldstein DB, Sasaran LH, Stadtmauer L, Popa R: Selective salpingostomy-salpingectomy (SSS) and medical treatment prior to IVF in patients with hydrosalpinx. (Abstracts). Fertil Steril 1998; 70(Suppl 1): S320. 19. Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev 2004; (3): CD002125. 20. Kontoravdis A, Makrakis E, Pantos K et al. Proximal tubal occlusion and salpingectomy results in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx. Fertil Steril 2006; 86: 1642–9. 21. Strandell A, Lindhard A, Waldenstrom U, Thorburn J. Hydrosalpinx and IVF outcome: cumulative results after salpingectomy in a randomized controlled trial. Hum Reprod 2001; 16: 2403–10. 22. Choe J, Check JH. Salpingectomy for unilateral hydrosalpinx may improve in vivo fecundity. Gynecol Obstet Invest 1999; 48: 285–7. 23. Aboulghar MA, Mansour RT, Serour GI. Spontaneous intrauterine pregnancy following salpingectomy for a unilateral hydrosalpinx. Hum Reprod 2002; 17: 1099–100. 24. Sagoskin AW, Lessey BA, Mottla GL et al. Salpingectomy or proximal tubal occlusion of unilateral hydrosalpinx increases the potential for spontaneous pregnancy. Hum Reprod 2003; 18: 2634–7. 25. Verhulst G, Vandersteen N, van Steirteghem AC, Devroey P. Bilateral salpingectomy does not compromise ovarian stimulation in an in-vitro fertilization/ embryo transfer programme. Hum Reprod 1994; 9: 624–8. 26. Lass A, Ellenbogen A, Croucher C et al. Effect of salpingectomy on ovarian response to superovulation in an in vitro fertilization-embryo transfer program. Fertil Steril 1998; 70: 1035–8. 27. Bredkjaer HE, Ziebe S, Hamid B et al. Delivery rates after in-vitro fertilization following bilateral salpingectomy due to hydrosalpinges: a case control study. Hum Reprod 1999; 14: 101–5. 28. Dar P, Sachs GS, Strassburger D, Bukovsky I, Arieli S. Ovarian function before and after salpingectomy in artificial reproductive technology patients. Hum Reprod 2000; 15: 142–4.

29. Stadtmauer LA, Riehl RM, Toma SK, Talbert LM. Cauterization of hydrosalpinges before in vitro fertilization is an effective surgical treatment associated with improved pregnancy rates. Am J Obstet Gynecol 2000; 183: 367–1. 30. Strandell A, Lindhard A, Waldenstrom U, Thorburn J. Salpingectomy prior to IVF does not impair the ovarian response. Hum Reprod 2001; 16: 1135–9. 31. Surrey ES, Schoolcraft WB. Laparoscopic management of hydrosalpinges before in vitro fertilizationembryo transfer: salpingectomy versus proximal tubal occlusion. Fertil Steril 2001; 75: 612–17. 32. Tal J, Paltieli Y, Korobotchka R et al. Ovarian response to gonadotropin stimulation in repeated IVF cycles after unilateral salpingectomy. J Assist Reprod Genet 2002; 19: 451–5. 33. Gelbaya TA, Nardo LG, Fitzgerald CT et al. Ovarian response to gonadotrophins after laparoscopic salpingectomy or the division of fallopian tubes for hydrosalpinges. Fertil Steril 2006; 85: 1464–8. 34. Murray DL, Sagoskin AW, Widra EA et al. The adverse effect of hydrosalpinges on in vitro fertilization pregnancy rates and the benefit of surgical correction. Fertil Steril 1998; 69: 41–5. 35. Rosenfield RB, Stones RE, Coates A et al. Proximal occlusion of hydrosalpinx by hysteroscopic placement of microinsert before in vitro fertilizationembryo transfer. Fertil Steril 2005; 83: 1547–50. 36. Darwish AM, El Saman AM. Is there a role for hysteroscopic tubal occlusion of functionless hydrosalpinges prior to IVF/ICSI in modern practice? Acta Obstet Gynecol Scand 2007; 86: 1484–9. 37. Sowter MC, Akande VA, Williams JA et al. Is the outcome of in-vitro fertilization and embryo transfer treatment improved by spontaneous or surgical drainage of a hydrosalpinx? Hum Reprod 1997; 12: 2147–50. 38. Van Voorhis BJ, Sparks AE, Syrop CH et al. Ultrasound-guided aspiration of hydrosalpinges is associated with improved pregnancy and implantation rates after in-vitro fertilization cycles. Hum Reprod 1998; 13: 736–9. 39. Hammadieh N, Coomarasamy A, Ola B et al. Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum Reprod 2008; 23: 1113–17. 40. Andersen AN, Lindhard A, Loft A et al. The infertile patient with hydrosalpinges-IVF with or without salpingectomy. Hum Reprod 1996; 11: 2081–4. 41. Levi AJ, Segars JH, Miller BT, Leondires MP. Endometrial cavity fluid is associated with poor ovarian response and increased cancellation rates in ART cycles. Hum Reprod 2001; 16: 2610–15. 42. Chien LW, Au HK, Xiao J, Tzeng CR. Fluid accumulation within the uterine cavity reduces pregnancy rates in women undergoing IVF. Hum Reprod 2002; 17: 351–6. 43. Hinckley MD, Milki AA. Rapid reaccumulation of hydrometra after drainage at embryo transfer in patients with hydrosalpinx. Fertil Steril 2003; 80: 1268–71. 44. Hurst BS, Tucker KE, Awoniyi CA, Schlaff WD. Hydrosalpinx treated with extended doxycyclin does not compromise the success of in vitro fertilization. Fertil Steril 2001; 75: 1017–19.

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The patient with tubal disease 45. Lang EK, Dunaway HE Jr: Efficacy of salpingography and transcervical recanalization in diagnosis, categorization, and treatment of fallopian tube obstruction. Cardiovasc Intervent Radiol 2000; 23: 417–22. 46. Dubuisson JB, Chapron C: Single suture laparoscopic tubal re-anastomosis. Curr Opin Obstet Gynecol 1998; 10: 307–13. 47. Yoon TK, Sung HR, Kang HG et al. Laparoscopic tubal anastomosis: fertility outcome in 202 cases. Fertil Steril 1999; 72: 1121–6. 48. Watson A, Vandekerckhove P, Lilford R: Techniques for pelvic surgery in subfertility (Cochrane Review). In: The Cochrane Library, Issue 2. Oxford: Update Software, 2003.

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49. Inovay J, Marton T, Urbancsek J et al. Spontaneous bilateral cornual uterine dehiscence early in the second trimester after bilateral laparoscopic salpingectomy and in-vitro fertilization. Hum Reprod 1999; 14: 2471–3. 50. Hsu CC, Yang TT, Hsu CT. Ovarian pregnancy resulting from cornual fistulae in a woman who had undergone bilateral salpingectomy. Fertil Steril 2005; 83: 205–7. 51. Zolghadri J, Momtahan M, Alborzi S, Mohammadinejad A, Khosravi D. Pregnancy outcome in patients with early recurrent abortion following laparoscopic tubal corneal interruption of a fallopian tube with hydrosalpinx. Fertil Steril 2006; 86: 149–51.

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24 The couple with unexplained infertility Gamal I Serour, Mohamed Aboulghar

The terms infertility, sterility and infecundity are often used loosely, without regard to precise definition. Moreover, definitions of the terms may differ substantially between demographic and medical usage, and between languages.1 In English demographic terminology, primary infertility (also called primary sterility) is defined as the inability to bear any children, due to either the inability to conceive or the inability to carry a pregnancy to a live birth. In medical studies, however, infertility is usually defined as the inability to conceive. In English demographic language, the term infecundity refers to the inability to conceive after several years of exposure to the risk of pregnancy. Inability to conceive within 2 years of exposure to the risk of pregnancy is the epidemiological definition recommended by the World Health Organization.2,3 Clinical studies often use a 1 year period of exposure. In demographic studies it is common to use a period of 5 years of exposure. Accepted categories of infertility include male factor, tubal disease, anovulation, endometriosis and unexplained infertility.4 In unexplained infertility as the name implies, the mechanism(s) resulting in infertility are unknown. Occult problems in either the sperm or the oocyte leading to fertilisation failure or dysfunctional embryos may be the underlying mechanism of unexplained infertility. Alternatively at the level of the endometrium implantation failure, in spite of availability or replacement of morphologically good quality embryos in assisted reproductive technology (ART), may be the mechanism of unexplained infertility.

When diagnostic laparoscopy was included in the work-up of infertility diagnosis, by the same authors unexplained infertility was diagnosed in only 3.3% of 1488 infertile patients.7 Templeton and Penney 1982 reported an incidence of 15%.8 Smith et al reported an incidence of 30–40% in couples in whom standard investigations of semen analysis, tests of ovulation and tubal patency tests had failed to detect any gross abnormality.9 Differences among the study populations, selection bias and the duration of infertility of various study groups add to this wide range of incidence of unexplained infertility. In clinical settings the term unexplained infertility includes a wide group of couples suffering from infertility. This is due to the widely prevalent dismissive attitude in respect to the value of many diagnostic procedures of infertility. There is a widely held concept, based on the correlation of the diagnostic tests with the occurrence of pregnancy, that a diagnosis of unexplained infertility is appropriate, as long as ovulation is confirmed, tubal patency has been proven and the semen analysis is normal. Other additional investigations contribute relatively little to the effective diagnosis of unexplained infertility and so are not mandatory.10 It is not surprising therefore that an unexplained infertility diagnosis was reported to represent the single most frequent female infertility “diagnosis” with a prevalence of approximately 25–30% of all infertility.9,11

Incidence of unexplained infertility

There are no universally accepted methods for diagnosing unexplained infertility. Diagnosis of unexplained infertility is based on exclusion of other recognised causes of infertility. The European Society of Human Reproduction and Embryology (ESHRE) workshop on unexplained infertility reported that the diagnosis is one of exclusion and it is therefore important to seek agreement on which diagnostic tests are required to be done before concluding that a couple have unexplained infertility. The presumptive diagnosis of unexplained infertility is made only after, whatever diagnostic work-up has been pursued, no obvious cause of infertility can be identified. Unexplained

In clinical practice a couple is designated as having unexplained infertility when no definite cause of infertility can be found after complete evaluation of the couple. As there is no agreement in the literature on what is complete evaluation of the infertile couple, it is not surprising that the incidence of unexplained infertility varies widely between 0 and 37%.5 Serour and Hefnawi in a series of 1764 infertile patients reported an incidence of unexplained infertility in 12.8% before diagnostic laparoscopy was included in the work-up of diagnosis of infertility.6

Diagnosis of unexplained infertility

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infertility therefore does not describe a specific clinical condition with specific diagnostic findings but is used to define a negative, the absence of specific diagnostic findings. Negatives are, however, practically impossible to prove.12 Absence of evidence is not evidence of absence. The diagnosis of unexplained infertility therefore greatly varies between practitioners and what is considered unexplained infertility in one infertility centre may have a very specific diagnosis in another infertility centre depending upon the tests used for the diagnosis of the cause of infertility and also upon the interpretation of these tests. Some authors argue that the utility of any tests other than basic tests of semen quality, ovulation and tubal patency in the diagnosis and management of infertility has yet to be proven.4,10,13 Given our present treatment options, further investigations leading to a more “accurate” diagnosis are unlikely to change our management in these cases. The necessity of identifying a specific cause of infertility is linked to the availability of targeted interventions.14 If such a dismissive attitude in respect to the value of many diagnostic procedures is followed many causes of infertility will be missed.

Misdiagnosis in unexplained infertility The common approach to the diagnosis of unexplained infertility by means of the three basic tests, semen analysis, tubal patency and tests of ovulation, has been questioned by Gleicher and Barad.12 The diagnosis of unexplained infertility is dependent on the accuracy and range of the various investigations and the interpretation of the tests as well. The clinical conditions most likely to be misdiagnosed as unexplained infertility include mild tubal disease, endometriosis, immunological infertility, prematurely ageing ovaries and failure of implantation.

Mild tubal disease Tubal assessment tests include hysterosalpingography, laparoscopy and hysterosalpingo contrast sonography (HyCoSy). The diagnostic accuracy of hysterosalpingography has been questioned. It is generally believed that hysterosalpingography is a less accurate in detecting and evaluating tubal disease than laparoscopy.6,7,12,15–18 Hysterosalpingography also suffers from considerable observer’s variability.19 However, hysterosalpingography is widely considered as a corner stone of infertility diagnosis and still represents the principal first-line tool to assess tubal status.10 However, laparoscopy is considered to be the gold standard.20 Hysterosalpingography can miss conditions such as tubal dysfunction, spasm, proximal occlusion and anatomical and physiological function abnormality.6,16,17,21,22 Mol et al reported a sensitivity of 0.81 and a specifity of 0.75 for hysterosalpingography in identifying tubal occlusion detected at laparoscopy. In terms of

predicting pregnancy, laparoscopy was more reliable (fecundity rate ratio of 0.38 and 0.19 when a one- and two-sided occlusion appeared, respectively) compared with hysterosalpingography.17 Some women with a diagnosis of unexplained infertility actually are infertile because of undiagnosed tubal disease often secondary to undiagnosed endometriosis or tubal disease.7,12

Endometriosis The prevalence of endometriosis in the infertile female has been reported to be as low as 5.6–10%7,9 or as high as 30–50%.23 It may be suspected when there is dyspareunia, severe dysmenorrhoea or unexplained abdominal pain. Pelvic examination may show tenderness, nodules of endometriosis on the uterosacral ligaments or an enlarged ovary with endometrioma. The diagnosis is generally confirmed by ultrasonography and laparoscopy. However, in reality, even in the hands of an experienced laparoscopist, an accurate diagnosis of endometriosis can be difficult because the disease is often microscopic and presents visually with a variety of atypical lesions. Guidice and Kao have indicated that there is a similar patient profile in women with mild endometriosis and unexplained infertility. Thus, endometriosis may be under-diagnosed and unexplained infertility may, in many cases, represent a non-visible and/or only microscopic stage of endometriosis.24 Severe endometriosis affects the outcome of in vitro fertilisation in infertile couples. In a meta-analysis of 22 studies, pregnancy rates were found to be lower in women with endometriosis compared with controls (women with tubal disease).25 If endometriosis exerts this effect in vitro, it can also be expected to exert the same effect in vivo due to a disturbed milieu within the pelvis.12,26 However, interventions for minimal/mild endometriosis are not dissimilar to those used for unexplained infertility namely superovulation/intrauterine insemination (IUI) and IVF.4 This questions the justification of diagnosing minimal/mild endometriosis separate from unexplained infertility.11 Furthermore, laparoscopic resection or ablation of minimal and mild endometriosis is associated with contradictory results in terms of improvement of infertility.27,28 A multivariant analysis showed that endometriosis does not affect cumulative conception rates in the absence of anatomical distortion of the pelvis.29

Immunological Infertility Some authors have questioned the purpose of making a conclusive diagnosis of immunological infertility in the absence of any targeted treatment strategies.14 However, it was reported that autoimmune disease affects up to 20% of men and women in the industrial world.30 Some evidence was reported to support the

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role of autoimmune factors in female infertility by several workers.31–34 As a result of these reports antiphospholipid, antinuclear, antithyroid and antisperm antibodies, and generalised immune testing were widely requested from infertile couples for the diagnosis of immunological infertility. However, little scientific evidence exists to guide physicians as to which population should be tested and the nature and timing of the tests. More rigorous studies have failed to confirm a causal effect between abnormal immune function and early reproductive failure.35 Association between peripheral blood natural killer (NK) cells and the outcome of IVF have yet to be confirmed.36 Thum et al reported that women with a peripheral NK cell level of >12% do not have a higher number of previous pregnancy losses or lower pregnancy rate.37 Some studies reported elevated peripheral NK activity in patients with unexplained infertility suggesting an immunological cause of infertility in these patients.38 The absence of good treatment options does not necessarily mean that abnormal autoimmune function may not be an aetiological factor associated with infertility.12 The resistance towards investigations of immunological causes of infertility is because it cannot be followed up with effective treatment. However, one has to assume that at least some cases of unexplained infertility may be a reflection of decreased fecundity because of abnormal immune function, and not totally unexplained.

Premature ovarian failure At the age of 37–38 years a critical point in the reproductive potential of women is reached with approximately 25 000 follicles remaining in the ovaries. Follicular depletion accelerates towards menopause, which is reached when the follicular count reaches approximately 1000, at an average age of 51 years.39–42 Several authors have shown that the time period between accelerated decline in infertility (age 37–38 years and 25 000 follicles) and menopause (age 51 years and 1000 follicles) is fixed at approximately 13.5 years.41,42 Thus, a woman who reaches her acceleration point of fertility decline early will most likely reach menopause early. It was reported that approximately 10% of women experience early menopause before 45 years and 1% before 40 years.43 These women would present with evidence of diminished fertility when nobody would expect such a decline, based on their age. These women, as they do not have symptoms, will be erroneously diagnosed as unexplained infertility. However, they can be correctly diagnosed if women alleged to have unexplained infertility are carefully investigated for signs of premature ovarian failure. Assessment of basal FSH level at day 3 of the cycle, antiMullerian hormone level, antral follicular count, previous ovarian response to gonadotrophin stimulation and family history of early menopause will help

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in diagnosing this group. However, currently it is unclear whether an effective diagnostic test for poor ovarian reserve exists.44 As a reliable and accurate marker for ovarian reserve does not exist, older women will be offered the same treatment options. Thus, it is questionable whether formal identification of women with poor ovarian reserve could improve their chances of a live birth.14

Implantation failure It has been suggested that there may be an association between the expresssion of endometrial integrin αvβ3 and repeated implantation failure often labelled as unexplained infertility. A prospective study was performed using a semiquantitative immunohistochemical analysis on the staining intensity of integrin αvβ3 in the midsecretary endometria derived from ten fertile and 57 infertile patients with a history of repeated IVF/embryo transfer (ET) failure by Tei et al.45 Nine patients were randomly selected from 22 patients with unexplained infertility and were treated with oral dianazol administration for 12 weeks. There was significantly decreased expression of endometrial integrin αvβ3 suggesting that functional but not morphological endometrial defect may be one of the causes for patients with unexplained infertility. Danazol may have therapeutic potential in improving endometrial function together with upregulation of αvβ3.45 Also, the role of thrombophilia and thyroid autoimmunity on implantation in unexplained infertility was investigated by several workers.A total of 119 women were prospectively investigated including 31 patients with unexplained infertility, 26 with implantation failure, 30 with recurrent spontaneous abortion and 32 oocyte donors by Bellver et al.46 There was a trend towards a higher prevalence of thyroid autoimmunity in the unexplained infertility and implantation failure groups than in the control group. The prevalence of thrombophila was high and similar among groups. The authors concluded that when embryo aneuploidy is ruled out, thrombophila could constitute an aetiological factor in unexplained infertility and thyroid autoimmunity is strongly related to unexplained infertility and implantation failure. Restricting the diagnosis of unexplained infertility to couples in whom standard investigations including semen analysis, tests of ovulation and tubal patency are normal is liable to miss the diagnosis of some aetiological factors such as mild tubal disease, immunological infertility, mild/minimal endometriosis, premature ovarian failure and implantation failure. However, missing the correct diagnosis of the cause of infertility in these groups of patients is not likely to change the treatment offered to the patients. The implications of cost, inconvenience and side-effects of the additional tests must be weighed against the expected benefit. The existence of the entity of unexplained infertility has been recently challenged by some authors who

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suggested that diagnosis of unexplained infertility always has to be seen as provisional and subject to revisions.12 Efforts should be undertaken to develop reliable tools to diagnose endometriosis, tubal disease, premature ovarian failure, immunological infertility and implantation failure, which are often misdiagnosed for unexplained infertility. Diagnostic terminology should be based on positive diagnostic findings and not on their absence. However, applying the best and most accurate diagnostic tools will leave some patients without a specific diagnosis. These patients may be considered as couples with “undiagnosed infertility” rather than unexplained infertility couples.

Treatment of unexplained infertility The most effective way of obtaining pregnancy for couples with unexplained infertility has not yet been clearly demonstrated.47,48 In unexplained infertility there is no known defect which can be corrected by a uniform treatment protocol the risks, benefits and efficacy of which can be evaluated. This is because the population of unexplained infertility is a heterogeneous group including fertile couples who merely by chance have failed to conceive before seeking medical consultation and couples with abnormalities not yet detected by the methods of investigations used. The majority of the first group will conceive spontaneously simply after a time without any medical intervention. On the other hand, the majority of the second group will probably conceive only after some sort of medical intervention. The outcome of the interventions will depend on the aetiology and the extent of the underlying cause of the infertility. Options available for patients with unexplained infertility include expectant treatment, ovulation enhancement with clomiphene citrate, letrozole, gonodotrophins, IUI with or without controlled ovarian hyperstimulation (COH), tubal flushing or pertubation, fallopian sperm perfusion and ART.

Expectant treatment Expectant treatment may be the first option for unexplained infertility in young women with short infertility duration. Acumulative pregnancy rate over 3 years of 30–80% was reported by Hull et al, varying according the female age and infertility duration.49 After >3 years of infertility the cumulative pregnancy rate deceased by 2% for each year of age after 25.7 years.50 Several workers have shown that only one-third to one-half of infertile couples sought medical care for their infertility. There were no differences in the proportions of the patients who got pregnant among those who sought medical help and those who did not.51–53 In a randomised clinical trial on 253 couples with unexplained infertility and an intermediate prognosis a large beneficial effect of COH-IUI versus expectant management could not be found. Expectant management for 6 months was therefore justified in these couples.54 However, in persistent infertility,

Hughes performed a meta-analysis of 22 trials on the effectiveness of ovulation induction and IUI compared with no treatment. It was concluded that the best available evidence indicated that average fecundity is more than 2-fold higher in a cycle with either IUI or stimulation and 5-fold higher when both treatments are used compared with no treatment cycles.55 The author realised the complexity of the studies in this meta-analysis and called for further studies of COH-IUI versus no treatment.

Controlled ovarian hyperstimulation Ovarian stimulation improves the cycle fecundity rate in part by increasing the number of follicles available for fertilisation and correcting subtle, unpredictable ovulatory dysfunctions. Several trials have been published on the value of ovulation enhancement with clomiphene citrate and/or gonadotrophins in patients with unexplained infertility.

Clomiphene citrate In a systematic Cochrane review of clomiphene citrate for unexplained infertility Hughes et al found no evidence that clomiphene citrate was more effective than no treatment or placebo. The odds ratios for clinical pregnancy per patient were 2.4 with a 95% confidence interval (CI) 0.70–8.19 (p=0.16) for clomiphene citrate with IUI; 0.99 (95% CI 0.61–1.60, p=0.96) without IUI and 1.66 (95% CI 0.56–4.80, p=0.35) without IUI and using human chorionic gonadotrophin. The heterogeneity between the studies ranged from 33.5 to 57.6% using the I2 statistics. The authors concluded that there does not appear to be any clinical benefit from the use of clomiphene citrate for unexplained infertility, although the lack of homogeneity among studies should be noted.56 Although the absolute treatment effect is small, the low cost of clomiphene citrate, its ease of administration and its relatively low risk make the use of clomiphene citrate common clinical practice as a first choice option for some couples seeking treatment for their unexplained infertility by many physicians in spite of lack the of strong evidence. N-acetyl cysteine was found to be ineffective in inducing or augmenting ovulation in patients with unexplained infertility and cannot be recommended as an adjuvant to clomiphene citrate in these patients.57 The risks of clomiphene citrate include increased incidence of multiple pregnancy, very low risk of ovarian hyperstimulation and a suggestion of a potential increase in ovarian cancer.

Gonadotrophins Gonadotrophins alone or in combination with clomiphene citrate are commonly used for superovulation in patients with unexplained infertility. However, most of the studies to date have been retrospective, uncontrolled and included non-homogenous groups of patients. The use of gonadotrophins also increases the

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cost and the risks of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. A randomised controlled trial by Hughes et al of three low-dose gonadotrophin protocols for unexplained infertility revealed a very low pregnancy rate and significant difference between protocols suggesting that an individualised and more intensive approach to ovarian stimulation is necessary for many women with unexplained infertility.58 A prospective randomised study on the addition of gonadotrophin releasing hormone agonist and/or two inseminations with husband’s sperm did not improve the pregnancy rate in superovulated cycles in patients with unexplained infertility.59 Zikopoulos et al, in a prospective randomised study, found that homologous IUI has no advantage over timed natural intercourse when used in combination with ovulation induction for the treatment of unexplained infertility.60 Another prospective randomised trial of IUI versus timed intercourse in cycles stimulated with gonadotrophins or clomiphene citrate found no difference in the pregnancy rate.61 However, prospective randomised studies by other workers on COH with or without IUI for the treatment of unexplained infertility found significantly higher pregnancy rates after IUI.65,66

Danazole A recent systematic review by Hughes et al on danazole for unexplained infertility revealed that there was no statistically significant difference in the live birth/ongoing pregnancy rates between dianozole and placebo at the end of treatment (OR 1.16, 95% CI 0.0–8.29, p=0.36) or at the end of follow-up (OR 2.41, 95% CI 0.59–9.82, p=0.22). There was no significant difference in clinical pregnancies following treatment. Multiple side-effects were reported. The authors concluded that available data demonstrate no evidence of the benefit of danazol for unexplained infertility. The need for contraception during treatment and adverse effects and costs makes its use for unexplained infertility unwarranted.64

Controlled ovarian hyperstimulation and intrauterine insemination Ovulation enhancement with gonadotrophins combined with IUI had been extensively used for the treatment of unexplained infertility. However, most of the studies performed have been retrospective, uncontrolled and included heterogeneous groups of patients. Simon et al, in a retrospective study of 87 couples with unexplained infertility who underwent 446 cycles of COH-IUI, reported a cumulative pregnancy rate of 34%.65 In another retrospective study, by Aboulghar et al, of 268 couples with unexplained infertility of more than 4 years duration who were treated with COH-IUI

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for 463 treatment cycles, the cycle fecundity was 20.1% per cycle. The fecundity of 112 comparable couples, who did not have any treatment during the same period, was 8.9%.66 A meta-analysis of eight prospective randomised studies comparing IUI with timed intercourse in cycles superstimulated with gonadotrophins in unexplained infertility showed a significantly increased pregnancy rate in IUI patients (OR 1.84, 95% CI 1.3–2.62).67 In a prospective study on 485 patients with long standing unexplained infertility who underwent 921 cycles of COH-IUI with a maximum of three cycles/ patient, the pregnancy rate was 15.7% per cycle and 29.8% per patients.68 Sahakyan et al showed that there is a clear agerelated decline in fecundity associated with COH-IUI and suggested that the number of IUI trials should be limited to four.69 A randomised study investigated the effect of bed rest on the results of IUI and concluded that a 10minute interval of bed rest after IUI has a positive effect on the pregnancy rate.70 Whether the use of prostaglandin E1 analogue misoprostol (400 mg) vaginally at the time of IUI improves the pregnancy rate was investigated by Brown et al in a prospective placebo controlled randomised double blinded study. The study included 274 women who underwent 494 IUI cycles. The cumulative pregnancy rate in the misoprostol group was significantly greater than in the placebo group.71 In a prospective randomised trial comparing the different gonadotrophin preparations in IUI cycles for the treatment of unexplained infertility it was found that recombinant FSH (rFSH) may result in a significantly better outcome in IUI cycles (25.9%) compared with urinary FSH (uFSH) (13.8%) and human menopausal gonadotrophin (hMG) (12.5%) (p=0.04). The mean FSH dose consumed per cycle was significantly lower in the rFSH group compared with others (825 IU in rFSH, 1107 IU in uFSH, and 1197 IU in hMG group) (p=0.001).72 Increased female age >35 years and male age >40 years were found to negatively influence pregnancy rates with COH-IUI.73 No pregnancies occurred when >35 ampoules of FSH were used in one cycle irrespective of the age.74 A recent meta-analysis was performed by Verhulst et al to determine whether IUI in couples with unexplained infertility improves the live birth rate compared with timed intercourse both with and without ovarian hyperstimulation.75 Truly randomised controlled trials with at least one of the following comparisons were included: (1) IUI versus timed intercourse both in a natural cycle; and (2) IUI versus timed intercourse both in a stimulated cycle. The study showed that there is evidence that IUI improves the odds of becoming pregnant for couples with unexplained infertility compared with timed intercourse. The addition of fertility drugs to IUI treatment to

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induce ovulation also improves the chances. There are insufficient data on multiple pregnancies and other adverse events after treatment with ovarian hyperstimulation. Therefore, couples should be fully informed about the risks of IUI and ovarian hyperstimulation as well as alternative treatment options. The complications of COH-IUI are few. Possible complications include infection, OHSS, multiple pregnancy and ectopic pregnancy. The risk of infection is negligible. OHSS is rare in these patients because of the use of soft stimulation protocols. However, the multiple pregnancy rate is rather high and is considered to be one of the most serious complications of this line of treatment. Should ovarian hyperstimulation occur the cycle is cancelled, converted to an IVF/ICSI cycle or some of the antral follicles are aspirated.76

Tubal flushing or perturbation Tubal flushing or perturbation has been previously proved to increase the chance of achieving pregnancy for couples with unexplained infertility and early stage endometriosis.77 Edelstam et al suggested that perturbation treatment can be administered in an outpatient clinic and represents a less invasive treatment alternative.78 The positive effect of perturbation can be mechanical as well as immunological through inhibiting phagocytosis of sperm, or affecting levels of peritoneal factors such as cytokines.79–81 Edelstam et al investigated the effect on pregnancy rate of perturbation with lignocaine in a balanced salt solution the day before ovulation in a prospective randomised open study. A total of 130 cycles were studied and randomised to either perturbation with low-dose lignocaine n=67) or no perturbation (n=63) before IUI. There were 14.9% (n=10) clinical pregnancies in the perturbated group compared with 3.2% (n=2) in the group without preovulatory perturbation (p<0.05). The perturbation treatment significantly enhanced the clinical pregnancy rate and was well tolerated with no complications.82 The authors recommended that the combined treatment of clomiphene citrate, perturbation and IUI can be used as a cost-effective first-line treatment for couples with unexplained infertility. The effectiveness of flushing with the oil-soluble contrast medium lipiodol in women with unexplained infertility was examined by Johnson et al in an open randomised controlled trial. Lipiodol flushing was tested compared with no intervention. Clinical pregnancy was assessed at 6 months following randomisation. Lipiodol flushing was associated with a significant increase in pregnancy in (33.3 versus 20.8%, RR 1.60, 95% CI 0.81–3.16) and live birth (27.1 versus 14.6%, RR 1.86, 95% CI 0.81–4.25).83

Fallopian sperm perfusion Fallopian sperm perfusion (FSP) was used in the treatment of unexplained infertility by suspending the

sperm in a large volume (4 ml) of solution which was injected to reach the fallopian tubes via the cervix.84 Mamas et al in a prospective randomised study on patients with unexplained infertility reported a higher pregnancy rate in FSP compared with IUI.85 A metaanalysis by Trout and Kemmann showed that FSP significantly improved the pregnancy rate in unexplained infertility patients who underwent ovarian hypertstimulation by gonadotrophins.86 However, other investigators in randomised controlled studies did not find a higher pregnancy rate in FSP compared with IUI.87,88

In vitro fertilisation and intracytoplasmic sperm injection IVF and ICSI are widely used for the treatment of unexplained infertility. With the estimated live birth rates per cycle varying between 13 and 28%, the effectiveness of IVF/ICSI had not been rigorously evaluated in comparison with other less invasive treatments such as expectant management and IUI. Furthermore, concerns about complications of IVF/ICSI such as multiple pregnancy, OHSS, bleeding, infection, cost, availability and access to IVF/ICSI particularly in developing countries89,90 render IVF/ICSI, in most cases, the final option for patients with unexplained infertility. IVF/ICSI increases the number of oocytes available for fertilisation to facilitate the sperm oocyte interaction, enhance fertilisation and evaluate the embryo quality, all of which may be the underlying mechanism of unexplained infertility. A fertilisation rate of 60.4% was reported in couples with unexplained infertility which was significantly lower than fertilisation rate of 87.3% in patients with tubal infertility.91 Despite the decreased fertilisation rate in unexplained infertility, cleavage rates and implantation rates are similar to those of tubal infertility.92 Aboulghar et al in a prospective study, performed IVF and ICSI on sibling oocytes of 22 patients with unexplained infertility. There was total failure of fertilisation in five of the 22 patients with IVF and none in ICSI. The study showed that 22.7% of unexplained infertility patients would have lost their chance of embryo transfer completely because of total failure of fertilisation if ICSI was not performed on some oocytes in the cycles.93 In another prospective randomised study by Ruiz et al of 63 patients with unexplained infertility, sibling oocytes were randomised to IVF or ICSI. There was no significant difference in fertilisation rate between ICSI and IVF, and no difference in the embryo quality between both groups. However, there was a total failure of fertilisation in IVF in 11.4% and no total failure of fertilisation in ICSI oocytes.94 Fishel et al reported that ICSI, as a first option, offers a higher incidence of fertilisation, maximises the number of embryos and minimises the risk of

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complete failure of fertilisation for all cases requiring IVF including unexplained infertility.95 To evaluate IVF for unexplained infertility ten randomised controlled trials were identified by Pandian et al, comparing IVF with other lines of management of unexplained infertility. There was no evidence of a difference in live birth rates between IVF and IUI either without (OR 1.96; 95% CI 0.88–4.4) or with (OR 1.15, 95% CI 0.55–2.4) ovarian stimulation. There were significantly higher clinical pregnancy rates with IVF in comparison to expectant management (OR 3.24, 95% CI 1.017–9.80). There was no significant difference between IVF and gamete intrafallopian transfer (GIFT) in live birth rate (OR 2.57, 95% CI 0.93–7.08). However, there was a significant difference in the clinical pregnancy rates between IVF and GIFT (OR 2.14, 95% CI 1.08–4.2).48 The authors concluded that IVF might result in more pregnancies than other options for unexplained infertility, but this is still uncertain and more research is needed on birth rates, adverse outcomes and costs. IVF is complicated and can have many adverse effects. It is also expensive and often unaffordable or inaccessible, particularly in low and middle resourced countries. Other less expensive and accessible modalities of treatment of unexplained infertility should be tried first before referring the couple for IVF.7,89,90,96,97 The use of natural cycle IVF in unexplained infertility has also been described by some authors. Zayed et al examined the outcome of natural cycle IVF in 117 couples with unexplained infertility who underwent 162 attempts at natural cycle IVF between 1991 and 1993. The implantation rate per embryo was 16/89 (18.0%) which translated into a live birth rate per egg collection of 9/138 (6.5%). They concluded that in couples with unexplained infertility the outcome following natural cycle IVF is affected by both egg and sperm quality, and by age of the woman.98 They reported a 6.5% live birth rate per egg collective per unexplained infertility using natural cycle IVF. A prospective cohort study was carried out by Omland et al on unexplained infertility (33 couples), minimal peritoneal endometriosis (30 couples) and tubal factor (24 couples) in 223 natural cycle IVF cycles using hCG for ovulation induction. Periovulatory follicular growth monitored from the day of hCG administration to oocyte aspiration was significantly lowered in the unexplained infertility group compared with the groups with minimal endometriosis and tubal factor infertility. The fertilisation rate (62.2%) and clinical pregnancy rate per initiated cycle (2.6%), per successful oocyte retrieval (5.4%) and per embryo transfer (8.7%) for unexplained infertility was significantly lower than that for minimal endometriosis or tubal infertility.99 This could be explained by the suboptimal follicular development with possibly reduced oocyte quality, intrinsic embryo quality factors or by impaired implantation. Natural cycle IVF is therefore less suited to couples with unexplained infertility.

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In clinical practice couples with unexplained infertility who have had unsuccessful IUI often receive further treatment with IVF or ICSI. Peterson et al found that a course of therapy with one to four cycles of hMG and IUI was just as effective as one cycle of IVF in achieving pregnancy. They recommended four cycles of COH-IUI before IVF is attempted.100 Based on an observational prospective study on 594 couples with unexplained infertility who were treated with COH-IUI for up to three cycles before IVF/ICSI, Aboulghar et al recommended that IVF/ICSI be performed in patients with unexplained infertility after failure of three trials of COH-IUI.68

References 1. Rutstein SO, Shah IH. Infecundity, Infertility and Childlessness in Developing Countries. DHS Comparative Reports No. 9. Calverton, Maryland: ORC Macro and the World Health Organization. Available from http://www.measuredhs.com/ (accessed 10 October 2006). 2. World Health Organization, The Epidemiology of Infertility. Technical Report Series No. 582. Geneva: World Health Organization, 1975. 3. World Health Organization. Reproductive Health Indicators for Global Monitoring. Report of the second Interagency Meeting. Geneva: World Health Organization, 2001: WHO/RHR/01.19. 4. NICE. National Collaborating Centre for Women’s and Children’s Health. Fertility: Assessment and Treatment for People with Fertility Problems. Clinical Guidelines. London: RCOG Press, 2004. 5. Collins JA, Crosignani PG. Unexplained infertility: a review of diagnosis, prognosis, treatment efficacy and management. Int J Gynaecol Obstet 1992; 39: 267–75. 6. Serour GI, Hefnawi FI, Kandil O et al. Laparoscopic ventrolsuspension: a new technique. Int J Gynecol Obstet 1982; 20: 129–31. 7. Serour GI, El Ghar M, Mansour RT. Infertility: a health problem in Muslim world. Popul Sci 1991; 10: 41–58. 8. Templeton AA, Penney GC. The incidence, characteristics, and prognosis of patients whose infertility is unexplained. Fertil Steril 1982; 37: 175–82. 9. Smith S, Pfiefer SM, Collins J. Diagnosis and management of female infertility. JAMA 2003; 290: 17. 10. Crosignani PC, Collins J, Cooke ID, Diczfalusy E, Rubin B. Unexplained infertility (recommendations of ESHRE workshop). Hum Reprod 1993; 8: 977–80. 11. Evers JLH, Female subfertility. Lancet 2002; 360: 151–59. 12. Gleicher N, Barad D. “Unexplained infertility: does it really exist?” Hum Reprod 2006; 21: 1951–5. 13. Steures P, Van der Steeg JW, Hompes PG et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomized clinical trial. Lancet 2006; 368: 216–21. 14. Siristatidis C, Bhattacharya S, Unexplained infertility: does it really exist? Does it matter? Hum Reprod 2007; 22: 2084–7.

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15. Opsahl MS, Miller B, Klein TA. The predictive value of hysterosalpingography for tubal and peritoneal factors. Fertil Steril 1993; 60: 444–8. 16. Karande VC, Pratt DE, Gleicher N. The assessment of tubal functional status by tubal perfusion pressure measurement. Hum Reprod 1996; 2: 429–33. 17. Mol BWJ, Collins JA, Burrows EA, van der Veen F, Bossuyt PMM. Comparison of hysterosalpingography and laparoscopy in predicting infertility outcome. Hum Reprod 1999; 14: 1237–42. 18. Tanahatoe S, Hompes P, Lambalk CB. Accuracy of diagnostic laparoscopy in the infertility work-up before intrauterine insemination. Fertil Steril 2003; 79: 361–6. 19. Glatstein IZ, Sleeper LA, Lavy Y et al. Observer variability in the diagnosis and management of the hysterosalpingogram. Fertil Steril 1997; 67: 233–7. 20. World Health Organization. Comparative trial of tubal insufflations, hysterosalpingography, and laparoscopy with dye hydrotubation for assessment of tubal patency. Fertil Steril 1986; 46: 1101–7. 21. Karande V, Pratt D, Rabin DS, Gleicher N. The limited value of hysterosalpingography in answering tubal status and fertility potential. Fertil Steril 1995; 63: 1167–71. 22. Papaioannou S, Afnan M, Girling AJ et al. The potential value of tubal perfusion pressure measured during selective salpingography in predicting fertility. Hum Reprod 2003; 18: 358–63. 23. The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril 2004; 81: 1441–6. 24. Guidice LC, Kao LC, Endometriosis. Lancet 2004; 364: 1789–99. 25. Barnhart K, Dunsmoor R, Coutifaris C, Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77: 1148–55. 26. Arici A, Oral E, Bukulmez O et al. The effect of endometriosis on implantation: results from the Yale university in vitro fertilization and embryo transfer program. Fertil Steril 1996; 65: 603–7. 27. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997; 337: 217–22. 28. Parazzini F. Ablation of lesionsor no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per 10 Studio dell’ Endometriosi. Hum Reprod 1999; 14: 1332–4. 29. Olive DL, Schwartz LB. Endometriosis. N Engl J Med 1993; 328: 1759–69. 30. Cervera R. The epidemiology and significance of autoimmune diseases in health care, Scand J Clin Lab Invest 2001; 235: 27–30. 31. Geva E, Amit A, Lerner-Geva l et al. Autoimmune disorders; another possible cause for in-vitro fertilization and embryo transfer failure. Hum Reprod 1995; 10: 2563. 32. Roussev RG, Kaider BD, Price DE, Coulam CB. Laboratory evaluation of women experiencing reproductive failure. Am J Reprod Immunol 1996; 35: 415–20. 33. Shatavi SV, Lanes BL, Judith L. Association of unexplained infertility with gonadotropin and

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ovarian antibodies. Am J Reprod Immunol 2006; 56: 286–91. Schoenfeld Y, Carp HJP, Howard JA et al. Autoantibodies and prediction of reproductive failure. Am J Reprod Immunol 2006; 56: 337–44. Kallen CB, Arici A. Immune testing in fertility practice: truth or deception? Curr Opin Obstet Gynecol 2003; 15: 225–31. Somigliana E, Vigano P, Vignali M. Endometriosis and unexplained recurrent spontaneous abortion: pathological states resulting from aberrant modulation of natural killer cell function? Hum Reprod Update 1999; 5: 40–61. Thum MY, Bhaskaran S, Bansal AS et al. Simple enumerations of peripheral blood natural killer (CD56+NK) cells, B cells and T cells have no predictive value in IVF treatment outcome. Hum Reprod 2005; 20: 1272–6. Matsubayashi H, Hosaka T, Sugiyama Y et al. Increased natural killer-cell activity is associated with infertile women. Am J Reprod Immunol 2001; 46: 318–22. Guzick DS, Grefenstette I, Baffone K et al. Infertility evaluation in infertile women: a model for answering the efficacy of infertility testing. Hum Reprod 1994; 9: 2306–10. Velde ER, Scheffer GJ, Douland M, Broekmans FJ, Fauser BCJM. Development of endocrine aspects of normal ovarian aging. Mol Cell Endocrinol 1998; 145: 67–73. Faddy MJ, Follicle dynamics during ovarian aging. Mol Cell Endocrinol 2000; 163: 43–8. Nikolaou D and Templeton A. Early ovarian aging: a hypothesis. Detection and clinical relevance. Hum Reprod 2003; 18: 1137–9. Van Noord PA, Dubas JS, Douland M, Broekmans FJ, te Velde E. Age at natural menopause in a population-based screening cohort: the role of menarche. Fertil Steril 1997; 68: 95–102. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006; 12: 685–718. Tei C, Maruyama T, Kuji N et al. Reduced expression of alphavbeta3 integrin in the endometrium of unexplained infertility patients with recurrent IVFET failures: improvement by danazol treatment. J Assist Reprod Genet 2003; 20: 13–20. Bellver J, Soares SR, Alvarez C et al. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod 2008; 23: 278–84. Guzick DS, Sullivan MW, Adamson GD et al. Efficacy of treatment for unexplained infertility. Fertil Steril 1998; 70: 207–13. Pandian Z, Bhattacharya S, Vale L, Templeton A. In vitro fertilization for unexplained subfertility. Cochrane Database Syst Rev 2005; (2): CD003357. Hull MGR, Glazener CMA, Kelly NJ et al. Population study of causes, treatment, and outcome of infertility. BMJ 1985; 304: 1693–7. Collins JA, Rowe TC. The age of the female partner is a prognostic factor in prolonged unexplained

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51.

52. 53.

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59.

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61.

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infertility: a multi center study. Fertil Steril 1989; 52: 15–20. Shalev J, Goldenberg M, Kukia E et al. Comparison of five clomiphene citrate dosage regimens: follicular recruitment and distribution in the human ovary. Fertil Steril 1989; 52: 560–3. Gindoff PR, Jewelewiez R. Reproductive potential in the older woman. Fertil Steril 1986; 46: 989–1001. Pearlstone AC, Fournet N, Bambone JC, Pang SC, Buyalos RP. Ovulation induction in women age 40 and older: the importance of basal follicle-stimulating hormone level and chronological age. Fertil Steril 1992; 58: 674–9. Steures P, van der Steeg JW, Hompes PG et al. Collaborative Effort on the Clinical Evaluation in Reproductive Medicine. Lancet 2006; 368, 9531: 216–21. Hughes EG. The effectiveness of ovulation induction and intrauterine insemination in the treatment of persistent infertility: a meta-analysis. Hum Reprod 1997; 12: 1865–72. Hughes E, Brown J, Collins J, Vandekerckhove P, Clomiphene citrate for unexplained subfertility in women. Cochrane Database of Systematic Review 2000 Issue 2. Copyright© 2008 The Cochrane collaboration. Published by John Wiley & Sons, Ltd Art. No. CD000057. DOI 10.1002/1465185.CD000057. Badawy A, El Nashar AB, El Totongy M. Clomiphene citrate plus N-acetyl cysteine versus CC for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial. Fertil Steril 2006; 86: 647–50. Hughes EG, Collins JA, Gunby J. A randomized controlled trial of three low-dose gonadotrophin protocols for unexplained infertility. Hum Reprod 1998; 13: 1527–31. Karlstrom PO, Bergh T, Lundkvist. Addition of gonadotrophin-releasing hormone agonist and/or two inseminations with husband’s sperm do not improve the pregnancy rate in superovulated cycles. Acta Obstet Gynecol Scand 2000; 79: 37–42. Zikopoulos K, West CP, Thong PW et al. Homologous intrauterine insemination has no advantage over timed natural intercourse when used in combination with ovulation induction for the treatment of unexplained infertility. Hum Reprod 1993; 8: 563–7. Karlstom PO, Bergh T, Lundkvist O. A prospective randomized trial of artificial insemination versus intercourse in cycles stimulated with human menopausal gonadotropin or clomiphene citrate. Fertil Steril 1993; 59: 554–9. Gregoriou O, Vitoratos N, Papadias C et al. Controlled ovarian hyperstimualtion with or without intrauterine insemination for the treatment of unexplained infertility. Int J Gynaecol Obstet 1995; 48: 55–9. Crosignani PG, walters DE, Soliani A. The ESHRE multicenter trial on the treatment of unexplained infertility: a preliminary report. European Society of Human Reproduction and Embryology. Hum Reprod 1991; 6: 953–8. Hughes E, Brown J, Tiffin G, Vandekerckhove P. Danazol for unexplained infertility. Cochrane Database Syst Rev 2007; (1): CD000069.

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65. Simon A, Avidan B, Mordel N et al. The value of menotrophin treatment for unexplained infertility prior to an in vitro fertilization attempt. Hum Reprod 1991; 6: 222. 66. Aboulghar MA, Mansour RT, Serour GI et al.Ovarian superstimulation and intrauterine insemination for the treatment of unexplained infertility. Fertil Steril 1993; 60: 303–6. 67. Zeynogloglu HB, Arici A, Olive DL, Duleba AJ. Comparison of intrauterine insemination with timed intercourse in superovulated cycles with gonadotropins: a meta-analysis. Fertil Steril 1998; 68: 486–91. 68. Aboulghar MA, Mansour RT, Serour GI et al. Controlled ovarian hyperstimulation and intrauterine insemination for treatment of unexplained infertility should be limited to a maximum of three trials. Fertil Steril 2001; 75: 88–91. 69. Sahakyan M, Harlow BL, Hornstein MD. Influence of age, diagnosis, and cycle number on pregnancy rates with gonadotropin-induced controlled ovarian hyperstimulation and intrauterine insemination. Fertil Steril 1999; 72: 500–4. 70. Saleh A, Tan SL, Biljan MM, Tulandi T. A randomized study of the effect of 10 minutes of bed rest after intrauterine insemination. Fertil Steril 2000; 74: 509–11. 71. Brown SE, Toner JP, Schnorr JA et al. Vaginal misoprostol enhances intrauterine insemination. Hum Reprod 2001; 16: 96–101. 72. Demirol A, Gurgan T. Comparison of different gonadotrophin preparations in intrauterine insemination cycles for the treatment of unexplained infertility: a prospective, randomized study. Hum Reprod 2007; 22: 97–100. 73. Brzechffa PR, Daneshmand S, Buyalos RP. Sequential clomipheme citrate and human menopausal gonadotropin with intrauterine insemination: the effect of patient age on clinical outcome. Hum Reprod 1998; 13: 2110–14. 74. Brzechffa PR, Buyalos RP. Female and male partner age and menotropin requirements influence pregnancy rates with human menopausal gonadotropin in combination with intrauterine insemination. Hum Reprod 1997; 12: 29–33. 75. Verhulst SM, Cohlen BJ, Hughes E, te Velde E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2008; (4): CD001838. 76. Serour GI, Multiple pregnancy an ongoing epidemic: What can we do about it. Egyptian J Fertil Steril 2006; 10: 1–4. 77. Johnson N, Vandekerckhove, P, Watson A et al. Tubal flushing for subfertility. Cochrane Database Syst Rev 2005; (2): CD003718. 78. Edelstam GAB, Sjosten ACE. Wernekink Salamon AC, Pertubation with lignocaine-a possible new treatment for women with endometriosis and impaired fertility, Ups J Med Sci 2001; 106: 51–7. 79. Oak M, Chantler EN, Vaughan Williams CA, Elstein M, Sperm survival studies in peritoneal fluid from infertile women with endometriosis and unexplained infertility. Clin Reprod Fertil 1985; 3: 297–303.

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80. Edelstam GA, Andersson E, Radestad A, Flam F, Gottlib C. The effect of lignocaine on sperm phagocytosis in the peritoneal fluid from women with or without endometriosis. Hum Reprod 1998; 13: 1353–45. 81. Agic A, Xu H, Finas D et al. Is endometriosis associated with systemic subclinical inflammation? Gynecol Obstet Invest 2006; 62: 139–47. 82. Edelstam G, Sjosten A, Bjuresten K et al. A new rapid and effective method for treatment of unexplained infertility. Hum Reprod 2008; 23: 852–6. 83. Johnson NP, Farquhar CM, Hadden WE, Suckling J, Sadler L. The flush trial-flushing with lipiodol for unexplained infertility (and endometriosis related) subfertility by hysterosalpingography: a randomized trail. Hum Reprod 2004; 19: 2043–51. 84. Kahn JA, Sunde A, Koskemies A et al. Fallopian tube sperm perfusion (FSP) versus intra-uterine insemination (IUI) in the treatment of unexplained infertility: a prospective randomized study. Hum Reprod 1993; 8: 890–4. 85. Mamas L. Higher pregnancy rates with a simple method for fallopian tube sperm perfusion, using the cervical clamp double nut bivalve speculum in the treatment of unexplained infertility: a prospective randomized study. Hum Reprod 1996; 11: 2618–22. 86. Trout SW, Kemmann E. Fallopian sperm perfusion versus intrauterine insemination: a randomized controlled trial and meta-analysis of the literature. Fertil Steril 1999; 71: 881–5. 87. Gregoriou O, Pyrgiotis E, Konidaris S, Papadias C, Zourlas PA. Fallopian tube sperm perfusion has no advantage over intrauterine insemination when used in combination with ovarian stimulation for the treatment of unexplained infertility. Gynecol Obstet Invest 1995; 39: 226–8. 88. El Sadek MM, Amer MK, Abdel-Malak G. Questioning the efficacy of fallopian tube sperm perfusion. Hum Reprod 1998; 13: 3053–6. 89. Serour GI, Aboulghar MA, Mansour RT et al. Complications of medically assisted conception in 3500 cycles. Fertil Steril 1998; 70: 638–42.

90. Serour GI. Medical and socio-cultural aspects of infertility in the Middle East. Hum Reprod 2008; ESHRE special task force on Developing Countries and Infertility. DOI: dri10.1093/humrep/den143, p 34–41. 91. Mackenna AI, Zergers-Hochchild F, Fernandez EO, et al. Fertilization rate in couples with unexplained infertility. Hum Reprod 1992; 7: 233. 92. Trouson AO, Leeton JF, Wood C et al. The investigation of idiopathic infertility by in vitro fertilization. Fertil Steril 1980; 34: 431. 93. Aboulghar MA, Mansour RT, Serour GI, Sattar MA, Amin Y. Intracytoplasmic sperm injection and conventional in vitro fertilization for sibling oocytes in cases of unexplained infertility and borderline semen. J Assist Reprod Genet 1996; 13: 38–42. 94. Ruiz A, Remohi J, Minguez Y et al. The role of in vitro fertilization and intracytoplasmic sperm injection in couples with unexplained infertility after failed intrauterine insemination. Fertil Steril 1997; 68: 171–3. 95. Fishel S, Aslam I, Lisi F, et al. Should ICSI be the treatment of choice for all cases of in vitro conception? Hum Reprod 2000; 15: 1278–83. 96. Shahin A, The problem of IVF cost in developing countries: has natural cycle IVF a place? Reprod Biomed Online 2007; 15: 51–6. 97. Serour GI, El Ghar M, Mansour RT. In vitro fertilization and embryo transfer in Egypt. Int J Gynecol Obstet 1991; 36: 49–53. 98. Zayed F, Lenton EA, Cooke ID. Natural cycle invitro fertilization in couples with unexplained infertility: impact of various factors on outcome. Hum Reprod 1997; 12: 2402–7. 99. Omland AK, Fedorcsâk P, Storeng R et al. Natural cycle IVF in unexplained, endometriosis associated and tubal factor infertility. Hum Reprod 2001; 36: 2587–92. 100. Peterson CM, Hatasak HH, Jones KP et al. Ovulation induction with gonadotropins and intrauterine insemination compares with in vitro fertilization and no therapy: a prospective nonrandomized cohort study and meta-analysis. Fertil Steril 1994; 62: 535–44.

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25 The patient from the developing world William Ombelet, Geeta Nargund

Introduction For most people, infertility or childlessness is a devastating experience. Its implications are strongly related to and mediated by different sociocultural factors. Especially in developing countries, most societies are organised such that children are necessary for the care and maintenance of older parents. Moreover, in the absence of social security systems, older people are economically completely dependent on their children. Consequently, the inability to bear children is a tragedy and childlessness can be considered as one of the most important and underappreciated reproductive health problems in developing countries.1,2 In many cultures womanhood is defined through motherhood and infertile women usually carry the blame for their inability to conceive. Negative psychosocial consequences of childlessness are common and often severe, and relationships between couples can become very strained when children are not forthcoming.3–8 Childless women are frequently stigmatised, resulting in isolation, neglect, domestic violence and polygamy.9–17 Women who have never had a child are more likely to be divorced and separated, and childless women are also more likely to have been married more than once.18 There is no doubt that the consequences of infertility are much more severe for couples in developing countries compared with couples in developed countries.19 On the other hand, it is generally believed that more than 70 million couples suffer from infertility worldwide, most being residents of developing countries.20,21 Bilateral tubal occlusion due to sexually transmitted diseases (STDs), unsafe abortion or postpartum infections is the most common underlying cause.22,23 Infertility caused by STDs, whether female or male, is potentially treatable by assisted reproductive technologies (ART). Unfortunately, in most developing countries infertility treatment and ART methods are either unavailable or very costly12,23,24 despite the fact that many citations and recommendations can be found in the literature highlighting the importance of infertility (Fig 25.1). Many concerns overshadow the possible role of ART in developing countries such as whether expensive techniques which

Men and women of full age, without any limitation due to race, nationality or religion, have the right to marry and to found a family UN declaration of Human Rights, Article 16.1 And when Rachel saw that she bare Jacob no children, Rachel invites her sister; and said unto Jacob: Give me children or else I die Holy Bible: Genesis: 30:1 Infertility should be recognized as a Public Health issue worldwide, including developing countries WHO meeting, Geneva 2001 Reproductive health implies that people have the capability to reproduce and the freedom to decide if, when and how often to do so UN International Conference for Population and Development, Cairo, 1994

Fig 25.1 Important citations and recommendations on the issue of infertility and childlessness.

have a low success rate can be justified in countries where poverty is still an important issue.3,4,25,26 Another concern might be the observation that many health care systems in developing countries still struggle with the immense problem of infectious diseases such as malaria, tuberculosis, gonorrhoea and HIV. Last but not least, during the past decades national and international health strategies have only focused on reducing total fertility rates while infertility care has received almost no attention.27

Differences between childlessness and/or infertility in developed versus developing countries WHO reports clearly show that the aetiological factors associated with infertility are different in most developing countries when compared with developed countries.22 This does not necessarily mean that the prevalence of infertility differs substantially, it only shows us that the reasons for infertility and the resulting treatment options might be different.

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Aetiological factors of infertility In sub-Saharan Africa over 85% of women have an infertility diagnosis attributable to infection compared with 33% of women worldwide and a history of STDs was reported by 46% of men.22,28,29 Another large study performed in 33 WHO centres showed that almost 50% of the African couples had infectious tubal disease compared with 11–15% of patients in other parts of the world.30 Approximately 70% of pelvic infections are caused by STDs while the other 30% are attributable to pregnancy-related sepsis.31 Similarly, most cases of male factor infertility are caused by previous infections of the male genitourinary tract.32 STDs are obviously the most important risk factor for infertility in developing countries. Chlamydia trachomatis and Neisseria gonorrhoea are most commonly involved,33–35 but also pelvic tuberculosis may result in tubal infertility with high incidences reported in the Indian subcontinent and Ethiopia.36–38 Individual studies from Nigeria, South Africa and Egypt have reported prevalence rates of tubal factor infertility ranging from 42% to 77%.39–42 HIV-1 is also an important sexually transmitted organism associated with infertility and a reduced fecundity in HIV-infected individuals has been previously reported.37,43 This can be explained by tubal factor infertility through the greater susceptibility to other STDs, weight loss-related anovulation and amenorrhoea, male hypogonadism, altered spermatogenesis and an increased risk of miscarriages.44–46 An odds ratio of 4.05 for spontaneous abortions was described in a meta-analysis comparing HIV-positive women with healthy controls for both developed and developing countries.43 Marital instability and polygamy secondary to infertility can also increase the spread of HIV-1 infection. Related risk factors for STDs include poor education, poverty, negative cultural attitudes to women, early age at first marriage, lack of access to contraception, polygamy and the adverse effects of migrant labour.47 Studies from non-African developing countries (Asia, Latin America) on the causes of infertility are scarce, but available data indicate that infectionrelated infertility also plays a prominent role in these countries.48,49 The most important factors associated with the high prevalence of tubal factor infertility and STDs in developing countries are shown in Table 25.1. Out of the 20 million illegal abortions that take place every year, almost 97% occur in developing countries.50,51 Because illegal abortions are mostly carried out by unqualified personnel in unsafe and unsterile conditions, infections are much more likely to occur.2,52 Moreover, access to appropriate medical treatment if complications occur is often insufficient or not present at all.2 Due to a lack of access to appropriate medical care, especially in rural areas, postpartum pelvic infections are extremely common in developing countries. Home deliveries, performed in unhygienic circumstances by

Table 25.1 The most important factors associated with the high prevalence of tubal factor infertility in developing countries.

Organisms most commonly involved [Neisseria gonorrhoea, Chlamydia trachomatis, tuberculosis, HIV-1, schistosomiasis, etc Sexually transmitted infections Lack of timely diagnosis Lack of appropriate treatment Other factors: low condom use, polygamy, poor education, poverty, adverse effects of migrant labour, etc Unsafe deliveries Lack of appropriate treatment High risk for vesicovaginal fistula Political indifference: lack of interest, lack of preventive measures Other factors: poor reproductive health education, poverty, urban versus rural areas, etc Illegal abortions Mainly influenced by religious and sociocultural differences Lack of appropriate treatment Other factors: teenage pregnancies, poverty, urban versus rural areas, etc

inadequately trained or equipped birth attendants, increase the risk of complications and postpartum infections dramatically. Only about 40% of births in sub-Saharan Africa are attended by trained personnel.53 The most important complications of obstructed or unassisted labour are trauma, sepsis and obstetric fistulas. All these complications compromise the future reproductive potential of these women substantially.

Prevalence of infertility Reports of papers on the prevalence of infertility in developing countries are limited. Substantial geographical differences in the prevalence are noted, and these differences can be explained by different environmental, cultural and socioeconomic influences. In subSaharan Africa the prevalence differs widely from 9% in the Gambia54 and 11.8% in Ghana55 to 21.2% in north-western Ethiopia56 and between 20 and 30% in Nigeria.57–60 Data available from Asia and Latin America are scarce, but a WHO report61 showed a prevalence of infertility in these regions within the globally expected range of 8–12% of couples of reproductive age. Boivin et al21 recently published the results of an international survey on the estimates of prevalence of infertility. They studied 25 population surveys sampling 172 413 women. The estimated overall median prevalence in this study was 9%. The 12-month prevalence rate ranged from 6.9 to 9.3% in less-developed nations compared with 3.5 to 16.7% in more developed nations. The proportion of couples seeking

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medial care was, on average, 51.2% in less developed countries and 56.1% in more developed countries. They also described that the proportion of people actually receiving care in developed and less-developed countries was only 22.4%. The results are remarkably similar between more and less developed countries, although the underlying mechanisms contributing to these data might be very different between continents and countries. In developing countries most cases of infertility are associated with pelvic infections and tubal factor infertility, which are not a frequent cause of infertility in more developed countries. On the other hand, age-related infertility, sterility due to female or male sterilization and severe endometriosis are more frequently reported as a cause of infertility in developed countries. Considering the proportion of infertile couples seeking medical care, the low incidence of 51.2% in less-developed countries can partly be explained by the fact that in most developing countries the number of infertility services are limited and in many countries such services are even unavailable.

Consequences of infertility: sociocultural and psychological The problem of involuntary childlessness is undoubtedly a neglected problem in most developing countries.12,13 Most societies in developing countries place a high value on fertility and children. The inability to conceive creates many psychological, social and economic burdens, particularly for women.5,6,17 The psychological and social aspects of infertility in developing countries are clearly shown in Table 25.2. Although childlessness almost always leads to great suffering, especially for women, the impact of infertility varies between different regions and is influenced by religious, sociocultural and legal factors. Different religious customs, moral and legal rules may influence and explain the way a community regards childlessness.9,10,12 In sub-Saharan Africa procreation is usually considered the most important purpose of marriage.16,59 As a result, infertility is often associated with marital instability and many other sociocultural and psychosocial consequences. There is an enormous demand for ART in African countries, especially because in the large majority of cases infertility is infection-related and therefore only treatable by ART. Clinics providing ART mostly work in private settings in the bigger cities, operating on Western lines, this means that they are only accessible for selected couples who can afford the treatment.62–64 In the Middle East area, the behaviour, attitudes and policy-making surrounding the problem of infertility and childlessness are largely influenced by three major religions, namely Islam, Judaism and Christianity.65,66 One of the stumbling blocks to acceptance of ART as a method of infertility treatment was the unacceptability to the main religious groups of the

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Table 25.2 Most common psychological and sociocultural consequences of infertility in developing countries.

Psychological consequences • Fear, guilt, self-blame, depression, helplessness, marital stress, sense of worthlessness Marital instability • Sexual dissatisfaction, mild to severe marital violence, migrant labour, polygamy, divorce Social isolation – loss of social status • Excluded from and marginalised in community/family • Accused of “witchcraft”, ostracism • Excluded from contact with children Economic deprivation • Divorce, return of bride wealth, lack of old age security • Starvation, disease, suicide Lost dignity in death • No burial, no child to organise funeral, excluded from reincarnation

involvement of a third party in the act of procreation.67 This means that gamete donation, embryo donation and surrogate motherhood are in many cases not allowed. Artificial insemination with husband’s semen is permissible for all religions. Judaism allows the practice of all techniques of ART, whereas among Christians the practice of assisted reproduction is not accepted by the Vatican.68 However, it may be practiced by Protestants and Anglicans. In the Middle East tubal block due to STDs and pregnancy-related infections is the most common aetiological factor related to infertility. Male infertility is commonly found, mostly due to infections as well.67 The high prevalence of Roman Catholicism has a great impact on reproductive issues in Latin America.69 Although infertility does have severe consequences including social isolation and severe psychological distress, the number of in vitro fertilisation (IVF) intracytoplasmic sperm injectior (ICSI) cycles reported by Latin-American centres only accounts for 2.9% of all procedures performed worldwide and is by far under the estimated need of the population.70 Most countries only provide infertility investigations but cannot offer ART. Private centres exist but are very expensive and are commonly perceived as a luxury for wealthy couples. Cross-border reproductive care is very popular, once again only for those who can afford it. Because the influence of the Catholic Church is growing in many regions,70 there is an urgent need for open dialogue and debate surrounding the issue of ART in Latin America in order to improve access and quality of infertility care. In India, children and especially boys, give the woman status as well as psychological and emotional security within patriarchal families. Childlessness can

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be associated with stigmatisation, social isolation and sometimes violence.71,72 Infertility in India has to be interpreted in a context of poverty, class and gender inequality, and unequal access to health care resources.73 Despite the importance of motherhood, preventive and curative services for infertility have not yet been a priority in India. As observed in most developing countries, ART is only provided in private centres and is only accessible for a small number of couples. Another major problem in India is the lack of laws and regulation. Consequently there is great concern from health care providers and infertile couples about the quality and safety within existing ART centres.

Prevention and education Prevention of infertility should be the primary goal of any strategy that seeks to reduce the impact of infertility in developing countries.74 The preventive approach is even more justified because of the inaccessibility of curative treatments including ART in most countries. Therefore, prevention of STDs and pregnancy-related sepsis should be regarded as the most important and cost-effective strategy to decrease infertility rates. Cure without prevention would be a waste of effort and most available resources should be directed towards programmes to prevent infertility.59,75 Three major arguments support this statement: (1) prevention programmes are less expensive and more effective in eliminating the social consequences of infertility, (2) prevention programmes will also improve the health status of women in other ways and (3) programmes for prevention of infertility could be linked to other (existing) prevention programmes such as family planning and mother care.74 Many variables will influence the success of different prevention strategies such as the target group, the constraints to overcome and the right strategies for prevention.76 Okumu et al77 studied the past reproductive and sexual characteristics of patients with tubal infertility and found that, when compared with fertile controls, women with tubal disease were younger at first coitus, were more likely to have had first coitus premenarche, had more sexual partners, more abortions before marriage, more induced abortions, were more likely to have been diagnosed with STDs and had fewer years of schooling. These data suggest that reproductive and sexual events during teenage years determine the future prospects of fertility and highlight the importance of education. A better reproductive health care education can also reduce total fertility rates as studies have demonstrated that education, especially of women, is an important variable determining the desired number of children.78 All these studies support the statement that reproductive health care education is probably the cornerstone of success in the issue of infertility in developing countries. Governments should be aware of this important observation.

False perceptions and misunderstandings surrounding the issue of infertility in developing countries The most important misunderstandings surrounding the problem of infertility are commonly known. First is the population growth perception suggesting that the problem of overpopulation can only be solved by well organised educational and family planning programmes leaving little or no room for other initiatives such as infertility diagnosis and treatment. Another well known argument against the implementation of infertility services in developing countries is the “limited resources argument”. Considering this argument, most health care providers in developing and developed countries seriously question whether infertility diagnosis and treatment are an appropriate use of a country’s resources. Proponents of this argument maintain that the resources of resource-poor countries should not be allocated for expensive technology but should be directed only towards “more important medical needs” and prevention of infertility. Because overpopulation has been correctly regarded as one of the most important health concerns in developing countries, the implementation of a very effective family planning strategy has been proposed as the only goal for developing countries when talking about reproductive care. It is not surprising that governments only invest in prevention of infertility rather than putting money into expensive technologies which are unlikely to be cost-effective. This strategy has to be seen in combination with scarcity of health resources and against a backdrop of limited funds. Therefore, talking about infertility problems in developing countries seems contradictory to common sense, although the infertility problem is a major one for more than 70 million women. Important constraints and difficulties that can hinder the treatment of infertility in developing countries are (1) a lack of knowledge of the impact, importance and prevalence of infertility, (2) a lack of knowledge of the attitudes, practices and beliefs of different populations with respect to infertility, (3) the absence of any political commitment and (4) a shortage of protocols and initiatives to integrate infertility services into existing reproductive health care centres. In our opinion, diagnosis and treatment of infertility should be integrated within the concept of family planning and mother care, emphasising that family planning is not only about prevention of unwanted pregnancies but also includes promoting the chance of pregnancy in case of involuntary childlessness. Therefore, the fertility clinics should be integrated within health care clinics which focus on family planning, health education, maternity and child care, and prevention and treatment of STDs and HIV. Instead of ignoring the problem of infertility due to the “population growth argument”, a better strategy would be to increase the efforts made on family planning with the aim of decreasing fertility rates

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substantially. At the same time subfertility needs to be taken seriously and cost-effective techniques of diagnosis and treatment should be implemented. In short, the problem of overpopulation in developing countries can no longer be used as a reason to disguise the problems of millions of infertile couples. According to the 2006 Revision United Nations data prepared by the Population Division of the Department of Economic and Social Affairs of the United Nations Secretariat, the world population is expected to increase from 6.7 billion inhabitants in 2005 to 9.2 billion in 2050.79 To achieve these figures it is essential that access to family planning services expands in the least developed countries. On the other hand, if fertility remains constant at the levels estimated for 2000–2005, the world population would increase to 10.6 billion instead of the expected 7.9–9.2 billion. This means that future population growth is highly dependent on the path that future infertility prevention and treatment takes. Because of their low fertility rate the population of developed countries will remain unchanged between 2007 and 2050 (1.2 billion), whereas the population of the 50 least developed countries will increase from 0.8 billion to 1.7 billion by 2050. The worldwide global fertility rate (number of children per woman) was 5.0 in 1950–1955, 4.5 in 1970– 1975, 2.75 in 2005–2010 and is projected to decline further to 2.02 per woman by 2045–2050, i.e. close to the replacement level of 2.1.79 In the majority of developing countries the mean fertility rate has already dropped as low as 2.58 per woman and is expected to decline to 1.92 by mid-century. Nevertheless, in 27 of the 150 developing countries the fertility rate still remains above 5.0 and those countries account for 19% of the world population.79 Another factor contributing to the expected population growth in developing countries is caused by improved life expectancy.79 Because of a rapid decline in mortality, even in the least developed countries, life expectancy is set to rise from an average of 54 years currently to 67 years in 2045–2050. For Africa the life expectancy at birth is expected to rise from 53 to 66 years in 2045–2050 but this increase is contingent on reducing the spread of HIV and combating successfully other infectious diseases. Family planning services and educational programmes have already resulted in a substantial fertility decline in most developing countries. However there is still a need to support and optimise these programmes. The important message of including infertility care in reproductive health care centres might convince some politicians and health care providers to increase their awareness for better family planning strategies as well.80

Strategies for implementing infertility services in developing countries Although prevention of infertility and reproductive health care education will remain the priority in

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developing countries, a considerable reduction of the cost of infertility diagnostic procedures and treatment, including ART, would surely help in convincing local governments and health care providers to provide at least some public funding for those who still remain infertile despite preventative actions.

Diagnosis of infertility: low cost “one-stop clinics” The majority of infertility problems related to ovulatory disorders and male subfertility can be identified by an accurate history of the couple’s personal and medical details together with a simple light microscopy semen analysis.81 Tubal factor infertility can easily be diagnosed by hysterosalpingography (HSG) or hysterosalpingo-contrast-sonography (HyCoSy).82,83 Both of these techniques are simple, reliable, easy to interpret and inexpensive. An ultrasound-based “one-stop fertility assessment” could be done within 1 hour.89 Even laparoscopic techniques and office mini-hysteroscopy have been simplified over the years and can now be conducted in a one-step ambulatory approach without major costs and side-effects, at least if appropriate training is provided.81,84 Moreover, all of these procedures can be performed by a small team of health care providers within a short period of time in an inexpensive setting.81 Future studies should assess the reproducibility of “one-stop infertility clinics” in different developing countries.

Non-in vitro fertilisation assisted reproduction and endoscopic surgery If tubal patency is demonstrated and severe male factor subfertility has been excluded, fertility awareness programmes are an efficient and inexpensive first-line approach to infertility management.85 By instructing couples about the fertile time and detection of cervical mucus secretion, good results were achieved. Another advantage is that infertility awareness counselling, which should also incorporate education on infertility prevention, can be given by nurses and paramedical staff working in existing reproductive health care centres. For ovulatory dysfunction, clomiphene citrate (CC) can be used. This medication is very cheap, can be taken orally with minimal discomfort and the results are rewarding. Ovulation can be induced in 50–70% of cases and, together with timed intercourse, the pregnancy rate varies between 15 and 25% per cycle with a low multiple pregnancy rate of 6–8%.86,87 In case of resistance to CC, a low dose ovarian stimulation regimen with gonadotrophins or recombinant follicle stimulating hormone (FSH) aimed at monofollicular growth is advisable, although this medication is more expensive at least if the pharmaceutical companies are not willing to reduce their prices substantially. Intrauterine insemination (IUI) with husband’s semen in natural cycles or after CC-stimulation can be

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promoted as a first-line treatment without major costs and without expensive infrastructure in case of unexplained and moderate male factor infertility, provided tubal patency has been documented.88 Cost-effectiveness studies showed that three IUIs were as successful, but much cheaper than one IVF/ICSI cycle. IUI programmes can also be run by well-trained paramedical staff, another advantage for resource-poor countries. Appropriate protocols and effective training programmes are needed to minimise this risk of multiples, a particularly important issue in developing countries where the consequences of multiple pregnancies can be devastating. Hysteroscopy is another important tool to diagnose and treat uterine septa, endometrial polyps, submucosal myomas and intrauterine adhesions. Good resolution two-dimensional ultrasound is a non-invasive technique which can be very cost-effective.89 Laparoscopic ovarian drilling can be performed in case of ovulatory disorders associated with polycystic ovary syndrome (PCOS) when weight reduction and/or ovarian stimulation are unsuccessful. Laparoscopic surgery can also be recommended if large ovarian cysts or hydrosalpinges are found, before starting ART.90 Because hydrosalpinges and uterine myomata are commonly found in infertile patients in developing countries, training in endoscopic surgery is mandatory, especially in centres of excellence or tertiary referral centres.

Simplified and accessible in vitro fertilisation The aim is to establish low-cost, accessible, effective and safe IVF centres in developing countries. Therefore simplifying the methods is inevitable, not only concerning the laboratory procedures, but also at the level of ovarian stimulation and monitoring of the IVF cycle. Gonadotrophins and/or FSH, gonadotrophin releasing hormone (GnRH) agonists and GnRH antagonists are too expensive to be used routinely in developing countries. If used without sufficient experience they also carry a high risk of ovarian hyperstimulation syndrome (OHSS), a life threatening disease. Mild ovarian stimulation should therefore be considered as a reasonable and potential option in resource-poor countries. The success rates of natural cycle IVF can be low per cycle due to high cancellation rates because of premature luteinising hormone (LH) rise and premature ovulation. But the use of indomethacin to block ovulation helps to reduce cancellations. Cumulative pregnancy and live birth rates after four consecutive cycles could reach 46% and 32%, respectively, making it a costeffective, safe and patient-friendly option.91 The use of a low-dose clomiphene citrate regimen in IVF is another option with reportedly acceptable results, minimal side-effects and a very low complication rate.92,93 Monitoring of follicular development in an IVF cycle, as well as the timing of the human chorionic gonadotrophin (hCG) administration can be done solely on sonographic criteria with basic inexpensive

ultrasound equipment thereby avoiding the need for expensive endocrine investigations.94 Simplified laboratory procedures and equipment represent another challenge. One possible approach is the use of a “humidicrib”, a plastic box which is commonly used for keeping newborns snug, instead of an expensive laminar flow hood.93 For one-tenth of the price this box can be modified to be used as a portable, near sterile environment for the handling of gametes and embryos. Expensive cylinders of carbon dioxide required to incubate the embryos may be abandoned in favour of exhaling across the culture medium before sealing it in a plastic bag. This bag, containing the Petri dish with the gametes or embryos, can be dropped into a warm bath without the need for expensive incubators. This technique has been successfully used for more than 10 years for cow embryos in veterinary IVF.95 Another possibility is intravaginal or intrauterine fertilisation and culture. Intravaginal culture had already been described about 20 years ago.96 A tube filled with culture medium containing the oocytes and about 30 000 washed spermatozoa is hermetically closed and is placed in the vagina. It is held by a diaphragm for incubation for 44–50 hours. Over 800 cycles cycles have been published worldwide with a clinical pregnancy rate of 19.6%.97 Minimising the risks and complications of ART such as OHSS and multiple pregnancies should be crucial.98 The importance of avoiding multiple pregnancies cannot be overemphasised when considering the risks against a backdrop of inadequate health care facilities. Nowadays, a policy of elective single embryo transfer (eSET) is reported as the most efficacious measure of reducing the incidence of multiple pregnancies in ART.99 In a large retrospective study it was shown that with the implementation of eSET multiple pregnancy delivery rates could drop from 25 to 5%.100 IUI in natural cycles and/or CC-stimulated cycles have a reported multiple pregnancy rate of less than 8% which is acceptable.88 With the use of human gonadotrophins (hMG) or recombinant FSH, IUI success rates are significantly higher but multiple pregnancy rates may rise to 20–30%.

Training The implementation of new reproductive technologies in developing countries will require adequate training. Training courses on semen analyses and laparoscopic procedures have already been successfully conducted in some African countries.101,102 Since 2005 and under the auspices of the International Federation of Fertility Sciences (IFFS) education programme workshops have been organised in many different countries such as Uruguay, the Philippines and Nigeria. If we succeed in simplifying IVF procedures in so far that this technique will be accessible for a large part of the population in resource-poor countries, regular training courses in ultrasound scanning

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and procedures have to be organised and will be extremely important. Following training, quality control, regular audit and systems of accreditation and registration should be implemented in order to maintain appropriate standards of care.

Documentation of treatment access and treatment outcomes in developing countries Before promoting infertility treatment services in developing countries, it is necessary to understand the country-specific magnitude of the problem, as well as to know about existing national resources, so that the national “resource gap” can be identified.103 Before an ART project can be started, a specific country profile on infertility should be prepared. This profile should be based on a needs assessment and a resources assessment, resulting in a national strategy plan. The needs assessment includes an evaluation of the national prevalence of infertility, its country-specific causes, obstacles to seeking treatment and current treatment access. The resources assessment will document national financial and organisational resources.103 A system of monitoring treatment characteristics and outcomes, and collection of key data should be implemented from the beginning. This can be done with the help of the International Committee of Monitoring of ART (ICMART). The available data should be audited and published on a yearly basis.

The Arusha project In December 2006 the executive committee of the European Society for Human Reproduction and Embryology (ESHRE) agreed upon the foundation of a new “special task force” on “Developing countries and infertility”.104 This special taskforce aimed to document the problem of infertility in developing countries, to develop and test the effectiveness of a simplified “one-step clinic” for the diagnosis of infertility, to develop and test the effectiveness of simplified IVF-related procedures, to develop strategies for minimising the risks of ART and to promote the linkage of family planning, maternal and neonatal care, and infertility treatment. Another important goal of the taskforce was the search for the optimal management strategy for subfertile couples in developing countries with emphasis on non-IVF treatment and other (surgical or medical) options before starting IVF. A first expert meeting was held in Arusha, Tanzania from 15 to 17 December 2007. During and after the meeting, seven recommendations were agreed upon (Table 25.3). As a result of the Arusha meeting, five working groups and five study groups were established, with specific aims and fields of interest (Table 25.4).

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Table 25.3 The seven recommendations proposed at the Arusha meeting.105

1. The ultimate aim is to establish low-cost fertility clinics in developing countries, with affordable, effective and safe diagnostic and therapeutic procedures 2. Documentation of the problem of infertility in developing countries has to be organised 3. Studies have to be performed on the health economics of infertility in developing countries 4. Treatment of infertility should be integrated within settings of general health care where opportunities exist for contraception, health education, maternal and child care, as well as prevention and treatment of STIs and HIV (Reproductive and Sexual Health Care Centres) 5. The terminology “affordable ART” has a relative meaning depending on the region of the world or within a health care setting 6. The start of an ART project should be related to the obstetric capacities and educational level of the country. If no appropriate obstetric service is offered this should be the first goal of the reproductive health clinics in collaboration with the government 7. The necessary instruments and laboratory material for infertility treatment should be robust, simple to use, easily replaced and standardised STI, sexually transmitted infections; ART, assisted reproductive technologies.

Conclusion Reproductive autonomy and the huge emotional and social burden of infertility in developing countries justify providing infertility treatment in these countries. Without ignoring the importance of prevention of infertility and the value of reproductive health care education, the moment has come to consider the possibility of implementing “new reproductive technologies” in developing countries. The integration of infertility services into sexual and reproductive health care programmes and a reduction of costs are prerequisites in this regard. Simplifying diagnostic procedures, simplifying ART, minimising complication rates and organising training courses for medical and paramedical personnel will be mandatory if new reproductive technologies are to be accessible for a large part of the population. The success and sustainability of ART in resource-low settings will depend to a large extent on our ability to optimise these techniques in terms of availability, accessibility and effectiveness. New reproductive technologies can only be successfully introduced in developing countries if sociocultural and economic prerequisites are fulfilled and governments can be persuaded to support their introduction. The integration of infertility, contraceptive and maternal health services within existing or new reproductive health care centres seems to be crucial.

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Table 25.4

ESHRE Special Task Force on “Developing countries and infertility”: Working and Study Groups.

Working Groups 1. The 1 day diagnostic phase Aim: to make a protocol for the anamnesis and examination of the infertile couple and to determine which simple diagnostic tests have to be performed. As many couples come from far all tests have to be performed (if possible) in 1 day. The consequences of the results for the management of the couple have to be discussed with them on that same day. This may vary from simple advice regarding the fertile period and when to have intercourse (fertility awareness methods) to an appointment for IVF treatment in case of blocked tubes 2. Ovarian stimulation for IUI and IVF/ICSI Aim: to determine which stimulation schemes are most appropriate for IUI and IVF/ICSI in developing countries. How to monitor the cycle? Has the natural cycle without any stimulation a place? How to give simple and effective information to the couple about this phase? 3. Laboratory phase for IUI and IVF/ICSI Aim: the often complex and expensive procedures and instruments used in Western countries have to be translated into the circumstances of developing countries. How to give simple and effective information to the couple about this phase? 4. Documentation, registration and quality control Aim: how to implement a simple registration and quality control system in the middle of nowhere? The preparation of ‘country profiles’. How to make a simple but realistic annual report? 5. Funding Aim: To raise funds for the project Study Groups 1. Reproductive health education, prevention and awareness Aims: how to make the general population aware about the importance of lifestyle factors and the prevention of STDs for their reproductive health? Can awareness of reproductive health be integrated in already existing programmes on general health education? How to make politicians and health providers aware of the importance of education on reproductive health and prevention of infertility ? 2. Burden-of-disease and cost-effectiveness Aim: Is it possible to measure the reduction in the quality of life by infertility and compare this to the reduction caused by other common diseases in developing countries? How cost-effective is fertility treatment in comparison with other measures aimed to improve health? Are we not increasing the inequality of the poor and the rich by introducing relatively expensive and sophisticated fertility treatment? 3. Training courses Aim: is it feasible to establish integrated, simple and standardised training courses for personnel of fertility clinics on the anamnesis and examination of the infertile couple, semen analysis, embryology, traditional hysterosalpingography, modern imaging techniques, documentation and quality control? 4. Intravaginal/intrauterine culturing Aim: to investigate the value of intrauterine and intravaginal culturing techniques as an alternative for conventional culturing in IVF 5. Study and differences in ethics/law/culture/religion/level of care in developing countries Aim: To investigate the sociocultural differences between different geographical areas and to study the ethical considerations on the issue of childlessness in developing countries IVF, in vitro fertilisation; IUI, intrauterine insemination; ICSI, intracytoplasmic sperm injection; STD, sexually transmitted disease.

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26 The older woman wishing to conceive CB Lambalk, FJ Broekmans

Introduction Over the past two decades, predominantly in the developed world, many women have chosen to postpone having children for a number of reasons. In many countries the age at which women deliver their first child is reaching or surpassing the age of 30 years. This happened in the first place because optimal versatile safe contraceptive methods became available which were widely accepted. Second, and probably not unrelated to the progressive availability of contraceptives, came the movement of women’s liberation and emancipatory awareness which led women to become much more keen to pursue a career instead of taking care of the household and raising children. Consequently, today a number of particular issues in relation to the child wish and having children in later life are of current concern. In the following chapter, the most salient points to consider for older women and for those responsible for their health, their well-being and that of their future offspring are discussed. These include the influence of ageing on the natural decline of fertility, on the increased chance of natural twinning, and

also on the rate of early pregnancy loss and chromosomal and congenital abnormalities. Also, the limited success rates when fertility treatment is required and the limitations of tests that could predict reproductive consequences after both natural and assisted conception are addressed. Furthermore, the consequences of being an older mother with regard to the course of the pregnancy and delivery, and effects on general health are presented.

Reproductive ageing and fertility decline The human species can be considered as relatively subfertile compared with animals.1,2 The average monthly fecundity rate of about 20% implies that among human couples trying to conceive many exposure months may be needed to achieve the goal. On top of this, average female fecundity drops with increasing age, especially after the age of 303 and leads to a woman becoming sterile at an average age of 41 years4–6 (Fig 26.1). Although the probability of conception is believed to remain

Optimal fertility

Number of follicles

106

Declining fertility

End of fertility

Menopause

Irregular cycle I

105

100 104 75 50

103

25

102 0

10

20

30 Age (years)

40

50

60

Proporation of poor quality oocytes (%) - - -

107

Fig 26.1 Quantitative (solid line) and qualitative (dotted line) decline of ovarian follicle pool, which is assumed to dictate the onset of important reproductive events. Reproduced and adapted from reference 7, with permission.

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Hypothalamus

Younger

Older

Pituitary

Pituitary

Inhibin A AMH

--

FSH LH

Ovary

Inhibin B

Inhibin A E

AMH

FSH LH

Ovary

unchanged until the age of 40, an increasing number of these conceptions will be lost before the recognition of clinical pregnancy,8–10 or as a miscarriage.11 In assisted reproduction technology (ART; ie. in vitro fertilisation (IVF)) programmes, the chance of producing a live birth decreases steadily after a mean female age of about 35 years and will be below 10% per treatment cycle in women over 40 years of age. Reproductive ageing is the gradual decrease in both the quantity and the quality of the oocytes and follicles held within the ovaries.12,13 At birth a few million primordial follicles are present from which at the onset of puberty only some 400 000 are left.14–17 At a mean age of 45, numbers have fallen to a few thousand, when menstrual cycles become irregular, and at the time the menstrual cycle ceases (menopause) follicle counts have clearly fallen to below a thousand.18–20 The reduction in oocyte quality is caused by increasing meiotic non-disjunction at higher female ages.21,22 This mechanism is exemplified by an increasing incidence of Down syndrome (trisomy 21),23–26 and the increasing proportion of IVF embryos showing chromosomal abnormalities with increasing maternal age.27–30 Furthermore, the increased early pregnancy loss rate in older women is a further support for the contention that the age-related infertility is largely oocyte quality-dependent.31–34 Both the decay in follicle numbers as well as the fall in oocyte quality operate without clinical signs. A shortening of the menstrual cycle length by some 2–3 days may be noticed, while regularity remains unaffected.35,36 At the time cycles start to vary in length or are missed out and flushes appear, fertility is considered zero. At the endocrine level, antiMüllerian hormone (AMH) produced by the cohort of small antral follicles marks the size of the residual antral follicle

Inhibin B

E

Fig 26.2 Illustration of the changes in follicle reserve with increasing female age and the effect of these quantitative changes upon several endocrine factors AMH, antiMüllerian hormone; LH, luteinising hormone; FSH, follicle stimulating hormone; E, estradiol. Adapted from reference 47.

pool and describes the ageing process in a gradual fashion.37–41 In spite of clear changes in AMH levels over the years, basal follicle stimulating hormone (FSH) levels, that are indirect indicators of cohort size, remain largely unaffected, while at the oocyte level dramatic changes occur.42–45 Elevated levels of FSH, that drive the slight reduction in the length of the menstrual cycle, are therefore consistent with already advanced stages of the ovarian ageing process46 (Fig 26.2). Menopause, an event that can easily be recognised in individuals, represents an almost exhausted primordial and antral follicle pool.48 The mean age at menopause is 51 years with variation ranging from 40 to 60 years,49 but possibly even into younger age ranges.50 This range of variation seems also to be true for the occurrence of cycle irregularity during the menopausal transition (average age 46),51 the advent of natural sterility (41 years on average)51,52 and the start of increasing subfertility (age 31).51,53 Between all these events a fixed temporal relationship is believed to be present51,54 (Fig 26.3). With the postponement of childbearing in Western societies rates of subfertility related to female age have increased considerably.55–58 Although the majority of women at older age will obtain the desired pregnancy within a 1-year period, the chance of becoming subfertile increases about 6-fold in comparison with very young women. The fact that regular menstrual cycles remain until an age when natural fecundity has already been reduced to zero, means that women are largely unaware that this process is taking place. An increasing proportion of couples nowadays seek medical help for subfertility and ultimately will depend on ART to achieve a pregnancy. For evaluation and treatment of subfertility, ovarian reserve assessment in addition to knowledge of the

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275

100

se

arity

Men

le irr Cyc

opau

egul

ility Ster

ty fer til i

50

Sub

Cumulative percentage

75

25

0 21

31

41 Age (years)

woman’s calendar age would enable clinicians to provide an individually tailored treatment plan. For instance, in older women the finding of a sufficient ovarian reserve may justify the decision to allow ART treatment, while in young women with exhausted reserve either early application or even refusal of ART could be the consequence. Preventive measures regarding female subfertility would certainly be embraced by many in order to allow individual planning of education, career and family. Age at menopause, which is determined by remaining follicle numbers, is considered a proxy variable for age at loss of natural fertility, with a fixed time period of 10 years in between. The correct prediction of menopause in an individual woman in her early twenties would therefore provide valuable information regarding her fertile life span and hence aid in preventing future subfertility. At present, however, reliable means of such prediction remain elusive, but may be developed from studies on genetic factors.59–61

Increased risk of twinning with ageing Over the past decades twinning rates, in particular the rate of dizygotic twinning, have strongly increased.62 The rapidly increasing application of IVF and intracytoplasmic sperm injection (ICSI) and intrauterine insemination with ovarian stimulation (IUI) have led to a strong increase of multiple pregnancies. Recent data from The Netherlands show, however, that the largest contribution has come from natural conceptions. It seems that the increase in age at which women start to have their children plays a pivotal role in these demographic changes. Intriguingly, for many years already, advanced maternal age has been documented as a factor influencing the incidence of spontaneous dizygotic multiple pregnancies. In women over 35 years the chance of becoming pregnant with twins is about double that of women under 25 years of age.67 It has even become

51

61

Fig 26.3 Variations in age at the occurrence of specific stages of ovarian ageing. For explanation of the background of data, see reference 54. Reprinted with permission.

clear that ageing may indeed be the major contributor to the current worldwide “epidemic ” of twinning, given the previously mentioned tremendous increase of age at which women decide to start to procreate. Dizygotic twin pregnancies must be aetiologically linked with multiple follicular growth and multiple ovulations. The prevalence of multiple follicular growths according to maternal age in natural ovulatory cycles has been recently examined.64 Since FSH concentrations rise with increasing age, the relation between FSH concentrations and the incidence of multiple follicular growth was also studied. In naturally ovulating women with multiple rather than single ovulations, the mean age and mean basal FSH concentrations were significantly greater than those with monofollicular development. Thus, the prevalence of multifollicular development increases with age. Because of a decline in ovarian feedback capacity, in particular due to lower levels of inhibin secretion, the FSH levels increase and overshoot the threshold.65,66 This will generally not lead to multiple pregnancies because of the low number of available follicles with less oocytes of high quality. However, if two or more follicles containing good quality oocytes are available then a multiple pregnancy is more likely.67 The scenario that the well documented, increased prevalence of twin pregnancy in an advanced fertile age group is caused by an increased tendency towards multiple follicular development is highly plausible. Women choosing to become pregnant at a higher age must be aware of this scenario. A multiple pregnancy may follow a complicated course with adverse outcome affecting both the mother and the offspring. Pregnancy induced hypertension, pre-eclampsia and gestational diabetes occur much more often. Delivery is often complicated with consequently much more need to intervene, for example with a Caesarean section. The most prominent problem is premature delivery of the infant which can lead to life threatening

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situations and serious lifetime disabilities. The influence in this respect of older maternity should not be underestimated. In The Netherlands is has been estimated that with each year that average maternal age increased there was one more twin per thousand deliveries born according to population statistics.68 This implies that the average increase of the maternal age during the past decades of about 2–3 years has lead to the birth of 300–400 more twin births per year. There would be approximately 20 fewer neonatal deaths and 200 fewer Neonatal Intensive Care Unit admissions if this had not happened.69

Increased risk of genetic and congenital abnormalities in offspring For women who achieve a pregnancy at an advanced maternal age there is a greater likelihood of foetal aneuploidy and possibly of structural anomalies. However, in the absence of congenital structural abnormalities, perinatal mortality is probably not much increased in older mothers. Aneuploidy is the most common chromosomal abnormality in humans, and is the leading genetic cause of miscarriage and congenital birth defects. Since the identification of the first human aneuploid conditions nearly half a century ago,70,71 a great deal of information has accrued on their origin and a etiology. Most cases of foetal aneuploidy derive from errors in maternal meiosis I due to non-disjunction of chromatids.72 These meiotic errors in oogenesis may occur during three distinct developmental stages: the meiotic initiation in the foetal ovary, follicle formation in the perinatal period, and oocyte growth and maturation in the adult female. The most common, female age-related, autosomal aneuploid abnormalities are trisomies, with trisomy 16 being the most common anomaly found in human conceptions.73 All trisomies have been observed in spontaneous abortion, except trisomy of chromosome 1. Maternal age is a risk factor for most, if not all, human trisomies. It is the basis for the increase in the rate of early pregnancy loss in older women, and also for the increased birth of trisomic children. Still, only trisomy 13, 18 and 21 are regularly observed at birth, although the early pregnancy loss rate is still high at 97%, 95% and 80%, respectively. For the other autosomal trisomies this figure is approximately 99.9% and therefore these pregnancies will only very rarely proceed beyond the first trimester. Sex chromosome aneuploidies (47,XXY, Klinefelter and 45,XO, Turner syndrome) will often survive normally, with the exception of 45,XO, which is lethal in over 95% of cases.74 However, for the sex chromosome aneuploidies no evidence exists for a role of female age. Down syndrome is the most commonly identified genetic form of mental retardation and the leading cause of specific birth defects and medical conditions. Cardiovascular, skeletal and renal malformations are common and may cause limitation of survival. In the

long term many Down syndrome cases will develop Alzheimer disease at relatively young age and generally have a clear reduction in longevity.75 Trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) are characterised by the same combination of disturbed psychomotor development and major birth defects. However, the severity of abnormalities will lead to neonatal death in a very large proportion and in those cases surviving the infancy period, many face demise in early childhood. First trimester risk assessment for foetal aneuploidy has developed greatly over the past decade. Especially the combination of first trimester serum (pregnancyassociated plasma protein (PAPP)-A, free ß- human chorionic gonadotrophin (hCG), inhibin A and α-1-foetal protein (FP)) and ultrasound (nuchal translucency) screening tests has enabled the allocation of high-risk populations, in which diagnostic testing by means of chorion villous biopsy or amniotic fluid collection with subsequent karyotyping will lead to correct identification of trisomies. The screening performance is exceptionally good, with detection rates of more than 80% at a screen positive rate of 5%. The association between maternal age and nonchromosomal birth defects has been analysed in several publications, but so far has appeared to be not very strong. In a large birth cohort study both teenage pregnancies as well as pregnancies in women aged over 35 were associated with birth defects,76,77 In older women a 1.2–1.8 increased risk was observed for the occurrence of heart defects, male genital defects and facial defects, compared with women in the age group between 20 and 35. The underlying causes for these associations have not become clear. As many birth defects can be related to environmental factors, like female stress, medication, exposure to industrial pollution and socioeconomic status, it can be suggested that in the effects of female age these factors may also act.78,79 Correction for such confounders has only been possible in some studies, showing that in addition to effects of occupational risks, female at birth may indeed be an independent factor.80 Other large databases also seem to support the contention that in older women the rate of birth defects may be slightly increased,81 although the inclusion of trisomies with their inherent presence of birth defects may partially be responsible for this difference.82 For women trying to conceive at older age who eventually have to rely on ART, there may be a small increase in the risk of having a child with structural birth defects. Whether this increase should be attributed to the technology of IVF, ICSI or in vitro maturation itself, or is inherent to the subfertility condition of the couple is still a matter of debate. The selection of control population data that serve as a reference may be another source of bias. At present, a small, but acceptable increase in the rate of major abnormalities after ART is the basis for the advice to perform second trimester ultrasound screening for foetal anatomy.83

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Table 26.1

277

Outcome of adjusted odds, ratios and parities of significant pregnancy complications for maternal age groups.87 Nullipari

Diabetes Chronic hypertension (<20 weeks) Pregnancyinduced hypertension Premature rupture of membranes Delivery <32 weeks Prolonged labour Dysfunctional labour Excessive bleeding Caesarean section Infant death

Multipari

30–34 (years)

35–39 (years)

40–44 (years)

≥45 (years)

35–39 (years)

40–44 (years)

≥45 (years)

1 1

1.39 1.66

1.81 2.69

2.19 3.7

1.38 1.65

1.91 2.88

2.58 4.89

1

1.13

1.28

1.55

1.20

1.59

2.13

1

1.11

1.14

1.02

1.16

1.37

1.38

1 1 1 1 1 1

1.31 1.27 1.15 1.17 1.9 1.41

1.65 1.36 1.22 1.31 1.2 1.96

2.11 1.54 1.26 1.42 1.54 3.14

1.22 1.14 1.05 1.10 1.8 1.13

1.56 1.42 1.29 1.26 1.28 1.71

1.77 1.75 1.46 1.73 1.49 2.53

Pregnancy complications related to older maternal age In the USA and in many other developed countries the number of births in women over 30 years and in particular in much older (>40 years) women has increased tremendously over the past 3 decades. In The Netherlands, in recent years, more than 60% of mothers are >30 years.63 The large majority of these women become pregnant and deliver without difficulties. Nevertheless, compared with younger women, they are at increased risk of developing complications. In the first place the risk of very early termination increases. The risk of early pregnancy loss is about 15% in women under 30 years, whereas it increases to over 50% in women over 40 years.84 This strong increase is largely the result of the progressive decrease of good quality embryos due to increasing rates of aneuploidy and not to intrinsic maternal deterioration other than of the gametes. Early pregnancy loss does not seem to occur more often in older women who have become pregnant after egg donation using young donors.85 A higher risk of pre-existing chronic hypertension will exert its negative impact on the course of the pregnancy with all its possible negative sequelae such as superimposed hypertension of pregnancy, pre-eclampsia, growth retardation and premature birth. But also in women without pre-existing hypertension the risk of developing a pregnancy associated hypertensive disorder is increased86 Table 26.1. The risk of developing diabetes progresses with age. Furthermore, during pregnancy the risks increase for premature labour and premature rupture of membranes with consequently more need for tocolysis and premature delivery. At time of delivery there is an increased risk for primary

Caesarean section, prolonged and dysfunctional labour, excessive bleeding and consequently more secondary surgical interventions. In The Netherlands, compared with mothers of 23 years, the risk for a Caesarean section for a mother of 37 years doubles to 22%.88 It should be noted that these higher rates of Caesarean sections will further increase the risk of complications for subsequent pregnancies and deliveries89 (Table 26.1). There is a significantly increased risk for infant death with advancing age even after controlling for the presence of congenital anomalies. It seems that the higher rates of premature delivery play an important role.90 Older women undergo more infertility treatments. It is unclear to what extent being less fertile itself or these treatments per se contribute to adverse obstetric outcome. Although rare, the potentially lethal condition of amniotic fluid embolism is significantly associated with advanced maternal age.91 As mentioned earlier, multiple pregnancies are at increased risk for obstetric complications and adverse neonatal outcome. Probably to some extent the increased occurrence of a multiple twin pregnancy with older maternal age, both after natural conception and because of infertility treatments, contributes to the overall increase of a more often problematic course of pregnancy and its outcome on older women.

