Perinatal Stress, Mood And Anxiety Disorders: From Bench To Bedside (Bibliotheca Psychiatrica)

Perinatal Stress, Mood and Anxiety Disorders

Bibliotheca Psychiatrica No. 173

Series Editors

A. Riecher-Rössler Basel M. Steiner Hamilton

Perinatal Stress, Mood and Anxiety Disorders From Bench to Bedside

Volume Editors

A. Riecher-Rössler Basel M. Steiner Hamilton

11 figures, 1 in color, and 5 tables, 2005

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Singapore · Tokyo · Sydney

Bibliotheca Psychiatrica Formerly published as ‘Abhandlung aus der Neurologie, Psychiatrie, Psychologie und ihren Grenzgebieten’ (Founded 1917) Edited by K. Bonhoeffer, Berlin (1917–1939), J. Klaesi, Bern (1948–1952), J. Klaesi and E. Grünthal, Bern (1955–1967), E. Grünthal, Bern (1968), E. Grünthal and Th. Spoerri, Bern (1969–1971), Th. Spoerri, Bern (1973), P. Berner and E. Gabriel, Wien (1975–1986), B. Saletu, Wien (1986–2003)

Prof. Dr. med. A. Riecher-Rössler

M. Steiner, MD, PhD

Psychiatrische Poliklinik Universitätsspital Basel Petersgraben 4 CH–4031 Basel (Switzerland)

Department of Psychiatry McMaster University Women’s Health Concerns Clinic St. Joseph’s Healthcare Hamilton, Ont. (Canada)

Library of Congress Cataloging-in-Publication Data Perinatal stress, mood, and anxiety disorders : from bench to bedside / volume editors, A. Riecher-Rössler, M. Steiner. p. ; cm. – (Bibliotheca psychiatrica ; no. 173) Includes bibliographical references and indexes. ISBN 3-8055-7865-2 (hard cover : alk. paper) 1. Postpartum psychiatric disorders. 2. Childbirth–Psychological aspects. 3. Motherhood–Psychological aspects. 4. Postnatal care–Psychological aspects. 5. Mothers–Mental health. 6. Stress (Psychology) 7. Anxiety in women. 8. Postpartum depression. 9. Mental illness in pregnancy. 10. Pregnant women–Mental health. [DNLM: 1. Postpartum Period–psychology. 2. Anxiety Disorders. 3. Mood Disorders. 4. Pregnancy Complications–psychology. WQ 500 P4456 2005] I. Riecher-Rössler, Anita. II. Steiner, Meir. III. Series. RG850.P475 2005 618.7⬘6–dc22 2005006482 Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents® and Index Medicus. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2005 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) www.karger.com Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISSN 0067–8147 ISBN 3–8055–7865–2

Contents

VII Foreword Riecher-Rössler, A. (Basel); Steiner, M. (Hamilton) 1 A Historical Perspective on the Psychiatry of Motherhood Brockington, I. (Bredenbury) 6 Diagnostic Classification of Perinatal Mood Disorders Riecher-Rössler, A.; Rohde, A. (Basel) 28 Maternal Adversity,Vulnerability and Disease Matthews, S.G. (Toronto); Meaney, M.J. (Montréal) 50 Behavioral Perinatology Wadhwa, P.D. (Irvine, Calif.) 70 Maternal Depression: An Adverse Early Environment Beach, A.J.; Henry, A.L.; Stowe, Z.N.; Newport, D.J. (Atlanta, Ga.) 85 Perinatal Infanticide and Suicide Spinelli, M.G. (New York, N.Y.) 100 Relevance of Gonadal Hormones to Perinatal Mood and Anxiety Disorders Ahokas, A.; Kaukoranta, J.; Wahlbeck, K.; Aito, M. (Helsinki) 112 Pharmacotherapy for Psychiatric Disorders in Pregnancy Ross, L.E.; Gunasekera, S.; Rowland, M.; Steiner, M. (Hamilton)

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137 Maternal Depression in the Postpartum Period: Impact of Breast-Feeding on Treatment Planning Stowe, Z.N.; Ragan, K.; Newport, D.J. (Atlanta, Ga.) 150 The Use of Interpersonal Psychotherapy for Perinatal Mood and Anxiety Disorders Stuart, S.; O’Hara, M.W. (Iowa City, Iowa) 167 Group Psychotherapy for Depression in Early Stages of Motherhood Hofecker-Fallahpour, M.; Riecher-Rössler, A. (Basel) 182 Alternative Treatment Strategies for Perinatal Depression and Anxiety O’Higgins, M.; Glover, V. (London); Corral, M. (Vancouver)

194 Author Index 195 Subject Index

Contents

VI

Foreword

Mood and anxiety disorders are very common during the perinatal period and confront us with specific needs. Thus, help seeking is often delayed due to shame and stigma, and diagnosis is often missed due to misinterpretation of symptoms. Services often do not adequately meet the needs of the women concerned as they do not take into account their specific situation, problems and fears. Untreated, peripartum disorders can have especially severe long-term consequences, not only for the mother but also for the whole family and especially for the child. Recent research has shown how maternal stress, anxiety and depression can adversely influence a child’s early and later development. Despite this, perinatal mental health has until recently been very much neglected, overlooked, underdiagnosed and undertreated. A recent surge of clinical and research interest, prompted by some very active pioneers in this field and also by media exposures of several very tragic outcomes of mothers who committed infanticide and/or suicide during an episode of postpartum depression, is a most welcome change in this field. It is now widely accepted that mental disorders in the perinatal period need special attention and special treatments with modifications of the classical pharmacological, non-pharmacological and psychotherapeutic approaches. Universities around the world have started research programmes and implemented subspecialty clinics for perinatal mental health. Residency programmes in psychiatry and in obstetrics and gynaecology are including the topic in their curriculum and granting agencies have declared it a priority for research. We have assembled a group of internationally renown experts in the field to contribute to this volume. The twelve articles included here offer a comprehensive

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up-to-date overview of the most relevant research and treatment considerations in this neglected field. A brief, though very interesting introduction to the history of psychiatry of motherhood is followed by the discussion of the old question if perinatal disorders are specific entities and if they should have a specific place in our classification systems. Further articles focus on the effects of chronic maternal stress on fetal developmental outcomes and on the relationship between adversity in early pre- and postnatal life and the risk for later cognitive and behavioural impairments and chronic illness. Maternal depression during pregnancy and early childhood is shown to be one of the child’s earliest adverse life events which can contribute to a child’s vulnerability to later psychiatric illness. Both clinical as well as preclinical evidence is discussed. In an article of outstanding importance for each clinician, the danger of perinatal infanticide and suicide is reviewed. Further articles deal with specific forms and modifications of therapies for perinatal mental disorders. The relevance of gonadal hormones in the pathogenesis of perinatal mental disorders is discussed, an innovative field of research which could offer new therapeutic possibilities. The most important questions of pharmacotherapy during pregnancy and breast-feeding are discussed in depth. New psychotherapeutic approaches are presented such as interpersonal psychotherapy as well as a new form of group therapy for mothers with depression and anxiety disorders. Last but not least, ‘alternative’ treatment strategies for pregnant and breast-feeding women are reviewed. This book is aimed primarily at clinicians, teachers and researchers from the fields of psychiatry (adult as well as child and adolescent psychiatry), obstetrics and gynaecology, paediatrics, psychology, psychotherapy, neurobiology and psychoneuroendocrinology as well as their students and learners. The editors wish to thank all contributors as well as our administrative assistants, Ms. Cindy Tasch, Hamilton, Mrs. Elisabeth von Castelmur and Ms. Brigitte Howald, Basel, and the staff of S. Karger AG, Basel, for their professional help with the publication of this volume. Anita Riecher-Rössler Meir Steiner

Foreword

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 1–5

A Historical Perspective on the Psychiatry of Motherhood Ian Brockington Bredenbury, Herefordshire, UK

The early literature on the psychiatric disorders of reproduction was focused on psychosis. Hippocrates [1] may have encountered postpartum delirium complicating infections, as in the women from Thasos and Cyzicus (3rd book of epidemics, cases 2 and 14), and possibly the enigmatic 40th aphorism from the 5th book of aphorisms. The next case was published in Basel about 2,000 years later in 1593 by Plater [2]. In the 17th and 18th centuries, there were 30–40 other brief reports, before the Göttingen obstetrician Osiander [3] (1797) wrote the first full description of puerperal mania. A 3rd form of psychosis – posteclamptic psychosis – was described by Mercatus [4] in 1614. At the same time, Society became aware of another group of disorders, apparently a disturbance of the ‘maternal instinct’. Murder of the newborn became a major public health problem between the 17th and mid 19th centuries and led to the development of a whole branch of forensic medicine. The fury of the mother was shown in some cases by extreme violence, such as beheading or butchering the infant. Almost all cases followed clandestine illegitimate births, but occasionally neonaticide was reported within marriage, e.g. Biermann [5] (1839). Simultaneously, parental child abuse came to light, initially in older children. Brutal assaults betrayed parental rage, but children dying from starvation – first described by Rothamel [6] in 1845 – indicated persistent states of hatred and rejection. Tardieu’s [7] classic paper (1860) showed that this cruelty could extend to very young children. Of his 32 cases, 5 concerned breast-fed infants and 1 was only 15 days old. He wrote: When we consider the tender age of these poor defenceless beings, subjected daily and almost hourly to savage atrocities, unimaginable tortures and harsh privation … and when we face the fact that their tormentors are the very mothers who gave them life, we are confronted with one of the most appalling problems that can disturb the soul of a moralist, or the conscience of justice.

A year later, Boileau de Castélnau [8] coined the term misopédie (hatred of children) to denote this maternal disorder. Just as the phenomenon of child abuse met obstinate resistance, until forced on the profession by advances in paediatric radiology nearly 100 years later, child hatred is still resisted by many practitioners, who prefer to regard it as a manifestation of ‘postnatal depression’. A paper by Luft [9] in 1964 indicated that these disorders were common: he collected 40 cases of Wochenbettdepression – all following legitimate, not unwanted, pregnancies – in which the most prominent symptom was hostility to the newborn. In the USA, Robson and Moss [10] (1970) made a survey and found that a delay in the maternal emotional response was found in about 10% of mothers. From the standpoint of psychological medicine, childbearing is the most complex event in human experience. This is reflected in the large number of disorders described. Plater [2] may have been the first to observe obsessions of fetal and child harm, and Woodward [11] described another case in 1757. Kirkland [12] (1774) described the delirium that sometimes complicated the most painful stage of parturition, before analgesics were introduced. Moll [13] (1920) drew attention to the prevalence of persistent anxiety in the care of young children, which he called Maternitätsneurose. De Armond [14] (1954) and Weightman et al. [15] (1998) described specific forms of anxiety, and Sved-Williams [16] (1992) wrote about phobia of the newborn. Bydlowski and Raoul-Duval [17] (1978) drew attention to post-traumatic stress disorder following prolonged and painful parturition, and a parallel state of Querulantenwahn or ‘bitterness disorder’ is also seen. As for postpartum depression, some claim that the oracular remark of Trotula of Salerno [18], an 11th century professor of medicine or a 13th century midwife, is the first recognition of this entity. If the womb is too moist, the brain is filled with water, and the moisture running over the eyes, compels them to involuntarily shed tears.

A clearer, though brief, description was given by Joao Rodrigues de Castello Branco (Amatus Lusitanus) [19] – a Portuguese physician practising in Rome – in 1547. The beautiful wife of Carcinator (a merchant) who always enjoyed the best of health, was attacked after childbirth by melancholy, and remained insane for a month, but recovered with treatment.

About the same epoch, Plater [2] described a ‘melancholic country lass’, who, when breast-feeding, hanged herself, but was cut down by ‘one that chanced to see her’. Other cases were described by Ledelius [20] (1696) and Schulzius [21] (1705). As reports of puerperal melancholia began to multiply, recurrent

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prepartum and postpartum depression became a focus. Esquirol [22] (1818) observed a woman who developed depression during each of 5 pregnancies, and about a dozen other authors reported multiple episodes, culminating in Menzies [23] (1893) whose patient had 12 episodes. As for postpartum depression, Castro [24] (1617) – another Portuguese physician (practising in Hamburg) – described recurrent episodes in another merchant’s wife. Hoppe [25] (1893), Meyer [26] (1901) and Cruickshank [27] (1940) all encountered mothers with 8 episodes of depression after childbirth. Interest in puerperal melancholia was sharpened by reports of melancholic filicide. Calmeil [28] described a case which occurred in 1557, and Hume [29] (1797) another that occurred in Aylesbury in 1668. Dapping [30] (1823) and Teilleux [31] (1865) described mothers who killed all 3 infants. There are two relevant French theses: Dumas [32] (1892) wrote on Libéricide or ‘murder of small children by their parents’: 47 of his 92 cases (collected from the literature) involved the mother alone. There were many cases of child abuse, but some mothers were melancholic. Equally common is combined suicide and filicide. Dumas described a woman reduced to penury, who sold everything to provide her children with new clothes and a farewell feast, then, before attempting suicide, strangled all 5 of them one by one while they were sleeping. Perrussel [33] (1923) wrote his thesis on ‘altruistic homicide’ committed by melancholic patients. Depressive filicide is probably the commonest setting for the killing of a child more than 24 h old. In Denmark, Harder [34] (1967) studied 92 parents (84 of them mothers) who poisoned their children: 82 completed suicide. After the Second World War, psychiatry turned its attention to milder, more frequent disorders. The Gordons of New Jersey [35] deserve the credit for drawing attention to the frequency of milder forms of emotional disturbance after delivery. They studied the aetiology, pioneered follow-through studies and conducted a prophylactic trial. Main [36], in 1948, was the first to introduce a child into the psychiatric ward where its mother was receiving treatment. This courageous initiative led to the development of psychiatric mother-and-baby units which, particularly in England and Australia, have accelerated the growth of knowledge, as illustrated by the brilliant contributions of the late Prof. Channi Kumar, who founded the largest of these units at the Bethlem Royal Hospital in London. The multitude of psychiatric disorders seen in pregnancy, parturition and the puerperium is due to the complexity of the life event itself, with somatic, social and psychological components. The pioneers were general physicians on the continent of Europe, but the full picture has emerged through the labours of many disciplines. The study of these disorders has now spread to every corner of the world.

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References 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

26 27 28 29

Hippocrates. English translation by WHS Jones. Cambridge, Heineman, 1962. Plater F: Praxeos medicae. Basel, Conradi Waldkirchii, 1602, 1656. Osiander FB: Neue Denkwürdigkeiten für Aerzte und Geburtshelfer. Göttingen, Rosenbusch, 1797. Mercati L: Consultationes, observation 30, 1614. Biermann LCA: Gerichtsärztliches Gutachten über ein von einer Ehefrau heimlich gebornes und bald nach der Geburt durch Erstickung getötetes Kind. Henkes Z Staatsarzneik 1839;38:303–322. Rothamel, of Fulda: Eine Mutter führt durch allmälige Entziehung der Nahrungsmittel den Tod ihres ehelichen Kindes herbei. Henkes Z Staatsarzneik 1845;50:139–156. Tardieu A: Étude médico-légale sur les vices et mauvais traitements exercés sur des enfants. Ann Hyg 1860;15:361–398. Boileau de Castélnau P: Misopédie ou lésion de l’amour de la progéniture. Ann Méd Psychol (Paris) 1861;7:553–568. Luft H: Die Wochenbettdepression. Klinik und pathogenetische Faktoren. Nervenarzt 1964;35: 185–194. Robson KS, Moss HA: Patterns and determinants of maternal attachment. J Pediatr 1970;77: 976–985. Woodward J: Autochthonous delusion (1757); in Hunter R, McAlpine I (eds): Three Hundred Years of Psychiatry. London, Oxford University Press, 1963. Kirkland T: A Treatise on Childbed Fevers and on the Methods of Preventing Them. London, Baldwin & Dawson, 1774. Moll L: Die Maternitätsneurose. Wien Klin Wochenschr 1920;33:160–162. De Armond M: A type of postpartum anxiety reaction. Dis Nerv Syst 1954;15:26–29. Weightman H, Dalal BM, Brockington IF: Pathological fear of cot death. Psychopathology 1998;31:246–249. Sved-Williams AE: Phobic reactions of mothers to their own babies. Aust NZ J Psychiatry 1992;26:631–638. Bydlowski M, Raoul-Duval A: Un avatar psychique méconnu de la puerpéralité: La névrose traumatique post-obstétricale. Perspect Psychiatr 1978;4:321–328. Trotula of Salerno (11th Century): The diseases of women. A translation of Passionibus mulierum curandorum by Elizabeth Mason-Hohl. The Ward Ritchie Press, 1940. de Castello Branco RJ: Second Century. 1551, 1620. Ledelius S: Melancholia in praegnantibus. Miscellanea curiosa sive ephemeridum medico-physicarum germanicorum academiae naturae curiosorum, observation 28, 1696. Schultzius G: De melancholia ex utero; in puerpera observata et curata; thesis, Frankfurt, 1705. Esquirol JED: Observations sur l’aliénation mentale à la suite de couches. J Gén Méd Chir Pharm Fr Étrang 1818;1:148–164. Menzies WF: Puerperal insanity. An analysis of 140 consecutive cases. Am J Insanity 1893;50: 148–185. Castro R: De universa mulierum medicanovo et antehac a nemine tentato ordine. Hamburg, 1617, p 314. Hoppe H: Symptomatologie und Prognose der im Wochenbett entstehenden Geistesstörungen (zugleich ein Beitrag zur Lehre von der acuten hallucinatorischen Verwirrtheit). Arch Psychiatr Nervenkr 1893;25:137–210. Meyer E: Zur Klinik der Puerperalpsychosen. Allg Z Psychiatr 1901;58:700–706. Cruickshank WH: Psychoses associated with pregnancy and the puerperium. Can Med Assoc J 1940;74:571–576. Calmeil LF: De la folie, considérée sous le point de vue pathologique, philosophique, historique et judiciaire. Paris, 1845. Hume D: Commentaries on the law of Scotland, respecting the description and punishment of crimes. Edinburgh, Bell; in Hunter R, McAlpine I (eds): Three Hundred Years of Psychiatry. London, Oxford University Press, 1963.

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30 31 32 33 34 35 36

Dapping S (Frankenthal): Gutachten über den Seelenzustand der Charlotte Sorg, welche am 10ten März 1822 drei ihrer Kinder tötete. Henkes Z Staatsarzneik 1823;5:340–375. Teilleux: Triple infanticide. Rapport médico-légal sur l’état mental d’Adèle-Hélène BrevardLacroix, femme Donnier-Blanc. Ann Méd Psychol (Paris) 1865;5:419–454. Dumas E: Du libéricide ou meurtre des enfants mineurs par leurs parents; thèse, Lyon, 1892. Perrussel G: L’Homicide altruiste des mélancoliques et des persécutés; thèse, Paris, 1923. Harder T: The psychopathology of infanticide. Acta Psychiatr Scand 1967;43:196–245. Gordon RE, Gordon K: Some social-psychiatric aspects of pregnancy and childbearing. J Med Soc NJ 1957;54:569–572. Main TF: Mothers with children in a psychiatric hospital. Lancet 1958;ii:845–847.

Prof. emer. Ian Brockington Lower Brockington Farm Bredenbury Herefordshire HR7 4TE (UK) E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 6–27

Diagnostic Classification of Perinatal Mood Disorders Anita Riecher-Rössler, Anke Rohde Psychiatrische Poliklinik, Universitätsspital Basel, Basel, Schweiz

About 25–40% of mothers suffer from mood lability and mild depression during the first week after parturition called postpartum blues or postpartum dysphoria, about 10–15% suffer from a depressive disorder and one or two of every thousand women present with psychosis during the infant’s first year [1–5; for reviews, see ref. 6–9]. These disorders were traditionally called ‘postpartum disorders’. But what is so special about these disorders that we even use a specific diagnostic label for them? Do they have a specific aetiology? And, if not, is it nevertheless justified to use this term, as these disorders confront us with specific problems and needs? Recently, attention has also been drawn to the fact that depression during pregnancy is not less frequent than at any other given time in a woman’s life [10] and that other disorders, especially anxiety and posttraumatic stress disorders, can emerge in the postpartum period, at times with very unique presentations and causing very specific problems. Thus, the question to be put forward is whether these disorders should have a separate entry in our classification systems. ‘Postpartum Depression’ and ‘Postpartum Psychosis’ – Should We Keep These Diagnostic Labels?

Methodological Problems The traditional ‘textbook’ presentation of the diagnostic classification of perinatal mood disorders usually includes a table labelled as ‘the continuum of

Table 1. Mental disorders in the postpartum period Characteristics

Frequency, %

Postpartum blues

mild depression with mood lability and tearfulness, during the first postpartum week, self-limiting

25–40 (80)

Postpartum depression

all types of depressive disorders, during the first postpartum months/year

10–15

Postpartum psychosis

depressive, manic, schizo-affective, schizophrenic or atypical symptoms, during the first postpartum months

0.1–0.2

postpartum emotional reactions’ listing maternity blues at one end, postpartum depression in the middle and psychosis at the other end of the spectrum (table 1). However, reviewing the literature, neither the diagnostic categories ‘postpartum depression’ nor ‘postpartum psychosis’ or ‘postpartum blues’ have so far been exactly defined [for reviews, see ref. 6, 7, 11]. Thus, for example, psychotic depression is in some studies categorised as psychosis, but in other studies as depression. Moreover, the time period ‘postpartum’ is not unequivocally defined, differing between 6 weeks [e.g. 12, 13] and 12 months [e.g. 14, 15]. While some studies refer to an incidence, i.e. new onset of a disorder during this period, others refer to new-onset episodes and others to prevalence, i.e. including pre-existing ongoing diseases as well. Postpartum blues is even less clearly defined [for reviews, see e.g. ref. 6, 16, 17], with the consequence of very strongly differing prevalence rates in the different studies. This unclear definition and classification of postpartum disorders has lead to severe problems in research. In fact, although using the same diagnostic labels, different studies have examined quite different patient groups with the consequence of quite inconsistent results. Thus, e.g. in a study examining women during the first 6 weeks postpartum only, the kind and frequency of disorders found will quite distinctly differ from the results of a study looking at the entire postpartum year. Inconsistent and contradictory results are of course not only due to the described problems of definition and classification, but also to other methodological shortcomings of studies. Thus, only few studies have been based on representative populations or examine control groups. Standardised diagnostic systems have not always been used and some studies rely on self-assessments only [e.g. 18–20]. However, problems of definition and classification have in our opinion so far been one of the main obstacles for research.

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Table 2. ICD-10 classification of postpartum depression Code (1) Presenting psychiatric disorder ⫹ (2) O 99.3 for ‘mental disorder complicating puerperium’ Only use exceptionally F53: Mental and behavioural disorders associated with the puerperium, not elsewhere classified commencing within 6 weeks of delivery not meeting the criteria for disorders classified elsewhere because of insufficient information or because of special additional features F53.0 Postpartum depression F53.1 Postpartum psychosis F53.8 Other disorders F53.9 Unspecified

Current Classification Systems The current diagnostic systems have different approaches to the classification of postpartum disorders. ICD-10 [21] suggests to code mental disorders associated with the puerperium according to the presenting psychiatric disorder, i.e. with the usual classification number, while a second code (O 99.3) indicates the association with the puerperium. However, in exceptional circumstances, ICD-10 also allows a special code, F53, to be used if there is ‘insufficient information’ to classify according to given classification criteria or if ‘special additional features’ are noted (table 2). This latter statement has opened the door for too many options with the consequence that classification has become somewhat arbitrary. In fact, F53 is sometimes used just because symptomatology – such as the content of depressive thoughts – is influenced by the specific situation of motherhood. Theoretically, F53 only refers to cases with onset within 6 weeks after delivery. However, it has also often been used if the onset was earlier (pre-existing disorder) or later and in fact, ICD does not clearly state if this time criterion refers to the first onset of a disorder only or also to the onset of an episode of a recurrent disorder. This makes classification even more problematic. Therefore, F53 should only be a ‘rest’ category for cases which do not fulfil the other criteria (i.e. depressive episode). DSM-IV [22] only offers special classification possibilities for mood disorders, i.e. a ‘postpartum onset specifier’ can be applied to all mood disorders in

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Table 3. DSM-IV classification of postpartum depression Postpartum onset ‘specifier’ Can be applied to mood disorders only Refers to current or most recent episode Onset of episode within 4 weeks postpartum Cannot be coded

addition to standard classification. It refers to the current or most recent episode if the onset of the episode lies within the first 4 weeks postpartum (table 3). However, this specifier cannot be coded in DSM-IV. There is no specific classification of maternity or postpartum blues as this is a very brief, self-limiting episode with mild depression and mood lability with minimal dysfunction. It occurs in the first days after delivery and usually resolves within hours or days without any treatment. In the following sections, we will therefore focus on postpartum depression and postpartum psychosis.

Specific Entities? What is so specific about ‘postpartum depression’ and ‘postpartum psychosis’ that these terms were coined? Are they really different diagnostic entities with descriptive, construct and predictive validity according to the criteria of Spitzer and Williams [23]? If this were the case, they should e.g. show a specific symptomatology, specific risk factors and a specific course [11]. Specific Symptomatology? Postpartum depression does not show a very specific symptomatology, i.e. no high descriptive validity. Patients with postpartum depression may rather present with all different symptoms of the classical forms of depression [3, 24]. These symptoms are principally not different from the symptoms known to occur with mood disorders not related to childbearing. However, additionally, emotional lability similar to that seen in the blues has often been described. Furthermore, having a newborn also influences the cognitive content of depression. Postpartum depressed mothers often feel guilty for not being good enough mothers, are preoccupied with, at times, irrational worries about the wellbeing of the infant and many of them report obsessional thoughts, e.g. of harming their child [25–27]. Many mothers complain about their inability to have any warm feelings for their newborns. This is very often the reason to seek help.

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In severe or psychotic depression, again, symptoms may be non-specific, but in addition to the risk of suicide [28], there is also the added risk of infanticide as part of an ‘extended suicide’ [25] (also compare Spinelli, this volume). All in all, symptomatology is not specific, but influenced by the specific situation of being a mother of a newborn. In other words, the special situation of the mother only plays a ‘pathoplastic’ role. The same seems to be true for postpartum psychoses [8, 29–33]. Patients with postpartum mania (usually as part of a bipolar disorder) may for example present with delusions of grandiosity which are projected onto the child (e.g. the baby is believed to be Jesus). Besides these postpartum-specific contents of delusions, symptomatology of psychoses in the postpartum period usually does not differ from that of psychoses occurring independently from parturition. Also the frequency distribution of the different types of psychoses (affective vs. schizophrenic psychosis and their subtypes) seems to correspond to the usual distribution [3, 34]. Although a strong link to bipolar affective and schizoaffective psychoses has been noted [8, 35], it has not clearly been shown that these disorders are overrepresented in women with newborns as compared to women of the respective age group without delivery. The majority of the so-called ‘atypical’ psychoses with disorientation, confusion and amentia, as often described some decades ago [36], might have been of organic or exogenous origin due to obstetric complications, e.g. sepsis or eclampsia [9]. With the progress in medical care, these presentations have become very rare. If atypical psychoses still occur in the postpartum time, diagnosis should be made according to the diagnostic system used (e.g. delirium). Specifically High Incidence or Prevalence? The prevalence of postpartum depression depends on the diagnostic criteria used and the time period observed. Looking at studies with standardised diagnoses only, the reported prevalence rates vary between 6.5 [14] and 22% [13, for review, see ref. 6]. Based on a meta-analysis of 59 studies, the mean 1-year prevalence rate is as high as 13% [37]. In studies which used self-rating scales only, such as the Edinburgh Postnatal Depression Scale (EPDS) [38], the estimated rates were even higher [e.g. 18, 19, 22]. However, probably not all of those depressive syndromes would meet diagnostic criteria if a standardized instrument for diagnosis was applied. There has been some controversy about the question whether the risk for depression is increased in the postpartum period. Most studies, however, find prevalence rates comparable to that in the non-childbearing population [for reviews, see ref. 6, 25]. O’Hara et al. [1], in a case-control study, compared 182 childbearing with 179 non-childbearing women matched for age, marital status, job and number of children. Using research diagnostic criteria for major

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depression, in the first 9 postpartum weeks no significant differences in prevalence were found. However, postpartum women suffered from milder subthreshold depression associated with physical complaints, sexual dysfunction and partner problems. Cox et al. [39], who also conducted a case-control study using research diagnostic criteria, could not find an enhanced prevalence during the first year either, but he observed an enhanced incidence of depression in the first 5 postpartum weeks. Thus, there might be an enhanced risk of mild depression and possibly also a slightly enhanced incidence of major depression in the first postpartum weeks; however, thereafter, risk seems to be similar to that of other women of the same age group who – according to the large epidemiological studies [e.g. 40–42] – have quite a high risk for depression anyway. The 1-year prevalence rate of depression reaching the diagnostic threshold does not seem to be enhanced. This is obviously quite different in psychosis. The incidence of psychosis in the postpartum period seems to be significantly enhanced. Kendell et al. [5] reported a 22-fold increased risk in the first postpartum month and an only slightly less increased risk during the next 2 postpartum months as compared to the 2 years before childbirth. Terp and Mortensen [2] compared admission rates of puerperal women (within 91 days after delivery) with admission rates among non-puerperal women in the general Danish female population and found especially the risk of first admissions increased. Specific Aetiology or Pathogenetic Mechanisms? If postpartum disorders were specific entities, they would also show a specific aetiology, i.e. a ‘construct validity’ [23]. When the diagnostic labels ‘postpartum disorders’ and ‘postpartum psychosis’ were introduced, some researchers hypothesized that these were specific entities with specific aetiologies. Nowadays, most researchers have abandoned this theory. They rather agree that in the postpartum period, we see in principle the same disorders that can also be seen independently from parturition [e.g. 3, 8, 9, 43]. There does not seem to be a specific aetiology in the strict sense. However, there might be a specific psychoneuroendocrine vulnerability in some of the mothers concerned. Moreover, delivery and the changes and burdens of the perinatal situation might act as specific triggers. The main risk factor which has been identified is an individual predisposition for the respective disorder quite independent of parturition. About one third of all women with postpartum depression and about 15% of all women with postpartum psychosis had already been suffering from similar episodes earlier on even without a delivery, and there is often a corresponding family history [12, 13, 31, 34, 36, 44, 45; for a review, see ref. 6]. A further sign of the underlying

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general vulnerability of many of these mothers is the risk of relapse, which also exists independently of further deliveries (especially in psychosis), although it is especially high just after further deliveries [46–48]. This vulnerability mainly seems to be genetically transmitted. Thus, genetic factors have been shown to explain 25–38% of the variance of postnatal depression in a twin study [49]. A vast amount of other risk factors and predictors have been found in different studies, but have not consistently been replicated [for reviews, see ref. 6–8, 11, 50, 51]. Thus, women with postpartum depression as compared to women who stay healthy after delivery show neither differences regarding actual hormonal or obstetrical factors nor regarding psychosocial factors like age, family status, education or socio-economic status. Apart from the individual, partly genetic predisposition, the only additional predictors consistently found were anxiety and depression already during pregnancy, baby blues, stress in child care or general stress, little social support and marital problems [for meta-analyses, see ref. 37, 52, 53]. However, it is not clear to what extent these predictors are of pathogenetic relevance and to what extent they are early consequences of the beginning depression [7, 11]. Thus, the pathogenetic model for developing postpartum depression or psychosis seems to correspond to the general vulnerability-stress model of depression. If a woman is predisposed to depression or psychosis, normal parturition and normal postpartum changes can trigger the outbreak of the disorder or enhance a pre-existing disease and also influence its symptomatology and course. Giving birth to a child with all its consequences seems to act as a major stressor – not only in the sense of a psychosocially stressful life event, but also in the sense of a biological stressor. Concerning biological stressors, we know for example that during pregnancy, the oestrogen serum level is increased about 200-fold and drops to normal values within a few days after delivery. If a woman is breast-feeding, values even drop to subnormal. On the other hand, we know that oestrogens can modulate many neurotransmitter systems like the serotonergic, the noradrenergic, the dopaminergic, the GABA system and also influence many other brain activities in a way that they have even been called ‘nature’s psychoprotectants’ [54–56]. The sudden drop of oestrogens might especially contribute to the mood lability of the postpartum blues [6, 16] and to the outbreak of psychosis [55, 57]. However, it might also be relevant in postpartum depression, especially if oestrogen deficiency is sustained during breast-feeding. Interestingly, Bloch et al. [58] found that an artificial induction of a drop in oestrogen levels provoked depression in 63% of women with a history of postpartum depression, but not in women without such a history. This underlines the importance of a specific vulnerability, but also of the oestrogen withdrawal as a specific trigger.

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On the other hand, there is probably hardly any life event which is emotionally more stirring than giving birth to a child. In the period thereafter, the mother has to cope with massive psychosocial changes in almost all areas of her life, with multiple burdens, role changes and role conflicts, losses and ambivalences. Thus, new motherhood can also be a massive psychosocial stressor which can trigger the outbreak of a disease in the postpartum period. This does not seem to be true for depression only, but also for psychosis. Thus, the observation that in primiparae the risk of psychosis is even more severely enhanced than in multiparae [5, 43, 47] could be a consequence of these psychosocial stressors, which are probably higher for first-time mothers than for experienced mothers. All in all, while hormonal influences seem to be very important for provoking blues and psychosis in (genetically) vulnerable women, psychosocial factors might be of more relative importance in depression. Specific Course? The third prerequisite required for a specific entity would be a predictive validity, e.g. a specific course. It has sometimes been reported that postpartum psychoses show a slightly better course than disorders occurring at other times of women’s lives [31, 59]. However, long-term studies could not confirm this. It could rather be demonstrated that course and outcome are similar to the respective diagnostic category without postpartum onset [60]. If there are any differences, they are not very marked and could be explained in the framework of the vulnerability-stress model. Thus, giving birth and adapting to the new mother role are obviously major stressors. If a disorder is provoked by such a massive stressor only, the underlying vulnerability to the respective disorder might not be very high. After waning of this stressor, the further course of these disorders might thus be quite mild due to the relatively low underlying vulnerability. In conclusion, it has to be stated that postpartum depression or postpartum psychosis do not seem to be valid entities with a specific aetiology, symptomatology or course. Nevertheless, depression as well as psychotic disorders can be strongly influenced by parturition and early motherhood.

Specific Needs Specific Consequences of Postpartum Disorders Depression as well as psychosis in the postpartum period need our special attention and specific treatment, as they can have particularly severe consequences not only for the mother, but also for the infant and the whole family.

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We very often see vicious circles in these cases, which we have to interrupt at a very early stage. Thus, the early mother-infant bonding is often severely impaired, as the mothers concerned often have difficulties in making emotional contact with their infants [61]. Depressed mothers realize this, react with feelings of guilt, which enhances depression, and the vicious circle starts. In fact, the children of these mothers may not only develop emotional and behavioural difficulties, but also a delay of their cognitive development, especially if the mother-infant interaction is disturbed [for reviews, see ref. 8, 62–64]. Pawlby et al. [65] presented very alarming results from a prospective study showing cognitive deficits, especially in boys, even until the end of primary school. Mothers with psychotic disorders might have even severer problems of interaction. During acute psychosis, they might not only neglect the child, but even show dangerous behaviour. In severe cases, they might harm or even kill their own child, e.g. due to delusions or imperative voices, although this is very rare [66] (see also Spinelli, this volume). Specific Treatment Delay Unfortunately, diagnosis and treatment of depressive disorders in the postpartum period are often seriously delayed [67, 68]. Feelings of shame and many fears prevent mothers from seeking help. Furthermore, they often do not realize that they suffer from a disease. Depressed mothers might rather feel that they fail as a mother. In a working class population in Scotland, McIntosh [69] could show that only one quarter of the women concerned sought professional help. Most women stated that medicine could not help anyway. They also feared to be stigmatized as mentally ill or to be separated from their babies. Furthermore, in some cases, doctors and midwives might not listen sensitively enough or misinterpret symptoms as stemming from normal exhaustion due to delivery and child care. Mothers with psychosis in the acute stages of their disease often show an illness-inherent lack of illness insight. During phases of remission, they might nevertheless be reluctant to seek help because of the realistic fear that the infant could be taken away from her care. A lack of specific, low-threshold treatment offers and facilities further contributes to the treatment delay [68]. Specific Therapeutic Needs Having the vulnerability-stress model as pathogenetic model in mind, therapy must be directed not only to the underlying vulnerability, but also to the actual biological and psychosocial stressors/triggers. This means that therapy – although in principle the same as the classical therapy for these disorders – has to put a special emphasis on the needs of the postpartum period.

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In depressed mothers, education about the fact that this is a disease and not due to failure as a mother is of utmost importance to relieve the patients from feelings of guilt. Counselling and practical advice for the mother and her family is often needed as well as the help of a midwife, a family nurse, a social worker and/or other health care professionals. A good mother-infant bonding and relationship should be a main concern from the start [8]. This means that the mother should not be separated from her infant for longer periods of time. However, she needs a lot of help in order to allow for relaxed contacts with the infant. Baby massage and mother-infant play therapy can be helpful, especially if there are bonding problems [25, 70, 71] (see also O’Higgins et al., this volume). Psychotherapy should be initiated as soon as possible and should be very supportive in the beginning. It has only recently been realized that this specific situation might need specific psychotherapeutic approaches taking into account specific problems such as the role changes of the women or the relationships with the infant and the partner. Thus, e.g. Stuart and O’Hara [72] developed a specific manualized interpersonal psychotherapy for women with postpartum depression, whereas Riecher-Rössler and Hofecker-Fallahpour [11] and Hofecker-Fallahpour et al. [73, 74] have developed a specific group therapy for depressed mothers with young children (see also Hofecker-Fallahpour and Riecher-Rössler, this volume). Fathers should be involved as much as possible [7, 8], as father-infant bonding and good care by the father seem very important, especially if the mother suffers from recurrent illness. In some cases, also couple therapy might be indicated, as we know that the relation of couples can be severely disturbed in postpartum depression [1]. If medication is needed, breast-feeding has to be discussed with the mother, as all psychotropics are secreted into breast milk (although to different degrees) and effects of even trace amounts of medication on the developing brain cannot be safely excluded, as so far there have been not enough methodologically sound long-term studies with sufficient numbers of cases [for reviews, see e.g. ref. 10, 75, 76] (see also Stowe et al., this volume). Mothers are often reluctant to stop breast-feeding, and it might be helpful to offer baby massage as a substitute regarding the physical contact part of breast-feeding and potentially also regarding its positive psychological, physiological and hormonal effects (compare O’Higgins et al., this volume). However, the risks of ongoing psychosis or severe depression or a relapse are certainly higher than the potential risks of medication [77]. Thus, if after balanced information about the potential risks, a mother still decides to breast-feed, she has to be educated about side-effects and the baby has to be carefully monitored regarding these effects [75, 77] (for review, see also Stowe et al., this volume).

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In the meantime, some studies have also shown positive effects of oestrogen treatment in postpartum depression [78–80] and psychosis [81] (see also Ahokas et al., this volume) especially if there is a sustained postpartum oestrogen deficiency, although large controlled studies are still lacking. Non-pharmacological treatments such as bright light therapy could also be promising new approaches [82] (see also O’Higgins et al., this volume). Hospitalization is often needed, especially if the safety of the mother or infant cannot be guaranteed because of acute psychosis or severe depression. However, mothers are often very reluctant, as they cannot bear the separation from their child, and develop even more feelings of guilt. Moreover, the motherchild relationship can be severely hampered by the separation. In some countries, starting in Great Britain [83], mother-baby units have therefore been implemented, which allow the admission of mothers together with their infants. These units can also offer evaluation of the quality of the relationship and care for the infant as well as a respective training and therapy if needed. However, it has to be stated that in most countries, the number of available mother-baby units does not meet the needs. Domiciliary assessment, home treatment, day hospital and day care centre, motherhood classes or playgroups for parents with their children are also urgently needed. Very important to note is also that women in the peripartum period have a special need to be cared for by multidisciplinary teams including not only psychiatrists and psychologists, but also gynaecologists/obstetricians, paediatricians, midwives, social workers and sometimes also lawyers for medicolegal advice or child protection agencies.

Specific Classification? In conclusion, it has to be stated that neither postpartum depression nor psychosis are specific entities which would need separate entries in classification systems. There is neither evidence for a specific aetiology nor for a clearly distinct psychopathology or long-term course and outcome [6, 11]. The prevalence of severe depression is not significantly enhanced in the first year postpartum as compared to women of the same age group without delivery who have quite a high prevalence of depression anyway. Only in the first postpartum weeks might the prevalence of mild, subthreshold depression be slightly enhanced and potentially also the incidence of depressive disorders. It is mainly in the first postpartum months that first onset and probably also the remanifestation of pre-existing psychosis seem to present excessively in vulnerable women.

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Giving birth and adapting to the new mother role seem to be stressors which can trigger the outbreak of depression and especially of psychosis in vulnerable, predisposed women or enhance a pre-existing disorder. Biological, especially hormonal, as well as psychosocial factors can be relevant stressors in this situation. Although these are no specific entities, the diagnostic terms or better specifiers ‘postpartum depression’ and ‘postpartum psychosis’ might still be justified, as these disorders in early motherhood show many important specificities. Apart from the fact that giving birth seems to be a special trigger, there are also specific needs in diagnosis, treatment and care. Diagnosis is particularly difficult, as women, due to shame, stigma and many fears, do not seek help, and doctors, due to misinterpretation of symptoms, sometimes do not recognize the severity of the situation. Untreated, these disorders can have severe consequences, not only for the mother, but also for the child and the whole family. Therefore, these disorders need our special attention. They also need special treatment with modifications of our pharmacological, non-pharmacological and psychotherapeutic methods. Furthermore, new services are necessary, such as special low-threshold outpatient clinics with attached child care, mother-baby units, day clinics and day centres for mothers. Support for the mother and the father for establishing a good bonding and relationship with the infant is of utmost importance, not only to improve the course of the disorder in the mother, but also to avoid traumatization of the infant with all its potential long-term consequences. This means that – as suggested in the DSM and ICD – depressive and psychotic disorders associated with the postpartum period should primarily be coded according to the presenting psychiatric disorder. However, the diagnostic specifier or additional coding of ‘during postpartum period’ should be allowed for and encouraged. This additional coding should in the future be used according to clearer criteria as concerns incidence or prevalence or the exact time period covered. Thus, as the above-named specific problems do not only concern new-onset cases, the specifier should also be used for pre-existing disorders, and as the specific needs involve at least the first postpartum year, this time period should be covered. Used in this way, such an additional coding would be of great practical value. Coding of postpartum blues has as such not been possible so far. In line with our argumentation, it would be feasible to classify it as an ‘adjustment disorder of short duration’ with a postpartum onset specifier – if the psychiatric classification is necessary at all. One would, however, have to bear in mind that it is not a psychological adjustment only, but also a physiological, probably hormonal one [6, 16, 17].