Ovarian reserve testing for prediction of natural conception chance and after assisted conception Although female age remains a first choice predictor, the substantial variation in ovarian reserve decline has urged the search for markers to identify women with

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Table 26.2

Listing of currently known ovarian reserve tests.

Basal hormones FSH, inhibin B, AntiMüllerian hormone, oestradiol Sonographic parameters Antral follicle count, ovarian volume, ovarian vascular flow

Challenge tests Clomiphene citrate, GnRH and FSH Combination of tests Repeating tests in subsequent cycles FSH, follicle stimulating hormone; GnRH, gonadotrophin releasing hormone.

either severely reduced or highly adequate pregnancy prospects for their age. These so called ovarian reserve tests have been evaluated on their capacity to predict some defined outcome related to ovarian reserve (Table 26.2). The gold standard outcome of prediction studies would be live birth after a series of exposure cycles, but other outcomes (especially oocyte yield or follicle number and pregnancy in IVF treatment) are in fact the most common. Most, if not all, ovarian reserve tests relate to the size of the follicle cohort that is at any time responsive to FSH. The antral follicle count (AFC) assessed by transvaginal ultrasonography92 and the endocrine markers AMH and inhibin B which are released from the antral follicles provide direct markers of this cohort, which is proportionally related to the number of remaining primordial follicles.93–95 Basal FSH is an indirect marker of cohort size, and will rise with advancing age as a response to reduced negative inhibin B feedback on pituitary FSH release.96 High FSH levels therefore represent small cohort size. Endocrine challenge tests like the exogenous FSH ovarian reserve tests (EFORT), the gonadotrophin releasing hormone (GnRH) agonist stimulation test (GAST) and the clomiphene citrate challenge test (CCCT) are considered to be too laborious for screening purposes and will not add much predictive value compared with static tests like AMH or the AFC.97–100 Ovarian reserve tests may best be considered as screening tests, where an abnormal test necessitates confirmation by another test. This other test may for instance be a first IVF attempt where ovarian response to hyperstimulation will provide additional information, or other independently predictive ovarian reserve tests.101–106

Prediction of spontaneous and intrauterine insemination related pregnancy in subfertility patients In a considerable proportion of subfertility patients, no obvious explanation for the failure to become pregnant can be found. In these couples, prediction models (including factors like duration of infertility, previous pregnancies and female age) can be used to estimate the remaining chances of pregnancy.107 The additional

value of ovarian reserve tests has been shown to be highly disappointing. Neither a single nor a combination of tests has significantly improved the prediction of time to pregnancy by the Hunault model.108,109 Routine ovarian reserve testing as part of the infertility work up should therefore not be recommended. In addition, for the assessment of chances for success of treatments like IUI (with or without ovarian stimulation), ovarian reserve tests have appeared not to be useful, although large studies on this subject are lacking.110,111

Ovarian reserve testing prior to in vitro fertilisation The vast majority of studies on ovarian reserve testing in infertile patients have focused on the prediction of outcome of IVF treatment. In a recent review, the predictive performance of all known tests was analysed by using the approach of the systematic review and meta-analysis.112 Test accuracy and value for clinical management for the prediction of two distinct outcomes in IVF treatment (poor ovarian response and non-pregnancy) from all the studies providing data on 2 × 2 tables were assessed.

Poor response prediction For the majority of available tests the areas under the receiver operator characteristic curve (AUC-ROC) for baseline FSH, the AFC, AMH and ovarian volume indicated that the overall accuracy in poor response prediction is sufficient (Fig 26.4). The clinical value analysis suggested that the AFC, AMH and basal FSH had the best sensitivity and specificity combination for predicting ovarian response.112 At cut-off values yielding a positive likelihood ratio higher than 6, an abnormal AFC or AMH test result will result in the probability of poor ovarian response being about 70%. Thereby, these two tests could be clinically valuable for poor response prediction, as an abnormal test result would be found in approximately 12% of patients.113 However, several studies have shown that in observed poor responders in a first IVF cycle no clear benefit can be expected from various changes in management like increasing the dosage, applying comedication, or changing the approach of the GnRH agonist administration.114–118 Prior prediction may only be useful for cases with a poor response due to FSH underdosing related to obesity or FSH receptor polymorphisms. If the individual stimulation dose was based on a model with AFC, ovarian volume, ovarian flow, female age and smoking, this resulted in a higher proportion of appropriate ovarian response and also higher pregnancy rates compared with a standard dose of 150 IU/day.120–121 In contrast, another randomised study showed that predicted poor responders based on the AFC did not have better pregnancy rates with higher (300 IU recFSH) compared with normal doses (150 IU).122

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only very small proportions of the non-pregnant cases will be predicted correctly and false positives remain even with extreme cut-offs for an abnormal test (Fig 26.4). This finding should not be regarded as a surprise, as most tests relate to the quantitative aspects of ovarian reserve that are constantly present (i.e. antral follicle cohort size), while the quality perspective is only tested against a single exposure which certainly will not be a good expression of a couple’s fertility potential (only tested properly in a series of ART cycles).

Accuracy poor response prediction 1 0.9 0.8 0.7 Sensitivity

279

0.6 0.5 0.4 0.3

First cycle poor response

0.2 0.1 0 0

0.1

0.2

0.3

0.4 0.5 0.6 0.7 1 − specificity

sROC curve AFC sROC curve FSH AMH

0.8

0.9

1

sROC curve AMH AFC FSH

Accuracy nonpregnancy prediction 1 0.9 0.8

Sensitivity

0.7 0.6 0.5 0.4 0.3 0.2

A poor response to stimulation, defined as a low number of mature follicles developed or oocytes obtained after ovarian hyperstimulation, is regarded as proof of diminished ovarian reserve and reduced prognosis for pregnancy.123,124 Still, a poor response may also be caused by conditions like submaximal stimulation in obese women or carriers of a FSH receptor polymorphism or simply by chance. In such poor responders, prospects in the actual and subsequent cycles are not so unfavourable that refusal of treatment is justified. Only if a poor response occurs in cases with an unfavourable additional profile (female age over 38, abnormal ovarian reserve test, repeated poor response) does prognosis for subsequent cycles becomes cumbersome enough for further denial of treatment.125–127 Therefore, without prior ovarian reserve testing, a first cycle poor response in IVF could direct the decision to apply an ovarian reserve test and, if abnormal, would classify the female as having poor ovarian reserve with very poor prospects for pregnancy in subsequent cycles. In women over 40 years prior testing could identify those cases with still adequate ovarian reserve for age and with an acceptable prognosis in ART.128

0.1 0 0

0.1

0.2

0.3

0.4 0.5 0.6 0.7 1 − specificity

0.8

0.9

1

Management options for the older woman wishing to conceive Counselling

sROC curve AFC sROC curve FSH AMH

sROC curve AMH AFC FSH

Fig 26.4 Example of ovarian reserve test performance antral follicle count (AFC), antiMüllerian hormone (AMH) and follicle stimulating hormone (FSH) showing receiver operator characteristic (ROC) curves for the prediction of poor response (upper panel) and non-pregnancy (lower panel) in in vitro fertilisation. Data were based on a recent meta-analysis on ovarian reserve tests.112

Pregnancy prediction From the meta-analysis of the various reserve tests the predictive ability towards the occurrence of pregnancy after one IVF cycle has shown to be only marginal, as

Counselling is helpful simply to provide information about all the special aspects in relation to higher maternal age as discussed in this chapter. Older women wishing to conceive should know that: (1) It may take longer to become pregnant. (2) They have a higher chance of conceiving a dizygotic multiple. (3) They have a higher risk of losing the pregnancy early. (4) They are at a higher risk for offspring with chromosomal abnormalities. (5) They may have more complications with the pregnancy and delivery. But obviously the most useful pre-pregnancy counselling is when conditions can be traced that may have negative

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consequences but through pre-conceptional intervention could be improved leading to a better course and outcome of the pregnancy. Ironically the most useful moment to counsel in the context of advanced maternal age is when the women are young because then they have the opportunity to choose the most effective measure to prevent ageing-related problems, namely, the decision not to wait too long before trying to become pregnant. However, even if women and their spouse at younger age were to become more aware of the adverse effects of conceiving and childbearing at higher age, many social conditions in modern society make it not simple for them to easily decide for young parenthood. Moreover, for the majority of couples earlier family building would not be necessary, as they will not face fertility problems at all and adequate antenatal care may prevent many of the age-related adverse conditions. So far it seems useful to verify of presence of good general health. In particular tracing ageing-related pre-existing hypertension followed by adequate treatment before pregnancy may be a beneficial. A systematic review reported that from the evidence, it was difficult, to generalise observed absolute benefits in the situation of pre-conception management of treating hypertension before conception (three trials). But in particular in older women some yield may be expected. In women aged 30–54 years, approximately 259 women need to be treated annually to prevent one fatal or non-fatal cardiovascular event such as stroke (95% confidence interval (CI) 158–1606). In younger women, approximately 8000 women would need to be treated annually to prevent one cardiovascular event (95% CI 2500–50 000). 129 Whether any other pre-conceptional interventions in relation to age-related health deterioration will exert satisfying benefits for future pregnancy remains to be determined.

Evaluation infertility work-up Conventionally, standard infertility evaluation is justified after 1 year of unsuccessfully attempting to become pregnant while having a regular cycle and with regular intercourse. As discussed previously, with advanced age time to pregnancy is naturally prolonged in the absence of apparent fertility disorders. Therefore, a longer period before fertility work-up starts seems justified. However, paradoxically many older women who pursue pregnancy seek help early because they fear permanent childlessness due to their advanced age and they ask for an early check-up. This does seem to have some rationale provided that interventions based upon abnormal findings during the work-up indicate necessity of intervention for example if a male factor or a tubal factor surfaces. A year waiting at the age of 25 seems less problematic than when one is already 38 years of age. However, it is unlikely that advancing the infertility work up in older women, which is notoriously paradoxical, will

become cost-effective. Currently, there are no published studies in this area. Basically, in older couples, standard infertility work-up should be executed in the same way as in younger couples, which implies a standard semen analysis, assessment of ovulation, assessing tubal and uterine abnormalities, and execution of a postcoital test. The (limited) value of performing ovarian reserve tests in general and in older women in particular is discussed in separate paragraphs. The standard infertility work-up serves two important purposes. First it is meant to find problems that can be solved by an intervention such as ovulation induction, surgery or assisted reproduction. The other purpose is to be able to tell a couple whether there are any problems. In particular with older female age it could be of value to identify that there are no problems because absence of clearly identified fertility disorders may help to convince the couple that the chance of a natural conception is not absent, provided that monthly ovulation is maintained and that there is regular intercourse. Therefore, despite the fact that the effectiveness of many infertility treatments in older women is limited, a number of reasons exist why infertility investigations should not be severely limited. On the other hand, healtheconomic arguments justify the raising of age thresholds beyond which no detailed infertility work-up should be reimbursed. At the moment no strict and universal criteria are available which should be adhered to in this respect.

Paradox of more time needed but less time to wait Women who have postponed childbearing until after the age of 32 have a clearly increased risk of not having conceived within 1 year. As explained in a previous section, prospects may still be good for some, especially if tubal pathology, anovulation and severe semen abnormalities have been excluded. For some, however, further efforts to obtain a spontaneous pregnancy may also be accompanied by a further decrease in fecundability. This emphasises the importance of correct timing of initiation of ART treatment in order to optimise the chances for success. At the same time, however, the occurrence of spontaneous pregnancy may still be possible and discussion may be raised as to the added value of early treatment. Currently, prognostic models for spontaneous pregnancy are available that help to identify those couples with a 1-years’ chance of ongoing pregnancy below 30%. In these cases ART therapy seems justified.130,131 Still, other policies, like duration of infertility of 2 years in women over 35 as a minimal requirement, may protect from overtreatment.132

Assisted reproduction Treatment choices in older women seem to be quite limited. IUI treatment with ovarian stimulation in

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cases with otherwise unexplained subfertility has been proven effective,133 but whether this is true also for older women has not been established. Other studies have indicated that factors like female age and diminished ovarian reserve make this treatment modality suboptimal.134,135 IVF for unexplained subfertility has been shown to be only marginally more effective compared with IUI with ovarian stimulation,136 while comparison with expectant management has been shown to be effective. From uncontrolled review studies, IVF in older women was suggested to be more valuable compared with IUI treatment.137 Treatment in older women who are believed to have a still adequate prognosis should include the most powerful tool available in assisted reproduction and prevent low effective treatment.

Ovarian reserve testing prior assisted conception Age of the woman is a simple way of obtaining information on the extent of her ovarian reserve.138 In view of the variation in reproductive age within age classes, information on ovarian reserve status is needed. Ovarian reserve testing aims at identifying those subfertile cases with a high risk of producing a poor response to ovarian hyperstimulation and/or a very low probability of becoming pregnant through IVF, as well as those who still produce enough oocytes and are likely to become pregnant even if female age is advanced. Routine screening for ovarian reserve status prior to ART is currently not to be advised. In older women the challenge is to make sure that prospects for pregnancy are still realistic. Currently, cases of 40 years and over have only reasonable prospects if the response of the ovaries to hyperstimulation is adequate.139 Prior prediction of a good response may be possible by using ovarian reserve tests like AMH and the AFC. However, a first cycle response to maximal stimulation may provide the best answer to the question as to whether proceeding to a next cycle is worthwhile.

Preimplantation genetic screening One explanation for the increased risk for early pregnancy loss and prolonged infertility is that the monthly ovulating oocytes become progressively more aneuploid with age. Therefore, theoretically, the idea to select, under IVF/ICSI conditions, an euploid embryo for transfer seems logical. With this in mind, over recent years preimplantation genetic screening (PGS) has been progressively applied. With this technique one or two embryonic cells are removed and tested for chromosomal make-up. If sound then the embryo, considered devoid of aneuploidy, is transferred. Promising data that suggested higher pregnancy rates and reduced miscarriage rates after such screening have been reported over the past decade. Recently two large randomised trials have shown no benefit of

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preimplantation aneuploidy screening on pregnancy and delivery rates.140,141 The conclusion seems justified that, on the basis of current evidence, aneuploidy screening should be considered as a research tool and not be advocated for routine care of patients.142

References 1. Moce E, Lavara R, Vicente JS. Influence of the donor male on the fertility of frozen-thawed rabbit sperm after artificial insemination of females of different genotypes. Reprod Domest Anim 2005; 40: 516–21. 2. Viudes-de-Castro MP, Vicente JS. Effect of sperm count on the fertility and prolificity rates of meat rabbits. Anim Reprod Sci 1997; 46: 313–9. 3. Evers JL. Female subfertility. Lancet 2002; 360: 151–9. 4. Spira A. The decline of fecundity with age. Maturitas 1988; (Suppl 1): 15–22. 5. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002; 8: 141–54. 6. Wood JW. Fecundity and natural fertility in humans. Oxf Rev Reprod Biol 1989; 11: 61–109. 7. de Bruin J, te Velde ER. Female reproductive aging: concepts and consequences. In: Tulandi T, Gosden RG, eds. Preservation of Fertility. London, UK: Taylor & Francis, 2004: 3. 8. Boklage CE. Survival probability of human conceptions from fertilization to term. Int J Fertil 1990; 35: 75, 79–5, 94. 9. Hakim RB, Gray RH, Zacur H. Infertility and early pregnancy loss. Am J Obstet Gynecol 1995; 172: 1510–7. 10. Wilcox AJ, Weinberg CR, O’Connor JF et al. Incidence of early loss of pregnancy. N Engl J Med 1988; 319: 189–94. 11. O’Connor KA, Holman DJ, Wood JW. Declining fecundity and ovarian ageing in natural fertility populations. Maturitas 1998; 30: 127–36. 12. te Velde ER, Dorland M, Broekmans FJ. Age at menopause as a marker of reproductive ageing. Maturitas 1998; 30: 119–25. 13. te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002; 8: 141–54. 14. Block E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel) 1952; 14: 108–23. 15. Block E. A quantitative morphological investigation of the follicular system in newborn female infants. Acta Anat (Basel) 1953; 17: 201–6. 16. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7: 1342–6. 17. Gougeon A. Ovarian follicular growth in humans: ovarian ageing and population of growing follicles. Maturitas 1998; 30: 137–42. 18. Gosden RG, Faddy MJ. Ovarian aging, follicular depletion, and steroidogenesis. Exp Gerontol 1994; 29: 265–74.

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36. van Zonneveld P, Scheffer GJ, Broekmans FJ et al. Do cycle disturbances explain the age-related decline of female fertility? Cycle characteristics of women aged over 40 years compared with a reference population of young women. Hum Reprod 2003; 18: 495–501. 37. Fanchin R, Schonauer LM, Righini C et al. Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3. Hum Reprod 2003; 18: 323–7. 38. Seifer DB, MacLaughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum Mullerianinhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002; 77: 468–71. 39. van Rooij I, Broekmans FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH et al. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod 2002; 17: 3065–71. 40. van Rooij I, Tonkelaar I, Broekmans FJ et al. AntiMullerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 2004; 11: 601–6. 41. van Rooij I, Broekmans FJ, Scheffer GJ et al. Serum antiMullerian hormone levels best reflect the reproductive decline with age in normal women with proven fertility: a longitudinal study. Fertil Steril 2005; 83: 979–87. 42. de Koning CH, Popp-Snijders C, Schoemaker J, Lambalk CB. Elevated FSH concentrations in imminent ovarian failure are associated with higher FSH and LH pulse amplitude and response to GnRH. Hum Reprod 2000; 15: 1452–6. 43. Fitzgerald CT, Seif MW, Killick SR, Elstein M. Age related changes in the female reproductive cycle. Br J Obstet Gynaecol 1994; 101: 229–33. 44. Klein NA, Pergola GM, Rao-Tekmal R, Dey TD, Schenken RS. Enhanced expression of resident leukocyte interferon gamma mRNA in endometriosis. Am J Reprod Immunol 1993; 30: 74–81. 45. van Zonneveld P, Scheffer GJ, Broekmans FJ, te Velde ER. Hormones and reproductive aging. Maturitas 2001; 38: 83–91. 46. Levi AJ, Raynault MF, Bergh PA et al. Reproductive outcome in patients with diminished ovarian reserve. Fertil Steril 2001; 76: 666–9. 47. Soules MR, Battaglia DE, Klein NA. Inhibin and reproductive aging in women. Maturitas 1998; 30: 193–204. 48. Faddy MJ, Gosden RG, Gougeon A, Richardson SJ, Nelson JF. Accelerated disappearance of ovarian follicles in mid-life: implications for forecasting menopause. Hum Reprod 1992; 7: 1342–6. 49. Treloar AE. Menstrual cyclicity and the premenopause. Maturitas 1981; 3: 249–64. 50. Broekmans FJ, Faddy MJ, Scheffer G, te Velde ER. Antral follicle counts are related to age at natural fertility loss and age at menopause. Menopause 2004; 11: 607–14. 51. den Tonkelaar I, te Velde ER, Looman CW. Menstrual cycle length preceding menopause in relation to age at menopause. Maturitas 1998; 29: 115–23. 52. Broekmans FJ, Faddy MJ, Scheffer G, te Velde ER. Antral follicle counts are related to age at natural

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71. Penrose LS, Delhanty JD. Triploid cell cultures from a macerated foetus. Lancet 1961; 1: 1261–2. 72. Hunt PA, Hassold TJ. Human female meiosis: what makes a good egg go bad? Trends Genet 2008; 24: 86–93. 73. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 2002; 8: 333–43. 74. Hassold T, Hunt P. To err (meiotically) is human: the genesis of human aneuploidy. Nat Rev Genet 2001; 2: 280–91. 75. Sherman SL, Allen EG, Bean LH, Freeman SB. Epidemiology of Down syndrome. Ment Retard Dev Disabil Res Rev 2007; 13: 221–7. 76. Hollier LM, Leveno KJ, Kelly MA, McIntire DD, Cunningham FG. Maternal age and malformations in singleton births. Obstet Gynecol 2000; 96: 701–6. 77. Reefhuis J, Honein MA. Maternal age and nonchromosomal birth defects, Atlanta–1968–2000: teenager or thirty-something, who is at risk? Birth Defects Res A Clin Mol Teratol 2004; 70: 572–9. 78. Carmichael SL, Yang W, Herring A, Abrams B, Shaw GM. Maternal food insecurity is associated with increased risk of certain birth defects. J Nutr 2007; 137: 2087–92. 79. Yang J, Carmichael SL, Canfield M, Song J, Shaw GM. Socioeconomic status in relation to selected birth defects in a large multicentered US case-control study. Am J Epidemiol 2008; 167: 145–54. 80. Chia SE, Shi LM, Chan OY, Chew SK, Foong BH. Parental occupations and other risk factors associated with nonchromosomal single, chromosomal single, and multiple birth defects: a populationbased study in Singapore from 1994 to 1998. Am J Obstet Gynecol 2003; 188: 425–33. 81. Tan KH, Tan TY, Tan J et al. Birth defects in Singapore: 1994–2000. Singapore Med J 2005; 46: 545–52. 82. Crider KS, Olney RS, Cragan JD. Trisomies 13 and 18: population prevalences, characteristics, and prenatal diagnosis, metropolitan Atlanta, 1994– 2003. Am J Med Genet A 2008; 146: 820–6. 83. Allen VM, Wilson RD, Cheung A. Pregnancy outcomes after assisted reproductive technology. J Obstet Gynaecol Can 2006; 28: 220–50. 84. Heffner LJ. Advanced maternal age–how old is too old? N Engl J Med 2004; 351: 1927–9. 85. Toner JP, Grainger DA, Frazier LM. Clinical outcomes among recipients of donated eggs: an analysis of the U.S. national experience, 1996–1998. Fertil Steril 2002; 78: 1038–45. 86. Luke B, Brown MB. Elevated risks of pregnancy complications and adverse outcomes with increasing maternal age. Hum Reprod 2007; 22: 1264–72. 87. Luke B, Brown MB. Elevated risks of pregnancy complications and adverse outcomes with increasing maternal age. Hum Reprod 2007; 22: 1264–72. 88. te Velde ER, Habbema JD, Hilders CG, Merkus JM. The consequences of postponing pregnancy. Ned Tijdschr Geneeskd 2007; 151: 1593–6. [in Dutch] 89. Kwee A, Bots ML, Visser GH, Bruinse HW. Obstetric management and outcome of pregnancy in women with a history of Caesarean section in the Netherlands. Eur J Obstet Gynecol Reprod Biol 2007; 132: 171–6.

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90. Luke B, Brown MB. Elevated risks of pregnancy complications and adverse outcomes with increasing maternal age. Hum Reprod 2007; 22: 1264–72. 91. Abenhaim HA, Azoulay L, Kramer MS, Leduc L. Incidence and risk factors of amniotic fluid embolisms: a population-based study on 3 million births in the United States. Am J Obstet Gynecol 2008 Feb 21. 92. Hendriks DJ, Broekmans FJ, Bancsi LF et al. Single and repeated GnRH agonist stimulation tests compared with basal markers of ovarian reserve in the prediction of outcome in IVF. J Assist Reprod Genet 2005; 22: 65–73. 93. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006; 12: 685–718. 94. Kevenaar ME, Themmen AP, Rivadeneira F et al. A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Hum Reprod 2007; 22: 2382–8. 95. Seifer DB, MacLaughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum Mullerianinhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril 2002; 77: 468–71. 96. Klein NA, Houmard BS, Hansen KR et al. Agerelated analysis of inhibin A, inhibin B, and activin a relative to the intercycle monotropic follicle-stimulating hormone rise in normal ovulatory women. J Clin Endocrinol Metab 2004; 89: 2977–81. 97. Hendriks DJ, Broekmans FJ, Bancsi LF et al. Single and repeated GnRH agonist stimulation tests compared with basal markers of ovarian reserve in the prediction of outcome in IVF. J Assist Reprod Genet 2005; 22: 65–73. 98. Hendriks DJ, Mol BW, Bancsi LF, te Velde ER, Broekmans FJ. The clomiphene citrate challenge test for the prediction of poor ovarian response and nonpregnancy in patients undergoing in vitro fertilization: a systematic review. Fertil Steril 2006; 86: 807–18. 99. Jain T, Soules MR, Collins JA. Comparison of basal follicle-stimulating hormone versus the clomiphene citrate challenge test for ovarian reserve screening. Fertil Steril 2004; 82: 180–5. 100. Kwee J, Elting MW, Schats R et al. Comparison of endocrine tests with respect to their predictive value on the outcome of ovarian hyperstimulation in IVF treatment: results of a prospective randomized study. Hum Reprod 2003; 18: 1422–7. 101. Bancsi LF, Broekmans FJ, Eijkemans MJ et al. Predictors of poor ovarian response in in vitro fertilization: a prospective study comparing basal markers of ovarian reserve. Fertil Steril 2002; 77: 328–36. 102. Bancsi LF, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Impact of repeated antral follicle counts on the prediction of poor ovarian response in women undergoing in vitro fertilization. Fertil Steril 2004; 81: 35–41. 103. Ng EH, Tang OS, Ho PC. The significance of the number of antral follicles prior to stimulation in predicting ovarian responses in an IVF programme. Hum Reprod 2000; 15: 1937–42.

104. Popovic-Todorovic B, Loft A, Lindhard A et al. A prospective study of predictive factors of ovarian response in ‘standard’ IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dosage normogram. Hum Reprod 2003; 18: 781–7. 105. Popovic-Todorovic B, Loft A, Bredkjaeer HE et al. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in ‘standard’ patients undergoing IVF/ICSI treatment. Hum Reprod 2003; 18: 2275–82. 106. van Rooij I, Tonkelaar I, Broekmans FJ et al. AntiMullerian hormone is a promising predictor for the occurrence of the menopausal transition. Menopause 2004; 18: 601–6. 107. Hunault CC, Laven JS, van Rooij I et al. Prospective validation of two models predicting pregnancy leading to live birth among untreated subfertile couples. Hum Reprod 2005; 20: 1636–41. 108. van der Steeg JW, Steures P, Eijkemans MJ et al. Predictive value and clinical impact of basal follicle-stimulating hormone in subfertile, ovulatory women. J Clin Endocrinol Metab 2007; 92: 2163–8. 109. van Rooij I, Broekmans FJ, Hunault CC et al. Use of ovarian reserve tests for the prediction of ongoing pregnancy in couples with unexplained or mild male infertility. Reprod Biomed Online 2006; 12: 182–90. 110. Chang MY, Chiang CH, Hsieh TT, Soong YK, Hsu KH. Use of the antral follicle count to predict the outcome of assisted reproductive technologies. Fertil Steril 1998; 69: 505–10. 111. van Rooij I, Broekmans FJ, Hunault CC et al. Use of ovarian reserve tests for the prediction of ongoing pregnancy in couples with unexplained or mild male infertility. Reprod Biomed Online 2006; 12: 182–90. 112. Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006; 12: 685–718. 113. Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of antiMullerian hormone in prediction of outcome after IVF: comparison with the antral follicle count. Fertil Steril 2008; in press. 114. Franco JG Jr., Baruffi RL, Mauri AL et al. GnRH agonist versus GnRH antagonist in poor ovarian responders: a meta-analysis. Reprod Biomed Online 2006; 13: 618–27. 115. Klinkert ER. Clinical significance and management of poor response in IVF. 2005. 116. Land JA, Yarmolinskaya MI, Dumoulin JC, Evers JL. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril 1996; 65: 961–5. 117. Shanbhag S, Aucott L, Bhattacharya S, Hamilton MA, McTavish AR. Interventions for ‘poor responders’ to controlled ovarian hyperstimulation (COH) in in-vitro fertilisation (IVF). Cochrane Database Syst Rev 2007: CD004379. 118. Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 2003; 9: 61–76.

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The older woman wishing to conceive 119. Popovic-Todorovic B, Loft A, Lindhard A et al. A prospective study of predictive factors of ovarian response in ‘standard’ IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dosage normogram. Hum Reprod 2003; 18: 781–7. 120. Popovic-Todorovic B, Loft A, Bredkjaeer HE et al. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in ‘standard’ patients undergoing IVF/ICSI treatment. Hum Reprod 2003; 18: 2275–82. 121. Popovic-Todorovic B, Loft A, Ziebe S, Andersen AN. Impact of recombinant FSH dose adjustments on ovarian response in the second treatment cycle with IVF or ICSI in “standard” patients treated with 150 IU/day during the first cycle. Acta Obstet Gynecol Scand 2004; 83: 842–9. 122. Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial. Hum Reprod 2005; 20: 611–15. 123. de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, van Leeuwen FE. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003; 18: 1544–52. 124. van der Gaast MH, Eijkemans MJ, van der Net JB et al. Optimum number of oocytes for a successful first IVF treatment cycle. Reprod Biomed Online 2006; 13: 476–80. 125. de Boer EJ, den Tonkelaar I, te Velde ER et al. A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause. Fertil Steril 2002; 77: 978–85. 126. Klinkert ER, Broekmans FJ, Looman CW, te Velde ER. A poor response in the first in vitro fertilization cycle is not necessarily related to a poor prognosis in subsequent cycles. Fertil Steril 2004; 81: 1247–53. 127. Lawson R, El-Toukhy T, Kassab A et al. Poor response to ovulation induction is a stronger predictor of early menopause than elevated basal FSH: a life table analysis. Hum Reprod 2003; 18: 527–33. 128. van Disseldorp J, Eijkemans MJ, Klinkert ER et al. Cumulative live birth rates following IVF in 41- to 43-year-old women presenting with favourable ovarian reserve characteristics. Reprod Biomed Online 2007; 14: 455–63.

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129. Mulrow CD, Chiquette E, Ferrer RL et al. Management of chronic hypertension during pregnancy. Evid Rep Technol Assess (Summ) 2000: 1–4. 130. Steures P, van der Steeg JW, Hompes PG et al. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368: 216–21. 131. van der Steeg JW, Steures P, Eijkemans MJ et al. Predictive value and clinical impact of basal follicle-stimulating hormone in subfertile, ovulatory women. J Clin Endocrinol Metab 2007; 92: 2163–8. 132. National Institute for Clinical Excellence (NICE). Fertility: assesment and treatment for people with fertility problems. London, UK: Royal College of Obestetricians and Gynaecologists (RCOG) Press, 2004. 133. Verhulst SM, Cohlen BJ, Hughes E, Te Velde E, Heineman MJ. Intra-uterine insemination for unexplained subfertility. Cochrane Database Syst Rev 2006: CD001838. 134. Chang MY, Chiang CH, Chiu TH, Hsieh TT, Soong YK. The antral follicle count predicts the outcome of pregnancy in a controlled ovarian hyperstimulation/intrauterine insemination program. J Assist Reprod Genet 1998; 15: 12–17. 135. Magendzo A, Schwarze JE, Diaz de la Vega C et al. Clomiphene citrate challenge test predicts outcome of intrauterine insemination in women aged under 37 years. Reprod Biomed Online 2006; 12: 423–7. 136. Pandian Z, Bhattacharya S, Vale L, Templeton A. In vitro fertilisation for unexplained subfertility. Cochrane Database Syst Rev 2005: CD003357. 137. Broekmans FJ, Klinkert ER. Female age in ART: when to stop? Gynecol Obstet Invest 2004; 58: 225–34. 138. Templeton A, Morris JK, Parslow W. Factors that affect outcome of in-vitro fertilisation treatment. Lancet 1996; 348: 1402–6. 139. Tsafrir A, Simon A, Revel A et al. Retrospective analysis of 1217 IVF cycles in women aged 40 years and older. Reprod Biomed Online 2007; 14: 348–55. 140. Donoso P, Staessen C, Fauser BC, Devroey P. Current value of preimplantation genetic aneuploidy screening in IVF. Hum Reprod Update 2007; 13: 15–25. 141. Mastenbroek S, Twisk M, van Echten-Arends J et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007; 357: 9–17. 142. Devroey P, Fauser BC. Preimplantation aneuploidy screening: a research tool for now. Lancet 2007; 370: 1985–6.

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27 Psychosocial issues in periconceptional care Laura Bunting, Jacky Boivin

Achieving pregnancy depends not only on biology but also on numerous psychological and social factors. Cognitive, emotional and social processes can hinder the project to have a child by affecting, for example, sexuality, treatment motivation or the effectiveness of stimulation regimens in in vitro fertilisation (IVF). The periconceptional consultation provides an excellent opportunity to identify such issues. The aim of the present chapter is to describe psychosocial issues that may interfere with the project to have a child among those trying to conceive naturally and/or with treatment as well as how these issues can be addressed in the context of a periconceptional consultation.

Parenting motivation and ambivalence Parenting motivation and need for parenthood are important to consider in periconceptional consultations with couples trying to conceive because individual and couple ambivalence about the parenting project predict pregnancy and time-to-pregnancy. The experience of parenthood is central to individual identity and the life plan of most people in most societies and many psychosocial factors contribute to the decision to actively start trying to have children. People start on the project to have a child when the perceived benefits of having children begin to outweigh the perceived disadvantages of doing so.1 Many positive reasons motivate efforts to become a parent (e.g. pass on the family name, give and receive love, marital harmony, give life meaning) but having children can also interfere with the desire and freedom to focus on other life pursuits (e.g. career, humanitarian work) that would be at odds with parental responsibilities or their consequences (e.g. financial costs, lack of time) and these may influence fertility decisionmaking. Even if the individual or couple has strong motivation to have a child other demographic, social and lifestyle factors may create ambivalence about the project and intervene to postpone the start of childbearing attempts. Individual and couple ambivalence about the parenting project predict both pregnancy and time-topregnancy. In a prospective study among French couples trying to conceive naturally it was found that

ambivalence about childbearing, as reflected in factors related to poor integration of the desire for a child into the sexual relationship (men) as well as frequent fears or concerns about having a child (men and women), was related to reduced fertility 12 and 18 months later and, in those who did eventually achieve pregnancy, longer time to pregnancy.2 Ambivalence might reduce conception by making couples avoid sexual intercourse or engage in behaviours that would make conception more difficult, for example, scheduling business trips during the fertile period or continuing with lifestyle factors detrimental to conception (e.g. smoking, drinking alcohol). Ambivalence could also jeopardise diagnostic procedures and treatment if a fertility problem was eventually discovered. In further analyses of the French data it was found that women who were ambivalent were less likely to have completed all the medical procedures required to obtain a diagnosis at the 18-month follow-up.3 This finding is in line with other work showing that couples who drop out of infertility diagnostic testing do so because of a lower motivation to conceive.4 Furthermore, in one German study couples where the desire to have a child was mainly motivated by the desire to keep ‘marital harmony’ were less likely to persist with fertility treatment and to have conceived in 12 months than were couples where there was a greater desire for parenthood per se.5 It is important to make ambivalence conscious in the periconceptional consultation so that individuals and/or couples can address its cause and prevent negative effects on time to pregnancy. Although couples need not be united in their reasons for having a child, the findings make clear that the project to become parents will be much more successful if both are united in believing that the present time is, on balance of the positives and negatives of parenthood, a good time to start trying for a family. It would be impossible to list here all the causes of ambivalence about having children but the main issues factored into the decision in transition to parenthood studies concern age,6 career development, economic stability and financial cost of raising a child, physical effort and loss of leisure time.7 As noted previously marital conflict may also be a source of ambivalence and, if uncovered, couples should be

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referred for appropriate support. Couples may need to address and resolve sources of ambivalence before fully engaging in the project to have a child.

Sexual issues The success of natural attempts to conceive and some treatments depend on sexual intercourse taking place during the fertile period and therefore sexuality is a legitimate area of enquiry in the periconceptional consultation. Sexual health is considered the physical and emotional state of well-being that enables sexual enjoyment and acting on sexual feelings, whereas sexual dysfunction involves any impairment or disturbance in one or more of the phases of the sexual response cycle (desire, arousal, orgasm and satisfaction).8 Approximately 40–45% of adult women and 20–30% of adult men experience a sexual problem at some point9 and negative life events that exert pressure on the individual and/or couple (e.g. occupational stressors, illness, marital conflict) can negatively impact on efforts to conceive by affecting sexual life. Sexual dysfunction as an aetiological factor contributes to a very small percentage of cases of infertility though in some cultures couples may prefer to mask sexual dysfunctions as infertility.10 However, sexual issues need not be dysfunctions as certain religious and cultural practices can also interfere with fertile lovemaking. For example, in orthodox Judaic religions sexual intercourse is forbidden for a period of 12 days after the start of menstruation, a practice which can interfere with conception in short menstrual cycles.11 Furthermore, recent worldwide surveys show that people lack knowledge about the fertile period12–16 and though regular unprotected intercourse should overcome any knowledge barrier it can become more of a problem for couples who have infrequent coitus due to low sexual desire.17 The incidence of sexual problems in those trying to conceive is similar to that of the general population,18 but persistent lack of success can increase this percentage. As a consequence of repeated unsuccessful attempts to conceive the pleasurable experience of sexual intimacy becomes altered so that sex becomes methodical, predictable and unexciting as the meaning of sex focuses on procreation rather than intimacy.19 Furthermore, the lack of success in conceiving may cause mood disturbances, for example depressive symptoms, that are themselves associated with reduced libido and arousal.20 In such circumstances maintaining sexual motivation can become a problem. Takefman et al19 showed that 25% of couples reported sexual problems after the infertility diagnostic investigation that did not exist before couples started tests and procedures to identify the cause of their fertility problem. In a cohort observational study Saleh et al21 reported that 11% of men (46/412) reported erectile or orgasmic dysfunction subsequent to a diagnosis of semen abnormality. Taking a sexual history during a periconceptional consultation for suspected fertility problems is

important to identify problematic sexual areas and their potential contribution to any fertility problem. A detailed description is outside the scope of this chapter but 2–3 minute evaluations are possible to determine the presence of a problem (“Any sexual concerns or pain with sex?”) and whether the concern can be addressed (1) during the current appointment (e.g. problem due to lack of knowledge), (2) during a follow-up visit specifically focused on addressing the problem (e.g. problem due to medical problems requiring further examination) or (3) will require referral to a sex or marital therapist (e.g. sexual aversion disorder, poor marital communication) and/or need to involve multidisciplinary team (e.g. hypoactive disorder compounded by medical condition).22 Whether sexual problems are present or not, practitioners should avoid being too prescriptive about the timing and technique of intercourse during the fertile period23 or imposing restrictions on nonprocreative sexual activities (e.g. long periods of abstinence)18 to minimise the possibility of provoking sexual strain. Addressing sexual issues in couples early in the process of conception can prevent further deterioration in sexual function and can increase pregnancy rates. Tuschen-Caffier et al17 reported a decrease in marital distress and an increase in marital satisfaction and coital activity after their 8-month sex therapy intervention.

Engaging in the medical process Despite their best efforts a proportion of couples, about 9%,24 will not conceive naturally and at some point will start to question their fertility. Despite ongoing questioning and worry about their fertility, couples who suspect a fertility problem do not easily take action and on average only half will seek any kind of medical advice/treatment.24 Many theories have attempted to explain help seeking behaviour in a variety of medical contexts. Their full description is outside the scope of this chapter, but research supports these theoretical principles and has highlighted their importance in the fertility context and in accounting for the discrepancy between the desire to have children and the actual seeking of medical advice when a fertility problem is suspected. Where possible such issues should be addressed because they can undermine efforts to conceive. Unfortunately, as these individuals/couples are outside the medical system, interventions are more a matter of educational public health campaigns than individual intervention. Nevertheless, it is important to know what factors reduce the likelihood of seeking medical advice as such factors may also influence movement between categories of help (e.g. going from diagnostic investigation to treatment, or between different forms of treatment). First, and perhaps most obviously, people often do not realise they have a fertility problem. In a recent study we found that nearly 20% of women sampled

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(n=426) already met the definition for infertility (they had been trying to conceive for about 2 years) but surprisingly had not yet sought any kind of medical advice despite a stronger than average desire for children.25 Two explanations were offered for this paradox: women were not realising that risk information applied to them personally and, if they did, they were too afraid to get help in case it meant discovering they would never have children. People must perceive that information about fertility risk factors or indicators of fertility problems apply to them personally and in the case of fertility problems this often means realising how long is too long when it comes to lack of conception trying naturally.26 Furthermore, nobody likes to hear bad news, and the possibility of a threatening diagnosis may further inhibit people from seeking advice or medical help and the detrimental effects of fear have been demonstrated compellingly in many health areas (e.g. breast and prostate cancer screening27). The issue of infertility is still surrounded by taboos (religious, social) and it is often difficult for couples to address this problem openly, in turn, this lack of openness suppresses their chances to identify a solution and seek timely medical advice.15 A second factor inhibiting seeking medical advice is lack of knowledge about the effectiveness of treatment and/or negative portrayal of infertility treatment in the media. Steinbrook28 found that 75% of respondents polled relied on media coverage for medical information to aid their decision-making. The media offers important opportunities for large-scale educational campaigns informing the public about important medical issues; however, differences in the quality and presentation of data can undermine and misrepresent valuable information.29 With regard to infertility, the descriptions of “extreme” rather than “normal” cases often cited in the mass media may influence decision-making in a negative way.15 Research has demonstrated that people willing to undergo fertility medical interventions had more faith in and less anxiety about medical interventions30 and were more convinced that medical interventions could help them achieve their parenthood goal31 than women who did not seek medical interventions. A final factor that may delay seeking medical advice is that getting timely advice can be at odds with the instinctive way people seek help when they need help. The hierarchical-compensatory model of seeking support/advice proposes that professionals are consulted only when individuals cannot sort the problem out on their own or find help amongst their own network of family and friends.32 Accordingly people will likely first try to resolve a suspected fertility problem by first making behavioural changes and/or taking up solutions within their control. Couples may start looking at their lifestyle habits and modify those that are perceived to be problematic as this is an area in their life they can readily control. Indeed the internet is a valuable tool to many couples in this respect as it provides

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them with information about the conception process and fertility issues,33,34 including suggestions on what couples trying to conceive should adapt in their diet and lifestyle to improve fertility. If changing lifestyle habits does not resolve the problem then people may try to resolve it first by self-diagnosis and then selftreatment and this may follow and/or co-occur with lifestyle adaptations. There are a number of over the counter testing kits (e.g. Fertell, Ovukit) that provide information about ovarian reserve and ovulation in women, and/or motility and volume of sperm in men. Although people cannot self-medicate there is now increasing use of complementary and alternative medicines (CAM) to address a variety of health problems35,36 and about 30–60% of infertility patients use CAMs.37–39 In other health contexts a poorer prognosis and more severe disorders are key motivating factors for CAM use and the lack of success conceiving may similarly cause people to use CAMs in order to self-treat and resolve perceived fertility problems. Although there is a pervasive belief that CAMs are benign their use can delay seeking more effective intervention.40 Periconceptional interventions to help minimise interference caused by these psychosocial issues are difficult because the 45% of people with a suspected fertility problem not seeking medical advice24 are outside the medical process and, therefore, beyond the reach of practitioners who could correct misinformation, calm fears or provide timely referrals for specialist fertility care. As such, the main way practitioners can be involved in reducing delay is to participate in educational campaigns with such aims. A useful way of intervening with couples at this stage would, therefore, be to provide trustworthy websites and/or incorporate lifestyle advice in existing clinic websites. Tuil et al41 and Cousineau et al42 have recently developed websites for people with fertility problems that incorporate such advice.

Treatment burden The majority of couples (69.4%) who initiate treatment will achieve their goal of parenthood with about 3.7 treatments within 5 years.43 Given such odds the main psychosocial considerations during the treatment process will be to reduce the strain of fertility treatment and help people stay in treatment long enough to get pregnant. There are four well-established findings concerning reactions to fertility treatment and knowing these can help practitioners ease the burden of treatment.8,44 First, reactions (emotional, physical and social) to fertility treatment vary according to the practical demands and psychosocial challenges of each stage of treatment. For example, fatigue is highest when people attend clinic for scans or blood tests; side-effects (e.g. breast tenderness) highest when fertility drugs exert their greatest influence; stress reactions (e.g. anxiety, tension) highest when

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there is possibility of threatening test results (any eggs? any embryos? pregnant?); and so on.45 Second, unsuccessful treatment is associated with an acute period of depression, elevated anxiety, anger and frustration, and a variety of other reactions, including suicidal thoughts that can persist for more than 5 weeks in about 20% of patients46 and that the intensity of negative emotions for a cancelled IVF cycle (e.g. poor ovarian response, failed fertilisation) is as great as a negative pregnancy test.47 Third, results converge to show that the main difference in reactions between men and women is in intensity of reactions to IVF rather than in kind since men and women have a similar pattern of reactions.48 Finally, despite the considerable emotions experienced in IVF, 80% of women report that participation in the IVF programme did bring some benefits, especially with regard to satisfaction that they had tried all medical options available49 and greater closeness to their spouse.50 Although other fertility treatments (e.g. insemination, ovulation induction) will differ in side-effects, emotional reactions would be expected to be similar. The predictability in emotional responses to fertility treatment can be used to better prepare patients for what they can expect during treatment. Preparatory coping information has received considerable attention in areas as diverse as radiation therapy, cardiac surgery and dental check-ups, and has generally been found to be effective in reducing patient distress (for reviews see Ludwick-Rosenthal and Neufeld,51 Suls and Wan52) because it helps patients rehearse mentally how they will cope with emotional and physical effects of treatment,53 provides patients with accurate expectations for the future thereby reducing the unpredictability of the event54 and finally provides a desensitising experience that will reduce patients’ conditioned fear of medical procedures or their outcome.55 Laffont and Edelmann56 also found that patients ranked a pre-treatment booklet about the psychological aspects of IVF among the most important interventions they could have received to ease the strains of undergoing IVF treatment. Preparatory information would, thus, seem to be an ideal intervention for IVF patients who face considerable uncertainty about the medical procedures to be used and the reactions they may have during the treatment. Tuil et al41 recently demonstrated that access to personal medical records, especially an IVF day planner that gave a personalised timetable of treatment steps, was rated amongst the most useful aspects of an internet intervention, above even email communication with staff. The periconceptional consultation would be an ideal time to provide patients with preparatory coping interventions to aim to reduce the burden of forthcoming treatments.

Stress and treatment outcome Stress is increasingly viewed as having a negative effect on fertility. Stress can be defined in numerous

ways, as a stimulus (e.g. bereavement, high workload), response to such events (e.g. anxiety, tension, physiological reactivity) or the dynamic relation between stressor and response whereby events that exceed individual abilities or resources to cope produce emotional, cognitive and physiological stress responses that can compromise health.57 There is now converging evidence that stress plays a part in the process of conception though the precise critical threshold for such effects and the factors that moderate this psychobiological relationship are not yet known. For example, in healthy women trying to conceive naturally, negative affect (e.g. anxiety, depression) and/or negative personality traits have been associated with longer cycle lengths,58 ovulatory disturbance59 and reduced conception.60 There is also converging evidence that negative psychological traits and mood states contribute to fertility treatment failure. These effects have been found mainly in women trying to conceive with IVF61 but also with donor insemination.62,63 The association has been shown with diverse psychological measures: anxiety,64 depression,65 infertility-specific distress66 and overly intense desire for a child3 as well as diverse biological indicators of stress, for example, reactivity,67 hormonal62 and immunological64 parameters. In treatment cycles these are associated with a poorer biological response to treatment,68 a lower pregnancy69 and live birth rate.70 Finally, this psychobiological association remains if one controls for procedural stress effects (i.e. negative feedback from staff during treatment47) and/or negative lifestyle factors associated with stress that also compromise success rates (e.g. smoking or poor diet).70,71 A psychobiological link between stress and fertility has been contentious because women can and do conceive despite harsh conditions of war, poverty and famine, and indeed fertility per woman is highest in countries where such hardships are common, most likely due to the reduced likelihood of offspring survival.72,73 Moreover, despite the converging evidence in human studies noted previously, not all human studies find an association between stress and fertility potential and/or the effect size varies among studies (e.g. Anderheim et al;74 Merari et al75) and, in fact, some studies show benefits due to higher stress levels.71,76 However, variation in the association between stress and fertility across countries or studies need not question the existence of the association but it does point to the likelihood that stress-induced reproductive suppression can be augmented or diminished depending on the presence of other factors and/or that it can be over-ridden.77 More research is needed to identify what these factors are and how they can be used to minimise stress interference in fertility treatments. Periconceptional consultations should routinely include enquiries about stress factors and other negative lifestyle factors that covary with stress and which may themselves be the cause of the association

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between stress and fertility (e.g. smoking). If stress factors are a contributing cause to infertility, then individuals could be directed to appropriate psychosocial interventions. The two reviews of the intervention literature agree that psychosocial interventions (e.g. individual/ couple or group therapy, counselling, educational or comprehensive programmes) do effectively reduce emotional distress, especially anxiety, in people undergoing fertility interventions.78,79 However, there is more controversy about whether these studies also demonstrate a positive effect on pregnancy rates. Boivin78 reviewed the intervention data and found that three randomised controlled trials showed positive intervention effects on pregnancy whereas five did not. The positive randomised controlled trials used three different interventions: two sessions of couple psychodynamic psychotherapy with an 18month follow-up period,80 a 32-week course of couple sex therapy with a follow-up period of 6 months17 and a ten-week comprehensive educational and coping skills intervention with a 12-month follow-up period.81 The cumulative pregnancy rate in positive effects studies ranged from 30 to 60% with an average of 48.3%. In contrast, the cumulative pregnancy rate in the no-effect studies ranged from 15 to 40% with an average of 24.7%. These are substantial effects when one considers that the cumulative pregnancy rate reported for the positive effects studies was approximately similar to the cumulative pregnancy rate following five consecutive IVF cycles82 or 6 months of unprotected sexual intercourse in fertile couples.83 Although these results seemed promising it was concluded that much greater confidence could be had in effectiveness if future investigations were better controlled.78 Although deLiz and Strauss79 made the same conclusion they were more optimistic that the benefits in pregnancy rates realised from reducing distress were genuine and would be upheld in further investigations. The reviews also showed promising results for combined intervention that tackled multiple psychosocial factors. Clark et al84 found that 85% of women who lost weight following a group intervention that included diet, exercise and group support were able to conceive naturally. Domar et al81 showed that the time-to-pregnancy was significantly lower in people attending ten weekly sessions of the Mind/Body programme that involved nutritional and exercise advice, training in relaxation and mindfulness techniques, and group sharing and support compared with the control and support only groups. Together the results indicate that one is likely to improve quality of life for patients undergoing fertility treatment through psychosocial interventions but that such effects cannot guarantee a concomitant increase in pregnancy. It may be that such effects can be produced once the interventions have been made more potent by concentrating the active ingredients and eliminating ineffective components.

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Treatment persistence and treatment drop out There is accumulating evidence of substantial premature drop out from fertility treatment. By drop out we mean voluntarily ending treatment despite good prognosis and resources to carry on with treatment. The true rate and cause of drop out for fertility medical services is difficult to estimate because the treatment process is protracted (i.e. from the diagnostic investigation to IVF), prognostic and financial resources are not always factored into estimates, and whilst the causes of drop out are probably multifactorial only a single primary cause is listed, which may hide other important secondary causes. Despite these problems there is reasonable expectation that a significant proportion of individuals/couples that enter the medical process will drop out before they have realised their goal of parenthood. In a well-controlled prospective investigation 12.2% of women actively withdrew after the first IVF cycle and 18.3% after a second despite good prognosis and financial subsidies to continue with treatment, and the women who dropped out were more depressed and anxious at the start of treatment than those who continued.85 As noted previously all patients should receive preparatory coping interventions at the periconceptional consultation but findings about treatment drop out suggest that periconceptional consultations might additionally aim to identify those at risk for high distress during treatment so that preventative interventions can be implemented. Psychological screening and assessment prior to IVF is controversial because fertility experts operate more or less with the belief that their role is not to decide who has access to treatment (“gatekeepers”) but to provide fertility services for those who have barriers to conception.77,86 Having said this, most clinics have implicit policies that do limit access to fertility treatment in cases of active substance abuse, current physical abuse, severe marital strife, the presence of a major personality disorder or severe intellectual impairment and in cases where one spouse is being coerced by the other to undergo treatment.87 Outside of such extreme situations, the focus of screening should be to implement intervention programs that can minimise the impact of risk factors and help individuals/couples stay in treatment long enough to achieve conception. Very little work has been carried out on this topic but what has seems promising in terms of early detection. In a series of studies testing a stress vulnerability model in the context of fertility treatment Verhaak et al88,89 demonstrated that personality traits (neuroticism), marital factors (dissatisfaction), infertility related cognitions (helplessness) and information processing (attentional biases to infertility threat words) were vulnerability factors for greater depression and anxiety after a failed fertility treatment cycle (after controlling for pre-treatment distress), whereas social

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support and acceptance were protective. Furthermore, a screening tool based on these vulnerability and protective factors was predictive of post-treatment anxiety and depression in an IVF sample, with a 74% rate of correct classification (at risk, not at risk), sensitivity of 68% and specificity of 77%. If individuals at risk for distress can be identified then appropriate interventions can be recommended. The cause of premature drop out is likely to be multifactorial and accordingly the problem should be tackled from different angles. As noted, much can be done to ease the burden of treatment using preparatory interventions, however, those at risk for high distress might additionally benefit from interventions directed to meeting emotional rather than informational needs. Many such interventions exist (see Boivin78 for a review) but some seem particularly relevant to a treatment context. In a rigorously controlled experiment Cousineau et al90 demonstrated that a flexible online intervention that helped people identify their support needs and provided concrete coping skills and support opportunities significantly reduced infertility-specific distress and decisional conflict as well as improved fertility knowledge and self-efficacy compared with no treatment control groups. Benefits were markedly greater in women using the intervention for more than 1 hour. Van Balen91 reported on a telephone helpline managed by trained volunteers who had all experienced infertility. The helpline operated to full capacity, 90% of calls were from women and calls lasted between 20 and 30 minutes. Calls were mainly requests for medical or treatment information, but 30–40% of callers wanted emotional support, and support was rated as helping to cope with the strains of infertility and its treatment. Schmidt et al92 showed that an intervention focused mainly on communication skills training helped couples in treatment to better manage information exchange in their social network, which improved their quality of life. Finally, Lancastle and Boivin93 demonstrated that a self-administered coping intervention designed to promote positive reappraisal coping was perceived to be helpful and to sustain coping efforts during the 2 week waiting period prior to the pregnancy test in IVF. These recently developed interventions all have the potential to be easily administered in the treatment context with early promise as tools to reduce the burden of treatment and, individually or in combination, may provide sufficient support for the individual to stay in treatment long enough to achieve their goal of parenthood.

Summary and conclusions Achieving pregnancy depends not only on biology but also on numerous psychological and social factors that can at times undermine the project to have a child. The periconceptional consultation provides an ideal opportunity to determine to what extent such factors are

relevant to the individual or couple. Numerous interventions now exist to manage such issues and most could be adapted for the typical fertility clinic and adapted to individual patient need. Importantly, research demonstrates the effectiveness of such interventions in helping individuals achieve their goal of parenthood, whether that is by increasing motivation, reducing sexual dysfunction or negative lifestyle habits, promoting good coping skills or easing the burden of treatment.

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Psychosocial issues in periconceptional care 15. Adashi EY, Cohen J, Hamberfer L et al. Public Perception on infertility and its treatment: an international survey. Hum Reprod 2000; 15: 330–4. 16. Fuentes A, Devoto L. Infertility after 8 years of marriage: a pilot study. Hum Reprod 1994; 9: 273–8. 17. Tuschen-Caffier B, Florin I, Krause W, Pook M. Cognitive-behavioural therapy for idiopathic infertile couples. Psychother Psychosom 1999; 86: 15–21. 18. Keye RW. Female sexual activity, satisfaction and function in infertile women. Infertility 1983; 5: 275–85. 19. Takefman JE, Brender W, Boivin J, Tulandi T. Sexual and emotional adjustment of couples undergoing infertility investigation and the effectiveness of preparatory information. J Psychosom Obstet Gynaecol 1990; 11: 275–90. 20. Seidman SN, Roose SP. Sexual Dysfunction and Depression. Curr Psychiatry Rep 2001; 3: 202–8. 21. Saleh RA, Ranga GM, Raina R, Nelson DR, Agarwal A. Sexual dysfunction in men undergoing infertility evaluation: a cohort observational study. Fertil Steril 2003; 79: 909–12. 22. Kingsberg SA. Taking a sexual history. Obstet Gynecol Clin North Am 2006; 33: 535–47. 23. Agarwal SK, Haney AF. Does recommending timed intercourse really help the infertile couple? Obstet Gynecol 1994; 84: 307–10. 24. Boivin J, Bunting L, Collins JA, Nygren K. An international estimate of infertility prevalence and treatmentseeking: Potential need and demand for infertility medical care. Hum Reprod 2007; 22: 1506–12. 25. Bunting L, Boivin J. Decision-making about seeking medical advice in an internet sample of women trying to get pregnant. Hum Reprod 2007; 22: 1662–8. 26. Clark A, Mackenzie C. The national fertility study 2006 (1): Australians’ experience and knowledge of fertility issues. In: Program and Abstracts of the 23rd Annual Meeting of the European Society for Human Reproduction and Embryology. July 2007. Lyon. Hum Reprod 2007; 22: i29–i31. 27. Consedine NS, Magai C, Krivoshekova YS, Ryzewicz L, Neugut AL. Fear, Anxiety, Worry, and Breast Cancer Screening Behavior: A Critical Review. Cancer Epidemiol Biomarkers Prev 2004; 13: 501–10. 28. Steinbrook R. Medical journals and medical reporting, N Engl J Med 2000; 342: 1669–71. 29. Letterie GS. Multiple births: does the news media influence public perceptions? Hum Reprod 2004; 19: 2680–1. 30. van Balen F, Verdurmen J. Medical anxiety and the choice for treatment: The development of an instrument to measure fear of treatment. Psychol Health 1999; 14: 927–35. 31. Callan VJ, Kloske B, Kashima Y, Hennessey JF. Toward understanding women’s decisions to continue or stop in vitro fertilization – the role of social, psychological, and background factors. J In Vitro Fert Embryo Transf 1988; 5: 363–9. 32. Cantor MH. Neighbors and friends: an overlooked resource in the informal support system. Res Aging 1979; 1: 434–63. 33. Weissman A, Gotlieb L, Ward S, Greenblatt E, Casper RF. Use of the Internet by infertile couples. Fertil Steril 2000; 73: 1179–82.

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34. Huang JYJ, Al-Fozan H, Tan SL, Tulandi TT. Internet use by patients seeking infertility treatment. Int J Gynaecol Obstet 2003; 83: 75–6. 35. Fisher P, Ward A. Complementary medicine in Europe. BMJ 1994; 309: 107–11. 36. Eisenberg DM, Davis RB, Ettner SL et al. Trends in alternative medicine use in the United States, 1990–1997. Results of a follow-up national survey. JAMA. 1998; 280: 569–1575. 37. Coulson C, Jenkins J. Complementary and alternative medicine utilisation in NHS and private clinic settings: a United Kingdom survey of 400 infertility patients. J Exp Clin Assist Reprod 2005; 2: 2–5. 38. Stankiewicz M, Smith C, Alvino H, Norman R. The use of complementary medicine and therapies by patients attending a reproductive medicine unit in South Australia: A prospective survey. Aust N Z J Obstet Gynaecol 2007; 47: 145–9. 39. Zini A, Fischer MA, Nam RK, Jarvi K. Use of alternative hormonal therapies in male infertility. Urology 2004; 63: 141–3. 40. Domar A, Boivin J. Two views: should mental health professionals encourage infertile patients to try complementary therapies? Sexuality Reproduction and Menopause 2007; 5: 30–2. 41. Tuil WS, Verhaak CM, Braat DDM, de Vries Robbé RF, Kremmer JAM. Empowering patients undergoing in vitro fertilisation by providing internet access to medical data. Fertil Steril 2005; 88: 361–8. 42. Cousineau TM, Green TC, Corsini EA et al. Development and validation of the infertility selfefficacy scale. Fertil Steril 2006; 85: 1684–96. 43. Pinborg A, Schmidt L, Nyboe, Andersen A. Crude 5year follow-up on delivery and adoption rates among 1338 new couples treated with ART. In: Program and Abstracts of the 23rd Annual Meeting of the European Society for Human Reproduction and Embryology. July 2007. Lyon. Hum Reprod 2007; 22: i29–i31. 44. Boivin J, Kentenich H. ESHRE Monographs: Guidelines for Counselling in Infertility. London: Oxford University Press, 2002. 45. Boivin J, Takefman J. The impact of the in-vitro fertilization-embryo transfer (IVF-ET) process on emotional, physical and relational variables. Hum Reprod 1996; 11: 903–7. 46. Litt MD, Tennen H, Affleck G, Klock S. Coping and cognitive factors in adaptation to in vitro fertilisation failure. J Behav Med 1992; 15: 171–81. 47. Boivin J. Patient staff communication and its effect on reactions to treatment and treatment failure. In: van Balen F, Gerrits T, Inhorn M, eds. Proceedings of Social Science Research on Childlessness in a Global Perspective. Amsterdam: SCO-Kohnstam Instituut, 2000. 48. Boivin J, Andersson L, Shoog-Svanberg A et al. Psychological reactions during in vitro fertilization (IVF): Similar response pattern in husbands and wives. Hum Reprod 1998; 13: 3262–7. 49. Hammerberg K, Astbury J, Baker HWG. Women’s experience of IVF: a follow-up study. Hum Reprod 2001; 16: 374–83. 50. Brew TA. Benefit finding in women’s lives following unsuccessful infertility treatment. D.Clin.Psy [Thesis]. University of Wales Cardiff, 2002.

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51. Ludwick-Rosenthal R, Neufeld RWJ. Stress management during noxious medical procedures: An evaluative review of outcome studies. Psychol Bull 1988; 104: 326–42. 52. Suls J, Wan CK. Effects of sensory and procedural information on coping with stressful medical procedures and pain: A meta-analysis. J Consult Clin Psychol 1989; 57: 372–9. 53. Meichenbaum D, Turk D, Burstein S. The nature of coping with stress. In: Sarason IG, Spielberger CD eds. Stress and Anxiety. New York: Wiley & Sons, 1975: 337–60. 54. Johnson JE, Lauver DR, Nail LM. Process of coping with radiation therapy. J Consult Clin Psychol 1989; 57(3): 358–64. 55. Shipley RH, Butt JH, Horwitz B, Farbry JE. Preparation for a stressful medical procedure: Effect of amount of stimulus pre-exposure and coping style. J Consult Clin Psychol 1978; 46: 499–507. 56. Laffont I, Edelmann RJ. Perceived support and counselling needs in relation to in vitro fertilization. J Psychosom Obstet Gynaecol 1994; 15: 183–8. 57. Lazarus RS, Folkman S. Stress, Appraisal, and Coping. New York: Springer Publishers, 1984. 58. Hjollund NH, Jensen TK, Bonde JP et al. Distress and reduced fertility: a follow-up study of first-pregnancy planners. Fertil Steril 1999; 72: 47–53. 59. Berga SL. Functional hypothalamic amenorrhea. Curr Opin Endocrinol Diabetes Obes 2001; 8: 307–13. 60. Sanders K, Bruce N. A prospective study of psychosocial stress and fertility in women. Hum Reprod 1997; 12: 2324–9. 61. Eugster A, Vingerhoets AJJM. Psychological aspects of in vitro fertilization. Soc Sci Med 1999; 48: 575–89. 62. Demyttenaere K, Nijis P, Steeno O, Koninckx PK, Evers-Kiebooms G. Anxiety and conception rates in donor insemination. J Psychosom Obstet Gynaecol 1988; 8: 175–81. 63. Schover LR, Greenhalgh LF, Richards SI, Collins RL. Psychological screening and the success of donor insemination. Hum Reprod 1994; 9: 176–8. 64. Gallinelli A, Roncaglia R, Matteo ML et al. Immunological changes and stress are associated with different implantation rates in patients undergoing in vitro fertilization-embryo transfer. Fertil Steril 2001; 76: 85–91. 65. Thiering P, Beaurepaire J, Jones M, Saunders D, Tennant C. Mood state as a predictor of treatment outcome after in vitro fertilisation/embryo transfer technology (IVF/ET). J Psychosom Res 1993; 37: 481–91. 66. Boivin J, Takefman J. Stress reactions across an IVF cycle in pregnant and non-pregnant women using daily monitoring prospective data. Fertil Steril 1995; 64: 802–11. 67. Facchinetti F, Matteo ML, Artini GP, Volpe A, Genazzani AR. An increased vulnerability to stress is associated with a poor outcome of in vitro fertilization-embryo transfer treatment. Fertil Steril 1997; 67: 309–14. 68. Lancastle D, Boivin J. Dispositional optimism, trait anxiety and coping: unique or shared effects on biological response to fertility treatment? Health Psychol 2005; 24: 171–8.

69. Glezermann M. Two hundred and seventy cases of artificial donor insemination: management and results. Fertil Steril 1981; 35: 126–42. 70. Klonoff-Cohen H, Chu E, Natarajan L, Sieber W. A prospective study of stress among women undergoing in vitro fertilization and gamete intrafallopian transfer. Fertil Steril 2001; 76: 675–87. 71. Sanders K, Bruce N. Psychosocial stress and treatment outcome following assisted reproductive technology. Hum Reprod 1999; 14: 1656–62. 72. Moultrie TA, Hosegood V, McGrath N et al. Refining the criteria for stalled fertility declines: an application to rural KwaZulu-Natal, South Africa, 1990– 2005. Stud Fam Plann 2008; 391: 39–48. 73. Blacker J, Opiyo C, Jasseh M, Sloggett A, Ssekamatte-Ssebuliba J. Fertility in Kenya and Uganda: A comparative study of trends and determinants. Popul Stud 2005; 59: 355–73. 74. Anderheim L, Holter H, Bergh C, Möller A. Does Psychological stress affect the outcome of in vitro fertilization? Hum Reprod 2005; 20: 2969–75. 75. Merari D, Feldberg D, Elizur A, Goldman J, Modan B. Psychological and hormonal changes in the course of in vitro fertilisation. J Assist Reprod Genet 1992; 9: 161–9. 76. deKlerk C, Hunfeld JAM, Heijnen EMEW et al. Low negative affect prior to treatment is associated with a decreased chance of live birth from a first IVF cycle. Hum Reprod 2008; 23: 112–16. 77. Boivin J, Sanders K, Schmidt L. Age and social position moderate the effect of stress on fertility. Evol Hum Behav 2006; 27: 345–56. 78. Boivin J. A review of psychosocial interventions in infertility. Soc Sci Med 2003; 57: 2325–41. 79. de Liz TM, Strauss B. Differential efficacy of group and individual/couple psychotherapy with infertile patients. Hum Reprod 2005; 20: 1324–32. 80. Sarrel PM, DeCherny AH. Psychotherapeutic intervention for treatment of couples with secondary infertility. Fertil Steril 1985; 43: 897–900. 81. Domar AD, Clapp D, Slawsby EA et al. Impact of group psychological interventions on pregnancy rates in infertile women. Fertil Steril 2000; 73: 805–11. 82. Stolwijk AM, Wetzels AMM, Braat DD. Cumulative probability of achieving an ongoing pregnancy after in-vitro fertilization and intracytoplasmic sperm injection according to a woman’s age, subfertility diagnosis and primary or secondary infertility. Hum Reprod 2000; 15: 203–9. 83. van Balen F, Verdurmen J, Ketting E. Choices and motivations of infertile couples. Patient Educ Couns 1997; 31: 19–27. 84. Clark AM, Ledger W, Galletly C et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod 1995; 10: 2705–12. 85. Smeenk JMJ, Verhaak CM, Stolwijk AM, Kremer JAM, Braat DDM. Reasons for dropout in an in vitro fertilization/intracytoplasmic sperm injection program. Fertil Steril 2004; 81: 262–8. 86. Boivin J. Who is likely to need counselling? In: Boivin J, Kentenich H eds. ESHRE Monographs: Guidelines for Counselling in Infertility. London: Oxford University Press, 2002: 9–10.

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Psychosocial issues in periconceptional care 87. Leiblum SR, Williams E. Screening in or out of the new reproductive options: who decides and why. J Psychosom Obstet Gynaecol 1993; 14: 37–44. 88. Verhaak C, Lintsen A, Kraaimaat FW, Kremer JAM, Braat DDM. Who needs psychological treatment, and how do we know? In: Program and Abstracts of the 23rd Annual Meeting of the European Society for Human Reproduction and Embryology. July 2007. Lyon. Hum Reprod 2007; 22: i65. 89. Verhaak CM, Smeenk JMJ, van Minnen A, Kremer JAM, Kraaimaat FW. A longitudinal, prospective study on emotional adjustment before, during and after consecutive fertility treatment cycles. Hum Reprod 2005; 8: 2253–60.

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90. Cousineau TM, Green TC, Corsini E et al. Online Psychoeducational support for infertile women: a randomized controlled trial. Hum Reprod 2005; 23: 554–66. 91. van Balen F, Verdurmen JE, Ketting E. Assessment of a telephone helpline on infertility provided by a patient association. Patient Educ Couns 2001; 42: 289–93. 92. Schmidt L, Tjørnhøj-Thomsen T, Boivin J, Nyboe Andersen A. Evaluation of a communication and stress management training programme for infertile couples. Patient Educ Couns 2005; 59: 252–62. 93. Lancastle D, Boivin J. A feasibility study of a brief coping intervention (PRCI) for the waiting period before a pregnancy test during fertility treatment. Hum Reprod [submitted].

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28 The luteal phase Human M Fatemi, Bart Fauser, Paul Devroey, Nick S Macklon

To understand the luteal phase, one has to understand the follicular phase and the transition from the follicular to the luteal phase. The fundamental principle of follicular development and the luteal phase is the two-cell–twogonadotrophin theory.1,2 This theory states that there is a subdivision and compartmentalisation of steroid hormone synthesis activity in the developing follicle. According to the “two-cell–two-gonadotropin theory”,3 both follicle stimulating hormone (FSH) and luteinising hormone (LH) are necessary for ovarian follicular maturation and the synthesis of ovarian steroid hormones.4 LH promotes the production of androgens (dehydroepiandrosterone, androstenedione and testosterone) from cholesterol and pregnenolone, by stimulating 17α-hydroxylase activity in the thecal cells. The androgens then diffuse to the granulosa cells where FSH stimulates the expression of the cytochrome P450 aromatase, which converts the androgens to oestrogens.1 Rising oestrogen (and inhibin B) levels have a negative feedback effect on FSH secretion. Conversely, LH undergoes biphasic regulation by circulating oestrogens. At lower concentrations, oestrogens inhibit LH secretion. At higher levels of oestradiol (beyond 200 pg/ml) for more than 48 hours, oestrogen enhances the LH release.5 The local oestrogen–FSH interaction in the dominant follicle induces increasing numbers of FSH receptors as well as the generation of LH receptors on the granulosa cells that further increase oestrogen biosynthesis which eventually results in luteinisation of the granulosa cells, the conversion of steroid production to predominantly progesterone. Ovulation will occur in the single mature Graafian follicle 10–12 hours after the LH peak or 34–36 hours after the initial rise in midcycle LH.6 The midcycle LH surge creates an environment with a significant increase of prostaglandins and proteolytic enzymes in the follicular wall.7 Through these substances the follicular wall weakens and perforates. During the ovulation the oocyte leaves the follicle by a slow extrusion. The remaining follicular shell is transformed into the primary regulator of the luteal phase, i.e. corpus luteum.

Early history of the corpus luteum Coiter (1573)8 described the presence of cavities filled with a yellow solid in the ovary, but it was de Graaf

(1943)9 who gave the first definitive description of these structures. Malpighi (1689)10 provided an accurate microscopic description of the structures and was the first to apply the name corpus luteum, literally the yellow body. Beard (1897)11 postulated that corpora lutea were responsible for the suppression of ovulation and oestrus during pregnancy, and about that time, Prenant (1898)12 suggested that the corpus luteum might be a gland of internal secretion directly benefiting the egg with which it appeared to be associated. It was, however, Fraenkel (1903)13 who demonstrated that corpora lutea were necessary for implantation and the subsequent maintenance of pregnancy in the rabbit. Corner and Allen (1929)14 and Allen and Corner (1930)15 prepared a relatively pure alcoholic extract of corpora lutea from sows and showed that this extract maintained pregnancy in ovariectomised rabbits. A few years later, the isolation of the pure crystalline hormone was reported simultaneously by four groups.16–19 Slotta et al18 named the compound progesterone and suggested a structural formula, and in the same year, the compound was synthesised by Butenandt and Westphal (1934).16

The physiology of corpus luteum The corpus luteum is one of the few endocrine glands that forms from the remains of another organ and the function and survival of which are limited in scope and time. The corpus luteum is the site of rapid remodelling, growth, differentiation and death of cells originating from granulosa, theca, capillaries and fibroblasts. Angiogenesis is important for the development of the corpus luteum and maintenance of luteal function.20 The granulosa cell layer of the follicle is avascular until the time of the midcycle LH surge, and then under the stimulation of vascular endothelial cell growth factor (VEGF),21 vascular endothelial cells of the theca cell layer invade the avascular granulosa cell layer which is the first step of corpus luteum formation.21 Thereafter, blood vessels are rapidly formed in the corpus luteum, and the corpus luteum becomes one of the most highly vascularised organs in the body in the 7 days after ovulation.21 This angiogenic response allows large amounts of luteal hormones to enter the systemic circulation.20

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The production of steroids is dependent upon lowdensity lipoprotein (LDL) transport of cholesterol, therefore the vascularisation of the granulosa layer is essential to allow LDL cholesterol to reach the luteal cells to provide sufficient substrate for steroid (progesterone) production.22 The characteristic yellowish aspect of the corpus luteum is caused by the lipids taken up by the remaining granulosa cells in the follicle. The induction of LDL receptor expression occurs in granulosa cells during early stages of luteinisation in response to the midcycle LH surge. Studies in humans and primates have demonstrated that the corpus luteum requires a consistent LH stimulus in order to perform its physiological function.23 LH support during the luteal phase is entirely responsible for the maintenance and the normal steroidogenic activity of the corpus luteum.24 As a result, withdrawal of LH, causes premature luteolysis.25 Progesterone is the major secretory product of the corpus luteum; however, oestradiol and inhibin are also produced by the corpus luteum. A luteal phase progesterone level of 3–4 ng/ml or higher is indicative of ovulation. Levels at the middle of the luteal phase are normally greater than 10 ng/ml. Csapo et al26,27 demonstrated the importance of progesterone during the first weeks of a pregnancy. In their initial study, the removal of the corpus luteum prior to 7 weeks of gestation led to pregnancy loss.26 However, the authors found that pregnancy could be maintained even after removal of the corpus luteum by external administration of progesterone.27

Effect of progesterone As the major target of sex steroid hormones, the endometrium will undergo characteristic cycles of proliferation, secretory changes and tissue shedding in response to ovarian steroid hormones.28 The endometrial cycle is a reflection of the ovarian cycle, corresponding with two phases of cellular development, separated by ovulation, the follicular and the luteal phase. The primary control over endometrial maturation is considered to be exerted by progesterone and oestradiol. Studies on pregnancy outcome suggest that an optimal balance of the two hormones is necessary for a normal progression of pregnancy.29 The endometrium proliferates due to the stimulation of oestradiol produced by the granulosa cells in the follicular phase. The highest response is in the glands. First, there is an increase in mitotic activity and, second, there is formation of a loose capillary network in the spiral vessels (Fig 28.1).30 After ovulation, there is a secretory transformation of the endometrium due to the progesterone produced by the corpus luteum (Figs 28.2 and 28.3). Under the action of progesterone, endometrial proliferation ceases and glandular secretion is initiated. The endometrial glands become tortuous and spiral vessels coiled. In the glandular epithelium subnuclear intracytoplasmic glycogen vacuoles appear that start

Fig 28.1 Proliferative endometrium with small uncoiled glands, nuclear pseudostratification and mitotic activity. The stroma is loose. (Haematoxyline eosine staining ×100).

Fig 28.2 Early secretory phase endometrium with coiled glands, basally located vacuoles and nuclei pushed up towards the luminal edge of the gland. The stroma is slightly oedematous. Mitotic figures are sparse. (HES ×100).

Fig 28.3 Midluteal phase secretory endometrium with saw-tooth glandular pattern, inspissated secretion and enboidal epithelium. The stroma shows early decidual changes. (HES ×100).

to move towards the glandular lumen, followed by an active secretion of glycoproteins and peptides in the endometrial cavity. The vacuoles disappear by the end of the luteal phase.31 During the secretory phase, a short specific period of uterine receptivity toward embryonic implantation is designated as the “implantation

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window”.32 The peak of the secretory endometrial activity is around the 5th–7th postovulatory day, coinciding with the time of the embryo implantation. If conception and implantation occur, the developing blastocyst secretes human chorionic gonadotrophin (hCG). The role of hCG produced by the embryo is to maintain the corpus luteum and its secretions.33 The estimated onset of placental steroidogenesis (the luteoplacental shift) occurs during the 5th gestational week, as calculated by the patient’s last menses.34 Progesterone also promotes local vasodilatation and uterine musculature quiescence by inducing nitric oxide synthesis in the decidua.35 Excessive uterine contractility may lead to ectopic pregnancies, miscarriages, retrograde bleeding with dysmenorrhoea and endometriosis.35 The uterine-relaxing properties of progesterone were supported by a study of in vitro fertilisation (IVF) embryo transfer outcomes by Fanchin et al.36 This study investigated the consequences of uterine contractions as visualised by ultrasound during embryo transfer. Results indicated that a high frequency of uterine contractions on the day of embryo transfer hindered transfer outcome, possibly by expelling embryos out of the uterine cavity. A negative correlation between uterine contraction frequency and progesterone concentrations was detected underlining the benefits of progesterone in IVF.36

Luteal phase defect As early as 1949, the premature onset of menses was recognised as indicative of a luteal phase deficiency of progesterone production, which was shown to be correctable by exogenous progesterone administration.37 The prevalence of a luteal phase defect (LPD) in natural cycles in normo-ovulatory patients with primary or secondary infertility was demonstrated to be about 8%.38 Pathophysiological alterations of the complex reproductive process that lead to delayed endometrial maturation characteristic of LPD include disordered folliculogenesis, defective corpus luteum function and abnormal luteal rescue by the early pregnancy. A variety of clinical conditions, such as hyperprolactinaemia, hyperandrogenic states, weight loss, stress and athletic training, may result not in oligo- or anovulation, but rather may be manifest as LPD.39 The three main causes of LPD in unstimulated cycles include poor follicle production, premature demise of the corpus luteum and failure of the uterine lining to respond to normal levels of progesterone.

How to define a luteal phase defect? Although LPD has been clearly described in research settings, the clinical diagnosis and role of medical therapies remain controversial.40 A defective luteal phase in a natural cycle has been defined as when the

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serum midluteal progesterone levels are less than 10 ng/ml.40 However, midluteal progesterone levels do not always reflect the endometrial maturation.41 Therefore, in the literature the most reasonable consensus of a defective luteal phase is a lag of more than 2 days in endometrial histological development, according to Noyes et al,31 compared with the expected day of the cycle.23 The diagnosis of LPD requires two consecutive endometrial biopsies as 20% of patients have a single out-of-phase biopsy.42

How to treat a luteal phase defect in the natural cycle? Progesterone is the hormone of choice to treat a LPD. Various formulations of progesterone are available, including oral, vaginal and intramuscular administration routes. In an open-label trial in 1184 women from 16 US centres, Levine evaluated the clinical and ongoing pregnancy rates in IVF cycles involving vaginal and intramuscular progesterone. Vaginal and intramuscular progesterone were found to have comparable clinical (35.1% and 35.2%, respectively, not significant) and ongoing pregnancy rates (30.2% and 33.6%, respectively, not significant).43 Progesterone administered orally is subjected to firstpass prehepatic and hepatic metabolism. This metabolic activity results in progesterone degradation to its 5α- and 5β-reduced metabolites.33 Devroey et al44 and Bourgain et al45 reported an absence of the secretory transformation of the endometrium in patients with premature ovarian failure who had been treated with oral micronised progesterone when compared with patients treated with intramuscular injections or vaginal micronised progesterone. To overcome this problem, dydrogesterone was introduced. Dydrogesterone (9B, 10α-pregna-4,6diene-3,20-dione) has a molecular structure which is almost identical to that of natural progesterone. Its unique design makes it a potent, orally active progestogen. In the dydrogesterone molecule, the hydrogen atom at carbon 9 is in the beta position and the methyl group at carbon 10 is in the alpha position – a reverse of the progesterone structure, hence the term “retro” progesterone. Furthermore, it has a second double bond between carbon 6 and carbon 7 (the 4,6-diene-3-one configuration). These small differences in chemical structure account for the improved oral activity and metabolic stability of dydrogesterone (Fig 28.4). Recently, Chakravarty et al46 undertook a prospective, randomised study (n=430) that compared the efficacy, safety and tolerability of oral dydrogesterone with vaginal micronised progesterone as luteal phase support after IVF. Both dydrogesterone and progesterone were associated with similar rates of successful pregnancies (24.1% and 22.8%, respectively, not significant). However, Fatemi et al,47 demonstrated that after sufficient oestrogen endometrial priming in premature ovarian failure patients, exogenous vaginal micronised progesterone is

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CH3 CH3

CH3

CO

CH3

CH3

CO

CH3 H

O

H O

Dydrogesterone

Progesterone

more effective than oral dydrogesterone in creating an inphase secretory endometrium. Further prospective randomised studies are needed to confirm the beneficial effect of oral dydrogesterone for the treatment of LPD defect.

Stimulated IVF cycles are associated with a defective luteal phase in almost all patients (Fig. 28.5).48–50 The aetiology of LPD in stimulated IVF cycles has been debated for more than two decades. Initially, it was thought that the removal of large quantities of granulosa cells during oocyte retrieval might diminish the most important source of progesterone synthesis by the corpora lutea, leading to a defect of the luteal phase. However, this hypothesis was disproved when it was established that the aspiration of a preovulatory oocyte in a natural cycle neither diminished the luteal phase steroid secretion nor shortened the luteal phase.51 Another proposal suggested that the prolonged pituitary recovery that followed the gonadotrophin releasing hormone (GnRH) agonist co-treatment, designed to prevent spontaneous LH rise in stimulated cycles resulting in lack of support of the corpus luteum, would cause a LPD.52 It was also suggested that the hCG administered for the final oocyte maturation in stimulated IVF cycles could potentially cause a LPD by suppressing the LH production via a short-loop feedback mechanism.53 However, the administration of hCG did not downregulate the LH secretion in the luteal phase of normal, unstimulated cycles in normo-ovulatory women.54 The midcycle LH surge requires the secretion of native GnRH; therefore, it can also be prevented or

Hyperstimulated cycle

Progesterone concentrations

Luteal phase defect in stimulated in vitro fertilisation cycles

Fig 28.4 Biochemical structure of dydrogestrone (Duphaston®) vs progesterone.

Normal cycle

14 days Lutel phase length

Fig 28.5 Schematic representation of changes in luteal phase length and progesterone profile induced by ovarian hyperstimulation for IVF.50

inhibited by GnRH antagonist administration.55 GnRH antagonist action is characterised by an immediate suppression of pituitary gonadotrophin release and a rapid recovery of endogenous LH and FSH secretion to normal levels. The introduction of GnRH antagonists in IVF raised speculations that a rapid recovery of the pituitary function56 would obviate the need for luteal phase supplementation.57 Preliminary observations in intrauterine insemination (IUI) cycles seemed to favour this contention. Ragni et al58 explored the luteal phase hormone profiles in gonadotrophin-stimulated cycles both with and without GnRH antagonist therapy for IUI. No deleterious effects of GnRH antagonist administration

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could be noted on either the luteal progesterone concentration or the duration of the luteal phase in that study. However, various studies of GnRH antagonist cotreatment in IVF have since found different results. Luteolysis is also initiated prematurely in antagonist co-treated IVF cycles, resulting in a significant reduction in the luteal phase length and compromising the chances for pregnancy.59,60 Beckers et al60 evaluated the non-supplemented luteal phase characteristics in patients undergoing ovarian stimulation with recombinant FSH (150 IU/day) combined with a GnRH antagonist (antide; 1 mg/day). However, due to unacceptably low pregnancy rates (overall 7.5%), the decision was made to cancel this study after 40 patients were included. In addition, with the administration of GnRH antagonist luteolysis started prematurely. Despite the rapid recovery of the pituitary function in GnRH antagonist protocols,61 luteal phase supplementation remains mandatory.62 It now appears that the primary cause of the LPD in stimulated IVF cycles is related to the supraphysiological levels of steroids secreted by a high number of corpora lutea during the early luteal phase, which directly inhibit the LH release via negative feedback actions at the hypothalamic–pituary axis level.63,64 In the stimulated cycles, LH is below the detection limit of <0.01 IU/l.64 Studies in humans and primates have demonstrated that the corpus luteum requires a consistent LH stimulus in order to perform its physiological function.65 LH support during the luteal phase is entirely responsible for the maintenance and the normal steroidogenic activity of the corpus luteum.24

The treatment of luteal phase defect in stimulated in vitro fertilisation cycles Vaginal progesterone The intravaginal route of progesterone supplementation in IVF has gained wide application as a first choice luteal support regimen, mainly due to patient comfort and effectiveness.43 Following intravaginal administration of progesterone, high uterine progesterone concentrations with low peripheral serum values are observed, due to counter-current exchange in progesterone transport between anatomically close blood vessels66 and due to the uterine first pass effect, where liver metabolisation is absent.67 There is increasing evidence in the literature that vaginal progesterone is at least as effective as intramuscular progesterone at providing luteal support in induced cycles.68 In Europe, there are two different forms of intravaginal progesterone on the market, natural micronised progesterone (Utrogestan® Laboratories Besins International, Paris, France) and Crinone® 8% (Fleet Laboratories Ltd, Watford, UK), a controlled and sustained-release vaginal gel. Utrogestan 100-mg capsules are administered vaginally two capsules three

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times daily (600 mg/day), whereas Crinone 8% is administered vaginally once a day, i.e. 90 mg.68,69 To establish the minimal effective dose of vaginal micronised progesterone, Chanson et al70 conducted a small (n=40) prospective randomised study comparing two different dose regimens (400 mg versus 600 mg each day). No differences in clinical pregnancy rates were noted. However, further prospective randomised trials are essential to define the necessary dose of vaginal micronised progesterone for luteal phase support in IVF. In a prospective, randomised study Ludwig et al69 compared vaginal Crinone 8% with vaginal Utrogestan for luteal phase support. Clinical pregnancy rates, clinical abortion rates until 12 weeks of gestation and ongoing pregnancy rates were comparable between the two groups.69 Simunic et al68 and Ludwig et al69 evaluated the tolerability and acceptability of both preparations from the patients’ point of view. Crinone 8% gel proved more tolerable than Utrogestan vaginal capsules because of a lower number of side-effects.

Rectal progesterone A number of publications have evaluated the rectal use of natural progesterone in women undergoing IVF/intracytoplasmic sperm injection (ICSI).71,72 Chakmakijan and Zachariah71 studied the bioavailability of micronised progesterone by measuring sequential serum progesterone concentrations after a single bolus of 50–200 mg progesterone given sublingually, orally (capsule and tablet), vaginally and rectally (suppositories) during the follicular phase in normally menstruating women. When compared with other modes of progesterone administration, rectal application resulted in a serum concentration during the first 8 hours twice as high as other routes. However, to the best of our knowledge, there are no prospective randomised trails to compare the rectal administration of progesterone with other administration routes for IVF.

Intramuscular progesterone Intramuscular progesterone supplementation is given as an injection of natural progesterone in oil.73 In 1985, Leeton et al74 first demonstrated the extension of the luteal phase of stimulated IVF cycles treated with 50 mg intramuscular progesterone. The doses of intramuscular progesterone used for luteal phase support vary between 25 and 100 mg/day without any significant difference concerning the outcome.75 This route of administration is often associated with a number of side-effects, including painful injections and a rash,76 causing a lack of enthusiasm for this treatment modality.73 Injections of progesterone in oil can also lead to inflammatory reactions and abscess formation.77

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In addition, several case reports have been published in which patients receiving intramuscular progesterone for luteal supplementation have developed acute eosinophilic pneumonia.78,79 This druginduced disease shows that the use of intramuscular progesterone can also be associated with a severe morbidity in otherwise healthy young patients.78 In an open-label trial in 1184 women from 16 American centres, Levine evaluated the clinical and ongoing pregnancy rates in IVF cycles involving vaginal and intramuscular progesterone. Vaginal and intramuscular progesterone were found to have comparable clinical (35.05% and 35.2%, respectively) and ongoing pregnancy rates (30.2% and 33.64%, respectively).43 A meta-analysis published in 2002 by Pritts and Atwood75 included five prospective randomised trails comparing intramuscular administration of progesterone with vaginal. A total of 891 cycles were evaluated in the studies. Clinical pregnancy rate and delivery rate were significantly higher when intramuscular progesterone was used (clinical pregnancy rate/embryo transfer 1.33, 95% confidence interval (CI) 1.02–1.75; delivery rate 2.06, 95% CI 1.48–2.88).

Progesterone plus oestradiol The two most important hormones produced by the corpus luteum are progesterone and oestradiol.80 The role of progesterone for luteal support in stimulated cycles is well established.81 However, it has not yet been clearly demonstrated whether additional supplementation of oestradiol in stimulated IVF cycles is beneficial.82 In a prospective randomised study, Smitz et al83 evaluated the possible benefit of adding oestradiol valerate 6 mg/day orally to the vaginal micronised progesterone (600 mg daily) given as luteal supplementation in 378 women treated with a GnRH agonist and human menopausal gonadotrophins (hMG) for IVF.83 The clinical pregnancy rate was similar between the two groups (29.2% with the oestradiol co-treatment and 29.5% with progesterone only treatment). Also, Lewin et al84 in a prospectively randomised study, could not find any advantage in the addition of 2 mg oestradiol valerate to progesterone as luteal phase support of long GnRH agonist and hMGinduced IVF–ET cycles in 100 patients (clinical pregnancy rate 26.5% versus 28% with and without oestradiol co-treatment, respectively). A meta-analysis by Pritts and Atwood75 suggested that addition of oestrogen to progesterone might improve the implantation rates. However, the authors referred to only one study confirming the beneficial effect of oestradiol in the luteal phase.85 Any beneficial effect of adding oestradiol to progesterone might depend upon its dosage. Lukaszuk et al,86 in a prospective, randomised study, recently evaluated the effect of different oestradiol supplementation doses (0, 2 or 6 mg) during the luteal phase on implantation and pregnancy rates in women undergoing ICSI in

agonist cycles (n = 231). Significantly higher pregnancy rates were recorded in those who received low dose oestradiol supplementation compared with no oestradiol substitution (pregnancy rate 23.1% vs 32.8%). The best pregnancy results were found in the group with high dose oestradiol supplementation (pregnancy rate 51.3%). It was shown that the addition of a high dose of oestradiol to daily progesterone supplementation significantly improved the probability of pregnancy in women treated with a long GnRH analogue protocol for controlled ovarian hyperstimulation (COH). Farhi et al,85 in a prospective, randomised study, evaluated the effect of adding oestradiol to progestin supplementation during the luteal phase in 271 patients undergoing IVF who had oestradiol levels of higher than 2500 pg/dl at the day of hCG administration. All patients received progesterone supplementation at a dosage of 150 mg/day starting on the day after the oocyte retrieval. Patients were randomised into two groups: those receiving 2 mg of oestradiol (Estrofem; Novo Nordisk, Bagsvaerd, Denmark), given orally, starting on day 7 after embryo transfer; and those receiving no exogenous oestradiol supplementation during the luteal phase. It was shown that for the patients who had been treated with the long GnRH agonist protocol for COH, the addition of oestradiol to the progestin support regimen had a beneficial effect on pregnancy and implantation rates (39.6% and 25.6% with and without oestradiol co-treatment, respectively; p<0.05). However, such an effect could not be shown for patients with a short GnRH agonist protocol. The latest meta-analysis published in 2008, concluded that the addition of oestradiol to progesterone for luteal phase support in IVF/ICSI cycles has no beneficial effect on pregnancy rates.87 It is obvious that there is a need for further prospective randomised trials.

Human chorionic gonadotrophin It was found that the corpus luteum can be rescued by the administration of hCG, and this treatment modality has been the standard care for luteal support since the late 1980s.88 By stimulating the corpora lutea, hCG is an indirect form of luteal support. It is known to generate an increase in oestradiol and progesterone concentrations, thus rescuing the failing corpora lutea in stimulated IVF cycles.89 Moreover, placental protein 14,90 integrin αv91 and relaxin (luteal peptide hormone) concentrations, which have been shown to increase at the time of implantation, are higher with hCG support.92 hCG has been shown to be as effective as progesterone for luteal phase support with respect to pregnancy rates in the meta-analysis published by Pritts and Atwood in 2002.75 However, in the latest metaanalysis by Nosarka et al93 hCG seemed to be superior to progesterone. The meta-analysis of Nosarka et al differed from that of Pritts and Atwood in that the

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literature search covered a 20-year study period while Pritts and Atwood’s study period was only 7 years. Several studies showed significant increases in hyperstimulation rates when using hCG for luteal support compared with other treatments or no treatment at all.75,93 Luteal support with hCG should be avoided if oestradiol levels are above 2500–2700 pg/ml on the day of hCG administration85,94 and if the number of follicles is above ten.95 With regard to ovarian hyperstimulation syndrome, one should be cautious with the administration of hCG for luteal supplementation in stimulated IVF cycles.82

Gonadotrophin releasing hormone agonist: a novel luteal phase support? GnRH agonist was recently suggested as a novel luteal phase support that may act at the level of pituitary gonadotrophs, the endometrium and the embryo itself.96,97 It was hypothesised that GnRH agonist may support the corpus luteum by stimulating the secretion of LH by pituitary gonadotroph cells or by acting directly on the endometrium through the locally expressed GnRH receptors.97 In a prospective randomised study Tesarik et al96 evaluated the effect of GnRH agonist (0.1 mg triptorelin) administered in the luteal phase 6 days after ICSI on outcomes in both GnRH agonist (n=300) and GnRH antagonist (n=300) treated ovarian stimulation protocols. The pregnancy rates after GnRH agonist and GnRH antagonist treated ovarian stimulation cycles were enhanced. Luteal phase GnRH agonist administration also increased the luteal phase serum hCG, oestradiol and progesterone concentrations in both ovarian stimulation regimens. It was assumed that the beneficial effect would possibly be as a result of a combination of effects on the embryo and the corpus luteum. However, it is too early to adopt this treatment wholesale despite the initial encouraging results. With regard to safety, the greatest concern exists about possible adverse effects on oocytes and, more importantly, the embryos.98 To establish a potential positive role of GnRH agonist administration in the luteal phase of stimulated IVF cycles, further large prospective trials are needed.

Naloxone, an opiate receptor blockade for luteal phase support? Short-term opioid antagonism increases LH pulsatility during the luteal phase.99 It was postulated that prolonged opioid antagonism may also accelerate the LH secretory episodes,99 which could eventually rescue the LPD in stimulated IVF cycles. However, prolonged opioid blockade did not change LH secretory patterns of the luteal phase in eight normal cycling women, suggesting desensitisation of the opiate receptors. Moreover, naloxone failed to stimulate LH secretion during pregnancy, where, as in stimulated

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IVF cycles, supraphysiological steroid levels are present. To date there is no evidence to support the use of naloxone in the luteal phase of stimulated IVF cycles.

Onset of the luteal phase support Timing of luteal phase support remains the subject of much debate. Current clinical practice involves onset of luteal phase support on different days. A decrease of 24% was seen when luteal phase support was delayed until 6 days after oocyte retrieval compared with 3 days after oocyte retrieval.100 No difference in ongoing pregnancy rate was found when luteal phase support was started at oocyte retrieval compared with starting at embryo transfer.101 Mochtar et al102 compared the effect of three different times of onset of luteal phase support on ongoing pregnancy rate in infertile patients undergoing treatment with GnRH agonist downregulated IVF–ET cycles. The three groups were hCG group, oocyte retrieval group and the embryo transfer group (on day 3). A total of 385 women were randomised in the study. The luteal phase support was administered until 18 days following oocyte retrieval. There was no significant difference in ongoing pregnancy rate between the three groups (20.8% in the hCG group versus 22.7 and 23.6% in the oocyte retrieval group and embryo transfer group, respectively).102 Further studies are needed to establish the best timing for the onset of the luteal phase support. Referring to the published data, it is evident that the timing of luteal phase support should not be later than day 3 after the oocyte retrieval. The hCG administered for final oocyte maturation covers the luteal phase for a maximum of 8 days. However, taking the uterolytic effect of progesterone into account, it is recommended to start treating patients with progesterone on the day of embryo transfer (if day 3) or on day 5 following the hCG administration.

The duration of luteal phase support Until recently, there was no rationale for the generally accepted practice of prolonging progesterone supplementation during early pregnancy. Schmidt et al103 were the first to publish a retrospective study to compare the delivery rate with IVF or ICSI in women who did and did not receive progesterone supplementation in the first 3 weeks after a positive hCG test. The delivery rate of 200 pregnant women who did not receive progesterone and 200 who did received progesterone for 3 weeks after a positive hCG was compared. The results showed no difference in the delivery rate and a prospective randomised controlled trail was subsequently conducted. Nyboe Andersen104 evaluated, in a prospective randomised trial, whether the prolongation of luteal support during early pregnancy had any influence on the delivery rate after IVF. For the luteal phase support, 200 mg of vaginal progesterone three times daily was administered during 14

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days from the day of transfer until the day of a positive hCG test. The study group (n=150) had vaginal progesterone withdrawn from the day of positive hCG, while the control group (n=153) continued administration of vaginal progesterone during the next 3 weeks of pregnancy.104 Prolongation of progesterone supplementation in early pregnancy had no influence on the miscarriage rate, and thus no effect on the delivery rate. The increase in endogenous hCG level during early pregnancy makes up for any possible lack of endogenous LH, which is suppressed in stimulated IVF cycles. First trimester progesterone supplementation in IVF may support early pregnancy through 7 weeks by delaying a miscarriage but it does not improve live birth rates.105 Reconsidering that the cause of LPD in stimulated IVF cycles seems to be related to the supraphysiological levels of steroids,64 in future, attitudes towards hyperstimulation of patients for IVF, should be revised. Certainly with the growing tendency towards the transfer of a reduced number of embryos49 there is reduced need for the hyperstimulation of patients. In Europe, an increasing number of investigators advocate the use of single embryo transfer.106–108 With an increasing number of single embryo transfer in IVF, the stimulation should also equate to a more physiological approach, eventually without a LPD as a consequence.

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42. Rosenberg SM, Luciano AA, Riddick DH. The luteal phase defect: the relative frequency of, and encouraging response to, treatment with vaginal progesterone. Fertil Steril 1980; 34: 17–20. 43. Levine H. Luteal support in IVF using the novel vaginal progesterone gel Crinone 8%: results of an open-label trial in 1184 women from 16 US centers. Fertil Steril 2000; 74: 836–7. 44. Devroey P, Palermo G, Bourgain C et al. Progesterone administration in patients with absent ovaries. Int J Fertil 1989; 34: 188–93. 45. Bourgain C, Devroey P, Van Waesberghe L et al. Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure. Hum Reprod 1990; 5: 537–43. 46. Chakravarty BN, Shirazee HH, Dam P et al. Oral dydrogesterone versus intravaginal micronised progesterone as luteal phase support in assisted reproductive technology (ART) cycles: results of a randomised study. J Steroid Biochem Mol Biol 2005; 97: 416–20. 47. Fatemi HM, Bourgain C, Donoso P et al. Effect of oral administration of dydrogestrone versus vaginal administration of natural micronized progesterone on the secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept. Hum Reprod 2007; 22: 1260–3. 48. Macklon NS, Fauser BC. Impact of ovarian hyperstimulation on the luteal phase.J Reprod Fertil Suppl 2000; 55: 101–8. 49. Fauser BC, Devroey P. Reproductive biology and IVF: ovarian stimulation and luteal phase consequences. Trends Endocrinol Metab 2003; 14: 236–42. 50. Macklon NS, Stouffer RL, Giudice LC, Fauser BC. The science behind 25 years of ovarian stimulation for in vitro fertilization. Endocr Rev 2006; 27: 170–207. 51. Kerin JF, Broom TJ, Ralph MM et al. Human luteal phase function following oocyte aspiration from the immediately preovular graafian follicle of spontaneous ovular cycles. Br J Obstet Gynaecol 1981; 88: 1021–8. 52. Smitz J, Erard P, Camus M et al. Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol. Hum Reprod 1992; 7: 1225–9. 53. Miyake A, Aono T, Kinugasa T et al. Suppression of serum levels of luteinizing hormone by shortand long-loop negative feedback in ovariectomized women. J Endocrinol 1979; 80: 353–6. 54. Tavaniotou A, Devroey P. Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles. Fertil Steril 2003; 80: 654–5. 55. Macklon NS, Fauser BC. Regulation of follicle development and novel approaches to ovarian stimulation for IVF. Hum Reprod Update 2000; 6: 307–12. 56. Albano C, Smitz J, Camus M et al. Hormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix). Hum Reprod 1996; 11: 2114–18.

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57. Elter K, Nelson LR. Use of third generation gonadotropin-releasing hormone antagonists in in vitro fertilization-embryo transfer: a review. Obstet Gynecol Surv 2001; 56: 576–88. 58. Ragni G, Vegetti W, Baroni E et al. Comparison of luteal phase profile in gonadotrophin stimulated cycles with or without a gonadotrophin-releasing hormone antagonist. Hum Reprod 2001; 16: 2258–62. 59. Albano C, Grimbizis G, Smitz J et al. The luteal phase of nonsupplemented cycles after ovarian superovulation with human menopausal gonadotropin and the gonadotropin-releasing hormone antagonist Cetrorelix. Fertil Steril 1998; 70: 357–9. 60. Beckers NG, Macklon NS, Eijkemans MJ et al. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment. J Clin Endocrinol Metab 2003; 88: 4186–92. 61. Dal Prato L, Borini A. Use of antagonists in ovarian stimulation protocols. Reprod Biomed Online 2005; 10: 330–8. 62. Tarlatzis BC, Fauser BC, Kolibianakis EM et al. GnRH antagonists in ovarian stimulation for IVF Hum Reprod Update 2006; 12: 333–40. 63. Beckers NG, Platteau P, Eijkemans MJ et al. The early luteal phase administration of estrogen and progesterone does not induce premature luteolysis in normo-ovulatory women. Eur J Endocrinol 2006; 155: 355–63. 64. Fatemi HM, Popovic-Todorovic B, Donoso P et al. The endocrine profile of the luteal phase in IVF donor cycles with two different luteal treatment schemes: placebo vs. letrozole: a placebo controlled pilot study, RBM Online 2008; in press. 65. Jones GS. Luteal phase defect: a review of pathophysiology. Curr Opin Obstet Gynecol 1991; 3: 641–8. 66. Cicinelli E, de Ziegler D, Bulletti C et al. Direct transport of progesterone from vagina to uterus. Obstet Gynecol 2000; 95: 403–6. 67. De Ziegler D, Seidler L, Scharer E et al. Non-oral administration of progesterone: experiences and possibilities of the transvaginal route. Schweiz Rundsch Med Prax 1995; 84: 127–33.[in French] 68. Simunic V, Tomic V, Tomic J et al. Comparative study of the efficacy and tolerability of two vaginal progesterone formulations, Crinone 8% gel and Utrogestan capsules, used for luteal support. Fertil Steril 2007; 87: 83–7. 69. Ludwig M, Schwartz P, Babahan B et al. Luteal phase support using either Crinone 8% or Utrogest: results of a prospective, randomized study. Eur J Obstet Gynecol Reprod Biol 2002; 103: 48–52. 70. Chanson A, Germond K, Lagnaux Y et al. comparison of two progesterone dose regimens for luteal phase support after embryo transfer: a prospective randomized study. Hum Reprod 1996; 11: 170. 71. Chakmakjian ZH, Zachariah NY. Bioavailability of progesterone with different modes of administration. J Reprod Med 1987; 32: 443–8.

72. Ioannidis G, Sacks G, Reddy N et al. Day 14 maternal serum progesterone levels predict pregnancy outcome in IVF/ICSI treatment cycles: a prospective study. Hum Reprod 2005; 20: 741–6. 73. Costabile L, Gerli S, Manna C et al. A prospective randomized study comparing intramuscular progesterone and 17alpha-hydroxyprogesterone caproate in patients undergoing in vitro fertilization-embryo transfer cycles. Fertil Steril 2001; 76: 394–6. 74. Leeton J, Trounson A, Jessup D. Support of the luteal phase in in vitro fertilization programs: results of a controlled trial with intramuscular Proluton. J In Vitro Fert Embryo Transf 1985; 2: 166–9. 75. Pritts EA, Atwood AK. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials. Hum Reprod 2002; 17: 2287–99. 76. Lightman A, Kol S, Itskovitz-Eldor J. A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles. Hum Reprod 1999; 14: 2596–9. 77. Propst AM, Hill JA, Ginsburg ES et al. A randomized study comparing Crinone 8% and intramuscular progesterone supplementation in in vitro fertilization-embryo transfer cycles. Fertil Steril 2001; 76: 1144–9. 78. Bouckaert Y, Robert F, Englert Y et al. Acute eosinophilic pneumonia associated with intramuscular administration of progesterone as luteal phase support after IVF: case report. Hum Reprod 2004; 19: 1806–10. 79. Veysman B, Vlahos I, Oshva L. Pneumonitis and eosinophilia after in vitro fertilization treatment. Ann Emerg Med 2006; 47: 472–5. 80. Johnson MR, Abbas AA, Irvine R et al. Regulation of corpus luteum function. Hum Reprod 1994; 9: 41–8. 81. Maslar IA, Ansbacher R. Effect of short-duration progesterone treatment on decidual prolactin production by cultures of proliferative human endometrium. Fertil Steril 1988; 50: 250–4. 82. Ludwig M, Diedrich K. Evaluation of an optimal luteal phase support protocol in IVF. Acta Obstet Gynecol Scand 2001; 80: 452–66. 83. Smitz J, Bourgain C, Van Waesberghe L et al. A prospective randomized study on estradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation. Hum Reprod 1993; 8: 40–5. 84. Lewin A, Benshushan A, Mezker E et al. The role of estrogen support during the luteal phase of in vitro fertilization-embryo transplant cycles: a comparative study between progesterone alone and estrogen and progesterone support. Fertil Steril 1994; 62: 121–5. 85. Farhi J, Weissman A, Steinfeld Z et al. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization-embryo transfer cycles. Fertil Steril 2000; 73: 761–6. 86. Lukaszuk K, Liss J, Lukaszuk M et al. Optimization of estradiol supplementation during the luteal phase improves the pregnancy rate in women undergoing in vitro fertilization-embryo transfer cycles. Fertil Steril 2005; 83: 1372–6. 87. Gelbaya TA, Kyrgiou M, Tsoumpou I, Nardo LG. The use of estradiol for luteal phase support in in

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88. 89.

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95.

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vitro fertilization/intracytoplasmic sperm injection cycles: A systematic review and meta-analysis, Fertil Steril 2008; Jan 4 (Epub ahead of print). Whelan JG, Vlahos NF. The ovarian hyperstimulation syndrome. Fertil Steril 2000; 73: 883–96. Hutchinson-Williams KA, DeCherney AH, Lavy G et al. Luteal rescue in in vitro fertilization-embryo transfer. Fertil Steril 1990; 53: 495–501. Anthony FW, Smith EM, Gadd SC et al. Placental protein 14 secretion during in vitro fertilization cycles with and without human chorionic gonadotropin for luteal support. Fertil Steril 1993; 59: 187–91. Honda T, Fujiwara H, Yamada S et al. Integrin alpha5 is expressed on human luteinizing granulosa cells during corpus luteum formation, and its expression is enhanced by human chorionic gonadotrophin in vitro. Mol Hum Reprod 1997; 3: 979–84. Ghosh D, Sengupta J. Recent developments in endocrinology and paracrinology of blastocyst implantation in the primate. Hum Reprod Update 1998; 4: 153–68. Nosarka S, Kruger T, Siebert I et al. Luteal phase support in in vitro fertilization: meta-analysis of randomized trials. Gynecol Obstet Invest 2005; 60: 67–74. Buvat J, Marcolin G, Guittard C et al. Luteal support after administration of an LHRH analog for in vitro fertilization. Superiority of vaginal progesterone in comparison with oral progesterone. Presse Med 1990; 19: 527. [in French] Araujo E Jr, Bernardini L, Frederick JL et al. Prospective randomized comparison of human chorionic gonadotropin versus intramuscular progesterone for luteal-phase support in assisted reproduction. J Assist Reprod Genet 1994; 11: 74–8. Tesarik J, Hazout A, Mendoza-Tesarik R et al. Beneficial effect of luteal-phase GnRH agonist administration on embryo implantation after ICSI in both GnRH agonist- and antagonist-treated ovarian stimulation cycles. Hum Reprod 2006; 21: 2572–9. Pirard C, Donnez J, Loumaye E. GnRH agonist as novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin. Hum Reprod 2005; 20: 1798–804.

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98. Lambalk CB, Homburg R. GnRH agonist for luteal support in IVF? Setting the balance between enthusiasm and caution. Hum Reprod 2006; 21: 2580–2. 99. Rossmanith WG, Monn M, Benz R. Effects of chronic opioid antagonism on gonadotrophin and ovarian sex steroid secretion during the luteal phase. Clin Endocrinol 1998; 49: 343–35. 100. Williams SC, Oehninger S, Gibbons WE et al. Delaying the initiation of progesterone supplementation results in decreased pregnancy rates after in vitro fertilization: a randomized, prospective study. Fertil Steril 2001; 76: 1140–3. 101. Baruffi R, Mauri AL, Petersen CG et al. Effects of vaginal progesterone administration starting on the day of oocyte retrieval on pregnancy rates. J Assist Reprod Genet 2003; 20: 517–20. 102. Mochtar MH, Van Wely M, Van d, V. Timing luteal phase support in GnRH agonist down-regulated IVF/embryo transfer cycles. Hum Reprod 2006; 21: 905–8. 103. Schmidt KL, Ziebe S, Popovic B et al. Progesterone supplementation during early gestation after in vitro fertilization has no effect on the delivery rate. Fertil Steril 2001; 75: 337–41. 104. Nyboe AA, Popovic-Todorovic B, Schmidt KT et al. Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial. Hum Reprod 2002; 17: 357–61. 105. Proctor A, Hurst BS, Marshburn PB et al. Effect of progesterone supplementation in early pregnancy on the pregnancy outcome after in vitro fertilization. Fertil Steril 2006; 85: 1550–2. 106. Nygren KG, Andersen AN. Assisted reproductive technology in Europe, 1997. Results generated from European registers by ESHRE. European IVFMonitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod 2001; 16: 384–91. 107. Papanikolaou EG, Camus M, Kolibianakis EM et al. In vitro fertilization with single blastocyst-stage versus single cleavage-stage embryos. N Engl J Med 2006; 354: 1139–46. 108. Heijnen EM, Eijkemans MJ, De Klerk C, Polinder S et al. A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial. Lancet 2007; 369: 743–9.

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29 Implantation failure Juan A Garcia-Velasco, Eliseo Sánchez

Introduction

Table 29.1 Different conditions that may cause implantation failure.

According to large registries, nearly 30% of in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) cycles performed in both Europe and the US result in pregnancy, the rate being as high as 50–60% in patients with a very good prognosis being treated at highly successful units.1 However, even in these units, embryos from some patients repeatedly fail to implant, a condition which has been termed repeated implantation failure (RIF). There is no clear definition of RIF. For some groups it is an unsuccessful patient with more than ten good quality embryos transferred in subsequent cycles.2,3 This definition may seem too loose, according to the actual method of practice. Thus, we can consider that if a patient has undergone three good quality embryo transfers if she is <37 years old, or two good quality embryo transfers if she is ≥37 years old, without achieving a pregnancy, extended investigation is required (Fig 29.1). If an embryo fails to implant, it may be due to decreased endometrial receptivity, embryonic factors, and thus, gamete factors, and/or systemic maternal conditions (Table 29.1).

Decreased endometrial receptivity Altered endocrine milieu Inadequate endometrial development Undiagnosed uterine pathology Cytokine dysregulation Embryonic factors Chromosomal abnormalities Embryo fragmentation Zona pellucida hardening Embryo/maternal asynchrony Maternal conditions Autoantibodies Thrombophilias Endometriosis Hydrosalpinges Leiomyomas Difficult embryo transfer Psychological stress

inside the uterine cavity, which may impair embryo implantation.4 It is well known that uterine receptivity deteriorates during COH compared with natural cycles or even with hormone replacement therapy cycles.5 The fact that more oocytes need to be recruited in IVF yields, as a consequence, supraphysiological steroid hormone levels, which may induce morphological as

Decreased endometrial receptivity Altered endocrine milieu Controlled ovarian hyperstimulation (COH) has a tremendous impact on steroid production and concentration

Window of implantation

Maternal conditions?

Embryonic causes?

E2

14

15

16

17

18

19

20

Non-receptive endometrium?

21

Fig 29.1 Embryo implanation may be hampered by different maternal conditions, embryonic causes or even nonreceptive endometrium. E2 = Oestradiol.

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well as biochemical endometrial modifications that negatively impact on uterine receptivity.6,7 We have consistently shown that high responder patients show a lower implantation and pregnancy rate when oestradiol levels go above reasonable limits, a situation that may be reversed with milder stimulation protocols.8–10 Similarly, high oestrogen concentrations, such as those obtained after COH, are able to block embryo development as well as embryo adhesion in vitro.11 However, from the clinical point of view, not all authors agree.12 Apart from other considerations regarding patient health, the current trend towards milder stimulation protocols may reduce the amount of steroid levels secreted and available in the uterine cavity, diminishing the impact of steroids on early embryo development, embryo adhesion as well as normal endometrium development.

Inadequate endometrial development There is still an ongoing discussion about the minimal endometrial thickness necessary to achieve a pregnancy, with required thicknesses ranging from 4 to 7 mm. There is enough evidence to support that an endometrial thickness of ≥5 mm will not affect implantation and pregnancy rate.13 Endometrial thickness is probably a surrogate marker of COH outcome, as the better is the response, the higher are the oestradiol levels and, thus, the endometrial thickness. However, some patients do have difficulties growing endometrium. While some authors find a clear positive association between endometrial thickness and pregnancy rate,14 a well controlled study in donor egg recipients with similar embryo quality did not demonstrate any predictive value of endometrial thickness regarding pregnancy rate. A hyperechogenic, homogeneous endometrial pattern after follicle stimulating hormone (FSH) stimulation seems to be a prognostic sign of adverse outcome in assisted reproductive technologies (ART), as it may impair embryo ability to implant.15 On the other hand, a triple-line pattern appears to be associated with conception. Medical treatments, such as low dose aspirin, vaginal sildenafil, vaginal micronised oestrogens, pentoxifylline and vitamin E, have been investigated to determine whether they would improve endometrial thickness and appearance on the ultrasound with varying outcomes.16,17

Undiagnosed pathology Modern high quality transvaginal transducers used by experienced operators miss very little intrauterine pathology and, when in doubt, hysterosonography contributes to a precise diagnosis. However, some authors found 18–27% of women with RIF and previous normal pelvic examination to have undiagnosed pathology by repeated hysteroscopic visualisation, mainly synechiae, polyps, endometritis and endometrial hyperplasia.18 Correction of the misdiagnosed pathologies

significantly improved the pregnancy rates (32.5% vs 21.6%, p<0.01), however there is a lack of randomised trial to support this assertion. A detailed transvaginal ultrasound, with high quality equipment, performed in the early luteal phase of the menstrual cycle by an experienced operator and with the support of hysterosonography or even colour Doppler in cases of doubt will leave very little space, if any, for routine diagnostic hysteroscopy in cases of RIF.

Cytokine dysregulation Several distinct cytokines have been described to be differently expressed in the endometrium of women with RIF when compared with controls, such as interleukin (IL)-12, IL-15, IL-18, IL-1β interferon (IFN)-γ and IL-10.19,20 However, these changes as well as others described as being altered in RIF patients (pinopode expression, aromatase p450 mRNA, matrix metalloproteinase (MMPs) and integrins) have been described in just one cycle biopsy, and no data exist on how consistent these findings are in future cycles, and, for obvious reasons, in the conception cycle. The study of altered expression of single molecules, due to the fact that their function may be covered by other molecules a phenomenon redundancy retirved to as the need for invasive endometrial biopsy to evaluate it, and the new molecular techniques, capable of studying hundreds or even thousands of molecules at once, capable of identifying molecular profiles conducive to implantation are now most of the previous single-molecule studies obsolete.

Embryonic factors Chromosomal abnormalities Embryogenesis may be hampered by chromosomal abnormalities in the parent (male or female partner), in the gametes or in the embryo. In couples undergoing ART with at least ten embryos transferred that failed to achieve clinical pregnancy, 2.5% showed an overall chromosomal abnormality.21 The prevalence of chromosomal aberrations was even higher (15.4%) in a group of women with at least 15 embryos transferred.22 In these couples, genetic evaluation by peripheral blood karyotyping should be considered as part of their investigation. While studying the female gametes is complicated, this is not the case with sperm, as fluorescence in situ hybridisation (FISH) may provide very useful information.23 Rubio et al24 showed that patients with normal karyotype and RIF had an increased incidence of sperm chromomsomal abnormalities. Novel technologies such as global gene expression profiling of normal human testis by microarray technology will help to investigate further these couples. It is well known that embryo quality does not correlate with chromosomal anomalies, as beautiful looking

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blastocysts may be carriers of aneuploidies or another anomaly. Sandalinas et al showed that up to 37% of good looking blastocysts developed from trisomic embryos, 21% from polyploidic embryos and 9% from monosomic embryos.25 Data from our own group showed similar results: 40% of the trisomic embryos reached blastocyst stage, with the lowest percentage reaching blastocyst stage being from autosomic monosomies.26 When good quality embryos are transferred and pregnancy does not occur, aneuploidies are present in a significantly larger percentage of embryos (55% in RIF patients vs 36% controls).27,28 Thus, blastocyst development may be impaired in couples suffering from RIF, but blastocyst stage embryo transfer only partially prevents chromosomally abnormal embryo development. Consistent with the concept, preimplantation genetic screening (PGS), at least in theory, could help to select chromosomally normal embryos to be transferred and would, if the hypothesis is correct, increase implantation rates. Earlier work by Gianaroli,28,29 Munné30 and Pehlivan27 and colleagues showed, in retrospective studies in which three to eight chromosomes were analysed, that PGS improved cycle outcome. These results have been confirmed by more recent work by Platteau et al,31 who showed that patients with RIF and at least ten oocytes retrieved, eight normally fertilised and six embryos available for biopsy may benefit from aneuploidy screening by PGD. In a recent review, Donoso and Devroey32 considered that PGS has only diagnostic value, but further evidence is needed before it implemented into routine clinical practice in couples with RIF. Moreover a number of complex issues relating to PGD require further investigation. These include the fact that it informs about a limited number of chromosomes, has a 1–4% embryo loss rate due to the embryo biopsy procedure, self-correcting mosaicism can occur on day 3 of development, and the poor thawing rates after biopsy. Randomised trials with these well selected couples are urgently needed. Deeper knowledge acquired through new technology will help us to understand the reasons behind implantation failure of embryonic origin. For instance, by using comparative genomic hybridisation (CGH) we can extend the information obtained from the classical FISH analysis of five, seven or nine chromosomes. CGH will inform us about the whole set of chromosomes, with a higher accuracy: when analysing five chromosomes by FISH, 60% of the “normal” embryos are not normal by CGH; this percentage was still 40% when the FISH analysis covered nine chromosomes.33 Voullaire et al34 observed abnormalities in 60% of 126 embryos biopsied in 20 couples with RIF. Despite good morphological characteristics and cleavage rate, some embryos may have alterations in cell cycle control genes or certain cytoplasmic factors that may end up disrupting the normal sequence of chromosome replication and segregation, being the cause for RIF.17 Recently, it has been suggested that

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some of these aneuploidies may be induced by COH or embryo culture conditions. Hohmann et al,35 by starting COH as late as cycle day 5, obtained a lower response and higher cancellation rate, but embryos of significantly better quality with a very good pregnancy rate. Vigorous stimulation of the ovaries may result in poorer oocytes and hence lower quality embryos. This hypothesis was confirmed in a recent randomised trial by Baart et al36 who elegantly showed how mild stimulation of the ovaries – a more physiological approach to “natural” follicle selection – yielded a lower number of retrieved oocytes but a diminished percentage of aneuploid embryos compared with controls.

Embryo fragmentation and zona pellucida hardening Fragment aspiration and assisted hatching (AH) are two controversial procedures may prove beneficial in experienced hands, although no randomised trials have been correctly designed to confirm this. The AH is to enhance the ability of the embryo to escape from the zona pellucida. By the use of either mechanical or chemical disruption of the zona pellucida, AH is an attempt to facilitate embryonic–endometrial apposition. AH may be combined with lysed blastomere aspiration, which seems to have a benefitial effect on embryo development.37 This procedure is usually recommended in patients with advanced maternal age, poor quality embryos, thickened zona pellucidae (frozen–thawed embryos) and women with multiple IVF failures.37 Most of the available evidence is from retrospective studies, as it is methodologically complicated to perform a randomised trial. Although the indication for AH is mostly empirical and with no truly randomised trials to support it, retrospective data suggest a hypothetical beneficial effect in RIF couples.38,39 A recent meta-analysis on AH concludes that there is insufficient evidence to determine any effect of AH on live birth rates.40 Currently, there is insufficient evidence to recommend AH.

Embryo–maternal asynchrony The human embryo can not implant on the epithelial surface of the endometrium on any day of the cylce but only a few days in the mid-luteal phase. If it reaches the endometrial cavity either too early or too late it will not implant. Also, the embryo may benefit from being in close contact with the endometrium, as it may secrete embryotrophic factors, such as nutrients, growth factors, cytokines and chemokines, while detoxifying the culture media of free radicals or any other unwanted or harmful substances.41 Thus, some groups have proposed embryo–endometrium coculture as a means to facilitate embryo development and implantation. Spandorfer et al42 from Cornell University reported a pregnancy rate of 49% in a group of 1030 RIF patients undergoing homologous endometrial co-culture. We have also described a very

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good blastocyst formation rate (50.8%–58.2%), with encouraging implantation and pregnancy rates.43 Whether homologous endometrial co-culture provides any benefit compared with much easier-tohandle systems, such as the different commercially available sequential media, remains to be determined.

Maternal conditions Autoantibodies Autoantibodies have been intensively studied in the past decade, it seems that the immunological causes of RIF are very low. Some groups have described differences in antiphospolipid antibody levels between patients with RIF and controls, and in other antibodies such as annexin-V however no causative relationship has been demonstrated.44,45 Peripheral natural killer (NK) cell testing has been advocated as a useful tool to decide which patients may benefit from immunosuppressive therapies in RIF patients. Treatments proposed (e.g. intravenous immunoglobulin) are not risk-free, and more importantly, there is no evidence or scientific basis to support such therapies.46

Thrombophilias The role of thrombophilia in implantation failure is truly controversial and poorly understood. In recent years, it has been shown that the prevalence of hereditary thrombophilia is higher in women with RIF. Screening for thrombophilia is mainly antiphospholipid both anticardiolipin antibodies lupus anticoagulant, factor V Leiden, protein C and S deficiency and activated protein C resistance, antithrombin III deficiency, methylene tetrahydrofolate and factor II (prothrombin G2021OA) gene mutation. Azem et al47 reported that thrombophilias were present in 44% of patients with RIF, a significantly higher percentage than in healthy controls (18%); this prevalence was even higher if the patient belonged to the unexplained infertility subgroup, as high as 62%. Coulam et al,48 in a study screening for ten thrombophilic genes, confirmed that combined thrombophilias (three or more mutations) were much more frequent in patients with RIF than in control patients (74% vs 20%, p=0.0004). Qublan et al49 described a prevalence of combined thrombophilia of 35.6% in women with at least three failed IVF cycles, which is significantly higher than that found in healthy fertile controls, who have levels as low as 3%. We have recently shown a similar prevalence of thrombophilia (46.2%) in women with RIF, confirming that some thrombophilias, and especially combined thrombophilias, may undermine the possibility of embryo implantation after ART.50 Screening for these disorders, although still controversial, is suggested, as simple medical treatment may be implemented with heparin, corticosteroids and/or aspirin; however, there are still no definitive studies showing evidence for treatment benefit.

Endometriosis Endometriosis is a common gynaecological disease that can affect almost every step of human reproduction, including ovarian response to COH, oocyte and embryo quality, corpus luteum formation, sperm motility, tubal transport, and implantation and pregnancy rates.51 Apart from mechanical defects in moderate and severe cases, it seems clear that oocyte and embryo quality may be affected by endometriosis. Data from IVF cycles, and especially from egg donation cycles, where we can clearly dissect the effect of the disease on the oocytes or on the endometrium, showed that egg quality seems to be impaired in women with endometriosis, who may yield lower quality embryos and, thus, lower implantation rates.52–55,57 This itself may be a cause of infertility, although some patients with endometriosis do respond well to COH and produce good quality embryos. There is recent evidence that long-term gonadotropin releasing hormone (GnRH) analogue treatment may improve implantation in these patients. Treatment with 3–6 months of GnRH analogues may increase the odds of clinical pregnancy by four fold,56 with no deleterious effect on ovarian response to COH. However, these conclusions are based on small studies. Surgical treatment is indicated only in patients complaining of pain. Endometrioma removal prior to IVF does not seem to add any value, while increasing the risk of damaging the ovary due to the surgery itself and the surgical risk by itself.57 Non-ovarian endometriosis may benefit from surgical treatment, but this is still a highly controversial issue awaiting confirmation by randomised trials.58

Hydrosalpinges Today it is unquestionable that hydrosalpinges reduce the implantation rate by half, and that either tubal removal or sealing is strongly recommended in these patients after randomised trials were published. The mechanical or chemical effects of the fluid are thought to be responsible for the diminished fertility in these patients. Previous basic studies showed that the fluid that accumulated in the tubes of patients with hydrosalpinx was deleterious for embryo development.59 The spontaneous drainage of the fluid from the tube to the cervix could also impair embryo implantation if it happened at that stage. Clinical studies were undertaken at a later date.60 The first randomised trial to show a clear effect of salpingectomy in ultrasound visible hydrosalpinges confirmed the benefits of perfoming laparoscopy on this specific group of patients.61 Cost–benefit analysis62 as well as further studies63 confirmed this approach. Patients with ultrasound visible hydrosalpinx may double their chances of achieving a pregnancy if their tubes are either sealed or removed. For a comprehensive review of the value of visible hydrosalpine as IVF outcome, see Chapter 23.

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Leiomyomas The relationship between uterine fibroids and reproductive outcome has been a concern for many years, and recent data contribute to the clarification of this issue. The great variety in size, number and location of the fibroids make it very complicated to extract firm conclusions from the published data, considering that removing these myomas is not risk free. Retrospective analysis of the data suggests that myomas distorting endometrial cavity (submucous or intramural) impair fertility.64 Patients with intramural fibroids showed a 50% decrease in implantation rate, a decrease that was even higher for submucous fibroids. Thus, hysteroscopic removal of these fibroids is recommended, although no prospective studies are available. A recent meta-analysis confirmed that removal of submucosal fibroids seems to confer benefit to the decreased fertility outcome observed in these women, something that is not confirmed for subserosal fibroids. Regarding intramural myomas, further studies are required as no clear conclusion has yet been reached.65

Difficult embryo transfer Together with COH and embryo quality, embryo transfer is one of the key elements for success in IVF.66 The recent attention devoted to the technique of placing the embryo in the uterine cavity has, without any doubt, increased the results of ART. Furthermore, while the majority of embryo transfers are simple, easy and straightforward, it has been shown that appropriate training of the physician is required, as wide variability is observed among physicians unless the procedure is strictly standardised.67 Atraumatic negotiation of the cervical canal is a crucial step in the embryo transfer procedure, which may be anticipated by a mock embryo transfer and will benefit from the physician’s experience.65 Whether ultrasound guidance is used may not be so crucial as long as good technique is used. Most studies seem to favour ultrasound-guided embryo transfer, especially in very difficult cases.68 In some specific cases, tubal embryo transfer may be offered in order to avoid complicated or extremely difficult transcervical transfers that may induce uterine contractions and endometrial bleeding. However, a better approach would to perform a cervical dilatation a few weeks before the cycle. This can be done either by hysteroscopy under sedation, to first visualise the cervical canal and eliminate any obstacles (adhesions, polyps, etc.) and to perform a cervical dilatation.69

Psychological support Stress, anxiety and depression may affect natural conception. Whether they interfere with infertility treatment is still a matter of controversy. The situation is

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slightly different than with recurrent miscarriage, where tender loving care provides additional support. Most studies show a reduction in stress and anxiety with psychological intervention,70 but their efficacy at improving pregnancy rate is still lacking.

Conclusions Implantation is still the black box in reproductive medicine: improving implantation, especially in those couples with repeated implantation failure – a very vulnerable group71 – is a major challenge for physicians. A thorough work-up is mandatory in the couples to exclude the different known causes of RIF, even though many of them have a very low prevalence. If the cause of RIF, despite extensive investigation is not found, patients should be counselled accordingly.

References 1. http://apps.nccd.cdc.gov/ART2004/nation04.asp 2. Tan BK, Vandekerckhove P, Kennedy P, Keay SD. Investigation and current management of recurrent IVF treatment failure in the UK. Br J Obstet Gyneacol 2005; 112: 773–80. 3. ESHRE PGD Consortium data collection V: cycles from January to December 2002 with pregnancy follow-up to October 2003. Hum Reprod 2006; 21: 3–21. 4. Macklon NS, Fauser BC. Impact of ovarian hyperstimulation on the luteal phase. J Reprod Fertil Suppl 2000; 55: 101–8. 5. Simón C, Dominguez F, Valbuena D, Pellicer A. The role of estrogen in uterine receptivity and blastocyst implantation. Trends Endocrinol Metab 2003; 14: 197–9. 6. Bradford AJ, Najmabadi S, Paulson RJ. Ultrastructural characteristics of the luteal phase endometrium in donors undergoing controlled ovarian hyperstimulation. Fertil Steril 1997; 67: 625–30. 7. Simón C, Mercader A, Frances A et al. Hormonal regulation of serum endometrial IL-1β, and IL-1ra (IL-1 endometrial microenviroment of the human embryo at the apposition phase under physiologicaland supraphysiological steroid level conditions). J Reprod Immunol 1996; 31: 165–84. 8. Simón C, Garcia Velasco JJ, Valbuena D et al. Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Fertil Steril 1998; 70: 234–9. 9. Simón C, Cano F, Valbuena D, Remohí J, Pellicer A. Clinical evidence for a detrimental effect on uterin receptivity of high serum estradiol levels in high and normal responder patients. Hum Reprod 1995; 10: 2432–7. 10. Pellicer A, Valbuena D, Cano F, Remohí J, Simón C. Lower implantation rates in high responders: evidence for an altered endocrin milieu during the preimplantation period. Fertil Steril 1996; 65: 1190–5. 11. Valbuena D, Martin J, de Pablo JL et al. Increasing levels of estradiol are deletereous to embryonic implantation

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28. Gianaroli L, Magli MC, Ferraretti AP et al. Preimplantation genetic diagnosis increasis the implantation rate in human in vitro fertilization by avoiding the transfer of chromosomally abnormal embryos. Fertil Steril 1997; 68: 1128–31. 29. Gianaroli L, Magli MC, Ferraretti AP, Munné S. Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: identification of the categories for which it should be proposed. Fertil Steril 1999; 72: 837–44. 30. Munné S, Sandalinas M, Escudero T et al. Improved implantation after preimplantation genetic diagnosis of aneuploidy. Reprod Biomed Online 2003; 7: 91–7. 31. Platteau P, Staessen C, Michiels A et al. Which patients with recurrent implantation failure after IVF benefit from PGD for aneuploidy screening? Reprod Biomed Online 2006; 12: 334–9. 32. Donoso P, Devroey P. PGD for aneuploidy screening: an expensive hoax? Best Pract Res Clin Obstet Gynaecol 2007; 21: 157–68. 33. Wilton L. Preimplantation genetic diagnosis and chromosome analysis of blastomeres using comparative genomic hybridization. Hum Reprod Update 2005; 11: 33–41. 34. Voullaire L, Wilton L, McBain J, Callaghan T, Williamson R. Chromosome abnormalities identified by comparative genomic hybridization in embryos from women with repeated implantation failure. Mol Hum Reprod 2002; 8: 1035–41. 35. Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 2003; 88: 166–73. 36. Baart EB, Martini E, Eijkemans MJ et al. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum Reprod 2007; 22: 980–8. 37. Kelz MD, Skorupski JC, Bradley K, Stein D. Predictors of embryo fragmentation and outcome after fragment removal in in vitro fertilization. Fertil Steril 2006; 86: 321–4. 38. Sallam HN, Sadek SS, Agameya AF. Assisted hatching – a meta-analysis of randomized controlled trials. J Assist Reprod Genet 2003; 20: 332–42. 39. Dayal MB, Dubey A, Frankfurter D, Peak D, Gindoff PR. Second cycle: to hatch or not to hatch? Fertil Steril 2007; 88: 718–20. 40. Seif MM, Edi-Osagie EC, Farquhar C et al. Assisted hatching on assisted conception (IVF & ICSI). Cochrane Database Syst Rev 2006; (1): CD001894. 41. Simón C, Martín JC, Galan A, Valbuena D, Pellicer A. Embryonic regulation in implantation. Semin Reprod Endocrinol 1999; 17: 267–74. 42. Spandorfer SD, Pascal P, Parks J et al. Autologous endometrial coculture in patients with IVF failure: outcome of the first 1,030 cases. J Reprod Med 2004; 49: 463–7. 43. Mercader A, Garcia-Velasco JA, Escudero E et al. Clinical experience and perinatal outcome of blastocyst transfer after coculture of human embryos with human endometrial epithelial cells: a 5-year followup study. Fertil Steril 2003; 80: 1162–8.

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Implantation failure 44. Matsubayashi H, Sugi T, Arai T et al. Different antiphospholipid antibody specificities are found in association with early repeated pregnancy loss versus recurrent IVF-failure patients. Am J Reprod Immunol 2001; 46: 323–9. 45. Kwak-Kim JY, Chung-Bang HS, Ng SC et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod 2003; 18: 767–73. 46. Rai R, Sacks G, Trew G. Natural killer cells and reproductive failure – theory, practice and prejudice. Hum Reprod 2005; 20: 1123–6. 47. Azem F, Many A, Ben Ami I et al. Increased rates of thrombophilia in women with repeated IVF failures. Hum Reprod 2004; 19: 368–70. 48. Coulam CB, Kay C, Jeyendran RS. Role of p53 codon 72 polymorphism in recurrent pregnancy loss. Reprod Biomed Online 2006; 12: 378–82. 49. Qublan HS, Eid SS, Ababneh HA et al. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum Reprod 2006; 21: 2694–8. 50. Bellver J, Soares SR, Alvarez C et al. The role of thrombophilia and thyroid autoimmunity in unexplained infertility, implantation failure and recurrent spontaneous abortion. Hum Reprod 2008; 23: 278–84. 51. Navarro J, Garrido N, Remohí J, Pellicer A. How does endometriosis affect infertility? Obstet Gynecol Clin North Am 2003; 30: 181–92. 52. Simón C, Gutiérrez A, Vidal A et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod 1994; 9: 725–9. 53. Arici A, Oral E, Bukulmez O et al. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertil Steril 1996; 65: 603–7. 54. Díaz I, Navarro J, Blasco L et al. Impact of stage III-IV endometriosis on recipients of sibling oocytes: matched case-control study. Fertil Steril 2000; 74: 31–4. 55. Garrido N, Navarro J, García-Velasco J et al. The endometrium versus embryonic quality in endometriosis-related infertility. Hum Reprod Update 2002; 8: 95–103. 56. Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Longterm pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev 2006; (1): CD004635. 57. Garcia-Velasco JA, Arici A. Surgery for the removal of endometriomas before in vitro fertilization does not increase implantation and pregnancy rates. Fertil Steril 2004; 81: 1206.

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58. Littman E, Giudice L, Lathi R et al. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005; 84: 1574–8. 59. Strandell A, Lindhard A. Why does hydrosalpinx reduce fertility? The importance of hydrosalpinx fluid. Hum Reprod 2002; 17: 1141–5. 60. Zeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization-embryo transfer. Fertil Steril 1998; 70: 492–9. 61. Strandell A, Lindhard A, Waldenström U et al. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum Reprod 1999; 14: 2762–9. 62. Strandell A, Lindhard A, Eckerlund I. Cost–effectiveness analysis of salpingectomy prior to IVF, based on a randomized controlled trial. Hum Reprod 2005; 20: 3284–92. 63. Strandell A. Treatment of hydrosalpinx in the patient undergoing assisted reproduction. Curr Opin Obstet Gynecol 2007; 19: 360–5. 64. Oliveira F, Abdelmassih VG, Diamond MP et al. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization–intracytoplasmic sperm injection. Fertil Steril 2004; 81: 582–7. 65. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril 2008; in press. 66. Schoolcraft WB, Surrey ES, Gardner DK. Embryo transfer: techniques and variables affecting success. Fertil Steril 2001; 76: 863–70. 67. Hearns-Stokes R, Miller TB, Scott L et al. Pregnancy rates after embryo transfer depend on the provider at embryo transfer. Fertil Steril 2000; 74: 80–6. 68. Abou-Setta AM, Mansour RT, Al-Inany HG et al. Among women undergoing embryo transfer, is the probability of pregnancy and live birth improved with ultrasound guidance over clinical touch alone? A systemic review and meta-analysis of prospective randomized trials. Fertil Steril 2007; 88: 333–41. 69. Prapas N, Prapas Y, Panagiotidis Y et al. Cervical dilatation has a positive impact on the outcome of IVF in randomly assigned cases having two previous difficult embryo transfers. Hum Reprod 2004; 19: 1791–5. 70. de Liz TM, Strauss B. Differential efficacy of group and individual/couple psychotherapy with infertile patients. Hum Reprod 2005; 20: 1324–32. 71. Nap AW, Evers JL. Couples with infertility belong to a very vulnerable group, they should not be exploited. Hum Reprod 2007; 22: 3262–3.

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30 Early placental development and pregnancy outcome Graham J Burton, Eric Jauniaux

The placenta develops with the principal function of providing nutrients to the foetus. Any impairment in this process is therefore likely to have a profound impact on pregnancy outcome. Placentation in the human is precocious and complex compared with that in the majority of other mammals, starting from the time of implantation during the second week postconception. It is also a highly invasive process, and by day 10–11 postconception the conceptus has become totally embedded in the uterine wall. This form of interstitial implantation is only seen in the human and the great apes. In the majority of mammals, the conceptus remains within the uterine lumen, either with no invasion or with invasion being restricted to localised points around the surface of the chorionic sac.1 Placentation in most of these species involves the interdigitation of foetal and maternal membranes, with exchange occurring between the capillary networks contained within each. By contrast, in the human the invading trophoblast erodes into the endometrial vessels, releasing the maternal blood to bathe the placental villi. This mode of placentation poses unique challenges, in particular haemodynamic issues and those related to oxygen metabolism associated with tapping into the maternal arterial circulation. There is now considerable evidence that many of the major complications of human pregnancy can be traced back to a defect in this process.2 In this chapter we review recent advances in our understanding of placental development during the first and early second trimesters of pregnancy and relate these to pregnancy outcome.

Early placental development Very little is known of the earliest stages of villous development mainly due to the inaccessibility of specimens, and the Carnegie collection of embryos still remains the most important source of data.3 The human blastocyst implants with the polar trophectoderm cells overlying the inner cell mass establishing the initial contact with the uterine epithelial cells. These trophectoderm cells

undergo local differentiation, with the formation of an outer syncytial layer and an underlying layer of mononucleate cytotrophoblast progenitor cells. These events have been recreated in vitro, where it can be observed that tongues of syncytiotrophoblast penetrate between the endometrial cells rather than engulfing them or stimulating apoptosis.4 Gradually, as the conceptus moves into the superficial endometrium the layer of syncytiotrophoblast extends over the whole surface, forming a complete mantle. By day 8 postconception spaces begin to appear within the mantle, forming a series of lacunae separated by trabeculae of syncytiotrophoblast (Fig 30.1). As the mantle expands it encroaches upon the capillary network within the superficial endometrium and upon the ducts of the endometrial glands.5 The capillaries show localised dilatation in the vicinity of the conceptus, possibly hormonally induced.3 Connections are soon established with the lacunae, as evidenced by the appearance of erythrocytes within the latter, although Hertig et al remarked that they were not as numerous as might be expected.3 Whether these erythrocytes circulate through the lacunae is impossible to tell from static histological images, but if so any flow can only be of a slow capillary nature. Nonetheless, in many textbook accounts this is taken to be the onset of the maternal circulation to the placenta. In reality the situation is much more complex, for it has now been confirmed that maternal arterial connections are only permanently established with the placenta towards the end of the first trimester.6 Commencing around day 12 postconception the cytotrophoblast cells at the base of the trabeculae proliferate and penetrate into the mantle, reaching the tips of the trabeculae at approximately day 14 postconception. They then extend laterally, merging with those from neighbouring trabeculae to form the cytotrophoblastic shell that lies at the maternofoetal interface (Fig 30.1). This is an important structure in early placental development, as the extravillous trophoblast populations that play a key role in transforming the maternal spiral arteries arise from its maternal surface. These populations are considered in greater detail later.

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Fig 30.1 Schematic diagram representing the major events in placental development at (A) implantation and (B) during the third week postconception. Secretions from the uterine glands containing epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) are delivered into the lacunae, and may stimulate proliferation of the trophoblast cells and secretion of human chorionic gonadotropin (hCG). This may feedback positively on the glandular cells.

Shortly after the cytotrophoblast cells have penetrated the trabeculae they are followed by extraembryonic mesoderm cells. These form a loose meshwork, with processes from neighbouring cells uniting to form a series of fluid-filled longitudinal stromal channels.7 The mesoderm does not extend right to the tips of the trabeculae, leaving columns of cytotrophoblast cells connecting the developing villi to the shell (Fig 30.2). These are referred to as anchoring villi, although their tensile strength must be limited by that of the intercellular desmosomal contacts uniting the cells. Lateral branches then develop from the trabeculae, forming the earliest placental villi. These branches undergo further divisions, extending into the lacunae which can now be considered the forerunners of the intervillous space. Terminal villi, the functional units of the villous tree for maternofoetal exchange, are not formed in appreciable volume until around 18 weeks of pregnancy, but are formed exponentially thereafter.8 The early villi possess a thick covering of trophoblast, comprising an outer layer of multinucleated syncytiotrophoblast and an underlying complete layer of cytotrophoblast cells (Fig 30.3). The latter undergo proliferation, and daughter cells subsequently differentiate and then fuse with the syncytiotrophoblast, increasing its mass. The molecular mechanisms regulating fusion are complex and not fully understood, but expression of fusigenic retroviral proteins, formation of gap junctions and activation of the apoptotic cascade have all been implicated.9 Haemangioblastic cell precursors differentiate within the mesoderm, giving rise to the first capillaries around day 21 postconception.10,11 The central location of these vessels coupled with their small calibre means that these early villi are not well suited for diffusional exchange. Indeed, it is questionable whether there is significant circulation through these early villous vessels and

Fig 30.2 Photomicrograph of a developing placenta (4 weeks postconceptional age) showing cytotrophoblast cell columns (arrows) extending from an anchoring villus (AV) and feeding into the cytotrophoblastic shell (CS). DB, decidua basalis.

between the primitive placenta and the developing foetus during the first trimester. The fact that the vast majority (>90%) of the foetal erythrocytes are nucleated at this stage, and hence poorly deformable, undoubtedly ensures that the resistance to flow is high.12 Equally, serial reconstruction of a ten somite embryo revealed that the communication between the descending aorta and the umbilical vessels is extremely narrow.13 More likely, significant flow between the placenta and the foetus is only established towards the end of the first trimester, when the proportion of nucleated erythrocytes falls rapidly. Prior to the establishment of a continuous maternal flow in the intervillous space and of an efficient foetoplacental circulation nutrients must pass via the

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Fig 30.3 A villus from a developing placenta (4 weeks postconceptional age) illustrating the bilaminar trophoblast covering, with an outer layer of syncytiotrophoblast supported by a layer of pale-staining mononuclear cytotrophoblast cells. The loose stromal core contains foetal capillaries (arrow) filled with nucleated foetal erythrocytes.

extraembryonic coelomic cavity, most probably along the stromal channels, from where they may be taken up and transported to the embryo by the secondary yolk sac.14–16 Initially, villi develop over the entire surface of the chorionic sac, forming the chorion frondosum. By the end of the first trimester the villi over the abembryonic or superficial pole begin to show signs of regression, a process that also appears to be linked with the onset of the maternal arterial circulation to the placenta as is discussed later. This leaves the villi over the embryonic pole of the chorionic sac forming the discoid definitive placenta. The remainder of the chorionic membrane becomes the smooth chorion, or chorion laeve, and this transition is essential to allow for rupture of the extraembryonic membranes at birth. Normally the umbilical cord will be attached near the centre of the placental disc due to the orientation of the blastocyst at the time of implantation. Initial attachment through the polar trophectoderm cells overlying the inner cell mass ensures that when the connecting stalk, the forerunner of the umbilical cord, grows out from the caudal end of the embryonic disc it establishes contact with the trophoblast abutting the decidua basalis. Incorrect orientation may lead to velamentous insertion of the cord, and the risk of antepartum haemorrhage, in particular during the second month of pregnancy.

The contribution of the endometrium to early placental development Our appreciation of the role of the endometrium in supporting early placental development has undergone radical revision over the past few years. It is now realised that the glands play a major role by

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contributing histiotrophic nutrition to the conceptus during the first trimester before the placental circulations are established and are efficient (see above). Equally, recent evidence suggests that interactions between the invading trophoblast and the maternal immune cells are key to mediating physiological changes in the spiral arteries that will ultimately supply the placenta. At the time of implantation the human endometrium is approximately 8 mm thick,17 and contains numerous highly active glands with an areal density of approximately 15 per mm2.18 Therefore, it is likely that the expanding syncytiotrophoblastic mantle will encounter, and subsequently invade, the necks of glands shortly after implantation. This will allow secretions from the glands to enter the lacunae and bathe the developing villi, and also to diffuse out at the maternofoetal interface. Relatively little attention has been paid so far as to how these secretions might influence placental development. Potentially they could have highly significant effects as they are delivered through the cytotrophoblastic shell, and later the developing basal plate, into the intervillous space until at least the end of the first trimester.19 Experimental manipulations in the sheep have revealed that the equivalent secretions are essential for normal elongation and development of the conceptus prior to implantation.20 At 6 weeks of pregnancy (4 weeks postconception), the endometrial gland cells in the decidua basalis display morphological features indicative of high secretory activity, and closely resemble those of the midsecretory phase of the cycle. The apical portions of the cells are packed with glycogen whereas there are numerous lipid droplets towards the base, and the mixed secretions within the gland lumens reflect these different contributions. Villi close to the maternofoetal interface show accumulations of glycogen within those regions of the syncytiotrophoblast facing the openings of the endometrial glands, indicating uptake and storage.19 Further evidence of trophoblastic uptake of endometrial secretions comes from immunofluorescent studies that have demonstrated intense staining for glycodelin and MUC-1, two glycoproteins synthesised in the glands the mRNAs of which are not expressed in the trophoblast, within the syncytiotrophoblast. These proteins have been co-localised to the lysosomal pathway, suggesting that they may be broken down and their constituent amino acids used in anabolic pathways.19,21 Although there is no confirmatory evidence as yet that this is the case there do appear to be strong parallels with the uptake of nutrients by the rodent yolk sac during early pregnancy. In the rat 90% of maternofoetal amino acid transport during the period of organogenesis is through the uptake and breakdown of maternal proteins rather than transport of free amino acids.22

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Besides acting as an important source of nutrients the secretions also contain a number of growth factors and cytokines, such as epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β) and leukaemia inhibitory factor (LIF).21 Receptors for all these factors are present on first-trimester placental tissues, raising the possibility that the secretions might influence trophoblast proliferation and differentiation, or villous vasculogenesis.23 At present there are few experimental data to support this claim, but studies indicate that EGF might play a dual role depending upon gestational age. Receptors for EGF are seen on cytotrophoblast cells alone at 4–5 weeks, and then switch to the syncytiotrophoblast at 6–10 weeks.24 Addition of exogenous EGF to early villous explants leads to cytotrophoblast proliferation, whereas on later explants it stimulates secretion of human chorionic gonadotrophin (hCG) and placental lactogen.25 EGF from the glands may therefore promote formation of the syncytiotrophoblast mantle and ensure adequate development of the cytotrophoblastic shell during the first few weeks post-implantation. Intriguingly, there is strong evidence from animal species, such as the sheep and pig, that the conceptus is able to stimulate the secretory activity of the endometrial glands to meet its requirements.26 We have speculated that an equivalent servomechanism might operate in the human, effected through prolactin secreted by the decidual cells and possibly hCG, but this requires further investigation.23 Conversely, there is evidence that inadequate gland activity is associated with poor obstetric outcome. Concentrations of glycodelin and MUC-1 are lower in uterine flushings in women suffering spontaneous miscarriage compared with fertile controls.27,28 Equally, lower expression of glycodelin has been reported on the basis of immunohistochemistry and in situ hybridisation in the decidua of patients with pre-eclampsia or intrauterine growth restriction (IUGR) at the time of delivery.29 How these effects are mediated is not yet known, but overall the data support the conclusion that proper development and functioning of the endometrium is the key not only to successful implantation, but also to early placental development.

Physiological conversion of the spiral arteries Towards the end of the first trimester the secretory activity in the endometrial glands wanes.21 Also, as one moves from the embryonic to the foetal stage of development there is a need for a switch to haemotrophic nutrition in order to support the rapid rate of growth that characterises the latter. The establishment of the maternal arterial circulation inside the placenta represents a major challenge to an ongoing

pregnancy, most likely second only to that of implantation. Tapping into a high pressure, high velocity system is potentially hazardous, and recent evidence indicates that this must be carefully coordinated in order to succeed. If it occurs too early or incorrectly then the conceptus may be dislodged and miscarry or the placental tissue may be severely damaged by the haemodynamic forces. In addition, the early placental villi are highly sensitive to oxidative stress, and this appears to be another major factor determining pregnancy outcome. To avoid these potential dangers a number of strategies appear to have evolved, both in the endometrium and during placental development. First, it is notable that at the time of implantation the spiral arteries that will eventually supply the placenta do not penetrate more than half the thickness of the endometrium in the rhesus monkey, a model for the human endometrium.30 Instead they branch abruptly into a number of small calibre arterioles that follow a straight course towards the uterine epithelium, giving rise to a superficial capillary plexus running just beneath the surface. This arrangement will ensure that the pressure within that plexus is low, and that the invading trophoblastic mantle will not encounter a high-pressure vessel for several weeks after implantation. Second, the spiral arteries normally undergo physiological conversion during early pregnancy. This process appears to be mediated by the invading extravillous trophoblast derived from the maternal surface of the cytotrophoblastic shell. The extravillous trophoblast comprises two populations, the interstitial cells that migrate through the endometrial stroma and into the inner third of the myometrium, and the endovascular trophoblast cells that migrate down the lumens of the spiral arteries. The interstitial cells reach the myometrium towards the end of the first trimester, and at their limit of invasion they fuse to form multinucleated giant cells.31,32 The endovascular migration follows a little later, reaching the myometrial segments of the arteries in the early second trimester. Although the molecular mechanisms are not yet fully understood, the presence of the extravillous trophoblast is temporally and spatially associated with loss of smooth muscle and elastic fibres from the vessel walls and the deposition of an amorphous fibrinoid material.33–35 In addition, those vessels surrounded by the greatest concentration of trophoblast show the most advanced changes.36 Interactions between human leucocyte antigen (HLA)-C molecules expressed by the extravillous trophoblast and kinase inhibitory receptors (KIRs) on the uterine natural killer (NK) cells may be involved, for the latter release a range of chemokines and angiogenic factors.37,38 In the mouse it appears that interferon γ released by the NK cells is sufficient to cause loss of the arterial smooth muscle cells.39 Other features seen in the arteries during conversion, such as

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vacuolation of the intima and to a lesser extent swelling of the endothelial cells, occur in the myometrial segments of spiral arteries sampled from other sites in the uterus just as frequently as in those from the placental bed. This suggests they may be independent of trophoblast invasion, being mediated possibly by hormonal or other stimuli. Conversion of the spiral arteries has a major impact on the haemodynamics of the maternal circulation to the placenta. First, the distal portions of the arteries dilate approximately fourfold as they approach the placenta.40 Since the rate of flow in a vessel is dictated by Poiseulle’s law, and so is proportional to the fourth power of the radius, this abrupt dilatation will reduce the velocity of the incoming blood considerably. Such a reduction is essential to avoid the potentially jetlike spurt damaging the architecture of the placental villous trees. Thus, failure of spiral artery conversion is associated with the formation of villous-free placental lakes opposite the mouths of the arteries.41 The force of the incoming blood may also rupture the anchoring villi, resulting in a more globular placenta the consistency of which has been referred to as “jelly-like” or “wobbly”.41,42 As might be expected these placentae are associated with a poor obstetric outcome. In addition, conversion will reduce the pressure with which the blood enters the intervillous space. Measurements performed in the rhesus monkey indicate that the pressure in the spiral arteries just before they enter the placenta is as low as 12 mmHg.43 This reduction is essential to avoid compression of the foetal capillaries within the placental villi by the inherently higher maternal arterial pressure.44 In this way the maternal arterial inflow is modulated to a slow infusion into the intervillous space, better suited for placental exchange. The second benefit of spiral artery conversion relates to the loss of vasoreactivity within the vessels. In the non-pregnant state spiral arteries contain a large amount of smooth muscle within their walls and have a rich innervation.45 In particular, there is a highly contractile segment in the inner third of the myometrium, just beneath the endometrial/myometrial boundary in both humans and rhesus monkeys.40,45 The inner myometrium is now recognised to be a specialised region, often referred to as the junctional zone, and is highly responsive to steroid hormones and undergoes profound remodelling before and during pregnancy.46 Narrowings of the spiral arteries, almost to the point of occlusion, have been outlined in this zone radiographically in the human at midpregnancy, confirming that the constrictions are not fixation artefacts but physiological entities.47 In the non-pregnant state contraction of a spiral artery at this point serves to limit blood loss during menstruation, when the distal segment of the artery is eroded away.48 However, contraction during pregnancy could jeopardise placental blood flow. Physiological conversion

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may resolve this apparent paradox of conflicting demands placed on the vessel by removing the arterial smooth muscle in this zone during early pregnancy. It is notable that normally extravillous trophoblast invasion penetrates as far as this zone but no further, suggesting that arterial modifications further upstream are not necessary. A third benefit of conversion is that the increase in diameter of the distal segment combined with the loss of the contractility will reduce the resistance to maternal blood flow in the spiral and uterine arteries. Thus, both the resistance and pulsatility indices were reported to be lower in spiral arteries in the centre of the placental bed of normal pregnancies at 17–20 weeks of gestation compared with those at the periphery, matching the pattern of trophoblast invasion.49 A similar centre–periphery differential was also observed in cases of pre-eclampsia, but values for the indices were significantly higher than in normal pregnancies.50 Further evidence of a positive correlation between the extent of trophoblast invasion and Doppler assessment of spiral arterial resistance was provided by a recent study showing that the proportion of decidual vessels containing endovascular trophoblast at 10–14 weeks of gestation was greater in pregnancies displaying low arterial resistance compared with those with high-resistance.51

Onset of the maternal circulation in normal pregnancies Full conversion of the spiral arteries does not occur until 14–16 weeks of gestation and is only complete in normal pregnancy at 22–24 weeks of gestation. However, it is now appreciated that there is little flow through these arteries into the intervillous space during the first trimester. It appears that endovascular trophoblast derived from the cytotrophoblastic shell migrates into the lumens of the arteries in such quantities that it effectively plugs their tips (Fig 30.4).6,52,53 As a result, only a clear fluid is observed within the intervillous space.54 This fluid may arise from plasma seeping through the network of intercellular spaces between the endovascular cells, but it is also derived from the secretions of the endometrial glands, which are delivered into the intervillous space throughout the first trimester.19 The mechanism by which the plugs dissipate is not known, but in normal pregnancies this is a progressive phenomenon, starting in the periphery of the placenta at around 8 weeks of gestation (6 weeks postconception) and gradually extending into the central regions.55 This matches the extent of extravillous trophoblast invasion across the placental bed, which is not uniform but greatest in the central region where it has been in contact with the endometrium the longest.31

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Fig 30.4 Transverse profiles of the distal segment of a spiral artery at 8 weeks postconceptional age within the decidua basalis undergoing physiological conversion. The lumen is filled with invading endovascular trophoblast cells (arrows) that have virtually occluded the lower profile, blocking maternal blood flow into the intervillous space.

The onset of flow between the spiral arteries and the placenta is associated with a threefold increase in oxygen concentration within the intervillous space.56,57 First-trimester placental tissues, in particular the syncytiotrophoblast, are highly sensitive to oxygen as they contain only low concentrations of the principal antioxidant enzymes.58 Consequently, if exposed to ambient oxygen in vitro the syncytiotrophoblast undergoes rapid degeneration.59 Equivalent changes occur in vivo for elevated levels of oxidative stress, apoptosis and trophoblast degeneration are observed in the peripheral regions of the placenta in association with onset of the maternal intraplacental circulation.55 Confirmation that there are striking regional differences in villous morphology at this stage of gestation has come from the examination of archival placenta in situ specimens. In a specimen of approximately 60 days of gestation the villi over the superficial pole of the chorionic sac are shorter than those on the deeper surface in contact with the decidua basalis, and are enmeshed in maternal erythrocytes. They are also avascular, consistent with downregulation of angiogenic factors by hyperoxia, and the syncytiotrophoblast is thin and devoid of microvilli. By comparison, villi over the deep pole contain well-developed blood vessels and display a healthy two-layered trophoblastic covering. In later specimens the superficial villi have regressed further, being represented only by ghost-like structures with a collagenous core and a thin covering of trophoblast.55 This sequence of in vivo differences, in conjunction with our in vitro data of the sensitivity of early placental tissues to oxygen, led us to propose that localised physiological oxidative stress plays a key role in remodelling the chorion frondosum into the chorion laeve and the definitive placenta (Fig 30.5). Abnormalities in the pattern of onset of the maternal circulation may lead to excessive villous regression as is discussed later.

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Fig 30.5 Diagrammatic representation of onset of the maternal intraplacental circulation at the end of the second month in the periphery of the placenta (arrows) where trophoblast invasion, and hence plugging of the spiral arteries, is minimal. The high local oxygen concentration causes oxidative stress in the villi over the abembryonic pole, inducing apoptosis, villous regression and formation of the chorion laeve. AC, amniotic cavity; D, decidua; ECC, exocoelomic cavity; M, myometrium; P, placenta; SYS, secondary yolk sac. Reproduced from reference 15, with permission; copyright 2004, The Endocrine Society.

Abnormal trophoblast invasion The advent of ultrasound has revolutionised our understanding of placental development and function during early pregnancy, allowing placental size and shape to be visualised in utero in a repeatable and safe manner. Furthermore, the addition of Doppler technology has enabled blood flows to be profiled and vascular resistances to be calculated. Longitudinal studies have confirmed that many complications of later pregnancy have their pathophysiological roots in abnormal placental development during the first trimester. Thus, Hafner et al demonstrated that in cases of IUGR, with or without accompanying pre-eclampsia, the placenta is smaller at 12 weeks of gestation than in healthy controls.60 In cases of IUGR alone the placenta then grows at the normal rate, but if complicated by pre-eclampsia the rate of growth is slower than normal. By contrast, in late-onset pre-eclampsia the placenta is actually larger than normal at 12 weeks, but the rate of growth then slows between 16 and 22 weeks. Similar findings were presented by Thame et al who reported that measures of foetal anthropometry (abdominal and head circumferences, biparietal diameter and femur length)

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Fig 30.6 Diagrammatic representation of trophoblast invasion in normal (A) and abnormal (B) pregnancies. In abnormal pregnancies shallow invasion results in deficient plugging of the spiral arteries and early onset of the maternal intraplacental circulation. The force of the jet-like spurts of maternal blood damages the developing villi, rupturing anchoring villi, and high levels of oxidative stress cause local villous regression. In many cases the result is spontaneous miscarriage, but less severe damage may result in abnormal placental development, often with excessive villous regression. Reproduced from reference 73, with permission.

were all positively related to placental volume measured at 14 weeks of gestation and the rate of placental growth between 17 and 20 weeks.61 Other less direct measures of placental well-being, such as maternal serum concentrations of pregnancy-associated plasma protein (PAPP)-A, a protease synthesised and secreted by the syncytiotrophoblast, also show positive correlations between first-trimester values and birth weight.62 A pathological finding that links many of the major complications of pregnancy, such as miscarriage, IUGR, pre-eclampsia and premature labour (with or without pre-labour rupture of the membranes), is deficient conversion of the spiral arteries.63–71 This finding underlines the fundamental importance of ensuring an appropriate, progressive and adequate maternal blood supply to the placenta. Deficient conversion is generally associated with reduced trophoblast invasion, though the precise degree and whether this extends to both the interstitial and endovascular populations remains controversial.35,72 This is not surprising considering that most analyses are based on placental bed biopsies. The placental bed encompasses between 100 and 150 spiral arteries, yet only one or two arteries may be present in each biopsy sample. Marked differences in the degree of conversion have been reported across the normal placental bed, between vessels within the same biopsy and even within different segments of the same artery.31,67 The site of sampling, size and subsequent orientation of the biopsy can therefore have powerful influences on the subsequent data. There may also be contrasting pathophysiologies in the various conditions, creating genuinely different histological appearances. Nonetheless, there is general agreement that the myometrial segments of the spiral arteries are the most adversely affected in complications of pregnancy, whereas the decidual segments show varied degrees of conversion. Thus, physiological changes were seen in 100% of decidual segments and 76% of

myometrial segments in normal pregnancies, whereas the respective figures were 44% and 18% in preeclamptic pregnancies.67 There is also evidence of a gradation of severity across the different disorders. In another study, changes were observed in the myometrial segments of the spiral arteries in eight out of ten normal pregnancies, ten of 18 cases of IUGR and none of 15 cases of IUGR associated with pre-eclampsia.63 Trophoblast invasion is particularly shallow in the majority of cases of early pregnancy loss (Fig 30.6).65,66 This finding correlates well with a higher resistance and pulsatility indices in the uterine and spiral arteries and histological evidence of deficient arterial conversion.68 Onset of the maternal blood flow is both premature and disorganised throughout the whole placenta in cases of spontaneous miscarriage,57 most likely due to incomplete or complete absence of plugging of the arteries as in the peripheral regions of the normal organ. The result is overwhelming oxidative stress, and apoptotic and degenerative changes in the placental tissues that undoubtedly contribute to the pregnancy failure.74 Sensitivity of the early placental tissues to oxidative stress may be increased by deficiencies in micronutrients that play key roles as the active subunits in antioxidant enzymes. Thus, lack of selenium, an integral component of glutathione peroxidase, is associated with a higher incidence of both spontaneous and recurrent miscarriage.75,76 Equally, maternal diabetes and certain drugs induce additional oxidative stress, which may tip the balance and contribute to pregnancy failure.73 If the placenta is retained in utero for any length of time in these hyperoxic conditions then the foetal capillaries regress, and the villi become collagenous ghosts identical morphologically to those seen on the chorion laeve. We speculate therefore that abnormally early onset of the maternal circulation in particular areas of the placental bed, where trophoblast invasion has for some reason been restricted, may result in

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Endometrium Trophoblast invasion

Premature blood flow Miscarriage

Incomplete conversion ischaemia/reperfusion injury

Myometrium

Conversion of arteries normal blood flow Placental oxidative stress

PE + IUGR

Successful pregnancy IUGR

excessive villous regression and hence abnormal placental shapes. For example, excessive regression over one quadrant could lead to the insertion of the umbilical cord becoming eccentric. It is notable that such placentae are associated with poor obstetric outcome, in part due to the reduction in surface area but also to deficient conversion of the spiral arteries in the remainder of the bed. These findings led us to propose that miscarriage, IUGR and pre-eclampsia represent a spectrum of conditions dependent upon the degree of compromise of trophoblast invasion (Fig 30.7).77

Regulation of trophoblast invasion Extravillous trophoblast invasion is heavily dependent upon the expression of matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, that degrade basement membranes and extracellular matrix components.78 In normal pregnancies this is closely regulated and is likely to be influenced by many factors, some inherent to the genotype of the cytotrophoblast and others dependent upon the endometrial environment and interactions with the maternal immune cells.79–82 Thus, cytokines present at the maternofoetal interface may have a profound effect. For example, LIF and TGF-β, both of which are secreted by the endometrial glands, exert inhibitory effects on cytotrophoblast invasiveness in vitro.83,84 Equally, certain combinations of HLA-C ligands and KIRs appear to predispose to a higher risk of preeclampsia,85 whereas abnormal numbers of NK cells have been linked to recurrent miscarriage.80 Hormones, such as progesterone, thyroid hormones and glucocorticoids, may also play a role. Of particular interest is the hyperglycosylated form of hCG, hCG-H, which is secreted by the invading trophoblast cells and acts in an autocrine rather than an endocrine fashion. 86 By binding to the luteinising hormone (LH) choriogonadotrophin (CG) receptor hCG-H promotes cell proliferation and inhibits

Fig 30.7 A schematic representation of the relationship between trophoblast invasion, physiological conversion of the spiral arteries and pregnancy outcome. The common complications of pregnancy, such as miscarriage, early-onset pre-eclampsia (PE) and intrauterine growth restriction (IUGR) represent a spectrum of disorders secondary to the deficiency in invasion. Reproduced from reference 77, with permission.

apoptosis in JAR choriocarcinoma cells.87 A more direct effect on cell invasiveness was recently reported by Handschuh et al who found that invasion of an extravillous trophoblast cell line (HIPEC65) through Matrigel was stimulated strongly by conditioned medium from cultures of extravillous cytotrophoblast cells, in which the hyperglycosylated form accounted for 20% of the total hCG present.88 They speculated that the effect may be mediated through the actions of hCG on VEGF, which is known to stimulate secretion and activity of MMP-2 and MMP-9. The same authors also demonstrated that activation of the peroxisome proliferator-activated receptor (PPAR)-γ suppresses transcript levels of both the α and β subunits of hCG, and that this is associated with a reduction in cell invasiveness. It is therefore of great interest that low levels of maternal serum and urinary hCG-H have been reported in pregnancies that end in spontaneous miscarriage, indicating deficient trophoblast function and/or invasion. 89,90 This raises the possibility of developing an early pregnancy test with a high predictive value of a successful outcome. Given the change in intraplacental oxygenation during early pregnancy much attention has been focused on the role that oxygen may play in regulating invasiveness. Measurements taken in the decidua basalis immediately beneath the placenta have revealed that the oxygen tension is always higher than in the placenta, indicating that the trophoblast cells migrate up a concentration gradient.57 Studies in vitro have yielded contrasting data, most probably due to the different trophoblast-like cell lines and oxygen concentrations used.91 Some have shown that culture of trophoblast under the low oxygen concentrations (2–3%) that are physiological for the intervillous space during the first trimester57 stimulates proliferation, whereas higher levels of oxygen promote invasion and are associated with elevated levels of MMP-2.92,93 By contrast, others employing lower concentrations have found that hypoxia stimulates invasion.94 Resolving these conflicting data is

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Early placental development and pregnancy outcome

challenging, given that there are so many potential interactions that can mediate trophoblast invasion in vivo that cannot be taken into consideration in such reductionist systems. A different approach has been to take the rat as an animal model and expose pregnant dams to 11% oxygen between days 6.5 and 13.5 of gestation.95 Such treatment stimulates endovascular trophoblast invasion, and is associated with enlargement of the junctional zone from where the progenitor invasive cells originate. Finally, mention should be made of antiphospholipid syndrome in which again endovascular trophoblast invasion and plugging of the spiral arteries is markedly deficient.96

Conclusion Early placental development is fundamental to a successful pregnancy as it lays the foundations for effective maternofoetal exchange and immune tolerance. The recognition that pregnancy is not a simple continuum but that there are major changes in the way the placenta functions between the first and second trimesters provides an explanation for many complications of pregnancy that are more or less unique to the human. The endometrium plays a far greater role in supporting the early conceptus than previously realised, and glandular secretions may have a profound effect on placental differentiation. Equally, onset of the maternal arterial circulation to the placenta poses a major challenge, and well-regulated trophoblast invasion is required to ensure that this is correctly co-ordinated. Interactions between the invading extravillous trophoblast and the endometrium are of key importance, and further research needs to be focused in this area.

References 1. Wooding FBP, Flint APF. Placentation. In: Lamming GE, ed. Marshall’s Physiology of Reproduction, 4th edn. London: Chapman & Hall, 1994: 233–460. 2. Jauniaux E, Poston L, Burton GJ. Placental-related diseases of pregnancy: involvement of oxidative stress and implications in human evolution. Hum Reprod Update 2006; 12: 747–55. 3. Hertig AT, Rock J, Adams EC. A description of 34 human ova within the first 17 days of development. Am J Anat 1956; 98: 435–94. 4. Lindenberg S, Hyttel P, SjØgren A et al. A comparative study of attachment of human, bovine and mouse blastocysts to uterine epithelial monolayer. Hum Reprod 1989; 4: 446–56. 5. Hamilton WJ, Gladstone RJ. A presomite human embryo (Shaw): the implantation. J Anat 1942; 76: 187–203. 6. Burton GJ, Jauniaux E, Watson AL. Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy; the Boyd Collection revisited. Am J Obstet Gynecol 1999; 181: 718–24.

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7. Castellucci M, Kaufmann P. A three-dimensional study of the normal human placental villous core: II. Stromal architecture. Placenta 1982; 3: 269–86. 8. Jackson MR, Mayhew TM, Boyd PA. Quantitative description of the elaboration and maturation of villi from 10 weeks of gestation to term. Placenta 1992; 13: 357–70. 9. Potgens AJ, Schmitz U, Bose P et al. Mechanisms of syncytial fusion: a review. Placenta 2002; 23(Suppl A): S107–13. 10. Demir R, Kaufmann P, Castellucci M et al. Fetal vasculogenesis and angiogenesis in human placental villi. Acta Anat 1989; 136: 190–203. 11. Charnock-Jones DS, Burton GJ. Placental vascular morphogenesis. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14: 953–68. 12. Jauniaux E, Jurkovic D, Campbell S. In vivo investigations of anatomy and physiology of early human placental circulations. Ultrasound Obstet Gynecol 1991; 1: 435–45. 13. Corner GW. A well-preserved human embryo of 10 somites. Contrib Embryol 1929; 20: 81–102. 14. Jauniaux E, Gulbis B. Fluid compartments of the embryonic environment. Hum Reprod Update 2000; 6: 268–78. 15. Jauniaux E, Cindrova-Davies T, Johns J et al. Distribution and transfer pathways of antioxidant molecules inside the first trimester human gestational sac. J Clin Endocrinol Metab 2004; 89: 1452–9. 16. Jauniaux E, Johns J, Gulbis B et al. Transfer of folic acid inside the first-trimester gestational sac and the effect of maternal smoking. Am J Obstet Gynecol 2007; 197: 58 e1–6. 17. Basir GS, O WS, So WW et al. Evaluation of cycle-tocycle variation of endometrial responsiveness using transvaginal sonography in women undergoing assisted reproduction. Ultrasound Obstet Gynaecol 2002; 19: 484–9. 18. Boyd JD, Hamilton WJ. The Human Placenta. Cambridge: Heffer and Sons, 1970. 19. Burton GJ, Watson AL, Hempstock J et al. Uterine glands provide histiotrophic nutrition for the human fetus during the first trimester of pregnancy. J Clin Endocrinol Metab 2002; 87: 2954–9. 20. Gray CA, Taylor KM, Ramsey WS et al. Endometrial glands are required for preimplantation conceptus elongation and survival. Biol Reprod 2001; 64: 1608–13. 21. Hempstock J, Cindrova-Davies T, Jauniaux E et al. Endometrial glands as a source of nutrients, growth factors and cytokines during the first trimester of human pregnancy; a morphological and immunohistochemical study. Reprod Biol Endocrinol 2004; 2: 58. 22. Beckman DA, Brent RL, Lloyd JB. Sources of amino acids for protein synthesis during early organogenesis in the rat. 4. Mechanisms before envelopment of the embryo by the yolk sac. Placenta 1996; 17: 635–41. 23. Burton GJ, Jauniaux E, Charnock-Jones DS. Human early placental development: potential roles of the endometrial glands. Placenta 2007; 28(Suppl A): S64–9. 24. Ladines-Llave CA, Maruo T, Manalo AS et al. Cytologic localization of epidermal growth factor and its receptor in developing human placenta varies over the course of pregnancy. Am J Obstet Gynecol 1991; 165: 1377–82.

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25. Maruo T, Matsuo H, Murata K et al. Gestational agedependent dual action of epidermal growth factor on human placenta early in gestation. J Clin Endocrinol Metab 1992; 75: 1362–7. 26. Spencer TE, Johnson GA, Burghardt RC et al. Progesterone and placental hormone actions on the uterus: insights from domestic animals. Biol Reprod 2004; 71: 2–10. 27. Hey NA, Li TC, Devine PL et al. MUC1 in secretory phase endometrium: expression in precisely dated biopsies and flushings from normal and recurrent miscarriage patients. Hum Reprod 1995; 10: 2655–62. 28. Dalton CF, Laird SM, Estdale SE et al. Endometrial protein PP14 and CA-125 in recurrent miscarriage patients; correlation with pregnancy outcome. Hum Reprod 1998; 13: 3197–202. 29. Jeschke U, Kunert-Keil C, Mylonas I et al. Expression of glycodelin A in decidual tissue of preeclamptic, HELLP and intrauterine growth-restricted pregnancies. Virchows Arch 2005; 446: 360–8. 30. Bartelmez GW. The form and functions of the uterine blood vessels in the rhesus monkey. Contrib Embryol 1957; 36: 153–82. 31. Pijnenborg R, Bland JM, Robertson WB et al. The pattern of interstitial trophoblastic invasion of the myometrium in early human pregnancy. Placenta 1981; 2: 303–16. 32. Al-Lamki RS, Skepper JN, Burton GJ. Are human placental bed giant cells merely aggregates of small mononuclear trophoblast cells? An ultrastructural and immunocytochemical study. Hum Reprod 1999; 14: 496–504. 33. Kam EPY, Gardner L, Loke YW et al. The role of trophoblast in the physiological change in decidual spiral arteries. Hum Reprod 1999; 14: 2131–8. 34. Lyall F. Priming and remodelling of human placental bed spiral arteries during pregnancy – a review. Placenta 2005; 26(Suppl A): S31–6. 35. Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: facts and controversies. Placenta 2006; 27: 939–58. 36. Pijnenborg R, Bland JM, Robertson WB et al. Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy. Placenta 1983; 4: 397–413. 37. Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat Rev Immunol 2006; 6: 584–94. 38. Hanna J, Goldman-Wohl D, Hamani Y et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12: 1065–74. 39. Ashkar AA, Di Santo JP, Croy BA. Interferon gamma contributes to initiation of uterine vascular modification, decidual integrity, and uterine natural killer cell maturation during normal murine pregnancy. J Exp Med 2000; 19: 259–70. 40. Harris JWS, Ramsey EM. The morphology of human uteroplacental vasculature. Contrib Embryol 1966; 38: 43–58. 41. Jauniaux E, Nicolaides KH. Placental lakes, absent umbilical artery diastolic flow and poor fetal growth in early pregnancy. Ultrasound Obstet Gynecol 1996; 7: 141–4.

42. Toal M, Chan C, Fallah S et al. Usefulness of a placental profile in high-risk pregnancies. Am J Obstet Gynecol 2007; 196: 363 e1–7. 43. Moll W, Künzel W, Herberger J. Hemodynamic implications of hemochorial placentation. Eur J Obstet, Gynecol Reprod Biol 1975; 5: 67–74. 44. Karimu AL, Burton GJ. The effects of maternal vascular pressure on the dimensions of the placental capillaries. Br J Obstet Gynaecol 1994; 101: 57–63. 45. Ramsey EM, Donner MW. Placental Vasculature and Circulation. Anatomy, Physiology, Radiology, Clinical Aspects, Atlas and Textbook. Stuttgart: Georg Thieme, 1980. 46. Brosens JJ, Pijnenborg R, Brosens IA. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies. Am J Obstet Gynecol 2002; 187: 1416–23. 47. Borell U, Fernström I, Ohlson L et al. Influence of uterine contractions on the uteroplacental blood flow at term. Am J Obstet Gynecol 1965; 93: 44–57. 48. Bartelmez GW. Histological studies on the menstruating mucous membrane of the human uterus. Contrib Embryol 1933; 24: 141–86. 49. Matijevic R, Meekins JW, Walkinshaw SA et al. Spiral artery blood flow in the central and peripheral areas of the placental bed in the second trimester. Obstet Gynecol 1995; 86: 289–92. 50. Matijevic R, Johnston T. In vivo assessment of failed trophoblastic invasion of the spiral arteries in preeclampsia. Br J Obstet Gynaecol 1999; 106: 78–82. 51. Prefumo F, Sebire NJ, Thilaganathan B. Decreased endovascular trophoblast invasion in first trimester pregnancies with high-resistance uterine artery Doppler indices. Hum Reprod 2004; 19: 206–9. 52. Hamilton WJ, Boyd JD. Development of the human placenta in the first three months of gestation. J Anat 1960; 94: 297–328. 53. Hustin J, Schaaps JP, Lambotte R. Anatomical studies of the utero-placental vascularisation in the first trimester of pregnancy. Troph Res 1988; 3: 49–60. 54. Schaaps JP, Hustin J. In vivo aspect of the maternaltrophoblastic border during the first trimester of gestation. Troph Res 1988; 3: 39–48. 55. Jauniaux E, Hempstock J, Greenwold N et al. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental blood flow in normal and abnormal early pregnancies. Am J Pathol 2003; 162: 115–25. 56. Rodesch F, Simon P, Donner C et al. Oxygen measurements in endometrial and trophoblastic tissues during early pregnancy. Obstet Gynecol 1992; 80: 283–5. 57. Jauniaux E, Watson AL, Hempstock J et al. Onset of maternal arterial bloodflow and placental oxidative stress; a possible factor in human early pregnancy failure. Am J Pathol 2000; 157: 2111–22. 58. Watson AL, Skepper JN, Jauniaux E et al. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab 1998; 83: 1697–705. 59. Palmer ME, Watson AL, Burton GJ. Morphological analysis of degeneration and regeneration of syncytiotrophoblast in first trimester villi during organ culture. Hum Reprod 1997; 12: 379–82.