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Other Postpartum Disorders

Post-Traumatic Stress Disorders after Childbirth One important differential diagnosis if a patient is presenting severe depressive symptoms after childbirth is post-traumatic stress disorder (PTSD). This disorder has not been very well known in obstetrics as well as in psychiatry until recently, although epidemiological data show that it is not a rare event. In a Swedish cross-sectional study with 1,640 women, Wijma et al. [84] found a PTSD prevalence of 1.7% after childbirth. A prospective study in England [85] showed a comparable percentage of 1.8% women (out of 289) developing PTSD symptoms within 6 months after delivery. A current study from the USA found a percentage in the same range of 1.9% out of 103 women. Thirty-four per cent of these women reported traumatic birth experiences, 30.1% of them were only partially symptomatic [86]. All the typical symptoms of PTSD are present in severe cases. The trauma, in this case the delivery, is persistently re-experienced, nightmares and uncontrolled recollections (‘flashbacks’) occur. The patient avoids contact with other mothers or talking about the delivery. Other typical PTSD symptoms are enhanced physiological reactivity when exposed to internal or external cues, loss of interest, sleep difficulties and in some cases the wish for compensation or restitution. In clinical practice, the patients show affective symptoms like depressive mood, restlessness, loss of energy, feelings of insufficiency and numbing. Often anxiety symptoms can be found like worrying, feelings of concern or generalized anxiety. Also formal thought disorders such as ruminating, poor concentration or constricted thinking are reported. There seem to be certain predisposing factors for the development of PTSD. One important aspect is the patient’s personality. A high need for control, a distinct rationality or an intense sense of decency can rise the risk for PTSD after childbirth [87]. Other predisposing factors are an individual history of sexual abuse, former traumata or psychiatric disorders. Although the delivery method itself is not of importance, PTSD seems to occur more often when the delivery is finished by secondary caesarean section, in most cases after a long and painful period of trying to give birth in a normal way. Subjective perceptions, like the feeling of menace or threat in this situation, the feeling of helplessness or being at someone’s mercy seem to be more important than the ‘objective’ situation. Furthermore, a long duration, ‘unbearable’ pain, loss of control and offending the sense of decency is often reported as well as a lack of information during and after delivery and the perception that the people involved are insensitive, inconsiderate or thoughtless. Soet et al. [86], in their study of 103 patients mentioned above, identified the pain experienced during

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birth, levels of social support, self-efficacy, internal locus of control, trait anxiety and coping as significant predictors of the development of PTSD after childbirth. If the patient’s perceptions of a traumatic birth lead to a subsyndromal form or even full-blown PTSD and the symptoms are not treated, most women develop problems during future pregnancies, if they do not avoid to get pregnant again anyway. Further pregnancies are often accompanied by severe anxiety, panic and re-actualisation of PTSD symptoms. These patients have a higher need for medical care and not seldom the wish for a ‘controlled birth’, for example an elective caesarean section. The treatment of PTSD after childbirth is the same as for any other posttraumatic disorder, i.e. mainly a psychotherapeutic one, if possible using trauma-specific techniques. Psychopharmacological treatment with an SSRI can be useful, if depression and hyperarousal are prominent symptoms.

Obsessive-Compulsive Disorder Obsessional symptoms can occur in two ways in connection with a delivery. Rather frequent is the occurrence of obsessions of hurting the child (or even infanticide) as symptoms of postpartum depression (41% of postpartum depressed mothers compared to 6.5% of non-depressed mothers [27]). On the other hand, also an independent obsessive-compulsive disorder (OCD) can manifest for the first time after delivery [88, 89]. The exact incidence or prevalence rates of postpartum-onset OCD are unknown, but pregnancy and childbirth are by some authors believed to be among the main precipitants of obsessional disorders [for reviews, see ref. 9, 90]. If a patient already suffered from OCD before pregnancy, a worsening of the symptomatology is also possible. While obsessive symptoms as part of postpartum depression respond very well to the usual treatment strategies such as cognitive-behavioural psychotherapy and antidepressants (preferably a serotonergic agent), OCD with postpartum onset shows a tendency to chronicity.

Other Anxiety Disorders All anxiety disorders, especially panic disorder, can be influenced by pregnancy and delivery or manifest for the first time in the postpartum period [8, 91, 92]. All in all, postpartum anxiety disorders may be more common than depression [93, 94]. Regarding panic disorder, the postpartum period may be a

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time of particular vulnerability. Panic attacks can also be a prominent symptom of postpartum depression [95], which in clinical practice could justify the differentiation of a ‘panic type’ of postpartum depression [96]. Especially for pregnant and breast-feeding women, psychotherapy should be the first-line treatment, although in severe cases also the use of antidepressants can be indicated and without relevant problems. A serious risk-benefit discussion is, however, necessary in these cases.

Disorders during Pregnancy

The incidence of new mental disorders and their prevalence during pregnancy seem to be similar to the 12-month incidence of mental disorders in women of the same age group without pregnancy, according to a review recently published by Halbreich [97]. However, similarly to a disorder in the postpartum period, a mental disorder during pregnancy can have particularly severe short-term and long-term consequences. A higher rate of perinatal complications, preterm deliveries, low birth weight, postpartum depression and a longer-term impact on the child’s development have been reported [for a review, see ref. 97]. This means that questions of therapy, especially pharmacotherapy (for which we refer to the article by Ross et al., in this volume), are very specific ones, not only in the postpartum period, but also during pregnancy. It would therefore be of high clinical utility to label mental disorders during this period with the specifier ‘during pregnancy’.

Mood Disorders Changes of mood – positive as well as negative changes – and rapid mood swings are not unusual during pregnancy. They can be triggered for example by the individual perception of the pregnancy, the actual social situation and partnership or somatic changes and symptoms. Furthermore, an influence of the extreme hormonal changes during pregnancy can be postulated. The most frequent affective symptoms during pregnancy are depressive symptoms and anxiety, but also euphoria or hypomania and irritability. While euphoria or hypomania only rarely lead to a psychiatric consultation because the women in most cases do not suffer, depressive symptoms and anxiety are more frequent reasons for seeking help. Bennett et al. [10] have recently reviewed 29 studies carried out between 1985 and 2003, which investigated the number of depressive women during pregnancy using different instruments (i.e. BDI, SADS, SCID, EPDS). They calculated the average

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percentage of depressive patients with 18.3 (with a broad range from 2 to 50%). Rates determined by a structured interview were much lower and ranged from 2 to 21%. Not all instruments used have been validated for pregnancy and it is possible that pregnancy-related somatic symptoms have been measured and weighted as depressive symptoms, thus leading to false-positive diagnoses and too high estimations of incidence and prevalence rates. It might thus well be that incidence and prevalence of depression during pregnancy do not substantially differ from the rates at other times in women’s lives. Nevertheless, it can be argued quite similarly as in postnatal depression that depression during pregnancy needs our specific attention. Thus, a major percentage of the women concerned will not get adequate pharmacological treatment because of the fear of negative effects on the unborn child and yet, at the same time, the possible consequences of untreated depression are especially severe during this period including substance abuse, functional impairment, increased risk of postnatal depression and poor pregnancy outcomes [10, 98].

Anxiety Disorders Regarding panic disorder, pregnancy has for a long time been believed to be protective [for a review, see ref. 90], which has, however, not been supported by a prospective study [99]. The onset or worsening of OCD during pregnancy has also been frequently described [for a review, see ref. 90]. Symptoms of all anxiety disorders can be so severe that in some cases patients even consider an interruption of the pregnancy because they feel they cannot bear the symptoms until delivery and/or the fear of the adverse effects of medication on the unborn. Furthermore, anxiety during pregnancy has been associated with an increased incidence of perinatal complications [for a review, see ref. 90] and postpartum depression [100].

Psychoses If psychoses or bipolar disorder occur during pregnancy, it is rarely the first manifestation. More frequently, it will be the relapse of a pre-existing illness, i.e. when because of the pregnancy or because of the wish for a child a successful pharmacological prophylaxis was stopped – in some cases, very soon after diagnosing pregnancy. The danger of relapse after stopping the prophylaxis is especially high for bipolar disorders [101].

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Summary and Conclusions

The diagnostic terms ‘postpartum depression’ and ‘postpartum psychosis’ are still widely used. This paper discussed if this is still justified in the light of recent research and if also other postpartum disorders or disorders during pregnancy should have a special entry or term in our classification systems. Based on a comprehensive review of the literature, it has to be stated that ‘postpartum depression’ or ‘postpartum psychosis’ are no specific entities in terms of having a specific aetiology, symptomatology or course. Rather, giving birth to a child with all its biological and psychosocial consequences seems to act as a major stressor, which – within a general vulnerability-stress model – can trigger the outbreak of all classical disorders in predisposed women. Symptomatology, although sometimes influenced by the specific situation of (new) motherhood in a ‘pathoplastic’ way, principally corresponds to the typical symptomatology of the classical disorders. The same is true for the course. From a scientific point of view, the concept and term ‘postpartum depression’ should therefore be abandoned as it is not a specific valid entity. A further use of this concept might even hinder research as postpartum illnesses include – as we have shown – a variety of classical disorders which have to be clearly differentiated from each other [see also ref. 8]. So far, these illnesses might sometimes have been too uncritically categorized under ‘postpartum depression’. However, there are good reasons to continue to use ‘postpartum’ as a diagnostic ‘specifier’, i.e. as an addendum to the main diagnostic category (as in DSM-IV). Thus, in many cases, becoming mother in fact seems to trigger the onset or relapse of a disorder. Giving birth not only seems to be a unique psychosocial stressor in the sense of a life event, which is associated with a massive emotional upstirring, it also is a biological stressor inducing massive hormonal and other changes. Furthermore, some women seem to have a specific ‘psychoneuroendocrine’ vulnerability, which might lower the threshold for the outbreak of a disease and potentially also influence symptomatology, e.g. contribute to emotional lability. Most importantly, mental disorders in early motherhood confront us with specific needs and call for specific treatments. Thus, help seeking is often delayed due to shame and stigma, and diagnosis is often missed due to misinterpretation of symptoms. Services often do not adequately meet these women’s needs, as they do not take into account their specific situation, problems and fears. Untreated, post- and peripartum disorders can have especially severe long-term consequences, not only for the mother, but also for the child and the whole family. Therefore, special attention and special treatment is necessary; this includes modifications of our pharmacological, non-pharmacological and psychotherapeutic treatments as well as provision of new low-threshold mother-infant services.

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Finally, ‘postnatal’ depression has proven to be helpful as a lay term and concept [8, 9]. It reduces stigma and encourages mothers to seek help. In fact, a lay movement including self-help groups and lobby groups to improve services has developed based on this obviously very appealing concept. A careful use of the addendum with all the above-named restrictions could therefore be helpful in practice. In conclusion, although postpartum depression or postpartum psychoses are no specific entities from an aetiological point of view, the diagnostic specifier ‘postpartum’ should not be abandoned. Clinical utility would in this case be the criterion for the specifier rather than diagnostic validity, which has also been suggested as worthwhile by First et al. [102]. Other peripartum disorders, such as anxiety, OCD or PTSD, could also be marked with a corresponding ‘specifier’. In line with our argumentation, the postpartum specifier should be used not only for new-onset cases but for all cases prevalent during the first postpartum year – independent of onset – to indicate the specific needs for care and treatment during this period. A ‘pregnancy’ specifier should be introduced correspondingly. Both specifiers would, in our opinion, help to improve clinical practice and research if clearly defined and used as an addendum to the main diagnostic category.

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O’Hara MW, Zekoski EM, Philipps LH, Wright EJ: Controlled prospective study of postpartum mood disorders: Comparison of childbearing and nonchildbearing women. J Abnorm Psychol 1990;99:3–15. Terp IM, Mortensen PB: Post-partum psychoses. Clinical diagnoses and relative risk of admission after parturition. Br J Psychiatry 1998;172:521–526. O’Hara MW: Post-partum ‘blues’, depression, and psychosis: A review. J Psychosom Obstet Gynaecol 1987;7:205–227. Harding JJ: Postpartum psychiatric disorders: A review. Compr Psychiatry 1989;30:109–112. Kendell RE, Chalmers JC, Platz C: Epidemiology of puerperal psychoses. Br J Psychiatry 1987;150:662–673. Riecher-Rössler A: Psychische Störungen und Erkrankungen nach der Entbindung. Fortschr Neurol Psychiatr 1997;65:97–107. Riecher-Rössler A, Hofecker Fallahpour M: Die Depression in der Postpartalzeit – eine diagnostische und therapeutische Herausforderung. Schweiz Arch Neurol Psychiatr 2003;154:106–154. Brockington I: Postpartum psychiatric disorders. Lancet 2004;363:303–310. Brockington I: Diagnosis and management of post-partum disorders: A review. World Psychiatry 2004;3:89–95. Bennett HA, Einarson A, Taddio A, Koren G, Einarson TR: Prevalence of depression during pregnancy: Systematic review. Obstet Gynecol 2004;103:698–709. Riecher-Rössler A, Hofecker Fallahpour M: Postpartum depression: Do we still need this diagnostic term? Acta Psychiatr Scand 2003;418(Suppl):51–56. Paykel ES, Emms EM, Fletcher J, Rassaby ES: Life events and social support in puerperal depression. Br J Psychiatry 1980;136:339–346.

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41

42 43 44 45 46 47 48 49 50

51 52 53 54 55 56 57 58 59

60 61 62 63

64

65 66

Kessler RC, McGonagle KA, Zhao S, Nelson CB, Hughes M, Eshleman S, Wittchen HU, Kendler KS: Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994,51:8–19. Meyer C, Rumpf HJ, Hapke U, Dilling H, John U: Lifetime prevalence of mental disorders in a general adult population. Results of TACOS study. Nervenarzt 2000;71:535–542. Brockington I, Winokur G, Dean C: Puerperal psychosis; in Brockington I, Kumar C (eds): Motherhood and Mental Illness. New York, Grune and Stratton, 1982, pp 37–70. O’Hara MW: Social support, life events, and depression during pregnancy and the puerperium. Arch Gen Psychiatry 1986;43:569–573. Steiner M, Fairman M, Doyle W: Mood disorders with postpartum onset: A family study. Abstract presented at the XIXth CINP Congress, Washington DC. Neuropsychopharmacology 1994;10:176. Davidson J, Robertson E: A follow-up study of post partum illness, 1946–1978. Acta Psychiatr Scand 1985;71:451–457. Rohde A, Marneros A: Postpartum psychoses: Onset and long-term course. Psychopathology 1993;26:203–209. Garfield P, Kent A, Paykel ES, Creighton FJ, Jacobson RR: Outcome of postpartum disorders: A 10-year follow-up of hospital admissions. Acta Psychiatr Scand 2004;109:434–439. Treloar SA, Martin NG, Bucholz KK, Madden PA, Heath AC: Genetic influences on post-natal depressive symptoms: Findings from an Australian twin sample. Psychol Med 1999;29:645–654. Kumar R: Postpartum mood disorders: The psychoses; in Demers L, McGuire M, Phillips A, Rubinow D (eds): Premenstrual, Postpartum and Menopausal Mood Disorders. Baltimore, Urban & Schwarzenberg, 1989, pp 163–172. Boyce PM: Risk factors for postnatal depression: A review and risk factors in Australian populations. Arch Women Ment Health 2003;6(suppl 2):S43–S50. Wilson LM, Reid AJ, Midmer DK, Biringer A, Carroll JC, Stewart DE: Antenatal psychosocial risk factors associated with adverse postpartum family outcomes. CMAJ 1996;154:785–799. Beck CT: Meta-analysis of predictors of postpartum depression. Nurs Res 1996;45:297–303. Fink G, Sumner BE, Rosie R, Grace O, Quinn JP: Estrogen control of central neurotransmission: Effect on mood, mental state, and memory. Cell Mol Neurobiol 1996;16:325–344. Riecher-Rössler A: Oestrogens and schizophrenia. Curr Opin Psychiatry 2003;16:187–192. Bergemann N, Riecher-Rössler A: Estrogen Effects in Psychiatric Disorders. Wien, Springer, 2004. Mahe V, Dumaine A: Oestrogen withdrawal associated psychoses. Acta Psychiatr Scand 2001;104: 323–331. Bloch M, Schmidt PJ, Danaceau M, Murphy J, Nieman L, Rubinow DR: Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 2000;157:924–930. Whiffen VE, Gotlib IH: Comparison of postpartum and nonpostpartum depression: Clinical presentation, psychiatric history, and psychosocial functioning. J Consult Clin Psychol 1993;61: 485–494. Rohde A, Marneros A: Schizoaffective disorders with and without onset in the puerperium. Eur Arch Psychiatry Clin Neurosci 1992;242:27–33. Kumar RC: ‘Anybody’s child’: Severe disorders of mother-to-infant bonding. Br J Psychiatry 1997;171:175–181. Murray L, Cooper J: Postpartum depression and child development. Psychol Med 1997;27: 253–260. Brennan PA, Hammen C, Andersen MJ, Bor W, Najman JM, Williams GM: Chronicity, severity, and timing of maternal depressive symptoms: Relationships with child outcomes at age 5. Dev Psychol 2000;36:759–766. Grace SL, Evindar A, Stewart D: The effect of postpartum depression on child cognitive development and behavior: A review and critical analysis of the literature. Arch Women Ment Health 2000;6:263–274. Pawlby SJ, Hay DF, Sharp DJ: The effects of postnatal depression on the development of boys. Arch Women Ment Health 2001;3(suppl 2):5. Rohde A, Raic D, Varchmin-Schultheiss K, Marneros A: Infanticide: Sociobiographical background and motivational aspects. Arch Women Ment Health 1998;1:125–130.

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Parry BL: Postpartum psychiatric syndromes; in Kaplan HI, Sadock B (eds): Comprehensive Textbook of Psychiatry. Philadelphia, Williams & Wilkins 1995, vol 1, pp 1059–1066. MacArthur C: What does postnatal care do for women’s health? Lancet 1999;353:343–344. McIntosh J: Postpartum depression: Women’s help-seeking behaviour and perceptions of cause. J Adv Nurs 1993;18:178–184. Field T, Grizzle N, Scafidi F, Schanberg S: Massage therapy for infants of depressed mothers. Infant Behav Dev 1996;19:107–112. Onozawa K, Glover V, Adams D, Modi N, Kumar RC: Infant massage improves mother-infant interaction for mothers with postnatal depression. J Affect Disord 2001;63:201–207. Stuart S, O’Hara MW: Treatment of postpartum depression with interpersonal psychotherapy. Arch Gen Psychiatry 1995;52:75–76. Hofecker Fallahpour M, Riecher-Rössler A, Wüsten G, Zinkernagel C, Stieglitz RD: Gruppentherapie für depressive Mütter; in Riecher-Rössler A, Rohde A (eds): Psychische Erkrankungen bei Frauen – für eine geschlechtersensible Psychiatrie und Psychotherapie. Basel, Karger, 2001, pp 307–320. Hofecker Fallahpour M, Zinkernagel Burri C, Stöckli B, Wüsten G, Stieglitz RD, Riecher-Rössler A: Gruppentherapie bei Depression in der frühen Mutterschaft: erste Ergebnisse einer Pilotstudie. Nervenarzt 2003;74:767–774. Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E: The use of psychotropic medications during breast-feeding. Am J Psychiatry 2001;158:1001–1009. Yonkers A, Wisner KL, Stowe Z, Leibenluft E, Cohen L, Miller L, Manber R, Viguera A, Suppes T, Altshuler L: Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161:608–620. Newport DJ, Hostetter A, Arnold A, Stowe ZN: The treatment of postpartum depression: Minimizing infant exposures. J Clin Psychiatry 2002;63(suppl 7):S31–S44. Gregoire AJ, Kumar R, Everitt B, Henderson AF, Studd JW: Transdermal oestrogen for treatment of severe postnatal depression. Lancet 1996;347:930–933. Ahokas A, Kaukoranta J, Wahlbeck K, Aito M: Estrogen deficiency in severe postpartum depression: Successful treatment with sublingual physiologic 17beta-estradiol: A preliminary study. J Clin Psychiatry 2001;62:332–336. Lawrie TA, Herxheimer A, Dalton K: Oestrogens and progestogens for preventing and treating postnatal depression (Cochrane Review); in: The Cochrane Library. Chichester, Wiley, 2004. Ahokas A, Aito M, Turiainen S: Association between oestradiol and puerperal psychosis. Acta Psychiatr Scand 2000;101:167–169. Corral M, Kuan A, Kostaras D: Bright light therapy’s effect on postpartum depression. Am J Psychiatry 2000;157:303–304. MainTF: Mothers with children in a psychiatric hospital. Lancet 1958;ii:845–847. Wijma K, Soderquist J, Wijma B: Posttraumatic stress disorder after childbirth: A cross sectional study. J Anxiety Disord 1997;11:587–597. Ayers S, Pickering AD: Do women get posttraumatic stress disorder as a result of childbirth? A prospective study of incidence. Birth 2001;28:111–118. Soet JE, Brack GA, DiIorio C: Prevalence and predictors of women’s experience of psychological trauma during childbirth. Birth 2003;30:36–46. Pantlen A, Rohde A: Psychische Auswirkungen traumatisch erlebter Entbindungen. Zentralbl Gynäkol 2001;123:42–47. Abramowitz JS, Schwartz SA, Moore KM, Luenzmann KR: Obsessive-compulsive symptoms in pregnancy and the puerperium: A review of the literature. Anxiety Disord 2003;17:461–478. Brandes M, Soares CN, Cohen LS: Postpartum onset obsessive-compulsive disorder: Diagnosis and management. Arch Women Ment Health 2004;7:99–110. Levine RE, Oandasan AP, Primeau LA, Berenson AB: Anxiety disorders during pregnancy and postpartum. Am J Perinatol 2003;5:239–248. Shear MK, Mammen O: Anxiety disorders in pregnant and postpartum women. Psychopharmacol Bull 1995;31:693–703. Villeponteaux VA, Lydiard RB, Laraia MT, Stuart GW, Ballenger JC: The effects of pregnancy on preexisting panic disorder. J Clin Psychiatry 1992;53:201–203.

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93 Matthey S, Barnett B, Howie P, Kavanagh DJ: Diagnosing postpartum depression in mothers and fathers: Whatever happened to anxiety? J Affect Disord 2003;74:139–147. 94 Hertzberg T, Wahlbeck K: The impact of pregnancy and puerperium on panic disorder: A review. J Psychosom Obst Gynaecol 1999;20:59–64. 95 Metz A, Sichel DA, Goff DC: Postpartum panic disorder. J Clin Psychiatry 1988;49:278–279. 96 Rohde A: Psychiatrische Erkrankungen in der Schwangerschaft und im Wochenbett. Gynäkologe 2001;34:315–323. 97 Halbreich U: Prevalence of mood symptoms and depression during pregnancy: Implications for clinical practice and research. CNS Spectr 2004;9:177–184. 98 Freeman MP, Smith KW, Freeman SA, McElroy SL, Kmetz GE, Wright R, Keck PE Jr: The impact of reproductive events on the course of bipolar disorder in women. J Clin Psychiatry 2002;63: 284–287. 99 Cohen LS, Sicher DA, Faraone SV, Robertson LM, Dimmock JA, Rosenbaum JF: Course of panic disorder during pregnancy and the puerperium: A preliminary study. Biol Psychiatry 1996;39: 950–954. 100 Heron J, O’Connor TG, Evans J, Golding J, Glover V: The ALSPAC Study Team. The course of anxiety and depression through pregnancy and the postpartum in a community sample. J Affect Disord 2004;80:65–73. 101 Viguera AC, Nonacs R, Cohen LS, Tondo L, Murray A, Baldessarini RJ: Risk of recurrence of bipolar disorder in pregnant and nonpregnant women after discontinuing lithium maintenance. Am J Psychiatry 2000;157:179–184. 102 First MB, Pincus HA, Levine JB, Williams JBW, Ustun B, Peele R: Clinical utility as a criterion for revising psychiatric diagnoses. Am J Psychiatry 2004;161:946–954.

Prof. Dr. med. Anita Riecher-Rössler Psychiatrische Poliklinik Universitätsspital Basel Petersgraben 4 CH–4031 Basel Tel. ⫹41 61 265 51 14, Fax ⫹41 61 265 45 99, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 28–49

Maternal Adversity,Vulnerability and Disease Stephen G. Matthewsa, Michael J. Meaneyb a

Departments of Physiology, Obstetrics and Gynaecology and Medicine, Faculty of Medicine, University of Toronto, Toronto, and bMcGill Program for the Study of Behaviour, Genes and Environment, Douglas Hospital Research Centre, Montréal, Canada

The probability of chronic illness is strongly influenced by environmental conditions prevailing during development. The frequency of heart disease, diabetes and mental illness is substantially greater amongst those born and raised in poverty, regardless of social class in adulthood. Adversity associated with poverty produces incomplete, dysfunctional families often rife with domestic violence, drug use, child abuse and neglect. Reproduction within this context results in maternal stress, increased risks for infection and thus preterm labour, perinatal deaths, birth insults, poor nutrition for mother and offspring and serious compromises in the quality of parent-child interactions. These conditions define high-risk families. For the child, these conditions bear the potential to influence the development of physiological systems that regulate metabolism and cardiovascular function, as well as neural processes underlying emotion and cognition. These effects form the basis for vulnerability to illness in later life. Perhaps the most dramatic illustration of the relation between adversity in early life and the risk for later illness emerges from studies on birth weight, early growth and health in adulthood. Individuals that were small for gestational age, suggesting some measure of intra-uterine growth restriction (IUGR), are at significantly greater risk for type II diabetes, visceral obesity and hypertension (collectively referred to as the metabolic syndrome). The major predictors of fetal growth restriction and preterm labour are maternal stress, infections, malnutrition and tobacco/alcohol consumption. These risk factors are far more prevalent in low socio-economic status (SES) families and, predictably, low SES emerges as a major risk factor for both IUGR and preterm labour.

It is increasingly clear that growth restriction also predicts an increased risk for mood disorders [1]. Additionally, the risk factors (i.e., maternal stress, tobacco/alcohol use, nutritional deprivation) for IUGR are also the major predictors for attentional deficit disorder (ADD) and, predictably, ADD is far more prevalent in low SES environments. Follow-up studies of growthrestricted infants reveal evidence for problems associated with attention and impulse control, functions that are heavily dependent on the hippocampus and prefrontal cortex. These same brain regions are also among the major sites implicated in both depression and anxiety disorders. Interestingly, growth restriction is also associated with increased behavioural inhibition, shyness and timidity in childhood, all of which appear to be predictors of mood disorders in later life. Studies with primate and rodent models show that the development of the hippocampus is impaired by fetal glucocorticoid exposure or by prenatal stress, and glucocorticoids are a mechanism for fetal growth restriction. Thus, it emerges that impairments in the development of the hippocampus and prefrontal cortex serve as the mechanism for the relationship between fetal growth restriction and impaired cognitive and emotional development. These studies suggest that endocrine conditions that promote fetal growth restriction can also compromise neural development. However, follow-up studies with even very-low-birth-weight babies reveal an impressive level of variability in cognitive outcomes. Evidence from clinical intervention studies with high-risk infants and developmental neurobiology suggests that neurocognitive development is influenced by the quality of the postnatal environment. Thus, we can predict that the developmental outcomes associated with fetal adversity, reflected in growth retardation, are determined by the quality of the postnatal environment.

Intra-Uterine Growth Restriction and the Hypothalamo-Pituitary-Adrenal Axis

A major paradox of pregnancy involves the increased levels of the highly catabolic, adrenal glucocorticoids in the maternal circulation. Increased cortisol levels make perfect sense for the mother. Pregnancy represents a period of metabolic demand, and glucocorticoids increase the availability of energy substrates through both gluconeogenesis and lipolysis. However, since steroids readily cross the placental barrier, the same catabolic hormones could compromise the growth of the fetus. Glucocorticoids antagonize the anabolic effects of growth hormone through, among other effects, a disruption of the growth hormone-insulin-like growth factor pathway. Thus, increased fetal glucocorticoid exposure in animals can produce growth retardation.

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Nature’s resolution to the maternal-fetal glucocorticoid paradox is the presence of a placental enzyme, 11␤-hydroxysteroid dehydrogenase type 2 (11␤-HSD2). 11␤-HSD2 converts about 95% of cortisol to the biological inert, cortisone, thus maintaining about a 10:1 mother-fetus ratio in circulating cortisol. However, placental expression of 11␤-HSD2 is sensitive to environmental regulation and decreased 11␤-HSD2 function is associated with increased fetal exposure to cortisol and thus a risk for IUGR. Placental tissue obtained from low-birth-weight pregnancies show significant reductions in 11␤-HSD2 mRNA and a decreased capacity for the conversion of cortisol to cortisone [2–4]. Moreover, chord blood samples obtained from low-birth-weight babies reveal significant elevations in both corticotrophin-releasing factor (CRF) and cortisol [5]. Elevated fetal exposure to cortisol thus emerges as a mechanism for IUGR. Interestingly, maternal stress, protein deprivation, tobacco and alcohol all increase maternal adrenal glucocorticoid release, which increases placental CRF expression; hence the relationship between maternal and fetal glucocorticoidsplacental CRF in IUGR babies. Additionally, maternal stress and anxiety are commonly associated with an increased catecholamine output that could serve to impair uteroplacental circulation, further decreasing oxygen and nutrient passage to the fetus. Nevertheless small-birth-weight babies commonly show a postnatal ‘catch-up’ in growth, such that the evidence of growth retardation will largely have disappeared by 1 year of age. Why, then, would these children be at greater risk for illness in later life?

Fetal Programming of Gene Expression

Elevated exposure to biologically active glucocorticoids in fetal life can permanently alter the expression of hepatic genes (i.e., PEPCK, glucose kinases) that are key regulators of glucose and fat metabolism. Collectively, these effects increase the capacity for lipid metabolism, decrease glucose clearance and render the organism vulnerable to hyperlipidaemia, glucose intolerance and hyperglycaemia. Thus, administration of dexamethasone (which is not subject to conversion by placental 11␤-HSD2) to pregnant rat mothers results in offspring which, as adults, show increased blood pressure, hyperlipidaemia and decreased glucose tolerance, thus replicating the condition associated with IUGR. These findings represent examples of what is known as early life programming of gene expression: situations where events in early life exert an apparently permanent effect on gene expression, and thus phenotype. One recent finding from the Southampton studies dramatically expands the scope of the fetal programming hypothesis beyond that of the liver [6]. Among elderly male human subjects, birth weight was a highly significant predictor of

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Hippocampus

CA1

CA2 CA3

CA4

Dentate gyrus

– CRH mRNA AVP mRNA

Hypothalamic PVN

–

Glucocorticoid receptor

CRH AVP Anterior pituitary

Mineralocorticoid receptor

POMC mRNA POMC ACTH

–

Adrenal cortex Cortisol

Fig. 1. Schematic illustrating the HPA axis and the major routes of glucocorticoid feedback within the axis. CRH ⫽ Corticotropin-releasing hormone; AVP ⫽ vasopressin; POMC ⫽ proopiomelanocortin; ACTH ⫽ adrenocorticotropin.

basal cortisol levels. Individuals that were small for gestational age showed increased circulating levels of cortisol. This finding is actually predictable based on animal studies of the effects of prenatal stress or prenatal glucocorticoid exposure, both of which increase basal and stress-induced hypothalamic-pituitaryadrenal (HPA) activity in adulthood [4, 7–12]. These effects are associated with alterations in mineralocorticoid and glucocorticoid receptor expression in brain regions that mediate corticosteroid negative feedback inhibition (fig. 1). Decreased negative feedback sensitivity to circulating glucocorticoids is associated with enhanced hypothalamic CRF expression and increased glucocorticoid release. Moreover, prenatal stress/glucocorticoid exposure also programs CRF gene expression in the amygdala, further increasing HPA activity through the regulation of central noradrenergic projections to the hypothalamic CRF neurons (fig. 2).

Fetal Adversity and Neural Development

The effects of prenatal stress/glucocorticoid exposure on HPA activity in adulthood are also mediated by alterations in the structural development of

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mPFC

Sensory input (Stressor)

Basolateral complex

Hippocampus

Central n. (CRF)

BNST

Locus coer. PB n NTS

P V N

(NA)

(CRF)

Autonomic output

HPA output

Fig. 2. A simplified version of the neural circuits mediating behavioural, autonomic and HPA responses to stress. Note the critical role for the CRF from the central nucleus (central n.) of the amygdala in activating the release of noradrenaline from the noradrenergic cell body regions in the locus coeruleus, parabrachial nucleus (PB n.) and the nucleus of the solitary tract (NTS). Noradrenaline is released into virtually all areas of the corticolimbic regions, including the hippocampus and medial prefrontal cortex (mPFC). At the level of the PVN, noradrenaline stimulates the release of CRF from the PVN, activating the HPA responses to stress. BNST ⫽ Bed nucleus of the stria terminalis.

brain regions that normally serve to regulate hypothalamic CRF expression and HPA activity. The principal among such regions is the hippocampus. Prenatal exposure to glucocorticoids dramatically inhibits neuronal proliferation in the hippocampus in rodents as well as primates, resulting in a severely impaired pattern of hippocampal development. In adult rats, hippocampal lesions produce increased hypothalamic CRF expression and elevated HPA activity. Thus, prenatal stress can increase HPA responses to stress through effects on neural structures that normally inhibit CRF synthesis and release. The hippocampus and prefrontal cortex are also critical structures for impulse control and emotional states such as fear. As adults, animals exposed to stress during fetal development exhibit increased fearfulness and anxiety under conditions of stress. Interestingly, fetal dexamethasone administration in humans for congenital adrenal hyperplasia was associated with increased shyness and timidity in children. Both anxiety disorders and depression are accompanied by significant decreases in hippocampal volume and, in the case of

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depression, dramatically reduced volume and activity in the prefrontal cortex. The hippocampus and the prefrontal cortex are primary targets for both antidepressant and anti-anxiety medications. These correlational findings do not clarify whether decreased hippocampal volume is a pre-existing cause of depression. Indeed, studies with both rodent and primate models show that chronic stress can result in the shrinkage of dendritic branching and even neuron loss in the hippocampus. It is possible that the angst of severe mental illness might provoke hippocampal atrophy. Alternatively, we argue that the decreases in hippocampal and prefrontal cortical volumes occur as a function of early adversity and thus define a state of increased vulnerability for cognitive and emotional impairments. Studies in rhesus monkeys indicate that prenatal exposure to glucocorticoids has dramatic and lasting effects on hippocampal volume [13]. Hippocampal atrophy is not unique to depression. Patients with posttraumatic stress disorder (PTSD) also exhibit a decrease in hippocampal volume. Interestingly, recent studies of monozygotic twins where one of the pair suffers from PTSD, reveal that the non-traumatized, otherwise healthy sibling also shows evidence of reduced hippocampal volume. Moreover, individuals with a history of parental abuse in childhood show decreased hippocampal volume. These findings suggest that the origins of the decreased hippocampal volume might lie in early development and be considered a predisposing condition. This idea is consistent with clinical data, which shows that even among seriously traumatized individuals (e.g. rape victims) only about 25% develop chronic PTSD; the single best predictor of vulnerability to PTSD is the quality of early family life and parent-child relations. Epidemiological studies of depression and anxiety disorders reveal that early life events, including both fetal growth retardation and the quality of postnatal parental care, are major predictors of mood disorders. While these findings are entirely consistent with the results of animal studies (see below), the definitive developmental studies will require a longitudinal, within-subject design in which the effects of environmental adversity and family function are determined early in life. The hippocampus is, of course, intimately associated with cognitive function, notably episodic learning/memory, which refers to the ability to acquire ‘factual’ information, such as time and location (i.e., spatiotemporal relationships). The hippocampus and the prefrontal cortex are also critical in attentional processes. Predictably, in animal studies, including those with primate models, prenatal stress compromises hippocampal development and results in impaired attention [14]. These findings suggest that fetal adversity would be associated with both cognitive and emotional disturbances in childhood, and this is indeed the case. Both prematurity and IUGR are consistently associated with cognitive impairments; the existing data suggest that cognitive outcomes are more seriously compromised by growth restriction than by prematurity [15]. Earlier studies,

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using more global measures of cognitive development, such as IQ tests, reported significant impairments among IUGR children [e.g. 16–20]. As adults, IUGR babies are less likely to hold managerial/professional employment, and earn less income [21], suggesting that growth-related impairments in cognitive development are functionally relevant. Recent studies focus on more specific aspects of cognitive function. The Avon Longitudinal Study found that among low-birthweight children there were significant reductions in many cognitive functions, including attention and spatial learning/memory. Glover and O’Connor [22] and Van der Reijden-Lakeman et al. [23] found that at 2 years of age, IUGR children were impaired on tests of divided, focused and sustained attention. On such tests, the IUGR population was less accurate and more impulsive than controls. These findings suggest that low-birth-weight children might be at greater risk for the development of ADD. Indeed, the risk factors for IUGR, including maternal stress, maternal psychopathology, protein malnutrition, tobacco/alcohol consumption are identical to those for ADD. To date, no study has systematically examined whether low-birth-weight children are indeed at greater risk for ADD. These events occur against a genomic background and a number of genetic polymorphisms have been related to ADD. The first is a 40-bp repeat polymorphism in the 3⬘-region of the gene for the dopamine transporter (DAT), bearing 9 or 10 copies of the repeat. Such repeat polymorphisms influence gene expression and are therefore functionally relevant. Individuals heterozygous for the 9/10-repeat variant exhibit reduced DAT protein in the caudate putamen [24]. A second potentially relevant polymorphism resides in a 48-bp repeat in exon 3 of the dopamine D4 receptor (DRD4) gene and appears to be functionally relevant [25]. Linkage and association studies associated both the DRD4 7-repeat allele and the DAT polymorphism with ADD [26–28], although there are also negative reports [24]. Genes encode for proteins, not syndromes and ADD is a complex disorder that emerges from a persistent interaction between gene and environment. Linkage analysis studies rarely examine the influence of genomic variants within a developmental context. It is possible that the functional importance of the DRD4 or DAT variants for cognitive function might be best revealed within a high-risk population. Research in schizophrenia underscores this point. Birth insults (e.g. hypoxia) increase the risk for schizophrenia marginally in the normal population; amongst those with a family history of schizophrenia, there is an approximately 100-fold increase in the disorder. Maternal stress during gestation is a predictor of both fetal growth restriction and negative temperament (irritability, negative emotionality) and anxiety in children [22, 29]. Behavioural disorders, characterized by poor impulsive control, shyness, timidity and negative temperament (greater frequency of negative emotional states) are positively related to the degree of growth restriction [e.g. 30–32]. In one study, the risk for this constellation of behavioural problems

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increased by 30% for each kilogram below the average birth weight [33]. Interestingly, growth restriction, examined on a continuum, was associated with increased stress susceptibility [34]. This behavioural profile defines a condition described as behavioural inhibition and predicts a greater risk for adult depression and anxiety; IUGR is linked to an increased risk for depression [1]. It is important to note the potential for gene-environment interactions. Ebstein et al. [35] found a highly significant effect of the DRD4 repeat variant on infant temperament, with 2-month-olds bearing short DRD4 variants and showing more negative emotions than those bearing a longer number of repeats. Interestingly, this association was only apparent among children bearing the short variant of the 5-HT transporter (5-HTTP) gene [36]. Among children with the longer version of the 5-HTTP gene, the variants of the DRD4 gene were inconsequential with respect to temperament. Interestingly, variants of the DRD4 gene are also associated with attachment behaviour in the Stranger Situation Test at 1 year of age [37, 38]. Such effects are apparent even in a non-clinical, low-risk population. Certainly, infants with more negative emotions or those who differ in attachment elicit differential parenting. The early appearance of the functional correlates of these genetic variants underscores the potential gene ⫻ environment interactions. An example of such interactions emerges from non-human primate studies [39]. Rhesus monkeys show the same 5-HTTP polymorphism, with strong linkage to temperament and stress reactivity, as well as evidence for effects of central 5-HT activity. However, animals bearing the short variant of the 5-HTTP gene, but reared by highly nurturing mothers, do not differ from animals with the long 5-HTTP variant on measures of temperament, stress reactivity or 5-HT function. Fetal growth retardation is associated with problems of impulse control and attention. The preliminary results of recent imaging studies of low-birth-weight children reveal significantly decreased hippocampal volume. These clinical findings are entirely consistent with the results of animal studies described above. Indeed, alterations in hippocampal and prefrontal development might explain the unusually high level of comorbidity between attentional deficits, impulse control disorders and affective disorders. The findings to date suggest that adversity during fetal development can result in increased exposure to glucocorticoids which promote growth restriction and compromise neural development, resulting in vulnerability to both cognitive and emotional disorders (fig. 3).