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Early placental development and pregnancy outcome 60. Hafner E, Metzenbauer M, Hofinger D et al. Placental growth from the first to the second trimester of pregnancy in SGA-foetuses and pre-eclamptic pregnancies compared to normal foetuses. Placenta 2003; 24: 336–42. 61. Thame M, Osmond C, Bennett F et al. Foetal growth is directly related to maternal anthropometry and placental volume. Eur J Clin Nutr 2004; 58: 894–900. 62. Smith GC, Stenhouse EJ, Crossley JA et al. Earlypregnancy origins of low birth weight. Nature 2002; 417: 916. 63. Brosens I, Dixon HG, Robertson WB. Fetal growth retardation and the arteries of the placental bed. Br J Obstet Gynaecol 1977; 84: 656–63. 64. Gerretsen G, Huisjes HJ, Elema JD. Morphological changes of the spiral arteries in the placental bed in relation to pre-eclampsia and fetal growth retardation. Br J Obstet Gynaecol 1981; 88: 876–81. 65. Khong TY, Liddell HS, Robertson WB. Defective haemochorial placentation as a cause of miscarriage. A preliminary study. Br J Obstet Gynaecol 1987; 94: 649–55. 66. Hustin J, Jauniaux E, Schaaps JP. Histological study of the materno-embryonic interface in spontaneous abortion. Placenta 1990; 11: 477–86. 67. Meekins JW, Pijnenborg R, Hanssens M et al. A study of placental bed spiral arteries and trophoblast invasion in normal and severe pre-eclamptic pregnancies. Br J Obstet Gynaecol 1994; 101: 669–74. 68. Jauniaux E, Zaidi J, Jurkovic D et al. Comparison of colour Doppler features and pathologic findings in complicated early pregnancy. Hum Reprod 1994; 9: 243–7. 69. Kim YM, Chaiworapongsa T, Gomez R et al. Failure of the physiologic transformation of the spiral arteries in the placental bed in preterm premature rupture of membranes. Am J Obstet Gynecol 2002; 187: 1137–42. 70. Kim YM, Bujold E, Chaiworapongsa T et al. Failure of physiologic transformation of the spiral arteries in patients with preterm labor and intact membranes. Am J Obstet Gynecol 2003; 189: 1063–9. 71. Ball E, Bulmer JN, Ayis S et al. Late sporadic miscarriage is associated with abnormalities in spiral artery transformation and trophoblast invasion. J Pathol 2006; 208: 535–42. 72. Lyall F. The human placental bed revisited. Placenta 2002; 23: 555–62. 73. Johns J, Jauniaux E, Burton G. Factors affecting the early embryonic environment. Rev Gynaecol Perinat Pract 2006; 6: 199–210. 74. Hempstock J, Jauniaux E, Greenwold N et al. The contribution of placental oxidative stress to early pregnancy failure. Hum Pathol 2003; 34: 1265–75. 75. Barrington JW, Lindsay P, James D et al. Selenium deficiency and miscarriage: a possible link? Br J Obstet Gynaecol 1996; 103: 130–2. 76. Al-Kunani AS, Knight R, Haswell SJ et al. The selenium status of women with a history of recurrent miscarriage. Br J Obstet Gynaecol 2001; 108: 1094–7. 77. Burton GJ, Jauniaux E. Placental oxidative stress; from miscarriage to preeclampsia. J Soc Gynecol Invest 2004; 11: 342–52. 78. Cohen M, Meisser A, Bischof P. Metalloproteinases and human placental invasiveness. Placenta 2006; 27: 783–93.

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79. Goldman-Wohl D, Yagel S. Regulation of trophoblast invasion: from normal implantation to pre-eclampsia. Mol Cell Endocrinol 2002; 187: 233–8. 80. Anin SA, Vince G, Quenby S. Trophoblast invasion. Hum Fertil 2004; 7: 169–74. 81. Lyall F. Mechanisms regulating cytotrophoblast invasion in normal pregnancy and pre-eclampsia. Aust N Z J Obstet Gynaecol 2006; 46: 266–73. 82. Cohen M, Bischof P. Factors regulating trophoblast invasion. Gynecol Obstet Invest 2007; 64: 126–30. 83. Graham CH, Lala PK. Mechanism of control of trophoblast invasion in situ. J Cell Physiol 1991; 148: 228–34. 84. Bischof P, Haenggeli L, Campana A. Effect of leukemia inhibitory factor on human cytotrophoblast differentiation along the invasive pathway. Am J Reprod Immunol 1995; 34: 225–30. 85. Hiby SE, Walker JJ, O’Shaughnessy K M et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200: 957–65. 86. Cole LA. Hyperglycosylated hCG. Placenta 2007; 28: 977–86. 87. Hamada AL, Nakabayashi K, Sato A et al. Transfection of antisense chorionic gonadotropin beta gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis. J Clin Endocrinol Metab 2005; 90: 4873–9. 88. Handschuh K, Guibourdenche J, Tsatsaris V et al. Human chorionic gonadotropin produced by the invasive trophoblast but not the villous trophoblast promotes cell invasion and is down-regulated by peroxisome proliferator-activated receptor-gamma. Endocrinology 2007; 148: 5011–9. 89. Kovalevskaya G, Birken S, Kakuma T et al. Differential expression of human chorionic gonadotropin (hCG) glycosylation isoforms in failing and continuing pregnancies: preliminary characterization of the hyperglycosylated hCG epitope. J Endocrinol 2002; 172: 497–506. 90. Sutton-Riley JM, Khanlian SA, Byrn FW et al. A single serum test for measuring early pregnancy outcome with high predictive value. Clin Biochem 2006; 39: 682–7. 91. James JL, Stone PR, Chamley LW. The regulation of trophoblast differentiation by oxygen in the first trimester of pregnancy. Hum Reprod Update 2006; 12: 137–44. 92. Genbacev O, Zhou Y, Ludlow JW et al. Regulation of human placental development by oxygen tension. Science 1997; 277: 1669–72. 93. Caniggia I, Winter J, Lye SJ et al. Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta 2000; 21(Suppl A): S25–30. 94. Graham CH, Postovit LM, Park H et al. Adriana and Luisa Castellucci Award Lecture 1999: role of oxygen in the regulation of trophoblast gene expression and invasion. Placenta 2000; 21: 443–50. 95. Rosario GX, Konno T, Soares MJ. Maternal hypoxia activates endovascular trophoblast cell invasion. Dev Biol 2007; 314: 362–75. 96. Sebire NJ, Fox H, Backos M et al. Defective endovascular trophoblast invasion in primary antiphospholipid antibody syndrome-associated early pregnancy failure. Hum Reprod 2002; 17: 1067–71.

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31 The immunology of early pregnancy Sicco Scherjon

Introduction From the early 1950s onward, immunological interest has been dedicated to maternal tolerance to the allogeneic foetus.1–3 Initially the uterus was considered primarily as an “immunoprivileged site” (as are the brain, the testis and the anterior chamber of the eye), where no interaction with the maternal immune cells could take place.4 Nowadays interest is concentrated more specificly on the local intermingling of foetal and trophoblast derived cells and maternal decidual cells at the uterine wall.5 Pregnancy is increasingly considered to occur in the setting of antigen-specific responses, that upregulate cellular circuits, inducing a state of maternal tolerance to the semi-allogeneic foetus. This process of downregulation of the immune response is reversible and occurs only during pregnancy as has been shown in mice, where implanted tumour cells, carrying a paternal alloantigen, were rejected directly after delivery.6 This special state of “immunoprivilege” or “induced tolerance” is a relative state, as immune responses cannot and should not be prevented completely. Around 10–30% of the pregnant women already produce antibodies against paternal inherited human leucocyte antigens (HLA) of the foetus during pregnancy; a sensitisation which can persist for more than 10 years.7,8 Medawar suggested, in the early 1950s, that these foetally expressed antigens might be involved in a “tolerating process” in the mother.2 It is now well established that chimerism, the process of foetal cells, expressing transplantation antigens, trafficking into the mother9 (and also maternal cells circulating in the foetus10) is a physiologically occurring process in human pregnancy and that this process contributes to foetus-specific T- and B-cell responses.11,12

Genetics It is now accepted that an adequate immune response via maternal recognition is important for the normal development of human pregnancy. Both maternal and paternal antigens are expressed by the human foetus and by invasive trophoblast. Inadequate recognition is associated with pregnancy complications, while

histoincompatibility (inheriting differing paternal major histocompatibility complex (MHC) antigens from those of the mother) of the foetus, making maternal recognition possible, may indeed be a beneficial, selective advantage.13,14 Antigens are seen by antigen presenting cells (APCs) and are therefore important for the immune response. Antigens, so-called epitopes, are first internalised by the APCs and then digested, after which they are presented via class I or class II proteins for T-cell recognition. In this way foetal and trophoblast derived proteins, can be presented specifically via APC MHC class II molecules (especially HLADR) for recognition to CD4+ T-lymphocytes.15 It is of interest that in recurrent spontaneous abortion (RSA) patients, HLA compatibility with the partner, especially of the HLA-DR and HLA-DQ antigen system, is more prevalent.16–18 Matching at the HLA-C locus is reported to be associated with an increased risk for miscarriage.17 It appears also that in humans, pre-conceptional partner choice, from the perspective of HLA sharing is not random and that HLA genes have a possible role in partner choice. The mechanism of selection most probably works via the olfactory system, whereby women can discriminate even the difference in one allele:19 body odours are recognised as pleasant if they are from individuals with few matching HLA alleles.20 This mechanism results in a reduction in the expected frequency of HLA homozygous offspring and so will have a beneficial effect on pregnancy outcome.17 In humans it has been shown that a small intermediate number of MHC matches is preferred over zero matches or an identical MHC match.19 Inadequate immunological interactions, because of too much sharing of HLA (paternally derived) antigens results in a depressed immune response and this is associated with RSA. An increased RSA risk is found particularly in couples sharing on the HLA-DR locus.16 A point of consideration remains, however, that HLA genes, which are inherited in a possibly homozygous pattern, could be linked to other (recessive lethal) genes, a process (linkage disequilibrium) which could also be responsible for raised susceptibility for RSA. Also, in preeclampsia a genetic predisposition is evident, based both on epidemiological findings21 and on genetic

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Fig 31.1

Expression of HLA-G by villous and extravillous trophoblast. HLA-G5 and HLA-G6 are soluble isoforms.

findings such as HLA-DR4 sharing being higher in couples with pre-eclampsia.22,23 Of interest is that heterozygosity for the cytotoxic T-lymphocyte antigen (CTLA)-4 A49G allele, which is located on the chromosome 2 (a candidate susceptibility chromosome for preeclampsia) is increased in pre-eclampsia patients.24

Trophoblast and human leucocyte antigen expression Extravillous trophoblast which is invading the maternal decidua does not express the classical MHC transplantation class I and class II antigens, but expresses non-classical HLA class 1b genes, especially HLA-G. In humans, villous trophoblast does not express MHC molecules. Besides HLA-G, trophoblast also expresses the classical (and far less polymorphic) HLA-C antigen and two other non-classical HLAs: HLA-E and HLA-F (Fig 31.1). These antigens are specific ligands for uterine natural killer (NK) cells.

on the amino acid at position 80 of the α1 domain, as HLA-C1asn80 or HLA-C2lys80, which both can bind to activating (B haplotype, variable number of activating KIRs) or inhibiting (A haplotype) KIRs. 25 Both the variance in HLA pattern and in KIRs modulates the function of NK cells, via a balance of inhibiting and activating receptors; a precise regulation mechanism needed for a successful pregnancy. HLA-C2 has a more inhibiting effect than HLA-C1, which makes the maternal KIR genotype less important if the foetus has at least one HLA-C1 allele. The relationship between KIR expression on NK cells and the paternally derived HLA-C genotype expressed by the foetus shows an important regulatory possibility for invasive throphoblast growth. 26 The highest preeclampsia incidence is found when the KIR phenotype is AA and the HLA-C group in the foetus contains C2; an interaction whereby NK cells are strongly inhibited (Fig 31.2).26

Human leucocyte antigen G Human leucocyte antigen C It is of interest that HLA-C expression of paternal genes on extravillous trophoblast can be recognised by both maternal T-cells and NK cells. Killer immunoglobulin-like receptors (KIRs), KIR2DL2, KIR2DL3 and KIR2DL1, can bind the different HLA-C allotypes. Also, these KIRs have extreme genomic variation, so that both ligand (HLA-C in the foetus) and receptor (KIR in the mother) have a broad polymorphism. HLA-C is known to exist in two subtypes, depending

HLA-G, which has a restricted tissue expression, but is particularly abundantly expressed on trophoblast, is relatively monomorphic, so that trophoblast is seen by the mother as a “self” or “neutral” MHC, preventing an expected innate cytotoxic rejection response by allospecific T-cells and NK cells. The expression of HLA-G is restricted to a few normal tissues. Besides its expression in the placenta, it is also found in the thymus and prostate; however, tumours can also express HLA-G.27 There are, via alternative splicing,

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The immunology of early pregnancy MOTHER’S KIR

from the father and from the mother with environmental factors will explain some of the associated risk factors.

BABY HLA-C C1 C1

C1 C2

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C2 C2

A A

–

A B

–

–

–

B B

–

–

–

Fig 31.2 Certain HLA-C genotype and killer cell inhibitory receptor (KIR) genotype combinations have an increased risk (↑) of pre-eclampsia. Data derived from Reference 25.

seven distinct mRNAs encoding both the four membrane bound HLA-Gs (HLA-G1, -G2, -G3 and -G4) and the three soluble isoforms (sHLA-G5, -G6 and -G7). All these HLA-Gs are demonstrated in humans.28 Extravillous trophoblast and the chorionic membrane express all HLA-Gs; villous tissue only expresses the soluble HLA-G5 isoform (Fig 31.1).27 HLA-G interacts with leucocyte immunoglobulin-like receptor (LIR) B1 immunoglobulin-like transcript (ILT)-2 = LIR1 = CD85j), LIR B2 (ILT-4 = LIR2 = CD85d) and KIR2DL4 expressed on immunocompetent cells (Tcells, and possibly B-cells, NK cells and antigen presenting cells) as an inhibitory ligand,5,27,29–31 suppressing the immune response at the foetomaternal interface.27 Activation of the KIR2DL4 has been shown to induce interferon (IFN)-γ production and prevent cytotoxicity in resting NK cells, whereby a higher expression of this receptor was found in patients with normal pregnancies compared with those with RSA.5 HLA-G can suppress CD8+ cytotoxicity of activated T-cells and NK cells via the Fas/FasL apoptosis pathway.32,33 Via the interaction with HLAE, HLA-G can interact with the CD94/ NKG2A receptor on uterine NK (uNK) cells.27 Inter-action in vitro between soluble HLA-G and both decidual and peripheral leucocytes, possibly interacting with CD160, showed that soluble HLA-G is able to prevent leucocyte proliferation by selective inhibition of CD4+ T-cells34 and CD8+ T-cells. Plasmatic HLA-G, which is also produced by maternal APCs, reaches its peak levels during the third trimester,35 and stimulates macrophages to produce the immunosuppressive cytokine transforming growth factor (TGF)-β1, but not IL-10.27 Attenuated expression of placental HLA-G is reported and lower maternal levels of sHLA-G were found in pre-eclampsia,36,37 whereas HLA-G genotype is related to birth weight and to placental weight.38 It is unlikely that one single gene or a combination of genes is determinative for the development of pre-eclampsia; most probably a combination of certain genes coming

From the endometrium to the decidua Human (haemochorial) placentation is characterised by an extensive invasion of trophoblast cells into the myometrium: for this invasive process decidualisation of the endometrium is a prerequisite. This invasive process is essential for both the development of the anchoring villi and the structural modification of the maternal spiral arteries. Decidualisation is the process whereby the fibroblast-like endometrial cells proliferate and differentiate into polyploid decidual cells; a process which has already occurred before implantation, probably under the influence of progesterone, and for which no actual conceptus is needed.39,40 There are important changes, as have been shown in immunohistochemistry studies, in the number of immune cells during the menstrual cycle.41,42 Methods have been developed for the isolation and characterisation by flow cytometry of leucocyte (sub)populations derived from decidual tissues.43–45 Most isolation protocols now rely on enzymatic digestion in combination with a Percoll centrifugation step, as solely mechanical isolation results in a high percentage of non-viable cells and also possibly activation artefacts in the isolated cells.46 Using flow activated cell sorting (FACS) it was shown that during the menstrual cycle human NK cells can be found in the non-pregnant endometrium.47 Cell types contributing to the endometrial lymphocyte population show an increase in cell number, especially in the secretory phase, whereby the percentage of specific cell types, such as NK cells in the endometrium (eNK cells), remains constant at around 30%.48 In the peripheral blood two subpopulations of NK cells can be demonstrated. The majority, around 90%, have the CD56dimCD16+ phenotype, while the other subclass has the CD56brightCD16− phenotype. Both types develop in the bone marrow, although it has been suggested that they also can develop in other locations such as the lymph nodes.49 The CD56dim subclass is especially cytotoxic for tumour cells and cells infected by viruses; both cell types are able to secrete cytokines, whereby the CD56bright cells are an important source for immunomodulatory cytokines.50 Besides phenotypic differences, NK cell types can also be distinguished on the basis of expression of certain adhesion molecules, chemokine receptors and NK receptors. As CD56bright NK cells have a more immunomodulatory function and are not cytotoxic, they have important roles during both the secretory phase of the endometrium (eNK cells) and in early pregnancy (uterine) decidua (uNK cells).51 eNK cells have a specific phenotype, such as the expression of CD9, which makes them different from the CD56dim and the CD56bright as they are found in peripheral blood. They can produce both type 1 and type 2 cytokines as IFN-γ and interleukin (IL)-10, respectively.50

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Cell types present in the decidua Natural killer cells uNK cells are found in relatively high numbers in the human decidua in close proximity to trophoblast cells and have important functions in trophoblast migration. The majority of these uNK cells have the CD56brightCD16− phenotype. uNK cells express KIRs, being the receptors for the polymorphic HLA class I molecules.52 These KIRs form the basis for the maternal recognition of HLA-C, which is expressed on trophoblast. The variation in the expression of certain KIRs on uNK cells (density and percentage of cells expressing the receptor), differs according to the individual and is different from that of peripheral NK cells. Chemokine receptors are needed for migration, for instance CD56bright uNK cells express CXCL12 for migration to the deciduas.53 The expression of CXCL12 and its receptor CRCX4 is demonstrated in an in vitro trophoblast/decidua model. uNK cells, having the CD56bright CD16-phenotype, are the most abundant decidual lymphocytes in early pregnancy, accounting for up to 70% of decidual lymphocytes. Although this percentage decreases with gestational age, uNK cells are still present at term.121 Many of the uNK cells are positive for the activation markers CD69 and HLADR.54–57 It is suggested that uNK cells originate from the blood and that they undergo local differentiation and in situ proliferation to CD56bright CD16− cells.58 However, it may also be that already differentiated peripheral blood CD56bright CD16− cells are specifically guided to the decidua under the influence of CXCL12, which is expressed by extravillous trophoblast.59 It is also possible that they differentiate and proliferate from haematopoietic stem cells that dwell in the decidua. uNK cells contain large granules (containing perforin and granzyme) and express CD95/NKG92 and, similar to eNK cells, also express KIRs and ILT receptors.60,61 The presence of these potentially cytolytic molecules shows that the cells have effector functions in normal pregnancy. It is of interest that IL15, which can be produced by macrophages, induces a proliferative response in uNK cells (a response which is augmented by the addition of stem cell factor (SCF)) and a cytolytic activity against certain cell lines (e.g. K652) but no cytolytic activity was found against normal trophoblast.62 This specific effect of IL-15 on uNK cells might be related to the progesterone dominated milieu during gestation. The KIRs and C-type leptin heterodimer family (CD95/NKGs) both have activating and inhibiting receptors, dependent on their cytoplasmic domains. Most of these NK cell receptors have as their specific ligands the only HLA molecules expressed on extravillous trophoblast: HLA-C, HLA-E and HLA-G.63 However, uNK cells are, compared with peripheral blood NK cells, a unique cell population, as shown by gene expression profiles.64 Of importance is their overexpression of KIR2DL4, granzyme A and the C-type leptin-like activating receptors, NKG2C and NKG2E, needed for their specific function in decidual

tissue.5 During pregnancy and depending on from where they are isolated (peripheral blood or the foetomaternal interface) the cytokine profile of NK cells changes substantially. Depending on the cytokines produced, NK cells can be differentiated into NK1/NK2/NK3 and NKr1 (Fig 31.3). In normal early pregnancy NK3 cells, with a regulatory phenotype such as production of TGF-β, are noticeably present.66,67 Decidual NK cells produce also angiogenic growth factors such as vascular endothelial growth factor (VEGF), placental growth factor (PlGF), transforming growth factor (TGF)-β, angiopoeitin (Ang)1 and Ang2.59

Macrophages The essential role of macrophages is the phagocytosis of microorganisms and malignant cells as well as cellular debris, and the presentation of proteins to T-cells. They also have an important role in tissue remodelling and angiogenesis. They originate from monocytes, enter tissue under the influence of certain chemokines or cytokines such as monocyte chemoattractant protein (MCP)-1 and under the influence of colony stimulating factor (CSF)-1 they differentiate to macrophages.68 Activated macrophages, which upregulate the B7 costimulator molecules, produce inflammatory cytokines such as IL-1, IL-12 and tumour necrosis factor (TNF)-α. The B7 proteins are a family of immunomodulatory proteins which interact with the lymphocyte co-stimulatory receptor CD28 and the inhibitory receptor CTLA-4 (Fig 31.4). Human decidual macrophages are HLA class I positive and HLA-DR+ 70,71 and make up around 35% of the decidual leucocytes around implantation. Their number is stable during pregnancy.71 Macrophages interact functionally with trophoblast cells, where important functions can be recognised such as phagocytosis of trophoblast debris and, via HLA-G/ILT-2 and ILT-4 interaction between trophoblast and macrophages, they can also be seen as anti-inflammatory, more tolerogenic cells.72 The expression of stabilin-1 and coagulation factors XIIIa on the macrophages surface indicates that they are polarised (in the presence of IL-10 and IL-13) in a T helper (Th)2 fashion. There are relatively few markers which really make the distinction between macrophages and dendritic cells (see below). Of interest is that macrophages might interact very closely with dendritic cells possibly linking innate and adaptive immunity.

Dendritic cells Dendritic cells are well known as APCs having a promoting effect on T-cell responses; however, they might also induce suppression of T-cell response resulting in local tolerance, depending on the local circumstances. Dendritic cells might react to tolerogenic signals, of which the most important are IL-10 and TGF-β. Furthermore, in a more antigen-specific, adaptive way, dendritic cells might, in a cytotoxic T-lymphocyte

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IL−2, IFN−γ, TNF−β Immunoregulation Th1

Cellular immunity TGF−β+++, IL−10+

CD4+ Th2

Humoral immunity

Th3

IL−4, IL−5, IL−6, IL−13 Tr1

IL−2, IFN–γ, TNF–β Tc1

Cellular immunity

Tc2

Humoral immunity

IL−10+++, TGF−β+

CD4+CD25+ IL−10+, TGF−β+

CD8+

IL−4, IL−5, IL−6, IL−13

NK

NK1

IFN-γ, TNF-β

NK2

IL−4, IL−5, IL−6, IL−13

NK3

TGF-β

NKr1

IL−10

NK reg

TGF-β

Fig 31.3 CD4/CD8 cells and the Th1/Th2 paradigm. IL, interleukin; IFN, interferon; TNF, tumour necrosis factor; TGF, transforming growth factor; NK, natural killer cell Tr1; Tc. Reproduced from reference 65, with kind permission of Springer Science & Business.

antigen CTLA-4 dependent manner, interact with regulatory T-cells (Fig 31.4).73 The function of dendritic cells is partly related to their state of maturation, whereby immature dendritic cells having a low expression of MHC and co-stimulatory molecules, but a very efficient antigen uptake, might be essential in the induction of peripheral tolerance.72 In the human decidua both mature dendritic cells (CD83+) and immature dendritic cells (dendritic cell specific intercellular adhesion molecule (ICAM)-3 grabbing non-integrin DCSICTN+; CD209) and intermediate dendritic cells (DEC205+) can be found.74,75 Immature dendritic cells have absorptive receptors like DEC20575 and macrophage mannose receptor (CD206) which make them efficient in antigen uptake and thereafter for MHC class I and II presentation. During this process of maturation, mature dendritic cells upregulate class I and II MHC molecules (presenting proteins) on their surface and express co-stimulatory molecules such as CD40, CD80, CD83 and CD86, which leads to a specific and powerful T-cell activation.76,77 In the absence of CD40, there is no maturation of dendritic cells and immature dendritic cells can induce CD8+ regulatory T-cells and regulatory CD4+ T-cells, e.g. the CD4+CD25+ regulatory

T-cells,78 which are present but only at very low levels in the human endometrium.79 Also, the expression of indoleamine 2,3-dioxygenase by dendritic cells (and other cells as monocyte-derived macrophages and extravillous trophoblast80) at the human maternal interface results in inhibition of T-cell proliferation. Catabolism of the essential amino acid tryptophan promotes tolerance.81,82 It might not be the tryptophan depletion, but the increase of its metabolites, such as 3OH-kynurenine, that inhibits T-cell proliferation.69 In the human decidua a small proportion (1.7%) of the leucocyte fraction are decidual dendritic cells. They are negative for the haematopoietic lineage markers, but do express HLA-DRbright and CD11c, a marker for myeloid dendritic cells.75

T-cells Direct (foreign antigens are directly engaged by T-cells) and indirect antigen recognition (antigens are presented and recognised by T-cells via APCs) have not been well studied during pregnancy. In a mouse experimental model adoptively transferring CD4+ (indirect) and CD8+ (direct) T-cells gave strong evidence

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Immunoregulation by the up-regulation of IDO lr APC through LTLA-4/B7 pathway

mTGF-1β LAG-3 Galactin-1

Immunoregulation by cell to cell interaction

B7 CTLA−4 APC B7 CD28

Treg MHC-II Treg

TCR

Treg Lysosomic CTLA–4

TGF-β Treg IL-10

Immunoregulation by secretion of immuno regulatory cytokines

Stimulation

Fig 31.4 B7 interaction with CD28 and CTLA-4 on (regulatory) T cells. APC, antigen presenting cells; Treg, regulatory T-cell, regulatory T-cell IFN, interferon; TGF, transforming growth factor; IL, inter leukin. Reproduced from reference 69, with permission.

that foetal/placental antigen presentation and recognition of foetal antigens is exclusively by indirect recognition.83 The lack of direct recognition of foetal antigens is beneficial as this removes a direct threat to foetal survival. However, it is also not surprising because the placenta has no MHC class II expression, making the direct antigen presentation via CD4+cells impossible. T-cells can be classified by the cytokines they produce as Th1 cells, involved in cellular immunity and Th2 cells, involved in humoral immunity. Wegmann et al were the first to suggest that in normal pregnant mice, pregnancy is characterised by a dominance of the Th2 over the Th1 type immune response.84 This was later confirmed in humans,85 in endometrium samples taken peri-implantation,86 although locally no Th2 dominance could be demonstrated in term decidual samples acquired before or after labour.31 Using lymphocyte function markers in unstimulated peripheral blood samples, no change in pre-eclampsia patients in the Th1/Th2 ratio could be demonstrated, although there was an increase in Th2 cells in normal pregnancies. However, changes in the NK1/NK2 ratio were found, suggesting that it is not the changes in the adaptive immune system that are important, but rather changes in the innate system are more relevant.87 The regulation is more complex, especially in the human, where also Th3 (which produce TGF-β) and Tr1 cells (which produce IL-10) play an important role. Particular circumstances (suboptimal antigen presentation and a specific hormonal milieu, e.g. high progesterone levels88) might induce the development of adaptive Th3 and Tr1 cells66 and naturally arising regulatory T-cells (CD4+CD25+),89,90 which have a key role in local immune regulation. An important issue is that possible differences between local regulation and systemic changes in regulation have not been sufficiently taken into account. As pre-eclampsia has pathophysiological pathways resembling an systemic inflammatory response, it is

reasonable to accept changes in the systemic regulation during pre-eclampsia.87 In this concept pregnancy can be considered to be a state of systemic inflammatory response, which is increased during gestation and further intensified in pre-eclampsia.91 However, these changes might be different locally, at the foetomaternal interface and systemic changes might be the consequences of the disease, and not the cause. In humans the CD4+CD25bright subset have a regulatory potential as shown by the suppression of proliferation of CD4+ cells in vitro, while the CD4+CD25low subset remain cytotoxic. Other surface markers, expressed by natural occurring regulatory T-cells, are CTLA-4, glucocorticoid induced tumour necrosis factor receptor (GITR), OX40, CD62, CD38, CD122, CD132 and Foxp3.92,93 The regulatory function is related to the expression of Foxp3 as in mice mutation in the Foxp3 gene results in the loss of regulatory function.94 It was shown in early human pregnancy decidual tissue that regulatory T-cells have a high expression of CTLA-4 and that they mediated, most probably via cell–cell contact, a profound inhibition of T-cell proliferation in a dose dependent manner,93 most probably via membrane bound TGF-β, but other possible candidate binding molecules are LAG-3 and Galectin-1.69 Also, cytokine production (such as TGF-β and IL-10) by regulatory T-cells themselves or indoleamine 2,3-dioxygenase expression by macrophages or dendritic cells, induced by CTLA-4 expressing regulatory T-cells has been demonstrated. The understanding of regulatory T-cells’ contribution to mechanisms of maternal tolerance is of essential importance as shown in animal models95 and in the human.96 It is most likely that the regulatory Tcells in humans are also induced in peripheral lymphoid tissues and not in the thymus95 and that foetal antigens are a major factor in driving the expansion of the regulatory T-cell pool.96 This is also supported by the finding that in inbred mice (syngeneic breedings) the number of regulatory T-cells was substantially

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increased if the offspring were predominantly male. In these specific cases, but also probably in normal human pregnancies, the male specific H-Y antigen is considered to be a contributory factor for the induction of regulatory T-cells. Interestingly, in humans the population of non-tolerogenic T-cells in peripheral blood (CD4+CD25low) increased sharply at term. The dominance of the non-tolerogenic T-cells is thought to be associated with the induction of labour.95 The adoptive transfer of CD4+CD25+ regulatory T-cells into an abortion-prone mouse model (H2k female mice mating with H2d males) prevents spontaneous abortion, suggesting that regulatory T-cells are alloantigen specific.67

Integrating the role of the different cell types and their function during nidation and implantation Immunomodulation Multiple tolerance mechanisms are functional at the maternofoetal interface. Besides the dominance of a Th2 cytokine milieu (Fig 31.3),97 foetal antigen-specific regulatory T-cells93,94 and dendritic cells have a critical role in the downregulation of a possible cytotoxic immune response against foetal tissues. Functional cross communication between the immune and endocrine systems, especially for progesterone has been suggested.88 Galactin-1, a glycan-binding protein, is functional at the foetomaternal interface, not only by controlling proliferation and survival of effector Tcells, antagonising T-cell activation, but also by blocking the secretion of pro-inflammatory (Th1) cytokines and skewing the cytokine balance in a Th2 direction and by the recruitment of tolerogenic dendritic cell.52 These tolerogenic dendritic cells may be instrumental in the induction of regulatory T-cells. uNK cells have, although they are in close contact with extravillous trophoblast and invade the decidua and the myometrium, no cytolytic activity against trophoblastic cells. This is related to the inhibitory receptors on trophoblastic cells, such as KIR2DL4, CD94/NKG2A and LIR-1, which interact with the non-classical HLA class I MHC molecules HLA-G and HLA-E, and the classical HLA class I, HLA-C.59 The interaction of HLA-E with the inhibiting CD94/NKG2A receptor has been shown to inhibit uNK cell mediated lysis of extravillous trophoblast. The receptor of HLA-G and thereby the function of HLA-G is still unclear and might lie more in its capacity to induce production of immunomodulating cytokines by uNK cells.98 Possible candidate receptors on uNK cells for HLA-G are KIR2DL45 and ILT-2 and possibly ILT-4 on macrophages and dendritic cells. On the other hand, because of the many functions of uNK cells, these cells should be active, not in a cytotoxic manner, but in a more remodelling manner.99 It could be that with constant stimulation, of for example the receptor NKG2D, uNK cells might lose their cytotoxic function against foetal cells and become more important

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producers of specific growth factors.59 The role of HLAC, which is the only classical antigen and the only paternal allogeneic signal, which is expressed on trophoblast, is important with regard to this. Although being a less polymorphic antigen, there is an intriguing role for HLA-C at the foetomaternal interface, whereby more optimal trophoblast invasion is associated with activation of KIR on uNK cells via the interaction with activating HLA-C subtypes.26,100,101 A second important role for uNK cells, as has been demonstrated in mice, is their ability to help to modify the maternal spiral arteries to so-called low resistance vessels: a process which is crucial for the normal development of the placenta.102 Not only IFN-γ and many other cytokines and growth factors such as CSF-1,68 granulocyte macrophage (GM)-CSF, MIP-1α, leukaemia inhibitory factor (LIF), IL-8 and interferon inducible protein (IP)10, modulating T-cell and dendritic cell activity,103,104 but also angiogenic factors, suggesting vascular remodelling properties of uNK cells, such as VEGF, Ang-1, Ang-2, IFN-γ and PlGF, are produced by uNK cells59,102,105 (Fig 31.5). In the mice model, NK cell deficiency is related to an absence of pregnancy-associated vascular modification. Inhibitors of VEGF, PlGF and TGF-β, such as soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin, are associated with the development of pre-eclampsia.106 The conceptus might influence locally the number and function of uNK cells and the accumulation of these cells is associated with the production of, for example, IFN-γ, pro-IL-18 and IL15. IFN- γ and uNK cells are related to the dilatation and thinning of the spiral arteries.5,40,105 Especially, if activating receptors such as KIR3DS4 are expressed, relative to inhibitory receptors such as KIR2DL1, higher levels of these chemokines and angiogenic factors are produced by the uNK cells.59 There is a close bidirectional cell–cell contact, necessary for the interaction between immature dendritic cells and uNK cells, via the expression of DC-SIGN and ICAM-3, respectively, possibly both preventing the maturation of immature dendritic cells into mature dendritic cells and also preventing the interaction of dendritic cells with T-cells,107,108 crucial for an adaptive immune response. IL-10 and GM-CSF produced by uNK cells (and macrophages) inhibit dendritic cells maturation and help to maintain a tolerogenic phenotype by preventing the induction of co-stimulatory molecules CD80 and CD86. These cytokines could also be important for the induction of apoptosis.109 Activated NK cells will have an influence on the T-cell mediated adaptive immune responses via cytokines, as well as via cell–cell contact. Human NK cells have ligands for the T-cell co-stimulatory molecules, such as CD86, CD80 and OX40L; however, this has not been shown specifically for uNK cells. Possibilities of inhibiting CD4+ effector T-cells also occur via uNK release of perforin and via interaction of the NK cell receptor NKG2D with T-cell ligands such as MHC class I chain related A (MICA) and UL16 binding protein (ULBP) 1–3.

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Intervillous space

Anchoring villus

Endovascular cytotrophoblasts

uNK cell

Immature DC

Cytotrophoblast 2

Spiral artery 1

Myometrium MATERNAL SIDE

Fig 31.5 Uterine uNK cells (+cytokine production) and spiral artery modification. 1, invasive cytotrophoblast fusing to placental bed giant cells; 2, invasive cytotrophoblast clustering with immature DCs and uNK cells.

expression of adhesion molecules or apoptosis. By studying ectopic pregnancies, where no decidual layer is present and particularly the uNK are (nearly) absent, it was found that apoptosis is positively related to the number of uNK cells and reduced in ectopic pregnancies, and that apoptosis is an important factor limiting extravillous trophoblast invasiveness.119 The observation that impairment of spiral artery changes is related to pregnancy complication is not only found in pregnancies complicated by pre-eclampsia, but also the same impairment has been found in pregnancies complicated by foetal growth restriction and even in normal pregnancies, demonstrating that, although these arterial modifications are needed for a normal development of the placenta, even in normal pregnancies these abnormalities can be found.120

Remodelling of maternal vessels The changes to maternal spiral arteries, necessary for the development of the haemochorial placenta, are accomplished by the invading cytotrophoblastic cells, a process starting early in pregnancy and having a decisive effect on changes in the spiral artery vessel wall. Cytotrophoblasts fuse and form the characteristic multinucleated giant cells. Spiral artery changes occur particularly in those spiral arteries located in what will become the placental bed.111,112 This process is still poorly understood, however, interstitial cytotrophoblasts invade the lumen of spiral arteries and the myometrium and reach the myometrial arteries at around 10 weeks of human gestation. At that moment cytotrophoblasts are found in less than 5% of the spiral arteries; increasing to 32% at 16–18 weeks.113 Although it was believed that this process occurred in two waves, most probably this invasion is a gradual progressive process resulting in increasing disorganisation of the vascular smooth muscle, resulting in, for a normal pregnancy, the typical distended, low resistance spiral arteries.114 NK cells play an important role in this invasive process and in the vascular remodelling, including producing a wide range of factors and (angiogenic) substances such as VEGF (via hypoxia inducible factor (HIF)-1α), PIGF, matrix metalloproteinases (MMPs), tissue inhibitors for MMPs (TIMPs), TGF-β and cell adhesion molecules.59,112,115,116 In the animal (swine) model the essential importance of VEGF (and HIF-1α) both for the local recruitment of cells into a hypoxic environment (as the first trimester placenta certainly is)117 and for lymphocyte driven angiogenesis was demonstrated.118 The same NK cells might play two very important roles: (1) Direct action on the remodelling of the spiral artery by affecting the smooth muscle wall layer;115 (2) Controlling the depth of trophoblast cell invasion.39 The mechanism controlling and inhibiting this invasion are still unclear, but may be related to an altered

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The immunology of early pregnancy 13. Billington WD. Influence of immunologic dissimilarity of mother and foetus on size of placenta in mice. Nature 1964; 202: 317–18. 14. Beer AE, Billingham RE. The Immunobiology of Reproduction. Upper Saddle River, NJ: PrenticeHall, 1976. 15. Adams KM, Yan Z, Stevens AM, Nelson JL. The changing maternal “self” hypothesis: a mechanism for maternal tolerance of the fetus. Placenta 2007; 28: 378–82. 16. Beydoun H, Saftlas AF. Association of human leucocyte antigen sharing with recurrent spontaneous abortions. Tissue Antigens 2005; 65: 123–35. 17. Ober C. Studies on HLA, fertility and mate choice in a human isolate. Hum Reprod Update 1999; 5: 103–7. 18. Takakuwa K, Honda K, Yokoo T et al. Molecular genetic studies on the compatibility of HLA class II alleles in patients with unexplained recurrent miscarriage in the Japanese population. Clin Immunol 2006; 118: 101–7. 19. Jacob S, McClintock MK, Zelano B, Ober C. Paternally inherited HLA alleles are associated with women’s choice of male odor. Nat Genet 2002; 30: 175–9. 20. Wedekind C, Füri S. Body odour preferences in man an women: do they aim for specific MHC combinations or simply heterozygosity? Proc R Soc Lond B 1997; 264: 1471–9. 21. Esplin MS, Fausset MB, Fraser A et al. Paternal and maternal components of the predisposition to preeclampsia. N Engl J Med 2001; 344: 867–72. 22. Kilpatrick DC, Liston WA, Gibson F, Livingstone J. Association between susceptibility to pre-eclampsia within families and HLA DR4. Lancet 1989; 2: 1063–5. 23. Saftlas AF, Beydon H, Triche E. Immunogenetic determinants of pre-eclampsia and related pregnancy disorders. Obstet Gynecol 2005; 106: 162–72. 24. Dehaghani AS, Doroudchi M, Kalantari T, Pezeshki AM, Ghaderi A. Heterozygosity in CTLA-4 gene and severe preeclampsia. Int J Gynecol Obstet 2005; 88: 19–24. 25. Moffet A, Hiby SE. How does the maternal immune system contribute to the development of preeclampsia? Placenta 2007; 28 (Suppl A): S51–6. 26. Hiby SE, Walker JJ, O’Shaughnessy KM et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med 2004; 200: 957–65. 27. Hunt JS, Morales PJ, Pace JL, Fazleabas AT, Langat DK. A commentary on gestational programming and functions of HLA-G in pregnancy. Placenta 2007; 28 (Suppl A): S57–63. 28. Hunt JS, Petroff MG, McIntire R, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J 2005; 19: 681–93. 29. LeMaoult J, Krawice-Radanne I, Dausset J, Carosella ED. HLA-G1-expressing antigen presenting cells induce immunosuppressive CD4+ T cells. Proc Natl Acad Sci USA 2004; 101: 7604. 30. Naji A, Durrbach A, Carosella ED, Rouas-Freiss. Soluble HLA-G and HLA-G1 expressing antigenpresenting cells inhibit T-cell alloproliferation through ILT-2/ILT-4/FasL-mediated pathways. Hum Immunol 2007; 68: 233–9.

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31. Apps R, Gardner L, Sharkey AM, Holmes N, Moffet A. A homodimeric complex of HLA-G on normal trophoblast cells modulates antigen-presenting cells via LILRB1. Eur J Immunol 2007; 37: 1924–37. 32. Contini P, Ghio M, Poggi A et al. Soluble HLA-A, B, -C and -G molecules induce apoptosis in T and NK CD8+ cells and inhibit cytotoxic T cell activity through CD8 ligation. Eur J Immunol 2003; 33: 125. 33. Contini P, Ghio M, Merlo A et al. Apoptosis of antigen-specific T lymphocytes upon engagement of CD8 by soluble HLA class I molecules is Fas ligand/Fas mediated: evidence for the involvement of p561ck, calcium calmodulin kinase II and Calcium-independent protein kinase C signaling pathways and for NF-kappaB and NF-AT nuclear translocation. J Immunol 2005; 175: 7244–54. 34. van der Meer A, Lukassen HG, van Cranenbroek B et al. Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells. Mol Human Reprod 2007; 13: 123–33. 35. Alegre E, Diaz-Lagares A, Lemaoult J et al. Maternal antigen presenting cells are a source of plasmatic HLA-G during pregnancy: longitudinal study during pregnancy. Hum Immunol 2007; 68: 661–7. 36. Hackmon R, Koifman A, Hyobo H et al. Reduced third-trimester levels of soluble human leucocyte antigen G protein in severe preeclampsia. Am J Obstet Gynecol 2007; 197: 255e1–5. 37. Yie SM, Li LH, Li LM, Librach C. HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia. Am J Obstet Gynecol 2004; 191:525–9. 38. Hviid TV. HLA-G genotype is associated with fetoplacental growth. Hum Immunol 2004; 65: 586–93. 39. Moffet A, Loke C. Immunology of placentation in eutherian mammals. Nature Rev Immunol 2006; 6: 584–94. 40. Herrington JF, Banny BM. Effect of the conceptus on uterine natural killer cell numbers and function in the mouse uterus during decidualization. Biol Reprod 2007; 76: 579–88. 41. Starkey PM, Clover LM, Rees MC. Variation during the menstrual cycle of immune cell populations in human endometrium. Eur J Obstet Gynecol Reprod Biol 1991; 39: 203–7. 42. Pace D, Morrison L, Bulmer JN. Proliferative activity in endometrial stromal granulocytes throughout menstrual cycle and early pregnancy. J Clin Pathol 1989; 42: 35–9. 43. Vince GS, Starkey PM, Jackson MC, Sargent IL, Redman CGW. Flow cytometric characterization of cell populations in human decidua and isolation of decidual macrophages. J Immunol Methods 1990; 132: 181–9. 44. Tilburgs T, Roelen DL, van der Mast BJ et al. Differential distribution of CD4 +CD25 bright and CD8 +CD28 − T-cells in decidua and maternal blood during human pregnancy. Placenta 2006; 27(Suppl A): S47–53. 45. Starkey PM, Sargent IL, Redman CWG. Cell populations in human early pregnancy decidua: characterization and

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Textbook of Periconceptional Medicine isolation of large granular lymphocytes by flow cytometry. Immunology 1988; 65: 129–34. Vargas ML, Santos JL, Ruiz C et al. Comparison of the proportions of leucocytes in early and term decidua. Am J Reprod Immunol 1993; 29: 135–40. Croy AB, van den Heuvel MJ, Borzychowski AM, Tayade C. Uterine natural killer cells: a specialized differentiation regulated by ovarian hormones. Immunol Rev 2006; 214: 161–85. Ho HN, Chao KH, Chen CK, Yang YS, Huang SC. Activation status of T and NK cells in the endomtrium throughout menstrual cycle and normal and abnormal pregnancy. Hum Immunol 1996; 49: 130–6. Freud AG, Becknell B, Roychowdury S et al. A human (CD34+) subset resides in lymph nodes and differentiates into CD56bright natural killer cells. Immunity 2005; 22: 295–304. Santoni A, Zingoni A, Cerboni C, Gismondi A. Natural Killer (NK) cells from killers to regulators; distinct features between peripheral blood and decidual NK cells. Am J Reprod Immunol 2007; 58: 280–8. Manaster I, Mandelboim O. The unique properties of human NK cells in the uterine mucosa. Placenta 2007; 29S: 60–6. Verma S, King A, Loke YW. Expression of killer cell inhibitory receptors on human uterine natural killer cells. Eur J Immunol 1997; 27: 979–83. Hanna J, Wald O, Goldman-Wohl D et al. CXCL12 expression by invasive trophoblasts induces the specific migration from CD16− human natural killer cells. Blood 2003; 102: 1569–77. Jones RK, Bulmer JN, Searle RF. Cytotoxic activity of endometrial granulated lymphocytes during the menstrual cycle in humans. Biol Reprod 1997; 57: 1217–22. King A, Balendran N, Wooding P, Carter NP, Loke YW. CD3− leukocytes in the human uterus during early placentation: phenotypic and morphologic characterization of the CD56++ population. Dev Immunol 1991; 1: 169–90. Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated lymphocytes in human endometrium: histochemical and immunohistochemical studies. Hum Reprod 1991; 6: 791–8. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP et al. Differential distribution of NK cells in decidua basalis compared with decidua parietalis after uncomplicated human term pregnancy. Hum Immunol 2003: 921–9. Kämmerer U, Marzusch K, Kröber S et al. A subset of CD56+ large granular lymphocytes in firsttrimester human decidua are proliferating cells. Fertil Steril 1999; 71: 74–9. Hanna J, Goldman-Wohl D, Hamani Y et al. Decidual NK cells regulate key developmental processes at the human fetal-maternal interface. Nat Med 2006; 12: 1065–74. Trundley A, Moffet A. Human uterine leukocytes and pregnancy. Tissue Antigens 2004; 63: 1–12. King A, Wooding P, Gardner, Loke YW. Expression of perforin, granzyme A and TIA-1 by human uterine CD56+ NK cells implies they are activated and capable of effector functions. Hum Reprod 1993; 8: 2061–7.

62. Verma S, Hiby SE, Loke YW, King A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol Neonate 2000; 62: 959–68. 63. Tabiasco J, Rabot M, Aguerre-Girr M et al. Human decidual NK cells: unique phenotype and functional properties – a review. Placenta 2006; 27 (Suppl A): S34–9. 64. Koopman LA, Kopcow HD, Rybalov B et al. Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med 2003; 198: 1201–12. 65. Saito S, Shiozaki A, Sasaki Y et al. Regulatory ZT cells and regulatory natural killer (NK) cells play important roles in feto-maternal tolerance. Semin Immunopathol 2007; 29:115–22. 66. Shigeru S, Akitoshi N, Subaru M-H, Shiozaki A. The balance between cytotoxic NK cells and regulatory NK cells. J Reprod Immunol 2008; 77: 14–22. 67. Zenclusen AC, Gerlof K, Zenclusen MF et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4+CD25+ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol 2005; 166: 811–22. 68. Johki PP, Chumbley G, King A, Gardner L, Loke YW. Expression of the colony stimulating factor-1 receptor (c-fms product) by cells at the human uteroplacental interface. Lab Invest 1993; 68: 308–20. 69. Terness P, Kallikourdis M, Betz AG et al. Tolerance signaling molecules and pregnancy: IDO, galectins, and the renaissance of regulatory T cells. Am J Reprod Immunol 2007; 58: 238–54. 70. Bulmer JN, Sunderland CA. Immunohistochemical characterization of lymphoid cell populations in the early human placental bed. Immunology 1984; 52: 349–57. 71. Repnik U, Tilburgs T, Roelen DL, van der Mast BJ, Kanhai HH, Scherjon S, Claas FH. Comparison of macrophage phenotype between decidua basalis and decidua parietalis by flow cytometry. Placenta 2008; 29: 405–12. 72. Laskarin G, Kämmerer U, Rukavina D et al. Antigen-presenting cells and materno-fetal tolerance: an emerging role for dendritic cells. Am J Reprod Immunol 2007; 58: 255–67. 73. Fallarino F, Grohmann U, Hwang KW et al. Modulation of tryptophan catabolism by regulatory T cells. Nature Immunol 2003; 4: 1206–12. 74. Kämmerer U, Schoppet M, McLellan AD et al. Human decidua contains potent immunostimulatory CD83(+) dendritic cells. Am J Pathol 2000; 157: 159–69. 75. Gardner L, Moffet A. Dendritic cells in the human decidua. Biol Reprod 2003; 69: 1438–46. 76. Bonifaz L, Bonnyay D, Mahnke K et al. Efficient targeting of protein antigen to the dendritic cell receptor DEC-205 in the steady state leads to antigen presentation on major histocompatibility complex class I products and peripheral CD8+ T cell tolerance. J Exp Med 2002; 196: 1627–38. 77. Inaba K, Metlay JP, Cowley MT, Steinman RM. Dendritic cells pulsed with protein antigens in

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vitro can prime antigen-specific, MHC restricted T cells in situ. J Exp Med 1990; 172: 631–40. Yamazaki S, IyodaT, Tarbell K et al. Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 2003; 198: 1867–70. Heikkinen J, Mottonen M, Alanen A, Lasilla O. Phenotypic characterization of regulatory T cells in the human decidua. Clin Exp Immunol 2004; 136: 373–8. Kudo Y, Boyd CA, Sargent IL, Redman CW. Tryptophan degradation by human placental indoleamine 2,3-dioxygenase regulates lymphocyte proliferation. J Physiol 2001; 535: 207–15. Honig A, Rieger L, Kapp M et al. Indoleamine 2,3dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance. J Reprod Immunol 2004; 61: 79–86. Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan metabolism. Nature Rev Immunol 2004; 4: 762–74. Erlebacher A, Vencato D, Price KA, Zhang D, Glimcher LH. Constraints in antigen presentation severely restricts T cell recognition of the allogeneic fetus. J Clin Invest 2007; 117: 1399–411. Wegmann TG, Lin H, Guilbert L, Mossmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is succesful pregnancy a TH2 phenomenon? Immunol Today 1993; 14: 353–6. Marzi M, Vigano A, Trabattoni D et al. Characterization of type 1 and type 2 cytokine production profile in physiologic and pathologic pregnancy. Clin Exp Immunol 1996; 106: 127–33. Lim, KJH, Odukoya OA et al. The role of T-helper cytokines in human reproduction. Fertil Steril 200; 73: 136–42. Borzychowski AM, Croy BA, Chan WL, Redman CWG, Sargent IL. Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated bij natural killer cells. Eur J Immunol 2005; 35: 3054–63. Arck P, Hansen PJ, Mulac-Jeicevic B, Piccinni MO, Szekeres-Bartho J. Progesterone during pregnancy: endocrine-immune cross talk in mammalian species and the role of stress. Am J Reprod Immunol 2007; 58: 268–79. Sakaguchi S. Natural arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 2005; 6: 345–52. Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat immunol 2004; 5: 266–71. Sargent IL, Borzychowski AM, Redman CWG. NK cells and human pregnancy – an inflammatory view. Trends Immunol 2006; 27: 399–404. Aluvihare VR, Betz AG. The role of regulatory T cells in alloantigen tolerance Immunol Rev 2006; 212: 330–43. Sasaki Y, Sakai M, Miyazaki S et al. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Human Reprod 2004; 10: 347–53.

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94. Hori S, Nomura T, Kakaguch S. Control of regulatory T cell development by transcription factor Foxp3. Science 2003; 299: 1057–61. 95. Zhao J-X, Zeng Y-Y, Liu Y. Fetal alloantigen is responsible for the expansion of CD4+CD25+ regulatory T cell pool during pregnancy. J Reprod Immunol 2007; 71–81. 96. Tilburgs T, Roelen DL, van der Mast BJ et al. Claas FH. Evidence for a selective migration of fetus specific CD4+CD25bright regulatory T cells from the peripheral blood to the decidua in human pregnancy. J Immunol 2008; 180: 5737–45. 97. Lin H, Mosmann TR, Guilbert L, Tuntipopopat S, Wegmann TG. Synthesis of T helper 2-type cytokines at the maternal–fetal interface. J Immunol 1993; 151: 4562–73. 98. Rieger L, Hofmeister V, Probe C et al. Th1- and Th2-like cytokine production by first trimester decidual large granular lymphocytes is influenced by HLA-G and HLA-E. Mol Hum Reprod 2002; 8: 255–61. 99. Croy BA, Chantakru S, Esadeg S, Ashkar AA, Wei Q. Decidual natural killer cells: key regulators of placental development (a review). J Reprod Immunol 2002; 57: 151–68. 100. Moffet A, Regan L, Braude P. Natural killer cells, miscarriage, and infertility. BMJ 2004; 329: 1283–5. 101. Moffet-King A. Natural killer cells and pregnancy. Nature Rev 2002; 2: 656–63. 102. Ashkar AA, Croy BA. Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy. Semin Immunol 2001; 13: 235–41. 103. Hanna J, Fitchett J, Rowe T et al. Proteomic analysis of human natural killer cells: insights on new potential NK immune functions. Mol Immunol 2005; 42: 425–31. 104. Drake PM, Gunn MD, Charo IF et al. Human placental cytotrophoblats attract monocytes and CD56bright natural killer cells via the action of monocyte inflammatory protein 1α. J Exp Med 2001; 193: 1199–212. 105. Croy BA, Ashkar AA, Minhas K, Greenwood JD. Can murine uterine natural killer cells give insight into the pathogenesis of preeclampsia? J Soc Gynecol Investig 2000; 7: 12–20. 106. Levine RJ, Lam C, Qian C et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med 2006; 355: 992–1005. 107. Dietl J, Hönig A, Kämmerer U, Rieger L. Natural killer cells and dendritic cells at the human fetomaternal interface: an effective cooperation? Placenta 2006; 27: 341–7. 108. Geijtenbeek TB, Torensma R, van Vliet SJ et al. Identification of DC-SIGN, a novel dendritic cellspecific ICAM-3 receptor that supports primary immune responses. Cell 2000; 100: 575–85. 109. Lidstrom C, Matthiesen L, Berg G et al. Cytokine secretion pattens of NK cells and macrophages in early human pregnancy decidua and blood: implications for suppressor macrophages in decidua. Am J Reprod Immunol 2003; 50: 444–52. 110. Schott E, Bonasio R, Ploegh H. Elimination in vivo of developing T cells by natural killer cells. J Exp Med 2003; 198: 1213–24.

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111. Lyall F. Priming and remodeling of human placental bed spiral arteries during pregnancy – a review. Placenta 2005; 26(Suppl A): S31–36. 112. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med 2001; 345: 1400–8. 113. Pijnenborg R, Vercruysse L, Hanssens M. The uterine spiral arteries in human pregnancy: Facts and controversies. Placenta 2006; 27: 939–58. 114. Robson SC, Simpson H, Ball E, Lyall F, Bulmer JN. Punch biopsies of the human placental bed. Am J Obstet Gynecol 2002; 187: 1349–55. 115. Leonard S, Murrant C, Tayade C et al. Mechanisms regulating immune cell contributions to spiral artery modification – facts and hypothesis – a review. Placenta 2006; 27 (Suppl A): S40–6. 116. Kopcow HD, Karumanchi SA. Angiogenic factors and natural killer (NK) cells in the pathogenesis of preeclampsia. J Reprod Immunol 2007; 76: 23–9. 117. Jauniaux E, Hempstock J, Greenwold N, Burton GJ. Trophoblastic oxidative stress in relation to temporal and regional differences in maternal placental

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blood flow in normal and abnormal early pregnancies. Am J Pathol 2003; 162: 115–25. Tayade C, Fang Y, Hilchie D, Croy BA. Lymphocyte contributions to altered endometrial angiogenesis during early and midgestation fetal loss. J Leukocyte Biol 2007; 82: 877–86. von Rango U, Krusche CA, Kertschanska S et al. Apoptosis of extravillous trophoblast cells limits the trophoblast invasion in uterine but not in tubal pregnancy during the first trimester. Placenta 2003; 24: 929–40. Lyall F, Simpson H, Bulmer JN, Barber A, Robson SC. Transforming growth factor-b expression in human placenta and placental bed in third trimester normal pregnancies, preeclampsia and fetal growth restriction. Am J Pathol 2001; 159: 1827–38. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, Kanhai HH, Roelen DL, Claas FHJ. Comparison of decidual leucocytes following spontaneous vaginal delivery an elective cesarean section in uncomplicated human term pregnancy. J Reprod Immunol 2004; 62: 125–37.

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32 Nomenclature and mechanisms of early pregnancy loss Roy Farquharson, Niek Exalto

Introduction Early pregnancy loss before 12 weeks’ gestation is a common event that causes a great deal of distress to women and their partners alike. Approximately one in five pregnancies will end in pregnancy loss which represents a considerable burden on individuals as well as the health care providers. Recent guidance clearly sets standards for health care at the time of diagnosis and management of early pregnancy complications. The core standard should be that all patients are assessed and managed within an early pregnancy unit (EPU).1,2 As miscarriage causes such strong emotional reaction, it is apparent that the great majority of sufferers clearly remember the event process leading up to loss. Most early pregnancy complications will have undergone ultrasound scan assessment. Many women recall precise details of ultrasound findings before or at the time of diagnosis. As a consequence there is a need to improve our description of early pregnancy events so that care providers and patients understand each other and use the same language to describe these findings. Upon this basis and using a pragmatic approach an attempt to replace old and misunderstood terms like “blighted ovum” has been made.

Table 32.1

The nomenclature used to describe clinical events in early pregnancy has been criticised for lack of clarity and promoting confusion. There is no agreed glossary of terms or consensus regarding important gestational milestones. In particular, there are old and poorly descriptive terms such as “missed abortion” or “blighted ovum” which have persisted since their introduction many years ago3 and have not undergone revision despite the widespread application of ultrasound for accurate clinical assessment and diagnosis. The authors are aware of these shortcomings in terminology and are keen to provide an updated glossary. This paper hopes to facilitate the introduction of a revised terminology in an attempt to provide clarity and to enhance uptake and use in the literature as well as clinical assessment and documentation (Table 32.1).

Recognising the event The commonest early pregnancy complication of spontaneous miscarriage occurs in approximately 15–20% of all pregnancies, as recorded by hospital episode statistics. The actual figure, from community based assessment, may be up to 30%, as many cases are not reported to hospital.4 The great majority occur early

Pregnancy loss classification of the commonest pregnancy loss events and ultrasound features.

Type of loss Biochemical Loss

Typical gestation (range in weeks)

Foetal heart activity

Principal ultrasound finding

Beta HCG level

<6 (0–6)

Never

Pregnancy not located on ultrasound

Low then fall

Early pregnancy Loss

6–8 (4–10)

Never

Empty sac or large sac with minimal structures without foetal heart activity

Initial rise then fall

Late pregnancy Loss

>12 (10–20)

Lost

Crown rump length and foetal heart activity previously identified

Rise then static or fall

βhCG, β-human chorionic gonadotrophin.

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before 12 weeks’ gestational age and less than 5% occur after identification of foetal heart activity.5 Second trimester loss, between 12 and 24 weeks, occurs less frequently and constitutes less than 4% of pregnancy outcomes.6 The clinical assessment of every pregnancy loss history requires clarification of pregnancy loss type and accurate classification, whenever possible. The traditional grouping of all pregnancy losses prior to 24 weeks as “abortion” may have had pragmatic origins, but it is poor in terms of definition and makes little sense. The term abortion is also confusing for the patient. She may not realise that (spontaneous) abortion is not a termination of pregnancy because medical abortion or legal abortion is used in the same way. Increasing knowledge about early pregnancy development, with the more widespread availability of serum β human chorionic gonadotrophin (βhCG) measurement, the advent of high resolution ultrasound and a clearer description of gestational age at pregnancy loss make for a more sophisticated assessment of miscarriage history, but also help the couple’s awareness and perception from as early as 5 weeks’ gestation. The advent of these important information milestones has not been fully realised or incorporated into clinical event description for article publication. The emergence of EPUs in many hospitals has addressed the need for a dedicated clinical area for the diagnosis of miscarriage and patient support at a distressing time.7,8 With the establishment of an EPU network, it becomes more important that a standardised diagnostic classification system be employed for accurate and reproducible reporting of ultrasound findings and clinical outcomes, so that direct comparisons between units can be readily understandable for both research and audit purposes. The most recent Confidential Enquiry into Maternal Deaths conclusively demonstrated that mortality from ectopic pregnancy has not declined and is still on the increase from rates described 10 years ago.9 As the EPU represents the most likely point of ectopic pregnancy diagnosis, the importance of standardised reporting of very early pregnancy changes requires a robust approach following recent recommendations.10

Length of pregnancy Just as postnatal age begins at birth, prenatal age begins at fertilisation. The embryonic period occupies the first 8 post-fertilization weeks, during which organogenesis takes place. Thereafter, the foetal period is characterised by growth. Embryologists prefer the term embryonic age and assess this by using 23 internationally recognised morphological stages.11 Clinicians, however, conventionally calculate from the first day of the last normal menstrual period (LMP). Confusion about the definition of pregnancy duration derives from use of terms such as postovulatory age, conceptual age or even misnomers like menstrual age within the published literature.

Clinicians do have to acknowledge that a woman does not become pregnant during the LMP, or during ovulation but exclusively after conception. Gestation is the condition of being carried in the womb during the interval between conception and birth. The term gestational age (GA) is therefore confusing, although generally accepted, and its widespread use can only be legitimised using a proper definition. The appropriate way to overcome this confusion is to choose GA based on a theoretical ovulation plus 2 weeks. As early ultrasound measurements of the foetus (crown– rump length, CRL) are reproducible12 and more accurate than the use of the LMP there is a need in publications to define GA as based on LMP and/or ultrasound. The terms egg and ovum, sometimes used in clinical publications, should be avoided because they have been used incorrectly for both an oocyte and an embryo.13 This author suggested that an egg be reserved for a “nutritive object” only. Similarily, the use of the term embryo versus foetus is confusing as infertility specialists use embryo in the preimplantation period, while anatomists use embryo up until 8 weeks postimplantation.

Ultrasound criteria With the introduction of transvaginal ultrasound, longitudinal assessment of early pregnancy development can be made, in terms of viability and growth. Ultrasound plays a major role in maternal reassurance, where foetal cardiac activity is seen and is pivotal in the assessment of early pregnancy complications, such as vaginal bleeding.14 However, there are limits to the ultrasound resolution of normal early pregnancy development. Recent advice concludes that a diagnosis of an empty sac (previously termed anembryonic pregnancy, early embryonic demise or embryo loss) should not be made if the visible CRL is <6 mm, as only 65% of normal embryos will display cardiac activity.15 Repeat transvaginal ultrasound examination after at least a week showing identical features and/or the presence of foetal bradycardia is strongly suggestive of impending miscarriage.16 The possibility of incorrect dates should always be remembered by the alert clinician. In addition, it should be remembered that when the foetus has clearly developed and the foetal heart is absent, the term “missed abortion” should be replaced by “delayed miscarriage”.17 Gynaecologists and ultrasonographers acknowledge the “embryonic” period by speaking about foetal heart action and foetal activity before the end of organogenesis. This evidence is vital to the patient who sees them as clear signs of life. Embryologists, by contrast, may debate the meaning of embryo in early pregnancy but embryo is more synonymous with cells in an IVF laboratory than as the preclinical scientific description of anatomical organogenesis. Although a clear distinction between embryonic and foetal periods is

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significant in teratology, we have to accept that modern terminology should reflect daily clinical practice the description of which has changed in the past two decades and is more patient centred. The term foetus receives an ultrasound definition to include foetal heart activity and/or a CRL >10 mm.

Classification of events There has been a plea to classify pregnancy losses according to the gestational age at which they occur and detail the event, for example, in case of foetal demise at 8 weeks, define it as foetal death at 8 weeks’ gestational age. In this way, possible pathophysiological mechanisms may be postulated and studied. Historically, clinicians have grouped all pregnancy losses that occur at a gestational age prior to theoretical viability under the umbrella of “abortion”. Between 1 and 2% of fertile women will experience recurring miscarriage (RM).18 Recently, among researchers in the field of RM, it has been recognised that the classification of pregnancy loss is more complex as the developing pregnancy undergoes various important stages, and different pathology at the time of pregnancy loss is exhibited at these different stages. As the majority of RM cases following investigation are classified as idiopathic,18 it is generally accepted that within the idiopathic group there is considerable heterogeneity and it is unlikely that one single pathological mechanism can be attributed to the RM history. Furthermore, there is considerable debate about cause and association as the exact pathophysiological mechanisms have not been elucidated. Current research is directed at theories related to implantation, trophoblast invasion and placentation, as well as factors which may be embryopathic. No identifiable pregnancy on ultrasound examination in combination with a positive urine or serum hCG pregnancy test is termed a pregnancy of unknown location (PUL). Biochemical pregnancy loss is a better description than trophoblast in regression or preclinical embryo loss. After ultrasound identification of pregnancy a miscarriage can be classified as early, before 12 weeks, or late, after 12 weeks. Heterotopic pregnancy is a combination of an intrauterine pregnancy and an ectopic pregnancy. Hydatidiform mole pregnancies and partial mole would be better replaced by gestational trophoblastic disease, complete or partial.

Mechanisms of pregnancy loss Chromosomal causes The majority (90%) of karyotypically abnormal pregnancies miscarry while the majority of karyotypically normal pregnancies continue. Miscarriage, therefore, can be seen as a process of natural selection. The incidence of an abnormal karyotype in spontaneous miscarriage is about

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60%.19 In RM, however the embryo loss pattern is miscarriages predominantly with a normal karyotype.20 As a consequence normal conceptus karyotype in a previous pregnancy is a predictor of subsequent miscarriage.21,22 When stratified for maternal age, there is no difference in the distribution of cytogenetically abnormal miscarriages in couples with RM compared with controls.23 A precise morphological and cytogenetic documentation of the products of conception is essential in the management of RM patients. Without this information it is impossible to ascertain whether the pregnancy loss is the result of treatment failure or a de novo chromosomal anomaly. The magnitude of the size of the treatment effect will be affected without correction for the aneuploidy factor.24

Parental karyotype The individual risk of a structural chromosomal abnormality in couples with RM is already increased after two miscarriages from below 0.5% to 2.2%.25 At advanced maternal age, however, the risk of parental carrier status is decreased. Low maternal age at second miscarriage, a history of three or more miscarriages, a history of two or more miscarriages in a brother or sister, and a history of two or more miscarriages in the parents of either partner all increase the probability of carrier status.26 A probability of abnormal carrier status of ≥ 2.2% is obtained when these four factors are combined (see Table 32.2).

Maternal thrombophilia Acquired maternal thrombophilia is a well recognised cause of RM. All women with a history of three or more early pregnancy losses, i.e. before 10 weeks, or one or more unexplained deaths at >10 weeks of a morphologically normal foetus, or one or more premature births at <34 weeks with severe pre-eclampsia or placental insufficiency, should be offered a testing for lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), known collectively as antiphospholipid antibodies (aPL), to exclude an antiphospholipid syndrome (APS).27 Aspirin and/or heparins have become routine treatment for women with APS and a history of RM on the basis of limited evidence. Although it was reported in a randomised controlled trial that the combination of low dose aspirin and heparin was superior to aspirin alone,28,29 recent studies reported that aspirin as well as heparin as a stand-alone therapy are associated with similar live birth rates.30–32 However, so far no trials have compared the use of heparin and aspirin with placebo or no treatment in APS-positive RM patients. The data on the use of anticoagulants for the treatment of RM in women without APS are too limited to recommend their routine use within this context.33 An increased incidence of early and recurrent foetal loss has also been suggested in women with inherited

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Table 32.2 Probability of carrier status in couples with two or more miscarriages according to the multivariable logistic regression model. Modified from Franssen et al.26

RMparents + Maternal age at second miscarriage <23 years

≥3 miscarriages

RMparents − 2 miscarriages

≥3 miscarriages

2 miscarriages

(RMbs) + (RMbs) −

10.2% 5.7%

7.3% 4.0%

7.3% 4.1%

5.2% 2.8%

(RMbs) + (RMbs) −

10.0% 5.7%

7.2% 4.0%

7.2% 4.0%

5.1% 2.8%

(RMbs) + (RMbs) −

5.8% 3.2%

4.1% 2.2%

4.1% 2.2%

2.9% 1.6%

(RMbs) + (RMbs) −

4.0% 2.2%

2.8% 1.5%

2.8% 1.5%

2.0% 1.1%

(RMbs) + (RMbs) −

1.8% 1.0%

1.2% 0.7%

1.3% 0.7%

0.9% 0.5%

23–33 years

34–36 years

37–38 years

≥39 years

Bold, couples with a probability of carrier status <2.2%. Karyotyping can be withheld in these couples. RMparents, a history of ≥2 miscarriages in parents of either partner; ≥3 miscarriages, a history of ≥3 miscarriages in the couple; 2 miscarriages; a history of ≥2 miscarriages in the couple; RMbs, a history of ≥2 miscarriages in a brother or sister of either partner.

thrombophilia including factor V Leiden or prothrombin gene mutations and protein S deficiency34 or acquired activated protein C resistance,35 however, other authors have found no association between maternal thrombophilia and pregnancy loss <10 weeks of gestation.36 Some studies reported a decreased risk of miscarriage in women with inherited thrombophilia,37,38 whereas one study reported that multiple genetic thrombophilic mutations in either partner seem to increase the risk of miscarriage in a subsequent pregnancy.39 Larger epidemiological studies are clearly needed to justify testing a couple with RM for inherited thrombophilia in routine clinical practice.40 As a consequence, in these patients thromboprophylaxis is only indicated to prevent thrombosis in case of a high risk and not for improvement of the pregnancy outcome, unless factor V Leiden mutations are associated with other thrombophilic mutations.

Hyperhomocysteinaemia A high level of homocysteine (hyperhomocysteinaemia) can be associated with RM.41 Among the genetic causes of this condition, a common one is polymorphism at position 677 in the methyl tetrahydrofolate reductase (MTHFR) gene, which in the homozygous form leads to a thermolabile enzyme variant.42 Within this context, low plasma folate levels have been associated with an increased risk of first trimester miscarriage.43 Investigation for the above condition remains technically difficult and should not be performed outside a specific clinical context.

Immunology An excessive maternal immune response against paternal antigens resulting in abnormal immune cells and cytokines production has and is still thought to be one of the causes of RM.44 To date, there is no scientific basis for introduction of peripheral blood natural killer (NK) cells testing or cytokine peripheral level measurements into routine practice.45–47 Recent data have shown that a high number of uterine NK cells are found in the endometrium of women with RM and this could be reduced by therapy.48 However, prospective trials are needed to evaluate the possible use of this finding and, currently, endometrial sampling should only be offered to women within the context of research programmes. The reported association between RM and deficiency of mannin-binding lectin (MBL), a serum protein involved in the immune response, is another subject of research programmes.49 The use of intravenous immunoglobulin (IVIG), anti-tumour necrosis factor (TNF)α, glucocorticoids or cellular therapies in order to prevent or reduce an “excessive immune response” and/or abrogate maternal–foetal incompatibility in women with RM remains controversial. IVIG might be of benefit to women with unexplained RM,50 but, within this context, its use should only occur as part of a randomised controlled trial. IVIG could be more efficacious in women presenting with secondary RM or repeated second trimester intrauterine foetal deaths.51 The majority of trials using cellular treatment for RM have failed to find any beneficial effect. The most

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Table 32.3

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Revised nomenclature 2005

Avoid

Prefer

Ultrasound findings

Egg

Oocyte

Embryo

Foetus

Embryonic age Postovulatory age Conceptual age

Gestational age based on last menstrual period and/or ultrasound foetal measurement

Ultrasound based definition to include foetal heart activity and/or crown rump length >10 mm

Menstrual age Threatened abortion Spontaneous abortion

Threatened miscarriage Spontaneous miscarriage

Medical abortion Legal abortion

Termination of pregnancy

Recurrent abortion Habitual abortion

Recurrent miscarriage consisting of 3 early consecutive losses or 2 late pregnancy losses

Pregnancy test

Serum/urine level of human chorionic gonadotrophin (hCG)

Preclinical embryo loss

Biochemical pregnancy loss with description of falling low positive serum/urine human chorionic gonadotrophin

Trophoblast regression

Biochemical pregnancy loss

Menstrual abortion Preclinical abortion

Biochemical pregnancy loss

Pregnancy not located on scan

Early embryonic demise Anembryonic pregnancy

Empty sac

Gestation sac with absent structures or minimal embryonic debris without heart rate activity

Embryonic death

Foetal loss

Previous identification of crown rump length and foetal heart activity followed by loss of heart activity

Early abortion

Early pregnancy loss

Ultrasound definition of intrauterine pregnancy with reproducible evidence of lost foetal heart activity and/or failure of increased crown rump length over 1 week, or persisting presence of empty sac, at less than 12 weeks gestation

Missed abortion

Delayed miscarriage

Same as for early pregnancy loss (vide supra)

Late abortion

Late pregnancy loss

After 12 weeks’ gestational age where foetal measurement was followed by loss of foetal heart activity

Hydatidiform mole Partial mole Molar pregnancy Heterotopic pregnancy

Gestational trophoblastic disease (complete or partial) Intrauterine plus ectopic pregnancy (e.g. tubal, cervical, ovarian, abdominal) Pregnancy of unknown location (PUL)

common of the cellular treatments are transfusions of paternal leucocytes before conception. So far, metaanalyses have shown no significant benefit of paternal leucocytes, third-party donor leucocytes or trophoblast

No definition of pregnancy location

No identifiable pregnancy on ultrasound with positive blood/urine hCG

membranes on pregnancy outcome compared with placebo,52 however, in the three small trials that tested third-party donor leucocytes, the pooled odds ratio for live birth was 1.39 (95% CI 0.68–2.82) in the treatment

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Table 32.4 Pregnancy success predicition matrix. Following idiopathic recurrent miscarriage, the predicted probability (%) of successful pregnancy is determined by maternal age and previous miscarriage history. From Brigham et al.56 Number of previous miscarriages Age (years) 20 25 30 35 40 45

2

3

4

5

92 89 84 77 69 60

90 86 80 73 64 54

88 82 76 68 58 48

85 79 71 62 52 42

95% confidence interval <20% in bold.

group compared with the placebo group emphasising that this treatment should be further tested in randomised controlled trials.

Future direction The revision of early pregnancy nomenclature is both desirable and essential in raising the standard of reporting (Table 32.3). To improve the accuracy of observational studies it is desirable to present a clear and consistent description of the pregnancy event that can be universally understood by the reader. For randomised controlled trials of treatments, it is essential to have a clear classification of pregnancy loss type for both foetal and very early loss events. In addition, there is a strong argument for mandatory karyotyping of all pregnancy losses to exclude a lethal trisomy karyotype or triploidy. This is because, irrespective of treatment intervention, pregnancy loss has occurred and may have been ascribed as a “false” treatment failure. Recent papers testify to the high rate of abnormal chromosome type when pregnancy loss has occurred.20,23,53,54 The authors understand that a modernised classification system is not able to address every clinical scenario but the adoption of a revised terminology55 is a better way forward than persisting with an antiquated description that precedes the universal use of transvaginal ultrasound findings or serum hCG levels. High resolution transvaginal ultrasound provides surveillance and reassurance for the majority of women. By actuarial analysis, the success rate for the next pregnancy can be reasonably predicted based on maternal age and number of losses (Table 32.4).56

References 1. RCOG standards 2008. www.Rcog.org.uk. 2. AEPU 2007. www.earlypregnancy.org.uk/guidelines. 3. Robinson HP. The diagnosis of early pregnancy failure by sonar. Br J Obstet Gynaecol 1975; 82: 849–57. 4. Everett C. Incidence and outcome of bleeding before the 20th week of pregnancy: prospective study from general practice. BMJ 1997; 315: 32–4.

5. Brigham S, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurring miscarriage. Hum Reprod 1999; 14: 2868–71. 6. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flors and bacterial vaginosis: a randomized controlled trial. Lancet 2003; 361: 983–8. 7. Royal College of Obstetricians and Gynaecologists. The management of early pregnancy loss, 2006. Greentop Guideline No 25. 8. Twigg J, Moshy R, Walker JJ, Evans J. Early pregnancy assessment units in the United Kingdom: an audit of current clinical practice. J Clin Excellence 2002; 4: 391–402. 9. CEMACH report. Early Pregnancy. Confidential Enquiry into Maternal and Child Health. Why Mothers Die. London: RCOG Press. 2004 and 2007. 10. Kirk E, Condous G, Bourne T. Ectopic pregnancy deaths: what should we be doing? Hosp Med 2004; 65: 657–60. 11. O’Rahilly R, Muller F. Prenatal ages and stages: measures and errors. Teratology 2000; 61: 382–4. 12. Pedersen JF. Fetal crown rump length measurement by ultrasound in normal pregnancy. BJOG 1982; 89: 926–30. 13. O’Rahilly R. The embryonic period. Teratology 1986; 34: 119. (Letter) 14. Jauniaux E, Kaminopetros P, El-Rafaey H. Early pregnancy loss. In: Rodeck CH, Whittle MJ, eds. Fetal Medicine. Churchill Livingstone, 1999; 835–47. 15. Royal College of Radiologists/ Royal College of Obstetricians and Gynaecologists. Guidance and Ultrasound Procedures in Early Pregnancy. London: RCOG Press, 1995. 16. Chittacharoen A, Herabutya Y. Slow fetal heart rate may predict pregnancy outcome in first-trimester threatened abortion. Fertil Steril 2004; 82: 227–9. 17. Hutchon DJ, Cooper S. Missed abortion versus delayed miscarriage. Br J Obstet Gynaecol 1997; 104: 73. 18. Stirrat GM. Recurrent miscarriage: Definition and epidemiology. Lancet 1990; 336: 673–5. 19. Macklon NS, Geraedts JPM, Fauser BCJM. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update 2002; 8: 333–43.

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Nomenclature and mechanisms of early pregnancy loss 20. Morikawa M, Yamada H, Kato EH et al. Embryo loss pattern is predominant in miscarriages with normal chromosome karyotype among women with repeated miscarriage. Hum Reprod 2004; 19: 2644–7. 21. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril 2000; 73: 300–4. 22. Carp H, Toder V, Aviram A et al. Karyotype of the abortus in recurrent miscarriage. Fertil Steril 2001; 75: 678–82. 23. Stephenson MD, Awartini KA, Robinson WP. Cytogenetic analysis of miscarriages from couples with recurring miscarriage: a case-control study. Hum Reprod 2002; 17: 446–51. 24. Christiansen OB, Nybo Andersen AM, Bosch E et al. Evidenced-based investigations and treatments of recurrent pregnancy loss. Fertil Steril 2005; 83: 821–39. 25. Braekeleer de M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5: 519–28. 26. Franssen MTM, Korevaar JC, Leschot NJ et al. Selective chromosome analysis in couples with two or more miscarriages: case-control study. BMJ 2005; 331: 137–9. 27. Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: Report of an international workshop. Arthritis Rheum 1999; 42: 1309–11. 28. Rai RS, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253–7. 29. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 1584–9. 30. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002; 100: 408–13. 31. Derksen RHWM, Khamashta MA, Branch DW. Management of the obstetric antiphospholipid syndrome. Arthritis Rheum 2004; 50: 1028–39. 32. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; (2): CD002859. 33. Di Nisio M, Peters LW, Middeldorp S. Anticoagulants for the treatement of recurrent pregnancy loss in women without antiphospholipid syndrome. Cochrane Database Syst Rev 2005; (2): CD004734. 34. Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901–8. 35. Dawood F, Farquharson R, Quenby S, Toh CH. Acquired activated protein C resistance may be a risk factor for recurrent fetal loss. Fertil Steril 2003; 80: 649–50. 36. Roque H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. Maternal thrombophilias are not

37.

38.

39.

40.

41.

42. 43.

44.

45. 46.

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50.

51.

52.

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associated with early pregnancy loss. Thromb Haemost 2004; 91: 290–5. Carp H, Dolizky M, Tur-Kaspa I, Inbal A. Heriditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage. Fertil Steril 2002; 78: 58–62. Dunne FM van, Doggen CJ, Heemskerk M, Rosendaal FR, Helmerhorst FM. Factor V Leiden mutation in relation to fecundity and miscarriage in women with venous thrombosis. Hum Reprod 2005; 20: 802–6. Jivraj S, Rai R, Underwood J, Regan L. Genetic thrombophilic mutations among couples with recurrent miscarriage. Hum Reprod 2006; 21: 1161–5. Robertson L, Wu O, Langhorne P et al. Thrombophilia in pregnancy: a systematic review The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Br J Haematol 2006; 132: 171–96. Nelen WLDM, Blom HK, Steegers EAP, den Heijer M, Eskes TKAB. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000; 74: 1196–9. Makris M. Hyperhomocysteinemia and thrombosis. CIin Lab Haemat 2000; 22: 133–43. George L, Mills JL, Johansson AL et al. Plasma folate levels and risk of spontaneous abortion. JAMA 2002; 288: 1867–73. Laird SM, Tukerman EM, Cork BA et al. A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Update 2003; 9: 163–74. Moffett A, Regan L, Braude P. Natural killer cells, miscarriage, and infertility. BMJ 2004; 329: 1283–5. Wold AS, Arici A. Natural killer cells and reproductive failure. Curr Opin Obstet Gynecol 2005; 17: 237–41. Rai R, Sacks G, Trew G. Natural killer cells and reproductive failure, practice and prejudice. Hum Reprod 2005; 20: 1123–6. Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone reduces preconceptual natural killer cells in women with recurrent miscarriage. Fertil Steril 2005; 84: 980–4. Kruse C, Rosgaard A, Steffensen R et al. Low serum level of mannan-binding lectin is a determinant for pregnancy outcome in women with recurrent spontaneous abortion. Am J Obstet Gynecol 2002; 187: 1313–20. Christiansen OB, Nielsen HS, Pedersen B. Active or passive immunization in unexplained recurrent miscarriage. J Reprod Immunol 2004; 62: 41–51. Christiansen OB, Nielsen HS. Intravenous immunoglobulin in the prevention of recurrent miscarriage: does it work? Chem Immunol Allergy 2005; 88: 117–27. Porter TF, LaCoursiere YL, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2006; (2): CD000112. Philipp T, Philipp K, Reiner A, Beer F, Kalousek DK. Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod 2003; 18: 1724–32.

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54. Bricker L, Farquharson RG. Types of pregnancy loss in recurrent miscarriage: implications for research and clinical practice. Hum Reprod 2002; 17: 1345–50. 55. Farquharson RG, Jauniaux E, Exalto N. Updated and revised nomenclature for the description of

early pregnancy events. Hum Reprod 2005; 20: 3008–11. 56. Brigham S, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurring miscarriage. Hum Reprod 1999; 14: 2868–71.

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33 Antiphospholipid syndrome, heritable thrombophilia and early pregnancy loss Benjamin Brenner, Anat Aharon, Galit Sarig

Thrombophilia is common in the Caucasian population. Issues related to the clinical management of pregnancy loss and placental vascular complications in women with inherited or acquired thrombophilia are compelling.1 This chapter is focused on the epidemiology, pathophysiology and management of early pregnancy in women with thrombophilia.

Gestational haemostasis – physiological aspects During normal pregnancy there is a marked increase in the procoagulant activity characterised by an elevation of coagulation factors VII, X and VIII, fibrinogen, and von Willebrand factor. This is associated with an increase in prothrombin fragment 1 and 2, and thrombin–antithrombin complexes maximal augmentation around term.2 In parallel, there is a decrease in physiological anticoagulants manifested by a significant reduction in protein S activity3 and by acquired activated protein C (APC) resistance.4 Finally, the overall fibrinolytic activity is impaired during pregnancy but returns rapidly to normal following delivery.5 This is largely caused by the placenta-derived plasminogen activator inhibitor type 2 that is present in substantial quantities during pregnancy.6 D-dimer, a specific marker of fibrinolysis resulting from the breakdown of cross-linked fibrin polymer by plasmin, increases as pregnancy progresses.7

Foetomaternal cross-talk at the placental vascular bed Certain haemostatic features are dictated by the special structure and function of the placenta. Maternal blood flows in placental intervillous spaces, where it comes into contact with embryonic trophoblast cells. For this reason, the placenta is influenced by coagulation factors derived from two origins. The maternal system contributes the systemic blood components such as coagulation factors, protein C and protein S, while the placenta, of foetal origin, contributes the

cellular regulatory components such as tissue factor (TF) (the initiator of blood coagulation), anticoagulant proteins including thrombomodulin (TM), the endothelial protein C receptor (EPCR) and annexin V.8 Recent studies have focused on local placental haemostasis during pregnancy. Trophoblasts express vascular cell characteristics.9 Syncytiotrophoblasts (STB) have been shown to express high levels of TF and low levels of TF pathway inhibitor (TFPI) compared with human umbilical vein endothelial cells (HUVEC).10 Sood et al11 have recently identified a panel of genes that determine the ability of foetal trophoblast cells to regulate haemostasis at the foetomaternal interface. In addition, women with gestational vascular complications (GVC) have been shown to exhibit a decrease in TFPI levels in comparison to healthy pregnant women.12 The studies mentioned above demonstrate the critical role of proper placental haemostataic balance in maintaining normal placental function. Taken together, these findings may be relevant to the haemostatic phenotype (bleeding or thrombosis) in the placenta.

Role of protease activated receptors in placentation The involvement of protease activated receptors (PARs) in human placentation has been previously described by Even-Ram et al13 PAR1 mRNA expression was not detectable in placental biopsies during the first 6 weeks of gestation, increased dramatically between weeks 7 and 10, and then dropped precipitously after week 11, a pattern that correlates with the first invasive phase of placentation. Experiments with genetically modified mice displaying altered coagulation activation in the placenta have revealed a role for coagulation proteases during development. Mice lacking the TM anticoagulant or its co-receptor EPCR, thus unable to activate protein C, die during early midgestation.14,15 Proliferation and invasive behaviour of human and mouse trophoblast cells are modulated by protease-activated receptor (PAR)-1.16,17 Regulators of blood coagulation and receptors for coagulation

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proteases, which are required for trophoblast specific signalling, are locally expressed at the maternal–foetal interface within the placenta in humans and mice.9–11 However, uncontrolled coagulation activation resulting in unbalanced PAR-activation impairs placental development and function.16,17 The mechanism for platelet-mediated pregnancy failure can be precipitated by a foetal gene defect in factor V Leiden mice.18

Microparticles Microparticles (MPs) are circulating, phospholipid rich, submicron particles released from the membrane of several cells including endothelial cells, platelets, leucocytes and erythrocytes. MPs are released from the surface of cells following cell activation or apoptosis by triggers including chemical stimuli, such as cytokines, thrombin and endotoxin, or physical stimuli, such as shear stress or hypoxia. Following cell activation, a rise in the cytosolic calcium concentration results in activation of calpain and protein kinases, and inhibition of phosphatases. These changes result in cytoskeletal reorganisation, membrane blebbing and the formation of MPs.19 MPs contribute to haemostatic and inflammatory responses, vascular remodelling and angiogenesis, cell survival and apoptosis, well-known processes involved in atherothrombosis. Although hardly detectable in the peripheral blood of healthy individuals, procoagulant MPs circulating at elevated levels are often associated with thrombotic tendency.20

Microparticles and pregnancy-related complications Circulating MPs in pregnancy may have the same origin as in non-pregnancy in addition to MPs derived from syncytiotrophoblasts.21 MPs have been previously shown to be associated with pregnancy-related complications. Laude et al22 found increased levels of circulating MPs in 41 women out of 74, 29 belonging to the group of early pregnancy loss (59%) and 12 to the group of late pregnancy loss (48%). MPs may modulate or reflect several of the key processes in pre-eclampsia, including inflammation, coagulation, platelet activation and endothelial dysfunction. Data from various studies on circulating MPs in pre-eclampsia are inconsistent. Meziani et al23 found increased circulating levels of leucocyte- and platelet-derived MPs in preeclamptic women compared with healthy pregnant women. Unexpectedly, two studies found reduced platelet-derived MPs counts in pre-eclampsia despite equivalent circulating platelet levels and increased platelet activation, as measured by the expression of P-selectin (CD62).24,25 Although MPs are known to be associated with pregnancy related complications, the pathophysiological role of MPs in these complications is as yet unknown. It is not clear whether MPs are simply associated with the pregnancy-related

complications or are causally and mechanistically linked with the disease progression.

Thrombophilia and foetal loss A growing body of evidence suggests that hereditary thrombophilia is more common in women who experience foetal loss. For example, a case–control study in women with inherited thrombophilia, protein C, protein S and antithrombin deficiencies documented an increased risk for foetal loss. In 60 women with thrombophilia, 42 (22%) of 188 pregnancies were lost, compared with 23 (11%) of 202 control pregnancies (odds ratio (OR) 2.0, 95% confidence interval (CI) 1.2–3.3).26 In addition, a high incidence of gestational abnormalities was reported in 15 women who had dysfibrinogenaemia associated with thrombosis. Of 64 pregnancies, 39% ended with miscarriage and 9% ended with intrauterine foetal death.27 In a recent study, at least one thrombophilic defect was found in 96 (66%) of 145 women who had foetal loss, compared with 41 (28%) of 145 in control subjects (OR 5.0, 95% CI 3.0– 8.5).28 The association of factor V Leiden (FVL) mutation with pregnancy loss has been recently analysed by the College of American Pathologists Consensus Conference on Thrombophilia29,30 and at least 16 case– control studies found a high prevalence of FVL in women who had unexplained recurrent foetal loss (up to 30%) compared with 1–10% of control subjects (ORs ranging from 2 to 5). Despite differences in study populations and selection criteria, the results were consistent. No association between FVL and foetal loss was found by six other case–control studies. The latter studies were smaller and mostly included women who had early first trimester foetal losses (which often are caused by non-thrombophilia-related factors). There were three retrospective cohort studies that also found that FVL carriers have a significantly increased risk for recurrent foetal loss. The risk for foetal loss is greater in homozygotes than in heterozygotes with FVL and in female siblings of thrombophilic women who have FVL.31 Activated protein C resistance in the absence of FVL has also been associated with pregnancy loss.28,32 A recent meta-analysis demonstrated that FVL is associated with early (OR 2.01, 95% CI 1.13–3.58) and late (OR 7.83, 95% CI 2.83–21.67) recurrent foetal loss.33 Exclusion of women who had other pathologies associated with foetal loss strengthens the association with FVL. In this meta-analysis, APC resistance (APCR) also correlated with early recurrent foetal loss (OR 3.48, 95% CI 1.58–7.69). Foetal loss has also been associated with factor II 20210 but not with the methylenetetrahydrofolate reductase (MTHFR) TT polymorphism.28,33,34 The endothelial protein C receptor (EPCR) plays a key role in the protein C anticoagulant pathway. Lack of EPCR on vascular endothelial cells leads to thrombosis and diminished EPCR levels on trophoblasts may be associated with pregnancy loss. Autoantibodies to

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EPCR and certain polymorphisms of EPCR were implicated in vascular complications.35 Recently, a report from the group in Nimes suggests that a maternal and potentially a paternal EPCR polymorphism may be relevant to pregnancy outcome. In another study on the vitamin K dependent protein Z, low levels of the protein were associated with increased risk for unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia.36 Differences in type of pregnancy loss (i.e. primary or secondary, isolated or recurrent, consecutive or non-consecutive) and timing (i.e. first, second or third trimester) may also influence the magnitude of these associations.37 Recently, Lissalde-Lavigne et al38 reported findings from the NOHA first study, a large and carefully designed case–control trial, nested in a cohort of nearly 32 700 women, 18% of whom had pregnancy loss during the first gestation. After analysing the characteristics of 3496 pairs of women who had an unexplained pregnancy loss and normal pregnancy control subjects, the investigators describe the incidence of FVL and factor II G20210A in these groups. Notably in this study, the great majority (85%) of losses were after 10 weeks of gestation, partly because of careful exclusion of other causes of pregnancy loss. The findings of the multivariate analysis clearly demonstrate an overall association between unexplained first pregnancy loss and the two thrombophilic risks factors (OR 3.09 and OR 2.34, respectively). The association results from the 3065 women who had losses after 10 weeks of gestation (OR 3.46 and OR 2.60, respectively) but were not found in women who had losses between 3 and 9 weeks of gestation. As unexplained first pregnancy loss occurred in approximately 10% of gestations, the findings of this study may have significant clinical impact, because it suggests that women who had first unexplained pregnancy loss after 10 weeks of gestation should be screened for thrombophilia.

Antithrombotic prophylaxis during pregnancy The antithrombotics available for the prevention and treatment of venous thromboembolism (VTE) during pregnancy and gestational vascular complications (GVC) include unfractionated heparin (UFH), low molecular weight heparin (LMWH) and antiplatelet agents. In the past, UFH was the drug of choice for the prevention and treatment of VTE during pregnancy. However, because of its significant adverse effects, such as osteoporosis and heparin induced thrombocytopenia (HIT), as well as the need for laboratory monitoring, UFH is being replaced by LMWH.39 Both UFH and LMWH do not cross the placenta and are not secreted in breast milk; however, LMWHs exhibit a number of clinical advantages over UFH, including superior bioavailability, longer plasma half-life allowing once-daily dosing,

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and an improved safety profile.40 The anticoagulant effect of heparin is mediated largely through its interaction with ATIII; this produces a conformational change in ATIII and so markedly enhances its ability to inactivate the coagulation enzymes thrombin, factor Xa and factor IXa.41 In addition, LMWH increases production and secretion of TFPI from endothelial cells.42,43 Until recently, studies on treatment of women who have inherited thrombophilia and pregnancy loss were predominantly uncontrolled and included small series of patients treated mostly with LMWH. A recent collaborative study demonstrated the safety of using LMWH during 486 gestations.44 A successful outcome was reported in 83 (89%) of 93 gestations in women who had a history of recurrent pregnancy loss and in all 28 gestations in women who experienced pre-eclampsia during a previous pregnancy. A retrospective French study on the use of enoxaparin during 624 pregnancies revealed a good safety profile.45 More recently a review of close to 2800 treated pregnancies evaluated the safety and efficacy of LMWH in pregnancy.46 The main indications were prophylaxis of VTE and prevention of pregnancy loss. The rate of bleeding complications was low and thrombocytopenia was rare, with no cases of heparininduced thrombocytopenia. Likewise, clinically significant osteoporosis was extremely rare. The live birth rate was 85–96%, depending on the indication for treatment. Patients treated with LMWH during pregnancy did not present with an increase in bleeding complications compared with normal controls matched for the delivery route.46 The Thrombophilia in Pregnancy Prophylaxis Study (TIPPS) is a randomised open label controlled trial in which patients at high risk of pregnancy complications with confirmed thrombophilia were randomised to receive either dalteparin (5000 units/day until 20 weeks then 5000 units every 12 h until 37 weeks or onset of labour) or no treatment. Dalteparin prophylaxis resulted in a significant increase in anti-Xa activity during pregnancy (p<0.0001) compared with controls.47 However, prophylaxis with dalteparin at doses used in this study did not reduce coagulation activation measured by TAT, F1.2 and D-dimer in high-risk thrombophilic women during pregnancy.47 The author’s group has treated 61 pregnancies in 50 women who had thrombophilia and who presented with recurrent foetal loss with the LMWH enoxaparin throughout gestation and 4–6 weeks into the postpartum period.48 Enoxaparin dosage was 40 mg/day, except for patients who had combined thrombophilia or in the case of abnormal Doppler velocimetry suggesting decreased placental perfusion, in which case the dosage was increased to 40 mg twice a day. Of the 61 pregnancies, 46 (75%) resulted in live birth, compared with a success rate of only 20% in these 50 women in previous gestations without antithrombotic therapy.48 Carp et al49 reported a cohort study undertaken to assess the effect of enoxaparin on subsequent live birth

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rate in women who had three or more consecutive pregnancy losses and hereditary thrombophilia. Live birth rate was higher in women treated with enoxaparin: 26 (70.2%) of 37, compared with 21 (43.8%) of 48 in untreated patients. The beneficial effect was mainly seen in women who had primary abortions and in those who had five or more miscarriages. The optimal dosage of LMWH is as yet unknown and should be determined by prospective randomised trials. Ideally large placebo-controlled trials should be advocated. Logistic and ethical difficulties, however, limit such an approach. A recent study by Gris et al50 demonstrated that in women who had thrombophilia and one previous pregnancy loss after 10 weeks of gestation, enoxaparin at a dose of 40 mg/day resulted in a significantly better live birth rate compared with low-dose aspirin (86% versus 29%, respectively). The differences were found in women who had FVL and factor II G20210A, and in women who had protein S deficiency. LIVE-ENOX is a multicentre, prospective, randomised study recently conducted in Israel comparing two doses of enoxaparin, 40 mg/day and 40 mg every 12 h, starting at 5–10 weeks of gestation, throughout pregnancy, and for 6 weeks postpartum to women who had thrombophilia and pregnancy loss51,52 (defined as three or more first-trimester, two or more secondtrimester or at least one third-trimester loss). The primary efficacy endpoint was the delivery of a healthy infant. Other efficacy endpoints were duration of gestation, birth weight and incidence of gestational thrombosis and gestational vascular complications (pre-eclampsia, placental abruption and intrauterine growth retardation (IUGR). Safety endpoints included infant and maternal bleeding episodes, maternal thrombocytopenia, infant health (weight, gestational age, Apgar score at 5 min and any drug-related adverse events. Of the 180 women enrolled, live birth rate before the study was only 28%, but during the study, live birth rates were 84% for the 40 mg/day group and 78% for the 80 mg/day group. Late gestational complications decreased after enoxaparin treatment. The incidence of pre-eclampsia in the enoxaparin 40 mg/ day and 80 mg/day groups was 3.4% and 4.4%, respectively. In the LIVE-ENOX study, the incidence of pre-eclampsia in previous gestations in the enoxaparin 40 mg/day and 80 mg/day groups was 6.7% and 14.3%, respectively, and the incidence of placental abruption was 13.5% and 8.8%, respectively. Similarly, the incidence of placental abruption in the enoxaparin 40 mg/ day and 80 mg/day groups was 4.5% and 3.3%, respectively.52 Approximately one-quarter of the women in both groups had IUGR in previous gestations (22.5% and 24.2%, respectively). IUGR was rare during LMWH treatment. Both doses of enoxaparin seemed to be safe and well tolerated. The gestation period was greater than 36 weeks in more than 80% of patients in each group. Preterm delivery, however, occurred in 10%

and 18.5% of women in the enoxaparin 40 mg/day and 80 mg/day groups, respectively. Postpartum bleeding (1.1% of women in each group) and enoxaparinrelated allergic local skin reactions at the injection sites were observed in a small number of women (2.2% and 3.3% of those receiving 40 mg/day and 80 mg/day, respectively). Prophylaxis with enoxaparin (40 or 80 mg/day) is thus safe and effective for improving pregnancy outcome and reducing late pregnancy complications in thrombophilic women who have a history of pregnancy loss. While these studies are encouraging, large prospective randomised placebo controlled studies have not been performed. Several multicentre studies are currently ongoing and results are expected in the near future.

Antiphospholipid syndrome Classification of patients having antiphospholipid antibodies Antiphospholipid syndrome (APS) is diagnosed by a combination of clinical manifestations of vascular thrombosis and/or recurrent pregnancy losses and laboratory evidence for antibodies against phospholipids binding protein cofactors. Autoimmune APS can be primary53 or secondary – associated with other disease states.54 Antiphospholipid antibodies (aPL) are associated with infections55 or drugs.56 aPL are common in the general population with an estimated prevalence of 3–10% in young adults, especially women.57 Of interest, is that ß2-glycoprotein ß2 GPI)-null mice do not display an obvious disease phenotype;58 and a reduced number of homozygous offspring from heterozygote ß2GPI-deficient humans do not appear to have a thrombotic tendency. The antibodies in APS are directed to epitopes on phospholipid-binding proteins.59 While anti-ß2GP1 antibodies are highly specific for APS (98%), their sensitivity is low (40–50%), and therefore these antibodies were suggested to be unsuitable for clinical practice.60,61 Other antibodies such as antiphosphatidyl ethanolamine (aPE) may be a risk factor for early foetal loss by affecting trophoblast cells as well as for pregnancy loss through binding to PE–kininogen complexes resulting in thrombin-induced platelet aggregation.62 Several issues have been raised by a recent consensus paper which suggested modifications to APS classification and diagnostic criteria.63 First, in the criterion of three or more unexplained consecutive abortions before 10 weeks of gestation in patients with karyotypic anomalies in abortus should be excluded. Second, the criterion of one or more unexplained foetal death after 10 weeks of gestation with a morphologically normal foetus. Third, anticardiolipin antibody (ICL) (IgG or IgM) isotype in a titre above 40 GPL (IgG phospholipid) or MPL (IgM phospholipid) documented on two or more occasions at least 12 weeks apart. Fourth, ß2 GPI antibodies or ß2 GPI dependent aCL should be included.

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Pathophysiological mechanisms Annexin V is a member of the annexin family of calcium-dependent phospholipid-binding proteins which forms two-dimensional crystals on anionic phospholipid surfaces and is expressed by vascular endothelium and placental trophoblasts, among other cell types.64 Annexin V has potent anticoagulant activity via inhibition of phospholipids dependent coagulation reactions. Monocytes are regarded as the source of the majority of circulating TF-bearing MPs. Indeed, aside from the production of proinflammatory cytokines, TF upregulation is a major feature of monocyte activation in the APS.65 Platelet activation in the APS has been extensively studied. Addition of aPL or recombinant dimeric ß2GPI construct mimicking the antibody ß2-GPI complex to blood resulted in increased platelet adhesion to a collagen surface in an in vitro thrombosis model.66 The complement system has recently been linked to coagulation. C5a, an important mediator of the inflammatory response, has been shown to induce the expression of TF on endothelial cells and neutrophils.67 The complement system has also been associated with thrombosis and foetal loss in the APS. Fischetti et al demonstrated involvement of the complement system in fibrin deposition in a growing thrombus in an in vivo thrombosis model in rats after injection of aPL, presumably through the induction of TF expression.68 Likewise, C5a is thought to trigger TF production by neutrophilis, leading to inflammation of placental tissue in mice injected with aPL, which results in foetal loss.69

Management of antiphospholipid syndrome in pregnancy Several studies have reported a beneficial effect of antiplatelet agents and heparins in APS women with a history of pregnancy loss.70–74 Timing of LMWH introduction is at early pregnancy and in women with very early losses therapy can be started when the pregnancy is conceived. Previous studies demonstrated that heparin resulted in a better outcome compared with low dose aspirin.70,71 It is still unclear, which dose of LMWH should be given to pregnant APS patients. It has been suggested that APS women may need a higher dose of LMWH, especially when combined with another or in case of previous thromboembolic event where therapeutic doses of LMWH are advocated by thrombophilia. Traditionally aspirin is also given together with the LMWH, although the clinical benefit of added aspirin remains to be determined. While aspirin treatment has been suggested for the management of women with APS and previous pregnancy loss, aspirin alone did not significantly reduce pregnancy loss rate, RR 1.05 (95% CI 0.66–1.68). Steroids have little effect on pregnancy loss in APS.75

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Hydroxychloroquine, which is prescribed only if indicated for lupus, does not seem to be teratogenic.76,77 The role of IVIG in the management of women with APS and pregnancy loss is controversial; IVIG can inhibit the production and action of aPL. Reports by a number of researchers suggest other potential mechanisms including F(ab’) inhibition of the of aCL to cardiolipin in a dose dependent manner.78 Furthermore, IVIG F(ab’) are capable of inhibiting lupus anticoagulant activity.79 IVIG may contain antiidiotypic antibodies to aPL and can inactivate B cell clones leading to decreased autoantibody production.80 In mice immunised with aPL to induce APS,81 IVIG was shown to reduce foetal resorbtions.

Maternal monitoring Heparin requires frequent partial thromboplastin time (PTT) monitoring and is associated with heparininduced thrombopcytopenia and osteoporosis. In women with ASPa prolonged PTT can be due to LA, and the use of factor Xa levels is recommended in this situation. Assessment of factor Xa levels during LMWH therapy is controversial but due to physiological changes in pregnancy monitoring of anti-Xa levels is recommended.82 There are three levels of anticoagulation with LMWH according to 4-hour postinjection anti-Xa levels: standard prophylactic level (0.2–0.4 u/ ml), high prophylactic level (0.4–0.6 u/ml) and therapeutic level (0.6–1.0 u/ml).83

How do antithrombotics work in early pregnancy failure? aPL are found in 10–20% of women with recurrent pregnancy failure. While causality has been implied it is not proven in humans. A thrombotic mechanism has been implicated84 but alternative mechanisms may explain early losses, such as apoptosis of placental trophoblasts,85 disruption of the Annexin V shield86 and inflammatory processes. Several studies report on non-thrombotic mechanisms which may play a role in pregnancy failure in APS. These include inhibition of trophoblast proliferation,87 and inhibition of trophoblast invasion into the uterine spiral arteries.88,89 Heparin was reported to inhibit binding of ß2-GPI to phospholipids and heparin can enhance plasmin cleavage of ß2-GPI at a specific site. Lessons from gene targeting in mice suggest that platelets play a role in reproduction. In a mouse model, heparin, but not hirudin, prevented complement activation and pregnancy failure.89,90

Summary and future directions Substantial information has been obtained on the clinical manifestations, epidemiology and diagnosis

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of thrombophilia-related pregnancy loss. Insights into potential pathophysiological mechanisms have been gained from studies in mice and on human placentae. These form the basis for the management of women with thrombophilia and hopefully will improve pregnancy outcome.

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34 Ultrasound in early pregnancy Sangeeta Suri, Jemma Johns, Eric Jauniaux

The use of ultrasound in obstetrics and gynaecology was first described by Ian Donald in 1958,1 and subsequently the first demonstration of an early intrauterine pregnancy by means of transvaginal ultrasound was reported in 1967.2 Since then with the advent of high resolution ultrasound it has been possible to study normal human pregnancy development in vivo from as early as the 3rd week postimplantation onwards. Studies have shown that the transvaginal route is superior to the transabdominal route at gestations less than 10 weeks in particular for women who are overweight. It also offers the benefit that it does not require a full bladder, so can be performed immediately and is advantageous in those women who are nil by mouth or vomiting.3–5 Importantly, transvaginal scans have been shown to give clearer images at an earlier gestation as the transvaginal probe is much closer to the organs of interest.4 There is still, however, a use for transabdominal scans in early pregnancy, particularly in women with fibroid uteri and ovarian cysts. Improvements in early pregnancy imaging led to the evolution of the early pregnancy assessment unit,6 providing reassurance for those with normal pregnancies and earlier diagnosis and management for abnormal pregnancies. In order to successfully diagnose abnormal pregnancy development it is fundamental to first understand what is normal. In this chapter, we describe the first 14 weeks of development of a normal early pregnancy dealing exclusively with singleton gestation and then compare the ultrasound features of normal pregnancy with abnormal early pregnancy development.

Normal early pregnancy development (Table 34.1) Visualisation of the gestational sac is the earliest unequivocal sign of pregnancy.10 It can be first seen on transvaginal ultrasound at 4 weeks and 3 days of gestation (postmenstrual age). This structure sonographically resembles a fluid-filled sac, the exocoelomic cavity (ECC) surrounded by a bright echogenic ring, the deciduoplacental interface. The size of this sac

ranges from 2 to 5mm and it is usually eccentrically placed within the endometrium in the upper part of the uterine cavity (Fig 34.1). The corresponding β-human chorionic gonadatrophin (βhCG) level at this stage is approximately 400–800 mIU/ml (first International Reference Preparation, IRP).7 Once the level of βhCG reaches 1000–7200 mIU/ml, then the gestation sac should definitely be visualised. The gestation sac is initially spherical, but as it grows it becomes more oval in shape. In normal intrauterine pregnancies the gestational sac grows at a rate of approximately 1 mm/day in mean sac diameter,11,12 which is calculated by averaging its longitudinal, transverse and anteroposterior diameters.13 In the past gestational sac size and volume had been used as a means to estimate gestational age in women with uncertain last menstrual period (LMP), dates however, recent studies have shown this to be unreliable, with a prediction error of up to 2 weeks.14 The first structure to be seen inside the gestational sac before the embryo itself is the secondary yolk sac (SYS),15 and when seen this confirms an intrauterine pregnancy. This can be seen from the beginning of the 5th week or when the gestational sac reaches 10 mm in diameter16 which corresponds to a βhCG of approximately 7200–10 800 mIU/ml.7 The functions of the yolk sac include nutrition, metabolism, excretion and haematopoiesis.17 On ultrasound the yolk sac is circular with a sonolucent centre that measures 3–4 mm in diameter (Fig 34.2). The yolk sac continues to grow slowly reaching a maximum diameter of approximately 6 mm at 10 weeks.17 The foetal pole can be seen towards the end of the 5th week measuring 2 mm,8 it can be demonstrated as a linear thickening closely attached to the yolk sac in close proximity to the uterine wall (Fig 34.3). Using colour Doppler it may be possible to demonstrate cardiac activity at this gestation. However, in approximately one-third of viable embryos less than 5 mm it cannot be demonstrated.18,19 Between 5 and 9 weeks of gestation there will be a rapid increase in the mean heart rate from 110 to 175 bpm. The heart rate then gradually settles to 160–170 bpm.20–26 Measurements of heart rates in early pregnancy are of limited value and should not be measured in the routine assessment of early pregnancy.

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Table 34.1 Relationship between transvaginal ultrasound findings and hCG levels. Reproduced from Johns and Jauniaux9 with permission.

Gestational age (weeks)

Embryological features (transvaginal ultrasound)

Anatomical landmarks

hCG7 (mIU/ml)

4

Trophoblastic ring Gestational sac ~2 mm

600–1000

5

Secondary yolk sac Gestational sac 8–10 mm Embryo 1–2mm8 ± FHB

6

Embryo 4–9mm8 Gestational sac 16–40 mm FHB +

7

Embryo 10–15 mm8 Gestational sac FHB +

Rhombencephalon ± Upper limb buds

>10 000

8

Embryo 16–22 mm8 Gestational sac ± Foetal movements

± Midgut herniation ± Foetal stomach

>10 000

9

Embryo 23–30 mm8

Midgut herniation ± Foetal stomach

>10 000

10

Embryo 31–40 mm8

Midgut herniation ± Foetal bladder Clavicle/femur/skull Mineralisation ± Foetal stomach

>10 000

11

Embryo 41–52 mm8

± Midgut herniation ± Foetal bladder Foetal stomach Cranial vault mineralisation

>10 000

12

Embryo 53–66 mm8 Obliteration of SYS and ECC

Foetal bladder Cranial vault mineralisation Complete retraction of midgut herniation Four-chamber cardiac view

>10 000

600–10 000

>10 000

hCG, human chorionic gonadotrophin; TVS, transvaginal ultrasound; FHB, foetal heart beat; SYS, secondary yolk sac; ECC, exocoelomic cavity.

Trophoblastic Ring

ECC

Fig 34.1 Gestational sac within the uterine cavity. The trophoblastic ring consists of the decidua capsularis, chorion leave and exocoelomic cavity (ECC).

During the 6th week, the embryo grows rapidly with the crown–rump length (CRL) measuring 4–9 mm in size. It begins to separate from the yolk sac and changes from being linear to curved in shape. Cardiac activity should now be clearly visible. The CRL is the main reference of determining gestational age in early pregnancy,27 for the most accurate measurements the embryo should be visualised in the longitudinal plane and the embryonic length measured by placing callipers at the head and rump (Fig 34.4). The gestational sac at this stage in pregnancy measures approximately 15–40 mm in diameter and the βhCG remains above 10 000 mIU/ml for the duration of the first trimester.7 Towards the end of the 6th week and the beginning of the 7th week the first anatomical structure that becomes visible in the embryo on transvaginal ultrasound is the primitive neural tube, which can be seen as a hypoechoic structure running down the centre of the embryo in a coronal view.28 As transvaginal ultrasound provides better resolution and more accurate identification of embryological structures when

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UT

Foetal Pole

SYS

Fig 34.2 Gestational sac at 5 weeks containing a secondary yolk sac (SYS).

Fig 34.4 Gestational sac at the end of the 6th week with secondary yolk sac and foetal pole. (Note the callipers measuring the crown–rump length).

ECC AM RC

SYS Foetal pole

Fig 34.3 Gestational sac at the beginning of the 6th week with secondary yolk sac (SYS) with adjacent linear thickening representing the foetal pole.

compared with abdominal ultrasound, new charts for dating have been developed for the period of gestation prior to 7 weeks.8 By the 7th week the amniotic membrane and cavity containing the embryo and umbilical cord can be more clearly visualised. The SYS can be seen suspended in the ECC. The embryo now has a CRL of approximately 10–15 mm.8 It is at this stage that the foetal head becomes distinguishable from the rest of the body. The head at this stage is almost completely filled by a single sonolucent cavity called the rhombencephalon29 (Fig 34.5). At this gestation the upper limb buds can also be visualised.

SYS

Fig 34.5 Seven-week gestation with the appearance of the amniotic membrane (AM), the rhomboncephalon (RC) and the secondary yolk sac (SYS) suspended in the exocoelomic cavity (ECC).

The embryo has a CRL of 16–23 mm during the 8th week.8 The upper and lower limb buds become clearer and on close examination foetal movements may become apparent. By the middle of the 8th week the physiological midgut herniation (PMH) can be visualised (Fig 34.6) as can the early foetal stomach in 31% of pregnancies. This is visible in all cases by the 11th week.30 There are now several sonolucent areas in the foetal head, which in saggital view correspond to the prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hindbrain).29 During the 9th week the foetus and membranes are developing rapidly. At this stage the embryo has a

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Midgut Herniation

Nuchal thickness

Fig 34.6

Physiological midgut herniation at 8 weeks’ gestation.

CRL of 23–30 mm.8 The amniotic cavity enlarges as it fills with urine produced by the foetal metanephros.31 With the accumulation of this fluid the amniotic membrane moves towards the foetal plate of the placenta. The choroids plexus and the falx cerebri are clearly visualised with transvaginal ultrasound at this stage, with the choroids plexus occupying the majority of the cavity of the lateral ventricles. This is the earliest stage at which the cerebellum may be visualised (in approximately 20% of embryos). It will be visible in all pregnancies by the middle of the 10th week.29 At the end of the 9th week, the legs, arms and bones of the fingers and toes can be first visualised and the spinal canal seen as two parallel lines on the dorsal coronal section of the embryo. From the 10th week onwards, few new structures appear, however, those structures that were previously visualised on transvaginal ultrasound become clearer, and it becomes possible to carry out limited foetal biometry measuring the biparietal diameter (BPD), femur length and abdominal circumference. Longitudinal biometric studies on embryos have shown uniform growth of CRL, BPD, chorionic and amniotic cavities from 7 to 12 weeks.32 Uniform growth was also demonstrated with regard to the yolk sac until 9–10 weeks of gestation. It had been thought that the yolk sac disappeared as a result of compression between the expanding amniotic cavity and the chorion, however, it has now been shown that the yolk sac starts to degenerate around the 9th–10th week and disappears as a result of involution rather than compression.17 The CRL increases from 31–40 mm (10th week), 41–52 mm (11th week) to 53–66 mm (12th week).8 From the 12th to the 13th week, the foetal kidneys can be imaged using transvaginal ultrasound, and by the 12th week the foetal bladder can be imaged in 50% of cases.33,34 During the 12th week the foetal

Fig 34.7 Twelve-week gestation demonstrating the nuchal thickness.

abdominal capacity has increased so allowing the intestines to slide back resulting in resolution of the PMH. Ultrasonography for first trimester biometry is now routinely carried out between 11 and 14 weeks. During this scan the posterior nuchal area can be measured (Fig 34.7). Nuchal translucency thickness is used as a screening marker for chromosomal aneuploidies such as trisomies 13, 18 and 21, but also for structural abnormalities such as congenital heart disease. It should be possible to detect cardiac situs, and a four-chamber view in the majority of the foetuses by 12 weeks of gestation.35 In fact, it has been shown that the best time to perform an early foetal echocardiogram is at 13 weeks.36 Successful assessment of the vertebrae and overlying skin has also been demonstrated at this gestation.37 Bone mineralisation occurs in the clavicle and femur by 10 weeks and can be visible in the cranial vault at the same time. The bony structures of the face such as the nasal bone and palate can be visualised around 13 weeks.28 Advances in ultrasound technology have allowed us to have a better understanding of early embryological development and have provided us with the opportunity to carry out anomaly scans at a gestation earlier than the routine 20-week scan. The benefit this provides is that it allows earlier intervention where necessary.

Abnormal early pregnancy The introduction of early pregnancy units has revolutionised the management of early pregnancy complications. As well as the benefit of being cost-effective,6 these units have resulted in patient management moving away from surgery to a more expectant outpatient approach.38 Early pregnancy complications include miscarriages, ectopic pregnancies and molar pregnancies. The management of these conditions will be dealt

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RPOC

Gestational sac

Fig 34.8

An empty gestational sac in transverse view at 8 weeks.

with elsewhere; in this chapter we concentrate primarily on the ultrasound features of these complications.

Fig 34.9 Retained products of conception (RPOC) within the uterine cavity.

complete miscarriage at the first visit, i.e. no evidence of RPOCs on scan, care should be taken to ensure that an ectopic pregnancy has been excluded.

Miscarriages Miscarriages are the most common complication of early pregnancy. Approximately 15% of all clinically recognised pregnancies less than 14 weeks of gestation will miscarry,39 and the figure increases to 40% if biochemical pregnancies that miscarry before the menstrual period is missed are included.40 As stated earlier, in order to diagnose abnormal development, knowledge of the normal stages of development is mandatory. A gestation sac with a diameter of ≥20 mm with no evidence of a yolk sac is suggestive of an anembryonic pregnancy or early embryonic demise41,42 (Fig 34.8). If a gestation sac is present and the mean diameter is less than 15 mm then it is recommended that a repeat scan needs to be performed 7 days later to clarify the diagnosis. Similarly if an embryo with a CRL >6 mm and no detectable cardiac activity is present42 a repeat scan 7–10 days later is recommended. In view of the fact that there can be uncertainty with regard to gestational age and that one-third of viable embryos <5 mm will not show cardiac activity, a missed miscarriage or early foetal demise has been defined as an embryo with a CRL >10 mm with no evidence of cardiac activity on two separate occasions a minimum of 7 days apart.43 The appearance of hyperechoic retained products of conception (RPOCs) within the uterine cavity is diagnostic of an incomplete miscarriage (Fig 34.9). However, there appears to be a wide variation as to the optimal cut-off level of endometrial thickness for the differentiation between an incomplete and complete miscarriage with proposed cut-offs ranging from 8 to 15 mm.44,45 In women who are diagnosed with a

Ectopic pregnancy An ectopic pregnancy is one that implants outside the uterine cavity. It is the classic gynaecological emergency and remains a significant cause of maternal morbidity and mortality. In the UK the last triennial report on maternal death reported four deaths in approximately 11 000 cases of ectopic pregnancy, giving a mortality rate of 3.6/10 000.46 These figures have remained unchanged over the past 10 years. The most accurate method of diagnosing an ectopic pregnancy is a combination of ultrasound and serum βhCG.47 If an ectopic pregnancy is present, it should be visualised using transvaginal ultrasound in 80–90% of cases. However, there is considerable variation in the appearance of an ectopic pregnancy on transvaginal ultrasound; they can appear as a hyperechoic ring around a gestation sac in the adnexae (Fig 34.10), or they can be seen as a homogenous mass adjacent to the ovary.48 It has been demonstrated, however, that the most appropriate criterion to diagnose an ectopic pregnancy is a non-cystic adnexal mass.49 When looking for an ectopic pregnancy a useful feature to be aware of is the fact that it will be ipsilateral to the corpus luteum in more than 85% of cases.50 As well as the presence of an ectopic pregnancy, one should also comment on the presence of an embryo, any foetal cardiac activity and the presence of a haematocele. In 95% of cases the ectopic pregnancy will implant in the Fallopian tube, with the majority being in the ampullary region. Other sites, whilst only accounting for 5% of ectopic pregnancies, are associated with a significantly higher morbidity due to the difficulty in diagnosis.

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Cervix Ectopic

Uterine cavity Uterus Cervical ectopic

Fig 34.10 Transverse view of the uterus with an ectopic pregnancy posterior to the uterus.

1cm

Ectopic Uterine cavity

Fig 34.11 Interstitial ectopic pregnancy. Note the distance from the uterine cavity.

Approximately 2% of all ectopic pregnancies are found in the interstitial portion of the tube.51 The diagnosis can be made on transvaginal ultrasound when there is an empty uterine cavity with a gestational sac in the cornua of the uterus surrounded by a thin myometrial layer. The gestational sac should be located more than 1 cm from the lateral edge of the uterine cavity52 (Fig 34.11). Cervical pregnancies are rare, accounting for less than 1% of all ectopic pregnancies. They implant in the cervical mucosa, below the internal os. Authors have described the ultrasound appearances, as being those of an empty uterine cavity, with a ballooned cervical canal containing either a gestational sac or placental tissue with a closed internal os55 (Fig 34.12). Cervical ectopics can be confused with a detached gestational sac passing through the cervical canal, however, these tend to cause pain, whereas cervical pregnancies classically tend to be painless. Using colour Doppler, cervical pregnancies will demonstrate

Fig 34.12 Ballooned cervical canal containing an ectopic pregnancy.

blood flow around the sac54 and when gentle pressure is applied to the cervix using the transvaginal probe, a detached sac will slide through (‘sliding sign’).55,56 The rarest form of ectopic pregnancy is the Caesarean scar pregnancy, although due to a rising Caesarean section rate, its incidence is increasing. It can be diagnosed by visualising trophoblastic tissue between the bladder and the anterior wall of the uterus.57 The sliding organ sign can again be used to distinguish these pregnancies from those that are miscarrying.58 It is important to diagnose these pregnancies as early as possible, as these pregnancies are associated with a high risk of haemorrhage or placenta accreta if they progress to term (Fig 34.13). Heterotopic pregnancies are not common following spontaneous conception, but in women who have undergone assisted conception, the adnexae should be visualised thoroughly even with the presence of an intrauterine pregnancy as the incidence can be as high as 1%.59

Molar pregnancy Hydatidiform moles can either be complete or partial, based on their genetic components. Although early complete moles may be difficult to distinguish from degenerating chorionic tissue using ultrasonography, later complete moles may have the classic features of a uterine cavity filled with multiple sonolucent areas of varying size and shape (snow storm appearance) without associated embryonic or foetal structures (Fig 34.14) and also theca lutein cysts on the ovaries.61,62 In the case of partial moles the diagnosis can be more difficult, however, the two most common sonographic findings are focal cystic changes in the placenta and a ratio of the transverse to anteroposterior dimension of the gestational sac of greater than 1.5.63 However, at present histology still remains the gold standard for diagnosing partial moles.64

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Scar ectopic

(b) Uterus showing Caesarean section scar (a) and a scar ectopic (b).

Complete mole

Fig 34.14 Uterus containing a complete mole. Note sonolucent areas within the placenta.

Conclusion High-resolution transvaginal ultrasound has revolutionised our understanding of normal human development in the first trimester and has rapidly replaced all other techniques used to study this period. Knowledge of the ultrasound appearances of normal early pregnancy development and a good understanding of its pitfalls are essential for the diagnosis and management of abnormal early pregnancy. As ultrasound equipment and experience of operators have improved, abnormal pregnancy development is being diagnosed at earlier gestations. It is hoped that earlier diagnosis with or without intervention will improve morbidity and ultimately mortality rates.

References 1. Donald I, MacVicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet 1958; 1: 1188–95.

2. Kratochwill E, Eisenhut L. Der fruheste nachweis der fatalen herzaction durch ultrascall. Geburtshilfe Frauenheilkd 1967; 27: 176–80. 3. Shilito J, Walker JJ. Early pregnancy assessment units. Br J Hosp Med 1997; 58: 505–9. 4. Fossum GT, Davajan V, Kletzky OA. Early detection of pregnancy with transvaginal ultrasound. Fertil Steril 1988; 49: 788–91. 5. Cullen MT, Green JJ, Reece ES. A comparison of transvaginal and abdominal ultrasound in visualising the first trimester conceptus. J Ultrasound Med 1989; 8: 565–9. 6. Bigrigg MA, Read MR. Management of women referred to early pregnancy assessment unit: care and cost effectiveness. BMJ 1991; 302: 577–9. 7. Bree LR, Marn CS. Transvaginal sonography in the first trimester: embryology, anatomy and hCG correlation. Semin Ultrasound CT MR 1990; 11: 12–21. 8. Hadlock FP, Shah YP KDLJ. Fetal crown–rump length: re-evaluation of relation to menstrual age (5–18 weeks) with high resolution real time US. Radiology 1992; 182: 501–5. 9. Johns J, Jauniaux E. Normal findings and development in early pregnancy. In: Bourne T, Condous G, eds. Handbook of Early Pregnancy Care. Andover: Informa Healthcare, 2006. 10. Goldstein I, Zimmer EA, Tamir A, Peretz BA, Paldi E. Evaluation of normal gestational sac growth: Appearance of embryonic heartbeat and embryo body movements using the transvaginal technique. Obstet Gynecol 1991; 77: 885–8. 11. Nyberg DA, Mack LA, Laing FC, Patten RM. Distinguishing normal from abnormal gestational sac growth in early pregnancy. J Ultrasound Med 1987; 6: 23–7. 12. Jauniaux ER, Jurkovic D. The role of ultrasound in abnormal early pregnancy. In: Gruzinskas JG, O’Brien PMS, eds. Problems in Early Pregnancy: Advances in Diagnosis and Management, London, UK: Royal College of Obstetricians and Gynaecologists Press, 1997: 137. 13. Jurkovic D, Gruboeck, Campbell S. Ultrasound features of normal early pregnancy development. Curr Opin Obstet Gynaecol 1995; 7: 493–504.

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14. Warren WB, Timor-Tritsch I, Peisner DB, Raju S, Rosen MG. Dating the early pregnancy by sequential appearance of embryonic structures. Am J Obstet Gynecol 1989; 161: 747–53. 15. Sauerbrei E, Cooperberg PL, Poland JB. Ultrasound demonstration of the normal fetal yolk sac. J Clin Ultrasound 1980; 8: 217. 16. Timor-Tritsch IE, Farine D, Rosen MG. A close look at early embryonic development with the high frequency transvaginal transducer. Am J Obstet Gynecol 1988; 159: 166–81. 17. Jauniaux E, Jurkovic D, Henriet Y, Rodesch F, Hustin J. Development of the secondary yolk sac: correlation of sonographic and anatomic features. Hum Reprod 1991; 6: 1160–6. 18. Levi CS, Lyons EA, Zheng XH, Lindsay DJ, Holt SC. Endovaginal US: demonstration of cardiac activity in embryo’s of less than 5.0 mm in crown–rump length. Radiology 1990; 176: 71–4. 19 Goldstein SR, Snyder JR, Watson C, Danon M. Very early pregnancy detection with endovaginal ultrasound. Obstet Gynecol 1988; 72: 200–4. 20. Brown DL, Emerson DS, Felker RE, Cartier MS, Smith WC. Diagnosis of early embryonic demise by endovaginal sonography. J Ultrasound Med 1990; 9: 631–6. 21. Tezuka N, Sato S, Kanasugi H, Hiroi M. Embryonic heart rates: development in early first trimester and clinical evaluation. Gynecol Obstet Invest 1991; 32: 210–12. 22. Stefos TI, Lolis DE, Sotiriadis AJ, Ziakas GV. Embryonic heart rate in early pregnancy. J Clin Ultrasound 1998; 26: 33–6. 23. van Heeswijk M, Nijhuis JG, Hollanders HM. Fetal heart rate in early pregnancy. Early Hum Dev 1990; 22: 151–6. 24. Achiron R, Tadmore O, Mashiach S. Heart rate as a predictor of first-trimester spontaneous abortion after ultrasound proven viability. Obstet Gynecol 1991; 78: 330–4. 25. Coulam CB, Britten S, Soenksen DM. Early (34–56 days from last menstrual period) ultrasonographic measurements in normal pregnancies. Hum Reprod 1996; 11: 1771–4. 26. Yapar EG, Ekici E, Gokmen O. First trimester fetal heart rate measurements by transvaginal ultrasound combined with pulsed Doppler: an evaluation of 1331 cases. Eur J Obstet Gynecol Reprod Biol 1995; 60: 133–7. 27. Robinson HP, Flemming JEE. A critical evaluation of sonar ‘crown rump length’ measurements. Br J Obstet Gynaecol 1975; 82: 702–10. 28. Monteagudo A, Timor-Tritsch IE. First trimester anatomy scan: pushing the limits. What can we see now? Curr Opin Obstet Gynecol 2003; 15: 131–4. 29. Blaas HG, Eik-Nes SH, Kiserud T, Hellevik LR. Early development of the hindbrain: a longitudinal study from 7 to 12 weeks gestation. Ultrasound Obstet Gynecol 1995; 5: 148–9. 30. Blaas HG, Eik-Nes SH, Kiserud T, Hellevik LR. Early development of the abdominal wall, stomach and heart from 7–12 weeks gestation: a longitudinal ultrasound study. Ultrasound Obstet Gynecol 1995; 6: 240–9.

31. Jauniaux E, Gulbis B. Fluid compartments of the embryonic environment. Hum Reprod Update 2000; 6: 268–78. 32. Blaas HG, Eik-Nes SH, Bremmes JB. The growth of the human embryo. A longitudinal biometric assessment from 7 to 12 weeks of gestation. Ultrasound Obstet Gynecol 1998; 12: 346–54. 33. Bronshtein M, Kushnir O, Ben-Rafael Z. Transvaginal sonographic measurement of fetal kidneys in the first trimester of pregnancy. J Clin Ultrasound 1990; 18: 299–301. 34. Rosati P, Guariglia L. Transvaginal sonographic assessment of the fetal urinary tract in early pregnancy. Ultrasound Obstet Gynecol 1996; 7: 95–100. 35. Gembruch U, Shi C, Smrcek JM. Biometry of the fetal heart between 10 and 17 weeks of gestation. Fetal Diagn Ther 2000; 15: 20–31. 36. Haak MC, Twisk JW, Van Vugt JM. How successful is fetal echocardiographic examination in the first trimester of pregnancy? Ultrasound Obstet Gynecol 2002; 20: 9–13. 37. Braithwaite JM, Armstrong MA, Economides DL. Assessment of the fetal anatomy at 12 to 13 weeks of gestation by transabdominal and transvaginal sonography. Br J Obstet Gynaecol 1996; 103: 82–5. 38. Hemminki E. Treatment of miscarriage: current practice and rationale. Obstet Gynecol 1998; 91: 247–53. 39. Wilcox AJ, Weinberg CR, O’Connor JF et al. Incidence of early loss of pregnancy. N Engl J Med 1988; 319: 189–94. 40. Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. Br Med J 1989; 26: 541–5. 41. Luise C, Jermy K, Collins WP, Bourne TH. Outcome of expectant management of spontaneous first trimester miscarriage: observational study. BMJ 2002; 324: 873–5. 42. RCR/RCOG Working Party. Early Pregnancy Assessment. London: RCOG Press, 1996. 43. Hately W, Case J, Campbell S. Establishing the death of an embryo by ultrasound: report of public inquiry with recommendations. Ultrasound Obstet Gynecol 1995; 5: 353–7. 44. Neilson S, Hahlin M. Expectant management of first trimester spontaneous abortion. Lancet 1995; 345: 84–6. 45. Wong SF, Lam MH, Ho LC. Transvaginal sonography in the detection of retained products of conception after first trimester spontaneous abortion. J Clin Ultrasound 2002; 30: 428–32. 46. Lewis G, Drife JO. Why Mothers Die. Report on Confidential Inquires Into Maternal Deaths in the United Kingdom 2000–2002. London: RCOG Press, 2004. 47. Gracia C, Barnhart K. Diagnosing ectopic pregnancy: decision analysis comparing six strategies. Obstet Gynecol 2001; 97: 464–70. 48. Goldstein S, Timor-Tritsch IE. Ultrasound Evaluation of Ectopic Pregnancy. In: Laing FC, ed. Ultrasound in Gynecology, 2nd edition Churchill Livingstone: New York, 1995; 161–75. 49. Brown DL, Doublilet PM. Transvaginal sonography for diagnosing ectopic pregnancy: positivity criteria and performance characteristics. J Ultrasound Med 1994; 13: 259–66.

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Ultrasound in early pregnancy 50. Jurkovic D, Bourne TH, Campbell S, Collins WP. The diagnosis of ectopic pregnancy using transvaginal colour flow imaging. Fertil Steril 1992; 57: 68–73. 51. Kallchman GG, Meltzer RM. Interstitial pregnancy following homolateral salpingectomy: Report of 2 cases and review of the literature. Am J Obstet Gynecol 1966; 96: 1139–41. 52. Jafrie SZ, Loginsky SJ, Bouffard JA, Selius JE. Sonographic detection of interstitial pregnancy. J Clin Ultrasound 1987; 15: 253–7. 53. Condous G, Okaro E, Bourne T. The conservative management of early pregnancy complications: a review of the literature. Ultrasound Obstet Gynecol 2003; 22: 420–30. 54. Hofmann HMH, Urdl W, Hofler H. Cervical pregnancy: case reports and current concepts in diagnosis and treatment. Arch Gynecol Obstet 1987; 241: 63–9. 55. Timor Tritsch IE, Rottem S. Transvaginal ultrasonography study of the fallopian tube. Obstet Gynecol 1987; 70: 424–8. 56. Jurkovic D, Hackett E, Campbell S. Diagnosis and treatment of early cervical pregnancy: a review and a report of two cases treated conservatively. Ultrasound Obstet Gynecol 1996; 8: 373–80.

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57. Vial Y, Petignat P, Hohfeld P. Pregnancy in a Cesarean scar. Ultrasound Obstet Gynecol 2000; 16: 592–3. 58. Jurkovic D, Hillaby K, Woelfer B et al. First trimester diagnosis and management of pregnancies implanted into the lower uterine segment Cesarean section scar. Ultrasound Obstet Gynecol 2003; 21: 220–7. 59. Ludwig M, Kaisi M, Bauer O. Heterotopic pregnancy in a spontaneous cycle: do not forget about it! Eur J Obstet Gynecol Reprod Biol 1999; 87: 91–3. 60. Berkowitz RS, Goldstein DP. Chorionic tumors. N Engl J Med 1996; 335: 1740–8. 61. Santos-Ramos R, Forney JP, Schwarz BE. Sonographic findings and clinical correlations in molar pregnancy Obstet Gynecol 1980; 56: 186–92. 62. Baird AM, Beckly DE, Ross FG. The ultrasound diagnosis of hydatidiform mole. Clin Radiol 1977; 28: 637–45. 63. Fine C, Bundy AL, Berkowitz RS. Sonographic diagnosis of partial hydatidiform mole. Obstet Gynecol 1989; 73: 414–18. 64. Johns J, Greenwold N, Buckley S, Jauniaux E. A prospective study of ultrasound screening for molar pregnancies in missed miscarriages. Ultrasound Obstet Gynecol 2005; 25: 493–7.

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35 Evidence-based investigations and treatments of recurrent miscarriage Ole B Christiansen

Introduction Involuntary childlessness affects approximately 15% of all couples but the majority of cases are due to inability to conceive (infertility) and only 1–2% are due to recurrent miscarriage defined as three or more consecutive losses of intrauterine pregnancies before gestational week 22. Much research into the causes of infertility and their management have been performed, and a series of treatments with proven efficacy have been introduced into widespread clinical use. Research regarding the management of couples with recurrent miscarriage has been rarer and often of low-quality, which is partly due to the lower prevalence of recurrent miscarriage, the limited interest of pharmaceutical companies to support research in recurrent miscarriage treatment and the more complex, multifactorial background of RM compared with infertility.1 Which investigations and treatments should be undertaken in recurrent miscarriage therefore remain a matter of great controversy. There is an urgent need for the introduction of more evidence-based investigations and treatments as well as the abolition of many non-evidence-based interventions in the area of recurrent miscarriage. Evidence-based medicine is defined “as the systematic application of scientific evidence to clinical practice” and has been introduced in most medical specialties during the past decade. The major effort towards achieving this goal in recurrent miscarriage has been the performance and publication of several meta-analyses (e.g. Cochrane reviews) and clinical guidelines concerning investigations and treatments.2–6 These meta-analyses and guidelines have probably improved the overall management of the condition but some negative aspects have also become clear: meta-analyses and guidelines in recurrent miscarriage are now also published on topics where too few or too heterogeneous studies exist to justify their performance.1,7 Thus, some investigations and treatments become part of established management of recurrent miscarriage before sufficient good studies have been carried out

and, conversely, some treatments become abandoned at a premature stage if the Cochrane database says that a few small studies have so far not pointed towards a treatment effect. This negative statement often makes it very difficult to get funding to and continue investigation of a particular treatment option because the funding authorities often only read the overall conclusion of the Cochrane reviews.

Research problems characterising recurrent miscarriage Due to the multifactorial background recurrent miscarriage the patient population is extremely heterogeneous with regard to causes and prognosis. In randomised controlled trials of treatment, all or most causative factors must be equally distributed in the groups being compared but this is very difficult to ensure in recurrent miscarriage research since each patient probably carries several factors and many of the factors are not yet known. This problem, in addition to a series of methodological flaws, often invalidates observational and interventional studies in recurrent miscarriage and results in very different estimates of the frequencies and impact of risk factors and of the efficacy of various treatments. The methodological flaws found in recurrent miscarriage studies have been previously reviewed1,8 and here only an overview of some of the most typical is given (Table 35.1).

Evidence-based treatments and tests In clinical guidelines the highest level of evidence (Ia) for the efficacy of a treatment or test comes from a meta-analysis of randomised controlled trials and the second highest level of evidence (Ib) from at least one randomised controlled trial.2 Most of the treatment recommendations are based on such a classification but the method has shortcomings when the number of randomised controlled trials is few, and the trials are small and of very variable quality, which is unfortunately the general situation in the area of recurrent

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Table 35.1

Methodological flaws typical for studies of recurrent miscarriage (RM).

Study-related parameter

Effect on study outcome

Poor characterisation of miscarriage and subgroups of RM Definition of recurrent miscarriage, as two or more miscarriages Samples taken during or just after a miscarriage More than one pregnancy per patient included Older age of patients Comparison of pre- and post-treatment miscarriage rate Inclusion after detection of foetal heart action No exclusions of aneuploid abortuses

Renders comparisons between studies and performance of meta-analyses difficult Decreases difference in frequency of factor studied in CCSs or treatment effect in RCT Findings often a result of miscarriage and not a cause Flaws results in treatment trials Decreases treatment effect in RCT Produces invalid results due to the “regression to the mean” phenomenon Decreases treatment effect in RCT Decreases treatment effect in RCT

CCS: case–control study; RCT; randomised controlled trial.

miscarriage. Sometimes authors of Cochrane metaanalyses are aware of this and do not recommend a specific treatment although the meta-analysis indeed shows effect: an example is progesterone in recurrent miscarriage.6 Sometimes the authors become aware of the limitations of the conclusions in a completed review and consequently completely withdraw it.9 However, in other instances authors of Cochrane metaanalyses reject the possible efficiency of treatments on the basis of a meta-analysis that has lumped together studies of extremely variable quality performed according to very different protocols.4,7 In the area of recurrent miscarriage great caution should thus, at the present stage, be taken when deciding whether a particular treatment is evidence-based or not. One problem for the clinician is that even though there is some level Ia or Ib evidence for an association between a test result and recurrent miscarriage, one cannot be certain that the test should be offered to the patients. The reasons for performing a test in recurrent miscarriage couples can be divided into three categories (Table 35.2): (1) The result of the test can reveal the cause of the disorder, e.g. karyotyping of the couple; (2) The test may give information about the prognosis which can help the couple to decide whether or not to continue trying to conceive, e.g. testing for deficiency of mannose-binding lectin (MBL) or testing for autoantibodies; (3) The test can provide information about which treatment should be offered to improve the prognosis, e.g. testing for lupus anticoagulant (LAC). The expense and the degree of discomfort associated with the test may influence whether a specific test is performed or not. Some Danish clinics have now decided not to do parental chromosome testing in most recurrent miscarriage couples due to its high costs and uncertain clinical value (see next section). Hysteroscopy, although the best method to investigate the uterine cavity,

has increasingly been substituted with hydrosonography due to the discomfort associated with the former. In the following sections the main known causes of recurrent miscarriage will be reviewed, the scientific evidence for the tests used to identify each cause will be discussed and the existing evidence for the treatments used in the causal categories is given.

Chromosome abnormalities It is well documented that chromosomal abnormalities are involved in first trimester miscarriages. Approximately 5% of couples with recurrent miscarriage include a carrier of a balanced structural translocation.10 increasing the risk of producing embryos with unbalanced translocations – however, in almost all cases these will either not implant or miscarry very early.11 It is not clear whether the chance for a subsequent live birth in the next pregnancy is decreased in recurrent miscarriage couples with a carrier of a parental translocation since three relevant studies have reported very diverging results with two12,13 finding no decreased chance of live birth and one14 finding a decreased chance in the first pregnancy compared with recurrent miscarriage couples with no translocations. One study reported that due to the high spontaneous chance for live birth in carriers of translocations and the relatively low overall pregnancy rate after IVF with preimplantation genetic diagnosis (PGD), recurrent miscarriage couples with a translocation would after averagely 3.8 PGD attempts exhibit a cumulative live birth rate of 68% but without PGD the cumulative live birth rate would also reach 68% after 23 months.14 So far there is no scientific evidence that patients should be offered PGD when they are able to conceive spontaneously. The situation is different if the patients are candidates for IVF/ICSI due to infertility/subfertility. Investigations of specimens from miscarriages in couples with normal chromosomes have revealed an incidence of chromosomal abnormalities of 40–46%;15 In patients with recurrent miscarriage a lower but still

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Table 35.2

369

Evaluation of investigations used in recurrent miscarriage (RM).

Abnormality Uterine septa Parental chromosomal translocations Polycystic ovaries High luteinizing hormone Factor II and V mutations Lupus anticoagulant Anticardiolipin/ antinuclear antibody MBL deficiency HLA sharing between spouses HLA-DR1 or-DR3 in the patient NK cell activity in blood

Association to recurrent miscarriage

References

Prognostic impact

References

Yes Yes

24 10

Unknown Unclear

— 12–14

Yes

26

No

No

27

No

Yes

3

Unclear

Yes

3

Yes

Recommended tests

Reason for test*

Hydrosonography Karyotyping

1 1

26

No

—

28

No

—

44, 45

Yes

1

Yes

48

Yes

3

47, 53

Yes

48, 53, 54

Yes

2

Yes No

76, 77 79

Yes No

77 47, 93

Yes No

2 —

Yes

88

Unclear

47

No

—

57, 58, 59

Unclear

—

No

—

Unclear

MBL, mannose-binding lectin, NK, natural killer. HLA, human leucocyte antigen. *Reason for test classification 1, 2 and 3: (see text for details)

significant proportion of miscarriages is caused by foetal aneuploidy.16 The risk of chromosomal abnormalitics is especially high in patients aged >37 years and in these patients the use of preimplantation genetic screening (PGS), may in theory be a therapeutical option. By employing IVF and PGS, it is possible to select apparently euploid embryos for transfer. An uncontrolled trial reported a low miscarriage rate in recurrent miscarriage patients aged >34 years after PGS,17 whereas a retrospective study18 concluded that the miscarriage rate was not significantly different between patients with unexplained recurrent implantation failure aged >37 years treated with IVF with or without PGS. Recently another trial19 has raised doubt as to whether PGS is a useful technique for identifying embryos with the potential to develop into euploid pregnancies. The big problem regarding the use of PGS in recurrent miscarriage is chromosomal mosaicism. Approximately half of preimplantation embryos are observed to be mosaic euploid/aneuploid.20,21 However, Baart et al22 reported that half of day 3 embryos that were found to be mosaic normal/abnormal after biopsy of two blastomeres had become chromosomally normal after developing into blastocysts on day 5. When cell cycle checkpoints are established in embryos after the 4-cell stage many

mosaic embryos seem to “cure” themselves.23 Consequently, by discarding embryos with an aneuploid blastomere after PGS, many mosaic embryos, which probably would have developed normally, are lost and, conversely, mosaic embryos with an euploic blastomere biopsy will be transferred but may develop to aneuploid embryos.22 Prospective controlled trials and cost-effectiveness analyses to assess the real benefit of PGS in recurrent miscarriage according to the patient’s age and number of miscarriages are lacking and so far PGS cannot be recommended in the treatment of recurrent miscarriage.

Uterine anatomical anomalies Observational data suggest that a septate uterus is associated with an increased risk of miscarriage.24 The septum can be removed hysteroscopically; however, only uncontrolled studies reporting better pregnancy performance after surgery than before surgery in the same patients have been undertaken. No prospective trial with appropriate randomisation to surgery and no surgery has been undertaken. Observational data from IVF series also suggest that reproductive outcome is significantly compromised

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with submucous fibroids even when age matching between treated and untreated patients with fibroids was done.25 However, no prospective study of the subsequent miscarriage rate after random allocation to surgical removal of fibroids or no surgery has been undertaken. Thus, overall no evidence-based treatment of uterine anatomical anomalities exists.

Endocrine disturbances Polycystic ovary syndrome Women with polycystic ovary syndrome (PCOS) exhibit an increased rate of miscarriage. However, polycystic ovarian pathology is not predictive of pregnancy loss in women with recurrent miscarriage.26 The prevalence of high follicular phase luteinising homone (LH) levels in recurrent miscarriage patients is approximately 8%,27 but high LH levels seem not to be associated with an increased risk of miscarriage and the suppression of LH with gonadotrophin releasing hormone (GnRH) analogues does not affect the miscarriage risk.28,29 Follicular phase androgen levels seem to be higher in recurrent miscarriage patients than in controls,30,31 however, this may be secondary to an association between an increased risk of miscarriage and obesity.32 Obesity seems to increase the miscarriage rate independently of the presence of PCOS in multivariate analyses.33,34 An oocyte donation study suggests that the obesity-related factors are primarily exerting their harmful effect on the postimplantation embryo or the endometrium.35 Metformin treatment of PCOS patients has, in un-controlled studies, been claimed to decrease the risk of subsequent miscarriage. However, trials in PCOS patients without recurrent miscarriage36,37 found that women achieving pregnancy after metformin treatment had the same or a higher risk of first trimester miscarriage compared with patients given clomiphene treatment. These data render it very unlikely that metformin decreases the rate of miscarriage in recurrent miscarriage patients with PCOS but no randomised controlled trial has yet been conducted in these patients. In theory, weight loss is expected to improve pregnancy prognosis in obese recurrent miscarriage women. Ovulation and fertility rates are improved after even slight weight loss38 but documentation is still needed that miscarriage rate is also reduced. Repeated human choriogonadotrophin (hCG) administration has in one randomised controlled trial 39 been suggested to decrease the miscarriage rate in a subgroup of oligomenorrhoeic recurrent miscarriage patients (who may have PCOS) but it seems not to be of benefit in other recurrent miscarriage patients.9,39 Other suggested treatments of PCOS-related miscarriage indicate pre-conceptional contraceptive pill usage and ovarian diathermia. However none of these treatments have been evaluated in prospective randomised trials.

Luteal phase defects Inadequate secretion of progesterone by the corpus luteum in the luteal phase and in the early weeks of pregnancy has long been considered a causative factor in many cases of miscarriage and recurrent miscarriage. In one study using delayed maturation of repeated late luteal phase endometrial biopsies as a criterion for luteal phase deficiency, 17% of patients with recurrent miscarriage were diagnosed as having the disorder.40 A meta-analysis of all relevant randomised controlled trials of progestogen treatment for preventing miscarriage6 could not detect any effect: however, in a subset of 93 patients with recurrent miscarriage a significant treatment effect was found. These patients had entered three small trials from before 1964 with poor allocation concealment, a substantial number of post-randomisation exclusions or inclusion late in the first trimester. However, given the results in this meta-analysis and evidence that progesterone can switch cytokine production of lymphocytes from recurrent miscarriage women towards production of T-helper type 2 (Th2) cytokines that may be beneficial for pregnancy41 and can prevent preterm birth42 there is a need for more randomised controlled trials of progesterone treatment in recurrent miscarriage. Such trials should be of adequate size, test natural progesterone and treatment should start as soon as the hCG test is positive at the time of the missed period.

Thrombophilias A series of acquired non-antiphospholipid (APL) and congenital factors causing an increased blood clotting tendency have in some studies been found with a higher prevalence in women with recurrent miscarriage than in relevant controls. In a meta-analysis3 factor V Leiden mutation was weakly associated with early recurrent miscarriage (odds ratio(OR) 2.0, 95% confidence interval (CI) 1.1–3.6) but strongly associated to late recurrent miscarriage (OR 7.8, 95% CI 2.8–21.7) and the prothrombin G20210A mutation and protein S deficiency were weakly associated with recurrent miscarriage. Subsequently, a large study found no association between thrombophilic factors and first trimester recurrent miscarriage.43 Studies of the impact of the factor V Leiden mutation on the miscarriage risk in recurrent miscarriage patients found that carriers have an increased44 or a decreased rate45 of first trimester miscarriage. It is thus uncertain whether congenital thrombophilia factors cause first trimester recurrent miscarriage whereas the association to second trimester losses seems strong. Before this is clarified in more prospective studies, treatment of nonAPL thrombophilic patients with anticoagulation outside randomised controlled trials is not indicated. To date, two small studies of heparin and aspirin have been undertaken in recurrent miscarriage patients without APL with conflicting results. A meta-analysis

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of these studies46 concluded that so far there is no evidence supporting the use of empirical thromboprophylaxis to these patients.

Immunological disturbances Autoantibodies Autoantibodies, especially APLs and antinuclear antibodies (ANA), can be found with increased prevalence in women with recurrent miscarriage.47 APLs can give rise to a thrombophilic condition especially if lupus anticoagulant activity is present. APL antibodies without LAC activity affect the future miscarriage rate negatively48 but not as much as claimed in some small studies. The prevalence of positivity for anticardiolipin antibodies (ACA) and LAC varies significantly between studies.47 This can partly be explained by different definitions of a positive ACA/LAC test, the timing of the tests and the fluctuation of ACA levels.1 Some clinics only investigate IgG ACA, however, IgM ACA exhibits a much stronger negative impact on pregnancy outcome.48 A meta-analysis of randomised controlled trials comparing low-dose aspirin with placebo or no treatment in recurrent miscarriage patients with APL has not been able to find any beneficial effect of this treatment.5 Only three small non-blinded controlled trials of heparin/low-dose aspirin versus low-dose aspirin have been undertaken in APL-positive recurrent miscarriage patients, with contradictory results.49–51 Many patients in these trials were included late in the first trimester, the concealment of allocation was inadequate in one trial and the titres and type of APL in the patients were very different. Although a meta-analysis concluded that heparin/ low-dose aspirin is efficient in APL-positive recurrent miscarriage patients, it was concluded that there is a need for more and larger controlled trials of heparin/ low-dose aspirin versus no treatment (or preferably placebo) in these patients.5,52 The significance of other APLs and non-APL autoantibodies such as anti-thyroid antibodies and ANA in recurrent miscarriage is disputed.1 ANA can be found with increased prevalence in recurrent miscarriage patients47,53 and seem to display a negative impact on subsequent pregnancy outcome.48,54 ANA screening should therefore be part of the basic workup of recurrent miscarriage patients.

Natural killer cells One of the causes of pregnancy loss is thought to be the immunological rejection of the foetus. The endometrium from non-pregnant recurrent miscarriage patients harbours a higher frequency of CD16+CD56dim natural killer (NK) cells (exhibiting low expression of the CD56 marker) and a lower frequency of CD16− CD56bright NK cells (exhibiting high CD56 expression) than controls.55 CD56bright NK cells have been shown to produce high levels of a series of cytokines believed to

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be of importance for normal pregnancy development, whereas CD56dim cells exhibit high cytotoxicity.56 The number of activated NK cells may be increased in peripheral blood mononuclear cells (PBMCs) from non-pregnant recurrent miscarriage patients.57 The only studies of immune factors investigated at the time of miscarriage that really are informative as to the causality are those where comparisons are made between findings in recurrent miscarriage patients miscarrying pregnancies with euploid and aneuploid embryos. One such study confirmed that high NK cytotoxicity in PBMCs increases the risk of euploid miscarriage.58 More studies regarding the association between NK cytotoxicity and NK cell subpopulations in PBMCs and the risk of miscarrying euploid embryos are needed. However, NK cell numbers and activity varied significantly between two blood samples taken in the same recurrent miscarriage patients with 20-minute intervals casting doubt on the reproducibility of tests for NK cells.59

Cytokines Cytokines are immune molecules that control both immune and other cells. The Th1 cytokines, include interleukin (IL)-2, interferon (IFN)-γ and tumour necrosis factor (TNF)-α and the Th2 cytokines include IL-4, IL-6 and IL-10. In recurrent miscarriage patients, there is some evidence for a predominant production of Th1 cytokines or decreased production of Th2 cytokines in endometrial cells60,61 or PBMCs before pregnancy62–64 and in early pregnancy65 or in decidual cells66 or PBMCs at the time of miscarriage.67 In the two latter studies, the Th1 cytokine dominance might as well be a result of the miscarriage rather than a cause. Recurrent miscarriage women who subsequently miscarried had a significantly higher production of the Th1 cytokine TNF-α in PBMCs collected from the very early stages of pregnancy compared with those who subsequently gave birth.68 However, other studies found that in early pregnancy production of Th1 cytokines was higher in controls than in recurrent pregnancy loss patients.69 Much more basic knowledge about the complex cytokine networks in pregnancy, the correlation between cytokine production in PBMCs and decidual lymphocytes and whether T- or NK-cell derived cytokines are important must be collected70 before measurements of cytokine production can be introduced in clinical practice. Instead of measuring cytokines or cytokine production directly, many studies have studied the frequency of polymorphisms of cytokine genes in recurrent miscarriage patients and relevant controls. One meta-analysis71 found that genotypes associated with high production of IFN-γ, IL-10 and TNF-α were increased in recurrent miscarriage patients. These associations were later supported72 or rejected73 Several polymorphisms in the IL-1B gene have been reported in single studies but have not been confirmed in others. In one study no differences

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were found between recurrent miscarriage patients and fertile controls with regard to the individual prevalences of IL-6, IFN-γ, TNF-α and IL-10 polymorphisms; however the recurrent miscarriage patients carried genetic polymorphisms associated with low IL-10 expression in combination with polymorphisms associated with high IFN-γ and TNF-α production significantly more frequently than controls.74 So far the most convincing association is between polymorphism in the IFN-γ gene and recurrent miscarriage but larger case–control studies and prospective studies are needed.

Mannose-binding lectin Mannose-binding lectin (MBL) is a constituent of the innate immune system and modulates the cytokine production by monocytes.75 It has also been found that MBL binds to apoptopic cells and stimulates their ingestion by phagocytes, which may prevent and resolute inflammation at the foetomaternal interface since trophoblast cell debris has been suggested to be an important stimulus for NK cell mediated inflammatory reactions in normal and pathological pregnancy.70 Low levels of MBL are associated with recurrent miscarriage and both recurrent miscarriage patients and normal women with low MBL level exhibit a diminished prognosis for achieving ongoing pregnancy.76–78

Human leucocyte antigen Early studies on human leucocyte antigens (HLA) in recurrent miscarriage were based on the hypothesis that increased HLA similarity between partners would lead to inadequate maternal protective immune responses and foetal loss. Although a considerable number of studies on HLA sharing in couples with recurrent miscarriage have been performed, evidence for this hypothesis could not be accumulated.47,79 The non-classical HLA molecule HLA-G exhibits a limited tissue distribution and a low polymorphism HLA-G has attracted much attention since it is one of the few HLA antigens that is expressed on invasive trophoblast cells and it seems in vitro to modifiy cytokine production of mononuclear cells towards a profile beneficial for pregnancy.80,81 Serum levels of soluble (s-)HLA-G seem to be a predictor of pregnancy success82 and recurrent miscarriage patients who carry specific HLA-G alleles may have lower chances for a successful pregnancy.83,84 An HLA-G polymorphism (a 14 base pair insertion in exon 8 of the HLAG gene) is associated to differences in the levels of s-HLA-G in serum, which may explain the link between HLA-G alleles and pregnancy success.85,86 HLA-G polymorphisms associated with recurrent miscarriage and low sHLA-G levels are in linkage disequilibrium with both HLA-DR1 and -DR3,87 which

were significantly associated with recurrent miscarriage in a large case–control study88 and a meta-analysis of 18 relevant studies.89 HLA-DR1 and -DR3 also seem to confer susceptibility to miscarriage in prospective and family studies.47

Immunotherapy Randomised controlled trial using allogeneic lymphocyte immunotherapy (LIT) with paternal or third party PBMCs to women with recurrent miscarriage have provided conflicting results. Variations in cell numbers, number of injections, route of administration, type of placebo etc. make comparisons between the trials difficult. A Cochrane meta-analysis of relevant trials4 concluded that paternal and third party LIT provide no significant beneficial effect over placebo in preventing miscarriages in these patients. However, the meta-analysis may be partially flawed due to the inclusion of a large negative trial immunising with paternal PBMCs stored overnight,90 which impairs the anti-abortive effect of the procedure at least in mice.91 Moreover, it did not perform separate analysis in patients with primary recurrent miscarriage, which is surprising since LIT was found efficient in a previous meta-analysis of outcome in primary recurrent miscarriage patients from eight randomised controlled trials.92 In the Cochrane metaanalysis, the OR for live birth in all recurrent miscarriage patients given third party LIT was 1.39 (95% CI 0.68–2.82) but in a large randomised controlled trial, LIT with freshly prepared third party PBMCs exhibited a significant effect (relative risk for live birth 1.8, 95% CI 1.1–3.2) in patients with primary recurrent miscarriage.93 Further randomised controlled trials of freshly prepared third party LIT in primary recurrent miscarriage are thus needed. Intravenous immunoglobulin (IvIg) modulates cytokine production in addition to many other immune modulating effects. Randomised controlled trials using adequate doses of IvIg found a significant therapeutic effect in secondary recurrent miscarriage patients but no effect in primary recurrent miscarriage.94 However, most trials used IvIg doses much lower than normally used in autoimmune disorders. Indeed, the treatment was often started so late in pregnancy that the drug had not been given enough time to exert its effects and sometimes only patients with primary recurrent miscarriage were included. The Cochrane meta-analysis4 did not distinguish between trials according to these factors and concluded that there is no evidence for a treatment effect of IvIg. Another meta-analysis95 performing separate subanalyses in patients with primary and secondary recurrent miscarriage respectively, found that the OR for live birth in IvIg treated secondary recurrent miscarriage patients was 2.7 (95% CI 1.1–6.7) compared with placebo. More randomised controlled trials of IvIg

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Table 35.3 Recurrent miscarriage group

373

Evaluation of treatments used in recurrent miscarriage (RM) according to the degree of documentation of efficacy.

Treatment

Meta-analyses Effect Reference

No. of randomised controlled trials (no. of patients)

Comments on randomised controlled trials

All

Progesterone

Yes

6

3 (93)

All

hCG

Yes

39

4 (180)

Old studies of poor quality Two studies of poor quality

Autoantibody positive patients

Prednisone + LDA

—

—

1 (202)

APL positive patients

Heparin + LDA

Yes

5, 52

3 (214)

All

Allogeneic LIT

No

4

12 (797)

Primary recurrent miscarriage All

Allogeneic LIT

Yes

54, 92

8 (285)

IvIg

No

4

7 (345)

Secondary RM

IvIg

Yes

95

4 (91)

Improved live birth rate 9% but many side-effects Non-blinded studies, no real placebo, unclear allocation Very heterogenous regarding patients, treatment and effect Very heterogenous regarding treatment Very heterogenous patients, IvIg doses and effect Heterogenous regarding IvIg doses

Status/ recommendation More up-to-date RCTs needed More RCTs needed in patients with oligomenorrhoea More RCTs needed with lower doses and shorter duration More RCTs needed preferably with blinding No more RCTs needed

More RCTs needed using fresh cells in adequate doses More RCTs needed using adequate IvIg doses More RCTs needed using adequate IvIg doses

RCT, Randomised controlled trial; LDA, lowdose aspirin; APL, antiphospholipid; LIT, lymphocyte immunisation therapy; Ivlg, intravenous immunoglobulin.

using adequate doses starting from very early pregnancy (or from before conception) must be undertaken. Glucocorticoid (prednisone) treatment inhibits production of a series of inflammatory cytokines that may be harmful for pregnancy. In one randomised controlled trial, prednisone improved live birth rate non-significantly by 9% in recurrent miscarriage patients with autoantibodies treated during all of pregnancy with high doses.96 Its use was associated with a series of maternal and foetal side-effects. However, another study has suggested that lower doses of prednisone could normalise NK cell subpopulations in the endometrium of recurrent miscarriage patients.97 Therefore, randomised controlled trials in recurrent miscarriage patients where prednisone is administered only before conception and in early pregnancy are warranted.

Conclusions As previously discussed and stressed in Tables 35.2 and 35.3 there is limited evidence for the use of most investigations and almost all treatments of recurrent miscarriage. With regard to investigations there is quite good evidence for a series of abnormalities or genetic polymorphisms being associated with recurrent

miscarriage but how these associations can be applied to the management of patients in clinical practice remains unclear. Table 35.2 is an attempt to classify test results into three groups according to their clinical application: some (group 1) can only be used for giving the patients information about possible causative factors, others (group 2) can also give information about the prognosis and others still (group 3) can in addition give information about which treatment to choose. Since recurrent miscarriage is considered to have a multifactorial background 1 in the individual woman, patients should be screened for all factors that have been consistently associated to recurrent miscarriage; however, it is important not to put too much emphasis on one positive finding. The finding of several risk factors in a couple probably has a larger prognostic impact than the finding of a single factor. 98,99 Whatever is found in the screening programme, it is still the number of previous miscarriages and, after age 40, the age of the patient, which are the strongest prognostic factors.100 Genome-wide screening for genetic polymorphisms has during recent years been very successful in revealing the genetic background for many common diseases that are thought to have a multifactorial

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background. In the future, when these techniques are applied in recurrent miscarriage research we can expect to detect a series of polymorphisms in genes of importance for thrombophilia, regulation of immunological tolerance and inflammatory responses, and PCOS associated endocrine disturbances that will be weakly but significantly associated to recurrent miscarriage. Only when we have the opportunity to screen for all these factors will we be able to fully understand the background for the recurrent miscarriage syndrome in each individual patient/couple and select patients to the type of treatment that has the best chance for success.99 Strictly expressed, no evidence-based treatments of recurrent miscarriage is available at present. As indicated in Table 35.3, reviews based on meta-analyses have concluded that treatments in recurrent miscarriage are not effective or that the treatments may be effective but several of the included randomised controlled trials are deemed to be of generally poor quality. Optimally, from a scientific point of view, we should therefore now await the results of more randomised controlled trials to clarify matters and until then abandon all treatment of recurrent miscarriage patients. This is of course not realistic from a clinical point of view and until more randomised controlled trials are available the clinician must make a personal choice in each case and offer the treatment he/she considers optimal. These choices should be based on a combination of information from the published good quality randomised controlled trials and metaanalyses, consideration about economics and availabilty of the treatment, and not least the clinician’s previous experience with the treatments. Treatment of recurrent miscarriage patients today is still determined primarily by the gynaecologists’ personal experience and opinions, and in some cases, by the patients’ economic position. If management of recurrent miscarriage is to become move evidence based, more well designed RCTs are required (see Table 35.3). However, only when we more fully understand the multifactorial background of recurrent miscarriage through accurate phenotyping and genomic studies in large recurrent miscarriage groups will we be able to pinpoint the necessary RCTs and optimal therapies for individual patients.

References 1. Christiansen OB, Nybo-Andersen AM, Bosch E et al. Evidence-based investigations and treatments of recurrent pregnancy loss. Fertil Steril 2005; 83: 821–39. 2. Royal College of Obstetricians and Gynaecologists. Guideline 17: The Management of Recurrent Miscarriage, London: RCOG Press, 1998. 3. Rey E, Kahn SR, David M et al. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901–8.

4. Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev 2003; (1): CD000112. 5. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev 2005; (2): CD002859. 6. Oates-Whitehead RM, Haas DM, Carrier JA. Progestogen for preventing miscarriage. The Cochrane Library 2003; (4): CD003511. 7. Christiansen OB, Daya S, Bosch E, Delves PJ. Weighing the evidence – metaquality and immuological problems in in vitro fertilization cycles? Reply of the authors. Fertil Steril 2005; 84: 813–14. 8. Christiansen OB. Evidence-based investigations and treatment of recurrent pregnancy loss. Curr Opin Obstet Gynecol 2006; 18: 304–12. 9. Scott JR, Pattison N. Human chorionc gonadotrophin for recurrent miscarriage. Cochrane Database Syst Rev 1996; (1): CD000101. 10. De Braekeleer M, Dao TN. Cytogenetic studies in couples experiencing repeated pregnancy losses. Hum Reprod 1990; 5: 519–28. 11. Goddijn M, Joosten JH, Knegt AC et al. Clinical relevance of diagnosing structural chromosome abnormalities in couples with repeated miscarriage. Hum Reprod 2004; 19: 1013–17. 12. Carp H, Feldman B, Oelsner G, Schiff E. Parental karyotype and subsequent live births in recurrent miscarriage. Fertil Steril 2004; 81: 1296–301. 13. Stephenson MD, Sierra S. Reproductive outcomes in recurrent pregnancy loss associated with a parental carrier of a structural chromosome rearrangement. Hum Reprod 2006, 21: 1076–82. 14. Sugiura-Ogasawara M, Ozaki Y, Sato T et al. Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocations. Fertil Steril 2004; 81: 367–73. 15. Creasy R. The cytogenetics of spontaneous abortion in humans. In: Beard RW, Sharp F, editors. Early Pregnancy Loss: Mechanisms and Treatment. London: Springer Verlag; 1988: 293–304. 16. Carp H, Toder V, Aviram A et al. Karyotype of the abortus in recurrent miscarriage. Fertil Steril 2001; 75: 678–82. 17. Munné S, Chen S, Fischer J et al. Preimplantation genetic diagnosis reduces pregnancy loss in women aged 35 years and older with a history of recurrent miscarriages. Fertil Steril 2005; 84: 331–5. 18. Platteau P, Staessen C, Michiels A et al. Preimplantation genetic diagnosis for aneuploidy screening in women older than 37 years. Fertil Steril 2005; 84: 319–24. 19. Mastenbroek S, Twisk M, van Echten-Arends J et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007; 357: 9–17. 20. Bielanska M, Tan SL, Ao A. Chromosomal mosaicism throughout human preimplantation development in vitro: incidence, type, and relevance to embryo outcome. Hum Reprod 2002; 17: 413–19. 21. Ziebe S, Lundin K, Loft A et al. FISH analysis for chromosomes 13,16,18,21,22, X and Y in all blastomers of IVF pre-embryos from 144 randomly selected donated human oocytes and impact on preembryo morphology. Hum Reprod 2003; 18: 2575–81.

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Evidence-based investigations and treatments of recurrent miscarriage 22. Baart EB, Martini E, van den Berg I et al. Preimplantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF. Hum Reprod 2006; 21: 223–33. 23. Harrison RH, Kuo HC, Scriven PN et al. Lack of cell cycle checkpoints in human cleavage stage embryos revealed by a clonal pattern of chromsomal mosaicism analysed by sequential multicolour FISH. Zygote 2000; 8: 217–24. 24. Homer HA, Li TC, Cooke ID. The septate uterus: a review of management and reproductive outcome. Fertil Steril 2000; 73: 1–14. 25. Bajekal N, Li TC. Fibroids, infertility and pregnancy wastage. Hum Reprod Update 2000; 6: 614–20. 26. Rai R, Backos M, Rushworth F, Regan L. Polycystic ovaries and recurrent miscarriage; a reappraisal. Hum Reprod 2000; 15: 612–15. 27. Li TC, Spuijbroek MD, Tuckerman E et al. Endocrinological and endometrial factors in recurrent miscarriage. Br J Obstet Gynaecol 2000; 107: 1471–9. 28. Nardo LG, Rai R, Backos M et al. High serum luteinizing hormone and testosterone concentrations do not predict pregnancy outcome in women with recurrent miscarriage. Fertil Steril 2002; 77: 348–52. 29. Clifford K, Rai R, Watson H et al. Does suppressing luteinizing hormone secretion reduce the miscarriage rate? Results of a randomised controlled trial. BMJ 1996; 312: 1508–11. 30. Okon MA, Laird SM, Tuckerman E, Li TC. Serum androgen levels in women who suffer recurrent miscarriage and their correlation with markers of endometrial function. Fertil Steril 1998; 69: 682–90. 31. Bussen S, Sutterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortions. Hum Reprod 1999; 14: 18–20. 32. Hamilton-Fairley D, Kiddy D, Watson H et al. Association of moderate obesity with poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. Br J Obstet Gynaecol 1992; 99: 128–31. 33. Fedorcsak P, Storeng R, Dale PO et al. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gynecol Scand 2000; 79: 43–8. 34. Wang JX, Davies MJ, Norman RJ. Obesity increases the risk of spontaneous abortion during infertility treatment. Obesity Res 2000; 10: 551–4. 35. Bellver J, Rossal LP, Bosch E et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil Steril 2003; 79: 1136–40. 36. Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med 2007; 356: 551–66. 37. Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 2006; 332: 1485. 38. Norman RJ, Noakes M, Wu R et al. Improving reproductive performance in overweight/obese women with effective weight management. Hum Reprod Update 2004; 10: 267–80.

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39. Quenby S, Farquharson RG. Human chorionic gonadotropin supplementation in recurring pregnancy loss: a controlled trial. Fertil Steril 1994; 62: 708–10. 40. Stephenson MD. Frequency of factors associated with habitual abortion in 197 couples. Fertil Steril 1996; 66: 24–9. 41. Raghupathy R, Al Mutawa E, Makhseed M et al. Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. Br J Obstet Gynaecol 2005; 112: 1096–101. 42. Meis PJ, Klebanoff M, Thom E et al. Prevention of recurrent preterm delivery by 17 alphahydroxycaproate. N Engl J Med 2003; 348: 2379–85. 43. Roque H, Paidas MJ, Funai EF et al. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 2004; 91: 290–5. 44. Rai R, Backos M, Elgaddal S et al. Factor V Leiden and recurrent miscarriage – prospective outcome of untreated pregnancies. Hum Reprod 2002; 17: 442–5. 45. Carp H, Dolitzky M, Tur-Kaspa I, Inbal A Herditary thrombophilias are not associated with decreased live birth rate in women with recurrent miscarriage. Fertil Steril 2002; 78: 58–62. 46. Di Nisio M, Peters LW, Middeldorp S. Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome. The Cochrane Database Syst Rev 2005; (2): CD004734. 47. Christiansen OB. A fresh look at the causes and treatment of recurrent miscarriage, especially its immunological aspects. Hum Reprod Update 1996; 2: 271–93. 48. Nielsen HS, Christiansen OB. Prognostic impact of anticardiolipin antibodies in women with recurrent miscarriages negative for the lupus anticoagulant. Hum Reprod 2005; 20: 1720–8. 49. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 1997; 314: 253–7. 50. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996; 174: 1584–9. 51. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol 2002; 1000: 408–13. 52. Lassere M, Empson M. Treatment of antiphospholipid syndrome in pregnancy - a systematic review of randomized therapeutic trials. Thromb Res 2004; 114: 419–26. 53. Xu I, Chang V, Murphy A et al. Antinuclear antibodies in sera of patients with recurrent pregnancy wastage. Am J Obstet Gynecol 1990; 163: 1493–7. 54. Recurrent Miscarriage Immunotherapy Trialists Group. Worldwide collaborative observational study and meta-analysis on allogenic leukocyte immunotherapy for recurrent spontaneous abortion. Am J Reprod Immunol 1994; 32: 55–72. 55. Lachapelle MH, Miron P, Hemmings R, Roy DC Endometrial T,B, and NK cells in patients with

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Textbook of Periconceptional Medicine recurrent spontaneous abortion. Altered profile and pregnancy outcome. J Immunol 1996; 156: 4027–34. Cooper MA, Fehninger TA, Turner SC et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Immunobiology 2001; 97: 3146–51. Ntrivalas EI, Kwak-Kim JYH, Gilman-Sachs A et al. Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Hum Reprod 2001; 16: 855–61. Yamada H, Kato EH, Kobashi G et al. 2001 High NK Cell activity in early pregnancy correlates with subsequent abortion with normal chromosomes in women with recurrent abortion. Am J Reprod Immunol 2001; 46: 132–6. Shakhar K, Rosenne E, Loewenthal R, Shakhar G, Carp H, Ben-Eliyahu S. High NK cell activity in recurrent miscarriage: what are we really measuring? Hum Reprod 2006; 21: 2421–5. von Wolff, Thaler CJ, Strowizki T et al. Regulated expression of cytokines in human endometrium throughout the menstrual cycle; dysregulation in habitual abortion. Mol Hum Reprod 2000; 6: 627–34. Laird SM, Tuckerman EM, Cork BA et al. A review of immune cells and molecules in women with recurrent miscarriage. Hum Reprod Update 2003; 9: 163–74. Lim KJH, Odukoya OA, Ajjan RA et al. The role of T-helper cytokines in human reproduction. Fertil Steril 2000; 73: 136–42. Hill JA, Polgar K, Anderson DJ. T-helper 1-type immunity to trophoblast in women with recurrent spontaneous abortion. JAMA 1995; 273: 1933–6. Kwak-Kim JY, Chung Bang HS, Ng SC et al. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile with multiple implantation failures after IVF. Hum Reprod 2003; 18: 767–73. Muelller-Eckhardt G, Mallmann P, Neppert J et al. Immunogenetic and serological investigations in nonpregnant and in pregnant women with a history of recurrent spontaneous abortions. German RSA/ IVIG Study Group. J Reprod Immunol 1994; 27: 95–109. Piccinni MP, Beloni L, Livi C et al. Defective production of both leucemia inhibitory factor and type 2 T-helper cytokines by decidual T cells in unexplained recurrent abortions. Nat Med 1998; 4: 1020–4. Makhseed M, Raghupathy R, Azizieh F et al. Th1 and Th2 cytokine profiles in recurrent aborters with successful pregnancy and with subsequent abortions. Hum Reprod 2001; 16: 2219–26. Kruse C, Varming K, Christiansen OB. Prospective, serial investigations of the in-vitro lymphocyte cytokine production, CD62L expression and proliferative response to microbial antigens in women with recurrent miscarriage. Hum Reprod 2003; 18: 2465–72. Bates MD, Quenby S, Takawuwa K et al. Aberrant cytokine production by peripheral blood mononuclear cells in recurrent miscarriage? Hum Reprod 2002; 17: 2439–44.

70. Borzychowski AM, Croy BA, WL Chan et al. Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells. Eur J Immunol 2005; 35: 3054–63. 71. Daher S, Shulzhenko N, Morgun A et al. Associations between cytokine gene polymorphism and recurrent pregnancy loss. J Reprod Immunol 2003; 58: 69–77. 72. Prigoshin N, Tambutti M, Larriba J et al. Cytokine gene polymorphism in recurrent pregnancy loss of unknown cause. Am J Reprod Immunol 2004; 52: 36–41. 73. Pietrowski D, Bettendorf H, Keck C et al. Lack of association between TNFalpha gene polymorphisms and recurrent pregnancy loss in Caucasian women. J Reprod Immunol 2004; 61: 51–8. 74. Costeas PA, Koumouli A, Giantsiou-Kyriakou A et al. Th1/Th3 cytokine genotypes are associated with pregnancy loss. Hum Immunol 2004; 65: 135–41. 75. Jack DL, Read RC, Tenner AJ et al. Mannose-binding lectin regulates the inflammatory response of human professional phagocytes to Neisseria menigititis serogroup B. J Infect Dis 2001; 184: 1152–62. 76. Kilpatrick DC, Bevan BH, Liston WA. Association between mannan-binding protein deficiency and recurrent miscarriage. Hum Reprod 1995; 10: 2501–5. 77. Kruse C, Rosgaard A, Steffensen R et al. Low serum level of mannan-binding lectin is a determinant for pregnancy outcome in women with recurrent spontaneous abortion. Am J Obstet Gynecol 2002; 187: 1313–20. 78. Dahl M, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. A population-based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med 2004; 199: 1391–9. 79. Christiansen OB, Riisom K, Lauritsen JG, Grunnet N. No increased histocompatibility antigen sharing in couples with idiopathic habitual abortions. Hum Reprod 1989; 4: 160–2. 80. Van der Meer A, Lukassen HGM, van Lierop MJC et al. Membrane-bound HLA-G activates proliferation and interferon-γ production by uterine natural killer cells. Mol Hum Reprod 2004; 10: 189–95. 81. Maejima M, Fujii T, Kozuma S et al. Presence of HLA-G-expressing cells modulates the ability of peripheral blood mononuclear cells to release cytokines. Am J Reprod Immunol 1997; 38: 75–8. 82. Pfeiffer KA, Rebmann V, van der Ven K et al. Soluble histocompatibility antigen levels in early pregnancy after in vitro fertilization. Hum Immunol 2000; 61: 559–64. 83. Pfeiffer KA, Fimmers R, Engels G et al. The HLA-G genotype is potentially associated with idiopathic recurrent spontaneous abortion. Mol Hum Reprod 2001; 7: 373–8. 84. Aldrich CL, Stephenson MD, Karrison T et al. HLA-G genotypes and pregnancy outcome in couples with unexplained recurrent miscarriage. Mol Hum Reprod 2001; 7: 1167–72. 85. Hviid TV, Rizzo R, Christiansen OB et al. HLA-G and IL-10 in serum in relation to HLA-G genotype and polymorphisms. Immuogenetics 2004; 56: 135–41.

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Evidence-based investigations and treatments of recurrent miscarriage 86. Hviid TV, Hylenius S, Lindhard A, Christiansen OB Association between human leukocyte antigen-G genotype and success of in-vitro fertilization and pregnancy outcome. Tissue Antigens 2004; 64: 66–9. 87. Hviid TV, Christiansen OB. Linkage disequilibrium between human leukocyte antigen (HLA) class II and HLA-G – possible implications for human reproduction and autoimmune disease. Hum Immunol 2005; 66: 688–99. 88. Kruse C, Steffensen R, Varming K, Christiansen OB A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage. Hum Reprod 2004; 19: 1215–21. 89. Christiansen OB, Ring M, Rosgaard A et al. Association between HLA-DR1 and -DR3 antigens and unexplained repeated miscarriage. Hum Reprod Update 1999: 5: 249–55. 90. Ober C, Karrison T, Odem RR et al. Mononuclear-cell immunization in prevention of recurrent miscarriages: a randomized trial. Lancet 1999; 354: 365–9. 91. Clark DA, Chaouat G. Immunomodulation by CD200 as a basis for prevention of cytokine-dependent fetal loss syndrome. Am J Reprod Immunol 2003; 49: 350–1. 92. Daya S, Gunby J. The effectiveness of allogeneic leukocyte immunization in unexplained recurrent spontaneous abortion. Recurrent miscarriage immunotherapy trialists group. Am J Reprod Immunol 1994; 32: 294–302. 93. Christiansen OB, Mathiesen O, Husth M et al. Placebo-controlled trial of active immunization

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with third party leukocytes in recurrent miscarriage. Acta Obstet Gynecol Scand 1994; 73: 261–8. Christiansen OB, Pedersen B, Rosgaard A, Husth M. A randomized, double-blind, placebo-controlled trial of intravenous immunoglobulin in the prevention of recurrent miscarriage: evidence for a therapeutic effect in women with secondary recurrent miscarriage. Hum Reprod 2002; 17: 809–16. Hutton B, Sharma R, Fergusson D, Tinmouth A, Herbert, Jamieson J, Walker M. Use of intravenous immunoglobulin for treatment of recurrent miscarriage: a systematic review. BJOG 2007; 114: 134–42. Laskin CA, Bombardier C, Hannah ME et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Eng J Med 1997; 337: 148–53. Quenby S, Kalumbi C, Bates M et al. Prednisolone reduces preconceptual endometrial natural killer cells in women with recurrent miscarriage. Fertil Steril 2005; 84: 980–4. Jivraj S, Rai R, Underwood J, Regan L. Genetic thrombophilic matations among couples with recurrent miscarriage. Hum Reprod 2006; 21: 1161–5. Christiansen OB, Steffensen R, Nielsen HS, Varming K. Multifactorial etiology of recurrent miscarriage and its scientific and clinical implications. Gynecol Obstet Invest 2008; 66(4): 257–67. [Epub ahead of print]. Cauchi MN, Coulam CB, Cowchock S et al. Predictive factors in recurrent spontaneous aborters – a multicenter study. Am J Reprod Immunol 1005; 33: 165–70.

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36 Ectopic pregnancy after fertility treatment Bassem Refaat, Majedah Al-Azemi, William Ledger

Introduction Ectopic pregnancy is any pregnancy in which the fertilised ovum implants outside the endometrial lining of the intrauterine cavity. More than 95% of ectopic pregnancies occur in the Fallopian tubes (tubal pregnancy), mainly in the ampullary region. However, other parts of the tube are affected, such as the isthmic or interstitial regions. Another 2.5% occur in the cornua of the uterus, and the remainder are found in the ovary, cervix or abdominal cavity.1 Ectopic pregnancy is an increasing health risk for women throughout the world and continues to be the leading cause of maternal death in the first trimester.2 In the UK the incidence doubled from 4.9 to 9.6 per 1000 pregnancies between 1973 and 1993, whilst mortality decreased from 16 to 3 per 10 000 cases of ectopic pregnancy3 and it is the fourth leading cause of direct maternal deaths, accounting for 80% of first trimester deaths according to the confidential enquiry into maternal deaths.4 Infertility, or the inability to conceive, is a problem of global proportions, affecting between 8 and 12% of couples worldwide.5 A history of infertility and infertility treatment increases the risk of ectopic pregnancy and the incidence is two to three times greater than in general population.2 Infertility treatment may also result in a heterotopic pregnancy, which is an ectopic pregnancy together with an intrauterine pregnancy. Spontaneous heterotopic pregnancy was considered to be very rare with an incidence of one in 30 000 pregnancies. The incidence of heterotopic pregnancy has increased after assisted reproductive techniques (ART).6,7 Subsequent to in vitro fertilisation (IVF) treatment heterotopic pregnancy ranges from 1 to 3% of all clinical pregnancies8–10 and has been found to complicate one in 4000 to one in 7000 pregnancies following infertility treatment.6,7

Risk factors The main risk factor for ectopic pregnancy is tubal infertility.11–13 Anatomically damaged tubes are unable to propel the migrated embryo into the uterine cavity.11,14 Controversy still surrounds the exact aetiology of ectopic pregnancy; however, it contributes to

Table 36.1

Common risk factors for ectopic pregnancy.

Pelvic inflammatory disease (PID) Previous ectopic pregnancy Tubal surgery Endometriosis Smoking ART specific factors ART, assisted reproductive techniques

poor reproductive performance amongst women of childbearing age.15 Although a proportion of women with ectopic pregnancy have no identifiable causal factors, several factors increase the risk of ectopic pregnancy. These factors share a common mechanism of action, namely interference with Fallopian tube function (Table 36.1).16 Many women will undergo assisted conception treatment due to infertility secondary to blockage or damage of the Fallopian tubes. Although embryo transfer following fertilisation in vitro will relatively place the embryo(s) within the uterine cavity, it is possible for the embryo to enter the tube and establish an ectopic implantation. Risk factors associated with ART are treatment specific and will be explored in the following sections.