Postnatal Programming of Neural Development

The quality of family life influences the development of individual differences in vulnerability to illness throughout life. As adults, victims of childhood

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Prenatal

Nutrition

Maternal adversity

Maternal depression/anxiety

Maternal endocrine state

Tobacco/alcohol Fetal growth

Environmental factors Low SES High SES Partner relationship Violence Social support Relationship to mother Community Workplace Individual resources Self-esteem Optimism

Postnatal

Nutrition

Maternal adversity

Maternal depression/anxiety

Neural development

Adaptations Vulnerability

Family life

Tobacco/alcohol

Outcomes Cognition function Emotional well being Endocrine function

Fig. 3. A schema outlining the proposed major pathways by which environmental adversity influences development. Note that in the case of both pre- and postnatal life, this influence is mediated by maternal emotional well-being and behaviour.

abuse are at greater risk for mental illness, as well as for obesity, type II diabetes and heart disease [40–43]. Children need not be beaten to be compromised. Persistent emotional neglect, family conflict and conditions of harsh, inconsistent discipline compromise growth [e.g. 44], intellectual development [45, 46] and increase the risk for obesity [47], depression and anxiety disorders [48–50] to a level comparable to that for abuse. More subtle relationships exist. Low scores on measures of parental bonding (parental-infant attachment), reflecting cold, distant parent-child relationships increase the risk of depression and anxiety in later life [51–53]. Of course, the sword cuts both ways. Family life can also serve as a source of resilience in the face of chronic stress [54]. Thus, warm, nurturing families tend to promote resistance to stress and to diminish vulnerability to stress-induced illness [55]. The relationship between early life events and health appears to be, in part, mediated by parental influences on the development of neural systems which

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underlie the expression of behavioural and endocrine responses to stress [56–58]. Chronic exposure to elevated levels of the stress mediators, such as the glucocorticoids and catecholamines as well as CRF, are associated with increased visceral obesity, insulin resistance as well as mood and cognitive disorders [57, 59]. Interestingly, each of these disorders is associated with IUGR. This raises the possibility that, in part, increased HPA and catecholaminergic responses to stress might mediate the relationship between IUGR and multiple forms of chronic illness. Moreover, under most conditions, the forms of adversity that promote IUGR also prevail in postnatal life and the results from animal studies reveal that the nature of the postnatal environment also influences the development of stress responsess (fig. 3). Experimental manipulations during postnatal life that compromise the quality and stability of mother-infant interactions (e.g. prolonged periods of separation) in the rat or monkey increase HPA responses to stress in adulthood [60–62]. Moreover, maternal care directly influences the development of individual differences in HPA and behavioural responses to stress [39, 63]. In the rat, naturally occurring variations in maternal care are associated with the development of individual differences in HPA responses to stress. As adults, the offspring of mothers that exhibit increased levels of pup licking/grooming (LG) and arched-back nursing (ABN) are less fearful and show more modest HPA responses to stress [64, 65]. Cross-fostering completely reverses the phenotype. The biological offspring of low LG-ABN mothers fostered at birth by high LG-ABN dams are comparable on measures of stress reactivity to the normal offspring of high LG-ABN mothers; the reverse is also true for the offspring of high LG-ABN dams fostered by low LG-ABN mothers [66, 67]. The increased stress reactivity of the adult offspring of low LG-ABN mothers is associated with elevated CRF gene expression in both the paraventricular nucleus of the hypothalamus (PVN) and the amygdala [64] (fig. 1, 2). CRF activates both behavioural and HPA responses to stress, and this effect is, in part, mediated by CRF action at the noradrenergic cell bodies in the locus coeruleus and the nucleus of the solitary tract [68, 69]. Predictably, the offspring of the low LG-ABN mothers show increased stress-induced release of noradrenaline in the hypothalamus that then stimulates the release of CRF. Increased noradrenaline release is also associated with fear, and the offspring of low LG-ABN mothers show increased fearfulness in response to stress. Environmental effects on the development of stress responses involve systems that normally serve to constrain CRF synthesis and release, such as the hippocampal glucocorticoid receptor system. Glucocorticoids inhibit CRF mRNA expression in the PVN (i.e., glucocorticoid negative feedback; fig. 1). The hippocampus is a critical site for feedback regulation [70]. The adult offspring of high LG-ABN mothers show increased glucocorticoid receptor

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mRNA in the hippocampus, increased feedback sensitivity to glucocorticoids and thus reduced CRF mRNA levels in the PVN [64]. The GABAA receptor system also inhibits CRF activity, particularly at the level of the amygdala and locus coeruleus [71, 72] (fig. 2). Predictably, behavioural responses to stress are inhibited by benzodiazepines (BZs), which exert their potent anxiolytic effect by enhancing GABA-mediated Cl⫺ currents through GABAA receptors [73, 74] especially at the level of the amygdala. The adult offspring of high and low LG-ABN mothers differ in GABAA/BZ receptor binding in the amygdala [65]. The results of human studies are consistent with the idea that the quality of postnatal parent-infant interactions influences the development of behavioural and HPA responses to stress. Abuse in early life increases endocrine and autonomic responses to stress in adulthood. DeBellis et al. [75], Heim et al. [76] and Pruessner et al. [77] found that measures of maternal care predicted cortisol responses to stress in healthy human subjects: low maternal care was associated with significantly greater responses to stress. These findings suggest that family distress can lead to impairments in child care and increased HPA responses to adversity in the offspring. Such effects could compromise cognitive function. In human subjects, acute elevations of glucocorticoids disrupt hippocampal/prefrontal cortex function and thus learning/memory, while chronic elevations in cortisol are associated with decreased hippocampal volume and more severe impairments of attention and learning [78]. There is a remarkable potential for a feed-forward series of effects, since both the hippocampus and the prefrontal cortex provide inhibitory regulation over HPA activity [70, 79]. Parent-child interactions might influence cognitive and emotional development through even more direct pathways. Attentional processes are regulated by catecholaminergic innervation of the hippocampus and prefrontal cortex [80]. Stress increases dopamine and noradrenaline release and impairs attention through actions on D1 and ␣1 receptors in the prefrontal cortex. Increased dopamine release at the level of the ventral striatum (or nucleus accumbens in the rat) is associated with poor impulse control and hyperactivity. In the rat, postnatal maternal separation increases dopamine release to stress and produces behavioural hyperactivity [81]. Likewise, the offspring of low LG-ABN mothers show increased stress-induced release of dopamine in the prefrontal cortex and noradrenaline release in the hippocampus and prefrontal cortex [82]. Thus, in rodents, mother-pup interactions in early life regulate the development of the mesolimbic catecholamine systems. In humans, Pruessner et al. [77] found that in adults the magnitude of stress-induced increases in dopamine release in the ventral striatum is strongly correlated with the quality of maternal care. Poor maternal care was associated with increased dopamine responses to stress in a

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PET imaging study. Of course, the converse is also true: more nurturing forms of maternal care are associated with more modest stress-induced increases in cortisol and dopamine. Thus, parent-child interactions appear to influence the development of both HPA and central catecholamine responses to stress and might thus alter cognitive performance. These findings are consistent with the clinical literature that has identified ADD as a familial disorder [26]. Of course, disorders may run in families because of environmental as well as genetic factors – ‘pathogenic’ families are certainly defined by multiple gene ⫻ environment interactions. Indeed, family function and SES are important predictors of ADD [83, 84]. Family conflict, parental psychopathology and low SES are significant predictors of ADD, each accounting for a 7-fold increase in the risk for ADD. For children burdened with all three risk factors, as so commonly occurs, the odds ratio for ADD was increased by greater than 40-fold. These factors also predict impulse control disorders [33, 85]. Moreover, amongst non-ADD controls, these same conditions predicted learning disorders, reflecting a more general relationship between familial environment and cognitive development. Animal studies suggest that the quality of the maternal care exerts a substantial influence on neural development, in part, through the regulation of endocrine function in the pup. Tactile stimulation associated with maternal LG dampens adrenal sensitivity to ACTH, thus limiting adrenal glucocorticoid release even in response to acute stress. Prolonged deprivation of maternal care increases glucocorticoid levels, an effect that is reversed with experimental stroking, which mimics maternal LG. The next question is whether under normal circumstances tactile stimulation derived from maternal LG might alter neural development. A cDNA array study [86] showed that on day 6 offspring of high LG-ABN mothers exhibited significantly (i.e., ⬎3-fold levels) increased expression of (1) genes related to cellular metabolic activity (glucose transporter, fructose transporter, c-Fos, cytochrome oxygenase, LDL receptor, growth hormone receptor, insulin receptor), (2) genes related to glutamate receptor function, including NMDA receptor subunits and (3) genes encoding for growth factors, including BDNF, bFGF and ␤-NGF [87]. Both NMDA receptor activation and neurotrophic factor expression are primary regulators of neuronal development and thus the offspring of high LG-ABN mothers showed increased neuronal survival, enhanced synaptic development, as well as increased spatial learning/memory [88]. In contrast, maternal separation results in elevated levels of glucocorticoids which downregulate the expression of neurotrophic factors, such as BDNF and ␤-NGF, and impair hippocampal development [89–91]. Postnatal adversity might therefore contribute to the risk for cognitive impairments, such as ADD, through direct effects on the development of neural structures such as the hippocampus.

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Environmental Adversity and Parental Care

These findings suggest that positive forms of parental care can enhance neural development, dampen catecholamine and HPA responses to stress, and thus influence both emotional responses to stress and cognitive performance. The next question concerns the origins of these variations in parental care. If nurturing forms of parenting decrease the vulnerability to chronic illness and enhance cognitive development, then why should all parents not behave in this manner towards their children? Environmental adversity can compromise the emotional well-being of the parent and thus influence the quality of parent-child relationships. While many factors contribute to the quality of the mother’s attitude towards her newborn, none are correlated more highly than the women’s level of anxiety [92]. Mothers who feel depressed and anxious are, not surprisingly, less positive towards their baby. High levels of maternal stress are associated with less sensitive child care [93, 94]. The children of highly stressed primary caregivers tend to develop more insecure parental attachment [94, 95], which predicts behavioural inhibition in childhood and an increased risk for depression. Vaughn et al. [95] found that unstable/stressful environments were associated with greater variability in the quality of infant-mother attachments. When parents suffer from poverty or other environmental stressors, they experience more negative emotions, irritable, depressed and anxious moods, which lead to more punitive parenting [96–98]. The greater the number of environmental stressors (e.g. lesser education of parents, low income, many children, being a single parent), the less supportive the mothers were of their children; they were more likely to threaten, push or grab them, and they displayed more controlling attitudes toward child rearing. Generally, high levels of stress are associated with negative outcomes for both mothers and children [94]. Family dysfunction and low income are associated with significantly increased risks of psychopathology and cognitive development is inversely related to familial adversity [99]. Interestingly, the effects of poverty on intellectual and emotional development are mediated by variations in parental care. When the parental care factor is statistically factored out of the equation, there is no relationship between SES and child development [100–102]. Low SES serves as a potent source of adversity and Lupien et al. [103] found that children from low SES homes exhibited significantly higher levels of basal salivary cortisol by comparison to middle-class peers. Two points are important: first, elevated basal cortisol levels are associated with hippocampal dysfunction and cognitive impairments [104] and second, the effect of SES on basal cortisol levels was entirely accounted for by the level of maternal depression.

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Environmental adversity appears to compromise the quality of child care and thus alters neural development. For humans, these are not isolated conditions: 1 in 5 teenage females and 1 in 6 adult women experience abuse during pregnancy [105, 106]. Such severe forms of stress promote emotional states of depression and anxiety, and these states predict cold, punitive forms of parenting. Not surprisingly, highly anxious mothers are more likely to have children who are shy and timid, and the behaviour of the mother predicts the level of such behavioural inhibition in the child [107]. Moreover, there is evidence for the behavioural transmission of anxiety. Cross-fostering studies in the rat and monkey show that parental care can serve as a mechanism for the transmission of individual differences in stress reactivity from parent to offspring [39, 66]. In rats, stress during the latter half of gestation produces significant reductions in pup LG among high LG-ABN mothers, such that group differences between high and low LG-ABN mothers are eliminated [108]; gestationally stressed, high LG-ABN mothers lick/groom pups no more frequently than do stressed or control low LG-ABN mothers. Predictably, the offspring of stressed/high LG-ABN mothers do not differ from those of low LG-ABN mothers on measures of hippocampal development or stress reactivity. Of course, the influence of parental care can also function to enhance cognitive development and dampen stress reactivity. Protective environmental influences, such as social support, enhance the quality of parental care and thus improve developmental outcomes for the child. More nurturing forms of maternal care can enhance neurocognitive development and dampen emotional and HPA responses to stress. These considerations thus raise the question of whether a more nurturing home environment during postnatal life might offset the risk-associated fetal adversity.

Prenatal/Postnatal Interactions and the Question of Reversibility

The critical question here concerns the potential for the reversibility of the developmental effects associated with adversity in fetal life. The results of animal studies suggest ample potential for functional reversal. Postnatal handling, which increases maternal LG, reverses the effects of prenatal stress on HPA responses to stress, fearfulness and spatial learning/memory in the rat. Postnatal handling of the excessively fearful and intellectually challenged BALBc mouse produces a decrease in timidity and a marked improvement in cognitive performance [109]. Interestingly, evidence from embryo transfer experiments using BALBc and C57 mice [110] suggests that the increased fearfulness of the BALBc mouse develops during fetal life and is, in part at least,

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independent of the genome. Thus, the handling studies with these mice represent an example of postnatal reversibility of impairments derived from fetal life. Cross-fostering BALBc mice by C57 mothers also reverses the excessive fearfulness of the BALBc offspring as well as differences in GABAA/BZ receptor levels [111]. Importantly, C57 mothers lick/groom their pups about 3–4 times more frequently than do BALBc dams. Interestingly, animals that are more vulnerable by virtue of adversity in fetal life may actually be more susceptible to the effects of postnatal conditions. For example, the effects of postnatal handling are consistently greater in prenatally stressed than control animals [112]. In rhesus monkeys [39], anxious infants cross-fostered by highly nurturing mothers showed dramatic decreases in timidity and behavioral inhibition. Less anxious infants were unaffected by maternal care. This same point emerges from studies of environmental enrichment. Postweaning enrichment of the offspring of low LG-ABN mothers produces an increase in hippocampal synaptogenesis and cognitive performance, with little or no effect on the offspring of high LG-ABN dams [88]. The same also emerges from studies of human populations. Belsky [98] examined parenting styles over the 2nd and 3rd year of life in children, measuring positive (the degree to which parents were affectionate and sensitive to the child) and negative (hostile, irritable and intrusive) parenting and evaluated the timidity/behavioural inhibition in the children at 36 months of age. Parental style accounted for only 4% of the variance on the outcome measure among children who were evaluated as low on negative emotionality at the beginning of the study. Among those high in negative emotionality, parental style accounted for almost 30% of the variance in behavioural inhibition. Likewise, among children with a negative temperament in infancy, there are significant effects of the quality of parental care or day care on emotional problems in childhood; no such effects emerge amongst children exhibiting a positive temperament in infancy [113]. The NICHD [114] revealed a highly significant relationship between parental sensitivity and emotional/behavioural disorders in childhood, but only amongst those children with a negative temperament in infancy. Morris et al. [115] found that hostile/harsh maternal care predicted behavioural problems in children, but again, only in children scoring high on irritability distress in infancy. The more phlegmatic infants were not significantly affected by negative parental style. These findings suggest that high-risk infants are more susceptible to the influence of postnatal family life than are children low in vulnerability. Hence, the proverbial 0.3 correlation that so routinely emerges between parental rearing styles and developmental outcomes in children may likely be the result of a zero-order association in the non-susceptible child, with associations in the order of 0.5, 0.6 or greater in more susceptible (i.e., highly vulnerable) children.

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If true, the implications for early childhood treatment programs are enormous. The results of clinical intervention studies would seem to be consistent with this line of reasoning. Indeed, the rather moderate correlations between maternal care and infant attachment in the general population [116] contrast with clinical data. For example Van den Boom [117] randomly assigned low SES mothers with highly irritable infants to an experimental group that received an intervention structured to promote maternal sensitivity or to control conditions. As intended, the intervention significantly increased maternal sensitivity and secure forms of infant attachment. Among controls, 22% of the infants showed secure attachment, in contrast to 66% of those in the treatment group; a 300% increase. These findings suggest that very impressive treatment effects are observed when interventions focus on more vulnerable populations. Finally, Blair [118] found that among low-birth-weight babies from economically disadvantaged homes an enriched form of education day care, which included home visiting and parental support, significantly reduced the risk for emotional/behavioural disorders, but only amongst those children that exhibited highly negative emotionality in infancy; no treatment effect was detected amongst children with normal temperament in infancy. Interestingly, the same pattern of effects emerged in the analysis of cognitive outcomes. Among the infants of poor temperament, those enrolled in the enrichment program were 5 times less likely to exhibit cognitive impairments (⬍75 IQ) than those in the control group; there were no treatment effects on cognitive development among children with a normal or positive temperament in infancy. In each case, children with a history of negative mood and irritability in infancy were most affected by parental care. Evaluative research conducted with the Abecedarian Project shows that early (years 1–4) enrichment interventions have profound effects, in the order of 1–1.5 SD on IQ tests, in children from seriously disadvantaged homes. In children from more functional families and better educated parents, the program had no effect on cognitive development [119]. Taken together, these findings also suggest that the outcomes associated with fetal adversity are determined by the quality of the postnatal environment. Two studies on developmental outcomes in growth-restricted babies bear directly on this point. First, Barker et al. [120] found that the risk for cardiovascular disease among men that were small for gestational age was apparent only in low SES individuals; higher SES, low-birth-weight men were at no greater risk for heart disease than individuals born at normal weight. Second, Kelly et al. [33] found that the effects of fetal growth restriction on behavioural development were mediated by SES. Small babies reared in lower SES conditions showed increased evidence of behavioural disorders characterized by irritability and impulsivity. There was no effect of birth weight on behavioural/emotional disorders among children from higher SES settings.

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Conclusions

Not surprisingly, there is strong evidence for cognitive/behavioural impairments associated with fetal growth retardation. What is surprising is that not all IUGR babies are seriously impaired, even under conditions that produce severe growth restriction and prematurity. In populations of preterm, very-low-birthweight babies estimates are that 40% exhibit normal cognitive function in childhood and school performance within the normal range. We propose that the variability in the outcomes associated with fetal adversity is due to the influence of postnatal life. References 1 2 3

4 5

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85 Barkley RA: Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment. New York, Guilford Press, 1990. 86 Diorio J, Weaver ICG, Meaney MJ: A DNA array study of hippocampal gene expression regulated by maternal behavior in infancy. Abstr Soc Neurosci 2000;26:1366. 87 Liu D, Diorio J, Day JC, Francis DD, Mar A, Meaney MJ: Maternal care, hippocampal synaptogenesis and cognitive development in the rat. Nat Neurosci 2000;3:799–806. 88 Bredy TW, Humpartzoomian RA, Cain DP, Meaney MJ: The influence of maternal care and environmental enrichment on hippocampal development and function in the rat. Neuroscience 2003;118:571–576. 89 Rocceri M, Hendriks W, Racagni G, Ellenbroek BA, Riva MA: Early maternal deprivation reduces the expression of BDNF and NMDA receptor subunits in rat hippocampus. Mol Psychiatry 2002;7:609–616. 90 Huot RL, Plotsky PM, Lenox RH, McNamara RK: Neonatal maternal separation reduces hippocampal mossy fiber density in adult Long Evans rats. Brain Res 2002;950:52–63. 91 Zhang LX, Levine S, Dent G, Zhan Y, Xing G, Okimoto D, Kathleen Gordon M, Post RM, Smith MA: Maternal deprivation increases cell death in the infant rat brain. Dev Brain Res 2002;133:1–11. 92 Fleming AS: Factors influencing maternal responsiveness in humans: Usefulness of an animal model. Psychoneuroendocrinology 1988;13:189–212. 93 Dix T: The affective organization of parenting adaptive and maladaptive processes. Psychol Bull 1991;110:3–25. 94 Goldstein LH, Diener ML, Mangelsdorf SC: Maternal characteristics and social support across the transition to motherhood: Associations with maternal behavior. J Fam Psychol 1996;10: 60–71. 95 Vaughn B, Egeland B, Sroufe LA, Waters E: Individual differences in infant-mother attachment at twelve and eighteen months: Stability and change in families under stress. Child Dev 1979;50: 971–975. 96 Conger RD, McCarty JA, Yang RK, Lahey BB, Kropp JP: Perception of child, childrearing values, and emotional distress as mediating links between environmental stressors and observed maternal behavior. Child Dev 1984;55:2234–2247. 97 Grolnick WS, Gurland ST, DeCourcey W, Jacob K: Antecedents and consequences of mothers’ autonomy support: An experimental investigation. Dev Psychol 2002;38:143–155. 98 Belsky J: Theory testing, effect-size evaluation, and differential susceptibility to rearing influence: The case of mothering and attachment. Child Dev 1997;64:598–600. 99 Offord DR, Boyle MH, Racine YA, Fleming JE, Cadman DT, Blum HM, Byrne C, Links PS, Lipman EL, MacMillan HL, et al: Outcome, prognosis, and risk in a longitudinal follow-up study. J Am Acad Child Adolesc Psychiatry 1992;31:916–923. 100 Eisenberg L, Earls FJ: Poverty, social depreciation and child development; in Hamburg DA (ed): American Handbook of Psychiatry. New York, Basic Books, 1975, vol 6, pp 275–291. 101 Conger R, Ge X, Elder G, Lorenz F, Simons R: Economic stress, coercive family process and developmental problems of adolescents. Child Dev 1994;65:541–561. 102 McLloyd VC: Socioeconomic disadvantage and child development. Am Psychol 1998;53:185–204. 103 Lupien SJ, King S, Meaney MJ, McEwen BS: Child’s stress hormone levels correlate with mother’s socioeconomic status and depressive state. Biol Psychiatry 2000;48:976–980. 104 Lupien SJ, Nair NPV, Briere S, Maheu F, Tu MT, Lemay M, McEwen BS, Meaney MJ: Increased cortisol levels and impaired cognition in human aging: Implications for depression and dementia in later life. Rev Neurosci 1999;10:117–139. 105 Newberger EH, Barkan SE, Lieberman ES, et al: Abuse of pregnant women and adverse birth outcomes. Current knowledge and implications for practice. JAMA 1992;267:2370–2372. 106 Parker B, McFarlane, Soeken K: Abuse during pregnancy: Effects on maternal complications and birth weight in adult and teenage women. Obstet Gynecol 1994;84:323–328. 107 Hirschfield DR, Biederman J, Brody L, Faraone SV, Rosenbaum JF: Expressed emotion towards children with behavioral inhibition: Association with maternal anxiety disorder. J Am Acad Child Adolesc Psychiatry 1997;36:910–917. 108 Champagne FA, Meaney MJ: Stress during gestation alters postpartum maternal care and the development of the offspring in a rodent model. Submitted.

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109 Zaharia MD, Kulczycki J, Shanks N, Meaney MJ, Anisman H: The effects of early postnatal stimulation on Morris water-maze acquisition in adult mice: Genetic and maternal factors. Psychopharmacology (Berl) 1996;128:227–239. 110 Francis DD, Szegda K, Campbell G, Martin WD, Insel TR: Epigenetic sources of behavioral differences in mice. Nat Neurosci 2003;6:445–446. 111 Caldji C, Diorio J, Anisman H, Meaney MJ: Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice. Neuropsychopharmacology 2004;29:1344–1352. 112 Smythe JW, McCormick CM, Meaney MJ: Median eminence corticotrophin-releasing hormone content following prenatal stress and neonatal handling. Brain Res Bull 1996;40:195–199. 113 Deater-Deckard K, Dodge K: Spare the rod, spoil the authors: Emerging themes in research on parenting. Psychol Inquiry 1997;8:230–235. 114 NICHD Early Child Care Research Network: Early child care and self-control, compliance, and problem behavior at 24 and 36 months. Child Dev 1998;69:1145–1170. 115 Morris A, Silk J, Steinberg L, Sessa F, Avenevoli S, Essex M: Temperamental vulnerability and negative parenting as interactings predictors of child adjustment. J Marriage Fam 2002;64: 461–471. 116 De Wolff M, van Ijzendoorn M: Sensitivity and attachment: A meta-analysis on parental antecedents of infant attachment. Child Dev 1997;68:571–591. 117 Van den Boom D: The influence of temperament and mothering on attachment and exploration: An experimental manipulation of sensitive responsiveness among lower-class mothers and irritable infants. Child Dev 1994;65:1457–1477. 118 Blair C: Early intervention for low birth weight preterm infants: The role of negative emotionality in the specification of effects. Dev Psychopathol 2002;14:311–332. 119 Ramey CT, Ramey SL: Early intervention and early experience. Am Psychol 1998;53:109–120. 120 Barker DJ, Forsen T, Eriksson JG, Osmond C: Growth and living conditions in childhood and hypertension in adult life: A longitudinal study. J Hypertens 2002;20:1951–1956.

Dr. Stephen G. Matthews Department of Physiology, Faculty of Medicine, University of Toronto Medical Sciences Building, 1 King’s College Circle Toronto, ON M5S 1A8 (Canada) Tel. ⫹1 416 978 1974, Fax ⫹1 416 978 4940, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 50–69

Behavioral Perinatology Pathik D. Wadhwa Departments of Psychiatry & Human Behavior and Obstetrics & Gynecology, University of California, Irvine, Calif., USA

Developmental processes involved in transforming a single-cell human embryo into a fully functioning organism within a mere span of 40 weeks are exceedingly complex and fascinating; indeed, one would be hard pressed to come up with any other example in the physical or biological world that even begins to approximate the sheer elegance of intrauterine development. Biologists over the ages have asked the question: does the genetic material of the fertilized egg already contain a full set of building specifications for the organism? Over the last decade or so, there has been a major paradigm shift in developmental biology regarding fundamental concepts of how the central nervous system and the rest of the organism develops and functions. The answer to the above question is now believed to be an unequivocal ‘no’. Genes and environment are no longer considered to exert separate influences, and development is viewed not as a gradual elaboration of an architectural plan preconfigured in the genes, but rather as a dynamic interdependency of genes and environment characterized by a continuous process of interactions in a placeand time-specific dependent manner, and involving short- and long-term information storage, whereby genetic and epigenetic processes1, at every step of development, become represented in the evolving structural and functional design of the organism [2–4]. According to this epigenetic view of development, events at one point in time have consequences that are manifested later in

Major sections of this chapter are reprinted from an article that appeared in Wadhwa et al. [1], and are reproduced here with permission from Elsevier. 1 For the purpose of this discussion, we use the term ‘genetic’ to refer to the effects of variations in DNA sequences on protein physiology, and the term ‘epigenetic’ to refer to alterations in gene expression and protein physiology without changes in DNA sequences (e.g. genetic imprinting via DNA methylation).

the developmental process, and afferent activity has a profound influence on the developmental trajectory [5]. In other words, it appears that within the constraints imposed by the heritable germ line at conception, each developing organism plays an active role in its own construction. This dynamic process is effected by evolving various systems during embryonic and fetal life to acquire information about the nature of the environment, and to use this information to guide development. In the context of this formulation, not only does environment play a necessary role for development to occur, but the nature of the environment may play either an advantageous role for normal or optimal development, or may play a pernicious role to harm development [6]. The degree of congruence or discongruence between fetal, childhood and adult environments determines trajectories leading to either optimal or suboptimal developmental and health outcomes [7–9]. Behavioral perinatology is broadly defined as an interdisciplinary area of research that involves conceptualization of theoretical models and conduct of empirical studies of the dynamic time-, place-, and context-dependent interplay between biological and behavioral processes in fetal, neonatal and infant life using an epigenetic framework of development. The biobehavioral processes of particular interest to our research group relate to the effects of maternal pre- and perinatal stress and maternal-placental-fetal stress physiology. Our choice of stress and stress physiology is guided by the following two major considerations: first, empirical studies in humans and animals support a significant role for pre- and perinatal stress as an independent risk factor for adverse developmental outcomes [10]; second, stress and stress physiology offer an excellent model system for the study of early developmental processes because it appears that the developing fetus acquires and incorporates information about the nature of its environment via the same systems that in a developed individual are known to mediate adaptation and central and peripheral responses to challenge/stress (i.e., the neuroendocrine, immune and vascular systems) [11]. We propose that behavioral perinatology research may have important implications for a better understanding of the processes that underlie or contribute to the risk of at least three sets of outcomes: prematurity, adverse neurodevelopment, and chronic degenerative diseases in adulthood. Each of these classes of adverse health outcomes represent major public health issues in the United States and other developed nations, their prevalence is characterized by substantial disparities along factors associated with sociodemographic disadvantage and racial/ethnic minority status (which we and others have argued may, in part, reflect the effects of variations in stress and stress physiology in affected populations), and growing evidence supports a crucial role for an early developmental process in their origins [5, 8, 9, 12–14].

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Biobehavioral Model of Prenatal Stress and Stress Physiology in Human Fetal Development

From a biological perspective, the term ‘stress’ is used to describe any physical or psychological challenge that threatens or is perceived to have the potential to threaten the stability of the internal milieu of the organism (homeostasis). The neuroendocrine, immune and vascular systems play a major role in adaptation to stress. The principal effectors of these adaptive responses are the corticotropinreleasing hormone (CRH) and locus ceruleus-noradrenaline/autonomic (sympathetic) neurons in the hypothalamus and brain stem, which regulate the peripheral activities of the hypothalamic-pituitary-adrenal (HPA) axis and the systemic/ adrenomedullary sympathetic nervous system, respectively. Activation of the HPA axis and locus ceruleus-noradrenaline/autonomic system results in the systemic elevation of glucocorticoids and catecholamines, respectively, which act in concert on target tissues to mobilize and redistribute available resources, and also to maintain or effect a return to the state of homeostasis [15]. The adoption of an epigenetic framework for early development, wherein the organism plays an active role in its own construction by evolving systems to acquire and use information about the nature of the environment to guide development, gives rise to two important questions. First, how do the fetal and maternal compartments communicate with one another? And second, in light of the fact that the fetal nervous system is itself in a state of evolution and has yet to acquire its full repertoire of structural and functional capabilities, what are the modalities available to the developing fetus to receive, process and act on information acquired from the environment? There are no direct neural, vascular or other connections between the mother and her developing fetus. One of the remarkable adaptations of pregnancy is the evolution in early gestation of a transient organ of fetal origin – the placenta. All communication between the maternal and fetal compartments is mediated via the placenta through one or both of two mechanisms: the actions of maternal and fetal factors on placental activity, or transplacental passage of blood-borne substances [13]. In addition to the long-recognized multiple roles played by the placenta, it now appears that the placenta may also take on some functions that are usually ascribed to the central nervous system, i.e., the capability of receiving, processing and acting upon certain classes of stimuli. Indeed, we propose one of the important roles of the placenta is to act on behalf of the fetus as both a sensory and effector organ to facilitate the transduction and incorporation of environmental information into the developmental process. Based on our understanding of the ontogeny of human fetal development and physiology of pregnancy and fetal development, we have articulated a neurobiological model of pre- and perinatal stress. Our model proposes that chronic maternal stress may exert a significant influence on fetal developmental

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Maternal prenatal stress nature, timing, duration

Neuro-endocrine

Immune

Vascular

Utero-placental function

Intrauterine environment

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Fetal, newborn and infant development and health

Fig. 1. Biobehavioral model of prenatal stress and human fetal developmental and health outcomes.

outcomes [8–10]. The effects of maternal stress may be mediated through biological and/or behavioral mechanisms. Maternal stress may act via one or more of three major physiological pathways: neuroendocrine, immune/inflammatory, and vascular. We further suggest that placental CRH plays a central role in coordinating the effects of endocrine, immune/inflammatory and vascular processes on fetal developmental outcomes. Finally, we hypothesize that the effects of maternal stress are modulated by the nature, duration and timing of occurrence of stress during gestation (fig. 1). We specifically postulate that individual differences in maternal stress appraisals exert a larger impact than exposure per se to stressful events; that prenatal stress in early gestation exerts a larger impact on outcomes related to the length of gestation and fetal growth than stress in the latter part of gestation; that among spontaneous births (i.e., those following spontaneous labor or rupture of fetal membranes) prenatal stress directly influences the length of gestation, whereas among elective births, prenatal stress indirectly influences the length of gestation by contributing to increased risk of obstetric complications (e.g. preeclampsia) that are indicators for elective delivery, and that the maternal-placental-fetal neuroendocrine system is the primary physiological mediator of the effects of prenatal stress on adverse fetal outcomes because it constitutes the fundamental substrate for fetal growth, development and parturition, and because pathways through which alterations in other systems (e.g. immune, vascular) produce pathophysiological consequences are mediated, in part, by maternal-placental-fetal neuroendocrine processes.

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Placental CRH in human pregnancy CRH CRH ⫺ ACTH

⫺

ACTH ⫹

⫹ CRH Placenta Cortisol Non-pregnant state

⫹ Cortisol Pregnant state

Fig. 2. Placental CRH in human pregnancy. In pregnancy, the placenta is a major extrahypothalamic site for CRH production and action. In contrast to the negative control exerted on the brain and pituitary, cortisol stimulates the production of CRH in the placenta, establishing a positive feedback loop that terminates upon delivery.

Starting very early in gestation, the placenta produces hormones, neuropeptides, growth factors and cytokines, and appears to function in a manner resembling that of compressed hypothalamic-pituitary target systems [16]. The physiology of placental CRH serves as an excellent illustration of our concept that the placenta acts in some ways as a sensory and effector organ on behalf of the fetus. CRH, a 41-amino acid neuropeptide of predominantly hypothalamic origin, is one of the primary mediators through which the brain regulates the activity of the HPA axis and the physiological responses to stress and inflammation [17, 18]. During human pregnancy, the CRH gene and receptors are also richly expressed in the placenta. Placental CRH is identical to hypothalamic CRH in structure, immunoreactivity, and bioactivity [19]. The expression of the CRH gene increases exponentially in the placenta over the course of gestation, resulting in the production of placental CRH and its release into the maternal and fetal compartments (fig. 2). With respect to the role of the placenta as an effector of fetal development, we and others have proposed various crucial roles for placental CRH in regulating human reproductive biology, including implantation [20], modulation of maternal and fetal pituitary-adrenal function, participation in fetal cellular differentiation, growth and maturation, and involvement in the physiology of parturition [19, 21–23]. With respect to the role of the placenta as a sensory organ, several lines of evidence have now converged to suggest that the activity of placental CRH is, in turn, regulated by characteristics of the maternal and intrauterine environment. For example, in vitro and in vivo studies have demonstrated placental CRH output is modulated in a

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positive, dose-response manner by all the major biological effectors of stress, including cortisol, catecholamines, oxytocin, angiotensin II, both forms of interleukin (IL)-1, and hypoxia [19, 24, 25].

Prenatal Stress and Fetal Developmental Outcomes: Overview of Epidemiological Findings

Disruption of reproductive function in mammals is a well-known consequence of stress. Results from experimental approaches in animal models strongly support a causal role for prenatal stress as a developmental teratogen, with large effects of even relatively mild behavioral perturbation in pregnancy on outcomes including, but not limited to, maternal-fetal physiology, length of gestation and fetal growth [10, 26–29]. Psychosocial/behavioral stress in human pregnancy has also been associated with outcomes at various points along the developmental continuum, including fertilization and conception, early pregnancy loss (spontaneous abortion), fetal structural and functional developmental outcomes (malformations, physiological activity, neurobehavioral maturation, growth), the length of gestation, infant birth weight, neonatal neurological optimality, neonatal complications, infant neurodevelopmental indices related to cognition, affect and behavior, and childhood and adult psychopathology [for a review, see ref. 10]. In humans, the length of gestation and fetal growth/infant birth weight are the outcomes that have been most commonly studied and found to be associated with maternal stress during pregnancy. We have recently conducted a comprehensive review of human empirical research published in English language journals over the past 14 years (1990–2004) and identified empirical reports that examined the association of maternal psychosocial stress and/or social support with pregnancy outcomes related to the length of gestation and birth weight. Findings from this review are consistent with our own previously published studies in this area [30–33] and support the notion that pregnant women reporting high levels of psychosocial stress and/or low levels of social support during pregnancy are significantly more likely to deliver earlier/preterm and to deliver a smaller/low-birth-weight infant. Moreover, the effects of maternal stress appear to be independent from those of other established obstetric and sociodemographic risk factors. The effects of maternal stress are observed across the entire range of the outcome distribution, as opposed to only at one end of the distribution. Subjective measures of stress perceptions and appraisals are more strongly associated with adverse outcomes than measures of exposure to potentially stressful events or conditions. In many instances, the effects of stress are moderated by other person or situation characteristics, such as maternal age, body mass index,

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occupation, personality and coping styles. In terms of the magnitude of the effect, pregnant women reporting high levels of stress are at approximately doubled risk for preterm birth or fetal growth restriction compared to women reporting low levels of stress (the adjusted relative risk ratios vary between 1.5 and 2.5). Based on these findings, we suggest the following two implications: first, maternal psychosocial processes in pregnancy are at least as important and warrant the same degree of further consideration and study as other established obstetric risk factors because the overall magnitude of their independent effect size on prematurity-related outcomes is comparable to that of most other obstetric risk factors; second, the translation of this knowledge to clinical application for risk assessment and intervention has, however, been limited by the fact that commonly used measures of maternal stress and related constructs have low sensitivity and specificity in predicting adverse outcomes at the individual (as opposed to population) level. Thus, there is a need to better capture and quantify determinants of inter- and intraindividual variability in the link between maternal stress and adverse birth outcomes, to identify which subgroup(s) of pregnant women, under what circumstances, and at what stage in pregnancy, are especially susceptible to the deleterious effects of prenatal stress on birth outcomes. For any individual, the probability of a stress-related adverse health outcome is a joint function of not only cumulative stress exposure but also individual’s biological responsivity to stress. Biological stress responsivity refers to an individual’s propensity for biological perturbation upon stress exposure. Two major limitations of the maternal stress and birth outcome literature are that (a) previous studies have considered only the stress exposure side of the above equation, but not the issue of individual differences in biological responsivity to stress, and (b) the approach to the measurement of maternal stress has relied exclusively on selfreport, retrospective recall measures of psychological state or affect over time, which may be prone to numerous biases that undermine validity. Self-report, summary measures of an individual’s states and experiences over time rely on autobiographical memory (as opposed to semantic memory), which is as much a matter of reconstruction as of accurate recall, and is known to be highly susceptible to numerous, systematic biases that adversely impact accuracy [34, 35].

Prenatal Stress and Physiological Processes in Human Fetal Development: Role of Placental Corticotropin-Releasing Hormone

Fetal growth and development involves a complex interplay of factors and signaling molecules within the maternal, placental and fetal tissues. Pregnancy

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Fetus

Placenta

Mother CRH Cholesterol

CRH Progesterone ACTH

CRH

Estrogens

⫺

ACTH

Myometrial contractility cervical softening ⫹

DHEA-S Liver Lungs Gut

Cortisol

Cortisol 11-␤HSD 1 and 2

Fig. 3. Maternal-placental-fetal neuroendocrine axis in human pregnancy and fetal development.

is associated with major alterations in physiological function, including changes in hormone levels and control mechanisms (feedback loops) that are crucial in providing a favorable environment within the uterus and fetus for cellular growth and maturation and conveying signals when the fetus is ready for extrauterine existence [16]. Fetal maturation and parturition are tightly synchronized processes. Recent advances have implicated placental CRH as one of the primary endocrine mediators of parturition and fetal development (fig. 3) [for reviews, see ref. 19, 21, 36–38].

Placental Corticotropin-Releasing Hormone and Parturition It is well recognized that a shift in the balance from a progesteronedominant to an estrogen-dominant milieu over the course of gestation results in a sequence of events in the gestational tissues to promote labor, including gap junction formation, expression of oxytocin receptors, and synthesis of prostaglandins [for reviews, see ref. 19, 21]. In most mammals, this shift is effected by the conversion of progesterone to estrogen in the placenta. However, unlike most other mammals, the human (primate) placenta cannot convert progesterone to estrogen because it lacks the enzyme 17-hydroxylase required for this conversion. Instead, the placenta utilizes another precursor hormone – dehydroepiandrosterone sulfate (DHEA-S) – which is produced by the fetal adrenal zone, to synthesize estrogen [estriol (E3)] [for reviews, see ref. 38–41].

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Placental CRH is believed to coordinate and control the physiology of parturition via its actions on the fetal endocrine system (fetal HPA axis) and also within the gestational tissues. Placental CRH has recently been shown to directly and preferentially stimulate DHEA-S secretion by human fetal adrenal cortical cells [42]. Placental CRH also exerts direct actions on the uterus and cervix to augment changes produced by estrogen on these tissues by interacting with both prostaglandins and oxytocin, the two major uterotonins that stimulate and maintain myometrial contractility at term and during labor [43, 44]. The overwhelming evidence from clinical studies of CRH and parturition conducted by us and others suggests that women in preterm labor have significantly elevated levels of CRH compared to gestational age-matched controls, and that these elevations of CRH, assessed in some studies as early as 15 weeks of gestation, precede the onset of preterm labor [22–24, 45–53]. Studies that conducted serial assessments of CRH over the course of gestation found that compared to term deliveries, women delivering preterm had not only significantly elevated CRH levels but also a significantly accelerated rate of CRH increase over the course of their gestation [47, 50, 54]. Moreover, we have shown that the effects of placental CRH on spontaneous preterm birth are independent from those of other biomedical risk factors [22, 23].

Placental Corticotropin-Releasing Hormone and Fetal Growth Placental CRH is believed to also regulate fetal growth via its effects on placental perfusion and fetal cortisol production. Placental CRH elevations are associated with decreased uteroplacental flow and hypoxemia – known risk factors for fetal growth restriction [55]. Fetal cortisol plays a critical role in organ growth and maturation [56], and placental CRH may also participate in this process via its positive feedback loop with fetal cortisol [37, 38, 41]. Several clinical studies have found that CRH levels in maternal and/or cord blood during gestation or at the time of delivery are significantly higher in low birth weight/small-for-gestational-age births [23, 57–59].