Pelvic inflammatory disease In the general population, PID is the most common risk factor associated with ectopic pregnancy.17 A history of PID is particularly important and has been implicated in the increased incidence of ectopic pregnancy.18,19 Organisms that preferentially attack the Fallopian tubes include Neisseria gonorrhoeae, Chlamydia trachomatis, and mixed aerobes and anaerobes. The most common causative organism of PID in the UK is C. trachomatis.20,21 Unlike mixed aerobes and anaerobes, N. gonorrhoeae and C. trachomatis can produce silent infections and may still cause tubal damage. C. trachomatis infection is the most common sexually transmitted infection throughout the world. The highest incidence of Chlamydia is in teenage and young adults from the ages of 15 to 25 years.22 Chlamydia is a small

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intracellular bacterium that needs living cells to multiply. There are 18 distinct serotypes of C. trachomatis, with serotypes D through K causing sexually transmitted genital infections and neonatal infection. C. trachomatis is the most important cause of mucopurulent cervicitis in women. Chlamydial cervicitis is usually asymptomatic and may be associated with ascending infection to the upper genital tract resulting in PID.21 Women are at risk for serious long-term consequences of Chlamydia infection, because ascending chlamydial infection can result in colonisation of the endometrium and Fallopian tube epithelial cells.20,21 The immune response to this infection may result in tubal occlusion, ectopic pregnancy and infertility.22 Many studies have examined the association between chlamydial infection and the development of ectopic pregnancy. One study using ligase chain reaction (LCR) showed that the majority of Fallopian tube biopsies collected at the time of salpingectomy expressed chlamydial DNA.23 Another research group detected Chlamydia mRNA in Fallopian tube specimens and suggested that the chlamydial cells were viable and metabolically active at the time of tissue biopsy.24 Other researchers suggested that chlamydial DNA can persist in tissue specimens when the organism cannot otherwise be detected.25 Several other studies using either paraffin embedded archival Fallopian tubes or fresh frozen specimens reported negative results using both cell culture and polymerase chain reaction (PCR) for testing tubal tissue from ectopic pregnancies. However, serological markers indicated prior chlamydial infections in many of these cases.26–28 A recent study investigated fresh frozen tubal tissue from patients diagnosed with ectopic pregnancy for the presence of C. trachomatis DNA by PCR and blood samples were analysed for antibodies to C. trachomatis including heat shock protein 60 (hsp60). The authors reported that all samples were negative for chlamydial DNA using PCR and real-time quantitative PCR. Both IgA and IgG antibodies to C. trachomatis were detected in both the patient and control groups. However, only IgA antibody concentrations were significantly different between both groups, being higher in the patient group. The results also showed that the combination of IgG antibodies and chlamydial hsp60 was associated with ectopic pregnancy.29 The precise mechanism by which chlamydial infection results in tubal damage is still unclear. In women infected with these organisms, even early treatment does not necessarily prevent tubal damage.30,31 After acute salpingitis, the risk of an ectopic pregnancy is increased by sevenfold.18 Comprehensive programmes to prevent chlamydial infection not only decrease the incidence of C. trachomatis infections, but also the rate of ectopic pregnancies.32,33

Previous ectopic pregnancy Previous ectopic pregnancy becomes a more significant risk factor with each successive occurrence.34

With one previous ectopic pregnancy treated by linear salpingostomy, the recurrence rate ranges from 15 to 20%, depending on the integrity of the contralateral tube.18,35 Two previous ectopic pregnancies increase the risk of recurrence to 32%, although an intervening intrauterine pregnancy lowers this rate.18,36

Endometriosis Several studies have reported an association between endometriosis and ectopic pregnancy.36–39 Endometriosis results in pelvic and tubal adhesions and abnormal tubal function. The Fallopian tubes may also be affected by other, less clearly understood causes of infertility,38,39 as well as many of the hormones that are administered to aid ovulation and improve fertility.36

Cigarette smoking Cigarette smoking has a dose dependent effect on the risk of ectopic pregnancy.18,40,41 Smoking is known to affect ciliary action in the nasopharynx and respiratory tract.42,43 A similar effect has been observed within the Fallopian tube. Smoking decreased tubal ciliary beat frequency and caused coordination impairment, which may lead to the development of ectopic pregnancy.41

Infertility treatment The associations between infertility and ectopic pregnancy are complex, as simultaneously one of them could be a cause and the other a consequence.44–46 There is an increased risk of developing ectopic pregnancy following fertility treatment, which could be due to the effects of the treatment or the pre-existing disorder.13 Ovulation stimulation with clomiphene citrate or gonadotrophins is commonly used as part of most infertility treatments. It is not clear whether there is an association between ovulation stimulation and development of ectopic pregnancy. ARTs which result in high oestradiol levels have been implicated as a cause of reverse migration of embryos from the uterine cavity into the Fallopian tube.47 Some investigators showed increased incidence of ectopic 48,49 and heterotopic50 pregnancy following clomiphene citrate, while others found no such association.51 It has also been reported that the incidence of ectopic pregnancy following ovulation induction with human menopausal gonadotrophin (hMG) in anovulatory women with apparently normal Fallopian tubes was associated with rates of ectopic pregnancy between 2.7% 52 and 3.1% 53 of all conceptions. However, other investigators found no association between the type of ovarian stimulation protocol or oestradiol, luteinising hormone (LH) and progesterone concentrations at the time of ovulation induction and ectopic pregnancies.51

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Gamete intra-Fallopian transfer (GIFT) is associated with an ectopic pregnancy rate of 4% of all pregnancies and 1.5% of transfers, in an analysis of 1472 clinical pregnancies subsequent to 4202 GIFT cycles.54

In vitro fertilisation and ectopic pregnancy Although IVF-embryo transfer (ET) was developed to bypass tubal factor infertility, increasing numbers of unusual forms of ectopic pregnancies are being reported after IVF/ET.7,55 The first pregnancy reported after IVF and ET was in fact an ectopic pregnancy.56 Of all clinical pregnancies that occur with IVF, 4% are likely to be ectopic.11–13 The majority of these are tubal ectopic pregnancies.12 Several studies have associated technical aspects of IVF with increased risk of ectopic pregnancy, such as assisted hatching,57 frozen ET,14 higher transfer volume,58,59 deep fundal transfer60 and the practice of multiple ET.13 Proposed mechanisms to explain the development of tubal pregnancies after IVF include direct injection of the transfer media containing the embryos into the Fallopian tubes, or migration of embryos into the Fallopian tubes caused by uterine contractions.61,62 In a retrospective analysis of 623 clinical pregnancies conceived after IVF, a 5.4% ectopic pregnancy rate (14/258 clinical pregnancies) was found in cases where assisted hatching (AH) was performed compared with 2.2% (8/365) in the group without AH. However, it may be relevant to assess the effect of AH on the incidence of ectopic pregnancy in a large multicentre study before any firm conclusions are made.57 Blastocyst transfer may theoretically decrease the incidence of ectopic pregnancy following IVF-ET in view of the decreased uterine contractility reported by day 5 postegg collection.63 However, in practice blastocyst transfer does not appear to decrease the risk of ectopic pregnancy. Milki and Jun63 investigated the rate of ectopic pregnancy after ET on day 3 versus day 5 and found no significant difference between the two groups. Ectopic pregnancy rates have also been compared after frozen compared with fresh blastocyst transfer. In the frozen blastocyst group, there were five ectopic pregnancies out of 180 clinical pregnancies (2.8%), and there were ten ectopic pregnancies out of 564 clinical pregnancies (1.8%) in the fresh blastocyst group. It was concluded that the rate of ectopic pregnancy is not significantly increased after the transfer of frozen thawed blastocysts compared with fresh blastocyst transfer.64 Multiple ET is associated with high risk of ectopic pregnancy. A decrease in ectopic pregnancy rate has been reported when two or fewer embryos were transferred, but not when three or more embryos were transferred.13 Use of larger volumes of fluid at ET,58,59,62 and deep fundal transfer60 have also been implicated in ectopic implantation. Marcus et al9 observed that patients

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having ectopic pregnancies received a higher volume of culture medium than those having normal intrauterine pregnancies. Knutzen et al65 showed that after injection of 50 µl of radio-opaque fluid through a standard ET catheter, the material was passed either totally or partially into the Fallopian tubes in 44% of patients, suggesting that the chance of the embryo being carried into the tube immediately after transfer is high. The fact that most ectopic pregnancies occur in patients with damaged tubes supports the hypothesis that the embryo(s) is not transported back to the uterine cavity because of tubal dysfunction. A prospective randomised study was performed to compare the effects of midfundal versus deep fundal transfer on subsequent intrauterine and ectopic pregnancy rate after IVF. The clinical intrauterine pregnancy rate after the deep fundal transfer was 12.4% per cycle with a 1.5% ectopic pregnancy rate versus 14.2% intrauterine pregnancies per cycle with a 0.4% ectopic rate after midfundal transfers. The midfundal technique was found to be superior to deep fundal procedures because of a lower percentage of ectopic pregnancies without any sacrifice of the intrauterine pregnancy rate after midfundal transfers.59 The mechanism by which the technique of ET influences the rate of ectopic implantation is thought to be by forcing the embryo through tubal ostia by hydrostatic pressure, or due to the large volume of transfer medium used.8,66 Placing the transfer catheter beyond the mid-cavity or into the tube itself67 and retrograde migration of the embryos into the tubes have been also attributed to the increased incidence of ectopic implantation after IVF treatment.45 This effect has been explained by Lesny et al68 who studied junctional zone uterine contractility during mock ET. When the catheter was deliberately allowed to contact the uterine fundus, strong random contraction waves were observed in the fundal area and fluid was moved directly into the Fallopian tubes. Others have recommended performing ET in a position in which the fundus is at the highest point above the horizon and to slowly deliver the load not in less than 10 seconds.60 They also suggested that placement of the catheter tip near the fundus appeared to transfer the embryos into the tube when transfer was performed at fast speeds and possibly may lead to ectopic pregnancies.69 It has also been proposed that transfer of embryos to a standard midcavity position results in a lower ectopic pregnancy rate.6,7,60

Clinical picture The clinical picture of ectopic pregnancy occurring spontaneously has been well described. Historically, the hallmark of ectopic pregnancy has been a triad of a period of amenorrhoea (6–8 weeks), abdominal pain and vaginal bleeding (Table 36.2). This remains the most common presentation of tubal pregnancy in symptomatic patients.

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Table 36.2

Clinical picture of ectopic pregnancy.

SYMPTOMS History of amenorrhoea (6–8 weeks) Abdominal pain Vaginal bleeding Shoulder tip discomfort Pain on defaecation/micturition Syncope and/or hypovolemic shock in acute cases SIGNS Normal or slightly enlarged uterus Palpable adnexal mass Signs of intraperitoneal haemorrhage (rupture/leakage) Pain on movement of the cervix (cervical excitation)

Other presentations depend on the location of the ectopic pregnancy. Less commonly, ectopic pregnancy presents with pain radiating to the shoulder, syncope and/or hypovolemic shock. Up to 9% of women with ectopic pregnancy report no pain and onethird lack adnexal tenderness. Although the presence of known risk factors, abdominal pain and vaginal bleeding after an interval of amenorrhoea, increases suspicion, they are not sufficient to confirm or exclude a diagnosis of ectopic pregnancy.70–72 However, any sexually active woman presenting with abdominal pain and vaginal bleeding following a period of amenorrhoea should be considered to have an ectopic pregnancy until proved otherwise. Therefore, if there is any suspicion, hospital referral for investigation is compulsory.71

Diagnosis The incidence of ectopic pregnancy and heterotopic pregnancy has increased following ART procedures.13,73 This is mainly due to multiple ET and the pre-existing tubal pathology.73 Heterotopic pregnancy is an obstetric complication with potentially serious consequences and it represents diagnostic and therapeutic challenges, which in turn may increase the risk of adverse maternal outcomes such as tubal rupture, hypovolemic shock and blood transfusion.73,74 These complications may also adversely affect the viable intrauterine pregnancy. A single determination of serum human chorionic gonadotrophin (hCG), even as early as 11–12 days after ET, and transvaginal ultrasound have been found to be predictive of pregnancy outcome.2,75–77

Biochemical markers Human chorionic gonadotrophin hCG is one of the earliest placental secretory products. Its function in early pregnancy is to “rescue” the corpus luteum and maintain uterine quiescence by promoting luteal secretion of progesterone. Following conception, hCG can be detected in maternal serum

within 7 days and in maternal urine by the time the first period would have been due if conception had not occurred. After a careful history and physical examination, a standard pregnancy test may be performed by measuring urine ßhCG concentration. A modern urinary pregnancy test is 99% sensitive and 99% specific for pregnancy.78 Although used as the initial step in some settings, the urine pregnancy test is a qualitative rather than quantitative measure that identifies the presence of hCG in concentrations as low as 25 IU/l.78 Measuring serum ßhCG concentration is quantitative and provides better evidence in the diagnosis of ectopic pregnancy. The combination of serum ßhCG concentrations with imaging techniques defines the process of diagnosis of ectopic pregnancy.76 Furthermore, serial hCG monitoring is a very useful tool to follow up the patients until complete resolution of further intervention.76 Interpretation of hCG levels is very different for pregnancies following ART than from spontaneous pregnancies due to the high risk of multiple pregnancy. Additionally, the ART procedures and/or the pre-existing disorder may affect the course of hCG concentration.79 Several studies, which were conducted among IVF patients, have reported that a single plasma hCG assay can accurately differentiate viable and non-viable pregnancies.75,79 However, the threshold values vary between the different studies, depending especially on the exact day of the assay in relation to the date of ET or ovulation.79

Pregnancy associated plasma protein-A Pregnancy associated plasma protein-A (PAPP-A), which is a macromolecular glycoprotein produced by the trophoblast, increases throughout pregnancy.80 Although PAPP-A has no identifiable biological function, several studies investigated the clinical usefulness of its measurement during pregnancy. PAPP-A might be used as a marker for early pregnancy failure with sensitivity of 54.2% and specificity of 99%. However, it cannot distinguish between abnormal intrauterine pregnancy and ectopic pregnancy.81–83

Progesterone A single progesterone measurement has the ability to distinguish between early pregnancy failure and normal intrauterine pregnancy.84 However, its usefulness to differentiate between abnormal intrauterine pregnancy and ectopic pregnancy is subject to debate. Some studies showed that progesterone level was significantly decreased in abnormal intrauterine pregnancy compared with ectopic pregnancy;81,85 whereas a meta-analysis reported that a single progesterone measurement could not discriminate between abnormal intrauterine pregnancy and ectopic pregnancy86 as there is no specific cut-off for progesterone levels that accurately diagnoses ectopic pregnancy.

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Nevertheless, progesterone levels may still play a useful role in the evaluation and management of a suspected ectopic pregnancy.87 Rapid progesterone measurement can help in the diagnosis of two essential subgroups of patients in the emergency department with symptomatic first trimester bleeding or pain. Progesterone levels above 22 ng/ml in stable patients indicate a high, but not certain, likelihood of viable intrauterine pregnancy. On the other hand, patients with levels of 5 ng/ml or less will almost certainly have a non-viable pregnancy.88

Imaging techniques Ultrasound Ultrasound can be used to locate a pregnancy anatomically and to see whether the foetus is alive. In general, a gestational sac can be consistently identified by transvaginal ultrasound when the serum hCG level exceeds 1000–1500 IU/l.89,90 Kadar et al91 were the first to propose combining ultrasound with hCG for accurate diagnosis of early ectopic pregnancy. They introduced the concept of the discriminatory serum hCG “zone”. According to this concept, a diagnosis of ectopic pregnancy was likely whenever intrauterine pregnancy was not detected by transabdominal ultrasound at serum hCG concentrations above the threshold of 6500 IU/l. The clinical value of this combination was limited since many patients with ectopic pregnancy have serum hCG well below 6500 IU/l. The introduction of transvaginal sonography dramatically changed the situation. Transvaginal ultrasound can effectively detect much smaller intrauterine and ectopic pregnancies due to its superior resolution.88 This brought the “cut-off” level of serum hCG down to between 1000 and 2000 IU/l for those patients with sonographic findings suggestive of ectopic pregnancy.89,90 The finding of an empty uterine cavity can be associated with an ectopic pregnancy, early pregnancy and complete or incomplete miscarriage. This should be correlated with the ßhCG concentration. If the ßhCG level is below the predetermined discriminatory level, then hCG should be measured every 48 hours and a repeat ultrasound performed when the level has reached the predetermined discriminatory level.92 If no intrauterine pregnancy is detected when the ßhCG is above the predetermined threshold level or if the ßhCG stabilises or fails to increase normally, then the diagnosis of an ectopic pregnancy needs to be considered.92,93 Heterotopic pregnancy is a rare but potentially lifethreatening event and early diagnosis and treatment are essential. Delayed diagnosis should be prevented in order to rescue the viable intrauterine pregnancy and avoid maternal morbidity and mortality. It is mandatory to rule out this challenging condition in all patients who conceive following ART, regardless

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of the presence or absence of currently recognised risk factors. Therefore, investigation of the adnexa is still obligatory to exclude the possibility of heterotopic pregnancy.94 With the presence of an intrauterine pregnancy and an often appropriate increase in the level of the ßhCG, heterotopic pregnancies present an elusive and challenging diagnosis. ßhCG concentrations can double every 48 h during the early stages of an ectopic gestation as seen in intrauterine gestations, limiting the clinical significance of this laboratory test.95 Most cases of heterotopic pregnancy are missed on initial presentation, which could be due to a false sense of security provided by the sonographic finding of a viable intrauterine pregnancy and a failure to inspect the adnexa fully. The amount of fluid in the cul-de-sac, a space created by a peritoneal reflection that lies posterior to the uterus and anterior to the rectum, can assist in the diagnosis of heterotopic pregnancy. One study noted that patients with abnormal cul-de-sac fluid were five times as likely to have an ectopic pregnancy as patients without it.96 Even when pelvic ultrasound reveals a suspicious adnexal finding in the presence of an intrauterine pregnancy, the false diagnosis of corpus luteal cyst may be made.94,97 A moderate or large amount of free pelvic fluid, which is probably due to a physiological response to the distension of the Fallopian tube or bleeding from the damaged tube or the ectopic pregnancy itself, should warrant particular care when assessing the adnexa with ultrasound, even in the presence of an intrauterine pregnancy.94,96

Laparoscopy The introduction of laparoscopy in the late 1960s solved the dilemma of prolonged clinical observation and the risk of performing an unnecessary laparotomy in suspected cases.98,99 Laparoscopy remained the only reliable method for diagnosing and excluding ectopic pregnancy until well into the 1980s, and allowed combination of diagnosis and surgical treatment.100

Treatment Ectopic pregnancy is a major event in a woman’s reproductive life and may be particularly tragic after a long and difficult course of treatment for infertility. If ectopic pregnancy occurs following infertility treatment, counselling and psychological support should be given alongside clinical treatment. Tubal pregnancy can be treated surgically by laparotomy or laparoscopy, medically and occasionally by observation alone. With earlier diagnosis of ectopic pregnancy, has come a move towards more conservative approaches. These include surgical and non-surgical management. Treatment must be customised to the clinical condition and future fertility requirements of the patient.101 In stable cases the reproductive medicine specialist should remain in overall charge of

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clinical management and, if possible, perform the necessary surgical procedure in order to ensure the optimum approach to fertility preservation.

Surgical treatment Previously, salpingectomy by laparotomy was the gold standard for the treatment of ectopic pregnancy. A number of different approaches to conservative surgical treatment have been introduced, including excision of the affected segment, milking of the tube or linear salpingostomy using either cautery or laser. Both radical and conservative management may be performed by laparoscopy or laparotomy.101

Laparoscopy versus laparotomy The traditional treatment for ectopic pregnancy was laparotomy and salpingectomy. In the 1980s, the laparoscopic approach became more widely accepted, following the development of video laparoscopy and the publication of the first series of the successful use of laparoscopy for the treatment of ectopic pregnancy.102 In general, laparoscopic surgery is the preferred approach in haemodynamically stable patients and has largely replaced the need for laparotomy due to improved postoperative recovery time and reduced morbidity.103 Nonetheless, laparotomy is the preferred technique when the patient is haemodynamically unstable; if the surgeon has not been trained in laparoscopy or if laparoscopic surgery equipment is not available. Several randomised controlled trials104–107 comparing the procedures have shown that laparoscopy is associated with shorter operation times, less intraoperative blood loss, shorter hospital stay and lower analgesic requirements. There is no difference between these surgical approaches in subsequent reproductive outcome. However, there is a trend towards higher rates of persistent trophoblast associated with laparoscopic surgery for ectopic pregnancy.101,108

Salpingectomy versus salpingostomy Salpingectomy is preferable in patients with uncontrolled bleeding, extensive tubal damage or recurrent ectopic pregnancy in the same tube. Salpingostomy is indicated where the patient is haemodynamically stable, the patient wishes to conserve her fertility, there is an unruptured ectopic pregnancy of not more than 5 cm in diameter and, especially, when the contralateral tube is absent or damaged.101,109 Linear salpingostomy is the most commonly performed technique. The principle of this procedure is to open the affected portion of tube by either cautery or laser, to evacuate its content, with the incision being either sutured or left to heal by secondary intent. Although there is no randomised controlled trial comparing salpingectomy and salpingostomy, several studies have compared reproductive outcome following

the treatment of ectopic pregnancy by these techniques.45,110–113 Subsequent fertility, recurrent ectopic pregnancy and intrauterine pregnancy rates are higher, but not significantly so, following salpingostomy. Persistent trophoblastic tissues are less associated with salpingectomy.108,111 Patients who require IVF in order to conceive, because of tubal disease, will usually undergo salpingectomy. Salpingectomy should also be considered if there is hydrosalpynx, since treatment of hydrosalpynx is likely to improve chances of livebirth in subsequent IVF cycles.114 Although effort may be made to excise the entirely of the extrauterine tube by ‘complete’ rather than ‘partial’ salpingectomy, it is not possible to excise the intramural Fallopian tube and cornual ectopic pregnancies following salpingectomy have been reported.115

Medical treatment The effective early diagnosis of ectopic pregnancy without laparoscopy has allowed the use of medical management of ectopic pregnancy. Successful medical management of an ectopic pregnancy is inversely associated with initial hCG concentrations.116 Agents used for the treatment of trophoblastic disease include methotrexate (MTX), hyperosmolar glucose, prostaglandins and mifepristone (RU486).117 The most studied of these agents is MTX, a folic acid antagonist that is metabolised in the liver and excreted by the kidney. MTX is a cytotoxic agent which inhibits the synthesis of purines and pyrimidines. It prevents synthesis of amino acids, RNA and DNA, and destroys rapidly dividing trophoblastic tissue.116,117 MTX can be administered to suitable patients by intravenous or intramuscular injection, or by local injection under the guidance of either ultrasound or laparoscope.117 Criteria for MTX treatment of ectopic pregnancy are summarised in Table 36.3.117 Briefly, MTX can be used in haemodynamically stable patients, with minimal or no symptoms, initial serum hCG concentrations ≤ 3000 IU/l and ectopic pregnancy size <4 cm.117,118 There are two commonly used MTX treatment regimens: “single dose” and “multiple doses”. The dose of MTX is calculated by body surface area (50 mg/m²) or body weight (1 mg/kg).117 For most women this will be between 75 and 90 mg. Following MTX injection, nearly 75% of patients will experience abdominal pain due to tubal abortion, rise in serum hCG levels in the following 3 days, stomatitis, diarrhoea and some may need a second dose of MTX. Tubal rupture can still occur.117,118 The multiple-dose protocol is a regimen adapted from early experience with MTX treatment for trophoblastic disease and was the regimen first used to treat ectopic pregnancy.101,117 The variable dose regimen involves the addition of citrovorum, a reduced form of folate that blocks the effect of MTX, to prevent the adverse effects of MTX on other tissues.117 Patients should be advised to avoid sexual intercourse during treatment, becoming pregnant for 6 months post-treatment and excessive

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Table 36.3

Criteria for methotrexate treatment.

Indications Haemodynamically stable patients Minimal or no symptoms Serum hCG is ≤3000 IU/l No contraindications for methotrexate Patient are able to comply with the follow-up for several weeks Contraindications Liver disease Renal disease Blood disorder Breast feeding Presence of foetal cardiac activity Active peptic ulcer or colitis Side-effects Abdominal pain following treatment Stomatitis GIT upset Photosensitivity skin reaction Tubal rupture during follow-up hCG, human chorionic gonadotrophin; GIT, gastrointestinal tract.

exposure to sunlight and alcohol. Prior to the administration of MTX, a clear information sheet about the adverse effects and possible need for further treatment should be given to the patient, and written consent should be obtained.117 MTX is continued until hCG falls by 15% from its peak concentration.117 Approximately 50% of patients so treated will not require the full 8-day regimen.118 A serum hCG measurement is made on days 4 and 7, and a further dose is given if levels have failed to fall by more than 15% in 48 hours.118 Falling hCG levels do not exclude the possibility of tubal rupture. It has been reported that the combining of 600 mg mifepristone to a single dose of MTX was significantly more successful in eliminating ectopic pregnancy than methotrexate alone.101,119 Another pilot study reported that sonography guided local injection of potassium chloride (KCl) along with systemic MTX in patients with high hCG concentrations and the presence of foetal cardiac activity resulted in foetal cardiac asystole and successful resolution of ectopic pregnancy.120 Signs of treatment failure or suspected rupture are indications to stop medical treatment and to shift to surgical management. Signs indicating treatment failure or possible rupture include haemodynamic instability; increasing abdominal pain, regardless of trends in hCG levels; and rapidly increasing hCG concentrations (>53% over 2 days) after four doses in the multidose regimen or after two doses in the single-dose regimen.121

Methotrexate versus salpingostomy In general, when an ectopic sac is found at laparoscopy, either a linear salpingostomy with removal of the

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trophoblast or removal of the tube should be performed. In these cases, intramuscular MTX is indicated only when high serum hCG levels persist.101,117 Several studies have compared laparoscopic salpingostomy with MTX injection.101,117 In most cases, when appropriate inclusion criteria were used, “multiple doses” MTX treatment was almost as effective as surgery with success rates of 88.2% and 95.9%, respectively.101 Lipscomb et al122 reported that 14% of patients treated with MTX required more than one dose and less than 10% required surgical intervention. Post-treatment hysterosalpingography documented tubal patency in 78% of cases; 65% of patients who attempted subsequent pregnancies. The incidence of recurrent ectopic pregnancy was a relatively low 13%.101,117,122 Other studies showed that a single intramuscular dose of systemic MTX was significantly less successful than laparoscopic salpingostomy in the elimination of tubal ectopic pregnancy.101 These observations were mainly due to inadequacy in serum hCG decline for which additional MTX injections were given.101 The potential advantages of MTX are the avoidance of surgery and its complications and preservation of tubal patency and function. Furthermore, medical treatment may be more cost-effective.101,117

Single versus multiple doses of methotrexate There have been no randomised trials directly comparing the two different MTX treatment protocols. In a meta-analysis including data from 26 articles and 1327 cases, the overall success rate for MTX treatment was 89%.123 The success rate of the multiple-dose regimen was 92.7%, which was statistically significantly higher than that achieved with the single-dose regimen.123 After controlling for initial hCG values and the presence of embryonic cardiac activity, the failure rate for single-dose therapy was higher than that for multiple-dose treatment.123 Two recent studies, involving 159 women with a clinical diagnosis of ectopic pregnancy, reported no significant difference in primary treatment success between the “single” and “multiple” regimens.124 Mean serum hCG concentrations were similar in both groups.

Expectant management When serum hCG is below the discriminatory zone and there is no intra- or extrauterine pregnancy detected by transvaginal ultrasound, the pregnancy can be described as being pregnancy of unknown location.125 Several studies have reported that 44–69% of pregnancies of unknown location resolve spontaneously.126 Of these, 8.7–42.8% will represent early ectopic pregnancies, which are too small to visualise on ultrasound scan.126,127 Initially, patients with ectopic pregnancies may have a 50–66% increase in ßhCG concentrations every

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2 days.128 The fate of ectopic pregnancy is either spontaneous resolution or rupture. The explanation for these events is probably dependent on the activity of the trophoblast tissue.128 Less aggressive invasion of the trophoblast tissue is associated with spontaneous resolution. On the other hand, more aggressive invasion is related to tubal rupture. If the serum hCG concentrations increase, intervention is essential or the patients may suffer ruptured ectopic pregnancy. On the other hand, for patients at a more advanced stage, with greater gestational age and declining ßhCG titres, the risk of rupture is almost over.128 Expectant management is an option for clinically stable women with serum hCG levels below the discriminatory zone, minimal symptoms associated with either pregnancy of unknown location or ectopic pregnancy diagnosed on ultrasound.101,129 Regular follow-up is essential. Serial serum hCG concentrations should be measured until they reach less than 20 IU/l. If symptoms and signs of ectopic pregnancy develop, serum hCG concentrations rise above discriminatory zone or start to plateau, active intervention should be considered.101,129 Clear information about the importance of compliance with follow-up should be given to the patient if a policy of expectant management is followed.

Anti-D immunoglobulin It is recommended that anti-D immunoglobulin at a dose of 250 IU be given to all non-sensitised women who are rhesus negative and who have an ectopic pregnancy.

Complications of ectopic pregnancy Persistent trophoblastic tissue Persistent trophoblast is usually a complication of laparoscopic or open salpingostomy, with an incidence of 8.1% and 4%, respectively.130 It is detected by the failure of serum hCG concentrations to decline as expected after initial treatment. Risk factors for persistent trophoblastic tissue include high preoperative serum hCG (>3000 IU/l), a rapid preoperative rise in serum hCG and the presence of active tubal bleeding.101,130 Currently, there is no common protocol for the early diagnosis and initiation of treatment. One study has recommended initiating second-line treatment if the serum hCG is greater than 10% of the preoperative level 10 days after surgery. Another study has suggested starting treatment if serum hCG concentrations are more than 65% of their initial levels at 48 hours after surgery. A single dose (50 mg/m²) of MTX has been widely used instead of a second surgical procedure. In addition, one randomised controlled trial which compared the use of prophylactic MTX at the time of laparoscopic salpingostomy with simple salpingostomy alone, showed a reduction in the rate of persistent trophoblast by 19% and 14%, respectively.101,130

Effect of ectopic pregnancy and its treatment on subsequent IVF outcome The effects of the different lines of treatment for ectopic pregnancy, especially radical and medical managements, on subsequent IVF have been described. The significance of salpingectomy in the outcome of subsequent IVF-ET is controversial. Salpingectomy as a treatment for ectopic pregnancy or for the removal of a hydrosalpinx prior to an IVF-ET cycle may have an adverse effect on ovarian blood supply. The vascular support of the Fallopian tubes is derived from both the uterine and ovarian arteries, which together furnish distinct arcades of vessels along the length of the tube. The lateral part of the tube takes its blood supply from the lateral tubal artery, which is the terminal branch of the ovarian artery. The proximal part of the tube is irrigated by the terminal branches of the uterine artery, which ends approximately 1 cm from the tubal implantation site, giving rise to different branches. The most important vessel for the tubal blood supply is the medial tubal artery, which starts at the same anatomical site as the median ovarian artery.131 Therefore, it is mandatory to do the resection as close as possible to the Fallopian tube when performing a salpingectomy, especially in the proximal region, in order to minimise damage to the ovarian blood supply.132,133 Disruption in ovarian blood flow may have a negative impact on steroid production and further follicular development.132,133 There is also a disruption in the neural linkage between Fallopian tube and ovary following salpingectomy. The precise contribution of the nervous system to ovarian function is not understood, but it might play a role in folliculogenesis and/or hormonal production. Many investigators reported significantly fewer follicles and oocytes from either both ovaries134 or the ipsilateral ovary132 following salpingectomy. However, the total ovarian response in an IVF-ET cycle, in terms of number of retrieved oocytes, was found to be unaffected.132,135 In selected cases, where the second ovary is already compromised or absent, unilateral salpingectomy may reduce the total ovarian performance during an IVF-ET cycle.132 Surgical treatment of an ectopic pregnancy may also result in oophorectomy. This can follow either advanced ovarian pregnancy136 or when tubal pregnancy forms a tubo-ovarian mass due to the presence of extensive pelvic adhesions. Ovarian implantation may occur secondarily in the corpus luteum following spontaneous conception or extra-follicularly in the case of IVF-ET.137,138 Conflicting reports exist concerning the effect of unilateral oophorectomy on IVF outcome with different stimulation protocols. In an early study139 it was shown that women with two ovaries have higher serum oestradiol concentrations than women with a single ovary following ovulation stimulation; however, the number of oocytes retrieved was similar in both groups. In subsequent studies it was found that although patients

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with one ovary required a longer period of stimulation, the peak serum oestradiol concentrations, number of large follicles, number of oocytes retrieved and clinical pregnancy rate were the same as for women with two ovaries.140,141 Later, with the use of gonadotrophin releasing hormone (GnRH) agonist pituitary suppression during IVF superovulation, it was shown that women with one ovary are at no reproductive disadvantage when compared with women with two ovaries.142 However, more recent studies with higher patient numbers have shown that women who had undergone unilateral oophorectomy responded less well to ovarian stimulation than women with both ovaries in terms of number of follicles, oestradiol concentrations and number of oocyte retrieved.143,144 Moreover, these women required a higher dose of gonadotrophins.144 Pregnancy rates in women with one ovary were similar to those in women with both ovaries in majority of the studies. It appears therefore, that once women with a single ovary reach embryo transfer, they can be reassured that their chance of having a child is the same as that of women with two ovaries. Single-dose MTX is the most accepted alternative to surgical treatment of ectopic pregnancy. Although it inhibits DNA synthesis and cell division, which may affect growing preantral follicles, MTX at the doses and intervals that are used for ectopic pregnancy treatment does not appear to have any deleterious effect on ovarian reserve.145,146 MTX appears to affect growing preantral and antral follicles but not primordial follicles in the ovaries.147 Although MTX is an agent that is associated with low or no risk for infertility, female fertility may be compromised by any treatment that decreases the number of early follicles.148 Therefore, it is reassuring to show that the effects of MTX, after it is used as a medical treatment for an ectopic pregnancy, does not affect or further compromise a woman’s future reproductive potential.145,146 Fertility outcome after ectopic pregnancy has been extensively described in the literature. Fertility after ectopic pregnancy is usually described by the following three indicators: ectopic pregnancy recurrence, intrauterine pregnancy and livebirth. Pregnancy rates following ectopic pregnancy treatment range from 24%149 to 89%.150 These conflicting results could be population specific as in most of the studies fertility was evaluated in a hospital-based population after a specific treatment: conservative surgery, radical surgery, MTX, laparotomy and laparoscopy.101 Moreover, the majority of these studies did not consider whether the pregnancy was spontaneous or assisted, and IVF has seldom been dealt with separately.

Conclusion Ectopic pregnancy is a worldwide medical emergency. Fertility treatment increases the rate of ectopic pregnancy and may result in a heterotopic pregnancy. At the present time, the combination of transvaginal ultrasound

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and quantitative serum hCG is the most reliable diagnostic tool. Different approaches are available for the treatment of ectopic pregnancy but none can eliminate the risks of persistent trophoblast, recurrent ectopic pregnancy and infertility. Early diagnosis and intervention are crucial to diminish morbidity and mortality from ectopic pregnancy. Given the increased chance of ectopic pregnancy following ART it is essential that fertility clinics follow women with a positive pregnancy through early pregnancy. Ultrasound at 2 and 4 weeks following ET will reliably identify viable and non-viable intrauterine pregnancies. Persistent elevation of hCG coupled with ultrasound evidence of an empty uterus should trigger an established protocol for detection of ectopic pregnancy. Heterotopic gestation presents a particular diagnostic challenge and detection requires a high index of suspicious coupled with transvaginal ultrasound by an experienced operator.

References 1. Hankins GD, Clark SL, Cunningham FG, Gilstrap LC. Ectopic pregnancy. In: Operative Obstetrics. Norwalk, CT: Appleton & Lang, 1995: 437–56. 2. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of causes of maternal death: a systematic review. Lancet 2006; 367: 1066–74. 3. Rajkhowa M, Glass MR, Rutherford AJ et al. Trends in the incidence of ectopic pregnancy in England and Wales from 1966 to 1996. BJOG 2000; 107: 369–74. 4. Drife J. Fifty years of the confidential enquiry into maternal deaths. Br J Hosp Med (Lond) 2006; 67: 121–5. 5. Inhorn MC. Global infertility and the globalization of new reproductive technologies: illustrations from Egypt. Soc Sci Med 2003; 56: 1837–51. 6. Blazar AS, Frishman GN, Winkler N. Heterotopic pregnancy after bilateral salpingectomy resulting in near-term delivery of a healthy infant. Fertil Steril 2007; 88: 1676 e1–2. 7. Buckett WM, Chian RC, Holzer H et al. Obstetric outcomes and congenital abnormalities after in vitro maturation, in vitro fertilization, and intracytoplasmic sperm injection. Obstet Gynecol 2007; 110: 885–91. 8. Dor J, Seidman DS, Levran D et al. The incidence of combined intrauterine and extrauterine pregnancy after in vitro fertilization and embryo transfer. Fertil Steril 1991; 55: 833–4. 9. Marcus SF, Macnamee M, Brinsden P. Heterotopic pregnancies after in-vitro fertilization and embryo transfer. Hum Reprod 1995; 10: 1232–6. 10. Tal J, Haddad S, Gordon N, Timor-Tritsch I. Heterotopic pregnancy after ovulation induction and assisted reproductive technologies: a literature review from 1971 to 1993. Fertil Steril 1996; 66: 1–12. 11. Strandell A, Thorburn J, Hamberger L. Risk factors for ectopic pregnancy in assisted reproduction. Fertil Steril 1999; 71: 282–6. 12. Pandian Z, Templeton A, Serour G, Bhattacharya S. Number of embryos for transfer after IVF and ICSI: a Cochrane review. Hum Reprod 2005; 20: 2681–7.

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13. Clayton HB, Schieve LA, Peterson HB et al. Ectopic pregnancy risk with assisted reproductive technology procedures. Obstet Gynecol 2006; 107: 595–604. 14. Pyrgiotis E, Sultan KM, Neal GS et al. Ectopic pregnancies after in vitro fertilization and embryo transfer. J Assist Reprod Genet 1994; 11: 79–84. 15. Salman G and Irvine LM. Ectopic pregnancy, the need for standardisation of rate. J Obstet Gynaecol 2008; 28: 32–5. 16. Bouyer J, Coste J, Shojaei T et al. Risk factors for ectopic pregnancy: a comprehensive analysis based on a large case-control, population-based study in France. Am J Epidemiol 2003; 157: 185–94. 17. Crossman SH. The challenge of pelvic inflammatory disease. Am Fam Physician 2006; 73: 859–64. 18. Karaer A, Avsar FA, Batioglu S. Risk factors for ectopic pregnancy: a case-control study. Aust N Z J Obstet Gynaecol 2006; 46: 521–7. 19. Barnhart KT, Sammel MD, Gracia CR et al. Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies. Fertil Steril 2006; 86: 36–43. 20. Manavi K, A review on infection with Chlamydia trachomatis. Best Pract Res Clin Obstet Gynaecol 2006; 20: 941–51. 21. Bakken IJ, Skjeldestad FE, Nordbo SA. Chlamydia trachomatis infections increase the risk for ectopic pregnancy: a population-based, nested case-control study. Sex Transm Dis 2007; 34: 166–9. 22. Roan NR, Starnbach MN. Immune-mediated control of chlamydia infection. Cell Microbiol 2008; 10: 9–19. 23. Noguchi Y, Yabushita H, Noguchi M et al. Detection of Chlamydia trachomatis infection with DNA extracted from formalin-fixed paraffin-embedded tissues. Diagn Microbiol Infect Dis 2002; 43: 1–6. 24. Gerard HC, Branigan PJ, Balsara GR et al. Viability of Chlamydia trachomatis in Fallopian tubes of patients with ectopic pregnancy. Fertil Steril 1998; 70: 945–8. 25. Barlow RE, Cooke ID, Odukoya O et al. The prevalence of Chlamydia trachomatis in Fresh tissue specimens from patients with ectopic pregnancy or tubal factor infertility as determined by PCR and insitu hybridisation. J Med Microbiol 2001; 50: 902–8. 26. Osser S, Persson K. Chlamydial antibodies and deoxyribonucleic acid in patients with ectopic pregnancy. Fertil Steril 1992; 57: 578–82. 27. Maccato M, Estrada R, Hammill H, Faro S. Prevalence of active Chlamydia trachomatis infection at the time of exploratory laparotomy for ectopic pregnancy. Obstet Gynecol 1992; 79: 211–13. 28. Brunham RC, Peeling R, Maclean I, Kosseim ML, Paraskevas M. Chlamydia trachomatis-associated ectopic pregnancy: serologic and histologic correlates. J Infect Dis 1992; 165: 1076–81. 29. Bjartling C, Osser S, Persson K. Deoxyribonucleic acid of Chlamydia trachomatis in fresh tissue from the Fallopian tubes of patients with ectopic pregnancy. Eur J Obstet Gynecol Reprod Biol 2007; 134: 95–100. 30. Cates W, Jr, Rolfs RT, Jr, Aral SO. Sexually transmitted diseases, pelvic inflammatory disease, infertility: an epidemiologic update. Epidemiol Rev 1990; 12: 199–220.

31. Mardh PA. Is the prevention of genital chlamydial infections by community involvement possible? Best Pract Res Clin Obstet Gynaecol 2002; 16: 829–46. 32. Hillis S, Black C, Newhall J, Walsh C, Groseclose SL. New opportunities for Chlamydia prevention: applications of science to public health practice. Sex Transm Dis 1995; 22: 197–202. 33. Egger M, Low N, Smith GD, Lindblom B. Herrmann B, Screening for chlamydial infections and the risk of ectopic pregnancy in a county in Sweden: ecological analysis. BMJ 1998; 316: 1776–80. 34. Spandorfer SD, Barnhart KT. Role of previous ectopic pregnancy in altering the presentation of suspected ectopic pregnancy. J Reprod Med 2003; 48: 133–6. 35. Clausen I. Conservative versus radical surgery for tubal pregnancy. A review. Acta Obstet Gynecol Scand 1996; 75: 8–12. 36. Pisarska MD, Carson SA, Buster JE. Ectopic pregnancy. Lancet 1998; 351: 1115–20. 37. Toki T, Obinata M, Nakayama K, Oguchi O, Fujii S. Ovarian pregnancy associated with microscopic decidualized endometriosis of the ovary: report of a case. J Obstet Gynaecol Res 1998; 24: 45–8. 38. Hunter RH. Tubal ectopic pregnancy: a patho-physiological explanation involving endometriosis. Hum Reprod 2002; 17: 1688–91. 39. Bogdanskiene G, Berlingieri P, Grudzinskas JG. Association between ectopic pregnancy and pelvic endometriosis. Int J Gynaecol Obstet 2006; 92: 157–8. 40. Stergachis A, Scholes D, Daling JR, Weiss NS, Chu J. Maternal cigarette smoking and the risk of tubal pregnancy. Am J Epidemiol 1991; 133: 332–7. 41. Talbot P, Riveles K. Smoking and reproduction: the oviduct as a target of cigarette smoke. Reprod Biol Endocrinol 2005; 3: 52. 42. Phillips RS, Tuomala RE, Feldblum PJ et al. The effect of cigarette smoking, Chlamydia trachomatis infection, vaginal douching on ectopic pregnancy. Obstet Gynecol 1992; 79: 85–90. 43. Saraiya M, Berg CJ, Kendrick JS et al. Cigarette smoking as a risk factor for ectopic pregnancy. Am J Obstet Gynecol 1998; 178: 493–8. 44. Ory SJ, Nnadi E, Herrmann R, O’Brien PS, Melton LJ 3rd, Fertility after ectopic pregnancy. Fertil Steril 1993; 60: 231–5. 45. Job-Spira N, Bouyer J, Pouly JL et al. Fertility after ectopic pregnancy: first results of a populationbased cohort study in france. Hum Reprod 1996; 11: 99–104. 46. Bernoux A, Job-Spira N, Germain E, Coste J, Bouyer J. Fertility outcome after ectopic pregnancy and use of an intrauterine device at the time of the index ectopic pregnancy. Hum Reprod 2000; 15: 1173–7. 47. James WH. Women’s hormone concentrations and the increasing rates of ectopic pregnancy. Hum Reprod 1996; 11: 233–5. 48. Marchbanks PA, Coulam CB, Annegers JF. An association between clomiphene citrate and ectopic pregnancy: a preliminary report. Fertil Steril 1985; 44: 268–70. 49. Cohen J, Mayaux MJ, Guihard-Moscato ML, Schwartz D. In-vitro fertilization and embryo

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67. Yovich JL, Turner SR, Murphy AJ. Embryo transfer technique as a cause of ectopic pregnancies in in vitro fertilization. Fertil Steril 1985; 44: 318–21. 68. Lesny P, Killick SR, Tetlow RL, Robinson J, Maguiness SD. Embryo transfer and uterine junctional zone contractions. Hum Reprod Update 1999; 5: 87–8. 69. Eytan O, Elad D, Jaffa AJ. Bioengineering studies of the embryo transfer procedure. Ann N Y Acad Sci 2007; 1101: 21–37. 70. Tay JI, Moore J, Walker JJ. Ectopic pregnancy. BMJ 2000; 320: 916–19. 71. Abbott L. Ectopic pregnancy: symptoms, diagnosis and management. Nurs Times 2004; 100: 32–3. 72. Kriebs JM, Fahey JO. Ectopic pregnancy. J Midwifery Womens Health 2006; 51: 431–9. 73. Clayton HB, Schieve LA, Peterson HB et al. A comparison of heterotopic and intrauterine-only pregnancy outcomes after assisted reproductive technologies in the United States from 1999 to 2002. Fertil Steril 2007; 87: 303–9. 74. Barrenetxea G, Barinaga-Rementeria L, Lopez de Larruzea A et al. Heterotopic pregnancy: two cases and a comparative review. Fertil Steril 2007; 87: 417 e9–15. 75. Poikkeus P, Hiilesmaa V, Tiitinen A. Serum HCG 12 days after embryo transfer in predicting pregnancy outcome. Hum Reprod 2002; 17: 1901–5. 76. Kirk E, Papageorghiou AT, Condous G et al. The diagnostic effectiveness of an initial transvaginal scan in detecting ectopic pregnancy. Hum Reprod 2007; 22: 2824–8. 77. Levine D. Ectopic pregnancy. Radiology 2007; 245: 385–97. 78. Lazarenko GC, Dobson C, Enokson R, Brant R. Accuracy and speed of urine pregnancy tests done in the emergency department: a prospective study. Cjem 2001; 3: 292–5. 79. Fernandez H, Gervaise A. Ectopic pregnancies after infertility treatment: modern diagnosis and therapeutic strategy. Hum Reprod Update 2004; 10: 503–13. 80. Mueller MD, Raio L, Spoerri S et al. Novel placental and nonplacental serum markers in ectopic versus normal intrauterine pregnancy. Fertil Steril 2004; 81: 1106–11. 81. Dumps P, Meisser A, Pons D et al. Accuracy of single measurements of pregnancy-associated plasma protein-A, human chorionic gonadotropin and progesterone in the diagnosis of early pregnancy failure. Eur J Obstet Gynecol Reprod Biol 2002; 100: 174–80. 82. Ferrero S, Anserini P, Remorgida V, Ragni N. “Triple marker” for ectopic pregnancy. Fertil Steril 2004; 82: 986, author reply 986–7. 83. Daponte A, Pournaras S, Zintzaras E et al. The value of a single combined measurement of VEGF, glycodelin, progesterone, PAPP-A, HPL and LIF for differentiating between ectopic and abnormal intrauterine pregnancy. Hum Reprod 2005; 20: 3163–6. 84. Buckley RG, King KJ, Disney JD et al. Serum progesterone testing to predict ectopic pregnancy in symptomatic first-trimester patients. Ann Emerg Med 2000; 36: 95–100. 85. Katsikis I, Rousso D, Farmakiotis D et al. Receiver operator characteristics and diagnostic value of

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104. Murphy AA, Nager CW, Wujek JJ et al. Operative laparoscopy versus laparotomy for the management of ectopic pregnancy: a prospective trial. Fertil Steril 1992; 57: 1180–5. 105. Lundorff P, Thorburn J, Hahlin M, Kallfelt B, Lindblom B. Laparoscopic surgery in ectopic pregnancy. A randomized trial versus laparotomy. Acta Obstet Gynecol Scand 1991; 70: 343–8. 106. Lundorff P, Thorburn J, Lindblom B. Fertility outcome after conservative surgical treatment of ectopic pregnancy evaluated in a randomized trial. Fertil Steril 1992; 57: 998–1002. 107. Gray DT, Thorburn J, Lundorff P, Strandell A, Lindblom B. A cost-effectiveness study of a randomised trial of laparoscopy versus laparotomy for ectopic pregnancy. Lancet 1995; 345: 1139–43. 108. Tahseen S, Wyldes M. A comparative case-controlled study of laparoscopic vs laparotomy management of ectopic pregnancy: an evaluation of reproductive performance after radical vs conservative treatment of tubal ectopic pregnancy. J Obstet Gynaecol 2003; 23: 189–90. 109. Al-Sunaidi M, Tulandi T. Surgical treatment of ectopic pregnancy. Semin Reprod Med 2007; 25: 117–22. 110. Silva PD, Schaper AM, Rooney B. Reproductive outcome after 143 laparoscopic procedures for ectopic pregnancy. Obstet Gynecol 1993; 81: 710–15. 111. Mol BW, Matthijsse HC, Tinga DJ et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod 1998; 13: 1804–9. 112. Bangsgaard N, Lund CO, Ottesen B, Nilas L. Improved fertility following conservative surgical treatment of ectopic pregnancy. BJOG 2003; 110: 765–70. 113. Ahmad G, Watson AJ, Metwally M. Laparoscopy or laparotomy for distal tubal surgery? A meta-analysis. Hum Fertil (Camb) 2007; 10: 43–7. 114. Johnson NP, Mak W, Sowter MC. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev 2004; (3): CD002125. 115. Lee SM, Kang JH, Oh SY, Hong JS, Kim JW. A successfully treated case of primary tubal choriocarcinoma coexistent with viable intrauterine pregnancy. Gynecol Oncol 2005; 97: 671–3. 116. Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril 2007; 87: 481–4. 117. Lipscomb GH. Medical therapy for ectopic pregnancy. Semin Reprod Med 2007; 25: 93–8. 118. Guven ES, Dilbaz S, Dilbaz B et al. Comparison of the effect of single-dose and multiple-dose methotrexate therapy on tubal patency. Fertil Steril 2007; 88: 1288–92. 119. Rozenberg P, Chevret S, Camus E et al. Medical treatment of ectopic pregnancies: a randomized clinical trial comparing methotrexate-mifepristone and methotrexate-placebo. Hum Reprod 2003; 18: 1802–8. 120. Verma U, Jacques E. Conservative management of live tubal pregnancies by ultrasound guided potassium chloride injection and systemic methotrexate treatment. J Clin Ultrasound 2005; 33: 460–3.

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Ectopic pregnancy after fertility treatment 121. Dudley PS, Heard MJ, Sangi-Haghpeykar H, Carson SA, Buster JE. Characterizing ectopic pregnancies that rupture despite treatment with methotrexate. Fertil Steril 2004; 82: 1374–8. 122. Lipscomb GH, Bran D, McCord ML, Portera JC, Ling FW. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998; 178: 1354–8. 123. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a metaanalysis comparing “single dose” and “multidose” regimens. Obstet Gynecol 2003; 101: 778–84. 124. Alleyassin A, Khademi A, Aghahosseini M et al. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril 2006; 85: 1661–6. 125. Condous G, Lu C, Van Huffel SV, Timmerman D, Bourne T. Human chorionic gonadotrophin and progesterone levels in pregnancies of unknown location. Int J Gynaecol Obstet 2004; 86: 351–7. 126. Condous G, Timmerman D, Goldstein S et al. Pregnancies of unknown location: consensus statement. Ultrasound Obstet Gynecol 2006; 28: 121–2. 127. Banerjee S, Aslam N, Woelfer B et al. Expectant management of early pregnancies of unknown location: a prospective evaluation of methods to predict spontaneous resolution of pregnancy. BJOG 2001; 108: 158–63. 128. Elito Junior J, Camano L. Unruptured tubal pregnancy: different treatments for early and late diagnosis. Sao Paulo Med J 2006; 124: 321–4. 129. Elson J, Tailor A, Banerjee S et al. Expectant management of tubal ectopic pregnancy: prediction of successful outcome using decision tree analysis. Ultrasound Obstet Gynecol 2004; 23: 552–6. 130. Nathorst-Boos J, Rafik Hamad R. Risk factors for persistent trophoblastic activity after surgery for ectopic pregnancy. Acta Obstet Gynecol Scand 2004; 83: 471–5. 131. Kamina P, Dufrenot A, de Tourris H. [Fossae, recesses and culs-de-sac in the pelvic peritoneum of women (author’s transl)]. J Gynecol Obstet Biol Reprod (Paris) 1979; 8: 393–8. 132. Lass A, Ellenbogen A, Croucher C et al. Effect of salpingectomy on ovarian response to superovulation in an in vitro fertilization-embryo transfer program. Fertil Steril 1998; 70: 1035–8. 133. Sezik M, Ozkaya O, Demir F, Sezik HT, Kaya H. Total salpingectomy during abdominal hysterectomy: effects on ovarian reserve and ovarian stromal blood flow. J Obstet Gynaecol Res 2007; 33: 863–9. 134. Romeu A, Monzo A, Peiro T et al. Endogenous LH surge versus hCG as ovulation trigger after lowdose highly purified FSH in IUI: a comparison of 761 cycles. J Assist Reprod Genet 1997; 14: 518–24. 135. Verhulst G, Vandersteen N, van Steirteghem AC, Devroey P. Bilateral salpingectomy does not

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compromise ovarian stimulation in an in-vitro fertilization/embryo transfer programme. Hum Reprod 1994; 9: 624–8. Marret H, Hamamah S, Alonso AM, Pierre F. Case report and review of the literature: primary twin ovarian pregnancy. Hum Reprod 1997; 12: 1813–15. Philippe E, Renaud R, Dellenbach P, Dreyfus J. Ritter J, Muhlstein C, [Ovarian pregnancy. Apropos of 32 cases]. J Gynecol Obstet Biol Reprod (Paris) 1987; 16: 901–8. Marcus SF, Brinsden PR. Primary ovarian pregnancy after in vitro fertilization and embryo transfer: report of seven cases. Fertil Steril 1993; 60: 167–9. Diamond MP, Wentz AC, Herbert CM et al. One ovary or two: differences in ovulation induction, estradiol levels, follicular development in a program for in vitro fertilization. Fertil Steril 1984; 41: 524–9. Alper MM, Seibel MM, Oskowitz SP et al. Comparison of follicular response in patients with one or two ovaries in a program of in vitro fertilization. Fertil Steril 1985; 44: 652–5. Dodds WG, Chin N, Awadalla SG et al. In vitro fertilization and embryo transfer in patients with one ovary. Fertil Steril 1987; 48: 249–53. Penzias AS, Gutmann JN, Shamma FN, LaMorte AI, DeCherney AH. Ovulation induction with GnRH agonist and human menopausal gonadotropins: response in patients with one versus two ovaries. Int J Fertil Menopausal Stud 1993; 38: 270–3. Nargund G, Bromhan D. Comparison of endocrinological and clinical profiles and outcome of IVF cycles in patients with one ovary and two ovaries. J Assist Reprod Genet 1995; 12: 458–60. Lass A, Paul M, Margara R, Winston RM. Women with one ovary have decreased response to GnRHa/HMG ovulation protocol in IVF but the same pregnancy rate as women with two ovaries. Hum Reprod 1997; 12: 298–300. Orvieto R, Kruchkovich J, Zohav E et al. Does methotrexate treatment for ectopic pregnancy influence the patient’s performance during a subsequent in vitro fertilization/embryo transfer cycle? Fertil Steril 2007; 88: 1685–6. Oriol B, Barrio A, Pacheco A et al. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril 2007. Stern CJ, Toledo MG, Gook DA, Seymour JF. Fertility preservation in female oncology patients. Aust N Z J Obstet Gynaecol 2006; 46: 15–23. Maltaris T, Boehm D, Dittrich R, Seufert R, Koelbl H. Reproduction beyond cancer: a message of hope for young women. Gynecol Oncol 2006; 103: 1109–21. Sultana CJ, Easley K, Collins RL. Outcome of laparoscopic versus traditional surgery for ectopic pregnancies. Fertil Steril 1992; 57: 285–9. Lindblom B, Hahlin M, Lundorff P, Thorburn J. Treatment of tubal pregnancy by laparoscopeguided injection of prostaglandin F2 alpha. Fertil Steril 1990; 54: 404–8.

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37 Molar pregnancy: pathology and management Ross S Berkowitz, Donald P Goldstein

It is now well recognised that molar pregnancy comprises two distinct entities, complete and partial, which differ on the basis of chromosomal pattern, gross and microscopic histopathology and clinical presentation. In this chapter, our focus is on the pathology and management of complete and partial hydatidiform mole.

Pathology and cytogenetics Hydatidiform moles may be categorised as either complete or partial, based upon gross morphology, histopathology, and karyotype (Table 37.1).1–4 Complete hydatidiform moles (CHMs) have no identifiable embryonic or foetal tissues. The chorionic villi have generalised swelling and diffuse trophoblastic hyperplasia and the implantation-site trophoblast has diffuse, marked atypia.5,6 Complete moles usually have a 46,XX karyotype, and the molar chromosomes are derived entirely from paternal origin.7 Most complete moles appear to arise from an anuclear empty ovum that has been fertilised by a haploid (23X) sperm, which then duplicates its own chromosomes.8 Whereas most complete moles have a 46,XX chromosomal pattern, approximately 10% of complete moles have a 46,XY karyotype.9 The 46,XY complete mole arises from fertilisation of an anuclear empty ovum by two sperm. Whereas chromosomes in the complete mole are entirely of paternal origin, the mitochondrial DNA is of maternal origin.10 Recent reports have shed light on the rare occurrence of familial recurrent hydatidiform mole which is characterised by recurrent CHMs of biparental, rather than the more usual androgenetic origin. Although the specific gene defect in these families has not been identified, genetic mapping has shown that in most families the gene responsible is located in a 1.1 Mb region on chromosome 19q13.4.11 Mutations in this gene result in dysregulation of imprinting in the female germ line with abnormal development of both embryonic and extraembryonic tissue. Subsequent pregnancies in women diagnosed with this condition are likely to be CHM. Molar pregnancies in women with familial recurrent hydatidiform mole are associated with consanguinity and have a risk of progressing

Table 37.1 Complete versus partial molar pregnancy: histopathological and chromosomal features.

Foetal or embryonic tissue Hydropic swelling of villi Trophoblastic hyperplasia Scalloping of chorionic villi Trophoblastic stromal inclusions Implantation-site trophoblast Karotype

Complete mole

Partial mole

Absent Diffuse Diffuse Absent Absent

Present Focal Focal Present Present

Marked atypia 46XX (mainly), 46, XY

Mild atypia Triploid, 69XXY, 69XYY

to persistent gestational trophoblastic neoplasia similar to that of androgenetic CHM. During the 1960s and 1970s, CHMs were primarily diagnosed in the second trimester. However, currently, most patients with complete moles are diagnosed in the first trimester in the US and elsewhere.12–14 The pathological characteristics of a first trimester complete mole are different than the classic features in the second trimester. Mosher et al15 compared pathological findings of 23 current complete moles (1994–1997, mean gestational age 8.5 weeks) with 20 historic complete moles (1969–1975; mean gestational age, 17 weeks). Histologically, current complete moles had a smaller mean maximal villous diameter (5.7 vs 8.2 mm), less circumferential trophoblastic hyperplasia (39% vs 75%), more primitive villous stroma (70% vs 10%) and less global necrosis (22% vs 54%). Currently, complete moles are often characterised by subtle morphological alterations that may result in their misclassification as partial moles or non-molar abortions. The early and prompt use of ultrasound and hCG measurement in pregnant women with vaginal bleeding is probably the main factor leading to early diagnosis. Partial hydatidiform moles (PHMs) are characterised by the following pathological features: varying-sized chorionic villi with focal swelling and focal trophoblastic hyperplasia; focal, mild atypia of implantation-site trophoblast; marked villous scalloping and prominent stromal trophoblastic inclusions; and identifiable foetal or embryonic tissues.1–4 Partial moles

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generally have a triploid karyotype, which results from the fertilisation of an apparently normal ovum by two sperm.3 Lawler et al16 and Lage et al17 reported that 93% and 90%, respectively, of partial moles were triploid. When foetuses are identified with partial moles, they generally have stigmata of triploidy including growth retardation and multiple congenital anomalies. Genest et al18 reviewed 19 putative non-triploid PHMs using standardised histological diagnostic criteria and repeat flow cytometry and none of these cases on re-evaluation was convincingly a non-triploid partial mole. Nontriploid partial moles may not exist. First trimester clinical diagnosis of CHM has made the pathological diagnosis challenging because the characteristic histological features have become more subtle. Recently biomarkers have emerged that take advantage of parentally imprinted genes to distinguish CHM from other gestations. Because CHM results from diandry, paternally imprinted gene products, which are normally expressed only from maternally derived chromosomes, should be absent. Studies have recently shown that immunohistochemistry for p57 (paternally imprinted, maternally expressed gene product) is useful for confirming the diagnosis of CHM.19 Nuclei of decidua (maternally derived tissue) and extravillous trophoblast of all types of gestations stain positively for p57. Almost all complete moles have absent (or near absent) villous stromal and cytotrophoblastic nuclear activity for p57, while all other types of gestations (including partial moles) show nuclear reactivity in more than 25% of villous stromal and cytotrophoblastic nuclei. The use of flow cytometry and p57 immunostaining can be very helpful in distinguishing early CHM (diploid, p57 negative) from non-molar hydropic abortion (diploid, p57 positive) and PHM (triploid, p57 positive).

Presentation of complete molar pregnancy The following description of the clinical presentation of complete mole is partially based upon our experience with 308 patients between 1965 and 1975 at the New England Trophoblastic Disease Center (NETDC).1 The experience from our centre is consistent with the published observations of other investigators. However, partial mole was initially distinguished from complete mole by Vassilakos et al in 1977 and Szulman and Surti in 1978 on the basis of karyotype and histopathology.2–4 It is therefore important to note that all studies concerning molar pregnancy which include patients before 1980 may have included some patients with partial mole.

Vaginal bleeding Vaginal bleeding is the most common presenting symptom in patients with complete mole, occurring

in 97% of our cases. Curry et al and Kohorn also noted a high incidence of vaginal bleeding in 312 (89%) of 347 and in 188 (94%) of 200 patients with molar pregnancy, respectively.20,21 Molar chorionic villi may disrupt maternal vessels and the endometrial cavity may be distended by large volumes of retained blood. Retained blood may undergo oxidation and ‘prune juice-like’ fluid may leak into the vagina. Because bleeding may be prolonged, considerable and occult, 54% of our patients were anaemic at presentation (haemoglobin <10g/dl).

Excessive uterine enlargement The uterine size was palpably larger than gestational age in 51% of our patients with complete mole. Uterine size was larger than dates by 4 weeks in 46% and 38% of patients with complete mole in the studies by Curry et al and Kohorn, respectively.20,21 The endometrial cavity expands because of both retained blood and chorionic tissue. Excessive uterine size is usually associated with markedly elevated levels of human chorionic gonadotrophin (hCG) from trophoblastic overgrowth.

Theca lutein ovarian cysts The reported frequency of theca lutein ovarian cysts varies depending upon whether the diagnosis is established by clinical or ultrasound examination. Montz et al reported that theca lutein cysts were clinically palpable in 102 (26.4%) of 386 patients with molar pregnancy.22 However, Santos-Ramos et al, using ultrasound observed theca lutein ovarian cysts >5 cm in diameter in 23 (46%) of 50 patients with molar pregnancy.23 Theca lutein ovarian cysts are usually bilateral and multicystic, containing amber-coloured or serosanguineous fluid. Though usually in the 6–12 cm range, they may reach substantial proportions of >20 cm in size. While theca lutein cysts are generally noted at the time of presentation, they may develop shortly after uterine evacuation. Theca lutein cysts result from hyperstimulation of the ovaries by high circulating blood levels of hCG and are detected almost exclusively in patients with very high serum hCG values.24 Infrequently these patients may develop other signs of ovarian hyperstimulation such as ascites or pleural effusions. Montz et al reviewed the clinical records of 102 patients with molar pregnancy and theca lutein ovarian cysts to define their natural history.22 The mean regression time for the cysts was 8 weeks. Only two patients experienced an acute surgical complication involving ovarian torsion or rupture. Similarly, Kohorn reported that three (2.3%) of 127 patients with molar pregnancy developed torsion of ovarian theca lutein cysts.25 If patients have severe symptoms of pelvic pressure or pain, theca lutein cysts may be decompressed by either ultrasound-directed percutaneous or laparoscopic aspiration. Laparoscopy may

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also successfully manage cases of incomplete ovarian torsion or rupture.26

Toxaemia Pre-eclampsia including hypertension, oedema and/or proteinuria was observed in 27% of our patients with complete mole. Curry et al reported preeclampsia in 12% of patients with molar disease in the Duke series.20 Eclamptic convulsions occur rarely. In our experience toxaemia was limited almost exclusively to patients with markedly elevated hCG values and excessive uterine enlargement. Curry et al also noted that 81% of their patients with toxaemia had excessive uterine size.

Hyperemesis gravidarum Hyperemesis requiring antiemetic therapy developed in 26% and 20% of patients with molar pregnancy treated at our centre and at the Yale centre, respectively.25,27 Five (2%) of our patients required hospitalisation for correction of marked electrolyte disturbances. Hyperemesis is also associated with high hCG levels and excessive uterine size.

Hyperthyroidism Clinically evident hyperthyroidism was detected in 7% of our patients with complete mole. However, laboratory evidence for hyperthyroidism was more common. Galton et al measured thyroid function tests in 11 patients with molar pregnancy before and after evacuation.28 Pre-evacuation, all patients had elevated values for thyroidal 131I uptake and serum free thyroxine; the thyroid function tests rapidly returned to normal after evacuation even before the hCG level became undetectable. Hyperthyroidism occurs almost exclusively in patients with very high hCG levels. Some authors have suggested that hCG is the thyroid stimulator in patients with molar pregnancy. Kenimer et al reported that highly purified hCG appeared to have intrinsic thyroid-stimulating activity.29 Positive correlations have been reported in some studies between serum hCG levels and serum total thyroxine (T4) or triiodothyronine (T3) concentrations. However, Amir et al measured thyroid function tests in 47 patients with complete mole and observed no significant correlation between serum hCG levels and free T4 or T3 index values.30 The identity of the thyrotrophic factor in molar pregnancy is therefore still controversial. Patients with untreated or poorly controlled hyperthyroidism may develop thyroid storm at the time of anaesthesia induction and evacuation. Thyroid storm is characterised by hyperthermia, delirium, coma, atrial fibrillation and cardiovascular collapse. While blood samples should be drawn for laboratory confirmation, the diagnosis of thyroid storm must be made

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clinically so that treatment can be promptly instituted. The administration of β-adrenergic blocking agents prevents or rapidly reverses many of the cardiovascular and metabolic complications of thyroid storm. A pulmonary artery catheter may also be helpful to monitor cardiovascular status and guide fluid replacement.

Respiratory insufficiency Of our patients with complete mole 2% developed respiratory insufficiency. Pulmonary compromise generally only develops in patients with high hCG levels, excessive uterine size and very large theca lutein ovarian cysts. Twiggs et al reported that 12 (27%) of 44 patients with a molar pregnancy of at least 16 weeks size developed pulmonary complications.31 Patients may present with tachycardia, tachypnoea and anxiety or confusion in the recovery room after molar evacuation. Arterial blood gases may show evidence of hypoxia and respiratory alkalosis. Auscultation of the chest usually reveals diffuse rales and chest roentgenogram may show bilateral pulmonary infiltrates. The signs and symptoms of respiratory distress usually resolve within 72 hours with appropriate cardiovascular and respiratory support. However, it is important to recognise that some patients may require temporary mechanical ventilation to provide adequate oxygenation. While embolisation of molar tissue to the pulmonary vasculature may contribute to respiratory distress, it may also result from the cardiovascular complications of toxaemia, thyroid storm and massive fluid replacement. Patients with complete mole are now being diagnosed earlier before they develop the classic signs and symptoms. Earlier diagnosis of complete mole may be due to changing clinical practice such as the frequent use of hCG measurement and vaginal probe ultrasound in early pregnancy in women with vaginal staining and even in asymptomatic women. Soto-Wright et al reviewed the presentation of 74 patients with complete mole who underwent uterine evacuation at the NETDC between 1988 and 1993.14 Vaginal bleeding continued to be the most common presenting symptom, occurring in 62 (84%) patients. However, excessive uterine size (size larger than for gestational age), anaemia (haemoglobin <10 g/dl) and toxaemia were noted in only 21 (28%), four (5%) and one (1.3%) patient, respectively. Additionally, hyperemesis was observed in only six (8%) patients and no patient had clinical hyperthyroidism or respiratory insufficiency. Patients with complete mole in the recent series were diagnosed earlier in gestation. The mean gestational age at diagnosis in the earlier (1965–1975) and recent series was 16.5 and 11.8 weeks, respectively. It is important to emphasise that the incidence of postmolar gestational trophoblastic neoplasia did not change in the recent series; 15 of 64 (23%) patients with complete mole, who did not

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receive chemoprophylaxis, developed postmolar persistent tumour. Among the entire group of 74 patients, 19 (25.7%) patients developed postmolar persistent tumour. Similarly, Paradinas et al reported that most recent cases of complete mole are diagnosed in the first trimester in the UK.13 While patients with first trimester complete mole generally do not present with the classic signs and symptoms, the risk for postmolar tumour remains unchanged.

Presentation of partial molar pregnancy Patients with partial mole usually do not present with the classical features of complete mole. We reviewed the medical records of 81 consecutive patients with partial mole to delineate its clinical presentation and natural history.32 Excessive uterine size was noted in only three (4%) patients and hyperemesis, hyperthyroidism, prominent theca lutein ovarian cysts and respiratory insufficiency were observed in only one patient. The clinical diagnosis preoperatively was incomplete or missed abortion in 74 (91%) patients and molar pregnancy in only five (6%). Other investigators have noted similar findings. Szulman and Surti and Czernobilsky et al reported excessive uterine enlargement in nine (11%) of 81 patients and in two (8%) of 25 patients with partial mole, respectively.33,34 Toxaemia was reported in both studies in only 4% of patients. Other medical complications of complete mole such as hyperthyroidism and theca lutein cysts are uncommon with partial mole. Szulman and Surti also observed that the clinical diagnosis prior to evacuation was incomplete or missed abortion in 92% of their patients. Characteristically, the diagnosis of partial mole is made after histological review of curettage specimens from presumed incomplete or missed abortions. Feltmate et al reviewed the clinical presentation and outcome of partial moles at our centre from 1973–2003.35 Data were divided into two cohorts (1973–1989 and 1990–2003) to evaluate potential changes over time. Unlike CHM, gestational age at diagnosis did not appreciably change over time (14.9 vs 13.5 weeks) and nor did the presenting symptoms of PHM.

Diagnosis Ultrasound Ultrasonography has proved to be an accurate and sensitive technique for the diagnosis of complete mole. Complete mole produces a characteristic vesicular pattern due to generalised swelling of the chorionic villi. The chorionic villi in first trimester complete moles tend to be smaller and have less cavitation.15 However, the majority of first trimester complete moles still demonstrate a typical ultrasound appearance of a complex, echogenic intrauterine mass

containing many small cystic spaces.36 Among 24 cases of first trimester complete moles (mean gestational age 8.7 weeks), the initial sonographic interpretation was a complete mole in 17 (71%) cases. The specificity of the sonographic findings in complete molar pregnancy may be increased by correlation with the hCG level.37 A complete mole may be better differentiated from a missed abortion by considering the hCG value at the time of the ultrasound. Ultrasonography may also contribute to the detection of PHM. Fine et al studied ultrasound in patients with partial mole to determine if sonographic criteria could be established to detect partial mole before evacuation.38 Ultrasound from 22 partial moles and 33 first trimester missed abortions were reviewed independently by three radiologists who were unaware of the pathological diagnoses. Each radiologist evaluated the appearance of the placenta, the shape, dimensions and contents of the gestational sac, and the presence or absence of ovarian cysts. Two sonographic findings were significantly associated with the diagnosis of PHM: cystic spaces in the placenta and ratio of transverse to anteroposterior dimension of the gestational sac of more than 1.5. These changes in the shape of the gestational sac may be part of the embryopathy of triploidy. There was high interobserver correlation for both criteria. When both criteria were present, the positive predictive value for partial mole was 87%. When both criteria were absent, the positive predictive value for missed abortion was 90%.

hCG measurement Markedly elevated hCG levels are commonly seen in patients with complete molar pregnancy. Genest et al reviewed the clinical and pathological characteristics of 153 cases of complete mole managed at the NETDC between 1980 and 1990.39 Pre-evacuation hCC levels were >100 000 U/l in 46% of the patients. Similarly, Menczer et al reported that 30 (41%) of 74 patients with molar pregnancy had pre-evacuation hCG values of >100 000 U/l.40 The measurement of a high hCG level (>100 000 U/l) may therefore suggest the diagnosis of a complete molar pregnancy, particularly when associated with vaginal bleeding and uterine enlargement. In contrast, PHM is less commonly associated with markedly elevated hCG values. Only two (7%) of 30 patients with partial mole at our centre had pre-evacuation hCG levels of >100 000 U/l.32 Czernobilsky et al also reported that only one (6%) of 17 patients with partial mole had a pre-evacuation urinary hCG level >300 000 U/l.34

Treatment When a diagnosis of complete or partial molar pregnancy has been made, the patient should be evaluated for the presence of medical complications, including anaemia, toxaemia, hyperthyroidism and respiratory

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insufficiency. All patients should have baseline hCG performed in addition to routine blood work and urinalysis. After the patient has been medically evaluated and stabilised, a decision must be made concerning the most appropriate method of evacuation. If the patient no longer desires to preserve fertility, hysterectomy may be performed. Prominent ovarian theca lutein cysts can be aspirated at the time and the ovaries conserved. It is important to inform the patient that while hysterectomy eliminates the complications of local invasion, it does not prevent metastatic disease and therefore gonadotrophin follow-up is required. In patients who wish to retain fertility, suction curettage is the preferred method of evacuation regardless of uterine size.41,42 An oxytocin infusion should be started before anaesthesia induction to increase myometrial tone and facilitate contraction, and thus decrease blood loss. Concern has been expressed that oxytocin may promote metastasis of trophoblastic tissue. However, it has been reported that uterine stimulation before evacuation did not increase the risk of persistent tumour. The cervix should be carefully dilated to accommodate a cannula appropriate for the volume of trophoblastic tissue. A 12-mm cannula is generally satisfactory because it allows rapid evacuation and involution of the uterus. During dilatation, brisk bleeding may be encountered due to passage of copious amounts of blood retained in the endometrial cavity. However, it is best to proceed promptly to uterine evacuation. After the initiation of suction evacuation, the uterus generally shrinks rapidly and bleeding is well controlled. If the uterus is larger than 14 weeks size, one hand may be placed on top of the fundus to assess uterine size and to massage the uterus. When suction evacuation is thought to be complete sharp curettage should be performed to remove any residual chorionic tissue. Patients who are Rh negative should receive Rh immune globulin at the time of evacuation because the RhD factor is expressed on trophoblast.

Chemoprophylaxis The use of prophylactic chemotherapy at the time of molar evacuation remains controversial. However, several investigators have reported that chemoprophylaxis reduces the incidence of postmolar tumour. Goldstein reported that chemoprophylaxis reduced the risk of persistent tumour from 20 to 8% and eliminated metastases.43 Similarly, Kashimura et al noted that chemoprophylaxis in patients with complete mole reduced the frequency of postmole tumour from 18 to 7%.44 However, one of the main objections of exposing all patients with molar pregnancy to chemoprophylaxis is that only a small minority are at risk for persistence. Kim et al conducted a prospective, randomised trial of the use of prophylactic chemotherapy in patients

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with complete mole.45 Seventy-one patients with complete mole were randomised to be treated with either molar evacuation alone or molar evacuation with prophylactic methotrexate and folinic acid. Patients were categorised as either high or low risk based upon prognostic factors for the development of persistent disease (a discussion of these prognostic factors is given later in this chapter). Among patients with high risk complete mole, prophylactic chemotherapy reduced the incidence of postmolar tumour from 47 to 14%. Among patients with low risk complete mole, prophylactic chemotherapy did not influence the incidence of persistent disease (7.7 vs 5.6%). However, patients who developed persistent tumour after prophylactic methotrexate subsequently required more courses of therapeutic methotrexate to attain remission. Limpongsanurak also recently performed a prospective, randomised trial of prophylactic actinomycin D in 60 patients with high risk complete mole.46 The frequency of postmolar tumour in the chemoprophylactic group was 13.8% and in the control group was 50%. At our centre, 93 patients with high risk complete mole were treated with prophylactic actinomycin D and only ten (11%) developed persistent disease.47 All ten patients had non-metastatic tumour. Six patients were treated with methotrexate for persistent tumor and five required only one course of methotrexate to attain remission. In order to avoid drug resistance, it may be important to use a different chemotherapeutic agent for therapy following failed chemoprophylaxis. The risk for chemoprophylaxis failure was increased in patients with particularly high pre-evacuation hCG levels. Chemoprophylaxis may be particularly useful in patients with high risk complete mole when hormonal follow-up is either unavailable or unreliable. Molar pregnancy is more prevalent in certain global regions such as Asia and Africa where medical follow-up may be less available.48

Follow-up Patients with both complete and partial molar pregnancy should be monitored with serial hCG values after evacuation to ensure that they achieve complete sustained remission. Patients are followed with weekly hCG levels until non-detectable for 3 weeks and then monthly hCG levels until non-detectable for 6 months. After achieving a non-detectable serum hCG level (hCG <5 mIU/ml), the risk of developing relapse after both complete and partial mole appears to be very low.49 Data from multiple centres including the Charing Cross Hospital, Sheffield, Dallas, Hungary, Australia, The Netherlands and our centre indicate in several thousand women with molar pregnancy that the risk of relapse is <1% after achieving non-detectable hCG levels.49–58 For example, in 1986 Bagshawe et al reported that 27 of 4754 patients with mole (<1%) developed relapse after achieving at least one nondetectable hCG value of <5 mIU/ml in serum and/or

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Table 37.2

Postmolar gestational trophoblastic neoplasia (GTN) in the US.

Authors Goldstein and Berkowitz, 19821 Lurain et al, 198364 Curry et al, 197520 Morrow et al, 197765 Kohorn, 198225

No. of patients

Non-metastatic GTN (%)

Metastatic GTN (%)

Total GTN (%)

858 738 347 121 127

14.7 16.3 16.6 23.1 26.0

4.0 3.0 3.5 3.3 3.1

18.7 19.3 20.1 26.4 29.1

<25 mIU/ml in urine.50 Among clinical series published since 2004, only two patients with mole in more than 2000 patients developed persistent tumour after attaining non-detectable serum hCG values. It is possible that hCG follow-up can be safely abbreviated after molar evacuation without compromising patient’s health. Patients with molar pregnancy must be encouraged to use reliable contraception during the entire interval of hCG monitoring. An intrauterine device should be avoided before gonadotrophin remission because of the risk of uterine perforation with invasive tumour. Therefore, patients are confronted with the choice of barrier methods or steroidal contraception when they desire to preserve fertility. Stone and Bagshawe reported in 1979 that the use of oral contraceptives prior to gonadotrophin remission increased the frequency of postmolar tumour two- to threefold.59 However, data from our centre and the Gynecologic Oncology Group indicate that oral contraceptives do not increase the risk for postmolar persistent tumour.60,61 Costa and Doyle performed a systematic review of all published series concerning oral contraceptive use after molar evacuation and the risk of developing persistent tumour.62 They found no clear evidence for an association between oral contraceptive use after molar evacuation and risk for persistent gestational trophoblastic neoplasia. Therefore, we believe that following molar evacuation patients may be safely prescribed oral contraceptives during the entire interval of hormonal follow-up.

Persistent gestational trophoblastic neoplasia after complete molar pregnancy Complete molar pregnancy is well recognised to have a risk of developing persistent gestational trophoblastic neoplasia. However, the incidence of persistent tumour after complete mole has been reported to be from 8% to 29%.1,20,63–65 This marked variation in the reported incidence of postmolar tumour results from differences in diagnostic criteria. The development of internationally recognised criteria for persistent gestational trophoblastic neoplasia will hopefully lead to greater consistency and comparability of data from around the world.66 On the basis of the follow-up of more than 7000 patients, Bagshawe reported that only 7.9% of

patients with molar pregnancy required chemotherapy at the Charing Cross Hospital.63 The criteria for diagnosing postmolar tumour were as follows: hCG >20 000 U/l more than 4 weeks after evacuation; progressively rising hCG values with a minimum of three rising values over 2–3 weeks; metastasis to the brain, liver, kidney, gastrointestinal tract or lungs (>2 cm in diameter or three or more in number); or persistent hCG level 4–6 months after evacuation. Using similar criteria, Franke et al from The Netherlands reported that 10% of patients developed postmolar tumour.67 Importantly, the data from England and The Netherlands represent the experience when patients with molar disease are followed with an organised and systematic regional or national registry and health care system. In the US the incidence of postmolar tumour is reported to be from 18 to 29% (Table 37.2). Most centres in the US defined persistent postmolar disease by the presence of a re-elevation or persistent plateau in hCG for at least 3 consecutive weeks. However, it is important to acknowledge that even amongst American centres there has been some variation in the definition of persistence.68 The criteria for diagnosing persistent tumour after mole in the US have therefore been considerably less stringent than the criteria followed in England or elsewhere in Europe. Clearly, some patients who receive chemotherapy for postmolar tumour in the US would have achieved remission if gonadotrophin follow-up continued in the absence of therapy. The use of less stringent diagnostic criteria for postmolar tumour in the US was partly motivated by the concern that some patients may be lost to follow-up. Schlaerth et al reported that 19 (19%) of 99 patients with molar pregnancy were lost to follow-up at the University of Southern California.69 Massad et al reported that among 40 indigent patients with molar pregnancy, five (13%) were lost to follow-up before remission and 16 (40%) were lost before completing 6 months of follow-up.70 Similarly, Feltmate et al observed that among 333 patients with molar pregnancy 13 (3.9%) were lost to follow-up before remission and 109 (32.7%) were lost to follow-up before completing 6 months of follow-up.49 Several studies have shown that the risk for developing postmolar tumour is increased in patients with signs and symptoms of marked trophoblastic proliferation: excessive uterus enlargement, markedly elevated hCG values and prominent ovarian theca lutein cysts as well as associated medical factors such as toxaemia,

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hyperthyroidism and respiratory insufficiency. Curry et al reported that postmolar disease developed in 49% of patients with prominent theca lutein ovarian cysts and in 57% of patients with ovarian cysts and large-for-dates uteri.20 These findings were confirmed and extended by other investigators. Morrow also observed the occurrence of postmolar tumour in 55% of patients with theca lutein ovarian cysts or uterine size >20 weeks.71 At the NETDC, we reviewed the outcome of 858 patients with complete mole to assess prognostic factors for persistent tumour. Signs of marked trophoblastic growth such as excessive uterine size, theca lutein cysts >6 cm in diameter and pre-evacuation hCG level >100 000 U/l were present in 352 (41%) patients. Non-metastatic and metastatic gestational trophoblastic neoplasia developed in 31% and 8.8% of these patients, respectively. In contrast, 506 (59%) patients with complete mole did not present with signs and symptoms of marked trophoblastic proliferation. Nonmetastatic and metastatic disease developed in only 3.4% and 0.6% of these patients, respectively. Patients with complete mole who present with excessive uterine size, ovarian cysts and/or markedly elevated hCG values are therefore considered as high risk for developing postmolar tumour. Similarly, Kim et al observed postmolar persistent disease in 47.4% of high risk and only 7.7% of low risk complete moles using the same clinical risk criteria.45 The risk for postmolar tumour has also been observed to be increased in older patients. Tow72 and Xia et al73 reported that 37% and 33%, respectively, of women over 40 with molar pregnancy developed persistent tumour. Tsukamoto et al also observed that 56% of women over 50 developed postmolar tumour.74 Complete moles in older women are more commonly aneuploid, and aneuploidy may be a risk factor for persistent tumour.75 Martin et al reported that ten (77%) of 13 aneuploid complete moles developed persistent tumour.76 Patients with repetitive molar pregnancy are also at increased risk of developing persistent tumour in their later episodes of molar pregnancy. Parazzini et al reported a threefold increased risk of post-molar tumour in patients with repetitive molar pregnancy.77 Between June 1965 and November 2001, we treated 34 patients with repeat molar gestations at our centre.78 Each patient had at least two documented molar pregnancies and each molar gestation was diagnosed as either partial or complete on the basis of established histopathological criteria. Persistent tumor developed following the first mole in four (20%) of 20 complete moles. However, postmolar tumour occurred following the second mole in eight (44.4%) of 18 complete moles. It is possible to utilise the hCG regression curve to develop criteria that determine a patient’s risk of developing gestational trophoblastic neoplasia or achieving remission within a few weeks after molar evacuation. Growdon et al reported that a hCG level of >199 mIU/ml in the 3rd to the 8th week following partial

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molar evacuation was associated with at least a 35% risk of gestational trophoblastic neoplasia.79 Wolfberg et al demonstrated that postevacuation hCG values could predict the development of gestational trophoblastic neoplasia in patients with complete mole.80 Within 3 weeks of molar evacuation, more than half of the women with complete mole had their risk of gestational trophoblastic neoplasia modified to either >50% or <9%.

Persistent gestational trophoblastic neoplasia after partial molar pregnancy Between January 1979 and January 1989, 16 (6.6%) of 240 patients who were followed for partial mole at our centre developed persistent tumour.81 As more data have accumulated, it has been apparent that the risk of persistent tumour following a partial mole may be appreciably lower. Table 37.3 summarises the data from ten studies: 70 (1.0%) of 7235 patients with partial mole developed persistent tumour.2,33–35,82–87 Only one of our patients with persistent tumour following partial mole had metastatic disease. Similarly, in the collected series in Table 37.3, only nine (0.1%) patients had metastases. While Goto et al reported three patients with pulmonary metastases, all three patients had barely detectable metastases on computed tomography.86 Our patients with partial mole who developed persistent disease did not have pathological or clinical features that distinguished them from other patients with partial mole.81 Fifteen (94%) of the patients were thought to have a missed abortion prior to evacuation. Only one patient presented with the classic signs and symptoms of molar disease, including excessive uterine size, high hCG levels and ovarian theca lutein cysts. A recent update of our experience with partial moles found that 22 of 390 patients (5.6%) developed gestational trophoblastic neoplasia and that preevacuation clinical symptoms did not distinguish patients at risk for persistence.35 Teng and Ballon reported three patients with diploid partial mole who developed persistent tumour and suggested that diploid partial moles may have a high risk for postmolar disease.88 However, it is questioned whether true non-triploid partial moles exist.18 It may be difficult to distinguish pathologically a partial mole from a hydropic abortion or an early complete mole15

Multiple conceptions with complete or partial molar pregnancy and coexisting foetuses The estimated incidence of twin pregnancy consisting of a complete mole and coexisting foetus is one per

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Table 37.3

Persistent gestational trophoblastic neoplasia (GTN) after partial hydatidiform mole.

Series

No. of patients

No. with post-molar GTN

No. with metastases

Vassilakos et al, 19772 Czernobilsky et al,198234 Szulman and Surti,198233 Wong and Ma, 198482 Ohama et al, 198683 Bolis et al, 198884 Goto et al, 199386 Seckl et al, 200085 Feltmate et al, 200635 Hancock et al, 200687

56 25 49 35 56 86 349 3000 390 3189

0 1 2 4 0 2 10 15 22 14

0 0 0 2 0 0 3 1 1 2

Total

7235

70 (1.0%)

9 (0.1%)

22 000–100 000 pregnancies.89 We reviewed our experience with eight cases of twin pregnancy with complete mole and a coexisting foetus and reviewed 14 additional published cases by other investigators.90 Additionally, we described one case of a partial mole coexisting with a normal placenta and foetus. As compared with singleton complete moles, pregnancies consisting of complete moles and coexisting foetus are diagnosed later, have more markedly enlarged uteri and have higher pre-evacuation hCG values. Importantly, persistent tumour developed in 12 (55%) of 22 patients. There are limited data to guide antenatal management of multiple gestations consisting of complete mole and coexisting foetuses. Five (23%) foetuses survived and no foetal anomalies have been described. Prompt termination of pregnancy may be necessary if severe toxaemia or other medical complications arise. The occurrence of multiple gestation containing a molar pregnancy may increase with greater use of ovulation induction. Matsui et al91 reported 18 patients with proven androgenetic complete mole coexistent with a twin live foetus in a national collaborative study in Japan. Persistent tumour developed in nine (50%) patients and metastases were detected in six (33%) cases. Among the 13 patients, who intended to continue the pregnancy, the pregnancy was terminated in ten patients due to either maternal complications (toxaemia and/or haemorrhage) or intrauterine foetal demise.

Pregnancies after molar pregnancy Since our centre was established in 1965, we have been committed to collecting data about later pregnancy experience. All patients and referring physicians are requested to keep us informed about subsequent pregnancies when they complete gonadotrophin follow-up. Questionnaires are mailed to all of our patients every 2–3 years concerning later pregnancies and general health problems. Our patients who were treated for complete mole had 1337 subsequent pregnancies between June 1965 and December 2007. These later conceptions resulted

in 912 (68.1%) term live births, seven (0.5%) stillbirths, 101 (7.6%) premature deliveries and 11 (0.9%) ectopic pregnancies. Spontaneous abortion occurred in 245 (18.3%) conceptions and major and minor congenital anomalies were detected in 40 (3.9%) infants. Primary Caesarean section was performed in 81 (19.6%) of 414 later term and premature deliveries between January 1979 and December 2007. Importantly, chemoprophylaxis had no adverse effect on later pregnancy experience. Similarly, Ho et al and Kashimura et al reported that patients receiving chemoprophylaxis have a normal later reproductive experience.44,92 After partial mole, our patients had 294 later gestations between June 1965 and December 2007. These subsequent pregnancies resulted in 222 (75.5%) term live births, one (0.3%) stillbirth, five (1.7%) premature deliveries and one (0.3%) ectopic pregnancy. Spontaneous abortion occurred in 45 (15.3%) pregnancies and major and minor congenital anomalies were diagnosed in only four (1.8%) infants. Primary Caesarean section was performed in 39 (17.1%) of 228 term or premature deliveries. Therefore, in general patients with both complete and partial mole can anticipate normal future reproductive outcomes. However, patients with molar disease are at increased risk of developing molar pregnancy in subsequent conceptions.93 After one molar pregnancy, the risk of having molar disease in a future conception is about 1%.50,94 Between June 1965 and December 2007, we treated 35 patients with repeat molar pregnancy at our centre. We observed every possible combination of repeat complete and partial molar gestation. In six cases, the medical records clearly indicated that the patient had a different partner at the conception of different molar pregnancies.95 The experience in these six patients suggests that a primary oocyte problem may contribute to the development of molar pregnancy. Following two molar pregnancies, 24 patients at our centre had 39 later pregnancies resulting in 24 (61.5%) full term deliveries, seven (17.9%) molar pregnancies (six complete, one partial), three spontaneous abortions, three therapeutic abortions, one

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intrauterine foetal demise and one ectopic pregnancy. Therefore, among our patients with two molar pregnancies, the risk of developing molar disease in a subsequent conception was 18%. Bagshawe et al also reported that the risk of molar disease following two episodes of molar pregnancy was 15%.50 However, patients with repeat mole can achieve normal full term pregnancies. Similarly, Lurain et al reported that five of eight patients with repetitive mole later achieved normal term gestation.96 Because of the increased risk of later molar disease, we advise our patients with molar pregnancy to undergo ultrasound in the first trimester of subsequent pregnancies to confirm normal gestational development. Additionally hCG should be measured 6 weeks after the completion of any future pregnancy to exclude choriocarcinoma. While all patients with molar pregnancy are encouraged to use reliable contraception during gonadotrophin follow-up, some patients conceive before follow-up is completed. Seventy patients at our centre became pregnant prior to completion of six months of gonadotrophin follow-up.97 All of these patients achieved at least one non-detectable hCG level. Thirteen patients were lost to follow-up. No patient developed persistent tumour. Full term delivery with no congenital anomalies was documented in 35 (61.4%) patients. Pregnancies occurring before the completion of hCG follow-up in patients with molar pregnancy may be allowed to be continued under careful surveillance as long as the patient achieved at least one non-detectable hCG value.

References 1. Goldstein DP, Berkowitz RS. The diagnosis and management of molar pregnancy. In Gestational Trophoblastic Neoplasms: Clinical Principles of Diagnosis and Management. Philadelphia: Saunders, 1982: 143–75. 2. Vassilakos P, Riotton G, Kajii, T. Hydatidiform mole: two entities. Am J Obstet Gynecol 1977; 127: 167–70. 3. Szulman AE, Surti U. The syndromes of hydatidiform mole. I. Cytogenetic and morphologic correlations. Am J Obstet Gynecol 1978; 131: 665–71. 4. Szulman AE, Surti U. The syndromes of hydatidiform mole. II. Morphologic evolution of the complete and partial mole. Am J Obstet Gynecol 1978; 132: 20–7. 5. Berkowitz RS, Goldstein DP, Bernstein MR. Evolving concepts of molar pregnancy. J Reprod Med 1991; 36: 40–4. 6. Montes M, Roberts D, Berkowitz RS, Genest DR. Prevalence and significance of implantation site trophoblast atypia in hydatidiform moles and in spontaneous abortions. Am J Clin Pathol 1996; 105: 411–16. 7. Kajii T, Ohama K. Androgenetic origin of hydatidiform mole Nature 1997; 268: 633–4.

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8. Yamashita K, Wake N, Araki T, Ichinoe R, Makoto K. Human lymphocyte antigen expression in hydatidiform mole; androgenesis following fertilization by a haploid sperm. Am J Obstet Gynecol 1979; 135: 597–600. 9. Pattillo RA, Sasaki S, Katayama KP, Roesler M, Mattingly RF. Genesis of 46, XY hydatidiform mole. Am J Obstet Gynecol 1981; 141: 104–5. 10. Azuma C, Saji F, Tokugawa Y et al. Application of gene amplification by polymerase chain reaction to genetic analysis of molar mitochondrial DNA: the detection of anuclear empty ovum as the cause of complete mole. Gynecol Oncol 1991; 40: 29–33. 11. Fisher RA, Hodges MD, Newlands ES. Familial recurrent hydatidiform mole: a review. J Reprod Med 2004; 49: 595–601. 12. Felemban AA, Bakri YN, Alkharif HA et al. Complete molar pregnancy – clinical trends at King Fahad Hospital, Riyadh, Kingdom of Saudi Arabia. J Reprod Med 1998; 43: 11–13. 13. Paradinas FJ, Browne P, Fisher RA et al. A clinical, histopathological and flow cytometric study of 149 complete moles, 146 partial moles, 107 non-molar hydropic abortions. Histopathology 1996; 28: 101–9. 14. Soto-Wright V, Bernstein MR, Goldstein DP, Berkowitz R. The changing clinical presentation of complete molar pregnancy. Obstet Gynecol 1995; 86: 775–9. 15. Mosher R, Goldstein DP, Berkowitz RS, Bernstein MR, Genest DR. Complete hydatidiform molecomparison of clinicopathologic features, current and past. J Reprod Med 1998; 43: 21–7. 16. Lawler SD, Fisher RA, Dent J. A prospective genetic study of complete and partial hydatidiform moles. Am J Obstet Gynecol 1991; 164: 1270–7. 17. Lage JM, Mark SS, Roberts D et al. A flow cytometric study of 137 fresh hydropic placentas: correlation between types of hydatidiform moles and nuclear DNA ploidy. Obstet Gynecol 1992; 79: 403–10. 18. Genest DR, Ruiz RE, Weremowicz S et al. Do non-triploid partial hydatidiform moles exist? A histologic and flow cytometric reevaluation of non-triploid specimens. J Reprod Med 2002; 47: 363–8. 19. Thaker HM, Berlin A, Tycko B et al. Immunohistochemistry for the imprinted gene product IPL/PHLDA2 for facilitating the differential diagnosis of complete hydatidiform mole. J Reprod Med 2004; 49: 630–6. 20. Curry SL, Hammond CB, Tyrey L, Creasman WT, Parker RT. Hydatidiform mole: diagnosis, management, and long-term follow up of 347 patients. Obstet Gynecol 1975; 45: 1–8. 21. Kohorn EI. Molar pregnancy: presentation and diagnosis. Clin Obstet Gynecol 1984; 27: 181–91.