Placental Corticotropin-Releasing Hormone and Immune-Inflammatory Processes in Pregnancy Microbial infection and inflammation in the gestational tissues has emerged as one of the major risk factor for adverse birth outcomes such as early preterm birth (⬍30 weeks of gestation) and adverse neurodevelopmental

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Maternal systemic infection

Maternal local infection

Fetal inflammatory response

Cytokines (IL-1␤, IL-6)

Placenta and fetal membranes

CRH

Prostaglandins

Uterine contractility

Fig. 4. Endocrine-immune interactions in human pregnancy and fetal development.

outcomes such as white matter brain damage and cerebral palsy [60]. These adverse outcomes in the setting of infection are believed to result from the actions of proinflammatory cytokines secreted as part of the maternal and/or fetal host response to microbial invasion [61, 62]. Proinflammatory cytokines have been shown to promote spontaneous labor and rupture of membranes via their actions in the gestational tissues to stimulate the synthesis and release of prostaglandins and metalloproteases, in the fetus to stimulate the production of inflammatory cytokines, cortisol and DHEA-S, and in the placenta to stimulate CRH synthesis and release (fig. 4) [62–64]. Endocrine and immune processes extensively cross-regulate one another in pregnancy. For example, the proinflammatory cytokine IL-1 stimulates the production of placental CRH, and CRH in turn regulates cytokine production by immune cells. Because maternal stress is associated with preterm birth, abnormalities in the regulation of CRH and the production of proinflammatory cytokines may be a mechanism that could form the pathophysiological basis for this association [61]. Although maternal stress and infection have each been implicated as risk factors in preterm birth and the effects of stress on immune function are well established, very little research to date has examined the nature of the stress-infection-immune relationship in human pregnancy. Our review of the relevant literature found only two studies linking maternal stress with immune processes in human pregnancy [65, 66], and one in vivo study reporting that women in preterm labor with microbial invasion of the amniotic cavity had significantly higher CRH levels than those in preterm labor without infection [51].

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In collaboration with colleagues in Philadelphia, we have recently published a report that supports a role for maternal psychosocial stress in the development of reproductive tract infection in human pregnancy [67]. Moreover, our preliminary findings to date also support the notion that stress-related endocrine processes modulate immune function in the context of reproductive tract infection and inflammation [68, 69].

Placental Corticotropin-Releasing Hormone and Fetal Neurodevelopment The developing human central nervous system may be more vulnerable to environmental perturbations than any other system because it develops over a much longer period of time (11–12 years); it has limited repair capabilities; its units have highly specific functional roles; the blood-brain barrier is not fully developed in utero, and the sensitivity of neurotransmitter systems, which is set during critical developmental periods, affects the organism’s response to all subsequent experience [70]. However, the influence of the maternal and intrauterine environment on the developing human fetal brain is poorly understood, in part, because the assessment and quantification of human fetal brain development presents many theoretical and methodological challenges [71]. To date, we have performed four studies in an effort to quantify and examine the influence of biobehavioral processes on fetal brain development. The first study was performed on a sample of 84 fetuses at 31–32 weeks of gestation to examine the ability of the human fetus to learn and recall information. Three series of vibroacoustic stimuli were presented at pseudorandom intervals over the fetal head, and fetal heart rate (FHR) responses to the first series of 15 stimuli (S1) were compared to responses to an identical second series of 15 stimuli (S1) separated from the first set by the administration of a single novel stimulus of different intensity and frequency (S2). A significant habituation pattern of responses was observed across trials for both series of stimuli, but this habituation pattern was attenuated for the series following the novel stimulus. These findings suggest the 32-week-old human fetus may be capable of detecting, habituating, and dishabituating to an external stimulus, and support the premise that areas of the human fetal central nervous system critical for some aspects of learning and memory have developed by the early third trimester [72]. In a subsample of 33 mother-fetus pairs from the above study, the relationship was examined between maternal (placental) levels of CRH and the abovedescribed fetal pattern of habituation and dishabituation in response to external stimulation. Results indicated the fetuses of mothers with highly elevated CRH

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levels did not respond significantly to the presence of the novel stimulus, thereby providing preliminary support for the notion that abnormally elevated levels of placental CRH may play a role in impaired neurodevelopment, as assessed by the degree of dishabituation [73]. In the third study, the association of circulating maternal ACTH and BE levels with measures of fetal responses to challenge was determined in a sample of 132 women at 31–32 weeks of gestation. Fetal responses were measured by measuring heart rate habituation to a series of repeated vibroacoustic stimuli. Individual differences in habituation were determined by computing the number of consecutive responses above the standard deviation during a control (nonstimulated) period. There was no significant relation between levels of ACTH, BE and fetal responses to challenge. However, an index of POMC dysregulation – the degree of uncoupling between ACTH and BE – was significantly related to fetal responses, such that fetal exposure to relatively high levels of the maternal opiate, BE, relative to ACTH, was associated with a significantly lower rate of habituation [74]. In the fourth study, we performed nonlinear statistical analyses on our complete sample of 156 mother-fetus pairs studied at 31–33 weeks of gestation. These analyses of FHR arousal and reactivity data, using a nonlinear repeatedmeasures model with autocorrelated errors within subjects and independence across subjects, suggest a host of maternal processes, including factors related to prenatal stress, elevated levels of placental hormones, and the presence of obstetric risk conditions, exert significant influences on the fetus and predict individual differences in patterns of fetal responses to external challenges. Our results specifically indicate the following: fetuses exhibited a significant, nonlinear FHR increase in response to the vibroacoustic stimulation protocol; baseline FHR, the presence of uterine contractions during trials, and characteristics of the challenge protocol such as intertrial interval significantly influenced the magnitude of FHR responses; after accounting for the effects of baseline FHR, uterine contractions and characteristics of the challenge protocol, maternal conditions related to psychological and physiological stress (i.e., psychosocial stress levels, placental CRH concentrations, umbilical blood flow, and the presence of maternal medical risk conditions) were significantly associated with the pattern of FHR responses; after an initial response period, fetuses exhibited an FHR response decrement to subsequent stimuli, indicating habituation; a two-parameter growth curve (power) model to assess habituation rate accounted for approximately 70% of the variance in FHR response, and fetal sex and conditions related to maternal stress (i.e., maternal ACTH concentrations, the presence of medical risk conditions) were significantly associated with the rate of habituation [75]. Thus, this set of findings provides further support for the role played by the prenatal environment in modulating aspects

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of human fetal brain development that underlie processes related to recognition, appraisal, response, memory and habituation.

Stress and Placental Corticotropin-Releasing Hormone Function Placental CRH is stress-sensitive. As mentioned earlier, a series of in vitro studies by Petraglia et al. [25, 76, 77] have shown that CRH is released from cultured human placental cells in a dose-response manner in response to all the major biological effectors of stress, including cortisol, and catecholamines. In vivo studies by our group [78] and other investigators [79–81] have found significant correlations among maternal pituitary-adrenal stress hormones (ACTH, cortisol) and placental CRH levels. Moreover, we and others have reported that maternal psychosocial stress is significantly correlated with maternal pituitary-adrenal hormone levels (ACTH, cortisol) [82] – both of which are known to stimulate placental CRH secretion. Some [46, 47], but not all studies [83], have also reported direct associations between maternal psychosocial processes and placental CRH function. Thus, depending on the chronicity of the stressor, the resultant increase in CRH production may be a critical factor that contributes to the early initiation of spontaneous labor and impaired fetal growth [84]. The fetus may also be directly sensitive to maternal stress [85, 86]. Romero et al. [62] have recently described a condition, ‘fetal inflammatory response syndrome’, characterized by a multisystem fetal stress response in human pregnancy, with activation of endocrine and immune systems, including elevated fetal cortisol/DHEA-S ratio [87] and elevated levels of inflammatory cytokines in fetal circulation [87], all of which are important biochemical mediators of fetal development and spontaneous preterm birth.

Conclusions, Issues and Future Directions

Adverse fetal developmental outcomes and their sequela are recognized as significant health problems in the United States. Women reporting high levels of pre- and perinatal stress are, on average, twice as likely to experience an adverse outcome as women reporting low levels of stress. Although the magnitude of this effect of prenatal stress is comparable to that of other ‘established’ obstetric risk factors, the specificity and sensitivity of these measures as predictors of adverse outcome(s) in any individual pregnancy is, at best, only modest. These self-report measures of psychosocial stress rely exclusively on retrospective recall, and may

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be subject to numerous, systematic biases that undermine measurement validity. Moreover, these measures do not capture several important dimensions that are known to moderate the stress and adverse health outcome relation, such as individual differences in psychological or biological responsivity to potentially stressful circumstances in subjects’ everyday lives, and individual differences in the context specificity of stressful responses. Recent advances in momentary experience sampling methodology now afford the opportunity of not only minimizing biases associated with retrospective recall measures but also of assessing the dynamic interplay of psychological, behavioral and biological processes in natural, everyday settings. We suggest that these new methods hold great promise in addressing many of the shortcomings in the stress and fetal development literature, and recommend importing and adapting these methods to conduct ambulatory studies of psychological, biological and behavioral processes in human pregnancy. Stress-related physiological parameters such as placental CRH and proinflammatory cytokines have been shown to significantly predict the risk of adverse fetal developmental outcomes. However, studies have examined the role of these parameters separately and have uniformly reported low specificity and sensitivity. For example, low levels of placental CRH in pregnancy are a good negative predictor of preterm birth but high levels are a poor positive predictor. Similarly, absence of intrauterine infection is a good negative predictor of early preterm birth, but presence of intrauterine infection/inflammation is a poor positive predictor. This may suggest that parameters such as placental CRH and infection/inflammation are, in and of themselves, necessary but not sufficient causes of adverse outcomes. Rather than proposing other ‘novel’ physiological parameters, we suggest that these major parameters need to be examined simultaneously to determine the manner in which they interact to predict the risk of adverse developmental outcomes. We are not aware of any study that, for instance, has looked systematically at both endocrine and immune/inflammatory processes in human pregnancy. We suggest this is a critical future direction for this work because it is well known that endocrine and immune processes extensively regulate and counterregulate one another, and that the effect of either of these processes on a biological outcome of interest is modulated by the state/context of the other. We and others have uncovered evidence of stress-related dysregulation in adverse fetal developmental outcomes in early gestation [47, 50]. Moreover, measures of stress and stress-related physiological dysregulation in early gestation are better predictors of adverse outcomes than the same measures assessed later in gestation [33, 54]. This brings up the important question of the possibility of an underlying susceptibility to stress and stress-related physiological dysregulation that may even precede the index pregnancy. We are not aware of

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any studies that have examined stress and stress biology processes in women before they became pregnant to track the physiological and psychosocial transitions from the nonpregnant to the pregnant state, and we suggest this is an important direction in order to better understand individual vulnerabilities to the adverse effects of prenatal and perinatal stress. Finally, to return to the concept of an epigenetic framework of development, it appears that fetal developmental processes ultimately represent the dynamic interplay between two sets of information systems (i.e., fetal and maternal DNA) and two sets of cellular machinery (i.e., the fetal and maternal environments). It is crucial to identify the genetic and environmental determinants of fetal development, and to model the gene, environment, and maternal-fetal interactions that may underlie the risk of pathophysiological outcomes. In this context, the genetic architecture of fetal development and parturition is defined as the number of loci, their genomic positions, the number of functional alleles per locus, and the patterns of dominance, epistasis, pleiotropy, and geneenvironment interactions that characterize the transition from genotype to phenotype. Genomic imprinting is an epigenetic mechanism by which certain genes become repressed on one of the two parental alleles. Imprinting is now known to play important roles in many other aspects of mammalian development, and its deregulation may result in disease. Recent evidence supports a role for stress in dysregulating the imprinting process during development. Studies in the mouse, for example, demonstrate that environmental stress, such as in vitro culture, affect the somatic maintenance of epigenetic marks at imprinted loci [88]. Other studies have shown that bovine in vitro produced and nuclear transferderived embryos differ from their in vivo produced counterparts in a number of characteristics, including a complete lack of expression, an induced expression, or a significant up- or downregulation of a specific gene [89]. These alterations are considered a kind of ‘stress’ response of the embryos to deficient environmental conditions, are believed to be caused primarily by changes in the methylation patterns, and are associated with aberrant growth and morphology at fetal and perinatal stages of development. Nonimprinted genes can also undergo epigenetic change in response to the environment. For example, a recent study in rodents reported that the choice of exon usage in the glucocorticoid receptor gene is altered in both prenatal glucocorticoid exposure and neonatal behavioral manipulation via histone acetylation and DNA methylation in a transcriptional factor binding site, and that these changes persist throughout life as manifested in altered HPA activity [90]. We are not aware of any studies to date that have systematically examined the physiological genomics of maternal and fetal stress-related neuroendocrine systems and pathways in human pregnancy, and suggest this is yet another important future avenue for this line of research.

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Some 60 years ago, the Fels study of early development, probably the first systematic investigation of factors that affect development before birth, suggested that ‘such factors as.... [maternal] emotional life and activity level during gestation may contribute to the shaping of physical status, behavioral patterns, and postnatal progress of the children they bear’ [91]. Clearly, although we have come a long way since then, the study of the interface between biology and behavior in prenatal life continues now more than ever before to hold great promise in realizing the full implications of this statement to shed light on the nature of our origins and their consequences for our health and well-being.

Acknowledgement This study was supported, in part, by US PHS (NIH) grants HD-33506, HD-41696 and HD-28413 to P.D.W.

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Falkenberg ER, Davis RO, DuBard M, Parker CR: Effects of maternal infections on fetal adrenal steroid production. Endocr Res 1999;25:239–249. Gomez R, Romero R, Edwin SS, David C: Pathogenesis of preterm labor and preterm premature rupture of membranes associated with intraamniotic infection. Infect Dis Clin North Am 1997;11: 135–176. Arck PC, Rose M, Hertwig K, Hagen E, Hildebrandt M, Klapp BF: Stress and immune mediators in miscarriage. Hum Reprod 2001;16:1505–1511. Herrera JA, Alvarado JP, Matrinez JE: The psychosocial environment and cellular immunity in the pregnant patient. Stress Med 1998;4:49–56. Culhane JF, Rauh V, Farley-McCollum K, Hogan V, Agnew K, Wadhwa PD: Maternal stress is associated with bacterial vaginosis in human pregnancy. Matern Child Health J 2001;5:127–134. Culhane J, Rauh V, Hogan V, McCollum K, Wadhwa PD: Racial/ethnic differences in bacterial vaginosis in pregnancy: The role of individual and contextual-level maternal stress (abstract). Am J Obstet Gynecol 2001;185:S145. Wadhwa PD, Culhane J, Chicz-DeMet A, Barve SS, Rauh V, Farley-McCollum K, Hogan V: Maternal stress, endocrine/immune-inflammatory processes and vaginal infection in human pregnancy: Preliminary findings. Am J Obstet Gynecol 2001;185:S231. Rodier PM, Cohen IR, Buelke-Sam J: Developmental neurotoxicology: Neuroendocrine manifestations of CNS insult; in Kimmel CA, Buelke-Sam J (eds): Developmental Toxicology. New York, Raven Press, 1994, pp 65–92. DiPietro JA, Hodgson DM, Costigan KA, Hilton SC, Johnson TR: Fetal neurobehavioral development. Child Dev 1996;67:2553–2567. Sandman CA, Wadhwa PD, Hetrick W, Porto M, Peeke HS: Human fetal heart rate dishabituation at 32 weeks gestation. Child Dev 1997;68:1031–1040. Sandman CA, Wadhwa PD, Chicz-DeMet A, Garite TJ, Porto M: Maternal corticotropin-releasing hormone (CRH) and fetal habituation in human pregnancy. Dev Psychobiol 1999;34:163–173. Sandman CA, Glynn L, Wadhwa PD, Chicz-DeMet A, Porto M, Garite TJ: Maternal HPA dysregulation influences fetal behavior in human pregnancy. Dev Neurosci 2003;25:41–49. Wadhwa PD, Truszczynska H, Garite TJ, Porto M, Sandman CA: Maternal environment influences evoked fetal heart rate responses in human pregnancy. Ann Behav Med 1999;21:S104. Petraglia F, Sawchenko PE, Rivier J, Vale W: Evidence for local stimulation of ACTH secretion by corticotropin-releasing factor in human placenta. Nature 1987;328:717–719. Petraglia F, Volpe A, Genazzani A, Riveier J, Sawchenko P, Vale W: Neuroendrocinology of the human placenta. Front Neuroendrocinol 1990;11:6–37. Wadhwa PD, Sandman CA, Chicz-DeMet A, Porto M: Placental CRH modulates maternal pituitary adrenal function in human pregnancy. Ann NY Acad Sci 1997;814:276–281. Chan EC, Smith R, Lewin T, Brinsmead MW, Zhang HP, Cubis J, Thornton K, Hurt D: Plasma corticotropin-releasing hormone, ␤-endorphin and cortisol inter-relationships during human pregnancy. Acta Endocrinol 1993;128:339–344. Goland RS, Conwell IM, Warren WB, Wardlaw SL: Placental corticotropin-releasing hormone and pituitary-adrenal function during pregnancy. Neuroendocrinology 1992;56:742–749. Sasaki A, Shinkawa O, Yoshinaga K: Placental corticotropin-releasing hormone may be a stimulator of maternal pituitary adrenocorticotropic hormone secretion in humans. J Clin Invest 1989;84: 1997–2001. Wadhwa PD, Dunkel-Schetter C, Chicz-DeMet A, Porto M, Sandman CA: Prenatal psychosocial factors and the neuroendocrine axis in human pregnancy. Psychosom Med 1996;58:432–446. Petraglia F, Hatch MC, Lapinski R, Stomati M, Reis FM, Cobellis L, Berkowitz GS: Lack of effect of psychosocial stress on maternal corticotropin-releasing factor and catecholamine levels at 28 weeks’ gestation. J Soc Gynecol Investig 2001;8:83–88. Lockwood CJ, Kuczynski E: Markers of risk for preterm delivery. J Perinat Med 1999;27:5–20. Gitau R, Cameron A, Fisk NM, Glover V: Fetal exposure to maternal cortisol. Lancet 1998;352: 707–708. Gitau R, Fisk NM, Teixeira JM, Cameron A, Glover V: Fetal hypothalamic-pituitary-adrenal stress responses to invasive procedures are independent of maternal responses. J Clin Endocrinol Metab 2001;86:104–109.

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Pathik D. Wadhwa, MD, PhD Behavioral Perinatology Research Program, University of California, Irvine 3117 Gillespie Neuroscience Building Irvine, CA 92697–4260 (USA) Tel. ⫹1 949 824 8238, Fax ⫹1 949 824 8218, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 70–84

Maternal Depression: An Adverse Early Environment Aquila J. Beacha, Autumn L. Henrya, Zachary N. Stowea,b, D. Jeffrey Newporta Departments of aPsychiatry and Behavioral Sciences, and bGynecology and Obstetrics, Emory University School of Medicine, Atlanta, Ga., USA

Innate differences in the vulnerability to major depressive disorder (MDD) and other stress-related psychiatric illnesses have long been recognized. Some individuals tolerate stress of great magnitude without succumbing, whereas others exhibit a constitutional vulnerability to the deleterious effects of stress, i.e., a lower threshold of tolerance predisposing them to stress-induced illness. This inherent vulnerability, or diathesis, provides the basis for the diathesis/stress model of disease that has been applied to an extensive array of psychiatric and psychosomatic disorders. The origin of the diathesis, its components, and the contribution to individual vulnerability remain central foci of investigation. The relative contribution of genetic inheritance and environmental exposure has been deliberated in often contentious debates of nature vs. nurture. These arguments are frequently couched in overly absolute terms, but diathesis/stress models provide a more balanced consideration, recognizing that both genetic and acquired factors likely interact to contribute to the vulnerability to stressrelated illness (fig. 1). A burgeoning line of research has moved beyond the study of psychiatric syndromes to investigate individual vulnerability to the development of these disorders. This perspective acknowledges that both psychosocial and neurobiological factors mediate the diathesis. Furthermore, it works from the assumption that these factors can be characterized and potentially quantified with respect to the biobehavioral determinants of vulnerability engendered by genetic heritability and exposure to early adverse life events. Much of the extant early life stress research has focused on the persistent sequelae of traumatic childhood experiences such as child abuse and neglect. However, increasing

Early life stress

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Vulnerable phenotype

Later stress Illness

Fig. 1. Diathesis/stress model of illness.

evidence indicates that parental depression, particularly maternal depression, may have untoward effects on child development. Freud’s Oedipal conflict [1], Klein’s notion of infant splitting of the mother [2, 3], and Bowlby’s concepts regarding attachment [4] underscore the longstanding consensus within modern psychiatry that mother/child interaction is critical to normal human psychological development. It should not be surprising, therefore, that when conditions such as maternal depression impact the mother/infant dyad, child development suffers deleterious effects. Some of this risk is undoubtedly transmitted in part by genetic means, though other potential pathways of transmission include: (1) effects of exposure to the neurobiological aberrations associated with antenatal maternal depression, (2) effects of exposure to the affective, behavioral, and cognitive alterations of the depressed parent, and (3) effects of exposure to familial dysfunction that can occur when the child’s mother is depressed [5]. Because its effects can even be communicated prenatally, maternal depression, within the context of the diathesis/stress model, must be recognized as a child’s earliest adverse life event. This review assesses both the clinical and preclinical evidence that exposure to maternal depression and stress constitutes an aberrant change in the environment which comprises an adverse life event for the developing child. The discussion focuses first on the prevalence of maternal depression during the peripartum period, and then on the clinical data regarding the effects of maternal depression on child well-being. After reviewing the evidence from preclinical research of the harmful effects of maternal stress, the discussion concludes by addressing the clinical implications for depressed women who have children.

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Prevalence of Maternal Depression

It has been well established across a disparate array of ethnographic groups that the lifetime rate of MDD among women doubles that of men. However, the heightened vulnerability to MDD is not evenly distributed across the female reproductive life cycle but clusters within the childbearing years [6], raising the specter, of course, that depression is most likely to strike when a woman is raising children. Despite the concerns that should be raised by such findings, there persists the popular notion that pregnancy is a time of emotional well-being. Such clinical lore is not supported, however, by available research data, which indicates that the rate of antenatal depression is comparable to nonpuerperal depression [7–12]. Up to 70% of pregnant women endorse depressive symptoms, with 10–16% fulfilling diagnostic criteria for MDD [13–16]. In fact, over 10% of women presenting for evaluation of postpartum depression (PPD) report symptom onset actually occurred during pregnancy [17]. Whereas systematic research regarding antenatal depression is a relatively new area of investigation, PPD has been documented for millennia. PPD affects between 10 and 22% of adult women and up to 26% of adolescent mothers [18, 19]. Furthermore, there is a dramatic rise in psychiatric hospitalizations during the first postpartum month [20], and up to 12.5% of all psychiatric admissions for women occur during the first postpartum year [21].

Effects of Fetal Exposure to Antenatal Maternal Depression

The effects of depression during pregnancy on fetal development can be transmitted in any of 3 ways. First, the fetal sequelae of antenatal depression can be directly mediated by certain neurobiological substrates of depression, e.g. glucocorticoids and/or proinflammatory cytokines, that can cross the placenta into the fetal circulation. Although the direct mediation of fetal effects has not been incontrovertibly demonstrated, it is clear that many such substrates readily cross the placenta. Second, the fetus can be indirectly affected via neuroendocrine mechanisms whereby prenatal depression modulates the physiological maintenance of pregnancy. For example, there is convincing evidence that depression during pregnancy is associated with higher rates of preterm delivery [22–25]. Although the mechanism whereby antenatal depression might lead to preterm delivery is indeterminate and arguably multifactorial, it has been postulated that depression-associated hyperactivity of the pituitary-adrenal axis might induce placental hypersecretion of corticotropin-releasing factor [26–29], which in turn potentiates myometrial contractility and ultimately

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parturition [26, 30]. Finally, the effects of antenatal depression on fetal development can be mediated indirectly by its impact on maternal behavior. Indeed, depressed pregnant women are more likely to experience heightened stress, decreased social support, poor weight gain, and are more likely to use tobacco, drugs and alcohol than euthymic gravidas [31]. The pathways of fetal exposure in most cases remain obscure. However, several studies have documented the association of depression during pregnancy with deleterious obstetrical outcomes. As previously mentioned, antenatal depression is associated with a greater risk for preterm delivery [22–25]. Other data demonstrate that stress or depression during pregnancy may impede fetal growth, resulting in a higher rate of small-for-gestational-age babies [32–36] and smaller head circumferences at delivery [37]. Maternal stress during the embryonic phase of gestation has even been reported to increase the risk for congenital anomalies such as cranial neural crest deformities [38]. Children exposed to maternal stress, anxiety, or depression during pregnancy may also suffer adverse neurodevelopmental sequelae that affect various aspects of cognitive and psychosocial function. For example, newborns of depressed mothers perform poorly on neurological examinations, exhibiting poorer motor skills, activity, coordination, and resilience [39]. Additional evidence indicates that the neurodevelopmental effects of antenatal depression persist beyond infancy. Antenatal maternal stress is associated with higher rates of developmental delay and a variety of emotional and behavioral problems [40, 41] in preschool children. Furthermore, children of elementary school age have also demonstrated cognitive delay, behavioral and emotional difficulties [42, 44], in addition to maladaptive social interactions [42, 45]. Recent data have begun to delineate the neurobiological alterations in children exposed to antenatal depression that conceivably underlie the observed neurodevelopmental effects. For example, stress-associated elevations in maternal catecholamine and glucocorticoid secretion during late pregnancy are predictive of similar elevations in neonates 24 h after delivery [46]. The neuroendocrine effects of prenatal exposure to maternal depression may be persistent, as 6-month-old children of euthymic mothers who had been depressed during pregnancy exhibit heightened salivary cortisol responses to a standardized psychosocial stressor [47]. Fetal exposure to prenatal depression is also associated with increases in right frontal electroencephalograph (EEG) asymmetry evident at 1 month postpartum [48]. This EEG pattern is consistent with that of left hypofrontality commonly observed in depressed adults. Toddlers with this pattern of EEG asymmetry more often display negative facial expressions, hostility, aggression, reduced motor activity during observed play and fewer displays of affectionate behavior towards their mother regardless of infant temperament [49]. Preschool-aged children with right-sided EEG asymmetry

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also exhibit less emphatic responses both to novel emotional triggers and their mothers’ simulated distress [50].

Effects of Infant Exposure to Postnatal Maternal Depression

The effect of maternal depression after delivery on child development has been more extensively studied. The majority of these investigations have focused on postdelivery events with sparse documentation of antenatal events. Although the effects of postnatal depression can be theoretically mediated directly via depression-related alterations in the constituents of the breast milk of depressed lactating women [51], the children of depressed women are more likely to be effected indirectly by changes in maternal behavior. A meta-analysis of 46 observational studies of depressed mothers demonstrated a moderate association of maternal depression with negative (i.e. hostile, coercive) parenting behaviors and disengaged parenting behaviors [52]. Depressed mothers have recently been reported to be less likely to put their children in car seats, give vitamins to their children, talk with their children, or play with their children [53, 54]. These mothers may also have greater difficulty completing routine parenting tasks such as feeding [55] or bathing [56] their infants. Numerous studies indicate that alterations in the parenting behaviors of depressed women may in turn affect child development. For example, a metaanalysis of the relationship between maternal mental health and infant attachment, encompassing 35 studies and over 200 mother-infant pairs, indicated that maternal stress and depression are associated with a greater prevalence of insecure infant attachment [57]. Disordered attachment in the infants of depressed women is typically manifested by less facial expression, less frequent head orientation, less crying, and more fussiness [58]. As they age, the children of depressed mothers more frequently display ineffective emotional regulation when interacting with their mothers [59], and less prolonged and less efficient attachment behaviors even when interacting with other nondepressed women [58, 60]. The clinical consequences of impaired attachment in the infant of depressed women include difficulties in eating and sleeping observed as early as 3 months of age [56, 61], neurodevelopmental delays evident as early as 6 months of age [61, 62], and diminished verbal interaction and poorer performance on object concept tasks at 18 months of age [54]. Aberrant attachment behaviors have been proposed to result from a deranged interaction between mother and child in which the prototypical withdrawn or intrusive maternal styles of depressed mothers produce insufficient arousal and stimulation in their infants [63].

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Consistent with the implications of the diathesis/stress model, the neurobehavioral sequelae of exposure to postnatal maternal depression appear to persist well beyond infancy. Children of depressed mothers are ultimately more likely to exhibit emotional instability, suicidal behavior, conduct problems, and require psychiatric treatment [39, 64]. They are also more often troubled during the school years by low self-esteem [59], diminished social competence [45], more fear and anxiety [63], delayed language and cognitive development [43, 65], and a greater propensity to overt violence and aggression [60, 66]. Ultimately, the children of depressed mothers are more likely to experience social, educational, and vocational difficulties [59, 67, 68] as well as psychiatric illness [64, 67, 69–71]. Less studied are the neurobiological underpinnings of childhood exposure to postnatal maternal depression, but a few recent studies have begun to delineate the presence of neurobiological alterations in these children. For example, elevated serum cortisol concentrations in the elementary-school-aged children of depressed mothers were positively correlated in one study with the severity of maternal depression [72]. In addition, preschool-aged children of depressed women exhibit EEG alterations in frontal lobe activity that correlate with diminished empathy and other behavioral problems [49, 50].

Preclinical Evidence Regarding Child Exposure to Maternal Depression

Due to the ethical and logistical complexities of conducting psychiatric research during pregnancy or with children, clinical data regarding the effects of exposure to maternal depression have been understandably slow to accrue. Similarly, the myriad of variables encountered such as obstetrical complications, method of delivery, medication and environmental toxin exposure will require a considerable sample size to provide definitive information. This is particularly true when attempting to measure in children the neurobiological impact of exposure. Fortunately, these data are complemented by an extensive line of laboratory animal research bearing homology to maternal depression [73]. Prenatal stress studies in laboratory animals are largely consistent with the clinical data, demonstrating an adverse impact on offspring growth [74, 75], learning [76–78], and attainment of developmental milestones [79]. Furthermore, preclinical research indicates that certain biobehavioral aberrations induced by prenatal stress persist into adulthood. For example, prenatally stressed adult rats exhibit depression-like behaviors [80], anxiety-like behaviors in novel situations [81–87], and behaviorally exaggerated responses to stress [88–90]. The behavioral alterations associated with prenatal stress are accompanied by

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lasting neurobiological alterations. In particular, prenatally stressed animals demonstrate multiple alterations in hypothalamic-pituitary-adrenal axis function including: (1) increased basal concentrations of plasma corticosterone and adrenocorticotropin hormone [91–93]; (2) heightened production of corticotropin-releasing factor in the fetal hypothalamus [94], and (3) exaggerated corticosterone responses to subsequent mild stressors [79, 95–97]. The activity of catecholamine [95, 98–102] and serotonin [95, 103–106] systems are also altered in prenatally stressed laboratory animals. Because considerable evidence indicates that depression interferes with maternal parenting behavior, laboratory animal protocols that interfere with maternal care (e.g. maternal separation, variable foraging) serve as potential models of postnatal maternal depression. Like the prenatal stress models, these models reliably precipitate similar adverse biobehavioral outcomes in the offspring. Offspring subjected to neonatal maternal stress paradigms exhibit insecure attachment behaviors [107–110], depression-like and anxiety-like behaviors [111], and alterations in stress-respondent neurobiological systems [112–116].

Conclusions

An impressive array of evidence now demonstrates that early adverse life events contribute significantly to the vulnerability to adulthood psychopathology, medical illnesses, and maladaptive psychosocial functioning. Whereas parental nurture fosters adaptive responses to early life stressors that should protect the child from such vulnerability, studies indicate that parental depression, specifically maternal depression since it has been subjected to greater scrutiny than paternal depression, not only undermines this protection but can itself represent an early adverse life event. Considered in tandem, the clinical and preclinical data raise a persuasive argument that maternal depression during pregnancy or early childhood represents a child’s earliest adverse life event. From a developmental standpoint, fetal and infant exposure to maternal depression can thereby contribute to a child’s vulnerability to psychiatric illness in the same manner as other adverse childhood experiences such as child abuse or the loss of a parent. It is a unique feature of maternal depression, when compared to other childhood psychosocial stressors, that it can even effect the antenatal environment. Consequently, the effects of maternal depression add another level of definition to diathesis/stress models in that the vulnerability to psychiatric illness can be conveyed from mother to child even in the prenatal context via both genetic inheritance and environmental exposure (fig. 2).

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Maternal depression

Heredity

Antenatal depression

Postnatal depression

Vulnerable phenotype

Later stress Illness

Fig. 2. Maternal depression and the diathesis/stress model of illness.

Current findings regarding maternal depression carry profound clinical implications for the children of depressed women. It is imperative that we better understand the mechanisms whereby parental depression contributes to the development of the child’s subsequent psychiatric vulnerability. In particular, the animal data, because it more readily affords assessment of the neurobiological outcomes of exposure to maternal stress, may ultimately direct the development of pharmacological interventions for a child once a developmental insult from exposure to maternal depression has occurred. Such treatments could theoretically be useful either as a prophylactic intervention for children in the acute aftermath of exposure or a symptom-alleviating treatment for adults with a persistent vulnerability to illness that is, at least in part, a consequence of the long-term effects of exposure to maternal depression. Quantification of the severity or level of maternal depression/stress that poses these risks will serve to directly inform treatment guidelines for pregnancy and the postpartum period. The clinical implications of these data also extend to the psychiatric care of depressed women during the reproductive years. Due caution should be exercised when the decision to treat maternal depression would expose a fetus or nursing child to an antidepressant medication; however, the risk/benefit assessment is incomplete unless the adverse consequences of fetal or infant exposure to untreated maternal depression have been considered. Furthermore, if successful treatment of maternal depression protects the developing child from the untoward effects of exposure to this earliest of adverse life events, then the restoration of maternal mental health may in fact represent primary preventive care for the otherwise exposed child. Consequently, a thorough risk/benefit analysis for women at risk for experiencing depressive illness during pregnancy or lactation,

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given our present state of knowledge, should take into account clinical factors such as the potential deleterious effects of untreated illness on both mother and child, the possible adverse effects of offspring exposure to alternative psychotropic medications within particular developmental windows, and the maternal psychiatric history that is useful in predicting the likelihood and severity of maternal relapse in the event that treatment is withheld. These data also raise important research questions regarding the future of clinical investigation during pregnancy and lactation and the development of animal models appropriate to the study of maternal depression. Although it has been argued and is widely accepted that conducting clinical trials in pregnant and nursing women is on its face unethical [117], failing to conduct such studies arguably deprives women of available treatment and may over time increase the overall risk to women and their infants. Alternative ethical positions regarding perinatal clinical research have been raised. In considering alternative interventions following evidence of in utero failure to thrive, obstetrical researchers have advocated applying the uncertainty principle [118] to the ethical question of antenatal clinical research [119]. The uncertainty principle dictates that a patient, even a pregnant patient, should be ethically eligible to participate in a randomized clinical trial if the preferred clinical course of action is uncertain. Because the relative risks to fetus and infant of exposure to maternal depression versus exposure to maternal psychotropic medication is often unclear, the uncertainty principle may be readily applicable to the study of maternal depression and other psychiatric disorders during pregnancy and lactation. Such issues must be thoughtfully deliberated so that perinatal psychiatric research can be advanced in a productive, yet ethically responsible, manner. Finally, continued refinement of animal models of human parental behavior will undoubtedly hasten our understanding of the impact of depression and other disorders that interfere with parental nurture on offspring vulnerability to stress-related illness. Animal models offer several distinct advantages over human research that can serve to expedite the pace of research. Despite these advantages, an animal model with poor homology to the human experience is not particularly useful. Among the existing animal paradigms, the variable foraging model demonstrates the greatest face validity for human maternal depression. This model avoids direct interaction between researchers and animals, and it does not abolish maternal care but instead introduces an environmental stressor that challenges the maternal capacity for care giving [73]. Although this more closely parallels the difficulties confronted by depressed mothers than other animal models implemented to date, it must be acknowledged that the stress of a systematically controlled environmental perturbation is not fully homologous to the presence of a stress-related psychiatric disorder. To advance our understanding of the developmental effects of exposure to

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maternal depression, future preclinical studies should endeavor both: (1) to continue refining the homology of the models to the human experience (perhaps by using biparental species in which both mother and father routinely participate in care of the offspring), and (2) to expand the domain of neurobiological inquiry in the offspring beyond that of a single, isolated substrate such as cortisol or serotonin to the simultaneous exploration of the effects of maternal stress on multiple biological systems while tracing the association of any observed systemic changes with behavioral outcomes.

Acknowledgements This project was supported in part by a National Institutes of Health (NIH) PatientOriented Research Career Development Award (K23 MH-63507) and an NIH Specialized Center of Research Grant (P50 MH-68036).

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D. Jeffrey Newport, MD, MS, MDiv Emory University School of Medicine, Women’s Mental Health Program 1365 Clifton Road NE, Suite B6100 Atlanta, GA 30322 (USA) Tel. ⫹1 404 778 2524, Fax ⫹1 404 778 2535, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 85–99

Perinatal Infanticide and Suicide Margaret G. Spinelli College of Physicians and Surgeons of Columbia University, and The New York State Psychiatric Institute, New York, N.Y., USA

The subject of maternal infanticide is met with complex reactions. Worldwide estimates are grossly underreported, and infant death statistics are likewise underestimated. Similarly, there is a small literature on postpartum maternal suicide. The purpose of this work is to provide an overview of maternal infanticide and suicide. The goal is to identify deficiencies in postpartum research and literature on the causes, prevention and phenomenology of childbirth-associated disorders in order to prevent these tragedies.

History of Infanticide

In the year 2000, the worldwide prevalence of violent deaths of children (between birth and 4 years old) accounted for 55,000 of 702,000 deaths [1]. Infanticide or infant murder in the first year of life accounts for 1/3 of all US deaths due to injury. According to available data, one infant is killed every day in the USA [2]. Estimates double this number [3, 4]. Yet, data and research on infanticide are scarce. Infant death statistics are likewise glaringly underestimated [5]. In particular, there is a scarcity of data on infant fatalities from abuse or neglect particularly as related to the perpetrators. This underreporting is accounted for by poor documentation, infanticides reported as deaths from sudden infant death syndrome, lack of death certificates and undocumented births due to pregnancy denial and unfounded corpses [4, 6]. Undoubtedly, the very nature of such a tragedy makes it an unappealing subject of research.

Parts of this paper have been adapted from ‘Infanticide: A worldwide view’ in review at the Archives of Women’s Mental Illness.

Historically, the subject of infanticide has been treated with ambivalence. The very same tension between the demand for condemnation and the impulse towards mercy describes the evolution of infanticide laws [7] from ancient times in both Western society and non-Western, ‘primitive cultures’ [8]. In the Greek and Roman era, birth control and eugenic reasons were primary causes for infant murder by fathers who had absolute rule in the family. Infants were sacrificed to pagan gods, and unwanted newborns were exposed to the elements as a method of population control [9, 10]. As the practice of infanticide became more common, the Catholic Church was the first to institute penalties. ‘Overlaying’ was a practice in which mothers lay on the infant smothering it to death [7]. In the manuals for parish priests, overlaying was identified as a venial sin comparable to failing to teach a child proper manners. When the church elevated infant murder to a mortal sin, societies adopted laws in hopes for prevention [11], and secular penalties became increasingly severe. By the 17th century, infanticide was so common that concealment of a murdered newborn became a capital offense [7, 9]. Such punishments as sacking were initiated in which a woman was placed in a sack with a dog, a cock, and a snake and thrown into the water. In the 18th century, laws in the USA, Canada and Europe became increasingly strict particularly for unmarried women. In France, England and Russia, the growing public awareness of the problem of dead and live abandoned newborns led to the creation of the ‘foundling homes’, but they were unable to overcome the profound effects of infanticide and abandonment. In 1647, Russia became the first country to adopt a more humane attitude and by 1888, all European states except England established a legal distinction between infanticide and murder by assigning more lenient penalties to infanticide [7]. In 1922 and 1938, England passed the Infanticide Act in recognition of the time surrounding childbirth as biologically vulnerable and made infanticide a less severe crime proscribing sentences of probation and mandatory psychiatric treatment for women found guilty. Today, almost all Western societies have adjusted the penalty for infanticide [11] by recognizing the unique biological changes that occur at childbirth. These early legal statutes have evolved into contemporary and contrasting legal views across the USA, UK and other countries. Oberman [7] estimated that 29 countries describe statutes explicitly governing the crime of infanticide. All nations that have statutes make infanticide a less severe crime than ordinary homicide with sentences considerably less severe than for manslaughter or murder. This is the case for example in Austria, Finland, Greece, India, Italy, Korea, New Zealand, the Philippines, New South Wales, Western Australia, Tasmania and Canada. Moreover, New South Wales ascribes diminished responsibility to

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infant murder. However, there is one exception: Luxembourg provides a more severe penalty for killing a child than for other homicides. According to the Italian Penal Code, killing a parent is punishable by 24–30 years while ‘infanticide’ is punishable by 3–10 years. Furthermore, Italy’s law specifically provides for those who commit infanticide in order to ‘save their honor’ [7]. Killing an illegitimate compared to a legitimate child is a less serious crime in the Philippines and Austria. Some statutes also differ with regard to the infant’s age. For example New Zealand’s law includes infant murder from immediately after birth to age 10 with a maximum of 3 years in jail. Most statutes follow the British rule, which pertains to the first 12 months of life. Women are often given probation and mandatory psychiatric treatment in countries with such statutes [12]. Generally speaking, infanticide has been treated as a far different crime than other homicides. Yet contemporary cries for greater punishment can be heard from abolitionists in countries where law reformers propose a change in legislation by overturning the existing infanticide law. The United States has no particular laws governing infanticide. A woman who kills an infant is charged with the crime of homicide. If convicted in the American judicial system, she may face a long prison sentence or even the death penalty. Due to the scarcity of psychiatric treatment in the overcrowded US prison system, these women exit the system in their childbearing years with the same psychopathology that brought them into prison. Yet, there is no difference in the prevalence of infanticide between countries that mandate treatment and those that mandate punishment [13].

The Case of Andrea Yates: A Failure of Society and US Legislation

In 2001, when a psychotic Andrea Yates drowned her 5 children in the bathtub of her Houston, Texas home [14], the nation was riveted and the Western world responded. Andrea Pia Yates was a nurse, a devoted mother and wife who home-schooled her 5 children. She had a long history of psychiatric illness including previous postpartum psychotic episodes. Several hospitalizations were due to suicide attempts driven by efforts to resist satanic voices commanding her to kill her infant and children [15]. Six months after her 5th child was born, Andrea Yates’ family and friends described her as a ‘caged animal’ as she continued to deteriorate. For unclear reasons, her psychiatrist discontinued her antipsychotic medication, precipitating a florid psychotic delusional state. She believed that Satan was directing her to kill her children; otherwise they would be condemned to the fires of hell.

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Yates was found guilty of capital murder after only 3½ h of jury deliberation. Spared the death penalty by the same jury, she was remanded to prison for life [14]. Her trial attracted international attention. Organizations dedicated to postpartum disorders requested clarification of postpartum DSM-IV diagnostic criteria, improved medical education, guidelines for treatment and consideration of infanticide legislation. Advocates for the mentally ill blamed the inadequacy of the courts, the use of an archaic insanity [15] defense and the troubling nature of expert psychiatric witnesses whose opinions differed so remarkably.

US Insanity Laws

The outcome of Yates vs. Texas is representative of many insanity pleas in the US courts. A diagnosis of psychosis does not imply ‘insanity’ under the US law. Despite overwhelming agreement by the defense and the prosecution that Andrea Yates was psychotic at the time of her actions, she was found ‘not legally insane’ [16]. Diagnostic standards do not exist for postpartum psychiatric illness, and a woman who commits infanticide may receive sentences that vary remarkably [15, 17]. Depending on the state, the defendant must pass the test of that jurisdiction in order to be found ‘not guilty by reason of mental illness’. A woman who receives a prison sentence in one state may receive the death penalty in another despite the identical circumstances of the crime. Outcomes vary depending on the state, county or even the presiding judge [18]. While some states provide no defense of insanity, the insanity defense in most American jurisdictions is based on two main formulations for insanity: the M’Naghten Test (1843) and the Model Penal Code/American Law Institute Test (MPC). The MPC is the second test of insanity, which provides that a defendant is not responsible for a crime if she lacked capacity to ‘appreciate’ the criminality (right or wrong) of her conduct or was unable to conform her conduct to the law. The expert psychiatric witness makes these respective determinations. The M’Naghten Test, or the ‘right and wrong test’, was derived from the landmark English case decided in 1843 and represents the ‘cognitive’ test for insanity in the state of Texas where Andrea Yates was prosecuted. According to M’Naghton, the finding of ‘insanity under the law’ depends on the cognitive ability of the individual or the ability to ‘know’ right from wrong at the time of the crime. There are inherent problems with this test. First, the likelihood that a 160-year-old legal case can be applied to 21st century neuroscience to accurately determine a state of insanity is improbable. Second, this test relies on the

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defendant’s recall at the time of the crime. Since psychosis and particularly organic states are frequently associated with amnesia, the reliability of these retrospective reports is debatable. Finally, the psychiatric literature is replete with clinical case findings of postpartum psychosis and associated mood lability confounded by delirium, amnesia and impaired cognition. The MPC approach has been adopted by about half of the states and the majority of the federal circuit courts of appeal [19]. It recognizes that mental disease may impair functioning in several ways. The satisfaction of either the cognitive or volitional prong is grounds for an insanity verdict in a MPC jurisdiction. It is likely that Andrea Yates would have been found not guilty by reason of mental illness in a state using the MPC test. Ambiguity in the law is further complicated by psychiatry’s failure to provide diagnostic guidelines for postpartum psychiatric illness. Consequently, we have little to offer the legal justice system [19]. This presents a virtual ‘catch-22’. In a court of law, expert witness testimony must be founded on scientific standards that are recognized in the psychiatric community, yet few standards exist. Therefore, the defenses for these women are limited to early and outdated literature and laws. Our reluctance to place postpartum disorders within a diagnostic framework often leads to tragic outcomes for women, family and society. Moreover, it continues to result in disparate treatment for women in the legal system overall [20]. For example, when evidence for postpartum illness could assist women’s interests in criminal cases, it is often barred from admission [20, 21]. On the other hand, postpartum syndromes are readily admitted into evidence during civil proceedings [20] where they are almost always in opposition to a woman’s interests such as child custody or adoption decisions. Contemporary and Contrasting Views

Contrary to US legislation, those of England and Wales provide that a woman who has killed her infant aged under a year can be indicted for infanticide. This law contained in the Infanticide Act of 1938 [22] represents a model of infanticide legislation often described in the literature. Where a woman by any wilful act or omission causes the death of her child – aged less than a year – but at the time the balance of her mind was disturbed by reason of her not having fully recovered from the effect of giving birth to the child or by reason of the effect of lactation… the offence which would have amounted to murder is deemed to be infanticide and is dealt with and punished as if it were manslaughter.

The Infanticide Act assumes that should a woman kill an infant under 1 year of age, it is likely a consequence of mental instability. For example,

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a 19-year-old British mother who killed her 6-month-old baby was due to stand trial for murder, but the Crown Prosecution Service accepted a guilty plea to infanticide because she had suffered from postnatal depression [23]. She was given a 4-year sentence in a hospital to be treated for her psychiatric problems. Marks [13] describes the ongoing debate over the Infanticide Act in the UK. Proponents of abolition in the UK argue that ‘medicalisation’ of the offence encourages tolerance of infant murder. Marks argues that rather than abolish the Infanticide Act, what is needed is research into the reasons that lead the prosecution to bring charges of murder, manslaughter or infanticide. Further evidence to support this Act comes from a comparison of England and Wales with Scotland. Scottish legislation makes no special provision for maternal infanticide. A mother who kills her infant in Scotland will be charged with either murder or homicide. If harsher legislation is a deterrent, then rates should be lower. However, rates of the offence, the characteristics of victims and perpetrators and the patterning of both convictions and sentences are similar in the two regions [24]. Abolition of the Act is unlikely to result in a reduction in the number of infants killed, nor to facilitate research into the precursors of these crimes. The legislative debate and dilemma are not particular to the UK. The paradoxical responses to infanticide are aroused regardless of geography, legislation or social structure. China illustrates the paradoxical manner in which these cases are viewed from a social perspective. Despite a policy of sex selection and population control [25], a 15-year-old Hong Kong girl who threw a newborn to death went on trial for murder. Economic and cultural realities can contribute to the prevalence and even acceptance of infanticide. Although most countries have specific laws that rule out harsh sentences, there are no simple predictions to the United States experience of seemingly similar crimes, but radically different sentences. In this nation, states set their own policies for handling such cases. In Texas, Andrea Yates began serving a life prison term last year for drowning her 5 children in a bathtub. Despite overwhelming agreement by the defense and the prosecution that she was psychotic, she was found ‘not legally insane’. In the USA, the strong political and social basis for the failure of the insanity defense makes no provision for the scientific fact of mental illness. In a report by the Calgary Herald [26], psychologist Tana Dineen of Victoria opined in the case of Andrea Yates that psychiatric testimony should not be allowed in court. ‘All you get is a lot of speculation.’

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Law, Gender and Science

The basis of infanticide legislation in most countries reflects concern for the biologically ‘vulnerable’ state of women after childbirth. The Victorian Law Reform Commission challenges this accepted wisdom as it lobbies for abolition of the Infanticide Act. Journalist Janet Albrechtsen [27] demands that punishment for infanticide should be based on justice, not gender, with mothers and fathers treated equally. Patricia Pearson exclaims ‘if a hand rocks the cradle it must bear the blame… it comes with the territory of equality’ [27]. Ironically, the proponents of abolition claim that medicalization is outdated. Yet contemporary neuroscience overwhelmingly supports the neurohormonal basis for postpartum illness [28]. Despite evidence for physiological underpinnings of postpartum disorder, our limited diagnostic guidelines and the scarcity of research limit the role of the psychiatric community in the American court system. Contemporary perinatal psychiatrists have failed to demonstrate a unique phenomenology to postpartum disorders, precluding a distinct diagnostic category in the DSM-IV. Cognitive disturbance has been described and demonstrated by a formal systematic study. Wisner et al. [29] described a ‘cognitive disorganization psychosis’ in women with childbearing-related psychoses compared to women with non-childbearing-related psychoses. The clinical picture in the postpartum group demonstrated thought disorganization, bizarre behavior, confusion, delusions of persecution and impaired sensorium/orientation, all consistent with a clinical picture of delirium. This biologically driven state presents as any other toxic organic psychosis [28] such as thyrotoxicosis, severe B12 deficiency, and hypopituitary states. Unusual psychotic symptoms, such as tactile, olfactory and visual hallucinations [29] present in a woman who looks well at one moment, but floridly psychotic in the next. The lack of formal diagnostic criteria for postpartum disorders is particularly deleterious in the US courtroom where the judicial community relies on the DSM for testimony. In the legal arena, the systematic presentation of the perinatal literature is usually absent from the repertoire of psychiatric experts who testify in courtrooms. The consequence is that jurors responsible for the fate of these women are not informed about the illness associated with childbirth. Consequently, jurors are more likely to attribute secondary gain to pleas for insanity in order to avoid prosecution. Improved documentation in the psychiatric literature could indeed prompt major changes if communicated to the legal justice system and the juries who decide culpability. The challenge for psychiatry is to educate the legal community. The task for the expert witness is to communicate our scientific and biologically based

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knowledge to the jury, to use the courtroom as a classroom and encourage verdicts based on informed understanding of the facts. The trial of Andrea Yates represents further inequities in the American system. The very fact that two experts can find drastically different outcomes from one defendant speaks to the dearth of scientific evidence underlying these decisions. Psychiatric expert witnesses defer to the legal community and judicial system by ‘fitting’ our criteria into archaic laws that have no basis in fact. The medical ethics surrounding these cases demands that the patient defendant be given the best treatment based on our contemporary biopsychosocial model of psychiatry. After sentencing Andrea Yates, the American Psychiatric Association made a public announcement on the insanity defense and mental illness [30]. The American Psychiatric Association hopes that the Yates case will lead to broad public discussion of how our society and its legal system deals with defendants who are severely mentally ill. … Advances in neuroscience have dramatically increased our understanding of how brain function is altered by mental illness, and how psychotic illness can distort reality. … Unfortunately, public understanding has not kept pace with these advances. A failure to appreciate the impact of mental illness on thought and behavior often lies behind decisions to convict and punish persons with mental disorders. … Defendants whose crimes derive from their mental illness should be sent to a hospital and treated –not cast into a prison, much less onto death row.

The legal and medical consensus was that Andrea Yates was psychotic [31]. The prosecuting psychiatrist as expert witness testified that Yates ‘knew’ the act was wrong at the time of the killings. The psychiatric expert for the defense testified that the patient ‘knew’ that it was ‘legally’ wrong to kill. He also testified that Yates ‘knew’ it was ‘morally’ right to kill her children because Satan commanded that her children would suffer the fires of hell if she did not drown them – as if her delusional thinking and decision making could be applied to reality-based thinking of the law. As M’Naghton does not specify that cognition should apply to legal or moral knowledge suggests further distortion of the facts. The empathic human being might ask whether cognitive factors should be considered when a mother’s distorted reality demands that she save her children from an eternity of pain. We, in psychiatry, make decisions that conform to legal standards that have no application to our scientific determination and therefore cannot possibly determine culpability. The fact that we attribute decision-making capacity to a psychotic mother speaks to the inaccuracies in our system. Impaired cognition or inability ‘to know’ belongs to the pathophysiology that describes postpartum psychosis. How then can we use this phenomenon to indight an individual with postpartum psychosis?

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The single most important piece of judicial evidence for the existence of a clinical entity lies in the description of the phenomenology in peer-reviewed literature. The dearth of descriptive symptomatology on infanticide and postpartum psychosis leaves the expert witness with few scientific tools. The courts rely on scientific knowledge that is accepted in the medical community [32]. Absent systematic clinical descriptions or research-based case reports, each act is judged in isolation with little or no regard for similar cases [18]. And so, the case of Texas vs. Yates was tried in the media and courts with little intervention from the psychiatric community. Absent research-based information on the temporal relationship between childbirth and infanticide, and a clinical framework for understanding the diagnosis and phenomenology that underlie infanticide, we are in all likelihood missing the signs of potential tragedy as evidenced by the case of Texas vs. Yates [16].

The Tragedy of the Yates Family: What Can We Learn?

Before she killed her children, Andrea Yates spent days in her bed pulling out her hair to demonstrate ‘666’ (the mark of the beast) on her scalp. Was she begging to be safeguarded, to be recognized as Satan? Yates had a family and personal history of psychiatric illness. While pregnant or lactating over the past 7 years, she experienced three postpartum psychotic episodes complicated by infanticidal ideation, suicide attempts and hospitalizations. Mr. Yates seemed indifferent to his wife’s illness and the squalor of the household. During a 1999 hospitalization, Mrs. Yates reported to the staff that she was overwhelmed [16] living in a converted Greyhound bus with her growing family of 4 children [14]. The social worker filed the report with Children’s Protective Services but the state agency did not pursue the case. Mr. Yates testified that he gave his wife 2 weekly hours of personal time. He stated that their religious beliefs encouraged additional children to which Andrea agreed when she was feeling better after deliveries. The fact that both the inpatient and outpatient hospital team released a psychotic mother to her home and children then withdrew her antipsychotic medication speaks to poor medical education and management, and overall failure of the system. The final word of the legal system to determine her culpability using archaic laws and values was the ultimate failure of humanity. We, as a society, failed Andrea Yates. We share equal responsibility for the tragedy. Friends, neighbors and family failed to see or report as Mrs. Yates continued to decompensate. The medical community failed to provide appropriate protection, social work assistance and child services to a severely psychotic

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mother of 5 children. When the legal community and her state failed to appreciate the severity of her illness, they eliminated her last opportunity for appropriate treatment. After 80 years of using probation and treatment in lieu of incarceration, the British legal system has demonstrated that this method is as effective at preventing or deterring infanticide as is incarceration, while being considerably more efficient and cost-effective [7, 13]. The question then to ask ourselves is what we seek to gain by this punishment and how can we prevent these needless tragedies in the future? The fact that the insanity defense is nonexistent in some states and extremely limited in others speaks to our disregard for mental illness and the rights of those who suffer. The task for the psychiatric community is certain. Until we treat mental illness with the same dignity afforded to other illnesses, the course will remain unchanged.

Perinatal Suicide

One theme which has received even less attention in the epidemiological literature is perinatal suicide. Seen against the backdrop of the general population, the mortality rate of childbearing women from suicide is reportedly low [33]. However, measured against the backdrop of the perinatal population, the prevalence is considerably higher. In general, patients with affective disorders have significantly higher rates of mortality than age- and gender-matched controls [34]. In addition, the risk of suicide is highest in the first year after admission, particularly within the few weeks of discharge. Similarly, when measured against the mortality of new mothers with peripartum mental illness, the risk of suicide is surprisingly high [35]. Eighty-eight percent of homicide-suicides are perpetrated by family members. The victims of females tend to be their children. Premenopausal mothers will tend to kill their young children before they kill themselves [36]. There appear to be 2 primary motives for parents who murder their children and then commit suicide [37]. Some may kill on purpose or accidentally then commit suicide as a result of despair. The second motive is usually a result of suicide in a parent who feels that they cannot leave their children in a world that is so harsh and merciless. These ‘altruistic’ [38] filicides or ‘mercy killings’ are committed to relieve the real or imagined suffering of the children. In a qualitative study of filicide by mentally ill mothers, Stanton et al. [39] performed semi-structured interviews of 6 postpartum women with severe psychiatric illness (major depression, schizoaffective disorder or schizophrenia). Each described their motivation as altruistic or an extension of suicide. The

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children’s ages ranged from a few weeks to 7 years. They described an intense relationship with their children and little warning about their filicidal actions. Motives were altruistic and driven by delusions. ‘I thought that “they’’ were going to use my daughter, that the devil would take her in a cot death and she would be lost.’ This mother believed that if she herself killed her daughter, the child could ‘return her to the angels’. These women ‘rescued’ their children from some awful fate that was indicated by their delusional system. For those who described their killing in the context of their own suicide, a recurrent theme related a sense of identification with the children. ‘I did not want to live – and thought that if we could turn on the gas … we could all go to sleep and wake up in heaven.’ Another mother killed her infant because ‘I created her, because she was my responsibility’. In general, the filicides were ego-syntonic within the delusional system, but clearly ego-dystonic once the woman had recovered.

A Case of Infanticide-Suicide

In August 2003, the headline in the Philadelphia Inquirer [40] said ‘Professor charged with murder in baby’s death’. E., a tenured professor, distinguished academic and recognized expert on poverty was charged with murder for killing her 6-month-old baby. She faced 40 years in an American prison. E. had refused an amniocentesis at 20 weeks of gestation. Her infant daughter was born with Down’s syndrome, could not breast-feed and used a feeding tube. E. felt exceedingly guilty. She believed that she was to blame for her baby’s future ‘life of suffering’. She had been contemplating suicide for 2 or 3 weeks. Within days of her incarceration, she attempted to hang herself in the county jail. She was forced to wear Kevlar clothing because it cannot be tied into a noose. Her mattress was placed in the dayroom, in direct sight of jail deputies and other inmates at the detention center. Her last hours were chronicled by jail deputies who had orders to check E. every 30 min. She was seen on her mattress in the dayroom for the 2 p.m. check. At 2:45 p.m., a deputy noticed her feet moving under the Kevlar blanket. By 3:15, a deputy concluded that she was sleeping. But at 3:40, the deputy pulled the blanket away to find her dead. She suffocated herself with a plastic garbage bag in the presence of 12 inmates and jail deputies. E.’s attorney blamed law enforcement, which did not transfer E. to a psychiatric hospital after her first suicide attempt. This case describes one more tragedy triggered by the American judicial system’s treatment of our mentally ill.

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The literature is scarce on this subject. Although the presence of children is protective against parental suicide, it is greater with young and hospitalized psychiatrically ill children [41]. Suicide risk decreases with younger age and greater number of children, while parents of children who have died are at high risk for suicide. The risk of suicide in postpartum women is associated with severe mental illness. Appleby et al. [35] investigated the risk of suicide in women with postpartum illness by calculating standardized mortality ratio (SMRs) for patients discharged from the psychiatric hospital within 1 year. They found that suicides and deaths from unnatural causes were more likely to occur within the first year after childbirth. During the study (1973–1993), 1,567 women were admitted to a psychiatric hospital within 1 year of childbirth of whom 107 died (6.8%). There were 52 suicides (49% deaths, 3.3% of sample), of whom 14 (27% of suicides, 0.9% of sample) died within 1 year of childbirth. There were 71 unnatural deaths (66% of deaths, 4.5% of sample) of whom 19 (27% of unnatural deaths, 1.2% of sample) died within 1 year of childbirth. Although postpartum women seem to have a low rate of suicide, the rates of natural and unnatural deaths increase within the first year in women with severe postpartum illness. In summary, the rate of suicide increases 70-fold in the first postpartum year and the overall long-term risk increases approximately 17-fold. Forty-seven (3%) of the postpartum psychiatric admissions were associated with the death of an infant in the first year after birth, most occurring before admission and likely to have precipitated the maternal illness. Recent findings by Oates [42] identified suicide as the leading cause of maternal death. Of those maternal deaths reported to the Confidential Enquiries into Maternal Deaths (CEMD 2001), 12% were due to psychiatric causes and 10% to suicide. Although women are less likely to commit suicide in a violent manner, most postpartum suicides died violently, mainly by hanging or jumping. Only 3 died from overdose of medication. Oates estimates the suicide rate for puerperal psychosis as 2/1,000 sufferers and 0.3/1,000 for women referred to psychiatric service following childbirth. The fact that 46% of suicides were in contact with psychiatric services emphasizes the need for close supervision in this population of women. Oates described the profile of a woman who is likely to commit suicide as one who has had a previous experience of psychiatric hospitalization without her baby, who suffers from a severe mental illness with an early onset following childbirth, who is older and whose act of deliberate self-harm is violent. Furthermore, no death occurred in a woman admitted at any time to a mother and baby unit.

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In an interview follow-up study [43], 54 postpartum mentally ill women and 89 controls were followed for 6 years; the author describes the outcomes as dismal. One third of these mothers did not live with their child compared to only 3% of controls. Index mothers had more problematic relationships with their children predisposed by the mothers’ own poor parenting. Readmission rate was 46% for these mothers and the suicide rate was 4.2%. In 2003, 18 postpartum suicides in American women were reported to Postpartum Support International [pers. commun.]. Similar to infanticide, the prevalence of peripartum suicide is likely greater than reported. Suicides are less likely reported in the media. Suicide and/or the mother’s postpartum status may not be reported on death certificates.

Conclusion

As a major public health problem, postpartum psychiatric illness is predictable, identifiable, treatable and therefore, most importantly, preventable [44]. The request for greater understanding is hardly new to the 21st century. It is a long-standing plea for research and knowledge. The potential benefit of a formal diagnosis for postpartum illness is greater awareness, education and greater likelihood of early identification and treatment. The risk of challenging the standard method of choosing criteria for diagnostic consideration must be weighed against the potential benefit to maternal/ infant health. The great promise of prevention through education could play out in incalculable saved lives. We, as a world society, could do a far better job of preventing these tragedies.

References 1 2 3 4 5 6

Murray CJK, Lopez AD: The Global Burden of Disease. Boston, Harvard University Press, 1996, p 651. Overpeck MD, Brenner RA, Trumble AC, Trifilletti LB, Berendes HW: Risk factors for infant homicide in the United States. N Engl J Med 1998;339:1211–1216. McClain PW, Sacks JJ, Froehlke RG, Ewigman BG: Estimates of fatal child abuse and neglect, United States, 1979 through 1988. Pediatrics 1993;91:338–343. Herman-Giddens ME, Brown G, Verbiest S, Carlson PJ, Hooten EG, Howell E, Butts JD: Underascertainment of child abuse mortality in the United States. JAMA 1999;282:463–467. Overpeck MD: Epidemiology of Infanticide; in Spinelli M (ed): Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 3–18. Ewigman B, Kivlahan C, Land G: The Missouri child fatality study: Underreporting of maltreatment fatalities among children younger than five years of age, 1983 through 1986. Pediatrics 1986;91: 330–337.

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Oberman M: Mothers who kill: Coming to terms with modern American infanticide. Am Crim Law Rev 1996;34:1–110. Moseley KL: The history of infanticide in Western society. Issues Law Med 1986;1:346–357. Lagaipa SJ: Suffer the little children: The ancient practice of infanticide as a modern moral dilemma. Issues Compr Pediatr Nurs 1990;13:241–251. Langer WL: Infanticide: A historical survey. Hist Child Q 1974;1:353–365. Brockington I: Motherhood and Mental Health. Oxford, Oxford University Press, 1996, pp 400–449. Linzer L: When the blues turn deadly, where is the help? New Zealand Press Association, August 13, 2001. Marks MN: Infanticide in Britain; in Spinelli M (ed): Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 185–200. Yardley J: Despair plagued mother held in children’s deaths. New York Times at A-07, September 8, 2001. M’Naghten’s Case 8 Eng Rep 718 HL, 1843. Spinelli M: Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 61–80. Model Penal Code: 4.01(1) 1995. McFarlane J: Criminal Defenses in the Cases of Infanticide and Neonaticide; in Spinelli M (ed): Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 133–166. Robinson PH: Criminal Law Defenses. Minneapolis, West Publishing Co, 1984, vol 1–2. Meyer C, Spinelli MG: Medical and Legal Dilemmas of Postpartum Psychiatric Disorders; in Spinelli M (ed): Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 167–184. Meyer CL, Proano T, Franz J: Postpartum syndromes: Disparate treatment in the legal system; in Muraskin R (ed): It’s a Crime: Women and Justice. Englewood Cliffs, Prentice Hall, 1999, pp 91–104. Infanticide Act of 1938 1 & 2 Geo 6, Ch 36 sec, 1938. Watson P: Four years for disturbed mother who killed her baby. Press Association Limited, June 28, 2001. Marks MN, Kumar R: Infanticide in England and Wales, 1982–1988. Med Sci Law 1993;33: 329–339. Deutsche Presse Agentur: Teenager who threw newborn to death in Hong Kong on probation. January 4, 2003. Woodard J: Experts grapple with reasons for infanticide. Calgary Herald, August 13, 2001. Albrechtsen J: If a hand rocks the cradle, it must bear the blame. Sydney Morning Herald, August 28, 2001. Sichel DA: Neurohormonal aspects of postpartum depression and psychosis; in Spinelli M (ed): Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 235–256. Wisner KL, Gracious BL, Piontek CM, Peindl K, Perel JM: Postpartum disorders: Phenomenology, treatment approaches, and relationship to infanticide; in Spinelli M (ed): Infanticide: Psychosocial and Legal Perspectives on Mothers Who Kill. Washington, American Psychiatric Press, 2002, pp 36–60. APA Statement on the Insanity Defense and Mental Illness in response to the Andrea Yates case by Richard K. Harding MD, President, American Psychiatric Association Release No 02–08, March 2002. CourtTV: Texas mom drowns kids. Available at http://www.courttv.com/trials/yates, March 2002. Frye vs United States, 293 F 1013 (DC Cir 1923). Marzuk PM, Tardiff K, Leon AC, Hirsch CS: Lower risk of suicide during pregnancy. Am J Psychiatry 1997;154:122–123. Hoyer EH, Mortensen PB, Olesen AV: Mortality and causes of death in a total national sample of patients with affective disorders admitted for the first time between 1973–1993. Br J Psychiatry 2000;176:76–82.

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Appleby L, Mortensen PB, Faragher EB: Suicide and other causes of mortality after postpartum psychiatric admission. Br J Psychiatry 1998;173:209–211. Barraclough B, Harris EC: Suicide preceded by murder: The epidemiology of homicide-suicide in England and Wales 1988–1992. Psychol Med 2002;32:577–584. Collins Pl, Shaughnessy MF, Bradley L, Brown K: Filicide: Suicide in search of meaning. North Am J Psychol 2001;3:277–292. Resnick PJ: Child murder by parents: A psychiatric review of filicide. Am J Psychiatry 1969;126: 325–334. Stanton J, Simpson A, Wouldes T: A qualitative study of filicide by mentally ill mothers. Child Abuse Negl 2000;24:1451–1460. Gray C: Professor’s last hours chronicled. Philadelphia Inquirer, August 2003. Qin P, Mortensen PB: The impact of parental status on the risk of completed suicide. Arch Gen Psychiatry 2003;60:797–802. Oates M: Suicide: The leading cause of maternal death. Br J Psychiatry 2003;183:279–281. Bagedahl-Strindlund M: Parapartum mental illness: An interview follow-up study. Acta Psychiatr Scand 1992;95:389–395. Wisner KL, Peindl KS, Hanusa BH: Symptomatology of affective and psychotic illnesses related to childbearing. J Affect Disord 1994;30:77–87.

Margaret G. Spinelli, MD Assistant Professor of Clinical Psychiatry College of Physicians and Surgeons of Columbia University, Director of Maternal Mental Health, The New York State Psychiatric Institute PO Box 123, 1051 Riverside Drive, New York, NY 10032 (USA) Tel. ⫹1 212 543 5860, Fax ⫹1 212 543 6700, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 100–111

Relevance of Gonadal Hormones to Perinatal Mood and Anxiety Disorders Antti Ahokasa, Jutta Kaukorantaa, Kristian Wahlbeckb, Marjatta Aitoc a

Mehilainen Clinic and University of Helsinki, bNational Research and Development Center for Welfare and Health, and cAdnex Research Clinic of Gynecology, Helsinki, Finland

Epidemiological studies have repeatedly and consistently demonstrated that there is a gender difference in depression, with a 2-fold greater prevalence in women than in men [1–3]. The findings that the gender differences are manifested during reproductive age suggest an important involvement of hormonerelated processes, especially the hypothalamo-pituitary-ovarian (HPO) axis and hormonal changes in the pathophysiology of depression in women. Periods of hormonal fluctuations or low estrogen levels, namely prior to the first ovulation after menarche, premenstrually, postpartum and perimenopausally, have been associated with increased vulnerability to depression and psychotic disorders among susceptible women [4–10]. After our transition to the new millennium with increasing life expectancy, including hormonal fluctuation during the reproductive age and the use of low-dose oral contraceptive pills, women are likely to live a substantial part of their life in a hypoestrogenic state. Concomitantly with these demographic and physiologic changes, a wealth of information derived from basic, clinical and epidemiological research has increased our knowledge also of other areas such as cognitive disorders, Alzheimer’s dementia, cardiovascular diseases, and osteoporosis, as major factors affecting women’s health and the role that estrogen deficiency plays in contributing to those disorders. Given the fact that postpartum depression is common, it still often remains unrecognized, and thus, undiagnosed and undertreated. The incidence of depression has been estimated from 10 to 16% during the 6–12 weeks after delivery, and up to 22% during the first 6 months postpartum according to controlled epidemiologic studies [11–13]. Depression may also manifest with a longer delay and have a long duration; a quarter of the untreated women is still

depressed at the child’s first birthday [11]. Furthermore, postpartum depression can be resistant to conventional psychiatric treatment interventions [6, 14]. The postpartum period is typically described as a time of happiness and excitement. However, the expectations of happiness in a young family can shipwreck into deep depression and no less than 5% of women with severe postpartum depression may commit suicide [15, 16]. Instead of happiness, the postpartum period is often experienced as a time of significant stress. From a physiological point of view, hardly any other life event brings about changes that rival the neuroendocrine and psychosocial changes associated with pregnancy and childbirth. The drastic physiologic events occurring after delivery may offer a window for evaluating the effects of gonadal steroids on mood and behavior. Hormonal changes, increasing hormonal levels during pregnancy and abrupt postpartum withdrawal, and their multiple actions on the central nervous system (CNS) may constitute a precipitating factor for depression in vulnerable women. Besides the obvious significance of gonadal steroids in the pathophysiology of postpartum depression, the main circulating physiologic estrogen in the female, 17␤-estradiol, may be an option in the treatment of this condition.

Hormonal Physiology in Pregnancy and Postpartum

Levels of gonadal hormones, estrogens (estradiol, estriol, and estrone) and progesterone, increase steadily during pregnancy. The biologically active forms of estrogen, 17␤-estradiol and estriol, rise by 100-fold and 1,000-fold, respectively [17]. At the end of pregnancy, serum estradiol levels are very high (about 100,000 pmol/l), and this estradiol is mainly of placental origin [17]. With removal of the placenta at delivery, serum estradiol concentration declines sharply within a few days to 100 pmol/l or lower. The recovery of ovarian estradiol production can be slow, and thus, postpartum estradiol deficiency can be prolonged and profound, mimicking menopause. The sharp drop of estradiol concentration, however, differs from events in peri- and postmenopausal women, in whom the concentrations change in a slowly declining manner allowing more time for the brain to adapt to the changes [18]. Besides the elevations of the concentrations of gonadal steroids, levels of other bioactive substances also progressively rise during pregnancy. Levels of placental corticotrophin-releasing hormone, cortisol, human chorionic gonadotropin, prolactin, ␤-endorphin and thyroid hormone-binding globulin rise across pregnancy, reaching a maximum near term and declining at delivery [17, 19–22]. The levels of free thyroid hormones prior to delivery and postpartum remain relatively constant [19, 20].

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There is a complex interaction and feedback system between HPO and hypothalamic-pituitary-adrenal (HPA) axis. Stress is known to affect the reproductive axis, leading in the severest cases to amenorrhea or it may delay the recovery of estradiol production postpartum. The HPA axis abnormalities seen in depression suggest that activation of the HPA axis may be linked to inhibition of the HPO axis [23]. The increased activity of the HPA axis during the third trimester of human pregnancy may be a consequence of progressively increasing circulating levels of placental corticotrophin-releasing hormone [21, 22]. The resetting of the HPA axis during the postpartum period has not yet been studied in detail. A relatively high cortisol response has been reported, suggesting that postpartum women have hypertrophic adrenal cortices [22, 24]. Stresslike psychiatric symptoms (e.g. anxiety) may further trigger the activation of the HPA axis. This may result in a postpartum vicious circle, in which stresslike symptoms increase HPA activity inhibiting HPO function, which may further trigger psychiatric symptoms in vulnerable women [22]. Thus, the HPA axis exerts profound, mostly inhibitory effects on the reproductive axis inhibiting hypothalamic gonadotropin hormone-releasing hormone, pituitary luteinizing hormone and estrogen production [22]. Furthermore, elevation of prolactin and breast-feeding are known to inhibit HPO function [21, 22]. The hormonal levels in women with postpartum depression have not been investigated systematically and extensively. Those few studies that exist have not found significant differences in depressed and nondepressed women [20]. Thus, although quantitative hormonal levels do not appear to distinguish women with postpartum depression from normals, their susceptibility to changes or low levels of gonadal steroid concentration may differentiate them.

Effects of Gonadal Hormones on the Central Nervous System

Ovarian steroid hormones are neuroactive steroids and have a wide range of actions on the regulation of mood, behavior and cognition. These actions include modulation of the blood-brain barrier, glucose metabolism, neuronal growth, neurotransmitter activity, intraneuronal signal transduction, gene expression and multiple neuroprotection mechanisms [25–27]. Owing to their lipophilic nature, reproductive hormones easily cross the blood-brain barrier, and the central levels of estradiol are reported to correlate with plasma levels [28, 29]. Estrogens have their own receptors ␣ (ER␣) and ␤ (ER␤), or ␣ and ␤ estradiol receptors, that act in the CNS in the cell nucleus and at the neuronal membrane [25–27]. Estradiol nuclear receptors belong to nuclear ligand-activated transcription factors that act to turn genes on and off, and can interact with neuronal membrane receptors, neurotransmitter transporters and

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G-protein-linked receptors [25, 26]. ER␣ appears to dominate in the hypothalamus and amygdala, indicating that the ␣-subtype might modulate neuronal cells involved in autonomic and reproductive neuroendocrine functions as well as emotional interpretation and processing. The dominant areas of ER␤ appear to be hippocampal formation, entorhinal cortex and thalamus, suggesting a putative role for ER␤ in cognition, nonemotional memory and motor functions [25, 30, 31]. The distribution of estradiol receptors in different brain regions, and their distinct up- or downregulation by estradiol can contribute to the complexity of the effects of estrogen on the CNS. The experimental paradigms point to two general mechanisms of gonadal steroid hormones: a rapid, short-term nongenomic membrane effect and a slower, long-term, possibly genomic effect on neurotransmitter function [27, 31]. Considerable evidence from basic and clinical research demonstrates that gonadal hormones, especially estradiol, can modulate neurotransmission at multiple points in the serotonin (5-HT), norepinephrine [noradrenalin (NA)] and dopamine pathways as well as influence monoamine oxidase (MAO) activity. Estrogen modulation of the monoamine neurotransmitter system is a possible mechanism in the link between gonadal hormones and depression, considering that an imbalance in the neurotransmitter system is strongly hypothesized in the etiology of depression. Estradiol exerts an agonistic effect on 5-HT activity by increasing the number of serotonergic receptors, transport and uptake of the neurotransmitter as well as synthesis of 5-HT [27, 32–34]. Estradiol upregulates 5-HT1 receptors and downregulates 5-HT2 receptors, and decreases significant MAO changes in the density of 5-HT2 receptors in the anterior frontal, and cingulate activity [27, 33]. In ovariectomized animals, an acute drop in estrogen induces significant changes in the density of 5-HT2 receptors in the anterior frontal, cingulate and primary cortex and in the nucleus accumbens [35, 36] – higher centers of the forebrain associated with the control of mood, behavior and cognition. The changes could be restored towards normal levels by estradiol treatment. The findings were later confirmed in humans by positron emission tomography during the estradiol treatment of postmenopausal women [37, 38]. Thus, recent neuroimaging studies confirm that estrogen can modulate neurotransmitter function in the human brain. Estradiol selectively increases the activity of NA in the brain. Increased NA activity may be due to decreased reuptake of NA, and decreased metabolism due to inhibition of MAO [27, 31, 33]. Studies further indicate that estradiol modulates the dopamine-2 receptors and dopamine transport in various brain regions [39, 40]. Estradiol decreases dopamine-2 receptor sensitivity and probably that of other dopaminergic receptors as well, and can inhibit dopaminergic activity in various steps of dopamine transmission [27, 33, 41, 42].

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In contrast to estrogen, progesterone appears to have an inhibitory effect on most neuronal activities in the brain. Progesterone can increase MAO activity and thus counteract estrogen’s action of decreasing MAO activity [24, 25, 41]. With regard to neurotransmitter function and activity, progesterone has mainly an opposite effect to estrogen [27, 43]. Conclusively, estrogen/estradiol has antidepressant and antipsychotic properties, whereas progesterone exerts an opposite action to estrogen. Theoretically, this could possibly also explain the manifestation of mood changes called premenstrual dysphoric disorder in susceptible women at the luteal phase, in which the level of estradiol is decreasing and progesterone increasing, and perhaps progesterone is dominating.

Intervention Studies

Only limited clinical investigations have been conducted in depression and the influence of disrupted hormonal homeostasis postpartum. Direct evidence in support of the involvement of the reproductive hormones in the development of postpartum depression in vulnerable women is provided by a double-blind study, in which hormonal withdrawal was simulated [44]. In this study, the supraphysiologic hormonal levels of pregnancy and withdrawal from these high levels to a hypogonadal state were simulated by blocking estradiol production with leuprolide in euthymic women with and without a history of postpartum depression. Five of 8 (62.5%) women with a history of postpartum depression and none in the comparison group developed significant mood symptoms. Positive results have been reported from the treatment studies using different estrogens and regimens, including physiologic 17␤-estradiol in transdermal [45] and sublingual [6, 46, 47] form for postpartum depression, as well as highdose oral conjugated estrogen for the prevention of postpartum affective disorder [48]. The results of the double-blind, placebo-controlled study of 61 women with severe postpartum depression treated with transdermal 17␤-estradiol patches (200 ␮g/day) confirmed the presence of an antidepressant effect compared with placebo [45]. The onset of the effect was rapid and occurred within the first month of treatment. The adverse effect profile during the 6-month treatment period did not differ between the estradiol-treated and placebo groups. A limitation in evaluating the estradiol effect is that in the actively treated group nearly half the patients (47%) concomitantly used antidepressants and the serum concentration of estradiol was measured only once, i.e. after 3 months of treatment. The first published studies based on the measurement of estradiol concentration at baseline and monitoring the concentration during the treatment with

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Fig. 1. Serum estradiol (S-E2) concentration (mean ⫾ SD) and Montgomery-Åsberg Depression Rating Scale (MADRS) total scores during treatment with 17␤-estradiol [6].

sublingual physiologic 17␤-estradiol were presented in case series [46, 47] and in an open-label study lasting 8 weeks of 23 patients with severe postpartum depression [6]. Fourteen of the 23 patients had received psychiatric treatment without an adequate effect before estradiol treatment. The pretreatment values of serum estradiol were very low (mean 47.1 pmol/l, lower than the threshold value for gonadal failure, i.e. 110 pmol/l), suggesting estradiol deficiency. The estradiol dose was determined according to the serum concentration after a weekly measurement. The mean daily dose varied from 3.9 to 4.8 mg. During the treatment, the serum level rose similarly in all patients and approached the values of the follicular phase: mean 342 and 478 pmol/l at week 1 and 8, respectively. The concurrent rise in serum concentration of estradiol coincided with the decline in depressive symptoms (fig. 1). The estradiol level remained low in 2 patients, and in both cases the relief of the symptoms was minimal. The finding suggests that there may be an individual threshold effect of the concentration of bioavailable estradiol and psychiatric symptoms. The observation that depressive symptoms diminished rapidly may have important theoretical and clinical implications, because there is a typical delay of about 2 weeks before antidepressants begin to take effect. The results from studies on women with puerperal psychosis show promising evidence of estrogen’s antipsychotic efficacy. In a prophylactic study of 7 women with histories of puerperal psychosis and 4 with histories of postpartum major depression, only 1 experienced dysphoria again when high-dose oral conjugated estradiol was administered immediately following childbirth [48]. None of the women had histories of nonpuerperal affective disorder, and they

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were euthymic throughout the current pregnancy and delivery. In contrast, in a series of 29 patients with preexisting bipolar disorder or schizoaffective disorder, treatment with transdermal estradiol did not reduce the rate of recurrence [49]. These patients, however, represent rather the primary diagnosis than postpartum disorder. In case series [50, 51] and an open-label study [52] of patients with puerperal psychosis treated with sublingual physiologic 17␤-estradiol for 6 weeks, the treatment effect was positive and quite quickly achieved. Six of 10 patients had undergone psychiatric treatment without adequate effect prior to estradiol treatment. The baseline serum estradiol values were very low (mean 49.5, range 13–90 pmol/l), suggesting estradiol deficiency. By correcting the documented estradiol deficiency with physiologic estradiol, the psychotic symptoms declined. The role of progesterone in the treatment or prevention of postpartum depression has remained obscure, as can be expected theoretically. The results from the study of 180 women given long-acting synthetic progesterone (norethisterone) within 48 h of delivery show that the use of progesterone was associated with an increased risk of developing postnatal depression [53]. The promising effect of estradiol in the treatment of postpartum depression is in line with the reports from the treatment studies of estradiol for premenstrual syndrome [54], premenstrual psychosis [55], peri/postmenopausal depression [56, 57] and as an adjunct therapy for schizophrenia [58, 59].

Different Estrogens and Regimens

Various estrogen types are available in several forms and preparations. Different types include natural, physiological 17␤-estradiol normally produced by the ovary in women, artificial estrogens (e.g. ethinyl estradiol in oral contraceptives) and various conjugated equine estrogens extracted from the urine of pregnant mares [33]. They have a different nature, effects and adverse effect profiles, and thus, in evaluating the effect and clinical practice, the generalizing word ‘estrogen’ should be used with caution, and not without specifying the type of estrogen. Most data in the USA regarding the safety of estrogen therapy have been gathered from women taking conjugated estrogens alone or combined with progesterone [33, 60]. The results from studies of postmenopausal women using 17␤-estradiol or oral conjugated estrogen have yielded different results [33]. In Europe, the most commonly used estrogen is 17␤-estradiol, which is available in several forms, including oral pills, micronized tablets, transdermal patches and gels as well as intranasal spray [61–63]. Significant differences in the pharmacokinetic aspects of oral versus nonoral (e.g. transdermal, sublingual)

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estrogens may contribute to the lack of consistency across studies regarding the effect of estrogen treatment on mood [33, 60]. Oral estrogens are metabolized through the hepatic portal system, with extensive conversion to the less active estrone, whereas nonoral preparations avoid the first-pass metabolism and result in higher physiologic circulation ratios of estradiol to estrone [61, 62]. The transdermal delivery (patches) provides sustained near-constant release and nearly constant serum levels, but there is a noncompliance risk of poor absorption throughout the skin in some patients [64]. Sublingual administration of micronized resorbable estradiol tablets is easy and convenient, and avoids noncompliance sometimes associated with the transdermal system. The rapid but short duration of action via the sublingual route mimics the natural pulsatile ovarian function, and thus may contribute by feedback to a faster recovery of one’s own ovarian function to produce estradiol [22, 65]. Several daily doses are needed to maintain estradiol levels because of the rapid absorption, short halflife of 17␤-estradiol, and quick steroid metabolism in young women [61]. By treating young women with physiologic estradiol during the postpartum period, one of the most important issues is to measure the concentration of serum estradiol at the beginning and during the treatment [6, 52]. The measurement of the concentration is needed to ensure the absorption and to maintain the concentration within physiologic limits compared with the values across the normal menstrual cycle. The main problem in young women may be that the concentration does not reach the individual threshold value, but remains below the effective level [6], because young women have faster steroid metabolism than postmenopausal women [66, 67].