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22. Montz FJ, Schlaerth JB, Morrow, CP. The natural history of theca lutein cysts. Obstet Gynecol 1988; 72: 247–51. 23. Santos-Ramos R, Forney JP, Schwartz BE. Sonographic findings and clinical correlations in molar pregnancy. Obstet Gynecol 1980; 56: 186–92. 24. Osathanondh R, Berkowitz R, de Cholnoky C et al. Hormonal measurements in patients with theca lutein cysts and gestational trophoblastic disease. J Reprod Med 1986; 31: 179–82. 25. Kohorn EI. Hydatidiform mole and gestational trophoblastic disease in Southern Connecticut. Obstet Gynecol 1982; 59: 78–84. 26. Berkowitz RS, Goldstein DP, Bernstein MR. Laparoscopy in the management of gestational trophoblastic neoplasms. J Reprod Med 1980; 24: 261–4. 27. Berkowitz RS, Goldstein DP. The management of molar pregnancy and gestational trophoblastic tumors. In Knapp RC, Berkowitz RS, eds. Gynecologic Oncology, 2nd edn. New York: McGrawHill, 1993; pp. 328–38. 28. Galton VA, Ingbar SH, Jimenez-Fonseca J, Hershman J. Alterations in thyroid hormone economy in patients with hydatidiform mole. J Clin Invest 1971; 50: 1345–54. 29. Kenimer JG, Hershman JM, Higgins HP. The thyrotropin in hydatidiform moles is human chorionic gonadotropin. J Clin Endocrinol Metab 1975; 40: 482–91. 30. Amir SM, Osathanondh R, Berkowitz RS, Goldstein DP. Human chorionic gonadotropin and thyroid function in patients with hydatidiform mole. Am J Obstet Gynecol 1984; 150: 723–8. 31. Twiggs LB, Morrow CP, Schlaerth JB. Acute pulmonary complications of molar pregnancy. Am J Obstet Gynecol 1979; 135: 189–94. 32. Berkowitz RS, Goldstein DP, Bernstein MR. Natural history of partial molar pregnancy. Obstet Gynecol 1986; 66: 677–81. 33. Szulman AE, Surti U. The clinicopathologic profile of the partial hydatidiform mole. Obstet Gynecol 1982; 59: 597–602. 34. Czernobilsky B, Barash B, Lancet M. Partial moles: a clinicopathologic study of 25 cases. Obstet Gynecol 1982; 59: 75–7. 35. Feltmate CM, Growdon WB, Wolfberg AJ et al. Clinical characteristics of persistent gestational trophoblastic neoplasia after partial hydatidiform molar pregnancy. J Reprod Med 2006; 51: 902–6. 36. Benson CB, Genest DR, Bernstein MR, SotoWright V, Berkowitz RS. Sonographic appearance of first trimester complete hydatidiform moles. Ultrasound Obstet. Gynecol 2000; 16: 188–91. 37. Romero R, Horgan JG, Kohorn EI et al. New criteria for the diagnosis of gestational trophoblastic disease. Obstet Gynecol 1985; 66: 553–8. 38. Fine C, Bundy AL, Berkowitz RS, Boswell SB, Doubilet PM. Sonographic diagnosis of partial hydatidiform mole. Obstet Gynecol 1989; 73: 414–18.

39. Genest D, Laborde O, Berkowitz RS et al. A clinicopathologic study of 153 cases of complete hydatidiform mole (1980–1990): histologic grade lacks prognostic significance. Obstet Gynecol 1991; 78: 402–9. 40. Menczer J, Modan M, Serr DM. Prospective follow-up of patients with hydatidiform mole. Obstet Gynecol 1980; 55: 346–9. 41. Berkowitz RS, Goldstein DP. Chorionic tumours. N Engl J Med 1996; 335: 1740–8. 42. Tidy JA, Gillespie AM, Bright N et al. Gestational trophoblastic disease: A study of mode of evacuation and subsequent need for treatment with chemotherapy. Gynecol Oncol 2000; 78: 309–12. 43. Goldstein DP, Prophylactic chemotherapy of patients with molar pregnancy. Obstet Gynecol 1971; 38: 817–22. 44. Kashimura Y, Kashimura M, Sugimori H et al. Prophylactic chemotherapy for hydatidiform mole: five to 15 years follow-up. Cancer 1986; 58: 624–9. 45. Kim DS, Moon I-I, Kim KT, Moon YJ, Hwang YY. Effects of prophylactic chemotherapy for persistent trophoblastic disease in patients with complete hydatidiform mole. Obstet Gynecol 1986; 67: 690–4. 46. Limpongsanurak S. Prophylactic actinomycin D for high-risk complete hydatidiform mole. J Reprod Med 2001; 46: 110–16. 47. Berkowitz RS, Goldstein DP, Dubeshter B, Bernstein MR. Management of complete molar pregnancy. J Reprod Med 1987; 32: 634–9. 48. Palmer JR. Advances in the epidemiology of gestational trophoblastic disease. J Reprod Med 1994; 39: 155–62. 49. Feltmate CM, Bartorfi J, Fulop V et al. Human chorionic gonadotropin follow-up in patients with molar pregnancy: a time for reevaluation. Obstet Gynecol 2003; 101: 732–6. 50. Bagshawe KD, Dent J, Webb J. Hydatidiform mole in England and Wales 1973–1983. Lancet 1986; 2: 673–7. 51. Lavie I, Rao GG, Diego HC, Miller DS, Schorge JO. Duration of human chorionic gonadotropin surveillance for partial hydatidiform moles. Am J Obstet Gynecol 2005; 192: 1362–4. 52. Bartorfi J, Vegh G, Szepesi J et al.. How long should patients be followed after molar pregnancy? Analysis of serum hCG follow-up data. Obstet Gynecol 2004; 112: 95–7. 53. Wielsma S, Kerkmeijer L, Bekkers R et al. Persistent trophoblastic disease following partial molar pregnancy. Aust N Z J Obstet Gynecol 2006; 46: 119–23. 54. Kerkmeijer L, Wielsma S, Bekkers R et al. Guidelines following hydatidiform mole: a reappraisal. Aust NZ J Obstet Gynecol 2006; 46: 112–18. 55. Kerkmeijer LGW, Wielsma S, Massuger LFAG, Sweep FCGJ, Thomas CMG. Recurrent gestational trophoblastic disease after hCG normalization

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following hydatidiform mole in The Netherlands. Gynecol Oncol 2007; 106: 142–6. Wolfberg AJ, Feltmate C, Goldstein DP, Berkowitz RS, Lieberman E. Low risk of relapse after achieving non-detectable hCG levels in women with complete molar pregnancy. Obstet Gynecol 2004; 104: 551–4. Wolfberg AJ, Growdon WB, Feltmate CM et al. Low risk of relapse after achieving undetectable hCG levels in women with partial molar pregnancy. Obstet Gynecol 2006; 108: 393–6. Pisal N, Tidy J, Hancock B. Gestational trophoblastic disease: is intensive follow-up essential in all women. Br J Obstet Gynaecol 2004; 111: 1449–51. Stone M, Bagshawe KD. An analysis of the influences of maternal age, gestational age, contraceptive method, and the mode of primary treatment of patients with hydatidiform moles on the incidence of subsequent chemotherapy. Br J Obstet Gynaecol 1979; 86: 782–92. Berkowitz RS, Goldstein DP, Marean A, Bernstein, MR. Oral contraceplives and postmolar trophoblastic disease. Obstet Gynecol 1981; 58: 474–7. Curry S, Schlaerth J, Kohorn F et al. Hormonal contraception and trophoblastic sequelae after hydatidiform mole (a Gynecologic Oncology Group study). Am J Obstet Gynecol 1989; 160: 805–11. Costa HLFF, Doyle P. Influence of oral contraceptives in the development of post-molar trophoblastic neoplasia – a systematic review. Gynecol Oncol 2006; 100: 579–85. Bagshawe KD. Trophoblastic Neoplasia Holland JF, Frei III F, Bast Jr R et al eds. Cancer Medicine, 3rd edn. Baltimore: Williams & Wilkins, 1993; 1691–968. Lurain JR, Brewer JI, Torok, FE, Halpern B. Natural history of hydatidiform mole after primary evacuation. Am J Obstet Gynecol 1983; 145: 591–5. Morrow CP, Kletzky OA, DiSaia PT et al. Clinical and laboratory correlates of molar pregnancy and trophoblastic disease. Am J Obstet Oynecol 1977; 128: 424–30. Kohorn EI. Negotiating a staging and risk factor scoring system for gestational trophoblastic neoplasia: A progress report. J Reprod Med 2002; 47: 445–50. Franke HR, Risse EKJ, Kenemans P et al. Epidemiologic features of hydatidiform mole in the Netherlands. Obstet Gynecol 1983; 62: 613–16. Kohorn EI. Evaluation of the criteria used to make the diagnosis of non-metastatic gestational trophoblastic neoplasia. Gynecol Oncol 1993; 48: 139–47. Schlaerth JB, Morrow CP, Kletzky OA, Nalick RH, D’Ablaing GA. Prognostic characteristics of serum human chorionic gonadotropin titer regression following molar pregnancy. Obstet Gynecol 1981; 58: 478–82.

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70. Massad LS, Abu-Rustum N, Lee SS, Renta V. Poor compliance with post-molar surveillance and treatment protocols by indigent women. Obstet. Gynecol 2000; 96: 940–4. 71. Morrow CP. Post-molar trophoblastic disease: diagnosis, management and prognosis. Clin Obstet Gynecol 1984; 27: 211–20. 72. Tow WSH. The influence of primary treatment of hydatidiform mole on subsequent course. J Obstet Gynaecol Br Commonw 1966; 73: 544–52. 73. Xia Z, Song H, Tang M. Risk of malignancy and prognosis using a provisional scoring system in hydatidiform mole. Chin Med J 1980; 93: 605–12. 74. Tsukamoto N, Iwasaka T, Kashimura Y et al. Gestational trophoblastic disease in women aged 50 or more. Gynecol Oncol 1985; 20: 53–61. 75. Tsuji K, Yagi S, Nakano RI. Increased risk of malignant transformation of hydatidiform moles in older gravidas: a cytogenetic study. Obstet Gynecol 1981; 58: 351–5. 76. Martin DA, Sutton GP, Ulbright TM et al. DNA content as a prognostic index in gestational trophoblastic neoplasia. Gynecol Oncol 1989; 34: 383–8. 77. Parazzini F, Mangili G, Belloni C et al. The problem of identification of prognostic factors for persistent trophoblastic disease. Gynecol Oncol 1988; 30: 57–62. 78. Garner EO, Lipson E, Bernstein MR, Goldstein DP, Berkowitz RS. Subsequent pregnancy experience in patients with molar pregnancy and gestational trophoblastic tumor. J Reprod Med 2002; 47: 380–6. 79. Growdon WB, Wolfberg AJ, Feltmate CM et al. Post evacuation hCG levels and risk of gestational trophoblastic neoplasia among women with partial molar pregnancies. J Reprod Med 2006; 51: 871–5. 80. Wolfberg AJ, Berkowitz RS, Goldstein DP, Feltmate CM, Lieberman E. Postevacuation hCG levels and risk of gestational trophoblastic neoplasia in women with complete molar pregnancy. Obstet Gynecol 2005; 106: 548–52. 81. Rice LW, Berkowitz RS, Lage JM, Goldstein DP. Persistent gestational trophoblastic tumor after partial hydatidiform mole. Gynecol Oncol 1990; 36: 358–62. 82. Wong LC, Ma HK. The syndrome of partial mole. Arch Gynecol 1984; 234: 161–6. 83. Ohama K, Ueda K, Okamoto F, Takenaka M, Fujiwara A. Cytogenetic and clinicopathologic studies of partial moles. Obstet Gynecol 1986; 68: 259–62. 84. Bolis G, Belloni C, Bonazzi C et al. Analysis of 309 cases after hydatidiform mole: different follow-up program according to biologic behavior. Tumori 1988; 74: 93–6. 85. Seckl MJ, Fisher RA, Salerno F et al. Choricarcinoma and partial hydatidiform moles. Lancet, 2000; 356: 36–9. 86. Goto S, Yamada A, Ishizuka T, Tomoda Y. Development of postmolar trophoblastic disease after

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partial molar pregnancy. Gynecol Oncol 1993; 48: 165–70. Hancock BW, Nazir K, Everard JE. Persistent gestational trophoblastic neoplasia after partial hydatidiform mole – Incidence and outcome. J Reprod Med 2006; 51: 764–6. Teng N, Ballon SC. Partial hydatidiform mole with diploid karyotype: report of three cases. Am J Obstet Gynecol 1984; 150: 961–4. Vejerslev LO. Clinical management and diagnostic possibilities in hydatidiform mole with coexistent fetus. Obstet Gynecol Surv 1991; 46: 577–88. Steller MA, Genest DR, Bernstein MR et al. Clinical features of multiple conception with partial or complete molar pregnancy and coexisting fetuses. J Reprod Med 1994; 39: 147–54. Matsui H, Sekiya S, Hando T, Wake N, Tomoda Y. Hydatidiform mole co-existent with a twin live fetus: a national collaborative study in Japan. Human Reprod 2000; 15: 608–11.

92. Ho PC, Wong LC, Ma HK. Return to ovulation after evacuation of hydatidiform mole. Am J Obstet Gynecol 1985; 153: 638–42. 93. Brandes, J.A. and Peretz, A. Recurrent hydatidiform mole. Obstet Gynecol 1965; 25: 398–400. 94. Rice LW, Lage JM, Berkowitz RS, Goldstein DP, Bernstein MR. Repetitive complete and partial hydatidiform mole. Obstet Gynecol 1989; 74: 217–19. 95. Tuncer ZS, Bernstein MR, Wang J, Goldstein DP, Berkowitz RS. Repetitive hydatidiform mole with different male partners. Gynecol Oncol 1999; 75: 224–6. 96. Lurain JR, Sand PK, Carson SA, Brewer JI. Pregnancy outcome subsequent to consecutive hydatidiform moles. Am J Obstet Gynecol 1982; 142: 1060–1. 97. Tuncer ZS, Bernstein MR, Goldstein DP, Lu KH, Berkowitz RS. Outcome of pregnancies occurring within 1 year of hydatidiform mole. Obstet Gynecol 1999; 94: 588–90.

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38 Multiple pregnancy David LH Moore, Nicholas M Fisk, Jon Hyett

The dramatic increase in prevalence of multiple pregnancies owing to the widespread introduction of assisted reproductive technologies (ART) presents unique challenges to obstetricians: not only is the normal dynamic of caring for a mother and her fetus expanded, but also therapeutic intervention that benefits one fetus may result in iatrogenic damage to another. Virtually all pregnancy complications are more prevalent in multiple gestations, resulting in increased rates of maternal and perinatal mortality and morbidity, and leading to a disproportionate workload within obstetrics and fetal medicine. Monochorionic twin pregnancies are particularly at risk and require intensive serial ultrasound surveillance throughout gestation to detect fetal pathologies at an early stage and offer effective intervention. With the specific aim of updating the reproductive medicine specialist, this chapter reviews the complications associated with multiple pregnancy and their management, the roles of prenatal screening and diagnostic testing, and the importance of defining chorionicity at an early stage. Anxiety is high in this setting as many women undergoing fertility treatment want early reassurance about their risks of chromosomal and structural abnormalities on the one hand, but on the other are concerned about the miscarriage risk from invasive testing.

Epidemiology of multiple pregnancies Spontaneous twinning has been observed in approximately one in 80 (1.25%) spontaneous pregnancies and Hellin’s law, which assumes that multiple pregnancies result from multizygous conceptions, predicts spontaneous triplets and quadruplets in one in 6400 (802) and one in 512 000 (803) pregnancies, respectively. Twinning results either from the fertilisation of a single oocyte that then splits to form multiple embryos (monozygosity), or from the fertilisation of two oocytes (dizygosity). Rates of dizygotic twinning vary with ethnicity (approximately one in 50 in Africans to 1:140–1:500 in Asians), personal or family history (2–4-fold increase in risk), maternal age (3fold increase in risk at age 45), height and parity.1 The widespread use of ART over the past 20 years has also led to a very significant increase in the number of

multiple births, with reported 2-, 3–6- and 12-fold increases in the prevalence of twin, triplet and quadruplet pregnancies, respectively.2–6 Although the exponential growth in higher order multiple pregnancies has been reversed through restrictive embryo transfer policies, it is important to note that rates of monozygotic twinning also increase in ART and the trend to blastocyst transfer has resulted in a recent increase in the proportion of monozygotic twins.6–9 Unfortunately, most epidemiological studies report mortality and morbidity in multiple births en masse rather than on the basis of differences in zygosity and chorionicity. Australian perinatal mortality rates are 7.4, 25 and 63 per 1000 births for singleton, twin (relative risk (RR) 3.4) and triplet (RR 8.5) pregnancies, respectively, and similar rates are reported in the UK and US.10–12 There is then also a 4–6-fold increase in infant deaths (less than 1 year of age). While multiple pregnancies account for only 2% of births, they represent 12% of perinatal deaths.13 More perinatal mortality and morbidity are related to multiple birth, primarily due to prematurity, low birth weight and conditions specific to twins such as twin–twin transfusion syndrome, than are caused by obstetric complications such as placental abruption or congenital anomalies such as congenital heart disease (Table 38.1). Prematurity is common with 10% of twins (RR 10) and 40% of higher order multiples being born at less than 32 weeks (RR 40).10 In all, 25% of twins and 75% of triplets require admission to the neonatal intensive care unit where multiples account for 20% of all admissions and a disproportionate number of in utero and ex utero transfers.10,14 Low birth weight is often associated with prematurity, but these infants are also commonly growth-restricted, with birth weights of less than 2500g reported in 50% of twins (RR 10) and 95% of triplets (RR 19), respectively. The small, premature neonate has a higher risk of developmental delay and is more likely to develop diabetes, hypertension and heart disease later in life.15,18 The risk of cerebral palsy is 4-5-fold-times higher in twin, and 17-fold higher in triplet, compared to singleton pregnancies.11,16,19,20 This risk is independent of gestational age and low birth weight, and is not related to birth order, but is 10-fold higher following the intrauterine death of a co-twin. Risks of

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Table 38.1

A summary of the literature reporting perinatal outcomes of singleton and multiple pregnancies.5,12,14–16

Attribute Mean live birth weight Low birth weight (<2500 g) Mean gestational age at birth (weeks) Birth <32 weeks Neonatal intensive care units admissions Cerebral palsy (per 1000 births) Cerebral palsy (per 1000 pregnancies) Perinatal mortality (per 1000 births) Death by 1 year (per 1000 births) Death by 1 year (per 1000 pregnancies)

Singletons

Twins (RR)

High order multiples (RR)

3400 g 5% 39 1% 12% 1.6 1.6 7.4 15.6 15.6

2400 g 50% (10x) 35 10% (10x) 25% (2x) 7.4 (4.5x) 13.2 (8x) 25 (3.5x) 70.5 (4.5x) 93.8 (6x)

1700 g 96% (19x) 32 40% (40x) 75% (6x) 26.7 (17x) 75.9 (47x) 63 (9x) 92.8 (6x) 152 (10x)

RR, relative risk.

respiratory distress syndrome, necrotising enterocolitis and intraventricular haemorrhage appear similar in singletons, twins and triplets when adjusted for birth weight and gestation, suggesting that these pathologies are the consequence of prematurity and low birth weight rather than a direct reflection of multiplicity.21 Approximately 2% of ART conceptions are high order multiples, only 18% of which are conceived spontaneously.22,23 Risks of miscarriage, preterm delivery, growth restriction, maternal pre-eclampsia and obstetric haemorrhage are all increased in high order multiples compared with singleton and twin pregnancies. These risks may be reduced through multifetal pregnancy reduction, normally performed after nuchal translucency assessment at 11–14 weeks, allowing adequate opportunity for spontaneous reduction during the first trimester and for prognostic screening. Once again chorionicity is pivotal to selecting fetuses at risk of later pregnancy complications. Pregnancies may be reduced to either twins or singletons, although the fetal loss rate at less than 24 weeks is higher the more fetuses are reduced.24 This contrasts with a reduction in maternal obstetric complications, preterm birth and neonatal death through reduction to a singleton. Twins resulting from triplet reduction appear to have reduced risks which approach those of a normal twin pregnancy, albeit still with a higher rate of preterm delivery at less than 37 weeks (41% vs. 33%).25 Multifetal pregnancy reduction may be emotionally traumatic, especially against the background of longstanding infertility and feelings of guilt, remorse and grief for the loss of a child may persist after delivery.26,27 Recent consensus on adopting techniques that limit the incidence of high order multiples is a major step forward to improving long-term maternal and fetal health after ART. There are some data documenting mortality and morbidity in twin pregnancies on the basis of zygosity and chorionicity. While zygosity can easily be determined postnatally using molecular genetic techniques, this is unfortunately not routinely established in most epidemiological datasets and instead the

proportion of twins that are mono- or dizygotic is frequently estimated using Weinberg’s rule.28 Under the latter assumption, monozygosity has been shown to be associated with polyhydramnios, prematurity, low birth weight and stillbirth – which are incidentally all features of monochorionicity.29,30 Chorionicity describes the number of placentas present and has some relation to zygosity as the twothirds of monozygotic twins that split more than 3 days after conception are monochorionic. Prospective evaluation of a large cohort of twins has shown that seven out of nine will be dichorionic (six of the seven are dizygotic) and two out of nine twin pregnancies will be monochorionic.6 The potential significance of chorionicity, which can be simply established by placental inspection at birth, has been recognised for some time, but despite this many registries fail to collect this information routinely.31,32 Nowadays, chorionicity can be accurately and routinely determined by prenatal ultrasound, and review of series defined on this basis clearly shows that most mortality and morbidity in twin pregnancies occur in the monochorionic group. A UK study of 102 monochorionic twins identified through ultrasound at 12 weeks’ gestation showed a complicated antenatal course in 30% of cases, including 12% fetal loss at 24 weeks or less, 3% perinatal mortality, 9% preterm delivery at less than 32 weeks and 8% significant growth restriction.33 The fetal loss rate was 6-fold higher than that seen in dichorionic twins and the remaining complications were twice as common. Further series have confirmed that perinatal mortality rates are higher, being 11.6% and 5% in monochorionic and dichorionic twins, respectively, in one large Dutch cohort and showing a 5–8-fold increase in the risk of intrauterine fetal death at >32 weeks in series from the US and UK.34–36 The Dutch study also reported significant differences in perinatal morbidity (Table 38.2). Monochorionic twin pregnancies can be further differentiated on the basis of amnionicity. Blastocyst cleavage 4–9 days after conception results in a monochorionic diamniotic (MCDA) configuration, whereas

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Table 38.2 Effect of chorionicity on perinatal mortality and morbidity in 1407 twin pregnancies at two Dutch hospitals (1995– 2004). Adapted from reference 34, with permission. Outcome

All twins

Dichorionic

Monochorionic (RR)

P value

Perinatal mortality Stillbirth Stillbirth in ongoing pregnancies >32 weeks Neonatal death (to 28 days)

6.4% 2.4% 0.7% 4.0%

5.4% 1.5% 0.3% 3.9%

12.1% (2.2x) 7.6% (5x) 2.1% (7x) 4.5% (1.2x)

<0.001 <0.001 <0.05 NS

NICU admission

20.4%

19.0%

28.7% (1.5x)

<0.001

Length of stay in NICU (days), median (range) Neonatal death during stay in NICU

— 1.3%

13 (1–147) 5.8%

11 (1–81) 9.5% (1.6x)

0.114 0.185

Morbidity during NICU admission

37.0%

35.5%

45.6% (1.3x)

<0.001

Respiratory distress syndrome Intraventricular haemorrhage Periventricular leukomalacia Necrotising enterocolitis Sepsis

10.3% 3.8% 0.4% 1.3% 6.2%

9.8% 3.5% 0.3% 0.9% 5.8%

12.8% (1.3x) 5.5% (1.6x) 0.8% (3x) 3.8% (4x) 8.5% (1.5x)

0.09 0.07 0.16 <0.001 0.06

RR, relative risk; NICU, neonatal intensive care unit.

splitting after more than 9 days leads to a monochorionic monoamniotic (MCMA) twin pregnancy.37 While a substantial component of mortality and morbidity seen in the MCDA group is an imbalance in the intertwin circulation (vascular anastomoses run between the two twins in nearly all cases) integral to monochorionic placentae, MCMA twins frequently manifest cord entanglement and are at risk of cord accidents, either in utero or at vaginal delivery, leading to the death of one, or (more likely) both, fetuses.38 Determination of both chorionicity and amnionicity at an early stage therefore provides insight into the potential risks and allows these issues to be addressed further.

Determination of chorionicity Chorionicity and amnionicity can both be predicted with a very high degree of accuracy at early gestations, but chorionicity becomes more difficult to confirm as pregnancy advances. As the proportion of multiple births related to ART and diagnosed within reproductive medicine increases, it is important to recognise that most early scans occur in this environment and, thus, responsibility for making a clear diagnosis lies with the infertility team rather than the fetal medicine specialist. In addition to the risks of monochorionicity discussed above, accurate determination of chorionicity is essential for accurate prenatal screening, genetic counselling and planning interventional procedures, particularly in twin pregnancies discordant for fetal structural or chromosomal anomalies and/or growth restriction. In early pregnancy the chorionic plate completely encircles the amniotic sac and chorionicity can easily be defined at 5 weeks, before confirming fetal viability/number at 6 weeks and amnionicity at 8 or more weeks’ gestation (Fig 38.1).39–40 Most women are now offered a scan at 11–14 weeks’ gestation, primarily for

nuchal translucency assessment, but an added advantage of this is that chorionicity can still be readily determined in more than 97% of cases.41–43 In cases where there is a single placental mass, the intertwin membrane is thin, containing no intervening chorion laeve, and thus has a T-shaped insertion to the chorionic plate. This contrasts with abutting dichorionic placentas where a “peak” of chorionic tissue can still be seen between the amniotic membranes creating the “lambda” or “twin-peak” sign (Fig 38.2).44 At the routine 18–23-week anomaly scan, the finding of discordant fetal sex or separate placental masses allows a firm diagnosis of dichorionicity but in many cases where the placentas coalesce it is difficult to be confident about chorionicity. An additional marker involves assessment of the thickness of the intertwin membrane, but the wide level of intra-observer variability and relatively narrow distribution of monochorionic and dichorionic thicknesses mean that this is of limited value.44 In the event that chorionicity cannot be determined, it is best to manage the pregnancy as monochorionic to reduce the risk of missing adverse events due to a lack of surveillance, but this approach may impact on decisions regarding elective delivery late in the third trimester.

Prenatal diagnosis Chromosomal abnormality There are some data to suggest that Down syndrome is less prevalent in twin than in singleton pregnancies although the precise level of reduction in risk has not been defined.45 Most developed societies now recommend a policy of universal screening for Down syndrome and the current consensus is that this is best done using a combination of ultrasound and biochemical markers in the first trimester of pregnancy.46,47

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MCDA

DCDA

Fig 38.1 Chorionicity is best determined in the first trimester. The monochorionic (MCDA) twin pregnancy has a single chorion and two visible yolk sacs at 6 weeks’ gestation (the amnion is rarely visible). The dichorionic (DCDA) twin pregnancy has two distinct chorions at this stage.

“T-sign” (MCDA)

“Lambda” (DCDA)

Fig 38.2 Chorionicity can still be determined with more than 97% accuracy at the 11–14 week scan. In the monochoronico diamniotic (MCDA) pregnancy the thin amniotic membrane has a “T” insertion into the chorionic plate. In the dichorionic diamniotic (DCDA) pregnancy a wedge of chorionic tissue remains at this junction – recognised as the ‘lambda’ (λ) sign.

Screening test algorithms specific to multiple pregnancies are available, but the situation is complicated by zygosity, chorionicity and the considerable potential for aneuploidy to be discordant when present in twins.48 These complications effectively reduce the efficiency of screening in comparison with singleton pregnancies. Zygosity dictates whether twins are genetically identical; for some parents, the prospect of having one twin with Down syndrome may be daunting, but manageable, but having two affected children would be too much to bear. For others, the inherent risks associated with selective termination of an anomalous fetus within a multiple pregnancy may outweigh the potential

advantage of such a procedure. These are complex issues and parents need to be appropriately counselled before screening, so that they have some awareness of the potential decisions they may have to face. While all monochorionic twins must be monozygous and are almost always genetically identical, doubt about zygosity remains in seven out of nine twin pregnancies screened by ultrasound as only six out of seven dichorionic twins will be dizygous.6 Therefore, risks have to be developed for the individual fetus rather than for the whole pregnancy. First trimester biochemical screening involves analysis of the placental proteins free β-human chorionic gonadotrophin (βhCG) and pregnancy associated

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plasma protein (PAPP)-A, which are respectively increased and decreased in Down syndrome compared with euploid pregnancies.49 In a dizygotic twin pregnancy with twins discordant for trisomy 21, the altered maternal biochemical profile of one placental unit will in part be masked by the normal profile of the euploid placenta such that biochemical screening becomes less effective.50,51 In addition, while an alteration in maternal serum biochemistry may predict an increased risk for aneuploidy, it does not indicate which fetus is anomalous. In comparison, ultrasound screening using nuchal translucency (NT) assessment examines each fetus independently, giving individual risks based on crown–rump length (CRL) and NT.52 NT performs as well in dichorionic twin pregnancies as it does in singletons, but is associated with a higher false positive rate in monochorionic pregnancies. This is due to the fact that there is also an association between discordant fetal NTs and the subsequent development of twin–twin transfusion syndrome.53,54 While this association is far from absolute, the prevalence of twin–twin transfusion syndrome (10–15% of MCDA pregnancies) is higher than that of Down syndrome (approximately 0.2% of 12-week pregnancies) and leads to a significant reduction in the specificity and positive predictive value of screening. Individual fetus CRL and NT measurements are invariably different in monochorionic twins and will generate differing risks for aneuploidy, despite the fact that they are identical by definition. While rare cases of postzygotic mitotic errors resulting in monozygotic twins with chromosomal discordance have been reported, the consensus of opinion regards monochorionic twins as genetically identical and calculates a single risk for the pregnancy from the mean of the two risks produced by CRL and NT assessment.55,56 NT is currently the only reliable fetus specific screening tool for higher order multiple pregnancies and mean NT thicknesses in these pregnancies are comparable to singletons.57 NT provides a valuable method of assessing fetal well-being before selecting fetuses for reduction in higher order multiples. Notwithstanding the above limitations, combining first trimester NT with serum markers (free βhCG & PAPP-A) performs better in twin pregnancies than either NT or serum markers alone, with a 75–80% detection rate for a 5% false positive rate.51,58 In the future, the limitations for both biochemistry and NT delineated above may be reduced by incorporation of nasal bone assessment, which would be fetus specific and, thus, reduce false positive rates.59 Alternative ultrasound markers looking at the haemodynamic performance of the ductus venosus and tricuspid valve may be less useful, as they are likely to be affected by early transfusional imbalance in twin–twin transfusion syndrome in a similar manner to NT.60 The indications for invasive fetal testing in multiple pregnancies are similar to those in singleton pregnancies and include increased aneuploidy risk, discordant

409

structural abnormalities, previous pregnancy affected with a chromosomal abnormality and family history of monogenic disorders. The association of both spontaneous twinning and ART with advanced maternal age and the reduced effectiveness of combined first trimester screening in twin pregnancies leads to higher screen positive and, thus, invasive testing rates for aneuploidy. Invasive testing in twins is again complicated by issues of zygosity, chorionicity and the absolute level of risk of an anomaly that will require further intervention. Best practice dictates that these invasive procedures should only be performed by clinicians or clinical teams who can offer complete management, as a failure to sample or label fetuses correctly may result in the disastrous consequence of selective termination of the wrong fetus. In monochorionicity, the presumption is made that the fetuses are genetically identical so a single chorionic villus sample will confirm the karyotype of both fetuses. This arguably carries the same added risk of miscarriage as sampling a singleton pregnancy. If discordance for major structural anomalies or growth restriction leads to suspicion of a heterokaryotypic monochorionic twin situation, amniocentesis of the anomalous twin could be considered at a later stage.55 In the dichorionic situation, early chorionic villus sampling (CVS) has been advocated by some when the risk of trisomy is more than one in 50, as the risks associated with fetal reduction seem lower at earlier gestations.61,62 However, relatively high rates of contamination (2–5%) due to inadvertently sampling the same twin twice were reported in early series, such that some have argued that CVS is contraindicated in dichorionic twins.63 Double and single uterine puncture techniques have been described, aiming to minimise the risk of inadvertently sampling the same placenta twice. Molecular genetic analysis can be included with standard karyotyping to confirm that dizygous fetuses have been separately sampled, although this will of course not be helpful in one in seven of these situations. The procedure-related loss rate of 2.8% (prior to 20 weeks’ gestation) is similar to amniocentesis.64 If there is concern about contamination at CVS and/or the risk of aneuploidy is less pressing, then amniocentesis at 16 weeks is often preferred, and both single and double puncture techniques have been described. The double needle technique reduces the risk of intertwin contamination during sampling and removes the technical challenge of piercing rather than tenting and stripping the intertwin membrane. The limited data available suggest that the fetal loss rate is higher both compared to twin pregnancies where no procedure was performed and to singleton pregnancies undergoing amniocentesis – with an additional risk of adverse outcome in approximately 1 in every 64 amniocenteses.65,66 In some countries, late termination of pregnancy (at more than 24 weeks) is permitted and may offer an

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opportunity for late karyotyping and late selective reduction in multiple pregnancies discordant for structural anomaly.67 Although such management removes the risk of miscarriage and preterm delivery associated with earlier sampling and selective reduction, these benefits need be tempered by the potential psychological effects of delaying diagnostic and therapeutic procedures.

Structural abnormality In addition to screening for aneuploidy, the 12-week scan is a valuable screening tool for fetal structural anomalies.68 The prevalence of structural anomalies is increased in multiple pregnancies with a 3-fold increase in the monozygotic group, although typically the pair will be discordant for the anomaly.69–71 Significant discordance in CRL (defined as >9mm difference) is associated with a 7-fold increased rate of structural anomaly or aneuploidy in dichorionic twins and 5-fold increased risk of developing twin– twin transfusion syndrome in monochorionic pregnancies; once these anomalies are removed risks of poor outcome do not appear to be CRL dependent.72,73 Management of structural anomalies is complex, dependent not only on chorionicity but also on the prognosis for the affected fetus and the risk this imposes on the normal co-twin. Options may include termination of the whole pregnancy, early or late selective reduction, or expectant management with palliative care or aggressive intervention for the anomalous fetus, and these will in part depend on local legal, cultural and ethical attitudes. Selective reduction in a monochorionic twin pregnancy is complicated by the likely presence of intertwin vascular anastomoses and requires cord occlusion or ligation to ensure separation of the circulations.74 Selective fetocide is technically easier in the dichorionic diamniotic situation, entailing induction of cardiac asystole by intracardiac delivery of potassium chloride as in singletons. This has been shown to lead to loss of the unaffected dichorionic twin before 24 weeks in 7.5% of cases.75

Table 38.3

Monochorionicity and the complications of intertwin vascular anastamoses Twin–twin transfusion syndrome Virtually all monochorionic placentas have vascular anastomoses connecting the fetal circulations.76,77 These may be bidirectional arterioarterial (AA) or venovenous (VV), or unidirectional arteriovenous (AV) in nature. A relative paucity of anastamoses promotes unidirectional net imbalance in AV flow and is associated with twin–twin transfusion which occurs in 15% of monochorionic pregnancies.78 AA anastomoses being bidirectional tend to be protective against twin–twin transfusion, but are only found in 70% of cases; in one series their absence led to twin– twin transfusion in 80% of cases.79,80 Up to 20% of high order multiples include a monochorionic pair, which have the same risk related to intertwin vascular anastamoses as those seen in monochorionic twin pregnancies.81–83 Dichorionic triamniotic triplets have a several-fold greater risk of perinatal death than trichorionic triamniotic fetuses.84 Acute twin–twin transfusion syndrome most commonly occurs at 16–24 weeks’ gestation and if left untreated is associated with 80% perinatal mortality and a 15–20% risk of brain damage in survivors.85 An imbalance in the intertwin placental circulation results in one twin becoming hypovolaemic and growthrestricted, and the second being haemodynamically overloaded. The smaller twin becomes anuric and the larger twin polyuric, and this is the feature used to classify early stages of the disease.86 Traditional neonatal staging was based on discordant haematocrit and weight but these features are of limited value prenatally. The staging system described by Quintero et al is now used to judge disease severity and to determine therapeutic intervention (Table 38.3).86,87 As disease progresses, the smaller twin may die due to the severity of growth restriction and the larger twin may die due to cardiac failure as a result of both hypervolaemia and raised afterload. Alternatively, polyhydramnios resulting

The Quintero staging system for twin–twin transfusion syndrome (TTTS).86

Stage I

Mildest form with amniotic fluid discordance Polyhydramnios with DVP >8 cm in recipient and oligohydramnios with DVP <2 cm in donor Bladder still visible in donor

Stage II

Above features with lack of visible bladder in donor

Stage III

Critically abnormal Dopplers in either twin: Absent/reversed end diastolic flow in donor umbilical artery Reversed ductus venosus flow/pulsatile umbilical venous flow in the recipient or evidence of TTTS cardiomyopathy (atrioventricular valvular incompetence, ventricular hypertrophy and dysfunction)

Stage IV

Ascites or frank hydrops in either recipient or donor

Stage V

Consequent single or double twin death

DVP, deepest vertical pocket.

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from polyuria in the recipient leads to very preterm delivery of two inherently sick infants. Endoscopic ablation of the communicating intertwin circulation has been developed as a therapeutic option over the past 10 years, and is currently the only invasive therapy shown by randomised trial to improve fetal outcome with significant reductions in perinatal mortality and morbidity.88–90 Although features such as discordant NT, abnormal ductus venosus waveforms and the absence of AA anastamoses have been described in the first trimester, it is difficult to predict which monochorionic pregnancies will be affected and the importance of serial ultrasound every 2 weeks from 16 weeks’ gestation cannot be overstated.55,61,91 Disease does not necessarily progress though Quintero’s stages: many stage 1 cases regress – leading to controversy about the need for therapeutic intervention – whilst others show significant cardiac dysfunction at an early stage and this may provide an alternative approach to monitoring disease progression.92–95 The complexity of these issues means that these pregnancies are best managed within, or with advice from, tertiary fetal medicine centres. The long-term neurodevelopmental problems that have been described in survivors of twin–twin transfusion are reported as less likely after laser therapy than after either expectant management or serial amniodrainage in cohort studies, but this was not borne out in the randomised trial.96,97 It is important that families considering laser ablation are aware that a 5–10% risk of significant neurodevelopmental problems remains in survivors and termination of the pregnancy may be an appropriate alternative in some cases. The increased risk of late stillbirth seen in apparently normal monochorionic twin pregnancies is also likely to be related to acute intertwin transfusion, some of which will be acute twin–twin transfusion syndrome, and this risk seems more significant after 34 weeks’ gestation.33,35 This has led to vigorous debate about elective delivery by caesarean section in all MCDA twin cases at around 34 weeks although it is not clear that this improves mortality.34,98 Two per cent of apparently uncomplicated monochorionic twins develop neurodevelopmental problems in infancy and elective delivery may also reduce the risk of late hypotensive ischaemic damage, although no studies have assessed this.

Twin reversed arterial perfusion sequence A less common vascular aberration unique to monochorionic twins is twin reversed arterial perfusion (TRAP) sequence. This affects 1% of monochorionic twins – approximately one in 35 000 births and involves an “acardiac” twin that is kept alive through parasitic haemodynamic dependence on its structurally normal co-twin (the “pump” twin), via superficial AA anastomoses on the monochorionic placenta. The acardiac twin is not independently viable but causes high output failure in the pump twin in about

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Fig 38.3 A monochorionic monoamniotic pregnancy at 12 weeks’ gestation. The two cords are entangled, even at this early gestation, in most cases. There was a good outcome to this pregnancy.

50% of cases and is associated with a high level of mortality in this normal fetus.99 The diagnosis is classically missed in the first trimester when a monochorionic twin pregnancy is recognised on the basis of placentation but no fetal cardiac activity is seen in one twin. In this circumstance it is important to use colour Doppler to demonstrate whether there is blood flow in the acardiac fetus’ circulation, which should then be monitored with serial examination as earlier intervention is more successful than in the late second or early third trimester.100

Monoamniotic twins Monoamniotic (MCMA) twins are also very rare with a prevalence of approximately one in 10 000 pregnancies. Cord entanglement is seen in virtually all cases and may lead to cord accidents in later pregnancy once fetal mass and movement increases (Fig 38.3).38,101 Mortality increases by 1% per week to 32 weeks, 4% per week to 35 weeks, and 7% per week thereafter in ongoing pregnancies.102 Sulindac, a non-selective prostaglandin-H synthetase inhibitor has successfully been used to reduce fetal urine production and effectively cause mild oligohydramnios, reducing the risk of significant fetal movement and thus late fetal death.103 These pregnancies typically have intense observation through the second trimester and are delivered electively at 32 weeks’ gestation by caesarean section.

Fetal growth restriction in multiple pregnancies In addition to growth discordance related to twin– twin transfusion syndrome, selective growth restriction with more than 25% discrepancy in estimated

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fetal weights occurs in 15% of monochorionic and 8% of dichorionic twins.104 The management of growth restriction is, once again, primarily dictated by chorionicity and is addressed for dichorionic and monochorionic twins separately. In the dichorionic situation, the two-fetoplacental units are essentially independent. The death of a growth-restricted twin has relatively low impact on the normally grown co-twin, although risks of miscarriage and preterm delivery are slightly increased. The major risk to the co-twin is iatrogenic prematurity that needs to be given serious thought when a decision to deliver a viable growth-restricted twin is made. Although some growth discordance may be due to differing genetic potential of the two fetuses, placental insufficiency is the most likely cause of significant growth restriction, and thus the process of surveillance, through serial assessment of growth, liquor volume, umbilical and fetal Dopplers is similar to that used in singleton pregnancies.105 Prior to 24 weeks and with an estimated fetal weight less than 500 g the growth-restricted fetus can be considered non-viable, with non-intervention the preferred strategy.106 In this circumstance the parents need to be aware that deteriorating surveillance measures will be followed by the death of this twin, with the hope that the normal cotwin will continue to term without further incident. The dilemma about timing of delivery is greatest between 24 and 32 weeks, when the prognosis for the compromised growth-restricted fetus remains poor, and iatrogenic delivery of the co-twin places an otherwise normal fetus at significant risk of mortality and morbidity. In this circumstance parents need to be counselled about the relative risks of delivery versus continuing the pregnancy for each twin and engaged in the decision making process. The risk of mortality and morbidity for the healthy co-twin decline substantially after 32–34 weeks, particularly with good obstetric preparation for preterm birth. At this stage, decisions about delivery of a growth-restricted fetus become more straightforward. Monochorionic twins with significant growth restriction in the absence of signs of twin–twin transfusion syndrome face significantly different problems. Severe growth discordance is frequently related to unequal sharing of the single placental mass, and in some circumstances the placental area supplying the growth-restricted fetus is so small that it is actually reliant on AA anastomoses that run from the cotwin.107 While in utero death is of minimal significance in the dichorionic situation, it is frequently disastrous in monochorionic twins.108 A systematic review of 28 series showed risks of 12 and 18% for death and neurological abnormality of the co-twin, respectively (Table 38.4). Delivery is indicated in any circumstance postviability where death of the growthrestricted twin is imminent in order to protect the normal co-twin. As an extreme example, at 25 weeks’ gestation, a severely growth-restricted twin on the

verge of death would not be viable per se and, although the normally-grown co-twin would have only a 50% chance of survival, the chance of being neurologically intact or of having only minor neurodevelopmental problems would be arguably better than that associated with in utero death of the cotwin. Again, parental involvement in difficult decision-making in this context is recommended. Debate about the management of selective growth restriction in monochorionic twins is at present focused on two issues: methods of selective reduction prior to viability with occlusion of the communicating vasculature, and recognition of vascular imbalance at later gestations that may cause neurological damage without the death of one twin.109–111 These are two of the major challenges facing clinicians involved in fetal medicine over the next decade.

Preterm delivery Prematurity is responsible for more than 50% of all neonatal deaths with a significant risk of handicap and disability in survivors.112–114 While spontaneous prematurity at less than 34 weeks occurs in 1% of singleton pregnancies it affects 12% of twin births; after the exclusion of severe twin–twin transfusion syndrome, the incidence is similar in monochorionic and dichorionic twins.115 A reduction in preterm delivery requires an effective screening test to identify “highrisk” pregnancies and an effective intervention. In singleton pregnancies, ultrasound assessment of cervical length at 20–24 weeks’ gestation has been shown to be an effective means of predicting early preterm delivery.116 Data in twins are more limited, but one study demonstrated that the risk of prematurity increases significantly with decreasing cervical length, although women with long cervices still have higher risks of preterm delivery than those with singletons.115,117 Although there is an effective means of predicting risk of preterm delivery, no therapeutic intervention has been proven to be useful. Potential methods for the prevention of preterm delivery include bed rest, cervical cerclage and prophylactic administration of progesterone. Randomised controlled trials have shown that both bed rest and cerclage are associated with a significant increase, rather than decrease, in the rate of early preterm delivery while progesterone has not been shown to be effective.118,120 Further trials in this to date nihilistic area are ongoing.

Multiple pregnancy and maternal health Multiple pregnancies are associated with a 2–7-fold increase in maternal mortality.121–123 While some of this is related to the increased risk of obstetric haemorrhage, a proportion relates to complications of caesarean section, performed in 68% of twins, 92% of

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Table 38.4

413

Outcomes determined by chorionicity for the co-twin after foetal death in utero.107

Monochorionic Dichorionic Odds ratio (95% CI)

Co-twin demise

Neurological damage

Delivery at <34 weeks

12% 4% 6 (1.8–20)

18% 1% 4 (1.3–13)

68% 57% NS

CI, confidence interval.

higher order multiples but only 29% of singletons.124–126 Notwithstanding this, women are one-fifth less likely to die in the year they are pregnant than either the year before or afterwards, women with twins may be reassured that this protective effect extends to them as well, with a halving of the risk in the year in which they deliver.127 Normal maternal physiological changes associated with pregnancy are exaggerated and gestational diseases, such as hypertension, are more prevalent. Up to 20% of primiparous patients with twins become hypertensive, a 4-fold increase on singleton levels.128–130 Disease is typically more severe with earlier onset and is associated with an increased risk of preterm delivery, growth restriction and placental abruption. Women with multiple pregnancies are more likely to be anaemic and show a greater prothrombotic tendency than singleton counterparts.131 Cardiovascular changes place women with pre-existing cardiac disease at great risk and make women more susceptible to iatrogenic fluid overload.132,133 Obstetric cholestasis is twice as prevalent in multiple pregnancies and there is a strong association with acute fatty liver disease. In addition to these medical problems, multiple pregnancies are associated with higher levels of maternal anxiety and postnatal depression, and longer-term marital and financial difficulties are more common.134,135 Many of these factors are further increased in women undergoing ART.136

Conclusions The prevalence of twins has doubled and of higher order multiples has increased 5-fold since the widespread uptake of ART. In some centres “successful” in vitro fertilisation (IVF) is associated a 30% multiple pregnancy rate. If the goal of ART is to allow less fertile couples the chance to have children, then this should not be detrimental to the health of the mother or child’s health.137 Many women are unaware of the risks associated with multiple pregnancy and need to be given better information prior to making decisions about ART.138 Fortunately, the frequency of triplets has fallen markedly with more responsible recent ART practices and the shift to single embryo transfer. Good epidemiological data now show that chorionicity is the key factor in determining risks of perinatal

mortality and morbidity. Chorionicity can be demonstrated with almost 100% accuracy by ultrasound at less than 14 weeks’ gestation and should be the first reported scan feature in all multiples. With appropriate surveillance, many of the risks related to monochorionicity can be identified and effective therapeutic interventions are available in most instances. Risk factors for growth restriction and prematurity can also be recognised at an early stage, improving the outcome for a proportion of these pregnancies.

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Textbook of Periconceptional Medicine Western Australia in the 1980s. BMJ 1993; 307: 1239–43. ACOG Practice Bulletin No. 56 Multiple gestation: complicated twin, triplet, and high-order multifetal pregnancy. Obstet Gynecol 2004; 104: 869–83. Barker DJP. Adult consequences of fetal growth restriction. Clin Obstet Gynecol 2006; 49: 270–83. Blickstein I. Epidemiology of cerebral palsy in multiple pregnancies. In: Kilby M, Critchley H, Field D, eds. Multiple Pregnancy. London: RCOG Press, 2006. Laws PJ, Grayson N, Sullivan EA. Australia’s Mothers and Babies 2004. Perinatal Statistics Series No. 18. Sydney: AIHW National Perinatal Statistics Unit, 2006. Goldenberg RL, Culhane JF. Low birth weight in the United States. Am J Clin Nutrition 2007; 85: 584S–90S. Scher AI, Petterson B, Blair E et al. The risk of mortality or cerebral palsy in twins: a collaborative population-based study. Pediatr Res 2002; 52: 671–81. Williams K, Hennessy E, Alberman E. Cerebral palsy: effects of twinning, birthweight, and gestational age. Arch Dis Child 1996; 75: 178F–82F. Wolf EJ, Vintzileos AM, Rosenkrantz TS et al. A comparison of pre-discharge survival and morbidity in singleton and twin very low birth weight infants. Obstet Gynecol 1992; 80: 436–9. Wang YA, Dean J, Sullivan EA. Assisted Reproductive Technology in Australia and New Zealand 2005. Report No. 11. Sydney: AIHW National Perinatal Statistics Unit, 2007. Centre for Disease Control. Contribution of Assisted Reproductive Technology and Ovulation-inducing Drugs to Triplet and Higher-order Multiple Births – United States, 1980–97. Report No. 49. Centers for Disease Control and Prevention, 2000. Brambati B, Tului L, Camurri L, Guercilena S. Firsttrimester fetal reduction to a singleton infant or twins: outcome in relation to the final number and karyotyping before reduction by transabdominal chorionic villus sampling. Am J Obstet Gynecol 2004; 191: 2035–40. Cheang CU, Huang LS, Lee TH et al. A comparison of the outcomes between twin and reduced twin pregnancies produced through assisted reproduction. Fertil Steril 2007; 88: 47–52. Britt DW, Risinger ST, Mans M, Evans MI. Anxiety among women who have undergone fertility therapy and who are considering multifetal pregnancy reduction: trends and implications. J Matern Fetal Neonatal Med 2003; 13: 271–8. McKinney M, Downey J, Timor-Tritsch I. The psychological effects of multifetal pregnancy reduction. Fertil Steril 1995; 64: 51–61. Crowa JF. Hardy, Weinberg and language impediments. Genetics 1999; 152: 821–5. Hoskins RE. Zygosity as a risk factor for complications and outcomes of twin pregnancy. Acta Genet Med Gemellol. 1995; 44: 11–23. Fellman J, Eriksson AW. Estimation of the stillbirth rate in twin pairs according to zygosity. Twin Res Hum Genet 2007; 10: 508–13. Benirshke K. Accurate recording of twin placentation: a plea to the obstetrician. Obstet Gynecol 1961; 18: 334–7.

32. Fisk NM, Bryan E. Routine prenatal determination of chorionicity in multiple gestation: a plea to the obstetrician. Br J Obstet Gynaecol 1993; 100: 975–7. 33. Sebire NJ, Snijders RJ, Hughes K et al. The hidden mortality of monochorionic twin pregnancies. Br J Obstet Gynaecol 1997; 104: 1203–7. 34. Hack KE, Derks JB, Elias SG et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implications of a large Dutch cohort study. BJOG 2008; 115: 58–67. 35. Barigye O, Pasquini L, Galea P et al. High risk of unexpected late fetal death in monochorionic twins despite intensive ultrasound surveillance: a cohort study. PLoS Med 2005; 2: e172. 36. Lee YM, Wylie BJ, Simpson LL, D’Alton ME. Twin chorionicity and the risk of stillbirth. Obstet Gynecol 2008; 111: 301–8. 37. Benirschke K, Kim CK. Multiple pregnancy. N Engl J Med 1973; 288: 1276–84. 38. Allen VM, Windrim R, Barrett J, Ohlsson A. Management of monoamniotic twin pregnancies: a case series and systematic review of the literature. BJOG 2001; 108: 931–6. 39. Mahony BS, Filly RA, Callen PW. Amnionicity and chorionicity in twin pregnancies: prediction using ultrasound. Radiology 1985; 155: 205–9. 40. Devlieger RG, Demeyere T, Deprest JA et al. Ultrasound determination of chorionicity in twin pregnancy: accuracy and operator experience. Twin Res 2001; 4: 223–6. 41. Sepulveda W, Sebire NJ, Hughes K et al. The lambda sign at 10–14 weeks of gestation as a predictor of chorionicity in twin pregnancies. Ultrasound Obstet Gynecol 1996; 7: 421–3. 42. Carroll SG, Soothill PW, Abdel-Fataah SA et al. Prediction of chorionicity in twin pregnancies at 10–14 weeks of gestation. BJOG 2002; 109: 182–6. 43. Wood SL, St Onge R, Connors G, Elliot PD. Evaluation of the twin peak or lambda sign in determining chorionicity in multiple pregnancy. Obstet Gynecol 1996; 88: 6–9. 44. Stagiannis KD, Sepulveda W, Southwell D et al. Ultrasonographic measurement of the dividing membrane in twin pregnancy during the second and third trimesters: a reproducibility study. Am J Obstet Gynecol 1995; 173: 1546–50. 45. Cuckle H. Down’s syndrome screening in twins. J Med Screen 1998; 5: 3–4. 46. RANZCOG College Statement No. C-Obs 4. Prenatal screening tests for trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome) and neural tube defects. 2007. www.ranzcog.edu.au/ publications/statements/C-obs4.pdf. 47. National Collaborating Centre for Women’s and Children’s Health. Antenatal Care: Routine Care for the Healthy Pregnant Woman. Royal College of Obstetricians and Gynaecologists. London: RCOG Press, UK, 2008. 48. Spencer K, Kagan KO, Nicolaides KH. Screening for trisomy 21 in twin pregnancies in the first trimester: an update of the impact of chorionicity on maternal serum markers. Prenat Diagn 2008; 28: 49–52.

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Multiple pregnancy 49. Niemimaa M, Suonpaa M, Heinonen S et al. Maternal serum human chorionic gonadotrophin and pregnancy-associated plasma protein A in twin pregnancies in the first trimester. Prenat Diagn 2002; 22: 183–5. 50. Spencer K, Nicolaides KH. First trimester prenatal diagnosis of trisomy 21 in discordant twins using fetal nuchal translucency thickness and maternal serum free beta-hCG and PAPP-A. Prenat Diagn 2000; 20: 683–4. 51. Spencer K. Screening for trisomy 21 in twin pregnancies in the first trimester using free beta-hCG and PAPP-A, combined with fetal nuchal translucency thickness. Prenat Diagn 2000; 20: 91–5. 52. Sebire NJ, Snijders RJ, Hughes K et al. Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation. Br J Obstet Gynaecol 1996; 103: 999–1003. 53. Sebire NJ, D’Ercole C, Hughes K et al. Increased nuchal translucency thickness at 10–14 weeks of gestation as a predictor of severe twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol 1997; 10: 86–9. 54. Kagan KO, Gazzoni A, Sepulveda-Gonzalez G et al. Discordance in nuchal translucency thickness in the prediction of severe twin-to-twin transfusion syndrome. Ultrasound Obstet Gynecol 2007; 29: 527–32. 55. Lewi L, Blickstein I, Van Schoubroeck D et al. Diagnosis and management of heterokaryotypic monochorionic twins. Am J Med Genet A 2006; 140: 272–5. 56. Vandecruys H, Faiola S, Auer M et al. Screening for trisomy 21 in monochorionic twins by measurement of fetal nuchal translucency thickness. Ultrasound Obstet Gynecol 2005; 25: 551–3. 57. Maymon R, Dreazen E, Tovbin Y et al. The feasibility of nuchal translucency measurement in higher order multiple gestations achieved by assisted reproduction. Hum Reprod 1999; 14: 2102–5. 58. Spencer K, Nicolaides KH. Screening for trisomy 21 in twins using first trimester ultrasound and maternal serum biochemistry in a one-stop clinic: a review of three years experience. BJOG 2003; 110: 276–80. 59. Sepulveda W, Wong AE, Casasbuenas A. Nuchal translucency and nasal bone in first trimester ultrasound screening for aneuploidy in multiple pregnancies. Ultrasound Obstet Gynecol 2008; in press. 60. Matias A, Ramalho C, Montenegro N. Search for hemodynamic compromise at 11–14 weeks in monochorionic twin pregnancy: is abnormal flow in the ductus venosus predictive of twin-twin transfusion syndrome? J Matern Fetal Neonatal Med 2005; 18: 79–86. 61. Sebire NJ, Noble PL, Psarra A et al. Fetal karyotyping in twin pregnancies: selection of technique by measurement of fetal nuchal translucency. Br J Obstet Gynaecol 1996; 103: 887–90. 62. Taylor MJ, Fisk NM. Prenatal diagnosis in multiple pregnancy. Baillieres Best Pract Res Clin Obstet Gynaecol 2000; 14: 663–75. 63. Evans MI, Goldberg JD, Horenstein J et al. Selective termination for structural, chromosomal, and

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Mendelian anomalies: international experience. Am J Obstet Gynecol 1999; 181: 893–7. Brambati B, Tului L, Guercilena S, Alberti E. Outcome of first-trimester chorionic villus sampling for genetic investigation in multiple pregnancy. Ultrasound Obstet Gynecol 2001; 17: 209–16. Yukobowich E, Anteby EY, Cohen SM et al. Risk of fetal loss in twin pregnancies undergoing second trimester amniocentesis. Obstet Gynecol 2001; 98: 231–24. Millaire M, Bujold E, Morency AM, Gauthier RJ. Mid-trimester genetic amniocentesis in twin pregnancy and the risk of fetal loss. J Obstet Gynaecol Can 2006; 28: 512–18. Fisk NM, Fordham K, Abramsky L. Elective late fetal karyotyping. Br J Obstet Gynaecol 1996; 103: 468–70. Kalish RB, Gupta M, Perni SC et al. Clinical significance of first trimester crown-rump length disparity in dichorionic twin gestations. Am J Obstet Gynecol 2004; 191: 1437–40. Li S-J, Ford N, Meister K, Bodurtha J. Increased risk of birth defects among children from multiple births. Birth Defect Res (Part A): Clin Molec Teratol 2003; 67: 879–85. Rustico MA, Baietti MG, Coviello D et al. Managing twins discordant for fetal anomaly. Prenat Diagn 2005; 25: 766–71. Hall JG. Twinning. Lancet 2003; 362: 735–43. Tai J, Grobman WA. The association of crown-rump length discordance in twin gestations with adverse perinatal outcomes. Am J Obstet Gynecol 2007; 197: 369.e1–e4. Salomon LJ, Cavicchioni O, Bernard JP et al. Growth discrepancy in twins in the first trimester of pregnancy. Ultrasound Obstet Gynecol 2005; 26: 512–6. Lust A, De Catte L, Lewi L et al. Monochorionic and dichorionic twin pregnancies discordant for fetal anencephaly: a systematic review of prenatal management options. Prenat Diagn 2008; 28: 275–9. Evans MI, Goldberg JD, Horenstein J et al. Selective termination for structural, chromosomal, and Mendelian anomalies: International experience. Am J Obstet Gynecol 1999; 181: 893–7. Machin G, Still K, Lalani T. Correlations of placental vascular anatomy and clinical outcomes in 69 monochorionic twin pregnancies. Am J Med Genet 1996; 61: 229–36. Fisk NM, Galea P. Twin-twin transfusion – as good as it gets? N Engl J Med 2004; 351: 182–4. Weir PE, Ratten GJ, Beischer NA. Acute polyhydramnios – a complication of monozygous twin pregnancy. Br J Obstet Gynaecol 1979; 86: 849–53. Bajoria R, Wigglesworth J, Fisk NM. Angioarchitecture of monochorionic placentas in relation to the twin-twin transfusion syndrome. Am J Obstet Gynecol 1995; 172: 856–63. Denbow ML, Cox P, Taylor M et al. Placental angioarchitecture in monochorionic twin pregnancies: relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Am J Obstet Gynecol 2000; 182: 417–26.

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81. Chow JS, Benson CB, Racowsky C et al. Frequency of a monochorionic pair in multiple gestations. J Ultrasound Med 2001; 20: 757–60. 82. De Catte L, Camus M, Foulon W. Monochorionic high-order multiple pregnancies and multifetal pregnancy reduction. Obstet Gynecol 2002; 100: 561–6. 83. Geipel A, Berg C, Katalinic A et al. Prenatal diagnosis and obstetric outcomes in triplet pregnancies in relation to chorionicity. BJOG 2005; 112: 554–8. 84. Bajoria R, Ward SB, Adegbite AL. Comparative study of perinatal outcome of dichorionic and trichorionic iatrogenic triplets. Am J Obstet Gynecol 2006; 194: 415–24. 85. Lopriore E, van Wezel-Meijler G, Middeldorp JM et al. Neurodevelopmental outcome after laser therapy for twin-twin transfusion syndrome. Am J Obstet Gynecol 2007; 196: e20. 86. Quintero RA, Morales WJ, Allen MH et al. Staging of twin-twin transfusion syndrome. J Perinatol 1999; 19: 550–5. 87. Quintero RA, Dickinson JE, Morales WJ et al. Stagebased treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2003; 188: 1333–40. 88. Ville Y, Hyett J, Hecher K, Nicolaides K. Preliminary experience with endoscopic laser surgery for severe twin-twin transfusion syndrome. N Engl J Med 1995; 332: 224–7. 89. Senat MV, Deprest J, Boulvain M et al. Endoscopic laser surgery versus serial amnioreduction for severe twin-to-twin transfusion syndrome. N Engl J Med 2004; 351: 136–44. 90. Gray PH, Cincotta R, Chan FY, Soong B. Perinatal outcomes with laser surgery for twin-twin transfusion syndrome. Twin Res Hum Genet 2006; 9: 438–43. 91. Taylor MJ, Denbow ML, Tanawattanacharoen S et al. Doppler detection of arterio-arterial anastomoses in monochorionic twins: feasibility and clinical application. Hum Reprod 2000; 15: 1632–6. 92. Fisk NM, Tan TY, Taylor MJ. Stage-based treatment of twin-twin transfusion syndrome. Am J Obstet Gynecol 2004; 190: 1491–2. 93. O’Donoghue K, Cartwright E, Galea P, Fisk NM. Stage I twin-twin transfusion syndrome: rates of progression and regression in relation to outcome. Ultrasound Obstet Gynecol 2007; 30: 958–64. 94. Roberts D, Neilson J, Kilby M, Gates S. Interventions for the treatment of twin–twin transfusion syndrome. Cochrane Database Syst Rev 2008; (1): CD002073. 95. Rychik J, Tian Z, Bebbington M et al. The twin-twin transfusion syndrome: spectrum of cardiovascular abnormality and development of a cardiovascular score to assess severity of disease. Am J Obstet Gynecol 2007; 197: 392.e1–8. 96. Lopriore E, Nagel HT, Vandenbussche FP, Walther FJ. Long-term neurodevelopmental outcome in twin-to-twin transfusion syndrome. Am J Obstet Gynecol 2003; 189: 1314–9. 97. Graef C, Ellenrieder B, Hecher K et al. Long-term neurodevelopmental outcome of 167 children after intrauterine laser treatment for severe twin–twin transfusion syndrome. Am J Obstet Gynecol 2006; 194: 303–8.

98. Sau A, Chalmers S, Shennan AH et al. Vaginal delivery can be considered in monochorionic diamniotic twins. BJOG 2006; 113: 602–4. 99. Van Allen MI, Smith DW, Shepard TH. Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol 1983; 7: 285–93. 100. Tan TY, Sepulveda W. Acardiac twin: a systematic review of minimally invasive treatment modalities. Ultrasound Obstet Gynecol 2003; 22: 409–19. 101. Overton TG, Denbow ML, Duncan KR, Fisk NM. First-trimester cord entanglement in monoamniotic twins. Ultrasound Obstet Gynecol 1999; 13: 140–2. 102. Roque H, Gillen-Goldstein J, Funai E et al. Perinatal outcomes in monoamniotic gestations. J Matern Fetal Neonatal Med 2003; 13: 414–21. 103. Pasquini L, Wimalasundera RC, Fichera A et al. High perinatal survival in monoamniotic twins managed by prophylactic sulindac, intensive ultrasound surveillance, and cesarean delivery at 32 weeks’ gestation. Ultrasound Obstet Gynecol 2006; 28: 681–7. 104. Victoria A, Mora G, Arias F. Perinatal outcome, placental pathology, and severity of discordance in monochorionic and dichorionic twins. Obstet Gynecol 2001; 97: 310–15. 105. Kingdom J, Nevo O, Murphy KE. Discordant growth in twins. Prenat Diagn 2005; 25: 759–65. 106. Alexander GR, Kogan M, Bader D et al. US birth weight/gestational age-specific neonatal mortality: 1995–1997 rates for whites, hispanics, and blacks. Pediatrics 2003; 111: e61–6. 107. Wee LY, Taylor MJ, Vanderheyden T et al. Transmitted arterio-arterial anastomosis waveforms causing cyclically intermittent absent/ reversed end-diastolic umbilical artery flow in monochorionic twins. Placenta 2003; 24: 772–8. 108. Ong SSC, Zamora J, Khan KS et al. Prognosis for the co-twin following single-twin death: a systematic review. BJOG 2006; 113: 992–8. 109. Gratacós E, Antolin E, Lewi L et al. Monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end-diastolic flow (Type III): feasibility and perinatal outcome of fetoscopic placental laser coagulation. Ultrasound Obstet Gynecol 2008; 31: 669–75. 110. Gratacós E, Carreras E, Becker J et al. Prevalence of neurological damage in monochorionic twins with selective intrauterine growth restriction and intermittent absent or reversed end-diastolic umbilical artery flow. Ultrasound Obstet Gynecol 2004; 24: 159–63. 111. Wee LY, Taylor MJ, Vanderheyden T et al. Reversal of twin-twin transfusion syndrome: frequency, vascular anatomy, associated anomalies and outcome. Prenat Diagn 2004; 24: 104–10. 112. Marlow N, Wolke D, Bracewell MA, Samara M: Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005; 352: 9–19. 113. Petrou S: The economic consequences of preterm birth during the first 10 years of life. Br J Obstet Gynaecol 2005; 112: 10–15. 114. Saigal S, Doyle LW: An overview of mortality and sequelae of preterm birth from infancy to adulthood. Lancet 2008; 371: 261–9.

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Multiple pregnancy 115. To MS, Fonseca EB, Molina FS et al. Maternal characteristics and cervical length in the prediction of spontaneous early preterm delivery in twins. Am J Obstet Gynecol 2006; 194: 1360–5. 116. Iams JD, Goldenberg RL, Meis PJ et al. The length of the cervix and the risk of spontaneous premature delivery. National Institute of Child Health and Human Development Maternal Fetal Medicine Unit Network. N Engl J Med 1996; 334: 567–72. 117. Gibson JL, Macara LM, Owen P et al. Prediction of preterm delivery in twin pregnancy: a prospective, observational study of cervical length and fetal fibronectin testing. Ultrasound Obstet Gynecol 2004; 23: 561–6. 118. Crowther CA. Hospitalisation and bed rest for multiple pregnancy. Cochrane Database of Systemic Reviews 2001, Issue 1. 10. 1002/14651858. CD000110. 119. Berghella V, Odibo AO, To MS et al. Cerclage for short cervix on ultrasonography, Meta-Analysis of trials using individual patient-level data. Obstet Gynecol 2005; 106: 181–9. 120. Rouse DJ et al. A Trial of 17 Alpha-Hydroxyprogesterone Caproate to prevent prematurity in twins. N Engl J Med 2007; 357: 454–61. 121. Senat MV, Ancel PY, Bouvier-Colle MH, Breart G. How does multiple pregnancy affect maternal mortality and morbidity? Clin Obstet Gynecol 1998; 41: 78–83. 122. McDermorr JM, Steketee R, Wirima J. Mortality associated with multiple gestation in Malawi. Int J Epidemiol 1995; 24: 413–19. 123. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: Reviewing Maternal Deaths to Make Motherhood Safer – 2003– 2005. The Seventh Report on Confidential Enquiries into Maternal Deaths in the United Kingdom. London: CEMACH, 2007. 124. Rao A, Sairam S, Shehata H. Obstetric complications of twin pregnancies. Best Pract Res Clin Obstet Gynaecol 2004; 18: 557–76. 125. Laws P, Abeywardana S, Walker J, Sullivan EA. Australia’s Mothers and Babies 2005. Sydney: AIHW National Perinatal Statistics Unit, 2007.

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39 Cervical cerclage and pregnancy loss Manju Chandiramani, Andrew H Shennan

Introduction Cervical cerclage has been extensively used for many decades to treat cervical incompetence. However, spontaneous preterm labour (SPTL) secondary to true cervical insufficiency is rare. Despite this, in all cases of SPTL regardless of the aetiology, the cervix undergoes premature effacement and dilatation resulting in a preterm birth. Cervical cerclage therefore may prevent not only cervical incompetence, but also membrane exposure, which has recently, been shown to be key to outcome. Over the past decades, there have been major advances in understanding the pathophysiology and multifactorial nature of SPTL, although there has yet to be a major impact on improving outcome. Nonetheless, improved knowledge in the area of clinical risk assessment using a tiered approach incorporating history, transvaginal ultrasound assessment of cervical length and foetal fibronectin testing has changed practice. The selective use of cervical cerclage directed at high-risk women may prove useful in influencing outcome but needs a more robust evidence base, particularly in how and whom to target.

Prevalence and outcome Preterm birth (PTB) is a major obstetric challenge, resulting in up to 75% of perinatal mortality and over 50% of long-term morbidity.1 Defined as birth before 37 completed weeks of gestation, PTB is responsible for one in 13 live births in England and Wales, and almost two-thirds of all infant deaths.2 Spontaneous preterm births (SPTB) account for up to 70% of all PTBs and encompass both SPTL (45%) and preterm prelabour rupture of membranes or PPROM (25%);3 iatrogenic PTBs account for 30% of all PTBs but often account for up to 50% of all extremely premature births.4 Infant mortality is highest at the very low gestational ages: 986 deaths per 1000 live births among babies born before 22 weeks and 947 deaths per 1000 live births at 22 weeks.2 Mortality decreases with gestational age to 1.3 deaths per 1000 live births among babies born at 40 weeks’ gestation.2 Fig 39.1 shows a neonate born at 25 weeks in the neonatal intensive care unit.

Fig 39.1 A neonate on the neonatal intensive care unit born at 25+2 weeks’ gestation despite her mother having had a history-indicated cerclage in situ and progesterone pessaries illustrating that for most women, interventions do not make a difference.

In the UK, viability is generally accepted as 24 weeks (1992 Amendment to the Infant Life Preservation Act) with a corresponding foetal weight of 500 g.5 In the US in 2004, the annual societal economic burden associated with preterm birth was in excess of $26.2 billion.6 The increased risk of neurodevelopmental impairments (cerebral palsy, sensory and visual problems), and respiratory and gastrointestinal complications place a considerable physical, emotional and social burden on the involved woman and her family. With increasing survival rates of children born very preterm (i.e. before 33 weeks’ gestation), there is an increasing need for highly specialised childcare as over 9% of these children are being diagnosed with cerebral palsy by the age of 5.7

Pathophysiology SPTL has a complex aetiology possibly related to a variety of pathological events and/or an early maturation of physiological processes which usually occur at term.8 Various causative factors may interact to result in early effacement and dilatation, and subsequent SPTB.9 They include infection (ascending, haematogenous or iatrogenic), cervical insufficiency (the inability of the cervix to retain a pregnancy in the absence of contractions), decidual haemorrhage or

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placental abruption (release of thrombin stimulating contractions), uterine distension secondary to multiple pregnancy (myometrial stretch), maternal illness (e.g. intercurrent pyelonephritis) and foetal stress (e.g. polyhydramnios secondary to gastrointestinal atresias or twin–twin transfusion syndrome). PPROM is often secondary to infection or inflammation and carries the risk of chorioamnionitis, pulmonary hypoplasia (<22 weeks’ gestation), postural deformities and PTB. Some women are also thought to be at an increased risk of SPTL secondary to a genetic predisposition.10 The cervix is fundamental in supporting the pregnancy, providing both mechanical strength and acting as a barrier to ascending vaginal infection. The risk of SPTB increases exponentially as the cervix shortens;11 a cervical length of ≤15 mm is associated with almost a 50% risk of SPTB at ≤32 weeks,12 even in an otherwise low-risk woman. It is hypothesised that a short cervix is associated with an increased likelihood of ascending vaginal infection breaching the intrauterine space, resulting in stimulation of an inflammatory process, cervical ripening, increased risk of membrane rupture and SPTL. The crucial factor appears to be membrane exposure as even a short closed cervix (<10 mm) without visible membranes can result in a term pregnancy.13 The improved outcome noted in some studies with ultrasound-indicated cerclage supports the placement of cerclage before membrane exposure providing mechanical support and possibly allowing retention of the mucus plug.13 Further studies are needed to confirm the role of cerclage under these circumstances. Microbiological studies conservatively suggest that intrauterine infection may account for up to 40% of PTB, although at less than 24 weeks’ gestation, most SPTB are associated with histologically proven chorioamnionitis compared with only 10% at 35 weeks’ gestation.3 Traditionally, the cervix has been the focus of intervention to prevent SPTL. Regardless of the aetiology, premature cervical changes occur to facilitate spontaneous delivery. As the distinction between cervical insufficiency and cervical shortening attributable to the multifactorial aetiology of SPTL, is imprecise, the exact contribution of cervical insufficiency is unknown. It is estimated to complicate as many as one in 217 pregnancies.14 In women with a poor obstetric history or factors indicative of potential cervical insufficiency, cervical cerclage has become a commonplace prophylactic surgical intervention for PTB in modern obstetric practice despite its uncertain efficacy.

Prediction Preconceptual and antenatal risk assessments are important steps in identifying this high-risk population allowing primary prevention (such as behavioural modification), and preconceptual prophylactic measures (such as cervical cerclage) to be initiated. Other predictors such as transvaginal cervical length assessment from 14 weeks’ gestation and foetal

fibronectin testing from 23 weeks’ gestation substantially improve risk estimation allowing secondary prophylactic strategies such as cervical cerclage and progesterone to be initiated.

Pre-pregnancy assessment Risk factors including previous obstetric history, cervical disease and trauma, and maternal characteristics have been shown to be associated with PTB. Despite this, models using this information lack the predictive ability for SPTL, which would allow risk scoring systems with high sensitivity and positive predictive values to be useful for population-based screening. As a result, a thorough history in the pre-pregnancy period will highlight areas of modifiable risk and those women who would benefit from expert surveillance for SPTL. It should be remembered that more than half of PTB occurs in women without risk factors.

Previous obstetric history It is important to identify women at risk of pregnancy loss and PTB as it allows initiation of appropriate preconception advice and targeting of specific prophylactic treatment. Women with a history of a previous PTB or a second trimester loss are at high risk of PTB.15 Risk ranges from 42% (for women with two prior preterm deliveries), through 21% (term/preterm) and 13% (preterm/term), to 5% (term/term).16 Recurrence risk is highest (57%) for two deliveries between 21 and 31 weeks and lower (31%) for two deliveries between 32 and 36 weeks.16 This highlights the poor predictive ability of using history alone to identify those at risk. Women with true cervical insufficiency (inherent weakness) are notoriously even more difficult to identify. Nonetheless, a history of mid-trimester miscarriage or early PTB with progressive painless cervical dilatation culminating in bulging membranes or PPROM should alert the clinician to a possible diagnosis. There is no evidence that targeting women with this history with cerclage insertion results in better outcome. Women with classical painless dilatation will more often than not have a term pregnancy subsequently, independent of intervention. Women who have a SPTB in their first pregnancy are more likely to deliver preterm both spontaneously odds ratio ((OR) 3.6, 95% confidence interval (CI) 3.2–4.0) and iatrogenically (OR 2.5, 95% CI 2.1–3.0).17 This illustrates the heterogeneous aetiology of the condition. It is not surprising that cerclage rarely makes a difference. Almost a quarter of women with a previous birth at less than 27 weeks’ gestation will deliver at less than 28 weeks in a subsequent pregnancy.18 Two or more previous miscarriages are strongly associated with extremely preterm deliveries at less than 28 weeks’ gestation.19 Multiple pregnancies account for about one-fifth of all PTBs, although they only account for about 2–3% of all live births.3

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Cervical disease and trauma Other factors such as cervical disease resulting from congenital disorders (diethylstilbestrol exposure) and surgical or cervical trauma increase the likelihood of pregnancy loss or PTB, presumably through cervical weakness. Although the risk of SPTB is positively associated with two or more previous therapeutic abortions (hazard ratio 1.90, 95% CI 1.44–2.49),19 there is no evidence that a previous medical abortion compared with a previous surgical abortion, increases the risk of PTB relative risk ((RR) 0.88, 95% CI 0.66–1.18).20 However, women with more than one prior induced abortion (be it medical or surgical) and a short cervix (i.e. <25 mm) have over a 3-fold greater chance of SPTB compared with those who have a normal cervical length.21 In cases of uterine dilatation and curettage (surgical termination of pregnancy and evacuation of retained products of conception), the use of antiprogesterone priming and prostaglandin analogues may ensure avoidance of excessive force and resultant cervical trauma.22 Conservative methods to treat cervical intraepithelial neoplasia while preserving cervical function, i.e. cold knife conisation, laser loop excision of the transformation zone (LLETZ), laser conisation and laser ablation, have variable effects on subsequent pregnancy outcome.23,24 In a systematic review and meta-analysis by Kyrgiou et al, both cold knife conisation (RR 2.59, 95% CI 1.80–3.72) and LLETZ (RR 1.70, 95% CI 1.24–2.35) are significantly associated with PTB.23 Laser conisation does not have a significant effect on PTB (RR 1.71, 95% CI 0.93–3.14) but the size of effect could be important if real (i.e. this may be a type 2 statistical error).23 The use of diathermy is associated with an adjusted OR of 1.72, compared with 1.1 for women treated with laser ablation.25 Clinicians should carefully consider the least invasive therapies for cervical disease where appropriate to avoid adverse pregnancy outcomes, as procedures previously thought to be innocuous are increasingly being associated with later pregnancy complications.

Maternal characteristics Maternal demographic factors such as age, body mass index (BMI), ethnicity, socioeconomic factors, nutritional status, illicit drug use and smoking have all been associated with an increased risk of PTB. Rates of PTB in black women have been reported as 18% compared with 9% for white women with black women being up to four times more likely to have very early PTB compared with women from other ethnic groups.26,27 Socioeconomic factors may have an influence on a woman’s nutritional status; women with low levels of iron, folate and zinc have more PTBs.28,29 Although, there may be a genetic component to racial disparity, these differences may be compounded by socioeconomic factors and inequalities in access and uptake of routine antenatal care and maternal behaviour.

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Many maternal characteristics associated with PTB are modifiable, including BMI, interpregnancy interval, smoking and use of illicit substances, physical abuse and coitus. Women with a low BMI are at an increased risk for PTB.30 In a study by Merlino et al,30 women with a previous PTB whose BMI decreased by more than 5 kg/m2 had more frequent PTB in their second pregnancy than those who did not (80% versus 28%, p=0.01). An increase in weight is potentially harmful, even in women of a normal BMI, and should also be avoided. A short interpregnancy interval (<6 months defined as period of time between preceding delivery and subsequent conception) increases the risk of PTB <28 weeks’ gestation (adjusted OR 1.41, 95% CI 1.13–1.76) and recurrence of PTB (adjusted OR 1.44, 95% CI 1.19–1.75).31 In another study conducted only for SPTB, there was an increased risk only for SPTB <34 weeks’ gestation (OR 3.9, 95% CI 1.91–8.10) compared with later preterm births at 34–36 weeks (OR 0.8, 95% CI 0.32–1.83) in women who had <6 months between the preceding delivery and the first day of the last menstrual period for the index pregnancy.32 It is hypothesised that a short interpregnancy interval may prevent the uterus from reverting to its pre-pregnancy state, thus pre-disposing the subsequent pregnancy to an altered immune status.3 In the Generation R Study, smoking prior to pregnancy or in early pregnancy did not appear to be associated with PTB but continued smoking after pregnancy was recognised as associated with preterm birth (adjusted OR 1.36, 95% CI 1.04–1.78) and smoking more than nine cigarettes/day after 25 weeks’ gestation was associated with a 2.5-fold increase in the risk of PTB (CI 1.36–4.67).33 Physical abuse during pregnancy is associated with over a 3-fold increase in preterm birth even after controlling for confounding factors. There is a suggestion that abuse before conception is associated with an increased likelihood of a subsequent PTB.34 Limited evidence on a small cohort of women suggests that self-reported infrequent coitus during early pregnancy is not associated with an increased risk of recurrent preterm delivery, although an increasing number of sexual partners during a woman’s lifetime may be (four or more partners 44%, p=0.07).35 Further objective evidence is required to determine what advice should be given to highrisk women regarding unrestricted coitus during pregnancy and the effect of pre-pregnancy sexual behaviour on pregnancy outcome.

Pre-pregnancy tests Relying on a history of cervical insufficiency often means that it is a diagnosis made retrospectively. When determining whether a woman would benefit from prophylactic prevention in the pre-conception period or early in pregnancy using a cervical cerclage, it would be useful to have a reliable objective means to diagnose a cervix that would benefit from cerclage in

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both nulliparous and multiparous women. Numerous tests have been used by clinicians over the years to diagnose this entity. They include assessing ease of insertion of cervical dilators in the absence of resistance, radiological studies and the use of intracervical balloons to determine cervical resistance to exerted force.36 Unfortunately, these techniques have not been subject to rigorous clinical trials. Their effect on subsequent pregnancy outcome and in the context of the dynamic pregnant cervix is not clear. More recently, cervical resistance index (CRI), performed in the non-pregnant state, has been shown to be a useful objective technique to aid diagnosis of cervical weakness allowing rational targeting of prophylactic cervical cerclage. In an observational study37 of 175 patients with a history of one or more spontaneous mid-trimester losses, the relative risk of being classified incompetent by CRI based solely on a history of spontaneous mid-trimester miscarriage was 1.59. Women with this history had significantly lower CRIs than parous women who did not suffer a midtrimester loss. Although this technique has not been subject to randomised controlled trials, CRI measurements may allow a management plan incorporating cervical cerclage in subsequent pregnancy if there is diagnosis of true incompetence, but outcome studies relating CRI findings to benefit of cerclage need to be performed.

acceptance of limited embryo transfer in assisted reproductive techniques (ART) has begun to decrease the rate of higher-order multiple pregnancies, which will undoubtedly limit extreme prematurity in these pregnancies. Women should be made aware of the modifiable risks (BMI, interpregnancy interval and smoking). It may be appropriate to discourage women from losing weight from their pre-pregnancy weight in the pregnancy affected by a PTB. In addition, it may be useful to initiate smoking cessation programmes early, focusing on quitting smoking completely. Use of illicit drugs should be discouraged and linked to PTB, and appropriate programmes sought to help the woman. As a short interpregnancy interval increases the risk of PTB even after adjusting for confounding risk factors, women with either an initial term or PTB should be encouraged to wait at least 12 months between delivery and subsequent conception, particularly if they have had a previous PTB. Although the evidence is unclear regarding multivitamin supplementation prior to pregnancy, women should be encouraged to have a balanced diet ensuring they are getting their daily dietary vitamin and mineral requirements. Clinicians should enquire about domestic violence in the pre-pregnancy period as abuse may escalate once pregnant, and pre-conceptual abuse is linked to worse outcome.

Pre-pregnancy advice

Managing the high-risk pregnancy

An increased awareness of the risk factors associated with SPTL highlights the areas which may be targeted during pre-conception counselling. A good history will facilitate the identification of women at risk and allow management of the pregnancy to be individualised. Women thought to have a history suggestive of cervical insufficiency should be referred to a specialist obstetrician. They may consider preterm surveillance using cervical length assessment and foetal fibronectin testing, and appropriate targeting of interventions. There is increasing evidence to suggest that women with inherited and acquired thrombophilias are at increased risk of early and late pregnancy loss.38 Our own experience shows that the incidence of acquired thrombophilias in a population of women at risk of second trimester miscarriage and PTB is similar to that in an unselected pregnant population and lower than that of a population with early recurrent miscarriages. Although it may be appropriate to search for an acquired thrombophilia in the context of abruption, recurrent bleeding or intrauterine growth restriction in a previous pregnancy, the present lack of controlled trials of antithrombotic interventions to prevent later pregnancy complications make it difficult to justify clinically universal screening for thrombophilia in pregnancy.39 About 60% of twin pregnancies will result in preterm deliveries, of which 40% will have SPTL or PPROM possibly secondary to uterine overdistension.3 An increased awareness and

Antenatal preterm surveillance Women who are identified at risk of SPTL by their midwife or general practitioner at their booking visit or by their obstetrician should be referred to a specialist alongside planned visits for routine antenatal care monitoring for maternal and foetal well-being. A thorough history not only highlights aspects discussed above, but also further elucidation of histological findings of previous pregnancies may confirm chorioamnionitis in the context of cervical change. Once referred to a specialist, suitable surveillance can be planned to detect early cervical changes on transvaginal ultrasound or presence of foetal fibronectin in vaginal secretions. In this way, appropriate interventions such as cervical cerclage, progesterone, bedrest, antenatal corticosteroids and admission can be targeted to those likely to benefit. As composite risk scores incorporating history, socioeconomic factors, lifestyle, cervical length assessment and foetal fibronectin have not been evaluated in asymptomatic high-risk women, ascertainment of risk is largely determined by objective measures such as cervical length and foetal fibronectin. Despite this, a recent systematic review40 showed that cervical length and foetal fibronectin are clinically useful factors for predicting PTB and may be used in combination to potentially improve outcome, or at least target efforts to those most at risk.

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increases to 78% when the cervix is 5 mm.42 In the low-risk population, ultrasound-indicated cerclage for a short cervix does not prevent PTB,43 although progesterone has recently been shown to be beneficial.44 Despite this, routine cervical length assessment in low-risk women is not recommended. In high-risk women, i.e. with a previous SPTB at <32 weeks, a cervical length <25 mm between 16 and 18+6 weeks followed by serial monitoring up to 23+6 weeks is associated with a relative risk of 4.5 for SPTB at <35 weeks (95% CI 2.7–7.7, sensitivity 69%, specificity 80%, positive predictive value (PPV) 55%) when the shortest measurement <25 mm is used.45 Interestingly, high-risk women with a normal cervical length (>25 mm) between 14 and 18 weeks’ gestation have only a 4% risk of delivering early.41 Nonetheless, serial measurements at 2–3 weekly intervals may be useful in this population to target interventions as the use of cerclage in this group of women appears to be beneficial,46 at least in some studies. The use of cervical length assessment in other high-risk women, such as those with previous cervical surgery and uterine anomalies, is also predictive of PTB (Table 39.1),41 although the value of interventions in this group is unclear. Timing of effective cervical scanning is important. A retrospective study measuring cervical length from as early as 14 weeks showed a length of ≤15 mm had a PPV of 48% and a negative predictive value (NPV) of 97% for SPTB at ≤32 weeks.23 In a high-risk group, the risk of SPTB before 35 weeks decreased by approximately 6% for each additional millimetre of cervical length and by almost 5% for each additional week of pregnancy at which cervical length was measured (Fig 39.3).47 Although most studies45,48,49 have shown better predictability with cervical length assessment in the second trimester between 20 and 24 weeks, using a cut-off value of 25 mm, serial measurements starting as early as 14 weeks may allow preventative strategies such as cerclage and progesterone to be better targeted.

Fig 39.2 Transvaginal scan showing a short cervix at 19 weeks’ gestation in a high-risk woman with a previous second-trimester miscarriage in the preterm surveillance clinic. Cervical length 12.9 mm. Funnel 20.4 mm x 9.8 mm.

Transvaginal cervical length assessment Transvaginal cervical length assessment is a better predictor of SPTL than the use of history alone (Fig 39.2). It has the characteristics of a good screening test:41 it is safe and recognises disease in its asymptomatic stage. It is a well-described technique, reliable and reproducible with low inter- and intraobserver variability and it is valid. Finally, it is associated with interventions (cerclage, progesterone, indomethacin and antibiotics) that affect outcome. A short cervix carries an increased likelihood of a subsequent PTB.11 In low-risk groups, the sensitivity of this technique is low.42 Nonetheless, a cervical length of 22 mm at 24 weeks is associated with a 9-fold increase in the risk of SPTL at <35 weeks’ gestation.42 The risk of delivery at ≤32 weeks’ gestation with a cervical length of ≥25 mm between 22 and 24 weeks is only 1% but

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50 40 30 20 10 0 12

13

14

15

16

17

18 19 20 21 22 Week of pregnancy Cervical length

15 mm

20 mm

23

24

25 mm

25

26

27

Fig 39.3 Likelihood of delivery before 32 weeks’ gestation in asymptomatic high-risk women.47

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in its NPV which is about 99% in both groups of women.53,54 When fFN is present in asymptomatic high-risk women at 24 weeks’ gestation, the likelihood ratio for delivery at <30 weeks is 15.54 There have been few large analyses of fFN tests in conjunction with cervical length, although the limited evidence that does exist suggests that a short cervix and a positive fFN are associated with a higher risk of PTB than either marker alone.55 The value of a positive result following cerclage insertion is less certain. It is our practice to perform fFN testing in asymptomatic high-risk women at 23 weeks’ gestation and repeated testing is undertaken to determine changes in management in terms of admission, bedrest, corticosteroid and progesterone use. Although cervical length assessment and fFN testing are used in conjunction in our clinical practice, fFN detection in symptomatic women selected by cervical length assessment predicts PTB at <35 weeks with greater specificity than cervical length alone.56 There is limited available evidence of the performance of these tests when used in conjunction in asymptomatic high-risk women.

Screening asymptomatic high-risk women for abnormal vaginal flora

Fig 39.4 Foetal fibronectin test bedside kit: test strip, buffer solution and sterile polyester tipper high vaginal swab applicator.

Cervical length assessment is also of value in multiple pregnancies, with a similar increased risk of SPTB occurring at 25 mm in twin gestations compared with 15 mm in singleton pregnancies.50 Although it is likely that other mechanisms such as uterine stretch influence cervical length altering the predictive abilities of the test, it may still be of benefit considering the increased likelihood of this group delivering early. The presence of a funnel45 signifying disruption of the internal os and the presence of intra-amniotic particulate matter (“sludge”)51 may increase the likelihood of intrauterine infection but as independent findings, they do not add appreciably to the risk of PTB associated with a short cervix. However, a recent finding is that funnelling in the presence of a short cervix may be a worse predictor than a short cervix alone,52 although the significance of a funnel in the presence of a normal cervix is unclear.

Foetal fibronectin testing Foetal fibronectin (fFN), a glycoprotein which signifies choriodecidual disruption, is the most powerful biochemical marker for PTB.3 fFN is usually absent from cervicovaginal secretions between 22 and 34+6 weeks’ gestation. It has become well established as a useful predictive bedside test in both symptomatic and asymptomatic women (Fig 39.4). Its strength lies

National Institute for Clinical Excellence (NICE) guidelines for antenatal care encourage the screening and treating of asymptomatic bacteriuria to prevent pyelonephritis.57 Meta-analysis clearly shows that appropriate antibiotic therapy reduces the risk of PTB. As early SPTL is likely to be related to an infectious cause,58 numerous studies59–65 have examined the effect of screening and treating abnormal vaginal flora, bacterial vaginosis (BV) and group β streptococcus (GBS) with contradictory results. Daskalakis et al66 recently showed that BV is associated with a 2-fold increased risk of PTB (RR 2.19, 95% CI 1.21–3.98), whereas GBS colonisation has an inverse association (RR 0.43, 95% CI 0.19–1.00). The detection of BV in early pregnancy is high (39%) and in women with a previous miscarriage there is up to a 5-fold increase in the risk of adverse pregnancy outcome (miscarriage or PTB) associated with a positive vaginal smear (BV or abnormal flora).67 Interestingly, resolution of BV compared with its persistence (0 vs 5.7%, p=0.01) is associated with a reduced rate of SPTB (<34 weeks).68 It is hypothesised that latent genital infection established in early pregnancy may interfere with immunological quiescence and trigger biochemical events resulting in early birth. Although screening and treating BV in the second trimester has been largely ineffective at decreasing PTB, randomised controlled trials aimed at eradicating BV in the first trimester before cervical changes occur in those who have a decreased inflammatory response may prove useful. A meta-analysis by Simcox et al69 failed to show benefit, illustrating that treating high-risk asymptomatic women with antibiotics does not reduce the

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risk of subsequent preterm birth. In fact, the use of metronidazole in asymptomatic high-risk women, appears to increase their risk of SPTL,70,71 possibly due to changes in vaginal flora.72 These clinical studies suggest that the “best” antibiotic regimen has not effectively prevented PTB and it is possible that the inflammatory process, rather than the acute infection, is responsible for SPTL. One of the main reasons that antibiotics alone do not prevent infection-associated SPTL may be their failure to reverse the production of pro-inflammatory mediators (e.g. cytokines, prostaglandins and matrix metalloproteinases) which may play a key role in the initiation of cervical shortening and subsequent SPTL. Nonetheless, interventions such as cerclage prior to membrane exposure and progesterone with its immunoregulatory properties may still prove more useful in this scenario. It remains to be determined whether prolonging pregnancy in the setting of intrauterine infection is associated with poorer neonatal outcome, in light of prolonged exposure of the foetus to inflammatory cytokines in utero. In light of this contradictory evidence, it is not routine in our practice to screen all high-risk women for abnormal vaginal flora. However, if a clinician obtains a high vaginal swab in women with altered vaginal discharge and subsequent culture confirms BV, she is given a course of clindamycin.