Conclusions

Research on the etiology of postpartum psychiatric disorders, in particular postpartum depression, has been characterized by many claims but few confirmed findings. A better understanding of the physiologic bases of psychiatric symptoms postpartum may lead to the correction of the underlying pathology of postpartum depression and puerperal psychosis rather than treatment of symptoms. Postpartum psychiatric disorders are serious illnesses with a potentially long-lasting negative impact on the mother, the marital relationship and the child’s emotional, social and cognitive development. These disorders can also be resistant or respond with a long delay to conventional psychiatric treatment methods. Consequently, safe and rapidly effective therapies are needed that have a specific etiologic relation to the disorder. Accumulating data suggest intrinsic and complex interactions between reproductive hormones and brain functioning. Existing evidence supports the

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view that estrogen, or its absence, plays a significant role in the regulation of mood, behavior and cognition, as well as in the pathophysiology of mood disorders. Virtually no other life event brings changes for a woman that can compete with the hormonal, neuroendocrine and psychological changes associated with pregnancy and childbirth. The promising results of benefits of estradiol in treating postpartum depression and puerperal psychosis highlight the potential for new, rapid and clinically effective hormone treatments for women vulnerable to these disorders. When estradiol deficiency is documented together with psychiatric symptoms, hormonal intervention could be encouraged, without forgetting psychotherapeutic and social support. However, further research and clinical trials on the use of estradiol need to be performed before conclusive clinical guidance can be given.

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Antti Ahokas, MD, PhD, Ass. Prof. Merikannontie 3 A 14, FIN–00260 Helsinki (Finland) Tel. ⫹358 50 3699850, Fax ⫹358 9 43191550, E-Mail [email protected]

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Pharmacotherapy for Psychiatric Disorders in Pregnancy Lori E. Ross, Shiny Gunasekera, Mary Rowland, Meir Steiner Women’s Health Concerns Clinic, St. Joseph’s Healthcare, Hamilton, Canada

Historically, pregnancy was thought to be a time of protection from psychiatric disorders [1], but the available research has since demonstrated that rates of mood disorders are approximately equivalent in pregnant and nonchildbearing populations [2, 3]. While there is insufficient research evidence to allow for prevalence estimates of anxiety and psychotic disorders during pregnancy, these disorders are also commonly observed in clinical settings. Many have hypothesized a role for pregnancy-related changes in sex steroid hormone concentrations in prenatal psychiatric disorders, though to date, no consistent relationships between pregnancy-specific variables and psychiatric symptoms or syndromes have been established. As such, there is little evidence to suggest that the etiology of, or response to treatment for, psychiatric disorders will be substantially different during pregnancy relative to the non-pregnant state. However, very few studies have systematically examined the efficacy of treatment for perinatal psychiatric disorders: virtually all studies of prenatal use of psychotropic drugs have focused on infant, rather than maternal, outcomes. Treatment of any medical condition, including a psychiatric disorder, during pregnancy, is complicated by concerns about the safety of the fetus. Nearly all drugs, including psychotropic medications, pass through the placenta into the fetal circulation [4]. Therefore, there is concern that in utero exposure could result in complications to the fetal development and neonatal adaptation, or in long-term neurobehavioural sequelae. What is known about the risks to the fetus due to administration of psychotropic agents, therefore, is an important component of treatment decision making with pregnant patients. To aid in these decisions, this chapter will first review the medical literature on potential teratogenic effects and adverse neonatal outcomes associated with prenatal exposure to antidepressant, anxiolytic, mood-stabilizing and antipsychotic

medications. We close with a review of the literature on neurobehavioural development of children exposed to psychotropic medications in utero.

Antidepressant Medications

Selective Serotonin Reuptake Inhibitors Presently, selective serotonin reuptake inhibitors (SSRIs) are considered the first line of treatment for perinatal depression/anxiety of sufficient severity for pharmacotherapy [5]. The data that have been collected with respect to safety of the use of SSRIs during pregnancy are largely reassuring. Teratogenic Effects Of 5 controlled studies and a number of uncontrolled trials, there are no reports of an increased risk for major malformations in SSRI-exposed infants [6–10]. This finding is supported by the results of 2 meta-analyses [11, 12] and a recent chart review of 138 non-smoking women [13]. One study found an increased risk for minor malformations [6]; however, this study raises several methodological questions: data for minor malformations are reported for less than half of the exposed infants and no details are provided as to how infants were chosen for examination, leaving open the possibility of selection bias. In addition, minor malformation rates were not adjusted for potentially confounding variables, including the use of other psychotropic medications. In fact, when infants also exposed to benzodiazepines (BZs) were excluded from the analysis, the difference between the groups was no longer statistically significant. No differences in the frequency of minor malformations have been reported in other studies [10, 14]. Birth Outcomes Exposure to SSRIs has been associated with decreases in gestational age and/or increased risk for premature birth in some [6, 7, 10, 15] but not all [9, 13] studies. Shorter gestational duration was observed after the use of either SSRI or non-SSRI antidepressants [15]. However, in another study of infants with prenatal exposure to either SSRIs or tricyclic antidepressants (TCAs), only SSRI, but not TCA exposure, was associated with a 0.9-week decrease in gestational age, a 175-gram decrease in mean birth weight, and a decrease of 0.29 in the 5-min Apgar score. The differences in birth weight and Apgar scores were no longer significant when gestational age was controlled for [10]. These authors note that while SSRI exposure was associated with a twofold increase in premature delivery, the absolute risk for this adverse outcome was still only 10% and may therefore be outweighed by the potential benefits of SSRI use.

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With respect to the relationship between birth weight and prenatal SSRI exposure, a recent chart review of 138 non-smoking SSRI users revealed 4 cases of low birth weight (2.9%), all involving infants who had been exposed to fluoxetine throughout pregnancy [13]. However, the authors note that this rate was lower than the national low-birth-weight rate of 7.6% (although the national sample probably included a substantial proportion of cigarette smokers, which would be expected to result in a higher proportion of low-birth-weight babies). In another study of 969 babies exposed to various antidepressants, an increased rate of low-birth-weight infants was observed in the group exposed to antidepressants [15]. However, this difference was no longer statistically significant after stratification for maternal age, parity and smoking. It is notable that in the study by Chambers et al. [6], which did report increased rates of low birth weight in exposed infants, the results were not controlled for these potential confounding variables, nor for the use of other psychotropic medications. Risk for Spontaneous Abortion There have recently been some questions whether fetal exposure to SSRIs may result in an increased risk for spontaneous miscarriage [7, 9]. However, differences between exposed and non-exposed groups in the rates of spontaneous abortion do not attain statistical significance and do not seem to be specific to any particular drug or even drug class: similar findings have been reported in women using other antidepressant agents, including venlafaxine [16], trazodone and nefazodone [17]. This lack of specificity has led to the suggestion that it may be depression itself, rather than the antidepressant, that is responsible for any increased risk for early pregnancy loss [17]. Additional research is required to clarify this issue; however, clinicians can be reassured that the rate of spontaneous abortion in women with prenatal SSRI exposure remains within the expected range for the general population [7, 9]. Neonatal Complications Recently, a primary concern regarding the use of SSRIs during pregnancy has been potential effects of third-trimester SSRI exposure on neonatal adaptation. Symptoms of neonatal irritability, crying, shivering, increased tonus, respiratory distress and in rare cases, convulsions, have been associated with exposure to SSRIs at term. There has been a debate, however, as to whether these symptoms can be attributed to neonatal withdrawal from SSRIs or to serotonergic overstimulation [18]. In most reports, adverse neonatal adaptation has been described as a ‘neonatal withdrawal syndrome’. Earliest descriptions appear in case reports, including a case report of a neonate who developed symptoms of agitation and restlessness on the second postpartum day after third-trimester exposure to sertraline, described

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by the authors as potential sertraline withdrawal [19]. A further 2 case reports of jitteriness, hypertonia and/or respiratory distress after third-trimester exposure to fluoxetine were also published [20, 21]. The largest report of adverse neonatal adaptation found that infants with third-trimester fluoxetine exposure had higher rates of ‘poor neonatal adaptation’ (including respiratory distress and jitteriness) than did infants with first- and/or second-trimester exposure after adjustment for a number of potentially confounding variables [6]. However, as described above, neonatal adaptation data were available for only a subset of the infants in this sample. Case series and chart reviews have also reported on neonatal symptoms in infants with late-pregnancy SSRI exposure. In one chart review of 64 motherinfant pairs with prenatal exposure to fluoxetine, there was a threefold increase in the frequency of newborn complications (3 of 17 infants with neonatal complications were reported to be ‘jittery’, the other infants had non-specific symptoms) and a twofold increase in the frequency of special care nursery admissions for infants with third-trimester exposure, relative to infants with exposure in the first and/or second trimester of pregnancy. However, these effects did not reach statistical significance, perhaps due to the limited sample size. Similarly, a trend towards a longer duration of fluoxetine exposure among infants admitted to the special care nursery was observed, although again, this finding did not attain statistical significance [22]. A large case series review reported data from the worldwide fluoxetine pregnancy registry. One hundred and twelve prospectively identified pregnancies with third-trimester fluoxetine exposure were reported to Eli Lilly and it was found that 15 (13%) were associated with postnatal complications unrelated to malformations. In all but 1 case, the symptoms were mild and transitory. However, since there was no consistent pattern of symptoms (e.g. jitteriness reported in 2 infants, irritability in 4 infants, hyperbilirubinaemia in 4 infants and other non-specific symptoms in the remaining infants), and since the rate was similar to the frequency of complications reported in surveys of community samples, the author concluded that the complications were unlikely to be attributable to fluoxetine. It is notable, however, that these data are based on the reporter’s assessment of outcome and whether the assessment of the infant in each case is thorough and unbiased is unknown [23]. Another chart review of 138 infants of non-smoking mothers exposed to SSRIs found a number of transient, non-specific neonatal complications, but concluded that these occurred at expected rates [13]. A recent report of 5 cases of neonates with third-trimester exposure to paroxetine, citalopram or fluoxetine observed symptoms of irritability, crying, shivering, increased tonus, and in 1 case, convulsions. Four of these infants were treated with chlorpromazine (CPZ) to resolve the symptoms, and in 1, symptoms persisted for up to 4 weeks

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after birth [24]. Finally, a study of 17 SSRI-exposed full-birth-weight newborns found significantly more tremulousness in exposed infants aged between 14 and 39 h when studied for 1 h than in a non-exposed control group; however, the degree to which these groups are comparable on the basis of maternal use of other drugs, including marijuana and BZs, is debatable [25]. Concern has been expressed about third-trimester exposure to paroxetine in particular, since there are reports of serious discontinuation symptoms associated with adult use of this SSRI [26]. A search of the medical literature revealed a case report of ‘paroxetine withdrawal syndrome’ in a neonate with third-trimester exposure: at 12 h of age, this infant developed an increased respiratory rate and jitteriness, which was later followed by increased muscle tone and tremor. Symptoms gradually decreased without treatment over the third and fourth days postpartum [27]. A further 4 cases of infants with irritability, jitteriness and other symptoms which were considered to be associated with maternal use of paroxetine during the third trimester of pregnancy were reported [28]. However, 2 of these infants had increased serum paroxetine concentrations, raising the possibility of toxicity as opposed to withdrawal (see discussion below). A further study of this same group of 55 mother-infant pairs with thirdtrimester exposure to paroxetine found that complications necessitating treatment and prolonged hospitalization were reported for 12 infants (22%) [29]. The primary symptom in these infants was respiratory distress, and symptoms were alleviated within 1–2 weeks. It should be noted that unlike other studies of this group [9], data were based solely on maternal reports and were not corroborated by medical records, and therefore, these findings await replication. A large-scale prospective investigation of neonatal outcomes in 997 infants exposed in utero to a variety of antidepressants found that an increased risk for preterm birth, low birth weight, low Apgar score, respiratory distress, convulsions and hypoglycaemia was noted especially after exposure to tricyclic drugs. Most effects did not seem to be SSRI specific and outcomes after exposure to paroxetine were not worse than after exposure to other SSRIs [30]. The existence of a neonatal ‘serotonin withdrawal syndrome’ has recently been disputed, and instead it has been suggested that symptoms of jitteriness, irritability and/or respiratory distress represent SSRI toxicity [31]. This study reports on 20 mother-infant pairs with third-trimester exposure to either citalopram or fluoxetine. In comparison with 20 matched controls without psychotropic exposure, the exposed neonates had a fourfold increase in the serotonergic symptom score during the first 4 days of life, with the most prominent symptoms being tremor, restlessness and rigidity. The difference in serotonergic symptoms between the exposed and control groups was only apparent at days 1–4 postpartum; there was no difference between groups at either 2 weeks or 2 months postpartum. None of the exposed infants required treatment for these symptoms.

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When the exposed group was subdivided by the SSRI used, the difference between exposed and control groups in serotonergic symptoms was found to be largely attributable to the infants exposed to fluoxetine. What makes these data particularly notable is that the difference in serotonergic symptoms between SSRI-exposed and control groups was associated with significant decreases in umbilical vein whole blood serotonin and cord blood 5-hydroxyindoleacetic acid concentrations. Further, an inverse correlation was found between the serotonergic symptom score and venous umbilical 5-hydroxyindoleacetic acid concentrations, providing a physiological rationale for these symptoms [31]. While these findings require replication, the association of serotonergic symptoms with physiological markers of increased central nervous system serotonin activity suggests that adverse effects in neonates with third-trimester SSRI exposure may be the result of serotonergic overstimulation, rather than serotonin withdrawal. It should be noted, however, that the serotonergic symptoms that have been reported in infants with late-pregnancy SSRI exposure generally resolve quickly and do not usually require intervention. As the bulk of these data is drawn from case reports and case series, the proportion of exposed infants affected by this ‘neonatal withdrawal/discontinuation syndrome’ cannot be reliably estimated. As described below, similar symptoms have been described in infants with late-pregnancy exposure to TCAs. Prospective studies are required to determine whether neonates who develop these symptoms are at increased risk for additional exposure-related complications later in life. Although gradual discontinuation of maternal antidepressant treatment in the last weeks of pregnancy has been proposed to reduce the likelihood of neonatal complications [31], this regimen could predispose mothers to postpartum relapse, which would also be associated with potential adverse effects for the infant. The balance of evidence clearly indicates that discontinuation of clinically needed antidepressants in women near term is unwarranted and may put the mother at an unjustified perinatal risk. The neonatal discontinuation syndrome occurs in a minority of cases and is self-limited. However, it is extremely important to observe the infants of mothers taking antidepressants at term for more than the typical 1–2 days to be able to recognize and treat, if necessary, the discontinuation syndrome, when it occurs [18].

Tricyclic Antidepressants Teratogenic Effects A meta-analysis of 14 studies performed in 1996 investigating potential effects of TCA exposure during pregnancy detected no significant effects on rates of congenital malformations. This analysis included over 300,000 births [32].

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Furthermore, a report using data from the European Network of Teratology Information Services did not find higher than expected rates of congenital malformations in 109 infants exposed to TCA monotherapy and 174 infants exposed to TCAs plus other, non-antidepressant drugs [14]. More recently, a chart review of 209 infants exposed to TCAs (as determined by maternal prescriptions filled during the 270 days prior to delivery) found no effects on congenital malformations or neonatal outcomes (including gestational age, birth weight, and Apgar scores) relative to a group of unexposed matched control infants [10]. Neonatal Complications There are reports of a transient TCA withdrawal syndrome in neonates exposed during pregnancy: symptoms are reported to include jitteriness, irritability and convulsions [33–35]. These reports appear to be based on data solely from case reports, so the prevalence of the TCA withdrawal syndrome among all infants with late-pregnancy TCA exposure is unknown, nor is it clear whether these neonatal symptoms have any lasting clinical significance. However, as already mentioned above, a recent prospective study which included 395 mothers who used tricyclic drugs (mostly clomipramine) and 558 who used SSRIs has identified an increased risk of poorer birth outcomes and of withdrawal symptoms in the neonates notably after exposure to TCAs, suggesting that SSRIs may be the drugs of choice during pregnancy [30].

Monoamine Oxidase Inhibitors As a result of the development of safer and more convenient antidepressant agents, monoamine oxidase inhibitors (MAOIs) are now seldom used for the treatment of depression. Extensive interactions with food and other medications, together with their tendency to exacerbate hypertension, make these drugs problematic for many patients, but in particular for pregnant populations [36]. For patients who do not respond to, or cannot tolerate, other classes of antidepressants, clinicians may wish to consider the MAOIs; however, there are few data to suggest whether these agents can be safely used. An early study of 21 mother-infant pairs exposed to various MAOIs reported a relative risk of 3.4 for congenital malformations [37]; however, this report provided little data with respect to both the exposure and the malformations in question and so remains difficult to interpret. Two cases of phenelzine exposure throughout pregnancy have been reported with no congenital malformations in either case [38, 39]. Management of analgesia and anaesthesia during labour and delivery must be carefully considered in women using MAOIs due to potential drug interactions

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with opioid narcotics; successful use of epidural anaesthesia with bupivacaine has been reported [38]. In the context of these limited data, together with concerns about dietary restrictions and the potential risk for hypertension associated with MAOI use, these agents are recommended for pregnant patients only after all other treatment options have been exhausted.

Other Antidepressant Medications There are limited data with respect to the safety profiles of other classes of antidepressant medications for use during pregnancy. One study has reported on first-trimester exposure to venlafaxine. One hundred and fifty women exposed to venlafaxine were compared to women with first-trimester exposure to other SSRIs and to women with exposure to non-teratogenic drugs. There were no statistically significant differences between groups in the frequency of major malformations, spontaneous and therapeutic abortions, gestational age or birth weight as assessed by maternal report [16]. A report by the same group has examined the safety of trazodone and nefazodone during pregnancy. One hundred and forty-seven women with firsttrimester exposure (58 to trazaodone, 89 to nefazodone) were assessed by telephone at approximately 6 months postpartum and outcomes were compared to previously published data on women with exposure to another SSRI or to a non-teratogenic drug. There were no statistically significant differences in major malformations, spontaneous or therapeutic abortions, gestational age or birth weight between the three groups [17]. Further prospective research is required to confirm these promising results regarding safety of the newer antidepressants.

Clinical Management Any risk associated with treatment must be weighed against the known risks associated with untreated disease, particularly perinatal major depression. Risk-benefit decision making is best performed by the informed patient in consultation with a responsible health care provider on a case-by-case basis. When weighing the relative risk, one has to consider the diagnosis, the indication, the potential consequences of not treating and the safety of available treatments, i.e. teratogenic risk and neonatal discontinuation/withdrawal risk. Up to 70% of pregnant women endorse depressive symptoms, with up to 16% fulfilling criteria for major depressive disorder [5]. The diagnosis is hindered due to

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the overlap of symptoms between depression and normal effects of pregnancy, the limited assessment of comorbid medical conditions and the denial/reluctance to seek help. The indication to treat must always be 100%, but accepting the treatment should be a woman’s choice if at all possible. The pregnant woman and her partner should also be made aware of the risks of not treating depression. Controlled clinical studies of the effects of untreated prenatal stress and depression report a long list including a higher rate of both acute and developmental consequences of miscarriages, preterm deliveries, obstetrical complications, pre-eclampsia, admissions to the Neonatal Intensive Care Unit, small for gestational age, smaller head circumferences, lower Apgar scores, congenital anomalies, neurodevelopmental delays, cognitive, psychosocial, behavioural and emotional problems which persist beyond infancy and postpartum depression.

Anxiolytic Medications

Benzodiazepines The SSRIs are now widely prescribed for anxiety disorders, including obsessive-compulsive disorder and generalized anxiety disorder. However, BZs are still considered for administration to pregnant women, in particular, as sleeping aids. Teratogenic Effects Early reports suggesting a tenfold increase in cleft palate following firsttrimester exposure to BZs led to caution in prescribing this class of drug to pregnant women [40]. However, these findings have not been supported when data from multiple studies are pooled: in a meta-analysis of 23 controlled studies with BZ exposure in at least the first trimester, there was no significant association between fetal exposure and major malformations or oral cleft specifically. When only case-control studies were examined, however, the frequency of major malformations and of oral cleft alone were both increased in the exposed group (odds ratios of 3.01 and 1.79, respectively) [41]. The authors recommend that in the absence of additional data, level 2 ultrasonography should be used to rule out oral cleft in the case of first-trimester exposure to BZs. Others have recommended that since BZs are seldom urgently required, other options should be considered until patients are safely through the first trimester [42]. Neonatal Complications There is concern about neonatal withdrawal syndrome in infants exposed to BZs in the third trimester of pregnancy: there have been a number of case

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reports of symptoms of hypertonia and hyperreflexia after exposure to diazepam [43] and chlordiazepoxide [44], and apnoea, lethargy and hypotonia after exposure to clonazepam [45] and diazepam [46]. As for neonatal symptoms associated with third-trimester antidepressant use, symptoms associated with late-pregnancy BZ exposure generally remit gradually without treatment.

Mood Stabilizers

The following mood stabilizers are commonly used in the treatment of psychiatric illnesses, especially bipolar affective disorder: lithium, valproic acid, carbamazepine, lamotrigine, topiramate and gabapentin. Issues of fetal safety with in utero exposure to this class of medications will be discussed in this section.

Lithium Teratogenic Effects The overall risk of congenital abnormalities following the use of lithium in the first trimester is estimated to be 4–12%, an increase in the risk of 2–4% reported in the general population [47]. Lithium administration in early pregnancy has been associated with cardiac abnormalities in particular, including coarctation of the aorta, dextrocardia, patent ductus arteriosus, atresia of the tricuspid valve, mitral atresia and intraventricular septal defect [48]. However, the main cardiac defect of concern is Ebstein’s anomaly, a malformation in the tricuspid valve leading to downward displacement and adherence of portion of the valve to the right ventricular wall [47]. Depending on the severity of the anomaly, the presentation of the infant can range from asymptomatic to neonatal cyanosis. Older children with a minor form of this anomaly may become symptomatic with right ventricular failure only with exercise. Surgical correction of this condition is difficult since a major complication of the procedure is damage to the atrioventricular conduction system with significant mortality rates. However, the risk of Ebstein’s anomaly with the use of lithium is significantly lower than once estimated [47]. Moreover, lithium is not consistently found to be teratogenic: one prospective, multicentre study of 148 motherinfant pairs found no significant increase in congenital malformations in the exposed group relative to a matched control group [49]. If there has been exposure to lithium in the first trimester, a high-resolution ultrasound and echocardiogram at 16–18 weeks of gestation should be ordered to detect the presence of cardiac anomalies.

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Neonatal Complications In the newborns of women treated with lithium near term or during delivery, lithium toxicity can occur. The symptoms include lethargy, hypotonia, poor suck and grasp, muscle flaccidity, shallow respirations, cardiac arrhythmias and cyanosis, and they can take up to 10 days to resolve. Studies have reported an association between lithium use and premature delivery, macrosomia (large size for gestational age) [48], nephrogenic diabetes insipidus [50] and non-toxic goitres in the newborn [51]. If at all possible, lithium should be tapered and discontinued close to delivery to prevent lithium toxicity in the neonate; if this is not possible, the infant should be closely monitored for up to 10 days of life. Because renal excretion of lithium is increased in the third trimester and then falls to pre-pregnancy levels, a decrease in the lithium dose close to delivery may also be needed to prevent lithium toxicity in the mother.

Valproic Acid and Carbamazepine Teratogenic Effects The prevalence of congenital malformations associated with valproic acid and carbamazepine exposure has been reported to be 11.1% and 5.7%, respectively [52]. The main concern with the prenatal use of these medications is the risk of neural tube defects. In the general population, neural tube defects occur in 6/10,000 pregnancies. The prevalence of spina bifida with valporic acid exposure has been estimated to be 1–2% and 0.5% with carbamazapine exposure [53, 54]. This risk may be even higher with polytherapy and a positive family history of neural tube defects. Some studies suggest that with valproic acid, the teratogenic risk may be reduced when doses are kept below 1,000 mg/day and serum levels are less than 70 ␮g/ml [52]. A constellation of features, known as fetal anticonvulsant syndrome, has also been observed in children exposed to valproic acid and carbamazepine in utero. These features include: urogenital abnormalities, hypertelorism, epicanthal folds, microcephaly, minor skeletal abnormalities, transverse palmar creases, abnormal midface, congenital heart defects, respiratory tract abnormality and spina bifida [55]. If valproic acid and carbamezapine are used during the first trimester, an ultrasound at 16–18 weeks (with or without amniocentesis) should be performed to detect the presence of neural tube defects. Neonatal Complications The use of valproic acid during pregnancy has been associated with a number of adverse neonatal outcomes, including hypoglycaemia, hypocalcaemia, cholestasis, hyperbilirubinaemia and acute liver failure with hepatic necrosis, though these data are derived primarily from case reports [48]. Fetal distress

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during labour, low Apgar scores [56] and withdrawal symptoms (including jitteriness, irritability, abnormal tone, feeding difficulties and seizures) [57] have also been reported. As with lithium, an attempt should be made to decrease the dose of anticonvulsants close to delivery if possible. There are also a few case reports in the literature of hepatic dysfunction occurring in neonates of mothers using carbamazepine [58]. To prevent haemorrhagic diseases in the newborn, some authorities have suggested that pregnant women on anticonvulsants should receive vitamin K starting at 36 weeks and then the infant should receive a dose at birth [59].

Lamotrigine, Gabapentin and Topiramate Teratogenic Effects Because minimal data have been collected on pregnancies after exposure to lamotrigine, gabapentin and topiramate, it is not yet known whether these drugs have teratogenic effects. In postmarketing surveillance studies (with small sample sizes), the prevalence of birth defects was reported to be 1.8% and 4.5% with lamotrigine and gabapentin, respectively [60, 61].

Clinical Management Women of reproductive age who are prescribed mood stabilizers should be informed of the risks of these medications on a developing fetus. In turn, they should also be advised regarding effective methods of contraception to maximize the possibility of a planned pregnancy. For instance, carbamazepine (and to a lesser extent topiramate) are inducers of the cytochrome P450 3A4 enzyme, which also metabolizes oral contraceptives. Therefore, because these drugs can decrease the effectiveness of oral contraceptives, the latter should contain at least 50 ␮g of oestrogen; otherwise an additional or alternate method of contraception should be recommended [62]. Furthermore, because up to 50% of all pregnancies are unplanned, and because by 28 days after conception (i.e. before most women know they are pregnant) neural tube closure is completed, women of reproductive age who are being treated with valproic acid, carbamazepine and lamotrigine should consider prophylactic folate supplementation. Although folic acid has been shown to reduce the risk of neural tube defects in the general population, its ability to achieve similar results in offspring of women using anticonvulsants has been more equivocal. Although in 1997 the ACOG [63] recommended 4–5 mg/day of folic acid supplementation for women treated with anticonvulsants, the appropriate dose still remains unclear.

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If possible, mood stabilizers should be tapered and discontinued prior to conception (or at least during embryogenesis in the first trimester). However, this option must be carefully weighed against the risks to the mother and fetus resulting from untreated bipolar affective disorder (e.g. impaired judgment and psychosis leading to dangerous behaviour, poor prenatal care, fetal abuse and potential need for re-introduction of multiple medications at higher doses to treat a relapse). If medications are continued throughout pregnancy, one should aim for monotherapy at the lowest effective dose, especially during the first trimester. Serum concentrations of mood stabilizers should be monitored at least once each trimester since drug levels may drop as pregnancy progresses (especially in the third trimester). However, dosage adjustments should be clinically based and not solely decided upon by serum drug levels.

Antipsychotic Medications

Antipsychotic medications are used in the treatment of many psychiatric illnesses including schizophrenia, schizoaffective disorder, psychotic mood disorders and organic psychoses. The decision to start or continue antipsychotic medication during pregnancy must be made by weighing the risk of illness to the mother and fetus against the risk to the fetus from exposure. It is unlikely that psychotic illness will improve during pregnancy. In fact, a prospective study found that 59% of women reported deterioration in their mental health while pregnant and 29% cited improvement [64]. It has also been reported that when maintenance antipsychotics are discontinued during pregnancy, 65% of women with schizophrenia will relapse [65]. Younger women and those for whom the pregnancy was unwanted may be at increased risk for decompensation. Psychosis in pregnancy may lead to poor prenatal care, poor nutrition, elevated stress levels, substance abuse, impulsive behaviour, suicidality, failure to recognize signs of labour, delusional interpretation of pregnancy, attempts at premature self-delivery and violence.

Conventional Antipsychotics Teratogenic Effects While all antipsychotics diffuse across the placenta, it has generally been agreed that the class of butyrophenones (e.g. Haldol) is safer to use than phenothiazines (e.g. CPZ) during pregnancy. However, available studies looking at the teratogenic potential of traditional antipsychotics are plagued with certain limitations. In these studies, confounding variables (e.g. time of gestation, illness

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effect, substance abuse, intensity and duration of exposure, nutritional status, other medications) are not always well controlled for. Furthermore, most data have been collected from non-psychiatrically ill women receiving the antipsychotic to control hyperemesis gravidarum or for sedative purposes during labour; therefore, doses of antipsychotics and the length of exposure of the fetus to them are often much smaller than would be needed to control psychoses. Nevertheless, retrospective studies have found no increase in congenital abnormalities following in utero exposure to Haldol. In the largest study, 98 women were treated with Haldol with a mean dose of 1.2 mg/day for hyperemesis gravidarum over the course of a few days to a few weeks. No malformations were noted in these infants and Haldol was not found to effect duration of gestation, birth weight or fetal viability [66–68]. In a large series of case reports, no increase in congenital malformation has been found in offspring exposed to trifluoperazine in pregnancy. Again however, many of these women were on low doses for the treatment of nausea [69, 70]. Phenothiazines are the most extensively studied class of antipsychotics. A prospective, longitudinal controlled study of 1,952 infants exposed to phenothiazines during pregnancy showed a non-significant trend towards an increase in major congenital anomalies when exposed between week 4 and 10 [71]. A metaanalysis of large retrospective and small prospective controlled trials (conducted between 1963 and 1995) showed a small but statistically significant increase in non-specific congenital abnormalities by 0.4% [32]. However, there may be a differential effect to the individual phenothiazines. A prospective survey of 12,764 pregnancies exposed to CPZ and piperazine showed a significant increase in congenital malformations in infants exposed in utero to CPZ but not piperazine. The congenital anomalies noted in the CPZ group included cleft lip, cleft palate, limb deformities and cardiac abnormalities [72]. It should also be noted, however, that other studies report no association between in utero phenothiazines exposure and newborn malformations [73]. Finally, some authors have suggested that schizophrenia itself may be associated with an increase in congenital abnormalities as well as fetal and neonatal deaths [74]. Low socioeconomic class and non-compliance with prenatal care in this group of women may be contributory [74]. Treatment of extrapyramidal side-effects common to traditional antipsychotics may be problematic in pregnancy since antihistamines, anticholinergics and amantadine have all been associated with an increase in congenital malformations [37, 75]. If possible, these medications should therefore be avoided in the first trimester. Since low calcium levels can predispose to extrapyramidal sideeffects and since pregnancy is a time of high calcium demand, particular attention should be paid to diet and vitamin supplementation in these women [76].

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Neonatal Complications There have been case reports of perinatal effects in the neonate caused by late-pregnancy exposure to antipsychotics. These symptoms (including tremor, hypertonicity, motor restlessness, abnormal movements, poor suck, functional bowl obstruction and jaundice in preterm infants) are often transient and resolve within days [77]. As a result, some authors suggest discontinuing, or at least lowering the dose of the antipsychotic 1–2 weeks before delivery and then increasing the dose again following delivery. This recommendation should, however, be weighed against the risk of decompensation in an individual woman.

Atypical Antipsychotic Medications Only 1 study has prospectively investigated the risk for major malformations, low birth weight and prematurity after prenatal exposure to atypical antipsychotic medications [78]. Pregnancy outcomes of 151 women who took olanzapine (n ⫽ 60), risperidone (n ⫽ 49), quetiapine (n ⫽ 36) or clozapine (n ⫽ 6) were compared to those of a control group without psychiatric diagnoses exposed to a non-teratogen. No statistically significant increase was found in the rate of major malformations, low birth weight or prematurity among the infants with prenatal exposure to atypical antipsychotic medications. Despite the small sample size (and therefore modest power) of this study, the results are reassuring, particularly since women in the exposed group were more likely to endorse a number of risk factors previously associated with poor outcomes (e.g. smoking, alcohol consumption) than women in the control group. Similarly, many women in the exposure group were using other psychotropic medications besides atypical antipsychotics (including conventional antipsychotics, antidepressants and anticonvulsants). As a result of these potentially confounding factors, women in the exposed group would be expected to have a higher than usual risk for malformations, even in the absence of the exposure to atypical antipsychotic medications. In the sections that follow, we review the available data for specific atypical antipsychotic medications.

Olanzapine The manufacturer of olanzapine has maintained a safety database of information about the use of this drug in pregnancy and breast-feeding. From 1983 to 2001, there were 144 prospectively reported cases of olanzapine use during

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pregnancy for which the outcomes are known [79, 80]. In this data set, there were 12 spontaneous abortions, 3 stillbirths, 6 premature births and 6 major malformations. In addition, perinatal complications were reported in 12 cases. When compared to rates of adverse outcomes in the general population, these rates are within normal ranges. The manufacturer’s database also includes 98 retrospectively identified cases of olanzapine use in pregnancy within which higher rates of adverse outcome were observed; however, the retrospective nature of the reports makes it difficult to draw conclusions. The case report literature for olanzapine primarily describes healthy outcomes after prenatal exposure to doses ranging from 7.5 to 25 mg/day [81–85]. There is 1 report of a pregnancy complicated by a 79-lb weight gain as well as gestational hypertension, gestational diabetes and pre-eclampsia resulting in premature birth; however, the role of olanzapine in contributing to these complications is unclear [86]. It should be noted that there does not appear to be any specific pattern of abnormality or teratogenicity associated with prenatal exposure to olanzapine. Based on these findings, olanzapine may be used in pregnant women where benefits are felt to outweigh the risk to the fetus.

Risperidone The risks to human fetuses exposed to risperidone are largely unknown, as there have not been any adequate human studies to date. It has been shown to be fetotoxic, but not teratogenic, in animal studies [87]. There are 2 published case reports of human exposure to risperidone during all three trimesters of pregnancy, both of which reported healthy outcomes [88]. A postmarketing study of the tolerability of risperidone in 7,684 male and female patients included data from 9 patients who took the drug during 10 pregnancies. In this group, there were 7 live births and 3 therapeutic abortions; no abnormalities were reported among the live births [89]. The manufacturer of risperidone received 25 spontaneous reports of exposure to risperidone during pregnancy [Janssen-Ortho, written commun., 1997]. Of these 25 exposures, 10 resulted in normal outcomes. In addition, there were 9 spontaneous abortions, 3 therapeutic abortions, 1 episode of neonatal jitteriness which developed on the 7th day of life in a neonate whose mother was also taking sertraline, and 2 abnormal outcomes. These abnormalities consisted of a case of agenesis of the corpus callosum in a fetus whose mother had been on numerous medications including 3 days of risperidone at 13 weeks of gestation, and a baby who was delivered at 30 weeks and suffered an intracerebral bleed as a result of prematurity. This infant’s mother had also been on other neuroleptics in addition to anticonvulsants and antidepressants.

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Quetiapine Little is known about the reproductive safety of quetiapine. To date, there have been no reported cases of teratogenicity in humans; however, preliminary animal studies have shown some delay in skeletal ossification, decreased fetal weight and an increase in fetal and pup death [90]. There have been 2 published case reports of patients who conceived while taking quetiapine [91, 92]. In both cases, the drug was continued throughout pregnancy and healthy outcomes were reported. Until more data are available, quetiapine should only be used in pregnancy if the potential risks of discontinuing therapy are felt to outweigh the unknown potential risks to the fetus.

Clozapine The primary concerns with the use of clozapine during pregnancy and breast-feeding are the potential for agranulocytosis as well as its association with diabetes mellitus. Although agranulocytosis has not been reported in fetuses/infants exposed to clozapine, the theoretical possibility exists and the incapacity to monitor fetal hematology makes this a concern. Clozapine has been associated with both new onset and exacerbation of diabetes mellitus, besides its effects on weight gain [93]. This raises concerns about the potential sequelae of gestational diabetes including macrosomia, shoulder dystocia and fetal hypoglycaemia. Clozapine has not been associated with any congenital anomalies and is the only atypical antipsychotic to be considered a class B drug during pregnancy by the FDA (i.e. no evidence of risk in humans). The manufacturer received over 100 spontaneous reports of clozapine exposure during pregnancy between 1996 and 2000. Of these, 20% resulted in unknown outcomes, 6% in elective terminations and over 40 healthy babies were born. There were 5 spontaneous abortions and 2 intra-uterine deaths including a fetus with Reye’s syndrome and a pregnancy complicated by placenta previa marginalis [Novartis, Montreal, Quebec, Canada, pers. commun., 2001]. A review published in 1995 reported on 61 children born to 59 mothers who used clozapine during pregnancy. Of these, 51 babies were healthy, 5 had congenital malformations and 5 experienced neonatal complications [94]. There are 8 case reports of clozapine use in pregnancy in the literature: 2 were uncomplicated [95, 96], there are 2 cases of diabetes complicated by shoulder dystocia at delivery [97, 98], 1 report of f loppy baby syndrome (possibly confounded by concomitant use of lorazepam) [99], 1 infant with a cephalhematoma, hyperpigmentation folds and a coccygeal dimple who went on to have a seizure at 8 days of life [96] and 1 case of decreased fetal heart rate variability [100]. Finally, there is a report of a stillbirth at 32 weeks of an infant

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with intra-uterine growth retardation to a woman using clozapine who demonstrated very poor self-care [101].

Long-Term Neurodevelopment after in utero Exposure to Psychotropic Medications

Limited data are available to provide reassurance that fetal exposure to the psychotropic medications described here has no lasting consequences for neurodevelopment. Normal behavioural, cognitive and motor development has been reported in 3 samples of children exposed to TCA and/or SSRI antidepressants in utero: 1 set of 18 children exposed to TCAs followed up between 4 months to 3 years [102], an additional 80 children exposed to TCAs and 55 children exposed to fluoxetine followed up between 16 and 86 months [8] and most recently, a sample of 46 children exposed to TCAs and 40 children exposed to fluoxetine followed up between 15 and 71 months [103]. It is notable that in the latter study, both IQ and language development were negatively associated with the duration/number of episodes of depression since childbirth: this is strongly suggestive that untreated maternal depression can have significant effects on child development. Another recent study provided data on 31 children of depressed mothers treated with SSRIs, in comparison with 13 children of depressed mothers who elected not to take medication, assessed between ages 6–40 months. The exposed children had lower scores on the Bayley Psychomotor Development Indexes and the motor quality factor of the Bayley Behavioural Rating Scale and specifically exhibited more frequent tremulousness and inappropriate fine motor movements [104]. There are limitations to this study, particularly the lack of data on the concomitant use of other psychotropic medications, including BZs, and outcome testing across a wide age range. Thus, the findings await replication. A small study of 11 mother-infant pairs with prenatal citalopram exposure found normal neurodevelopment up to 1 year of age [105], as did a similar study of 11 infants exposed to fluoxetine [106]. However, the small sample size and non-specific assessment of infant neurodevelopment make the clinical significance of these studies questionable. There are some data with respect to child development after fetal BZ exposure. In 1 study of 17 infants with BZ exposure throughout gestation and 29 infants with no psychotropic exposure, the BZ-exposed infants had significantly lower scores on all subscales of the Griffiths’ Developmental Scale at 10 months of age and on the personal-social behaviour and hearing and speech subscales at 18 months of age [107]. However, the two groups were not matched

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for cigarette smoking or psychiatric diagnosis, variables which could account for effects on child development. Most recently, a Danish study has reported on a comparison between 435 women using a psychotropic medication during pregnancy and 1,304 women without psychotropic medication use who had given birth in the same region and time period. Public health records were extracted and scores on the Boel test (a test of psychomotor development which assesses hearing, sight and motor attention) at 7–10 months of age were compared for the infants in each group. Abnormal results on the Boel test were more frequent in the children who were presumed to be drug exposed (16%) than in those presumed not to be exposed (4%): the odds ratios were 4.5 for antidepressant medications, 4.6 for anti-epileptic medications, 3.9 for neuroleptic medications and 4.0 for BZs [108]. These odds ratios increased after adjustment for gestational age, birth weight, breast-feeding, type of residence and child’s age. However, it is notable that data were not available for other potentially important confounding factors such as smoking or use of illicit drugs. In addition, the authors note that assessments were not blinded and children who were suspected to have problems may have been more likely to undergo assessment with the Boel test. Thus, these findings await replication. Only limited data have specifically examined neurodevelopment after prenatal exposure to mood stabilizers. A follow-up study of 60 children born to mothers using lithium during pregnancy showed no difference in physical or mental difficulties compared to their unexposed siblings [109]. A few follow-up studies of offspring born to mothers having used valproic acid during pregnancy suggest that these children may experience some developmental delay and require more help in school [110, 111]; another study however found normal psychomotor development [112]. Similarly, some studies suggest an association between maternal carbamazepine use and lowered cognitive scores and developmental delays in the children [113], while other studies have not found an association with cognitive dysfunction [114]. No follow-up studies assessing neurobehavioural sequelae following lamotrigine, gabapentin and topiramate use are yet available. Data examining the neurodevelopmental effects on offspring exposed to traditional antipsychotics in utero remain limited. However, no adverse outcomes have been documented [115–118]. One study noted that children exposed to antipsychotics during pregnancy were taller and/or heavier than the matched control group [119]. In summary, methodological issues make the collection of long-term neurodevelopmental follow-up data difficult and the available studies have substantial weaknesses. While the results of Nulman et al. [8, 103] are reassuring with respect to the antidepressants, it should be noted that in each of these

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studies, children were assessed only once and over a very wide age range, potentially making the groups very heterogeneous and decreasing the likelihood of finding statistically significant differences in the exposed children. The recent studies that have identified subtle differences in drug-exposed children are concerning, and further research employing specific definitions of exposure, longitudinal methods and detailed, unbiased assessments of developmental functioning are urgently required.

Conclusions

Psychiatric disorders are common during pregnancy and pharmacotherapy will often be necessary. Unfortunately, there are few data to guide clinical decision making about the choice of medication or dosage regimen, neither with respect to efficacy nor with respect to fetal safety [120, 121]. Moreover, current guidelines and clinical practice for the use of antipsychotic drugs in women with psychotic disorders during pregnancy are not based on evidence from randomized controlled trials [122]. Furthermore, the current classification systems for teratogenic risk provide little help to clinicians, since specific drugs are not consistently rated across international systems [123] and in the US system, many of the psychotropic drugs are classified into category C (adverse effects demonstrated in animals but no human data available) [124]. Additional research on the effects of psychotropic medications, and in particular, the potential effects on long-term neurodevelopment, is sorely needed. Until such data become available, however, risk-benefit analyses must be made on a caseby-case basis, working towards the best possible outcomes for mother and baby as a unit.

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88 Ratnayake T, Libretto SE: No complications with risperidone treatment before and throughout pregnancy and during the nursing period. J Clin Psychiatry 2002;63:76–77. 89 Mackay FJ, Wilton LV, Pearce GL, Freemantle SN, Mann RD: The safety of risperidone: A postmarketing study on 7,684 patients. Hum Psychopharmacol Clin Exp 1998;13:413–418. 90 Ernst CL, Goldberg JF: The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 2002;63(suppl 4):42–55. 91 Tenyi T, Trixler M, Keresztes Z: Quetiapine and pregnancy. Am J Psychiatry 2002;159:674. 92 Taylor TM, O’Toole MS, Ohlsen RI, Walters J, Pilowsky LS: Safety of quetiapine during pregnancy. Am J Psychiatry 2003;160:588–589. 93 Popli AP, Konicki PE, Jurjus GJ, Fuller MA, Jaskiw GE: Clozapine and associated diabetes mellitus. J Clin Psychiatry 1997;58:108–111. 94 Dev V, Krupp P: The side-effects and safety of clozapine. Rev Contemp Pharmacother 1995;6: 197–208. 95 Barnas C, Bergant A, Hummer M, Saria A, Fleischhacker WW: Clozapine concentrations in maternal and fetal plasma, amniotic fluid, and breast milk. Am J Psychiatry 1994;151:945. 96 Stoner SC, Sommi RW Jr, Marken PA, Anya I, Vaughn J: Clozapine use in two full term pregnancies. J Clin Psychiatry 1997;58:364–365. 97 Waldman MD, Safferman AZ: Pregnancy and clozapine. Am J Psychiatry 1993;150:168–169. 98 Dickson RA, Hogg L: Pregnancy of a patient treated with clozapine. Psychiatr Serv 1998;49: 1081–1083. 99 DiMichele V, Ramenghi LA, Sabatino G: Clozapine and lorazepam administration in pregnancy. Eur Psychiatry 1996;11:214. 100 Yogev Y, Ben Haroush A, Kaplan B: Maternal clozapine treatment and decreased fetal heart rate variability. Int J Gynaecol Obstet 2002;79:259–260. 101 Mendhekar DN, Sharma JB, Srivastava PK, War L: Clozapine and pregnancy. J Clin Psychiatry 2003;64:850. 102 Misri S, Sivertz K: Tricyclic drugs in pregnancy and lactation: A preliminary report. Int J Psychiatry Med 1991;21:157–171. 103 Nulman I, Rovet J, Stewart DE, Wolpin J, Pace-Asciak P, Shuhaiber S, Koren G: Child development following exposure to tricyclic antidepressants or fluoxetine throughout fetal life: A prospective, controlled study. Am J Psychiatry 2002;159:1889–1895. 104 Casper RC, Fleisher BE, Lee-Ancajas JC, Gilles A, Gaylor E, DeBattista A, Hoyme HE: Followup of children of depressed mothers exposed or not exposed to antidepressant drugs during pregnancy. J Pediatr 2003;142:402–408. 105 Heikkinen T, Ekblad U, Kero P, Ekblad S, Laine K: Citalopram in pregnancy and lactation. Clin Pharmacol Ther 2002;72:184–191. 106 Heikkinen T, Ekblad U, Palo P, Laine K: Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation. Clin Pharmacol Ther 2003;73:330–337. 107 Viggedal G, Hagberg BS, Laegreid L, Aronsson M: Mental development in late infancy after prenatal exposure to benzodiazepines – A prospective study. J Child Psychol Psychiatry 1993;34:295–305. 108 Mortensen JT, Olsen J, Larsen H, Bendsen J, Obel C, Sorensen HT: Psychomotor development in children exposed in utero to benzodiazepines, antidepressants, neuroleptics, and anti-epileptics. Eur J Epidemiol 2003;18:769–771. 109 Schou M: What happened later to the lithium babies? A follow-up study of children born without malformations. Acta Psychiatr Scand 1976;54:193–197. 110 Ardinger HH, Atkin JF, Blackstone RD, Elsas LJ, Clarren SK, Livingstone S, Flannery DB, Pellock JM, Harrod MJ, Lammer EJ, Majewski F, Schinzel A, Toriello HV, Hanson JW: Verification of the fetal valproate syndrome phenotype. Am J Med Genet 1988;29:171–185. 111 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. 112 Granstrom ML: Development of the children of epileptic mothers – Preliminary results from the prospective Helsinki study; in Janz D, Dam M, Richens A (eds): Epilepsy, Pregnancy, and the Child. New York, Raven Press, 1982. 113 Onroy A, Cohen I: Follow-up studies of children born to epileptic women treated with carbamazepine. Teratology 1995;51:169.

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114 Scolnik D, Nulman I, Rovet J, Gladstone D, Czuchta D, Gardner HA, Gladstone R, Ashby P, Weksberg R, Einarson T, Koren G: Neurodevelopment of children exposed in utero to phenytoin and carbamazepine monotherapy. JAMA 1994;271:767–770. 115 Edlund MJ, Craig TJ: Antipsychotic drug use and birth defects: An epidemiologic reassessment. Compr Psychiatry 1984;25:32–37. 116 Slone D, Siskind V, Heinonen OP, Monson RR, Kaufman DW, Shapiro S: Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score. Am J Obstet Gynecol 1977;128:486–488. 117 Ayd FJ Jr: Children born of mothers treated with chlorpromazine during pregnancy. Clin Med 1964;71:1758–1763. 118 Kris EB: Children of mothers maintained on pharmacotherapy during pregnancy and postpartum. Curr Ther Res Clin Exp 1965;7:785–789. 119 Platt JE, Friedhoff AJ, Broman SH, Bond RN, Laska E, Lin SP: Effects of prenatal exposure to neuroleptic drugs on children’s growth. Neuropsychopharmacology 1988;1:205–212. 120 Cohen LS, Rosenbaum JF: Psychotropic drug use during pregnancy: Weighing the risks. J Clin Psychiatry 1998;59(suppl 2):18–28. 121 Patton SW, Misri S, Corral MR, Perry KF, Kuan AJ: Antipsychotic medication during pregnancy and lactation in women with schizophrenia: Evaluating the risk. Can J Psychiatry 2002;47: 959–965. 122 Webb RT, Howard L, Abel KM: Antipsychotic drugs for non-affective psychosis during pregnancy and postpartum (Cochrane Review). Cochrane Database Syst Rev 2004(2);CD004411. 123 Addis A, Sharabi S, Bonati M: Risk classification systems for drug use during pregnancy: Are they a reliable source of information? Drug Saf 2000;23:245–253. 124 Merlob P, Stahl B: Classification of drugs for teratogenic risk: An anachronistic way of counseling. Teratology 2002;66:61–62.

Meir Steiner, MD, PhD, FRCPC Professor of Psychiatry and Behavioural Neurosciences and Professor of Obstetrics and Gynecology, McMaster University Director, Women’s Health Concerns Clinic, St. Joseph’s Healthcare Fontbonne Building 6th Floor 50 Charlton Avenue E., Hamilton, ON L8N 4A6 (Canada) Tel. ⫹1 905 522 1155, ext. 3605, Fax ⫹1 905 521 6098, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 137–149

Maternal Depression in the Postpartum Period: Impact of Breast-Feeding on Treatment Planning Zachary N. Stowea,b, Kimberly Ragana, D. Jeffrey Newporta Departments of aPsychiatry and Behavioral Sciences, and bGynecology and Obstetrics, Emory University School of Medicine, Atlanta, Ga., USA

There are numerous prospective, cross-sectional, retrospective case series and review articles addressing the topic of maternal depression during the postpartum period. The majority of these articles often utilize the term ‘postpartum depression’. However, the accuracy of this classification is suspect. Several investigations have demonstrated that depressive symptoms often arise de novo during pregnancy [1–3] or represent exacerbations of preexisting mood disorders. The current diagnostic systems (DSM, ICD) do not require an individual to be asymptomatic during pregnancy to be classified ‘postpartum’. As such, this introduces considerable confounds to delineate the potentially unique etiological treatment and the impact of postpartum-onset maternal depression. This is further complicated by the imprecise media utilization of the term ‘postpartum’ when reporting a postnatal tragedy such as infanticide or when a celebrity/public figure publishes an autobiographical account of her own experience with maternal depression. Whether or not these cases represent postpartum onset versus exacerbation of a preexisting illness is not typically discussed. Regardless of the timing of symptom onset, there are unique issues in the treatment of maternal depression in nursing women, including: (1) unique hormonal environment; (2) potential exposure to nonpsychotropic medications that may influence mood (e.g. progestin-only birth control pills, galactagogues to increase milk production), and (3) pharmacological treatment options in breast-feeding women. These important treatment issues are further complicated by the changing psychosocial

environment (e.g. career decisions, financial strain, increased interactions with extended family). It is beyond the scope of this review to cover the purported benefits of breast milk for the neonate/infant and extended breast-feeding for the mother [4]. It suffices to note that virtually all professional organizations support breast milk as the ideal form of nutrition for infants. Over the past decade, the number of women choosing to breast-feed has been rising [5], and the postpartum duration of breast-feeding has increased [6]. As such, this review will focus on the unique treatment issues encountered during breast-feeding with empirical thoughts on the use of antidepressants in lactation.

Unique Hormonal Environment

There is an overwhelming tendency to view postpartum-onset mental illness as etiologically derived from the abrupt decline in sex steroids after parturition. The empirical scientific evidence to support this hypothesis is limited [7]. However, these previous studies are restricted by the dependence on peripheral measures of estrogens and progestins with limited access to central markers of gonadal steroid metabolism and activity. Furthermore, nursing itself engenders a distinct hormonal milieu that women do not experience outside of lactation. Elevations in serum prolactin, fluctuations in oxytocin, and the hypoestrogenic state may have a direct impact on mental functioning during breast-feeding. There is evidence that symptoms of depression may occur after weaning [8]. Empirically, our program has consistently recommended that women who choose to wean do so by tapering over 7–10 days to minimize further abrupt changes in the hormonal environment. There is limited data on the impact of medications taken by breast-feeding women on the incidence and/or severity of depression in the postpartum period. Some women may receive galactagogues to increase breast milk production. It is noteworthy that common side effects of the most commonly prescribed agent, metoclopramide (Reglan) [9], include agitation and depression [10]. Similarly, some women may elect to take oral contraceptives early in the postpartum period. In breast-feeding women, the progestin-only compounds are the most commonly prescribed. While there has been considerable debate, conflicting data, and differing clinical opinions regarding their psychotropic effects, the Physicians’ Desk Reference [10] lists ‘mood changes’ as a side effect of these agents. Empirically, nonpharmacological interventions for assistance with milk production and contraception should be first-line options for women at high risk for depression.

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Pharmacological Treatment Options in Breast-Feeding Women

The literature is replete with review articles on the use of antidepressants during pregnancy and breast-feeding [11–17]. To aid in processing the relatively large database on the use of antidepressants in lactating women, division into several sections is warranted. These sections include: (1) the breadth of the extant data; (2) quantitative comparisons of infant exposure; (3) documentation of adverse effects, and (4) the clinical decision. Antidepressants in Breast-Feeding: The Data As a class, antidepressants have more published data in breast-feeding than any other class of medications. A comprehensive literature search identified 86 separate reports including a total of 688 nursing infants exposed to antidepressants. Given the interest in this area, there will be additional reports prior to the release of this review. The current data are listed in table 1. Clearly, the majority of the reports (65%) and infant exposure cases (85%) involve the selective serotonin reuptake inhibitors. There have been numerous attempts to compare the extent of infant exposure and relative safety of individual antidepressants. Quantifying Nursing Infant Exposure The issues of what methodology most accurately defines a nursing infant’s exposure (i.e., dose) to a particular antidepressant and how to report such exposure for comparative analyses have generated some debate. Given that no human study has determined the central nervous system concentration or the receptor occupancy of a given neurotransmitter system associated with antidepressant exposure in nursing infants, only indirect measures are available for comparing individual medications. The historical standard for breast-feeding safety, i.e., medicines with an estimated infant daily dose during lactation that is less than 10% of the maternal daily dose, was adopted in a recent meta-analysis of antidepressants in breast-feeding [80]. Yet, this standard is essentially devoid of scientific justification and to a large extent empiric. Such conclusions are laden with confounds. (1) Infant dose estimates are typically based on unreliable extrapolations from the breast milk to maternal serum ratio (M/S). Our group [45, 51], in collaboration with others [29], has clearly demonstrated that antidepressant excretion into breast milk varies from the first portion of breast milk (foremilk) to the latter portion of breast milk (hindmilk) for sertraline, paroxetine, and

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Table 1. Data on antidepressant use in breast-feeding Medication

Separate reports

Selective serotonin reuptake inhibitors Citalopram 10 Fluoxetine 15 Fluvoxamine 7 Paroxetine 9 Sertraline 15 Subtotal 56

Exposed infants

References

120 198 14 90 162 584

[18–26] [25–39, 49] [24, 26, 40–44] [24, 26, 37, 44–49] [25, 26, 37, 44, 49–59]

Tricyclic antidepressants Amitriptyline Clomipramine Desipramine Dothiepin Doxepin Imipramine Nortriptyline Subtotal

2 3 1 3 3 2 5 19

3 8 5 25 3 6 23 73

Other antidepressants Bupropion Nefazodone Trazodone Venlafaxine Subtotal Total

3 2 1 5 11 86

4 3 6 18 31 688

[60, 61] [49, 61, 62] [61, 63, 64] [65–67] [49, 61] [49, 59, 68–70]

[71–73] [74, 75] [76] [25, 26, 77–79]

fluoxetine. Similarly, the excretion into human breast milk varies with time after dose. As such, estimation of infant dose from the M/S ratio based on spot breast milk sampling is unlikely to be accurate. (2) The decision to view ⬎10% as clinically meaningful represents an extension from previous investigations of nonpsychotropic medications. Our literature search failed to identify an investigation that supported the ⬍10% versus ⬎10% cutoff as clinically relevant, leading us to conclude that it is more a psychologically based limit rather than a scientifically established guideline. (3) The evidence that a higher M/S ratio reliably predicts higher infant serum concentrations is sparse, and there is no evidence that higher M/S ratios have been associated with a greater risk for adverse effects. These confounds limit the clinical utility of infant dose estimations derived from breast milk concentrations in random spot samples as the concentrations

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vary with the portion of milk and time after dose. A recent study with fluoxetine [29] compared the predictive value of dose estimates derived from M/S ratio, total breast milk concentration over 24 h, and mathematical modeling on nursing infant serum concentrations. The mathematical modeling (using a gradient from foremilk to hindmilk and excretion over time) was the best predictor of infant serum concentrations. Comparing serum concentrations in nursing infants has emerged over the past decade as the preferred method for comparing antidepressant exposure via lactation. This may indeed be a more reliable method of comparison, as confounds such as gastrointestinal absorption and infant metabolism are eliminated. However, other potential confounds limit definitive comparisons. (1) Nursing infant serum concentrations are low, usually ⬍20 ng/ml or below the limits of detection for high performance liquid chromatography (⬍2 ng/ml). The reliability of clinical laboratory assays in the range typically encountered is suspect. Research assays with confirmed detection limits are required. A single study of paroxetine using gas chromatography with mass spectroscopy [47] demonstrated that infant serum concentrations are often ⬍0.1 ng/ml. (2) Infant serum concentrations are reported in nanograms per milliliter and do not account for the significant differences in binding affinity [81–83] between particular antidepressants. For example, the binding affinity of paroxetine for the serotonin transporter is over 20 times greater than that of fluoxetine, 10 times greater than that of citalopram, and 4 times greater than that of sertraline [83]. Furthermore, estimates of ‘functional’ exposure should be extended to other sites such as norepinephrine and dopamine transporters to provide a comprehensive picture of infant exposure. Functional exposure via conversion to nanomoles and corrected for the individual medication’s binding affinities would provide a rational means, though complex, for comparing the relative exposures to two or more medications across studies. Such conversions and analysis have yet to be completed. (3) The correlation between serum concentration for antidepressants and central nervous system concentrations for the newer antidepressants is poor. In summary, infant serum concentrations have advantages over reliance on breast milk concentrations and the M/S ratio, but the data in their present form (ng/ml) are not a valid means for comparing antidepressants. One group has taken another approach to assessing the effects of antidepressants in nursing infants [32, 52]. They measured plasma serotonin as an indicator of central serotonin function in mothers and nursing infants before and during antidepressant treatment. While the sample sizes are limited, fluoxetine (n ⫽ 11) and sertraline (n ⫽ 14), no significant change in plasma serotonin was demonstrated.

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In summary, there have been myriad efforts to define nursing infant exposure to antidepressants and to compare individual medications. A definitive and widely accepted method remains to be established. Absent such standardized comparisons, it is important to consider any potential adverse effects reported. Adverse Effects in Nursing Infants Exposed to Antidepressants There remains continued concern about antidepressant use during lactation. The American Academy of Pediatrics Committee on Drugs categorizes most antidepressants as ‘unknown and may be of concern’ [84]. However, the latest report from this committee failed to cite the extant data set. A literature review identified 11 publications comprised of 40 infants (5.2% of total published breast-feeding cases) that noted purportedly adverse effects from antidepressant exposure during breast-feeding. These reports are listed in table 2. An empirically conservative appraisal of these reports is warranted given alternative feeding methods for infants are readily available. In the absence of controlled studies, the greatest evidence for causality that can be derived from the available case literature is that in some instances the infant symptoms were observed to resolve when breast-feeding was discontinued. In any event, the preponderance of adverse events consists of colic and other gastrointestinal disturbances and sleep disruptions. Simply put, the clinician, patient, and family must weigh the potential for gastrointestinal distress and difficulty sleeping versus the benefits of breast-feeding. The principal exception is doxepin, which in 2 cases appeared to cause clinically significant adverse effects in a nursing infant. The Clinical Decision There is an understandable reluctance on the part of many new mothers and their clinicians to use antidepressant medication during lactation. This decision is complicated by the lack of consensus with respect to infant monitoring, and an international disparity with respect to defining the infant’s exposure as discussed above. To date, all antidepressants investigated are found in human breast milk [85, 86]. The medication concentrations in breast milk (ng/ml) represent relatively low oral doses to the nursing infant; however, the significance of such exposure remains obscure. The breast-feeding baby is exposed to these medications regardless of whether it can be detected in their sera or not. Unfortunately, the terminology often utilized in breast-feeding studies can be misleading and even frightening. For example, some authors have described a fear of ‘accumulation’ of fluoxetine in breast-feeding infants [87] based on 2 case reports. Additional reports use the term ‘toxicity’ to describe effects in breast-feeding infants of sedation, sleep disturbance, and gastrointestinal

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distress, all of which are listed as side effects for the individual medications. Conversely, some investigators have used the essentially meaningless term ‘negligible exposure’. Until these children have reached adulthood without having demonstrated any sequelae of exposure, we cannot with certitude characterize any exposure as negligible. The clinician must take into account the large database on antidepressant exposure in breast-feeding, the risk of adverse effects related to medication exposure, the benefits of breast-feeding, and the adverse effects of untreated maternal depression [88]. It is noteworthy that nursing women often receive pharmacological treatment for a variety of conditions with limited concerns for nursing infant exposure to the medication. One of the best examples is the use of opiate analgesics following delivery. In addition, there has been a recent shift to support breast-feeding in women treated for epilepsy with medications that have far less data than antidepressants, and a higher proportion of adverse effects noted [89]. Where on the clinical care continuum does maternal depression/ anxiety lie? Our group has posited a detailed model aimed at minimizing infant exposure, as a guide to clinical decision making during the postpartum period [15, 17]. For example, if a breast-feeding mother is more likely to consume alcohol, smoke cigarettes, or take other medications (both prescription and over-the-counter) when she’s depressed or anxious, these exposures should be considered in the treatment planning. When treatment is indicated, the options for breast-feeding women are reasonably straightforward: (1) use nonpharmacological treatments; (2) wean and initiate pharmacological treatment, and (3) continue to breast-feed and initiate pharmacological treatment. Additional steps to minimize risk for option (3) include: (a) Use a medication appropriate for the diagnosis and any comorbid conditions. (b) Use a medication of prior response. The postpartum breast-feeding patient should not experiment with trials of new medications. (c) Use a medication of prior infant exposure. If a patient has taken a particular medication during pregnancy (even if discontinued at knowledge of conception), and it was clinically effective, then the choice for breast-feeding has already been made. Switching medications is not recommended (e.g. Med A in pregnancy ⫹ Med B in lactation ⫽ no/limited data). (d) Use a medication with data (i.e., ‘new and improved’ ⫽ no/limited data). (e) Monotherapy at any dose is preferable to introducing a second medication in women who are breast-feeding. (f) Infant serum monitoring is not recommended in the clinical setting, and if adverse effects are suspected – suspend breast-feeding.

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Table 2. Adverse effects of antidepressant exposure Medication

Exposed infants

Type of study

Selective serotonin reuptake inhibitors Citalopram 1 case report Fluoxetine Sertraline Paroxetine

1 2 1

case report, retrospectively obtained

Fluoxetine

2/14

case series

Fluoxetine

1

case report

Fluoxetine

26

Fluoxetine Fluoxetine

1 1

Paroxetine Subtotal

1 37

case-controlled retrospective identification, compared to 38 women without fluoxetine exposure case report case report

case report 8 reports

Tricyclic antidepressants Doxepin 1 case report

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Adverse effects

Comments

References

decreased sleep

sleep improved with dose reduction

[21]

agitation, difficulty feeding, somnolence, low muscle tone, hearing problems, suspected developmental delays colic

seizure-like episode at 3 weeks of age, limp and unresponsive episode at 4 months, peripheral cyanosis at 5 1/2 months growth curve significantly below that of infants without medication exposure

increased irritability colic, sleep disturbance, constant crying, difficult to console, watery stools, vomiting

possible withdrawal symptoms from pregnancy exposure (n ⫽ 2) neurological testing normal, mother also treated with carbamazepine, buspirone 7.7% of fluoxetine group ⫹ tobacco compared to 2.2% of comparison group

symptoms resolved with cessation of breast-feeding, and returned with resumption of breast-feeding

agitation

pale, limp, shallow breathing, drowsy

[38] [39]

[37]

breast-feeding stopped – child returned to normal within 24 h

144

Table 2. (continued) Medication

Exposed infants

Type of study

Adverse effects

Comments

References

poor sucking and swallowing, muscle hypotonia, vomiting, drowsiness

symptoms subsided within 48 h of stopping breast-feeding

[65]

drowsy, lethargic, unable to maintain body temperature, difficulty feeding in a 9-week-old born prematurely at 27 weeks

symptoms resolved within 72 h of stopping breast-feeding

Doxepin

1

case report

Subtotal

2

2 reports

Other antidepressants Nefazodone 1

case report

Subtotal

1 report

Total

1 40

(g) If unsure, get a consultation. There are several web sites devoted to women’s mental health and the reproductive safety of psychotropic medications. The majority of these links are available through www.emorywomensprogram.org.

Conclusion

The treatment of breast-feeding women will continue to raise important avenues for scientific investigation. While breast-feeding may complicate treatment, it by no means precludes it. If as a medical community we continue to advocate for breast-feeding, then we are responsible for understanding the impact of breast-feeding on medical conditions and their treatments. This mandates extending the data on the impact of maternal depression and anxiety on the constituents of breast milk and understanding the impact on successful breast-feeding. Similarly, we must extend our understanding of the impact of breast-feeding on the pharmacokinetics of medications and the impact of medication exposure on nursing infants. It is laudable that psychiatry is well ahead of most other subspecialties in investigating the reproductive safety of pharmacotherapeutic agents during lactation.

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Ilett KF, Hackett LP, Dusci LJ, Roberts MJ, Kristensen JH, Paech MJ, et al: Distribution and excretion of venlafaxine and O-desmethylvenlafaxine in human milk. Br J Clin Pharmacol 1998;45: 459–462. Hendrick V, Altshuler L, Wertheimer A, Dunn WA: Venlafaxine and breast-feeding. Am J Psychiatry 2001;158:2089–2090. Weissman AM, Levy BT, Hartz AJ, Bentler S, Donohue M, Ellingrod VL, et al: Pooled analysis of antidepressant levels in lactating mothers, breast milk, and nursing infants. Am J Psychiatry 2004;161:1066–1078. DeVane CL: Translational pharmacokinetics: Current issues with newer antidepressants. Depress Anxiety 1998;8(suppl 1):64–70. Taylor JE, Richelson E: High affinity binding of tricyclic antidepressants to histamine H1-receptors: Fact and artifact. Eur J Pharmacol 1980;67:41–46. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB: Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 1997;283:1305–1322. American Academy of Pediatrics Committee on Drugs: The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–150. Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC, Muntean E: The use of psychotropic medications during breast feeding. Am J Psychiatry 2001;158:1001–1009. Llewellyn A, Stowe ZN: Psychotropic medications in lactation. J Clin Psychiatry 1998;59(suppl 2):41–52. Pons G, Rey W, Matheson I: Excretion of psychoactive drugs into breast milk. Clin Pharmacokinet 1994;27:270–289. Beach A, Henry A, Stowe ZN, Newport DJ: Maternal depression: A child’s earliest life event. Bibl Psychiatr, in press. Ito S: Drug therapy for breast-feeding women. N Engl J Med 2000;343:118–126.

Zachary N. Stowe, MD Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine 1365 Clifton Road NE, Suite B6100 Atlanta, GA 30322 (USA) Tel. ⫹1 404 778 2524, Fax ⫹1 404 778 2535, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 150–166

The Use of Interpersonal Psychotherapy for Perinatal Mood and Anxiety Disorders Scott Stuarta–c, Michael W. O’Harab,c a

Department of Psychiatry, bDepartment of Psychology, and Iowa Depression and Clinical Research Center, University of Iowa, Iowa City, Iowa, USA

c

Pregnancy and the puerperium are life transitions writ large. Women and their families undergo major changes in relationships and role expectations. Many women are faced with decisions about returning to work or staying at home with their newborn. Conflicts often arise regarding child care, parenting, or sexual intimacy during pregnancy and the postpartum period. In short, the perinatal period is an interpersonal event that is characterized by relationship changes. Perinatal depression and anxiety are associated with difficulties in negotiating these interpersonal changes. Interpersonal Psychotherapy (IPT) [1, 2] is a well-defined treatment directed specifically at these interpersonal problems as well as the symptoms that women experience while depressed or anxious. It has proven to be an efficacious treatment for depression during pregnancy and the postpartum period, and because of its intuitive appeal to perinatal women, it has proven to be a highly acceptable and relevant treatment as well.

Perinatal Social Support: Impact on Depression and Anxiety

One of the most consistently replicated findings regarding perinatal depression is its association with poor social support [3]. Bernazzani et al. [4] demonstrated that levels of antenatal depression are correlated with satisfaction with interpersonal relationships. They also found that the impact of poor

interpersonal relationships on the risk for the development of depression was nearly as significant as having had previous psychiatric problems. Support from a woman’s spouse or significant other [5] and the degree of intimacy in their relationship [6] appear to be particularly important. The role of social support is also critical during the postpartum period. Support from spouse or partner appears to be particularly important [7]. Conflicts regarding child care responsibilities are common, as are disagreements regarding the degree of intimacy in the couple’s relationship. This often involves aspects of the couple’s sexual relationship, but even more frequently reflects dissatisfaction on the part of both partners with the degree of communication and connection. Men may describe feeling ‘displaced’ by the newborn, while women may describe feeling emotionally distanced, with little energy to give to the marital relationship. In all of these circumstances, problems in the spousal relationship can contribute to or exacerbate depression, anxiety, and poor psychological adjustment. During the puerperium, women often look to ‘mentors’ for both emotional and practical support. Mothers of postpartum women often fill this role, though other experienced female relatives or friends may substitute. The absence of such a mentor can contribute to poor psychosocial adjustment; this absence need not be physical but can also reflect the inability of important mentoring figures to meet the expectations of the perinatal woman. For instance, a woman may expect that her mother will provide practical physical support and emotional support postpartum, only to find that her mother is unwilling to do so, or is critical rather than supportive. Poor social support in general is also associated with postpartum psychiatric problems [7]. Women often rely on others for practical help with child care, and may use their social support network as a source of advice and feedback about caring for a newborn. Social isolation can contribute greatly to psychological distress, making social connections and relationships extremely important in the perinatal period. The ability of a woman’s social support network to respond to her new life circumstances, and the sustainability of her social connections are particularly crucial. For instance, being able to maintain important social support from work colleagues while on maternity leave may be important. Other social factors, such as having an unplanned pregnancy, have also been linked to an increased risk for postpartum depression [8]. Women from lower social classes and with lower incomes are at higher risk [7]. In sum, social support and psychosocial factors are clearly associated with perinatal distress and psychiatric problems. The biopsychosocial model supports the role of these factors in the context of the physical changes that occur in the perinatal period. A combination of biological vulnerabilities and

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inadequate social support met with the physical, emotional, and social changes occurring in pregnancy and the postpartum period form the diatheses and stressors which lead to depression or anxiety. All of these data suggest that psychosocial interventions directed towards social support and specific interpersonal problems should be effective in alleviating perinatal distress.

Interpersonal Psychotherapy

IPT [1, 2] is a time-limited, dynamically informed psychotherapy which aims to alleviate patients’ suffering and improve their interpersonal functioning. IPT focuses specifically on interpersonal relationships as a means of bringing about change, with the goal of helping patients to either improve their interpersonal relationships or change their expectations about them. In addition, the treatment also aims to assist patients in improving their social support networks so that they can better manage their current interpersonal distress. Both of these goals are highly relevant to women with perinatal mood and anxiety disorders, particularly because such problems are associated with perinatal depression. IPT was originally developed in a research context as a treatment for major depression and was codified in a manual developed by Klerman et al. in 1984 [2]. Since that time, a great deal of empirical evidence supporting its use has accumulated (for a comprehensive review, see Stuart and Robertson [1]). In addition, as clinical experience with the treatment has increased, the use of IPT has broadened to include not only the treatment of patients with a variety of well-specified diagnoses as described in DSM-IV [9], but also the treatment of patients presenting with a variety of interpersonal problems. Its application to perinatal women, therefore, should be considered not only when there is a clearly defined affective or anxiety disorder, but also when there is interpersonal distress to a degree that a woman wishes treatment. IPT is based on a biopsychosocial model of psychological functioning [10], which is consistent with the prevailing view of the perinatal period as one involving physical and hormonal changes, interpersonal changes, and social changes. Rather than narrowly viewing psychological distress or psychiatric problems as medical problems, the IPT approach is to view the patient’s functioning in broad terms as a product of her temperament, personality, and attachment style, based upon a foundation of biological factors such as genetics and physiological functioning, placed in the context of social relationships and broad social support. This model is particularly relevant for perinatal women because it incorporates the obvious biological changes of pregnancy and the postpartum period into the context of the interpersonal event of childbirth. In doing so, there is acknowledgment that even though IPT is directed towards

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relationship issues and communication, the use of medication and other somatic treatments may be of benefit and may be provided in conjunction with IPT. IPT is based on the premise that interpersonal distress is intimately connected with psychological symptoms. In the case of perinatal depression, this is a direct extension of the data regarding the impact of social factors during the puerperium. The foci of IPT treatment are twofold. One focus is the conflicts and transitions in relationships in which the perinatal woman is engaged: the aim is to help her to either improve communication within those relationships, or to change her expectations about those relationships. The second focus is helping the perinatal woman to build or better utilize her extended social support network so that she is better able to muster the interpersonal support needed to deal with the crises which precipitated the distress, e.g. to obtain more effective support for the perinatal transition. This approach is extremely well suited to the treatment of perinatal depression [11, 12]. Distress which is linked to conflicts with partners or to difficulties in making the transition from ‘working woman’ to ‘mother’ can be directly addressed. A therapist using IPT would help the patient to resolve the conflicts with her partner over issues such as division of child care labor, and would also assist the woman to garner more support from her social network. This might include connecting with and asking for support from other friends who have had children, from extended family members, or colleagues at work. It could also include encouraging the patient to get involved in a new mothers’ support group. Resolution of the particular interpersonal conflict, along with improved interpersonal support while the role transition is being negotiated then leads to symptomatic improvement. IPT is grounded in the interpersonal theories of Sullivan [13] and the attachment theories described by Bowlby [14] among others. These theories assert that humans have an innate biological drive to develop and establish interpersonal relationships, and that the principal feature of mental health is the capacity to form flexible attachments. In other words, mentally healthy individuals are able to develop relatively secure relationships in which they can depend on others to provide support and in which they are emotionally available to others. In contrast, individuals with less flexible styles of attachment, such as those with dependent or avoidant interpersonal styles, typically have relationships which are less satisfying and are less adaptable to stress. Attachment theorists further hypothesize that attachment styles develop primarily during childhood, and are a result of both genetically based temperament and environmental influences (usually the accumulated experiences with primary caregivers) [15]. Though these attachment styles tend to persist, they are not fixed, and can be modified either positively or negatively as a result of

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additional interpersonal interactions. In general, however, an individual’s pattern of attachment tends to be consistent both within relationships and across relationships, i.e., people tend to persist in their styles of relating to individuals whom they have known for some time, and tend to replicate their characteristic attachment styles with others with whom they have recently developed relationships. Psychiatric disorders are hypothesized to result from a combination of interpersonal and genetic factors following a biopsychosocial model [1]. Genetic vulnerability can be modified either positively by healthy attachment experiences or negatively by poor interpersonal experiences. Those patients with less secure attachments, who are unable to constructively request and receive psychological support in times of crises, have an increased vulnerability to the development of psychopathology. In addition, circumstances in which an individual’s primary attachments are disrupted, such as death, divorce, or illness, also tend to increase the chance that a psychiatric disorder will occur in a vulnerable individual. This model has direct application to the treatment of perinatal women. Such women who may have less secure attachment styles are at greater risk for depression or anxiety during the puerperium, both because they are more vulnerable to the interpersonal changes which accompany childbirth and because they have less extensive social support networks. Women are at additional risk if there are other adverse stressors, such as early delivery, previous perinatal loss, or medical problems with their infant. In such circumstances, even securely attached women may develop depression or anxiety disorders, given the magnitude of the stressor. IPT is therefore designed to treat psychiatric symptoms and to improve interpersonal functioning by increasing effective social support to meet the woman’s attachment needs more effectively and by focusing specifically on patients’ primary interpersonal relationships, particularly in the problem areas of grief and loss, interpersonal disputes, role transitions, and interpersonal sensitivities [1]. Though fundamental change in either personality or attachment style is unlikely during short-term treatment, symptom resolution is made possible when patients are assisted in repairing their disrupted interpersonal relationships and when they learn new ways to communicate their need for emotional support. The efficacy of IPT in the acute treatment of depression has been investigated in a number of studies [1], the most notable of which is the National Institute of Mental Health Treatment of Depression Collaborative Research Program [16]. In this landmark study, IPT was found to be equal to both imipramine and cognitive behavior therapy (CBT) in the treatment of mild to moderate depression [17]. IPT has also been found to be effective in preventing

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recurrence of depression for patients who have had at least three previous episodes [18]. Our own laboratory has been active in developing and testing modified forms of IPT for use with several populations in addition to perinatal women [11, 12, 19]. Included among these are patients with depression following myocardial infarction [20], social phobia [21], and somatization disorder [21, 22].