Cervical cerclage There are a number of established techniques for cerclage insertion, and each surgeon often has their own preferred method and variations. In modern-day obstetric practice, cervical cerclage placement has become commonplace with a limited evidence-base of efficacy. In the US, 1% of pregnancies receive a cerclage, amounting to an estimated 40 000 cerclages being inserted annually.73 The current incidence of cerclage insertion in the UK is unknown, as practice is extremely variable. Usually, the decision to insert a cervical cerclage is made by an experienced obstetrician, with some degree of specialist knowledge, as there are currently no established indications for their use. A history-indicated cerclage may be inserted based on a previous obstetric history of cervical insufficiency in a prophylactic, elective manner. An ultrasound-indicated cerclage may be inserted for a short cervix (usually at least 25 mm or less) on transvaginal assessment as a therapeutic measure. In the presence of dilatation and membrane exposure, a physical examination-indicated cerclage may be inserted as a ‘rescue’ procedure. Transabdominal cerclage placement preconceptionally or in early pregnancy may be undertaken for a past history of failed ‘history-indicated’ or ‘ultrasound-indicated’ vaginal cerclage or in the presence of insufficient intravaginal cervical tissue precluding the placement of a vaginal cerclage.73

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Surgical technique A cervical cerclage may be inserted transvaginally (purse-string (McDonald) or with bladder mobilisation (Shirodkar)) or transabdominally (laparotomy or laparoscopy). There are no robust published randomised trials comparing these techniques directly; however, there is a need for trials to be undertaken. A systematic review of abdominal versus vaginal cerclage after a failed transvaginal cerclage showed that a transabdominal cerclage may be associated with a lower risk of perinatal death or delivery at <24 weeks’ gestation (6% versus 12%), albeit with a higher risk of serious operative complications.74 A secondary analysis of Shirodkar versus McDonald cerclage for a short cervix demonstrated no significant difference in PTB at <33 weeks’ gestation (OR 0.55, 95% CI 0.2–1.3).75 Although both procedures involve placement of a purse-string suture, a Shirodkar suture is often thought to be theoretically better. Bladder dissection allows higher cerclage placement giving it a longer functional length (confirmed by serial transvaginal ultrasonography of cervical length) albeit it at a theoretical risk of complications of longer surgery and bladder damage without proven improved pregnancy outcome and neonatal survival. In the absence of available convincing data of superiority, many surgeons prefer to insert a McDonald cerclage as it is easy to insert and effective. In the situation where a Shirodkar cerclage has failed, some surgeons have even performed a double cervical cerclage (placing a second suture 2 cm below the first one placed at the internal os),76 although the value of this technique is unclear given the multifactorial nature of PTB. Transvaginal cervical cerclage may be inserted at any gestation or in the pre-conception period, although it is more common to insert them electively between 12 and 14 weeks’ gestation following a viability, dating and nuchal translucency scan, but before cervical changes occur. Transabdominal cerclages are usually inserted earlier in pregnancy, before 11 weeks, before the expanding uterus hinders surgical access. An ultrasound-indicated cerclage using the McDonald technique may be inserted after progressive cervical shortening on serial ultrasound surveillance. With greater degrees of dilatation and prolapse of membranes, a ‘rescue’ cerclage using the pursestring technique is technically feasible. In light of survival improvements at the limits of viability, the risk/benefit of cerclage insertion after 23 weeks should be carefully considered. Theoretically, placement may precipitate a slightly earlier delivery in very high-risk cases which may have a major impact on outcome. It is often best to insert a cerclage for a short or open cervix early, as delay increases the risk of ascending infection, and later insertion is more likely to be associated with a contracting and/or infected uterus.73 Earlier detection of a short cervix on ultrasound appears to benefit cerclage placement for PTB prevention.77

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Fig 39.5 Commonly used suture material for cerclage insertion: double nylon (left) and mersilene tape (right).

After gaining informed consent, a regional block may be used. A spinal anaesthetic is preferred over general anaesthetic as it is safer in pregnancy and the three procedures tend to take only 30–60 minutes. Some surgeons will request a general anaesthetic to ease positioning, and relax the uterus which may be helpful in the “rescue” scenario. However, this is not our practice, and we have not needed to give general anaesthetic for any cerclage placement for the past 5 years. After anaesthesia has been administered, the woman is placed in the lithotomy position with the cervix adequately exposed to facilitate insertion. The suture material used is based on the surgeon’s preference as there is insufficient evidence on which to base practice (Fig 39.5). Monofilament has the advantage of being more inert (to infection), but may “cut through” more easily; it is therefore increasingly common practice to insert two sutures. Although PPROM and/or intrauterine infection are absolute contraindications to cerclage placement, there is no evidence to dictate antibiotic prophylaxis at the time of cerclage placement but this may be prudent with “rescue” cerclages. Some clinicians suggest using indomethacin in the context of a short cervix for PTB at <24 weeks,78 although when used at the time of ultrasoundindicated cerclage insertion, there is a trend towards an increased risk.79 Foetal side-effects, involving the renal system and ductus arteriosus, are more common at later gestations and indomethacin is not recommended. The effects of cerclage and indomethacin do not appear to be additive, highlighting the need for further evidence. It is our practice to use mersilene tape for vaginal cerclage and double nylon (1.0) for abdominal procedures (Fig 39.6). We do not use intraoperative antibiotics and indomethacin but these issues are left to the surgeon’s discretion in the absence of evidence. Although there is no evidence that bedrest and reduced activity benefits women at risk, careful counselling must be undertaken to include the potential increased risks of thromboembolism in pregnancy associated with this behaviour. However, some beneficial

Fig 39.6 Insertion of a history-indicated cervical cerclage using the McDonald surgical technique. Suture material is mersilene tape.

strategies have included bedrest and/or hospital admissions, and we reserve admission for very high-risk cases at critical gestations, e.g. poor history with short cervix (<15 mm) and positive fFN between 23 and 26 weeks’ gestation. Although most cerclages may be inserted as day-case procedures, admission is required for transabdominal ones. Early stated complications of cerclage insertion include abdominal pain, vaginal bleeding, PPROM and miscarriage, although the rates of these complications may be high in women who receive cerclage independent of the procedure. Late complications include chorioamnionitis, suture displacement, maternal infection, miscarriage, preterm delivery, uterine rupture, increased use of tocolytics and cervical dystocia. Cervical scarring may necessitate cerclage placement in subsequent pregnancies. Following cerclage insertion, women should be counselled regarding complications and when to seek medical attention. Any woman with a cervical cerclage in situ should be encouraged to seek medical attention if she experiences symptoms suggestive of labour, pain, discharge or bleeding. This allows enough available time for cerclage removal avoiding trauma, if necessary.

Pre-conception cervical cerclage Both vaginal and abdominal cervical cerclage may be inserted in the pre-conception period, although it is more common to insert a pre-conception transabdominal cerclage than either of the transvaginal cerclages. Pre-conception transabdominal cervical cerclage has the advantage of operating on the non-pregnant uterus. Early miscarriage management does not appear to be a problem. However, pregnancy procedures also appear safe, but there are no good data comparing the two. This laparotomy technique has comparable foetal survival rates with fewer complications when inserted before pregnancy,80 although no randomised trials have been reported to define pregnancy outcome, complication rates and neonatal survival. There have been reported

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successes following laparoscopic insertion of transabdominal cerclage but the evidence is still limited.81–83

Who should have a history-indicated cervical cerclage? There are no established evidence-based indications for history-indicated cervical cerclage insertion. The decision is often based on a combination of risk factors and/or previous success with cerclage. In the three randomised controlled trials comparing history-indicated cervical cerclage with expectant management,84–86 women with specific histories of cervical insufficiency were not uniformly recruited. Even in the largest of these trials to date, the number needed to treat to prevent an early PTB was 25 with wide confidence intervals.84 As a result, there is insufficient evidence to support the use of cerclage in women with a previous history suggestive of cervical insufficiency. However, women with three or more prior second trimester miscarriages or PTBs do appear to benefit from cerclage insertion (15% versus 32% for PTB at <33 weeks).84 A history-indicated cerclage is not justified for other historical risk factors based on available evidence, although it may be appropriate in cases of extensive cervical trauma. In twin pregnancies, the risk/benefit of elective cerclage placement should be carefully considered as there is no proven reduction in PTB, probably because these pregnancies are subject to increased effects of uterine stretch rather than true cervical insufficiency. There is limited evidence to show that there is no measurable benefit to placement of two stitches over one stitch during cervical cerclage placement in early pregnancy in singleton pregnancies (n=150).87 A nonsignificant 7% reduction in PTB at <28 weeks’ gestation has been reported, which may indeed be clinically significant in light of the high morbidity associated with deliveries at this gestation if proven to be true. Further study of pregnancy and neonatal outcomes in a larger cohort may be warranted.

Who should have an ultrasound-indicated cerclage? In a meta-analysis of the four randomised trials (n=607)88 published to date on the use of ultrasoundindicated cerclage versus expectant management, there was no prevention of PTB (<35 weeks’ gestation) in all women with a short cervix. However, subgroup analysis of singleton pregnancies with a prior history of PTB did show benefit (RR 0.61, 95% CI 0.40–0.92). In twin pregnancies, cerclage was associated with a higher incidence of PTB (RR 2.15, 95% CI 1.15–4.01), reaffirming the hypothesis that uterine stretch may compromise cerclage success. Although larger randomised controlled trials are needed to confirm these findings and their effect on neonatal outcome, we insert cerclages in high-risk women with a previous PTB if their cervical length is <25 mm on transvaginal assessment. As the incidence of intra-amniotic infection in these women is

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about 1–2%,73 we do not routinely undertake amniocentesis prior to cerclage insertion, although this may be worth considering if there is clinical suspicion (e.g. the presence of “sludge”). Interestingly, individual patient data meta-analysis of seven randomised trials (n=2091)89 including both a short cervix and obstetric history not only confirmed this detrimental affect in twin pregnancies, but also failed to show convincingly that cerclage had a beneficial effect on pregnancy outcome. Although a possible reduction of up to 40% may exist with cerclage insertion, further large interventional trials and a better understanding of the mechanisms underlying premature cervical change are needed to determine the risks and benefits of the procedure. While further evidence is sought, we have found transvaginal ultrasound surveillance in a preterm surveillance clinic between 16 and 24 weeks is extremely beneficial to women with a previous history of second trimester miscarriage or PTB as it identifies women who do not need intervention. Almost 60% maintain a cervical length of >25 mm and over 90% of these women deliver after 35 weeks without intervention.73 In women who have had multiple losses/early deliveries or large cone biopsies, it may be reasonable to start surveillance earlier. It is reassuring that the four trials comparing history-indicated versus ultrasound-indicated cerclage show similar recurrent PTB rates in both groups.90–93

Who should have a physical examination-indicated cerclage? A physical examination-indicated cerclage may be inserted as a “rescue” procedure in the presence of a dilated cervix with bulging membranes, given the associated poor prognosis. Prior to cerclage insertion in women with advanced dilatation, amniocentesis may be considered as the risk of infection may be as high as 50%,73 possibly utilising new bedside interleukin tests. Robust evidence to support cerclage insertion is limited but survival rates are quoted as ranging from 13 to 63%.94,95 There has only been one randomised controlled trial96 of 23 women allocated to receive cerclage, indomethacin and bedrest versus bedrest alone between 22 and 23 weeks’ gestation, which resulted in prolongation of pregnancy (54 versus 20 days). Although other small case series 97,98 have confirmed a prolongation of pregnancy, this does not necessarily translate into improved neonatal outcome in light of potential infection following membrane exposure. In high-risk populations, the presence of visible membranes at the time of cerclage insertion, regardless of pre-operative cervical length is associated with poor outcome.13 As a result, further evidence is necessary before management can be recommended. In the interim, individualised management plans should be made by an experienced obstetrician.

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When should one insert an occlusion cerclage? An occlusion cerclage is inserted by some surgeons at the same time as the first cerclage, be it via the vaginal or abdominal route. It is thought to deal not only with the problem of cervical insufficiency in women with a failed cerclage, but also with the retention of the mucus plug. The mucus plug is hypothesised to be essential to maintenance of pregnancy, acting as a mechanical barrier with inherent adaptive immune protection to defend against ascending vaginal organisms. There is no randomised controlled evidence to date to suggest benefit from an occlusion cerclage. A trial99 is ongoing randomising women to history-indicated, ultrasoundindicated and physical examination-indicated occlusion cerclage. It is our view that occlusion sutures should not be placed outside of a clinical trial, until there is research to support their use. It would be irresponsible to do so given the poor evidence supporting cerclage in general. Observational data are always confounded by the high success rates independent of any intervention, and should not dictate practice in this crucial area.

Fig 39.7 Transvaginal ultrasound showing a history-indicated cervical cerclage inserted by the McDonald technique.

insertion is largely left to the clinician’s discretion. However, it does have good prognostic value, and it is our experience that women find it very reassuring.

Who should have a transabdominal cerclage? Transabdominal cerclage is sometimes inserted following a failed vaginal cerclage or extensive cervical surgery, although the evidence base is limited to case series and one controlled, non-randomised trial.100 There is an increased incidence in birth after 35 weeks with a transabdominal versus transvaginal cerclage (82% versus 58%) in women with a previous failed vaginal cerclage. In previously published retrospective cohorts of a total of 306 pregnancies where most women had only one previous loss, foetal survival was between 60 and 100%.101 A randomised controlled trial comparing transabdominal versus transvaginal cerclage in women with a previous failed vaginal cerclage is ongoing.

Adjuvant management Following cerclage insertion, transvaginal cervical length assessment is useful to determine whether there is progressive shortening despite cerclage placement (Fig 39.7). The outcome is usually good if there is remodelling of the cervix with an increase in length following cerclage insertion. A cervical length of <25 mm and <1 cm above the cerclage are good predictors of PTB,73 and better than the total cervical length. Although there is no available evidence to suggest benefit of interventions for worsening cervical length following cerclage insertion, some obstetricians consider the use of progesterone, indomethacin, hospital admission, activity restriction and/or bedrest and fFN testing after 23 weeks’ gestation to time delivery of antenatal steroids. As there are no proven adjuvant therapies to improve outcome in this clinical scenario, frequent ultrasound surveillance following cerclage

Removal of cervical cerclage McDonald and Shirodkar transvaginal cervical cerclages may be removed electively between 36 and 37 weeks’ gestation, when the risk of spontaneous labour remains low. A McDonald cerclage is usually removed without an anaesthetic by exposing the cervix and cutting the suture at any of the points where it is visible. A Shirodkar cerclage usually requires an anaesthetic for ease of removal. A patient with a transabdominal cervical cerclage is usually booked for a Caesarean section at 38–39 weeks’ gestation and the cerclage left in situ for future pregnancies. If this needs to be removed, this can be done at the time of Caesarean section or via a posterior colpotomy, but often will be left in situ for future pregnancies. Women with a cerclage in situ are advised to seek medical attention early if they suspect labour so that the cerclage can be removed early to avoid cervical trauma. In women with PPROM between 22 and 31 weeks, the risk of intrauterine and subsequent foetal infection, must be considered. At less than 22 weeks, the decision to remove a cerclage is very difficult as the probability of poor outcome of a periviable infected neonate must be considered and extensive discussion with the woman is imperative in decision-making so she understands the risks and feels cared for in the process. After 32 weeks’ gestation, neonatal outcome is usually good and it may be easier to make a decision to remove the cerclage in light of PPROM. Initial concern regarding high maternal risk with cerclage in situ with PPROM proved unfounded, but given the lack of evidence in benefit of maintaining the suture in situ in this situation, we have a low threshold for removal.

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Table 39.1 Preterm birth (PTB) prediction by cervical length in high-risk asymptomatic women. Primary outcome is PTB at <35 weeks’ gestation. Values are for singleton gestations.41

Included women

Gestational age at cervical assessment (weeks)

Cervical length (mm)

Positive predictive value

Relative risk

16–24 14–23+6 14–24 16–24 16–24

25 25 25 25 25

55 50 48 35 22

4.5 13.5 2.2 2.5 10.2

Previous PTB Uterine anomalies Repeated D&C Knife cone biopsy LEEP

D&C, dilatation and curettage; LEEP, loop electrosurgical procedure.

Delivery Although it is difficult to diagnose intrapartum hypoxia on cardiotocography below 26 weeks’ gestation, after this point, normal obstetric management is appropriate. A vaginal breech delivery of a preterm infant may be considered. In the case of a previous preterm Caesarean delivery, there is an increased risk of uterine rupture compared with previous term Caesarean section,102 and this must be taken into account when considering vaginal birth after Caesarean section.

Post-pregnancy counselling A term pregnancy following a prior preterm pregnancy has a recurrent risk of PTB of only 13%.16 As a result, we do not routinely recommend screening women with transvaginal ultrasound for cervical length or insertion of a history-indicated cerclage on an elective basis unless they have undergone extensive cervical surgery in the interim. It is important to clarify the indication for previous cerclage insertion. If it was inserted inappropriately and she achieved a term pregnancy, it may be reasonable not to repeat the procedure in the index pregnancy. Most high-risk women will have a term pregnancy without a cerclage, even with a previous “successful” cerclage. In this scenario, cervical scanning may reassure the clinician. Discussing pregnancy events especially in light of a very preterm birth is invaluable for the woman and this allows a plan to be formulated for subsequent pregnancies. Issues regarding modifiable behaviour such as BMI, interpregnancy interval, smoking, use of illicit substances and domestic abuse should be highlighted in post-pregnancy counselling.

References 1. McCormick MC. The contribution of low birth weight to infant mortality and childhood morbidity. N Engl J Med 1985; 312: 82–90. 2. Moser K, Macfarlane A, Chow YH et al. Introducing New Data on Gestation-specific Infant Mortality Among Babies Born in 2005 in England and Wales. London: Office of National Statistics, 2007.

3. Goldenberg RL, Culhane JF, Iams JD et al. Epidemiology and causes of preterm birth. Lancet 2008; 371: 75–84. 4. 8th Annual Report: Confidential Enquiries into Stillbirths and Deaths in Infancy (CESDI). London: Maternal and Child Health Research Consortium (MCHRC), 2001. 5. Bennett P. Preterm labour. In: Edmonds DK, ed. Dewhurst Textbook of Obstetrics and Gynaecology, 7th edn. London: Blackwell, 2007: 177–191. 6. CDC 2005: Preliminary Births for 2004. http:// www.cdc.gov/nchs/product/pubs/pubd/hcstats/pr elimbirths04/prelimbirths 7. Laroque B, Ancel PY, Marret S et al. Neurodevelopmental disabilities and special care of 5year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 2008: 371: 813–20. 8. Romero R, Espinoza J, Mazor M et al. The preterm parturition syndrome. In Preterm Birth, 1st edn (Critchley H, Bennett P, Thornton S, eds). London: RCOG Press, 2004: 28–60. 9. Chandiramani M, Shennan AH. Preterm labour: update on prediction and prevention strategies. Curr Opin Obstet Gynecol 2006; 18: 618–24. 10. Macones GA, Parry S, Elkousy M et al. A poly morphism in the promoter region of TNF and bacterial vaginosis: preliminary evidence of geneenvironment interaction in the aetiology of spontaneous preterm birth. Am J Obstet Gynecol 2004; 190: 1504–8. 11. Romero R, Espinoza J, Erez O et al. The role of cervical cerclage in obstetric practice: can the patient who could benefit from this procedure be identified? Am J Obstet Gynecol 2006; 194: 1–9. 12. Hassan SS, Romero R, Berry SM et al. Patients with an ultrasonongraphic cervical length ≤15 mm have nearly a 50% risk of early spontaneous preterm delivery. Am J Obstet Gynecol 2000; 182: 1458–67. 13. Groom KM, Shennan AH, Bennett PR. Ultrasoundindicated cervical cerclage: outcome depends on preoperative length and presence of visible membranes at the time of cerclage. Am J Obstet Gynecol 2002; 187: 445–9. 14. Lidegaard O. Cervical incompetence and cerclage in Denmark 1980–1990: a register-based epidemiological survey. Acta Obstet Gynecol Scand 1994; 73: 35–8.

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32. Rodrigues T, Barros H. Short interpregnancy interval and risk of spontaneous preterm delivery. Eur J Obstet Gynecol Reprod Biol 2008; 136: 184–8. 33. Active and passive maternal smoking during pregnancy and the risks of low birthweight and preterm birth: the Generation R Study. Paediatr Perinat Epidemio 2008; 22: 162–71. 34. Rodrigues T, Rocha L, Barros H. Physical abuse during pregnancy and preterm delivery. Am J Obstet Gynecol 2008; 198: 171.e1–6. 35. Yost NP, Owen J, Berghella V et al. Effect of coitus on recurrent preterm birth. Obstet Gynecol 2006; 107: 793–7. 36. Harger JH. Cerclage and cervical insufficiency: an evidence-based analysis. Obstet Gynecol 2002; 100: 1313–27. 37. Anthony GS, Walker RG, Robins JB et al. Management of cervical weakness based on the measurement of cervical resistance index. Eur J Obstet Gynecol Reprod Biol 2007; 134: 174–8. 38. De Santis M, Cavaliere AF, Straface G et al. Inherited and acquired thrombophilia: pregnancy outcome and treatment. Reprod Toxicol 2006; 22: 227–33. 39. Robertson L, Wu O, Langhorne P et al. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132: 171–96. 40. Smith V, Devane D, Begley CM et al. A systematic review and quality assessment of systematic reviews of fetal fibronectin and transvaginal length for predicting preterm birth. Eur J Obstet Gynecol Reprod Biol 2007; 133: 134–42. 41. Grimes-Dennis J, Berghella V. Cervical length and prediction of preterm delivery. Curr Opin Obstet Gynecol 2007; 19: 191–5. 42. Iams JD, Goldenberg RL, Meis PJ et al. The length of the cervix and the risk of spontaneous premature delivery. N Engl J Med 1996; 334: 567–72. 43. To MS, Alfirevic Z, Heath VCF et al. Cervical cerclage for prevention of preterm delivery in women with a short cervix: randomised controlled trail. Lancet 2004; 363: 1849–53. 44. Fonseca EB, Celik E, Parra M et al. Progesterone and the risk of preterm birth among women with a short cervix. N Engl J Med 2007; 357: 462–9. 45. Owen J, Yost N, Berghella V et al. Mid-trimester endovaginal sonography in women at high risk for spontaneous preterm birth. JAMA 2001; 286: 1340–8. 46. Berghella V, Obido AO, To MS et al. Cerclage for a short cervix on ultrasound: meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005; 106: 181–9. 47. Berghella V, Roman A, Daskalakis et al. Gestational age at cervical length measurement and incidence of preterm birth. Obstet Gynecol 2007; 110: 311–17. 48. Leitich H, Brunbauer M, Kaider A et al. Cervical length and dilatation of the internal cervical os detected by vaginal ultrasonography as markers for preterm delivery: a systematic review. Am J Obstet Gynecol 1999; 181: 1465–72. 49. Guzman ER, Walters C, Ananth CV et al. A comparison of sonographic cervical parameters; predicting spontaneous preterm birth in high-risk singleton pregnancies. Ultrasound Obstet Gynecol 2001; 18: 204–10.

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Cervical cerclage and pregnancy loss 50. Goldenberg RL, Iams JD, Miodovnik M et al. The Preterm Prediction study: risk factors in twin gestations. Am J Obstet Gynecol 1996; 175: 1047–53. 51. Kusanovic JP, Espinoza J, Romero R et al. Clinical significance of the presence of amniotic fluid ‘sludge’ in asymptomatic patients at high risk for spontaneous preterm delivery. Ultrasound Obstet Gynecol 2007; 30: 706–14. 52. Rust OA, Atlas RO, Kimmel S et al. Does the presence of a funnel increase the risk of adverse perinatal outcome in a patient with a short cervix? Am J Obstet Gynecol 2005; 192: 1060–6. 53. Peaceman AM, Andrews WW, Thorp JM et al. Fetal fibronectin as a predictor of preterm birth in patients with symptoms: a multicenter trial. Am J Obstet Gynecol 1997; 177: 13–18. 54. Shennan A, Jones G, Hawken J et al. Fetal fibronectin test predicts delivery before 30 weeks of gestation in high risk women, but increase anxiety. BJOG 2005; 112: 293–8. 55. Goldenberg RL, Iams JD, Das A et al. The Preterm Prediction Study: sequential cervical length and fetal fibronectin testing for the prediction of spontaneous preterm birth. Am J Obstet Gynecol 2000; 182: 636–43. 56. Schmitz T, Maillard F, Bessard-Bacquaert S et al. Selective use of fetal fibronectin detection after cervical length measurement to predict spontaneous preterm delivery in women with preterm labour. Am J Obstet Gynecol 2006; 194: 138–43. 57. National Institute for Clinical Excellence. NICE Guideline CG6 Antenatal Care – Routine Care for the Healthy Pregnant Woman. London: NICE, 2003. 58. Lamont RF. Can antibiotics prevent preterm birth – the pro and con debate. BJOG 2005: 112: 67–73. 59. McDonald H, Brocklehurst P, Parsons J. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev 2005: CD000262. 60. Okum N, Gronau KA, Hannah ME. Antibiotics for bacterial vaginosis or Trichomonas vaginalis in pregnancy: a systematic review. Obstet Gynecol 2005; 105: 857–68. 61. Larsson P-G, Bergstrom M, Forsum U et al. Bacterial vaginosis. Transmission, role in genital tract infection and pregnancy outcome: an enigma. Review article III. APMIS 2005; 113: 233–45. 62. Varma R, Gupta JK. Antibiotic treatment of bacterial vaginosis in pregnancy: multiple meta-analyses and dilemmas in interpretation. Eur J Obstet Gynecol Reprod Biol 2006; 124:10–14. 63. Larsson P-G, Fahraeus L, Carlsson B et al. Late miscarriage and preterm birth after treatment with clindamycin: a randomised consent design study according to Zelen. BJOG 2006: 113: 629–37. 64. Klebanoff MA, Hillier SL, Nugent RP. Is bacterial vaginosis a stronger risk factor for preterm birth when it is diagnosed earlier in gestation. Am J Obstet Gynecol 2005; 192: 470–7. 65. Andrew WW, Klebanoff MA, Thome EA et al. Midpregnancy genitourinary tract infection with Chlamydia trachomatis: association with subsequent preterm delivery in women with bacterial vaginosis and Trichomonas vaginalis. Am J Obstet Gynecol 2006; 194: 493–500. 66. Daskalakis G, Papapanagiotou A, Mesogitis S et al. Bacterial vaginosis and group B streptococcal

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colonization and preterm delivery in a low-risk population. Fetal Diagn Ther 2006; 21: 172–6. Guerra B, Ghi T, Quarta S et al. Pregnancy outcome after early detection of bacterial vaginosis. Eur J Obstet Gynecol Reprod Biol 2006; 128: 40–5. Hendler I, Andrews WW, Carey CJ et al. The relationship between resolution of asymptomatic bacterial vaginosis and spontaneous preterm birth in fetal fibronectin-positive women. Am J Obstet Gynecol 2007; 197: 488.e1–5. Simcox R, Sin WT, Seed PT et al. Prophylactic antibiotics for the prevention of preterm birth in women at risk: a meta-analysis. Aust N Z J Obstet Gynecol 2007; 47: 368–77. Shennan AH, Crawshaw S, Briley A et al. A randomised controlled trial of metronidazole for the prevention of preterm birth in women positive for cervicovaginal fetal fibronectin: the PREMET Study. BJOG 2006; 113: 65–74. Morency A, Bujold E. The effect of secondtrimester antibiotic therapy on the rate of preterm birth. J Obstet Gynaecol Can 2007; 29: 35–44. Carey JC, Klebanoff MA. Is a change in the vaginal flora associated with an increased risk of preterm birth? Am J Obstet Gynecol 2005; 192: 1341–7. Berghella V, Seibel-Seamon J. Contemporary use of cervical cerclage. Clin Obstet Gynecol 2007; 50: 468–77. Zaveri V, Aghajafari F, Amankwah K et al. Abdominal versus vaginal cerclage after a failed transvaginal cerclage: a systematic review. Am J Obstet Gynecol 2002; 187: 868–72. Odibo AO, Berghella V, To MS et al. Shirodkar versus McDonald cerclage for the prevention of preterm birth in women with short cervical length. Am J Perinatol 2007; 24: 55–60. Agameya AF, Sallam HN, Sallam AN et al. Double cervical cerclage: a successful option in patients with a previously failed Shirodkar’s suture. Fertil Steril 2006; 85: 13. Berghella V, Obido AO, To MS et al. Cerclage for short cervix on ultrasound: meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005; 106: 181–9. Berghella V, Rust OA, Althuisius SM. Short cervix on ultrasound: does indomethacin prevent preterm birth? Am J Obstet Gynecol 2006; 195: 809–13. Visintine J, Airoldi J, Berghella V. Indomethacin administration at the time of ultrasound-indicated cerclage: is there an association with a reduction in spontaneous preterm birth? Am J Obstet Gynecol 2008; 198: 643.e1–e3. Groom KM, Jones BA, Edmonds DK et al. Preconception transabdominal cervicoisthmic cerclage. Am J Obstet Gynecol 2004; 191: 230–4. Reid GD, Wills HJ, Shukla A et al. Laparoscopic transabdominal cervico-isthmic cerclage: a minimally invasive approach. Aust N Z J Obstet Gynaecol 2008; 48: 185–8. Carter JF, Soper DE. Laparoscopic abdominal cerclage. JSLS 2005; 9: 491–3. Mingione MJ, Scibetta JJ, Sanko SR et al. Clinical outcomes following interval laparoscopic transabdominal cervico-isthmic cerclage placement: case series. Hum Reprod 2003; 18: 1716–19.

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84. MRC/RCOG Working Party on Cervical Cerclage. Final Report of the Medical Research Council/ Royal College of Obstetricians and Gynaecologists Multicentre Randomized Trial of Cervical Cerclage. Br J Obstet Gynaecol 1993; 100: 516–23. 85. Rush RW, Isaacs S, McPherson K et al. A randomized controlled trial of cervical cerclage in women at high risk of preterm delivery. BJOG 1984; 91: 724–30. 86. Lazar P, Guerguen S, Dreyfuss J et al. Multicentre controlled trial of cervical cerclage in women at moderate risk of preterm delivery. BJOG 1984; 91: 731–5. 87. Woensdregt K, Norwitz ER, Cackovic M et al. Effect of 2 stitches vs 1 stitch on the prevention of preterm birth in women with singleton pregnancies who undergo cervical cerclage. Am J Obstet Gynecol 2008; 198: 396.e1–7. 88. Berghella V, Obido AO, To MS et al. Cerclage for a short cervix on ultrasound: meta-analysis of trials using individual patient-level data. Obstet Gynecol 2005; 106: 181–9. 89. Jorgensen A, Alfirevic Z, Tudur Smith C et al. Cervical stitch (cerclage) for preventing pregnancy loss: individual patient data meta-analysis. BJOG 2007; 114: 1460–76. 90. Althuisius SM, Dekker GA, van Geijn HP et al. Cervical incompetence prevention randomized cerclage trial (CIPRACT): study design and preliminary results. Am J Obstet Gynecol 2000; 183: 823–9. 91. Kelly S, Pollack M, Maas B et al. Early transvaginal ultrasonography versus early cerclage in women with an unclear history of incompetent cervix. Am J Obstet Gynecol 2001; 184: 1097–9. 92. To MS, Palaniappan V, Skentou C et al. Elective cerclage vs ultrasound-indicated cerclage in highrisk pregnancies. Ultrasound Obstet Gynecol 2002; 19: 475–7.

93. Berghella V, Haas S, Chervoneva I et al. Patients with prior second-trimester loss: Prophylactic cerclage or serial transvaginal sonograms? Am J Obstet Gynecol 2002; 187: 747–51. 94. Lipitz S, Libshitz A, Oelsner G et al. Outcome of second-trimester emergency cervical cerclage in patient with no history of cervical incompetence. Am J Perinatol 1996; 13: 419–22. 95. MacDougall J, Siddle N. Emergency cervical cerclage. Br J Obstet Gynaecol 1991; 98: 1234–8. 96. Althuisius SM, Dekker GA, Hummel P et al. Cervical incompetence prevention randomized cerclage trial: emergency cerclage with bed rest versus bed rest alone. Am J Obstet Gynecol 2003; 189: 907–10. 97. Olatunbosun OA, Al-Nuaim L, Turnell RW. Emergency cerclage compared with bed rest for advanced cervical dilatation in pregnancy. Int Surg 1995; 80: 170–4. 98. Yip SK, Fung HYM, Fung TY. Emergency cervical cerclage: a study between duration of cerclage in situ with gestation at cerclage, herniation of forewater, and cervical dilatation at presentation. Eur J Obstet Gynaecol Reprod Biol 1998; 78: 63–7. 99. Secher NJ, McCormack CD, Weber T et al. Cervical occlusion in women with cervical insufficiency: protocol for a randomised, controlled trial with cerclage, with and without cervical occlusion. BJOG 2007; 114: 649–e6. 100. Davis G, Berghella V, Talucci M et al. Patients with a failed transvaginal cerclage: a comparison of obstetric outcomes with either transabdominal or transvaginal cerclage. Am J Obstet Gynecol 2000; 183: 836–9. 101. Debbs RH, De La Vega GA, Pearson S et al. Transabdominal cerclage after comprehensive evaluation of women with previous unsuccessful transvaginal cerclage. Am J Obstet Gynecol 2007; 197: 317.e1–4. 102. Sciscione AC, Landon MB, Leveno KJ et al. Previous preterm caesarean delivery and risk of subsequent uterine rupture. Obstet Gynecol 2008; 111: 648–53.

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40 Are pregnancies conceived by IVF ‘high risk’? CE Fox, MD Kilby

Ovulation induction agents have been prescribed since the mid-1960s and in vitro fertilisation (IVF) was introduced in the 1970s. Since that time techniques have been further developed but the aim of achieving high rates of live birth has endured. Over the past few decades, therefore, it has been common place for obstetricians to manage pregnancies conceived “artificially” and to have to cope with some of the problems and potential problems associated with the maternal characteristics of such pregnancies and the pregnancies conceived using these techniques. IVF is the most commonly performed assisted reproductive technique (ART) and in the majority of cases results in a singleton pregnancy. However, it is still associated with higher rates of multiple pregnancy than are achieved through spontaneous conception and it is a misconception that such techniques are associated with an increased risk of dizygotic pregnancy. Indeed, the association of monozygotic twinning and higher order pregnancies is resulting in significant foetal morbidity and mortality in early pregnancy. The Human Fertilisation and Embryology Authority (HFEA) has indicated that approximately one in four births following IVF is a multiple pregnancy1 compared with “background” risk of 1 in 67 overall.2 In some quarters this used to be considered a desirable and cost effective outcome of subfertility treatment but over recent years opinion has shifted and focused upon rates of pregnancy loss and perinatal morbidity associated with such events. By definition this precludes the occurrence of multiple births which are associated with a three- to seven-fold increase in maternal complications and a four- to ten fold increase in perinatal morbidity and mortality.3 Notwithstanding this fact there is also evidence to suggest that singleton births associated with IVF treatment are also at an increased risk of complications. This may represent a fundamental difference in the subset of the population who undergo IVF or indeed the influence of the ART itself. This chapter briefly considers these issues and discusses how pregnancies following IVF should be managed. Subfertility increases with advancing maternal age resulting in a higher representation of women over

the age of 30 seeking investigation and ART than in the general background population. In addition, these women (and their partners) are more likely to require complex therapies to achieve a pregnancy, including the use of IVF and embryo transfer. Unfortunately, the risks of multiple pregnancy increase with an increase in maternal age4 and parity, and with the transfer of a higher number of embryos.5 As maternal age is outside the control of the ART fraternity, consideration should be given to the avoidance of multiple births by adaptation of ART. As stated previously, the number of embryos transferred after IVF is related to an increased risk of multiple birth. Initial IVF practice involved the transfer of multiple embryos (usually at least two embryos) to ensure increased pregnancy rates, albeit with the associated risk of multiple births. Over the intervening decades, it has been recognised that such practice may be associated with increased maternal risks (i.e. hyperstimulation syndrome) and foetal morbidity and mortality (i.e. miscarriage, preterm delivery and associated rarer risks of monochorionic multiple pregnancy). This has led to a recommended change in practice, so that the emphasis is on healthy pregnancy and birth. But such initiatives have not been embraced worldwide and are still controversial. However, audit and scrutiny by the worldwide community of experts involved in subfertility care has led to modification of techniques depending on the mother’s likelihood of successful treatment. There is little evidence from high quality trials regarding the optimum number of embryos that should be transferred but analyses of large datasets both in the United Kingdom and the United States has led to a recommended change in practice, with lower numbers of embryos being transferred post-IVF.5,6 These data suggest that in young women high pregnancy rates could be achieved by transferring two embryos instead of three, thus reducing the risk of triplets. Furthermore, there is an increasing move towards single embryo transfer. It is still commonplace for pregnancies conceived after subfertility treatment to be associated with multiple pregnancies. In an attempt to reduce the complications

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of multiple pregnancy, not least to reduce the gestational age of delivery and therefore to reduce perinatal morbidity and mortality. Such techniques include selective foetal reduction (in high order pregnancies) and either single blastocyst or embryo transfer. Selective foetal reduction, although of recognised benefit in higher order multiple pregnancies,7 raises acceptability issues on the part of both the parents and the healthcare professionals in twin pregnancies.8 Also, such techniques involve transuterine needling procedures with inherent risks of procedure related pregnancy loss and emotional sequalae. Blastocyst transfer availability is not widespread and can compromise the pregnancy rates by restricting the number of embryos available for transfer. However, elective single embryo transfer (eSET) has been recommended by the European Society for Human Reproductive Embryology9 and is now the mainstay of treatment in many European countries (e.g. Finland, Sweden). The HFEA has issued guidance that use of single embryo transfer in suitable patients can reduce the risk of twinning due to IVF from its current rate of 40% to 10%, and this is supported by research in Finland.10 To this end, by 2009, it has been recommended that all United Kingdom clinics offering such treatment will be required to implement a protocol to lower their multiple birth rates. Similarly guidelines from the American Society of Reproductive Medicine (ASRM) suggest that single embryo transfer should be considered in patients under the age of 35 years.11 Recent data from the Society for Assisted Reproductive Technology (SART) have demonstrated that the average number of embryos transferred in this group was 2.3 and only 3.3% of cycles utilised eSET.12 Nationwide policy is often a reflection of the proportion of treatment that is self-funded where success is seen in terms of the number of live births per cycle. Until the “mind-set” of both patients and clinicians shifts to success reflecting healthy rather than simply number of births then the problem of managing complications of IVF conception relating to multiple pregnancy will persist. It is essential that all couples are counselled both prior to undertaking ART and again if multiple pregnancy is diagnosed as to the associated risks to the family that the pregnancy involves as well as the possible management strategies available. Although strategies to reduce multiple births are gaining acceptability it is still commonplace for multiple pregnancies to occur, therefore the management of these pregnancies in order to reduce the inherent risks is paramount. This begins with early recognition of those pregnancies which are multiples, and the determination of chorionicity if a multiple pregnancy is diagnosed. Once a positive pregnancy test has been achieved, an early ultrasound scan (5–6 weeks) is routinely performed to monitor the ongoing success of the IVF treatment. If a multiple pregnancy is diagnosed protocols should be in place for timely referral to a suitable obstetric care facility where the pregnancy can be managed. The majority of multiple births after IVF treatment are

twins (24.7% vs. 4.2% vs. 0.2%, twins vs. triplets vs. quadruplets, respectively),13 which can be either monozygotic (MZ) or dizygotic (DZ). Dizygotic twins will always be dichorionic (DC), whereas monozygotic twins can be mono- or dichorionic depending on the timing of the zygote splitting. The importance of an early ultrasound (between 11 and 13 weeks) to determine chorionicity reflects the higher incidence of complications in monochorionic (MC), as opposed to dichorionic, twinning, which in turn dictates the level of monitoring the pregnancy requires. However, there is controversy as to the frequency of ultrasound surveillance and there are no high quality data to inform this question. There is some controversy as to whether IVF treatment increases the rate of monochorionic twinning. The vast majority of twinning after IVF is DZ, largely due to dual embryo transfer, but an increase in the MZ rate has been reported with all forms of ART.14–17 This increase is important as MC twins are at increased risk of both morbidity and mortality.18 In fact, foetal mortality in MC twinning is at least two-to three-fold higher than DC twins at approximately 10–25%.19 There are many reasons why this difference exists but the presence of a single placental mass and connecting angioarchitecture within the placenta between twins is highly significant. Almost all MC placentas have vascular anastomoses20 and it is these connections that facilitate the development of twin–twin transfusion syndrome (TTTS) and the features seen with an acardiac twin. TTTS occurs in approximately 10–15% of MC twin pregnancies21 and results from a chronic imbalance of intertwin haemodynamics and blood flow.22 This leads to the development of the characteristic phenotype of polyhydramnios/oligohydramnios, with underlying central circulatory dysfunction between the twin pair. Without treatment this condition carries a foetal mortality rate of 80– 90%.23,24 Conversely, it is the presence of intertwin anastomoses that allows perfusion, and therefore early survival of the acardiac twin in the rarer twin reversed arterial perfusion (TRAP) syndrome and other anomalies of twin separation (i.e. conjoining). However, this syndrome also rapidly results in circulatory decompensation and then intrauterine foetal death of the acardiac twin with a variable outcome for the pump twin. For this reason, it is recommended that multiple pregnancies have increased surveillance compared to singleton pregnancies and indeed there is a move towards management in dedicated clinics. It is worth remembering that most conceptions, spontaneous and assisted, result in a singleton pregnancy. Similarly it is true that there is a risk of spontaneous miscarriage regardless of the method of conception and that this risk increases with age.25 Early IVF data suggested that there was a high rate of pregnancy loss, 27– 43% in IVF pregnancies,26,27 in comparison with 13.5% in the general population.25 Early detection and more intensive monitoring in IVF pregnancies may go some

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way to explain this difference as a study looking at early pregnancy loss in fertile individuals, which used daily urinary testing, suggested that pregnancy loss was 31%.28 This difference may also represent the older maternal age in the IVF cohort but notwithstanding this difference other studies have shown that the rate of spontaneous loss in ART is similar to that seen in the general population at 14.7%.29 Interestingly, one study reported higher rates of spontaneous loss in singletons than with twins and triplets (20.4% vs. 7.5% vs. 5%, respectively). This study reported complete pregnancy loss not the loss rate per implanted embryo and further analysis in the multiples group confirmed that one or more embryos was often lost before delivery.29 Such data interpretation could allow the lower incidence of complete pregnancy loss in the multiple pregnancies to skew the overall incidence in favour of IVF. However, although studies have confirmed that the risk of early pregnancy loss is similar to that in the general population, the trend is towards marginally higher rates after IVF. This was quantified by Wang et al as an agecontrolled relative risk of 1.2 and that the risk was found to persist from the first to the second trimester, with the ART cohort twice as likely to have a spontaneous loss in the second trimester as controls.30 Although studies have reported pregnancy loss risks stratified for maternal age, other factors, such as the number of previous spontaneous losses, have also been shown to increase the risk.30 Interestingly it has been shown that where IVF is utilised, maternal age greater than 45 is associated with a higher rate of pregnancy loss even if donor oocytes are used.31 We must therefore consider treatment related factors. The risk of spontaneous abortion is highest when treatment was by IVF and lowest in those treated by gamete intra-Fallopian transfer (intracytoplasmic sperm injection (ICSI) showed intermediate risk). Other treatment related factors have also been studied and there is a significant trend noted between low level stimulation and lower level of loss and vice versa.30 Half of all miscarriages are thought to be secondary to a chromosome abnormality32 and, therefore, it is impossible to generalise about the factors influencing rate of pregnancy loss without considering how this may be affected by ART. The risk of foetal aneuploidy is influenced by maternal age due to the increased occurrence of meiotic non-disjunction.33 As those undergoing IVF represent an older subset of the reproductive population it is logical to assume that IVF would be associated with an increased risk of aneuploidy. Notwithstanding this fact, there have been concerns that ART themselves could be a risk factor associated with aneuploidy. Such concerns, at least in part, are supported by a study that found a high incidence of aneuploidy and mosaicism in young women undergoing IVF.34 However, ex vivo murine data examining the techniques of IVF, ICSI and round spermatid injection, were reassuring, indicating that genetic integrity was unaffected by these ART

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techniques.35 Concerns surrounding the introduction of micromanipulation techniques such as ICSI relate to the higher rate of chromosome abnormalities in the sperm of men with impaired spermatogenesis.36 Although the risk is reported to be relatively small, there epidemiology data note an increased risk of karyotypic abnormalities in ICSI offspring.37 Similarly, hormonal regimens and temperature changes at the time of fertilisation have been linked to an increase in chromosome abnormalities.38–41 The significance for the patient lies in the likelihood of the anomaly causing spontaneous pregnancy loss or a poor outcome for the pregnancy. To this end it has been suggested that pre-implantation genetic screening (PGS) would be of benefit to those at high risk of chromosome aberrations, for example women over 35 or men with impaired spermatogenesis. However, a recent randomised controlled trial has reported the opposite. It found that PGS, performed for advanced maternal age, was associated with a reduction in the rate of ongoing pregnancies and live births.42 There is also concern as to the sensitivity and specificity of PGS in reliably diagnosing aneuploidy prior to implantation and experts in many countries will consider foetal karyotyping in cases judged to be “high risk”, even if PGS has previously indicated low risk. As well as early pregnancy failure, aneuploidy and risks of multiple pregnancies there are other factors that have been associated with pregnancies conceived by ART. Some early reports suggested an increase in congenital anomalies by comparison of IVF pregnancies with the general population,43,44 whereas other studies have not confirmed these findings.44 There are methodological problems comparing IVF populations with the general pregnant population (due to differences in demographics) but a recent systematic review where analysis was restricted to singletons born at term, and adjustments made for parity, maternal age, sex of the infant, and correlation of the risk of birth defects between siblings ART foetuses were twice as likely to have congenital anomalies.46 Such conclusions are controversial and other studies have not demonstrated such a clear association and suggested that congenital anomalies were increased in singletons whereas multiples had a decreased risk.47 Stratification of results by gender and plurality has demonstrated an increased risk of congenital malformations in the cohort of singleton boys and a decreased risk for multiple girls. This increased risk for singleton boys may be partly accounted for by the inclusion of hypospadias as this has been shown to occur more frequently in IVF babies.47,48 Again, such findings are not universal and other studies have demonstrated no significant difference in congenital anomalies between the groups,49 even in matched singletons50 and particularly no increase in urogenital system malformation.51 It is also suggested that the small increase in congenital malformation, in some series, is attributable to differences in maternal characteristics as

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opposed to IVF itself. The odds ratio (OR) for congenital anomalies in IVF was 1.2 but improved to 1.03 when the data were corrected for maternal age, parity and ethnicity.51 Overall there is no agreement in the literature but a trend does seem to be evident towards an increase risk of congenital abnormalities. However, more research is needed to decide whether infertility or its treatment is the risk factor for congenital abnormalities.52 Irrespective of clinicians’ beliefs, it is imperative that these potential risks be explained to patients and that in pregnancies conceived by ART a detailed scan is performed between 18 and 24 weeks, as a minimum standard. Pregnancy outcomes after IVF, in terms of live birth rate, as related to assisted conception technique used have been extensively researched and maternal and perinatal outcomes have also been heavily scrutinised and various trends observed. These can and should influence the way we manage pregnancies conceived by ART, although it is apparent that in many areas controversy and uncertainty exists. When considering any data regarding perinatal outcome it is important to control for possible confounding variables, such as maternal age, parity and plurality (i.e. multiple pregnancy) as the incidence of pregnancy complications are known to differ with these variables.53–55 On this basis some studies suggest that when these confounders are controlled for no differences exist between spontaneous and assisted conception pregnancy outcomes.56 However, other studies have indicated that prenatal morbidities are increased in IVF pregnancies including the risk of threatened miscarriage, gestational diabetes and pregnancy induced hypertension.57 Risk of threatened miscarriage is thought to be increased predominantly in the first trimester but has been found to be significantly more prevalent in all trimesters (in the form of antepartum haemorrhage), as demonstrated by cohort studies50,58,59 and confirmed by a larger systematic review and meta-analysis.60 It is obviously important to inform patients that this may occur but also this is likely to generate more frequent antenatal surveillance, including regular ultrasound examination to exclude serious pathology such as placenta praevia or placental abruption.29,61–63 Such associations have been the focus of discussion as to why admission is more common in pregnancies conceived by ART.61 Other reasons linked to an increase in antenatal admission have been maternal hypertension/pre-eclampsia,61 but there is no agreement in the literature as to whether IVF is an independent risk factor for the development of preeclampsia/pregnancy induced hypertension. With the uncertainty displayed from the literature it confirms the importance of regular antenatal surveillance of women whose pregnancies are conceived by ART and regular blood pressure monitoring and urinalysis, not just those with multiple pregnancies who are known to have an increased risk of these maternal morbidities. Again, it reinforces the importance of detailed counselling prior

to commencement of ART treatment so that the couple are aware of possible maternal and perinatal complications. Serial ultrasound scanning is commonplace in multiple pregnancies, regardless of chorionicity, due to the increased risk of discordant foetal growth and intrauterine growth restriction, a situation with an incidence not significantly different between monochorionic and dichorionic pregnancies. There is some evidence to suggest that singleton pregnancies resulting from IVF conception are also at increased risk of growth restriction, perhaps secondary to increased risks of malplacentation. Originally, the increase in “low birth weight” babies after IVF pregnancy was largely thought to be attributable to the increased incidence of multiple births.45 However, further epidemiological data have shown that IVF is associated with an increase in small for gestation babies in singletons, rather than multiples that are at no greater risk than spontaneously conceived twins.63 The risk of low birth weight (less than 2500g) in IVF singletons is thought to 2.6 times that seen in spontaneous singletons and this excess risk is also seen in relation to very low birth weight (less than 1500g).63 These findings are confirmed by a number of studies, including a large meta-analysis60 but do not give any insight into the underlying cause. However, a large study suggested that incidence of very low birth weight is higher in IVF rather than ICSI pregnancies, 5.7% vs. 4.4%,64 but even higher after oocytes donation, 14.9%.65 This is important as it has been shown that low birth weight infants are at increased risk of dying in early infancy and that those who survive are more likely to suffer long-term medical problems.66 Unsurprisingly, admission to the neonatal intensive care unit and length of neonatal care mirror the findings of small for gestational age pregnancy.50,67 This is in no small part because of the risk of premature labour, especially in multiple gestation pregnancies. Perinatal outcome is dependent on a multitude of factors, of which birth weight is a significant contributor. Research looking at the influence of birth weight has also highlighted other factors related to perinatal outcome and found that IVF pregnancies tend to result in delivery earlier than spontaneous pregnancies. This is most often still around term, but a few days earlier;50 however, worryingly there are more premature deliveries (spontaneous and iatrogenic) in IVF pregnancies. Singleton pregnancies conceived by IVF are more likely to be born prematurely (less than 37 completed weeks), even after stratification for maternal age and parity44,68 and a large meta-analysis of epidemiological studies appears to confirm these findings.60 It has also been demonstrated that the risk of extreme prematurity (birth at less than 32 weeks) is significantly increased in these pregnancies,44,45 and confirmed by a large systematic review.67 These data noted a trend of prematurity being more common in ICSI than IVF (31.8% vs. 29.3%), although the trend was worryingly high for both compared to spontaneous conceptions.64 The risk has

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also been noted to be lower after oocyte donation at 14.9%.65 Overall perinatal mortality is reduced in ART twins in comparison with spontaneous twins.69 To influence outcome of pregnancies conceived by ART, it is necessary to consider why the incidence of prematurity and intrauterine growth restriction is increased after such therapies. It has been suggested that pre-conceptional factors related to pathology in subfertile couple may account for the poorer outcome in IVF pregnancy. However, comparison of singletons after controlled ovarian hyperstimulation and IVF with subfertile women who conceived spontaneously still show an increase in the risk of low birth weight/very low birth weight/preterm birth and very preterm birth suggesting an impact of IVF rather than subfertility per se.70 The power of such studies to inform these important clinical factors is low and further research is required. However, the limited data that exist to identify independent risk factors or perinatal mortality associated with such subfertility treatment have highlighted that bleeding in pregnancy is a risk factor for premature delivery and that maternal hypertension in pregnancy is a risk factor for both prematurity and intrauterine growth restriction.68 Similarly research detailing perinatal outcomes after oocyte donation has highlighted that prematurity and intrauterine growth restriction are significantly associated with pregnancy induced hypertension, second trimester bleeding and maternal smoking but not with advanced maternal age or pre-existing maternal ovarian failure.65 Whilst the risks of pregnancies conceived after IVF have been discussed it is would be short-sighted to expect that it is only in the antenatal period that professional input is required. The physical consequences must be considered and these will continue into the postnatal period. Mode of delivery has a significant impact on the postnatal period and it has been shown that the incidence of Caesarean section is increased in ART pregnancies49 for both singletons71 and twins.72 It is unclear from the data as to whether such redress to operative delivery is secondary to maternal wishes and physician concern. There is no objective evidence that pregnancies in which the foetus(es) are conceived by ART require redress to operative delivery compared to those conceived naturally. Indeed, we recommend that decisions on mode of delivery in these pregnancies (as in all pregnancies) are informed by obstetric complications. Increased risk of operative delivery may be associated with early postnatal problems, which may be exacerbated if the pregnancy is multiple. As well as physical repercussions of delivery, psychological/ emotional symptoms of depression have been reported to occur more commonly after multiple births conceived by IVF, although mothers of singletons were more likely to report having suffered transient “baby blues”.73 Other studies report similar findings with more parenting stress and depression in ART

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families with twins when compared with ART families with singletons.74 There is also concern in general terms, that foetuses of multiple pregnancies lag behind their singleton peers in language development and that twins conceived by IVF may have lower levels of cognitive functioning,74 that may track into paediatric life. It has also been suggested that children of pregnancies conceived by IVF have an increase in childhood illnesses, chronic illnesses and in the utilisation of healthcare but this is not a universal finding and there is some suggestion that this may be due to parental factors, such as increased anxiety after a long period of childlessness.75 Overall, it should be noted that ART is associated with an increased risk of maternal and perinatal complications. Singleton pregnancy aside it is important to remember that irrespective of method of conception twin pregnancies are higher risk for both the mother and her babies, and the high incidence of multiple pregnancies after ART must be regarded as a serious complication of the treatment. Pregnancy induced maternal complications occur three to seven times more often and perinatal morbidity and mortality is increased four- to ten-fold.3 The majority of risks detailed for singleton IVF pregnancies are apparent for IVF twin pregnancy, it is simply that in comparison with spontaneously conceived twins the risks are not always increased. This is an area where better initial counselling prior to ART treatment is required as even recent patient survey data have suggested over half of the patients questioned preferred to have twins.76 Worryingly the authors’ conclusion was therefore that obligatory single embryo transfer would be in conflict with the patient interests and wishes, further highlighting the need for a clinician’s mind-set to change to reflect the fact that multiple pregnancy must be regarded and explained as treatment failure before we can expect a change in patient opinion. It must be considered irresponsible to allow mothers to expose themselves to risks that would be substantially reduced if ART can be modified. The risk of growth restriction raises the question of whether all IVF pregnancies should be monitored by serial ultrasound scanning. A question that is impossible to answer without research to decide whether this would confer any benefit in terms of perinatal outcome. What is clear is that in the light of current evidence the organisations who inform ART practice need to produce national guidelines based on their country’s practice, such as those produced by the Society of Obstetricians and Gynaecologist of Canada and the Board of Canadian Fertility and Andrology Society in 2006. In conclusion, there is a need to register all IVF pregnancies and resulting children to allow identification and then planning and trial of intervention to improve outcomes. Long-term outcomes need careful scrutiny as well as just live birth rates.

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References 1. Human Fertilisation and Embryology Authority (HFEA) Spring 2008 update. www.hfea.gov.uk 2. Office for National Statistics (ONS) Births: 1938–2004, Maternities with Multiple Births. HMSO publications, 2006. 3. European Society for Human Reproductive Embryology Capri Workshop Group. Multiple gestation pregnancy. Hum Reprod 2000; 15: 1856–64. 4. Wood R. Trends in Multiple Births, 1938–1995. Popul Trends 1997; 87: 29–35. 5. Schieve LA, Peterson HB, Meilke SF et al. Live birth rates and multiple birth risk using in vitro fertilisation. JAMA 1999; 282: 1832–8. 6. Templeton A, Morris JK. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization. N Engl J Med 1998; 339: 573–7. 7. Evans MI, Wapner RJ, Carpenter R et al. International collaborative on multifetal pregnancy reduction (MFPR): dramatically improved outcomes with increased experience. Am J Obstet Gynecol 1999; 180: S28. 8. Berkowitz RL, Lynch L, Stone J, Alvarez M. The current status of multifetal pregnancy reduction. Am J Obstet Gynecol 1996; 174: 1265–72. 9. European Society for Human Reproductive Embryology Campus Course Report. Prevention of twin pregnancy after IVF/ICSI by single embryo transfer. Hum Reprod 2001; 16: 790–800. 10. Tiitinen A, Unkila-Kallio L, Halttunen M, HydenGranskog C. Impact of elective single embryo transfer on the twin pregnancy rate. Hum Reprod 2003; 18: 1449–53. 11. American Society for Reproductive Medicine. Guideline on number of embryos transferred. Fertil Steril 2006; 86: S51–52. 12. ASRM/SART Registry. 2006. Society for Assisted Reproductive Technology. IVF Success Rate Report 2006. 13. De Mouzen J, Lancaster P. World Collaborative Report on in vitro fertilization, preliminary data for 1995. J Assist Reprod Genet 1997; 14S: 251–65. 14. Derom C, Derom R, Vlietinck R, Van de Bergh H, Thiery M. Increased monozygotic twinning rate after ovulation induction. Lancet 1987; 1: 1236–8. 15. Derom R, Bryan E, Derom C, Keith L, Vlietinck R. Twins, chorionicity and zygosity. Twin Res 2001; 4: 134–6. 16. Blickstein I, Verhoeven HC, Keith LG. Zygotic splitting after assisted reproduction. N Engl J Med 1999; 340: 738–9. 17. Schachter M, Raziel A, Friedler S et al. Monozygotic twinning after assisted reproductive techniques: a phenomenon independent of micromanipulation. Hum Reprod 2001; 16: 1264–9. 18. Hack KEA, Derks JB, Elias SG et al. Increased perinatal mortality and morbidity in monochorionic versus dichorionic twin pregnancies: clinical implication of a large Dutch cohort study. Br J Obstet Gynaecol 2008; 115: 58–67. 19. Machin GA. Multiple pregnancies and conjoined twins: relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Potter’s Pathology of the Fetus and Infant. London: Mosby, 1997; 1: 281–321.

20. Denbow ML, Cox P, Taylor M, Hammal DM, Fisk NM. Placental angioarchitecture in monochorionic twin pregnancies: relationship to fetal growth, fetofetal transfusion syndrome, and pregnancy outcome. Am J Obstet Gynecol 2000; 182: 417–26. 21. Brackley K, Kilby MD. Twin–twin transfusion syndrome. Hosp Med 1999; 60: 419–25. 22. Machin GA. Some causes of genotypic and phenotypic discordance in monozygotic twin pairs. Am J Med Genet 1996; 61: 216–28. 23. Saunders NJ, Snijders RJ, Nicolaides KH. Therapeutic amniocentesis in twin-twin transfusion syndrome appearing in the second trimester of pregnancy. Am J Obstet Gynecol. 1992; 166: 820–4. 24. Van Gemert MJ, Umur A, Tijssen JG, Ross MG. Twintwin transfusion syndrome: etiology, severity and rational management. Curr Opin Obstet Gynecol 2001; 13: 193–206. 25. Nybo Anderson AM, Wohlfahrt J, Christens P, Olsen J, Melbye M. Maternal age and fetal loss: population based register linkage study. Br Med J 2000; 320: 1708–12. 26. Australian In-vitro Fertilisation Collaborative Group. High in cadence of preterm births and early losses in pregnancy after in vitro fertilisation. Br Med J 1985; 291: 1160–3. 27. Miller JF, Williamson E, Glue J et al. Fetal loss after implantation: A Prospective Study. Lancet 1980; 316: 554–6. 28. Wilcox AJ, Weinberg CR, O’Connor JF et al. Incidence of early pregnancy loss. N Eng J Med 1988; 319: 189–94. 29. Schieve LA, Tantham L, Petersn HB, Toner J, Jeng G. Spontaneous abortion among pregnancies conceived using assisted reproductive technology in the United States. Obstet Gynecol 2003; 101: 959–67. 30. Wang JX, Norman RJ, Wilcox AJ. Incidence of spontaneous abortion among pregnancies produced by assisted reproductive technology. Hum Reprod 2004; 19: 272–77. 31. Toner JP, Grainger DA, Frazier LM. Clinical outcomes among recipients of donated eggs: an analysis of the US national experience, 1996–1998. Fertil Steril 2002; 78: 1038–45. 32. Burgoyne PS, Holland K, Stephens R. Incidence of numerical chromosome anomalies in human pregnancy estimation from induced and spontaneous abortion data. Hum Reprod 1991; 6: 555–65. 33. Hassold T, Abruzzo M, Adkins K et al. Human Aneuploidy: Incidence, Origin, and Etiology. Environ Mol Mutagen 1996; 28: 167–75. 34. Baart EB, Martini E, van der Berg I et al. Pre-implantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF. Hum Reprod 2006; 21: 223–33. 35. Caperton L. Murphay P, Yamzaki Y et al. Assited reproductive technologies do not alter mutation frequency or spectrum. Proc Natl Acad Sci U S A 2007; 104: 5085–90. 36. Wilkins-Haug LE, Rein MS, Hornstein MD. Oligospermic men: the role of karyotype analysis prior to intracytoplasmic sperm injection. Fertil Steril 1997; 67,612–4.

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Are pregnancies conceived by IVF ‘high risk’? 37. Alboulghar H, Alboulghar M, Mansour R et al. A prospective controlled study of karyotyping for 430 consecutive babies conceived through intracytoplasmic sperm injection. Fertil Steril 2001; 76: 249–53. 38. Pickering SJ, Braude PR, Johnson MH, Cant A, Currie J. Transient cooling to room temperature can cause irreversible disruption to the meiotic spindle in the human oocytes. Fertil Steril 1990; 54: 102–8. 39. Munne S, Magli C, Adler A et al. Treatment related chromosome abnormalities in human embryos. Hum Reprod 1997; 12: 780–4. 40. Munne S, Marquez C, Reing A, Garrisi J, Alikani M. Chromosome abnormalities in embryos obtained after conventional in vitro fertilisation and intracytoplasmic sperm injection. Fertil Steril 1998; 69: 904–8. 41. Iwarsson E, Lundqvist M, Inzunza J et al. A high degree of aneuploidy in frozen-thawed human preimplantation embryos. Hum Genet 1999; 104: 376–82. 42. Mastenbroek S, Twisk M, van Echten-Arends J et al. In vitro fertilization with preimplantation genetic screening. N Engl J Med 2007; 357: 9–17. 43. Lancaster PAL. Congenital malformation after in vitro fertilization. Lancet 1987; 2: 1392. 44. Berg T, Ericson A, Hillensjo T, Nygren K-G, Wennerholm U-B. Deliveries and children born after in vitro fertilization in Sweden 1982–95: a retrospective cohort study. Lancet 1999; 354: 1579–85. 45. MRC Working Party on Children Conceived by In Vitro Fertilisation. Births in Great Britain resulting from assisted conception, 1987–87. Br Med J 1990; 300: 1229–33. 46. Hansen M, Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after intracytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002; 346: 725–30. 47. Klemetti R, Gissler M, Sevon T et al. Children born after assisted conception have an increased rate of major congenital anomalies. Fertil Steril 2005; 84: 1300–7. 48. Silver RI, Rodriguez R, Chang TS, Gearhart JP. In vitro fertilization is associated with an increased risk of hypospadias. J Urol 1999; 161: 1954–7. 49. Shevell T, Malone FD, Vidaver J et al. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol 2005; 106: 1039–45. 50. Koudstaal J, Braat DDM, Bruinse HW et al. Obstetric outcomes of singleon pregnancy after IVF: a matched control study in four Dutch University Hospitals. Hum Reprod 2000; 15: 1819–25. 51. Anthony S, Buitendijk SE, Dorrepaal CA, Braat DDM, den Ouden AL. Congenital malformation in 4224 children conceived after IVF. Hum Reprod 2002; 17: 2089–95. 52. Olson CK, Keppler-Noreuil KM, Romitti PA et al. In vitro fertilisation is associated with an increase in major birth defects. Fertil Steril 2005; 84: 1308–15. 53. Bianco A, Stone J, Lynch L, Lapinski R et al. Pregnancy outcome at age 40 and older. Obstet Gynecol 1996; 87: 917–22. 54. Prysak M, Kisly A. Age greater then thirty-four years is an independent pregnancy risk factor in nulliparous women. J Perinatol 1997; 17: 296–300. 55. Luke B, Brown MB. Contemporary risks of maternal morbidity and adverse outcomes with increasing

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maternal age and plurality. Fertil Steril 2007; 88: 283–93. Isaksson R, Gissler M, Tiitinen A. Obstetric outcomes among women with unexplained infertility after IVF: a matched case control study. Hum Reprod 2002; 17: 1755–61. Maman E, Lunenfeld E, Levy A, Vardi H, Potashnik G. Obstetric outcome of singleton pregnancies conceived by in vitro fertilization and ovulation induction compared with those conceived spontaneously. Fertil Steril 1998; 70: 240–45. Koudstaal J, Bruinse HW, Helmerhorst FM et al. Obstetric outcome of twin pregnancies after in-vitro fertilization: a matched control study in four Dutch University Hospitals. Hum Reprod 2000; 15: 935–40. Ochsenkuhn R, Strowitzki T, Gurtner M et al. Pregnancy complications, obstetric risks, and neonatal outcome in singleton and twin pregnancies after GIFT and IVF. Arch Gynecol Obstet 2003; 268: 256–61. Jackson RA, Gibson KA, Wu YW, Croughan MS. Perinatal Outcomes in Singletons Following In Vitro Fertilization: A Meta-Analysis. Obstet Gynecol 2004; 103: 551–63. Tan SL, Doyle P, Campbell S et al. Obstetric outcome of in vitro fertilization pregnancies compared with normally conceived pregnancies. Am J Obstet Gynecol 1992; 167: 778–84. Kallen B, Finnstrom O, Nygren KG, Otterblad Olausson P, Wennerholm U. In Vitro fertilisation in Sweden: obstetric characteristics, maternal morbidity and mortality. Br J Obstet Gynaecol 2005; 112: 1529–35. Schieve LA, Meilke SF, Ferre C et al. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Eng J Med 2002; 346: 731–7. Bonduelle M, Liebaers I, Deketalaere V et al. Neonatal data on a cohort of 2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum Reprod 2002; 17: 671–94. Sheffer-Mimouni G, Mashiach S, Dor J, Levran D, Seidman DS. Factors influencing the obstetric and perinatal outcome after oocytes donation. Hum Reprod 2002; 17: 2636–40. Luke B, Keith LG. The contribution of singletons, twins and triplets to low birth weight, infant mortality and handicap in the United States. J Reprod Med 1992; 37: 661–6. Helmerhorst FM, Perquin DAM, Donker D, Keirse MJNC. Perinatal outcome of singletons and twins after assisted conception: a systematic review of controlled studies. Br Med J 2004; 328: 261–65. Doyle P, Beral V, Maconochie N. Preterm delivery, low birth weight and small-for-gestational age in liveborn singleton babies resulting from in-vitro fertilization. Hum Reprod 1992; 7: 425–8. Fitzsimmons BP, Bebbington MW, Fluker MR. Perinatal and neonatal outcomes in multiple gestations: Assisted reproduction versus spontaneous conception. Am J Obstet Gynecol 1998; 179: 1162–7. Kapiteijn E, de Craen AJM, Bruger CW, van Leeuwen FE et al. Does subfertility explain the risk of poor perinatal outcome after IVF and ovarian hyperstimulation? Hum Reprod 2006; 21: 3228–34.

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71. Verlaenen H, Cammu H, Derde MP, Amy JJ. Singleton pregnancy after in vitro fertilization: expectations and outcome. Obstet Gynecol 1995; 86: 906–10. 72. Dhont M, De Sutter P, Ruysssinck G, Martens G, Bekaert A. Perinatal outcome of pregnancies after assisted reproduction: A case-control study. Am J Obstet Gynecol 1999; 181: 688–95. 73. Sheard T, Cox S, Oates M, Ndukwe G, Glazebrook C. Impact of multiple, IVF birth on post-partum mental health: a composite analysis. Hum Reprod 2007; 22: 2058–65. 74. Olivennes F, Golombok S, Ramogida C, Rust J and the Follow-Up Team. Behavioural and cognitive

development as well as family functioning of twins conceived by assisted reproduction: findings of a large population study. Fertil Steril 2005; 84: 725–33. 75. Ludwig AK, Sutcliffe AG, Diedrich K, Ludwig M. Post-neonatal health and development of children born after assisted reproduction: A systematic review of controlled studies. Eur J Obstet Gynecol 2006; 127: 3–25. 76. Hojgaard A, Ottosen LDM, Kesmodel U, Ingerslev HJ. Patient attitudes towards twin pregnancies and single embryo transfer – a questionnaire study. Hum Reprod 22: 2673–8.

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Index

Alcohol conception, and 15 pre-conception care, and 25–26 Amphetamines pre-conception care, and 27–28 Amyotrophic lateral sclerosis 195 Anovulation 215–222 Antiphospholipid syndrome 352–353 antithrombotics work in early pregnancy failure 353 classification of patients 352 management of antiphospholipid syndrome 353 maternal monitoring 353 pathophysiological mechanisms 353 Antithrombotic prophylaxis 351–352 Anxiety disorders 200 Arusha project 267 Bipolar affective disorder 200 Bleeding disorders 121–136 haemophilia A and B 128 heritable 128–130 issues to be addressed in haemophilia carrier planning pregnancy or assisted reproduction 129–130 management of carriers 129 physiological changes in haemostatic system 121 Caffeine conception, and 25 Cannabis pre-conception care, and 28 Cardiac disease 77–87 adaptation to pregnancy 78–79 anticoagulation 83–85 arrhythmias 82 cardiac evaluation 77–78 cardiomyopathies 82 conditions associated with aortic dilation 81 congenital heart disease 80–81 cyanotic lesions 80 delivery 85 dilated cardiomyopathy 82 ethocardiography 78 foetal risks 79 hypertrophic obstructive cardiomyopathy 82 ischaemic heart disease 82 management of heart failure 82–83 maternal risks 79 percutaneous management 85 peripartum cardiomyopathy 82 pharmacological treatment 82–85 physical examination 78 pre-pregnancy exercise testing 78 risk of recurrence 79–80 risk stratification 79–80 safety of cardiovascular drugs in pregnancy 84

surgical management 85 transposition of great arteries 80–81 valve prosthesis 81–82 valvular heart disease 81–82 valvular regurgitation 81 valvular strategies 81 Cervical cerclage 419–432 adjuvant management 428 antenatal preterm surveillance 422–425 cervical disease and trauma 421 delivery 429 foetal fibronectin testing 424 history-indicated 427 insertion of occlusion cerclage 428 managing high-risk pregnancy 422–429 maternal characteristics 421 outcome 419 pathophysiology 419–420 physical examination-indicated 427 post-pregnancy counselling 429 pre-conception 426–427 pre-pregnancy advice 422 pre-pregnancy assessment 420–421 pre-pregnancy tests 421–422 prediction 420–422 pregnancy loss, and 419–432 prevalence 419 previous obstetric history 420 removal of 428 screening asymptomatic high-risk women for abnormal vaginal flora 424–425 surgical technique 425–426 transabdominal cerclage 428 transvaginal cervical length assessment 423–424 ultrasound-indicated 427 Charcot-Marie-Tooth disease 194–195 general characteristics 194 molecular basis 194–195 Cocaine pre-conception care, and 27 Counselling pre-conception care, and 32 Couple with unexplained infertility 251–260 controlled ovarian hyperstimulation 254–257 clomiphere citrate 254 danazole 255 FSP 256 gonadotrophics 254–255 ICSI 256–257 intrauterine insemination, and 255–256 IVF 256–257 perturbation 256 tubal flushing 256 diagnosis 251–252 endometriosis 252 expectant treatment 254 immunological infertility 252–253

implantation failure 253–254 incidence of 251 mild tubal disease 252 misdiagnosis 252–254 premature ovarian failure 252 treatment 254 Conception, genetics of 1–11 aneuploidy 5–6 autosomal dominant inheritance 3–4 autosomal recessive inheritance 2–3 chromosomal translocations 6 chromosome abnormalities 5 chromosome rearrangements 7, 8 complex genetic inheritance 10 fragile X syndrome 4–5 gametogenesis 1 gene mutations 2 gonadal mosaicism 5–6 human karyotype 5 inheritance patterns 1–2 insertions 6 inversions 6–7 meiosis 1 Mendelian inheritance of monogenic disorders 2 mitochondrial disorders 8–9 myotomic dystrophy 4 numerical chromosome abnormalities 5 pedigree of Royal Family with X-linked disease Haemophilia 4 polymorphisms 2 ring chromosomes 7–8 segregation of mtDNA diseases in families 9–10 DNA methylation 9 genomic imprinting 9–10 histone modifications 9 X-chromosome inactivation 9 structural chromosomal rearrangements 6 X-linked inheritance 4 Cystic fibrosis 159–172 care of pregnant woman 168–169 classification of mutations 161, 162 clinical aspects 162–164 contraception 167–168 diagnosis 164–165 epidemiology 159 ethical issues 168 fertility in female patient 165 foetal monitoring 169 genetics and molecular biology 159–162 influence of pregnancy on 167 influence on pregnancy 167 management of delivery 169 management of pregnancy 168–169 management of puerperium 169 national registries 159 neonatal screening 165 pathophysiology 161 pre-conceptual assessment 167 predictors of poor prognosis 165

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Index

pregnancy after transplantation 167 pregnancy, and 165–166 prognosis 164–165 special considerations when partner is carrier 168 survival statistics 160 symptoms 165 Depressive disorders 200 Developing world 261–271 aetiological factors of infertility 262 Arusha project 267 consequences of infertility 263–264 psychological 263–2164 sociocultural 263–264 diagnosis of infertility 265 documentation of treatment access and outcome 267 education 264 endoscopic surgery 265–266 ESHRE Special Task Force 268 false perceptions 264–265 infertility in developed countries, and 261–264 low cost “one-stop clinics” 265 misunderstanding 264–265 non-in vitro fertilization assisted reproduction 265–266 prevalence of infertility 262–263 prevention 264 simplified and accessible in vitro fertilization 266 training 266–267 Diabetes mellitus 99–105 antihypertensive medication 102–103 assessment for complications 103 awareness of hypoglycaemia 102 diabetes education 103 early hypoglycaemia 102 early neonatal problems 101–102 fetal growth 100–101 fetal malformations 100 influence of pregnancy on severity of 101–104 influence on pregnancy outcome 100–102 management of glycaemic control 102 management of pregnancy 103–104 microvascular complications 102 miscarriage 100 nephropathy 102 obesity in offspring 101 obstetric risks associated with maternal obesity 103 perinatal mortality 101 preconception advice 102–104 progressive increase in insulin requirements 102 retinopathy 102 shoulder dystocia and birth trauma 101 weight control 103 Early placental development 317–327 abnormal traphoblast invasion 322–324 endometrium, contribution to 319–320 onset of maternal circulation in normal pregnancies 321–322 physiological conversion of spiral arteries 320–321 regulation of traphoblast invasion 324–325

Early pregnancy loss 341–348 chromosomal causes 343 classification of events 343 future direction 346 hyperhomocysteinaemia 344 immunology 344 length of pregnancy 342 maternal thrombophilia 343–344 mechanisms 341–348 nomenclature 341–348 parental karyotype 343 recognizing event 341–342 revised nomenclature 345 ultrasound criteria 342–343 Eating disorders 200–201 pre-conception care, and 28–29 Ectopic pregnancy after fertility treatment 379–391 anti-D immunoglobin 386 biochemical markers 382–383 cigarette smoking 380 clinical picture 381–382 complications 386–387 criteria for methotrexate treatment 385 diagnosis 382–383 effect in subsequent IVF outcome 386–387 expectant management 385–386 endometriosis 380 human chorionic gonadotrophin 382 imaging techniques 383 in vitro fertilization 381 infertility treatment 380–381 laparoscopy 383 laparoscopy versus laparotomy 384 medical treatment 384–385 methotrexate versus salpingostomy 385 pelvic inflammatory disease 379–380 persistent traphoblastic tissue 386 pregnancy associated plasma protein-A 382 previous 380 previous ectopic pregnancy 380 progesterone 382–383 risk factors 379–381 salpingectomy versus salpingostomy 384 single versus multiple doses of methotrexate 385 surgical treatment 384 treatment 383–386 ultrasound 383 Endometriosis 223–231 assisted reproduction, and 226 background 223–224 future directions in assisted reproduction research 228 gamete intrafallopian transfer 227 in vitro fertilization 226–227 infertility 224 influence of reproduction techniques on recurrence of 227–228 intracytoplasmic sperm injection 227 intrauterine insemination 226 postoperative medical treatment 225 preoperative medical treatment 225 spontaneous abortion 224–225 subfertility, and 224–225 surgical treatment 225–226

Epilepsy 107–119 antiepileptic drugs, effects 108 areas for consideration 107 classification of seizures 107 contraception 112–113 effects of pregnancy on 111–112 effects on developing embryo-foetus 108–111 effects on pregnancy 107–108 features of foetal valproate syndrome 110 fertility, and 113 folic acid 113–114 labour, management of 114–115 management 112–115 MCM rates for in utero exposure to antiepileptic drugs 108, 109 monitoring pregnancy in women with epilepsy 114 monitoring seizure control in pregnancy 114 pre-conception counselling 112 pregnancy registers, and 109 puerperium 115 seizures, effect of 108 vitamin K 114 Evidence-based fertility investigation 205–214 chlamydia antibody title 207–208 hystero-contract sonography 209 hysterosalpingogram 208 laparoscopy and dye test 208 ovarian reserve, assessment of 205–206 anti-Mullerian hormone 206 antral follicle count 206 clomiphere citrate challenge test 206 follicle stimulating hormone 205–206 ovulation, assessment of 205 postcoital test 207 prediction models for spontaneous pregnancy 210, 211 prediction models in reproductive medicine 209 prognostic variables for prediction of treatment-independent pregnancy 212 selective salpingography 208 transvaginal hydrolaparoscopy 208–209 tubal assessment 207–209 tubal catheterization 208 Exercise conception, and 17 Fasciocapulohumeral dystrophy 193–194 Genetics of conception 1–11 aneuploidy 5–6 autosomal dominant inheritance 3–4 autosomal recessive inheritance 2–3 chromosome abnormalities 5 chromosomal translocations 6 complex genetic inheritance 10 DNA methylation 9 fragile X syndrome 4–5 gameto genesis 1 gene mutations 2 genomic imprinting 9–10 gonadal mosaicism 5–6 histone modifications 9 inheritance patterns 1–2 insertions 6

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Index inversions 6–7 meiosis 1 mendelian inheritance of monogenic disorders 2 mitochondrial disorders 8 myotomic dystrophy 4 numerical chromosome abnormalities 5 polymorphisms 2 ring chromosomes 7–8 segregation of mtDNA diseases in families 9–10 structural chromosomal rearrangements 6 X-chromosome inactivation 9 X-linked inheritance 4 Hallucinogens pre-conception care, and 28 Health promotion pre-conception care 24–28 HIV 143–158 artificial reproduction 152 carcinogenicity of antiretroviral drugs 151 congenital malformations 148 disadvantages of antiretroviral therapy in neonate 147–148 epidemiology 143 haematological changes associated with use of antiretroviral therapy 151 influence of natural course 144 influence on pregnancy outcome 143–144 mitochondrial toxicity 148–150 mother-to-child transmission 144 prevalence of congenital malformations after first trimester exposure to different antiretroviral drugs 150 prevention of mother-to-child transmission 146–147 safety of antriretroviral therapy in pregnant women 151–152 summary of animal and clinical data on individual antiretroviral data 149 transmission during labour 145–146 transmission during lactation 146 transmission during pregnancy 144–145 US FDA pregnancy categories and antiretroviral drugs 150 Hydrosalpinx 242–246 antibiotic treatment 246 ovarian function after salpingectomy 243–245 salpingectomy 242–243 theories of action 242 transvaginal aspiration of fluid 245–246 treatment 242–246 tubal ligation 245 Hypertension 69–76 adverse effects on pregnancy outcome 70–71 antihypertensives 71–72 choice of antihypertensive agent 72–73 effect of pregnancy on 71 management of delivery 74 management of pregnancy 73–74 management of puerperium 74–75

medication 71–73 pre-conception advice 71 secondary causes 69 treatments to prevent pre-eclampsia 73 Hyperprolactinaemia 218–219 Hypothalamic anovulation 220 Hypothyroidism 219–220 Immunology of early pregnancy 329–340 cell types present in decidua 332–335 dendritic cells 332–333 macrophages 332 natural killer cells 332 T-cells 333–335 from endometrium to decidua 331–332 genetics 329–330 human leucocyte antigen C 330 human leucocyte antigen G 330–331 integrating role of different cell types 335–336 immunomodulation 335–336 remodelling of maternal vessels 336 trophoblast and human leucocyte antigen expression 330–331 Implantation failure 309–315 autoantibodies 312 conditions that may cause 309 decreased endometrial receptivity 309–310 altered endocrine milieu 309–310 cytokine dysregulation 310 inadequate endometrial development 310 undiagnosed pathology 310 difficult embryo transfer 313 embryonic factors 310–312 chromosomal abnormalities 310–311 embryo fragmentation 311 embryo-maternal asynchromy 311–312 zona pellucida hardening 311 endometriosis 312 hydrosalpingas 312 leiomyomas 313 maternal conditions 312–313 psychological support 313 thrombophilias 312 window of implantation 309 In vitro fertilization 433–440 congenital anomalies 435 foetal aneuploidy 435 growth restriction, risk of 437 high risk pregnancies, whether 433–440 multiple pregnancies, and 434 perinatal outcome 436 Infections pre-conception care, and 31–32 Inflammatory bowel disease 173–177 effect of pregnancy on 173–174 effect on pregnancy 173 pre-conceptive counselling 174–175 breast feeding 175 fertility 174 inheritance 174 safety of medication during breastfeeding 175 safety of medication during pregnancy 175 surgery during pregnancy 175 treatment during pregnancy 174–175

443

Lifestyle and conception 13–22 phenotypes 17–18 Lifestyle factors 13–17 alcohol 15 exercise 17 nutrition 16–17 periconceptual lifestyles in association with fecundity, fertility and semen parameters 14 recreational drug use 15–16 smoking 13–15 Limb-girdle dystrophy 193–194 Luteal phase 297–307 defect in stimulated in vitro fertilization cycles 300–301 defining luteral phase defect 299 duration of support 303–304 early history of corpus luteum 297 gonadotrophin releasing hormone agonist 303 human choriomic gonadotrophin 302–303 luteral phase defect 299 naloxone 303 onset of support 303 physiology of corpus luteum 297–298 progesterone, effect 298–299 progesterone plus oestradiol 302–304 treatment of defect in natural cycle 299–300 treatment of defect in stimulated in vitro fertilization cycles 301–302 intramuscular progesterone 301–302 rectal progesterone 301 vaginal progesterone 301 Medication pre-conception care, and 32–34 Mental illness 199–204 epidemiology 199 managing risk 203 early pregnancy 203 pre-pregnancy 203 medication issues 202–203 antidepressants 202 antipsychotics 202 mood stabilizers 202–203 normal emotional changes in early pregnancy 199–200 Miscarriage psychological aspects 201–202 Motor neurone disease 195 Molar pregnancy 393–404 chemoprophylaxis 397 coexisting foetuses 399–400 complete, presentation of 394–396 cytogenetics 393–394 diagnosis 396 excessive uterine enlargement 394 follow-up 397–398 HCG measurement 396 hyperemesis gravidarum 395 hyperthyroidism 395 management 393–404 multiple conceptions 399–400 partial, presentation of 396 pathology 393–404 persistent gestational trophoblastic neoplasia after 398–399 pregnancies after 400–401 respiratory insufficiency 395–396

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theca lutein ovarian cysts 394–395 toxaemia 395 treatment 396–397 ultrasound 396 vaginal bleeding 394 Multiple pregnancy 405–517 chorionicity, determination of 407 chromosomal abnormality 407–410 complications of intertwin vascular anastamoses 410–411 epidemiology 405–407 fetal growth restriction in 411–412 literature reporting perinatal outcomes 406 maternal health, and 412–413 monochorionicity 410–411 monoamniotic twins 411 prenatal diagnosis 407–410 preterm delivery 412 Quintero staging system 410 structural abnormality 410 twin reversed arterial perfusion sequence 411 twin-twin transfusion syndrome 410–411 Myotonic dystrophy 191–193 clinical classification 192 molecular basis 193 obstetric risks 192–193 periconceptual risks 192–193 type 1, general characteristics 191–192 typical facial appearance 192

Opiates pre-conception care, and 26–27 Organ transplantation 57–67 antenatal care 62–63 comorbid conditions 62 immunosuppressive therapy 62–63 breast feeding 63–64 care of offspring 63–64 contraception, and 64–66 delivery 63 gynaecological problems, and 66 kidney registry outcomes 58 literature 57–59 liver registry outcomes 58 management, summary of 65 maternal follow-up after pregnancy 64–66 NTPR: pregnancies in female transplant recipients 58 prepregnancy care 59–62 assessment 59 comorbid conditions 61–62 counselling 59, 60–61 immunization 62 immunosuppressive therapy 60–61 significant infections 62 timing of pregnancy 60 what patient needs to understand 59–60 what patient wants to know 59 Registries 57–59 registry outcomes 59

Neuromuscular disorders 191–197 inherited myopathies 191–194 inherited neuropathies 194–195 Nutrition conception, and 16–17 pre-conception care, and 30–31

Peritonatal adhesions 246–247 Personality disorder 201 Proximal tubal occlusion 246 Phenotypes of lifestyles conception, and 17–18 Polycystic ovary syndrome 137–141, 215–218 bariatic surgery 215–216 diagnosis 137 diet 215 disease, as 137 effect of pregnancy on 138–139 exercise 215 gonadotrophins 218 influence on pregnancy outcome 137–138 laparoscopic ovarian surgery 218 later pregnancy complications 218 Legro et al trial 217 lifestyle modifications 215 ovulation induction with pharmacological agents 216–217 pharmacological treatment 215–216 prenatal advice 139–140 summary of trials 216 Poor sperm quality 233–239 dealing with 234–237 defining 233 ICSI 237 in vitro fertilization 236 intracytoplasmic sperm injection 236–237 intrauterine insemination 234–236 investigating man 233–234 MESA 237 PESA 237 TESE 237 treating 234

Obesity pre-conception care, and 29–30 Older woman wishing to conceive 273–285 assisted reproduction 280–281 counselling 279–280 evaluation infertility work-up 280 fertility decline 273–275 increased risk of genetic and congenital abnormalities in offspring 276 increased risk of twinning with ageing 275–276 management options 279–281 ovarian reserve testing for prediction of natural conception chance and after assisted conception 277–279 currently known tests 278 first cycle poor response 279 poor response prediction 278 prediction of pregnancy in subfertility patients 278 pregnancy prediction 279 prior to in vitro fertilization 278 ovarian reserve testing prior assisted conception 281 paradox of more time needed but less time to wait 280 pregnancy complications 277 preimplantation genetic screening 281 reproductive ageing 273–275

Pre-conception care 23–39 alcohol 25–26 amphetamines 27–28 caffeine 25 cannabis 28 cocaine 27 counselling 32 drugs 26 drugs with teratogenic effect in humans 33 eating disorders 28–29 hallucinogens 28 health promotion 24–28 hepatitis B 32 HIV 31 infections 31–32 medications 32–34 nutrition 30–31 obesity 29–30 opiates 26–27 preconception intervention 32–34 radiation 31 risk assessment 23–24 rubella 31 smoking 24–25 syphilis 31 toxoplasmosis 31 Prolactinoma 179–189 clinical manifestations 179–180 diagnostic evaluation 180–181 differential diagnosis 180–181 effect of bromocriptive and cubergoline on 186 effect of pregnancy on 185–186 effects of dopamine agonists on foetus 186–187 epidemiology 179 evaluation 181 medical therapy 181–183 bromocriptine 182 cabergoline 182 dopamine 183 pergolide 182–183 quinagolide 183 pathogenesis 179 radiotherapy 184–185 surgery 183–184 treatment 181–185 Psychosocial issues in periconceptional care 287–295 ambivalence 287–288 engaging in medical process 288–289 motivation 287–288 sexual issues 288 stress and treatment outcome 289–290 treatment burden 289–290 treatment drop out 291–292 treatment persistence 291–292 Radiation pre-conception care, and 31 Recreational drug use conception, and 15–16, 26 Recurrent miscarriage 367–377 chromosome abnormalities 368–369 endocrine disturbances 370 luteral phase defects 370 polycystic ovary syndrome 370 evaluation of investigations 369 evaluation of treatments 373

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Index evidence-based investigations and treatments 367–377 evidence-based treatments and tests 367–368 immunological disturbances 371–373 autoantibodies 371 cytokines 371–372 human leucocyte antigen 372 immunotherapy 372–373 mannose-binding lectin 372 natural killer cells 371 methodological flaws typical for studies 368 research problems characterizing 367 thrombophilias 370–371 uterine anatomical anomalies 369–370 Renal disease 41–56 antenatal care 49–50 assessing renal function 41 clinical implications of specific renal diagnosis 46–48 end-stage/dialysis dependent 43 infertility, management of 49 influence of pregnancy on severity of 45–49 influence on pregnancy outcome 42–45 mild renal impairment 42–43 moderate renal impairment 43 monitoring renal function 41 nephritic syndrome 43–45, 50 obstetric management 50 physiological changes 41 practical management 49–53 pre-conception counselling 49 pre-eclampsia, versus 45 pregnancy outcomes 44 proteinuria in pregnancy 41–42 recommendations in dialysis patients 50–51 diagnosis of pregnancy 50 dialysis modality 50–51 haemodialysis regimen 51 obstetric management 51 peritoneal dialysis 51 pre-conception counselling 50 recommendations in renal transplant recipients 51–53 acute rejection risk 52 antenatal care 51–52 fertility treatment 52 immunosuppressive regimens 52 obstetric management 52–53 pre-conception counselling 51 renal transplant recipients 43 severe renal impairment 43 stages of chronic kidney disease 42 Risk assessment pre-conception care, and 23–24

Schizophrenia 200 Semen analysis 206–207 Smoking conception, and 13–15, 24–25 Spinal muscular atrophy 195 Substance use disorders 201 Thrombophilia 349–356 foetal loss, and 350–351 foetomaternal cross-talk at placental vascular bed 349 future directions 353 gestational haemostasis 349 microparticles 350 role of protease activated receptors in placentation 349–350 Thrombosis 121–136 acquired thrombophilias 122–123 agents for thromboprophylaxis 125 antenatal management 127 assisted conception outcomes 124 clinical sequelae 123–125 disorders 121–128 foetal loss 124 inclusions criteria for definitive antiphospholipid syndrome 122 indications for thrombophrophylaxis 125–127 infertility 124 inherited thrombophilias 121–122 intrauterine growth restriction 124–125 management 125–128 management of anticoagulation at time of delivery 127 management of anticoagulation in puerperium 127–128 maternal 123 placental absorption 125 pre-eclampsia 124 prepregnancy management 127 prevalence rates for thrombophilia 122 risk factors for serious thromboembolism 123 suggested management strategies 126 Thyroid disease 89–98 cancer 94–95 foetal thyroid 89 hyperthyroidism 91–94 foetal complications 92–93 influence of pregnancy on severity of 93 influence on pregnancy outcome 92–93 maternal complications 92 neonatal complications 92–93 pre-conceptual advice and management 93–94 hypothyroidism 90–91 foetal complications 91 influence of pregnancy on severity of 91

445

influence on pregnancy outcome 91 maternal complications 91 neonatal complications 91 pre-conception advice and management 91 interpretation of maternal thyroid function 90 maternal thyroid in pregnancy 89 measurement of maternal thyroid function 90 non-functional goitre 94–95 postpartum thyroiditis 95–96 pre-conceptional screening for thyroid dysfunction 96 thyroid nodules 94–95 Tubal disease 241–249 diagnostic methods 241 distal tubal occlusion 241 risks in early pregnancy 247 Ultrasound in early pregnancy 357–365 abnormal early pregnancy 360–363 ectopic pregnancy 361–362 ballooned cervical canal containing 362 interstitial 362 transverse view of uterus 362 empty gestational sac in transverse view at 8 weeks 361 gestational sac at beginning of 6th week 359 gestational sac at end of 6th week 359 gestational sac at 5 weeks 359 gestational sac within uterine cavity 358 miscarriages 361 molar pregnancy 362–363 normal early pregnancy development 357–360 physiological midgut herniation at 8 weeks’ gestation 360 relationship between transvaginal ultrasound findings and hcg levels 358 retained products of conception within uterine cavity 361 secondary yolk sac 357 seven-week gestation 359 twelve-week gestation demonstrating nuchal thickness 360 uterus containing complete mole 363 uterus showing caesarian section scar 363 Von Willebrand disease 130–131 classification 131

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