Psychosocial Treatment of Perinatal Mood and Anxiety Disorders: A Review of the Literature

Psychosocial treatments for perinatal depression can be placed in two categories. The first include preventive interventions which involve treatment of either large numbers of women from the general population, or involve only those who are at high risk for postpartum psychopathology. These prevention trials often begin during pregnancy. The second type of psychosocial intervention is designed to treat perinatal women who have already developed depression or anxiety. The interventions can also be characterized on a spectrum from ‘nonspecific’ to targeted. Nonspecific interventions often consist of supportive listening, empathy, and positive reinforcement [23], elements which are fundamental for all psychotherapies, but which, though essential, may not be sufficient to treat more severe psychiatric problems. In addition to these basic elements, targeted interventions rely on specific techniques such as communication analysis or cognitive restructuring which are ultimately directed towards symptom resolution. The literature regarding treatment of perinatal depression and anxiety is strongly skewed towards depression and postpartum depression specifically. At present, there are no controlled treatment trials of either medication or psychotherapy for anxiety disorders either during pregnancy or the postpartum period. This is obviously a huge gap, particularly as perinatal anxiety disorders are known to be prevalent and disabling [24–26]. Moreover, there are no controlled psychopharmacologic treatment trials for depression during pregnancy, and only three psychopharmacologic trials of any kind exist for the treatment of postpartum depression [27–29]. The majority of the empirical literature involves the use of psychosocial interventions for the prevention or treatment of postpartum depression; these studies are reviewed below. Treatment of Postpartum Depression – Prevention Treatment Trials Preventive interventions for postpartum depression have been applied to high-risk women as well as pregnant women in the general population who may

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not be at risk. Preventive interventions are divergent across a number of dimensions including the type of professional conducting the intervention (e.g. mental health vs. nonmental health professionals), individual versus group treatment, the type of interventions provided (e.g. psychoeducation vs. psychotherapy), number of sessions provided, and the timing of the intervention (e.g. prenatal only vs. pre- and postnatal sessions). The nondirective approaches to prevention include treatments such as psychoeducational classes [30, 31] and relaxation [32]. Midwife ‘debriefing’, which consists of psychoeducation about the birthing process delivered by a midwife, has also been described [33–35]. These interventions have great appeal because they require no specialized training for treatment providers; in addition, it might well be argued that such psychoeducation and debriefing should be included routinely in perinatal care as good medical practice. They do not, however, appear to be effective in preventing episodes of postpartum depression. In contrast to the provision of psychoeducational information, Wolman et al. [36] conducted a treatment trial in which 189 nulliparous women were randomly assigned to be accompanied by a ‘doula’ during their delivery, or were assigned to a group which received only standard medical care. Women with doula support had a mean score of 10.4 on the Pitt Depression Questionnaire [37] at 6 weeks postpartum, which was significantly better than the control group (mean ⫽ 23.3). The results of the study by Wolman et al. [36], however, are limited by several factors. First, depressive symptoms were not assessed during pregnancy, so that the effects of the intervention on reducing depression are not clear. Additionally, women continued to report moderate levels of depression even in the experimental group. This study does, however, support the hypothesis that social support is helpful in preventing postpartum depression. More traditional psychotherapeutic interventions, designed to include Rogerian factors such as a healing relationship, positive regard, and positive reinforcement [23], have been conducted by several investigators [38–40]. Brugha et al. [38] conducted a randomized prevention trial with 190 antenatal women at risk. The intervention consisted of six 2-hour group sessions during pregnancy with an additional session at 8 weeks postpartum. The sessions were educational and focused on social support and problem-solving approaches to avoid postpartum depression. The intervention had no effect with respect to depressive symptomatology or diagnostic status at 3 months postpartum. Roughly 55% of women completing the outcome assessment at 3 months postpartum were not compliant in attending sessions, a problem noted frequently in the prevention literature. It may be that women without acute symptoms are not highly motivated to engage in treatment. Oakley et al. [39] studied 509 women who had a history of at least 1 lowbirth-weight delivery. The women were randomly assigned to receive supportive

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counseling from midwives or routine antenatal care. The midwife intervention package consisted of a minimum of 3 home visits plus 2 telephone contacts during pregnancy. The first contact usually occurred at about 3–4 months of pregnancy. Midwives did not provide any clinical care, and were instructed to give advice or information to women only if specifically asked to do so. They were also instructed to assist women with referrals to other social agencies and other health professionals as needed – 80% of the women in the intervention group received such referrals. At 1 year, 95% of the women in the midwife group, and 90% of the women in the control group reported no postpartum depression, a nonsignificant difference. Elliott et al. [40] reported on the preventive effects of group treatment provided from early in pregnancy to 6 months postpartum. Women were selected for treatment if they had: (1) a previous psychiatric history; (2) high levels of anxiety; (3) a poor marital relationship, and (4) no confidant. The authors described the psychoeducational component of the treatment as ‘anticipatory guidance’ aimed at helping women to anticipate changes that would occur after childbirth, as well as providing practical advice on how to avoid potential problems. Therapists provided specific information about postpartum depression and the need to establish adequate social supports. Both first- and second-time mothers were treated, though in separate groups. First-time mothers attended an average of 7 of 11 sessions, while second-time mothers attended an average of only 4 of 11 meetings. There were significant differences in depressive symptomatology only with primiparous women at 3 months postpartum. Median Edinburgh Postnatal Depression Scale (EPDS) scores for treated and control subjects were 3.0 and 8.0, respectively. There have been 2 prevention trials which have targeted social support and interpersonal relationships specifically. Both were based on the interpersonal model utilized in IPT, though neither included all of the elements of a full course of IPT. Gorman [41] randomly assigned high-risk women to receive a modified and abbreviated course of IPT (n ⫽ 24) or to a no treatment control group (n ⫽ 21). The intervention consisted of 2 individual sessions during pregnancy and 3 weekly sessions between 2 and 4 weeks postpartum. The pregnancy sessions consisted of psychoeducation about postpartum mood disorders and discussion related to current or anticipated interpersonal difficulties. The postpartum sessions focused on the woman’s mood and how it was associated with the interpersonal issues discussed during pregnancy. At 1 month postpartum, women receiving the intervention were significantly less likely to have experienced a major depression compared to women in the no treatment control group (0 vs. 25%). At 6 months postpartum, this difference was not significant (15 vs. 23.5%). Zlotnick et al. [42] randomized 37 women at risk for postpartum depression to either 4 group sessions of interpersonally oriented psychoeducation

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(n ⫽ 18) or to a control group (n ⫽ 19). The group intervention included 4–6 women and involved four 60 -min group sessions over a 4-week period. The first session provided psychoeducation about the ‘baby blues’ and postpartum depression; the remaining 3 focused on the IPT problem areas of role transitions and interpersonal conflict along with goal setting. At 3 months postpartum, none of the women in the intervention group had developed postpartum depression compared to 33% in the control group, a significant difference. The mean Beck Depression Inventory (BDI) score for the intervention group at 3 months postpartum was 8.4 and it was 11.3 for the control group. The treatment trials designed to prevent postpartum depression have generally not demonstrated marked effects. However, there is some indication that the more directed treatments, particularly those which target interpersonal issues and social support, may be of benefit. The effect of these directed treatments may be even greater if they are provided to women at risk for developing postpartum depression, rather than towards perinatal women in general. Prevention research is needed in a variety of areas. First, the determination of ‘risk’ for postpartum depression is unclear. It seems clear from the data that intensive preventive interventions should not be used for women who are not at risk for postpartum depression. However, the factors that should be used to determine risk, and the extent of risk which makes preventive treatment viable from a cost-benefit standpoint are yet to be determined. In addition, the risk factors which are associated with likely response to a particular psychosocial intervention are not clear. Reasonable hypotheses, for example, might be that women with ‘psychosocial’ risk factors such as poverty might benefit from directive interventions designed to assist them to obtain practical financial support; those that face relationship conflicts may benefit more from an interpersonally based treatment, and those with ‘biological’ risk factors such as a family history of depression from a structured psychotherapy or medication. In sum, there is some evidence that the targeted preventive interventions studied to date are effective in preventing postpartum depression. The empirical data suggest that preventive interventions should be reconceptualized using the following guidelines: (1) the interventions should be directed towards high-risk women; (2) the risk factors for postpartum depression which are also associated with response to treatment need to be better characterized, and (3) the treatments should be based on clear rationales which direct the interventions, such as a focus on interpersonal issues and social support. Treatment of Postpartum Depression – Acute Treatment Trials Several acute interventions have been designed to treat the symptoms of postpartum depression. In contrast to preventive interventions, all of the women who receive acute treatment are specifically selected because they are

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experiencing postpartum depression. These interventions can also be characterized along a spectrum from those which are nondirective to those which target specific symptoms. The nondirective treatment trials include those conducted by Holden et al. [43], and Wickberg and Hwang [45]. Holden et al. [43] conducted a study involving 50 women who met Research Diagnostic Criteria (RDC) [44] for either major or minor depression at 12 weeks postpartum. The women were divided into two groups – those who received 8 weekly sessions of counseling provided by health visitors – most of whom had midwife experience and several of whom had additional psychiatric training – and those in a no treatment control group. The counseling was designed to be nondirective in orientation, and patients received a mean of 8.8 sessions of therapy over about 13 weeks. Twelve of the women in the study were receiving antidepressant medication in addition to the counseling. A significantly higher percentage of women in the treatment group (69%) no longer met RDC for either major or minor depression at the conclusion of treatment compared with the women in the control condition (38%). Additionally, the median score on the EPDS decreased from 15.5 to 12.0 in the control group compared to 16.0 at intake and 10.5 following treatment in the group receiving counseling, a significant change only for the treatment group. The outcome scores, however, were compared only within each group, rather than between the two groups. Wickberg and Hwang [45] studied the effects of nondirective counseling provided by child health nurses. Women were recruited during routine visits to a Child Health Care Clinic and were eligible for randomization if they had scores of 12 or more on the EPDS at both 2 and 3 months postpartum, had Montgomery-Asberg Depression Rating Scale (MADRS) [46] scores of 10 or more, and met DSM-III-R [47] criteria for major depression. The treated group received 6 weekly nondirective counseling sessions, and the control group received routine care. Twelve of 15 women in the treatment group compared to 4 of 16 women in the control group no longer met criteria for DSM-III-R major depression at the completion of treatment. The decrease in MADRS scores in the group receiving counseling (19.6–10.9) was significantly greater than in the control group (17.1–14.7). The authors reported that 4 severely ill women had to be dropped from the study, which limits the findings to postpartum women with mild to moderate depression. Cooper and Murray [48] and Cooper et al. [49] also used nondirective counseling in their study of postpartum depression, but compared it to 8 weeks of ‘cognitively oriented’ therapy, ‘psychodynamically oriented’ psychotherapy, and a no treatment control group. Routine care included care from general

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practitioners and health visitors, though the health visitors received no additional psychological training. The nondirective counseling was conducted by health visitors, and followed the model described by Holden et al. [43] above, in which the health visitors received specific training. The ‘cognitively oriented’ treatment was a modified form of the interaction guidance treatment described by McDonough [50]. Bearing little resemblance to the CBT described by Beck et al. [51], this therapy was described by the authors as directed towards problems identified by the mother in the management of her infant, as well as observed problems in the quality of the motherinfant interaction. The therapist often provided advice about infant care. The authors note that the treatment was not directed primarily at the maternal depression. The ‘psychodynamically oriented’ psychotherapy followed techniques described by Cramer et al. [52], in which ‘an understanding of the mother’s representation of her infant and her relationship with her infant was promoted by exploring aspects of the mother’s own attachment history’ [49]. There was no directed focus upon the postpartum depression. A total of 193 primiparous depressed women screened from the community using the EPDS were randomized to 1 of the 4 treatments. All of the treatments produced improvement in EPDS scores relative to the control, but only the psychodynamically oriented intervention reduced the rates of depression relative to the control. Remission occurred in 54% of the women receiving nondirective counseling, 57% of the women receiving ‘cognitively oriented’ counseling, 71% of the women treated with psychodynamically oriented psychotherapy, and 40% of the women in the control group. There were no differences between any of the groups at 9 months postpartum, and none of the treatments reduced the rate of subsequent postpartum episodes of depression. EPDS scores at 4.5 months ranged from 8.9 to 9.9 in the treatment groups compared to 11.3 in the control group. No information was provided regarding the EPDS scores at the beginning of the study, though study criteria required a score of only 12 for entry. Based on the limited degree of reported change on the EPDS, it appears that most women were only mildly depressed. Appleby et al. [29] reported on the treatment of postpartum depression using counseling based loosely on the CBT model. The counseling was based on the nondirective model used by health visitors in the British system, with the addition of some techniques from cognitive therapy. Each counseling session was structured to provide reassurance to mothers and to offer practical advice in four areas: feelings of difficulty in coping, lack of pleasurable activities, lack of practical support, and caring for any older children. The first session lasted about an hour, and subsequent visits lasted about 30 min and were provided once every 2 weeks for women who received 6 sessions of counseling.

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Eighty-seven women were randomized to treatment if they scored above 10 on the EPDS and met RDC for major or minor depressive disorder at 6–8 weeks postpartum. The interventions included: (1) treatment with fluoxetine and 1 session of counseling; (2) treatment with fluoxetine and 6 sessions of counseling; (3) treatment with placebo and 1 session of counseling, and (4) treatment with placebo and 6 sessions of counseling. The medication arm of the study was double-blinded, and the total duration of the study was 12 weeks. Significant improvements were seen in all 4 of the treatment groups, and fluoxetine was superior to placebo on all measures. Six sessions of counseling were superior to 1 session only on the Hamilton Rating Scale for Depression (HRSD). There were no interaction effects between medication and psychotherapeutic treatment. Women completing the fluoxetine plus 1 session of counseling treatment had a decline in their HRSD scores from 13.3 to 2.9, and ratings of the women in the fluoxetine plus 6 sessions group declined from 13.2 to 2.8. The HRSD scores of women receiving placebo and 1 session declined from 14.7 to 7.5 and from 13.3 to 3.7 if they received placebo and 6 counseling sessions. Both the studies by Cooper et al. [49] and Appleby et al. [29] are notable in several respects. First, neither utilized treatments targeted specifically at postpartum depression. The active counseling in Appleby et al. somewhat resembled cognitive therapy, but was oriented largely towards the provision of practical advice. In addition, it was delivered less intensively than standard CBT – both session duration and length of treatment were substantially reduced. Second, most of the women in both studies were mildly depressed. In addition, the magnitude of absolute change in depressive symptoms was relatively small. In sum, both studies support the hypothesis that women with mild depressive symptoms are likely to benefit from nonspecific treatments, but that such treatments are likely not to be effective with women with moderate to severe depression. O’Hara et al. [11] evaluated the use of IPT in a sample of 120 postpartum women from the community who met criteria for DSM-IV [9] major depression. Depressed women were assigned to either 12 weekly sessions of IPT or to wait for 12 weeks before receiving weekly IPT. Therapists were PhD clinical and counseling psychologists in clinical practice who were specifically trained as IPT therapists, and the treatment was specifically directed at depressive symptoms [1, 2, 12]. Treatment with IPT was found to be significantly superior as measured by both the HRSD and BDI. Average HRSD scores for the IPT condition dropped from 18.4 to 8.3 and in the waiting condition scores dropped from 19.8 to 16.8. Similar changes were noted for the BDI scores, which decreased from 23.6 to

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10.6 in the IPT group and from 23.0 to 19.2 in the control group. For both the HRSD and the BDI significant differences emerged by 4 weeks into therapy. At the conclusion of treatment, significantly fewer women in the IPT group met criteria for a major depressive episode (12.5%) compared to women in the control group (68.6%). Significant effects were also observed for several of the measures of social adjustment, including the Social Adjustment Scale [53] and the Postpartum Adjustment Questionnaire [54]. Women with moderate and severe levels of depression responded as well to treatment as women with mild depression. The empirical data regarding the treatment of acute postpartum depression are similar to the prevention data. Those treatments which are more specifically directed towards interpersonal issues and social support appear to have the greatest effects on depression. Nonspecific treatments do appear to be of help for mild depression, but their effect on moderate to severe depression is less impressive. Conversely, the nonspecific treatments tend to be less expensive, and are likely to be more readily available than the directed treatments. Though generally much easier to learn than CBT or psychodynamic psychotherapy, IPT does require advanced training. In contrast, the nonspecific counseling used in the British model can be delivered by health visitors. The ability of these providers to deliver nonspecific treatments also makes them more feasible. Taken together, these conclusions suggest that strong consideration ought to be given to a sequential program of treatment for perinatal depression. Preventive treatments are likely to be of benefit to those women at high risk for postpartum depression, but are not likely to be cost-effective when delivered to unselected groups of women. Acute treatment might begin with nonspecific counseling delivered by health visitors or other similar personnel; women who do not respond to such counseling could then be referred to more intensive directed psychotherapeutic treatments. This would provide quality care while minimizing cost and maximizing feasibility of treatment. Though there are very little data regarding the treatment of perinatal anxiety, the same is likely to be true for women with anxiety disorders. Supportive treatment and reassurance may be of help for mild symptoms, while more specifically directed treatments are likely to be of greater benefit for those women with moderate to severe disorders. In the case of anxiety, it is possible that CBT [55] may be a more plausible treatment than IPT, as the direct link between anxiety and social support is not as well established as it is in depression. In contrast, CBT is directed specifically towards anxiety symptoms, and is at present an established psychosocial treatment for anxiety disorders. This clinically intuitive treatment selection remains to be empirically tested.

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Treatment of Depression during Pregnancy: Acute Treatment Trials There are only 2 studies which have investigated the use of psychotherapy of any sort for depression during pregnancy, both of which used IPT. An additional large-scale study of IPT is currently under way at the University of Iowa. There are no medication treatment trials for depression during pregnancy, nor are there any treatment trials with pregnant women with anxiety disorders. Spinelli and Endicott [56] conducted a treatment trial comparing the outcomes of 17 depressed pregnant women who received 16 weeks of parenting education with 21 who received 16 weekly IPT sessions. All participants met DSM-IV criteria for major depressive episode and had HRSD scores ⱖ12. Assessments and interventions were conducted in either English or Spanish. The IPT intervention relative to parenting education resulted in significant improvement indexed by the EPDS, the BDI, and the HRSD. Moreover, a significantly greater proportion of women receiving IPT (60%) relative to the women receiving parenting education (15%) evidenced recovery on the Clinical Global Improvement Scale. Recovery based on the HRSD was not different across groups. It is notable that IPT did show a significant advantage over a presumably credible psychosocial intervention for depressed pregnant women. Moreover, these findings were obtained with a relatively impoverished population of women who spoke Spanish as well as English. Limitations include the fact that 24% of women initially randomized to treatment did not attend even 1 session and the study had a relatively small sample size. It does need to be replicated, but the results are quite encouraging. Stuart and O’Hara [12] conducted an open pilot study which included 7 depressed pregnant women who were treated with 12 weeks of IPT. At intake, all met DSM-IV [9] criteria for a major depressive disorder. None of the women took medication during the entire study, and all completed 12 weeks of IPT. Outcome data revealed highly significant improvements in both BDI scores and in HRSD scores [57]. BDI scores decreased from an average of 28.1 to 3.2 (p ⬍ 0.001), and mean HRSD scores decreased from 19.8 to 8.4 (p ⬍ 0.001). Only 1 of the 7 women met criteria for major depression at the completion of treatment. While the results are impressive, the scale of this open trial is too limited to draw meaningful conclusions. The results these 2 studies suggest that IPT has utility for the treatment of depressed pregnant women. Much more research is needed, both regarding the use of IPT and other psychosocial interventions. However, given the absolute lack of data regarding other treatments, IPT stands at present as the only empirically tested treatment for depression during pregnancy. It is likely that, as is the case with postpartum depression, specifically targeted psychotherapeutic treatments such as IPT are more effective for moderate to severe depression and anxiety than are nonspecific approaches.

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Conclusion

At present, empirical data clearly support the use of acute interventions for postpartum depression. The literature regarding both primary prevention and acute treatment suggests that treatment which specifically targets depressive symptoms is likely to be the most effective. Epidemiologic research also suggests that psychosocial interventions should target factors associated with perinatal depression, namely social support and interpersonal difficulties. A number of additional factors warrant further investigation. First, the efficacy studies of the treatment of acute postpartum depression suggest that there may be benefit to a stepwise approach to treatment. ‘Nondirective counseling’ provided by public health nurses appears to be of benefit for women with mild depression, while more intensive interventions such IPT are needed for moderate to severe depression. A reasonable approach would be to utilize less costly interventions as a first-line treatment for depressed perinatal women, with those that do not respond to a nondirective approach moving on to more intensive interventions such as IPT. There is clearly a great need for research regarding perinatal anxiety disorders. Intuitively, targeted treatments such as IPT would seem to be of benefit for these problems, though CBT may be of equal or greater benefit for perinatal anxiety. The efficacy of these targeted interventions remains to be empirically tested, as does the concept of stepwise treatment for anxiety. In sum, the efficacy of psychotherapeutic interventions for the treatment and prevention of perinatal depression is strongly supported by the data. The strength of study designs, the large number of subjects in the trials, and the impressive results all suggest that counseling is of benefit as a stand-alone treatment for postpartum depression. For more severe depressions, there is need for treatments such as IPT, which are specifically directed towards maternal depression and which target social and interpersonal problems.

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Small R, Lumley J, Donohue L, Potter A, Waldenstrom U: Randomised controlled trial of midwife led debriefing to reduce maternal depression after operative childbirth. BMJ 2000;321:1043–1047. Stamp GE, Williams AS, Crowther CA: Evaluation of antenatal and postnatal support to overcome postnatal depression: A randomized, controlled trial. Birth 1995;22:138–143. Wolman WL, Chalmers B, Hofmeyer GJ, Nikodem VC: Postpartum depression and companionship in the clinical birth environment: A randomized, controlled study. Am J Obstet Gynecol 1993;168:1388–1393. Pitt B: ‘Atypical’ depression following childbirth. Br J Psychiatry 1968;114:1325–1335. Brugha TS, Wheatley S, Taub NA, et al: Pragmatic randomized trial of antenatal intervention to prevent post-natal depression by reducing psychosocial risk factors. Psychol Med 2000;30:1273–1281. Oakley A, Rajan L, Grant A: Social support and pregnancy outcome: Report of a randomized controlled trial. Br J Obstet Gynaecol 1990;97:155–162. Elliott SA, Leverton TJ, Sanjack M, et al: Promoting mental health after childbirth: A controlled trial of primary prevention of postnatal depression. Br J Clin Psychol 2000;39:223–241. Gorman LL: Prevention of postpartum adjustment difficulties (doctoral dissertation, University of Iowa). Diss Abstr Int B Sci Eng 1997;58:2674. Zlotnick C, Johnson SL, Miller IW, Pearlstein T, Howard M: Postpartum depression in women receiving public assistance: Pilot study of an interpersonal-therapy-oriented group intervention. Am J Psychiatry 2001;158:638–640. Holden JM, Sagovsky R, Cox JL: Counseling in a general practice setting: Controlled study of health visitor intervention in treatment of postnatal depression. BMJ 1989;298:223–226. Spitzer RL, Endicott J, Robins E: Research Diagnostic Criteria: Rationale and reliability. Arch Gen Psychiatry 1978;35:773–782. Wickberg B, Hwang CP: Counseling of postnatal depression: A controlled study on a population based Swedish sample. J Affect Disord 1996;39:209–216. Montgomery SA, Asberg M: A new depression rating scale designed to be sensitive to change. Br J Psychiatry 1979;134:382–389. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3 revised. Washington, American Psychiatric Association, 1987. Cooper PJ, Murray L: Three psychological treatments for postnatal depression: A controlled comparison. Eighth Int Conf Marce Soc, Cambridge, 1994. Cooper PJ, Murray L, Wilson A, Romaniuk H: Controlled trial of the short- and long-term effect of psychological treatment of post-partum depression. Br J Psychiatry 2003;182:412–419. McDonough S: Interaction guidance: Understanding and treating early infant-caregiver relationship disorders; in Zeanah C (ed): Handbook of Infant Mental Health. New York, Guilford Press, 1993, pp 414–426. Beck AT, Rush AJ, Shaw BF, Emery G: Cognitive Therapy of Depression. New York, Guilford Press, 1979. Cramer B, Robert-Tissot C, Stern D: Outcome evaluation in brief mother-infant psychotherapy: A preliminary report. Infant Ment Health J 1990;11:278–300. Weissman MM, Bothwell S: Assessment of social adjustment by patient self-report. Arch Gen Psychiatry 1976;33:1111–1115. O’Hara MW, Hoffman JG, Phillips LHC, Wright EJ: Adjustment in childbearing women: The Postpartum Adjustment Questionnaire. Psycho Assess 1992;4:160–169. Beck AT, Emery G: Anxiety Disorders and Phobias. New York, Basic Books, 1985. Spinelli M, Endicott J: Controlled clinical trial of interpersonal psychotherapy versus parenting education program for depressed pregnant women. Am J Psychiatry 2003;160:555–562. Hamilton MA: Development of a rating scale for primary depressive illness. Br J Soc Cli Psychol 1967;6:278–296.

Scott Stuart, MD University of Iowa, Department of Psychiatry 1–293 Medical Education Building, Iowa City, IA 52242 (USA) Tel. ⫹1 319 353 4230, Fax ⫹1 319 353 3003, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 167–181

Group Psychotherapy for Depression in Early Stages of Motherhood Maria Hofecker-Fallahpour, Anita Riecher-Rössler Psychiatrische Universitätspoliklinik, Basel, Schweiz

Individual psychotherapy in the treatment of depression is well accepted and has a firm stand in terms of evidence replicated by numerous studies showing its efficacy particularly in the use of cognitive behavioral therapy (CBT) and interpersonal therapy (IPT) [2–4]. Furthermore, there is common agreement in clinical practice that psychotherapy and antidepressant medication show comparable effects in the treatment of mild depression, whereas in severer depression the combination of psychotherapy and medication is recommended. Initial treatment response is quicker with antidepressants compared to psychotherapy, but relapse is more effectively prevented by psychotherapy unless prolonged antidepressant maintenance treatment up to 1 year is administered [5, 6]. Group psychotherapy in comparison to individual psychotherapy has numerous additional benefits such as facilitating social contacts and reducing isolation and stigma by exchanging and working on similar symptoms and difficulties in a group of peers. Moreover, group psychotherapy is commonly regarded as being more cost-effective than individual psychotherapy. However, many patients hesitate to participate in group activities due to a number of fears such as feeling uncomfortable to talk about one’s own problems in a group or being overwhelmed by the severity of symptoms of others. In addition, group treatment restricts the amount of time and consideration allotted to the difficulties of a single patient as compared to individual therapy. When psychotherapy is offered to depressed mothers of infants, a number of specific demands arising from the particular needs of early motherhood have to be taken into consideration. In addition, many mothers feel ashamed to experience

Parts of this paper have been published in Hofecker-Fallahpour et al. [1].

difficulties in their new role and hesitate to seek professional help. Therefore, adaptations to conventional psychotherapeutic procedures and contents are necessary to meet the specific needs of this particular group of patients. However, specific psychotherapy for mentally ill mothers of infants had not been available until recently. Only in the past 5–10 years did a few therapists start to adapt standard treatment strategies to the needs of mentally ill mothers. For this reason, we decided to develop a manualized group therapy for mothers with depression (GMD) and evaluated it in the first 31 patients. In the following sections, existing specific psychotherapies for mothers of infants or small children with depression are described. Then we present the rationale for developing our specific group therapy and report on the results regarding effects and acceptance. The GMD is adjusted not only to a certain diagnostic group but also to the demands of a most significant period in the lives of women.

The Need for Specific Psychotherapy for Depression and Anxiety in Early Motherhood

Early Motherhood – A Period of Specific Demands Depression and anxiety disorders are known to be very frequent during pregnancy and the postpartum period in the otherwise mostly healthy women of childbearing age. Postpartum depression is found in 10–15% of new mothers and recent studies show similar rates of depression during pregnancy [7–9], which is at least as high as in women of the same age group without children. The investigation of anxiety disorders in perinatal women had been neglected to some extent until recently, when studies have shown that the prevalence of anxiety disorders is even higher than the prevalence of postpartum depression [10–12]. Matthey et al. [11] found rates of anxiety disorders such as phobia, panic disorder or generalized anxiety disorder (except time criterion) of up to 16% in a sample of 216 first-time mothers, which exceeded the rate of pure depression without anxiety by more than three times. Wenzel et al. [12] also reported a higher prevalence of generalized anxiety than postpartum depression in their general population sample of 68 women. It is important to note that the symptom range of pure anxiety disorders is largely independent of the depressive symptom range so that anxiety disorders will be missed by commonly used screening instruments for depression [13, 14]. Even though many mothers have a clear postpartum onset of depression or anxiety, other mothers already suffer during pregnancy, continue to have symptoms long after the postpartum period or even start to develop mental problems in the following years of early motherhood. Those mothers, suffering from a

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mental disorder outside the explicit perinatal period, are even more likely to be neglected and they themselves have even more difficulties seeking help since they have no group to identify with. All these mothers show specific needs for care due to their particular life situation. Therefore, we suggest to use a term like ‘depression in early motherhood’ in accordance with terms like ‘depression of old age’ or ‘depression in adolescence’. We suggest to include the time span from pregnancy up to prekindergarten age to define this period [15]. Due to an apparently high prevalence of anxiety disorders in early motherhood, both terms, depression and anxiety, should be commonly used. During that age, a considerable number of infants and small children in many western societies are cared for entirely or mainly by their mothers at home. Such mothers, especially if they are mentally ill, very often have given up their former jobs after childbirth and only have a restricted social network at their disposal. They also hesitate or refuse to seek help and have difficulties providing their children with an adequate environment and stimulation. Many of these children of mentally ill mothers only draw attention to themselves when entering kindergarten showing a variety of already long-lasting behavioral, emotional and cognitive difficulties. Therefore, caregivers to mothers of infants must be aware of the fact that many mental illnesses including depression and anxiety show a tendency to relapse or to worsen during this period of early motherhood and need our attention. The life event scale is ranking pregnancy as a potentially harmful life event on place 12, and the gain of a new family member ranks on place 14 out of a list of 43 items, underscoring the impact of childbirth on new parents even in the absence of any complication on the part of the mother or the infant [16]. In addition, the strain of caring for a newborn can be quite a challenge for a couple and even more so for a single mother. Moreover, the couple has to come to terms with far-reaching changes in social roles such as changes in working environment, social networking and close relationships. First-time mothers and fathers have to come along with a range of new tasks which cannot be simply delegated to others if the couple finds itself as not being fit to tackle the tasks. It is well accepted that new parents need time to adapt and to grow into the responsibility of parents. Not only does the mother experience considerable strain, the father does so as well. Several investigations have pointed out that perinatal depressive disorders exert a considerable amount of strain on the healthy partner and can lead to mental illness in himself. The couple concordance in developing mental illness, if the mother suffers from perinatal depression, is high [17, 18]. If the father falls mentally ill, the likelihood of the mother to develop symptoms herself is even higher. Matthey et al. [11] showed the same effect in postpartum anxiety disorders.

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The ‘Pathoplastic’ Influence of Early Motherhood Pitt [19], one of the first authors to investigate and describe postpartum depression, used the term ‘atypical depression’ to describe typical mood alterations following childbirth. In his sample, he found, alongside with 10–11% depressed mothers, other conditions which he classified as anxiety without depression, reactive anxiety and depression due to infant’s ill-health, prolonged fatigue, psychosomatic disorders, and diminution of libido. He described depressed mothers as weary, irritable, despondent and anxious about the baby [20]. The more recent studies clearly indicate that there is no evidence for a specific set of symptoms pertaining only to postpartum depression [21]. Yet, from a clinical point of view, mothers often complain about a marked increase in irritability and fears alongside with classical symptoms of depression, both resulting in particular difficulties when interacting with the baby or with their partners. Irritability is described as a distinct mood condition in premenstrual, perinatal, and perimenopausal mood disturbances [22]. Obsessive thoughts and compulsions were also found to be more common in postpartum depressed mothers (57%) as compared to depressed women without children (39%) [23]. The content of obsessive thoughts was primarily aggressive such as accidentally stabbing or drowning the baby or throwing it down the stairs or imagining most horrifying events happening to the baby.

Specific Psychotherapies in the Treatment of Perinatal Depression

Individual Psychotherapies Cooper et al. [24] investigated 193 women with postpartum depression by assigning them randomly to three different specific interventions including CBT, nondirective counseling and psychodynamic therapy and compared these interventions to routine primary care. The three specific therapies were carried out in the homes of women by weekly sessions from the 3rd to the 5th month after parturition, whereas routine care was performed in the usual way by general practitioners and health visitors. A significant short-term effect on improvement of mood in favor of the three specific interventions was shown immediately after treatment, whereas in the long term, no superior effect in comparison to routine primary care was evident. O’Hara et al. [25] performed a 12-week randomized controlled trial including 120 subjects by comparing patients attending weekly sessions of IPT

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with waiting list controls showing a significant improvement of depression in the treatment group. Appleby et al. [26] compared fluoxetine treatment of 87 subjects to placebo with additional counseling either once or six times after initiating medical treatment by randomly assigning women to the four different conditions. Fluoxetine treatment proved to be superior to placebo without any measurable additional effect of counseling regardless of the amount of counseling. The study had a remarkable dropout rate which might reflect reluctance to take medication, being common in mothers during the perinatal period. Two other studies compared counseling versus routine care without counseling showing that counseling was helpful in mild depression; however, additional therapy might be necessary in severer depression [27, 28]. At present, there are no reports on specific treatments of anxiety disorders in the perinatal period.

Group Psychotherapies Over the last 30 years, a number of group treatments for mothers with depressive disorders have been reported. Many of these reports merely described the experience and used simple evaluation strategies without control groups [29–35]. These descriptive studies give some insight into advantages and difficulties and possible procedures of group treatment for mothers of infants. Klier et al. [35] adapted IPT for the group setting and found it helpful as it focuses on interpersonal relationships and role transitions both of which represent important topics in new mothers. So far, only three studies on group therapy for depressed mothers have used a randomized control design [36–38]. Fleming et al. [36] used social support groups, in a total sample of 127 women controlling for interventions by mail and a nonintervention group. There were two major disadvantages of the study; on the one hand, the recruitment of mothers within 2 weeks after delivery, thereby including mothers who suffered from baby blues but fully recovered within a short period of time, and, on the other hand, healthy and depressed mothers attending the same group, leading to increased feelings of failure in the depressed mothers. Meager and Milgrom [37] reported on a pilot study comparing group therapy using CBT, educational and social support components to a waiting list control group. The 10-week group treatment resulted in a significant reduction of depressive symptoms, whereas women on the waiting list remained severely depressed. The same group of investigators then developed a manualized group program and evaluated a larger sample of group participants controlling for

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routine community care [38]. There was a significant improvement of depression in the CBT group compared to the group receiving routine community care. Furthermore, levels of perceived social support improved in the CBT group but not in the routine community care group, whereas parenting stress was not changed by either treatment. Mothers with postpartum depression were repeatedly reported as being reluctant to enter group-based treatment [24, 39], which seems to be even more the case in rural areas [40]. Despite these difficulties, depressed mothers of infants represent a very homogenous sample predisposing them to mutually support each other and benefit from each other within a group setting. There are also an increasing number of reports on antenatal group interventions primarily targeted at the prevention of postpartum depression by identifying and treating pregnant women at risk. Several group approaches reported on using psychoeducation classes, skill training and discussion of the challenges of new motherhood [41–49]. At present, there is no clear evidence regarding the prevention of postpartum depression by the use of such ante- and perinatal group interventions [50, 51].

The Basle Group Therapy for Mothers with Depression

Development of a Manualized Group Psychotherapy We developed the GMD following the descriptions given by Meager and Milgrom [37]. Well-established CBT techniques were primarily used adapting them to the needs and concerns of mothers in early motherhood and supplemented by a systemic and psychoeducative approach. A manual was developed to facilitate and standardize treatment performance. The GMD was designed for a closed group of 6–8 mothers with 12 weekly sessions of 1.5-hour duration. The group room was equipped with an overhead projector and a flip chart as well as colored post-it papers (to optimize visual anchoring of the 3- and 5-column technique) and pens. Therapeutic Techniques and Contents of GMD Group treatment was started by introducing and training cognitive techniques like the tracing of negative automatic thoughts and errors in logical thinking as well as the detection of dysfunctional core beliefs [52]. The cognitive concepts were illustrated by examples out of the daily routine of depressed, irritable and anxious mothers of infants. In further sessions, behavioral techniques like encouraging mothers to take up positive activities and to improve their

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help-seeking behavior were introduced. Psychoeducative elements of depression, mother-child interaction and couple relationship in the transition to parenthood were enclosed consecutively in the training program to provide sufficient background information in order to facilitate a change of attitudes and behavior. Two sessions were dedicated to rehearse cognitive and behavioral skills and another session was targeted at early recognition of relapse and strategies of crisis intervention. Group work was enhanced by homework to test different strategies in the reality of daily routine. Difficulties of the depressed mothers in parenting and interaction with the child and the spouse were approached with a systemic point of view by encouraging the mothers to reactivate their family bonds and other social contacts. The partner was invited to an additional couple session to air difficulties and to improve the understanding of his wife’s depression, irritability, and anxiety. Nursery was offered during group sessions paying respect to the fact that mothers of infants needed extra support to be able to attend psychotherapy. Topics of the sessions Session 1: Introduction into depression and 3-column technique Session 2: Automatic thoughts, dysfunctional core beliefs, logical errors and 5-column technique Session 3: Dysfunctional core beliefs, vicious circles, stressors in daily routine with children, positive activities Session 4: Modifying dysfunctional core beliefs, models of stress coping, help-seeking strategies Session 5: Other treatment options for depression beside CBT Session 6: Repetition of cognitive and behavioral strategies Session 7: Mother-child interaction Session 8: Role of parents and parenting Session 9: Couple relationship and sexuality Session 10: Relapse into depression, suicidality and crisis intervention Session 11: Conclusion of cognitive and behavioral strategies Session 12: Farewell to the group and planning of the near future

Evaluation Study In order to evaluate this newly developed group therapy, we conducted a first evaluation study in 31 mothers with depression. Mothers were referred to the Psychiatric Outpatient Department in Basle by family doctors, pediatricians, maternity centers or requested treatment by means of self-referral. The following hypothesis was formulated: group therapy will result in a significant reduction of depressive symptoms, which will remain stable in a 1-year follow-up.

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Inclusion and Exclusion Criteria Inclusion criteria were a youngest infant within an age range from thirdtrimester pregnancy up to prekindergarten age, and mothers with a clinical diagnosis of first or recurrent episodes of unipolar or bipolar depression (ICD10 F32, F33, F31.3, F31.4), dysthymia (ICD-10 F34.1) or adjustment disorder with depressive or mixed anxiety and depressive reaction (ICD-10 F43.2) [53]. Comorbidity with anxiety disorders (ICD-10 F40, F41), obsessive-compulsive disorder (ICD-10 F42) or eating disorders (ICD-10 F50) were accepted as long as the depressive disorder was the main complaint. In addition, fluent knowledge of the German language and willingness as well as ability to participate in a group therapy were afforded. Excluded were patients suffering from acute suicidality, severe degrees of hostility against their infant, psychotic symptoms, addiction disorders or personality disorders. Setting We formed five consecutive groups, which were conducted by one fully trained female psychiatrist and one female psychiatrist in training. The majority of therapists were mothers themselves. A nursery for the infants and children was available, since many depressed mothers have difficulties organizing a baby-sitter on their own due to a lack of energy or out of guilt and shame to give the baby away for their own treatment. The child minder responded sensitively to the needs of the depressed mothers who suffered from a lack of self-esteem and easily felt frustrated by the slightest comments on their children or on their own behavior. Therefore, we chose a child minder who was experienced in small talk and conversation with depressed mothers. For the nursery, age-specific toys were available. Sample From 1998 to 2001, 52 women were referred to us for group therapy. Five did not fulfill diagnostic criteria, and 1 decided not to participate before commencement of the therapy. Out of the remaining 46 women, 31 attended group therapy more than 6 times out of 12 sessions, whereas 15 women were regarded as drop-outs attending less than 6 times. Eight of them had attended only once. The majority of women who dropped out had a mother tongue different from German and followed different cultural concepts of motherhood. In addition, most of them had not achieved vocational qualification. The 31 fully attending mothers were on average 33.5 years old (SD ⫽ 4.1, range ⫽ 24.3–40.1). Twenty-six were married, 2 of them living separated from

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their spouse. Five were unmarried mothers, 2 of them living with their partner. The 31 mothers had 1.6 children on average (SD ⫽ 0.6, range ⫽ 1–3) who were 2.4 years old on average (SD ⫽ 2.1), ranging in age from the 3rd trimester of pregnancy (1 person) up to 9 years of age (older sibling of an infant). Twentyeight women were fully qualified in their former jobs, 7 mothers were working part-time, 1 woman was a university student and working part-time and 1 woman was in job training. As far as diagnosis was concerned, 11 women suffered from recurrent major depressive episodes, 1 being mild, 9 being medium and 1 being severe in degree. A first episode of major depression was the diagnosis in 9 women, 2 being mild, 3 medium and 4 severe in degree. Adjustment disorder with depressive reaction was diagnosed in 6 women, 3 being of short duration, 3 of prolonged duration. One woman suffered from panic disorder without depression and 1 woman from bipolar disorder with current depression. Three women were admitted to group therapy for prophylactic reasons. They had no current depression but postpartum onset of severe depression after previous childbirth. Comorbidity was found in 3 patients (panic disorder, dysthymia, and bulimia nervosa). At the beginning of group therapy, 14 women were on antidepressants, 8 of them having taken medication for more than 3 months, 1 woman for less than 2 months and 5 for less than 1 month. On average, patients attended the group program 10 times within a range of 6–12 times. Twenty-nine partners were attending an additional couple session, 3 of them living separated from their partner. Two single mothers refused to have a parent session due to severe discord with the father of the infant. Instruments of Evaluation and Statistics A clinical interview was performed to assess symptoms, diagnosis and inclusion criteria for group therapy. The diagnostic criteria of ICD-10, chapter F were used (WHO, 1992). For assessing the severity of psychopathology, we used the following self-rating scales: the Beck Depression Inventory (BDI) [54], Symptom Check List (SCL-90-R) [55] and a self-rating scale to evaluate couple relationship [Familienbögen-Zweierbeziehung (FB-Z)] [56]. The same instruments and an additional questionnaire to assess acceptance of group therapy and subjective changes in relationship attributed to group therapy were handed out at the end of the group therapy. The latter comprised 12 questions with a Likert scale ranging from ⫺3 (not at all true) to ⫹3 (very true). In addition, in a small number of patients, these instruments were handed out again 1 year after termination of group therapy. Means and standard deviations were calculated. One-tailed t tests were performed to calculate significance. To compare group participants who used

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antidepressant medication with those who did not, a one-factorial analysis of variance was performed. Effect sizes were calculated as suggested by Rosenthal [57]. Effect sizes between 0.40 and 0.79 indicate medium efficacy, below 0.40 poor efficacy and above 0.80 substantial effects of psychotherapy.

Results BDI scores showed a highly significant reduction in depressive symptoms from pretesting before group therapy to posttesting immediately after the last session of group therapy. Mean BDI scores dropped from 21.5 to 12.9 points (one-tailed t test, d.f. ⫽ 29, p ⬍ 0.001). Twenty patients showed a significant drop in BDI scores, 3 patients remained unchanged, 4 deteriorated in BDI scores and 4 showed scores below 10 before and after treatment. Follow-up evaluation after 1 year was only done in 10 patients. They showed a drop of initial BDI scores from 22.7 before treatment to 10.7 immediately after treatment and 13.6 1 year after treatment. The difference between pretesting and posttesting was significant (one-tailed t test, d.f. ⫽ 5, p ⬍ 0.001) just as between pretesting and 1-year follow-up (one-tailed t test, d.f. ⫽ 5, p ⬍ 0.01). From posttesting to 1-year follow-up, there was no significant deterioration, indicating that the achieved improvement was stable (one-tailed t test, d.f. ⫽ 5, p ⬍ 0.18). SCL-90-R scores were available for 24 patients. Similar reductions were achieved on the depression subscale of this scale comparing the scores before and after group therapy. A significant reduction in symptoms was also seen on other subscales of the SCL-90-R, e.g. ‘aggression/hostility’, ‘interpersonal sensitivity’ and ‘obsessive-compulsive’. Effect sizes were 1.01 in the BDI and 0.99 in the SCL-90-R, indicating substantial effects of psychotherapy. The instrument measuring couple relationship (FB-Z), which was available in 23 patients, showed scores higher than average at both measure points, indicating preexisting difficulties in couple relationship without improvement in the course of treatment. At the end of treatment, the patients expressed high levels of satisfaction, on a Likert scale ranging from ⫺3 (not at all true) to ⫹3 (very true), with the treatment (mean ⫽ 3, SD ⫽ 1.12) and the therapists (mean ⫽ 3, SD ⫽ 0.44), and agreed strongly that their stress-coping behavior in daily routine had improved with therapy (mean ⫽ 2, SD ⫽ 0.83). They felt, subjectively, that their relationship to the infant had strongly improved over the course of treatment (mean ⫽ 3, SD ⫽ 1.86), whereas couple relationship was felt to have slightly deteriorated (mean ⫽ 0, SD ⫽ 2.02).

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To control for the influence of medication, analysis of variance was performed to distinguish group treatment effects in patients with and without antidepressants. It was shown that both subsamples of patients improved significantly and to the same extent over the course of group treatment with a parallel decline of depressive symptoms in both groups. Patients who were on antidepressants had higher initial levels of depression compared to those without antidepressants. The 3 asymptomatic patients who had been admitted for primary prevention of depression and 1 patient with pure panic disorder were not included into this analysis of variance.

Discussion The GMD was developed to improve and facilitate the treatment of depressed mothers of infants and small children by adapting well-established antidepressant psychotherapeutic strategies to the specific needs and concerns of early motherhood. The significant drop in the scores of the BDI and in the depression subscale scores of the SCL-90-R down to almost symptom-free levels could be replicated in every single group of the five consecutive group treatments, indicating the efficacy of the therapy program. The significant symptom reduction was not only apparent in patients without antidepressants but also in patients on antidepressants who had not reached full remission before entering group therapy in spite of adequate medication. The symptom reductions on several other dimensions of the SCL-90-R such as ‘aggression/hostility’, ‘interpersonal sensitivity’, and ‘obsessive-compulsive’ also contributed to a mother’s ability to care for her baby and adapt to a different lifestyle. Participating mothers definitely benefited from feeling less hostile and tense in handling their babies and their social skills improved by attending the group therapy, which might have served as an incentive to resume social activities in general. The majority of women who had been offered group treatment showed spontaneous and clear interest in participating. Some women expressed some fears before entering group therapy, especially that their condition might be worsened being confronted with more severely depressed mothers. However, during the sessions, mothers repeatedly expressed their satisfaction with meeting other mothers who experienced similar difficulties. Some of them started to contact other group members between sessions, which was generally well tolerated by the women. The high level of acceptance was also reflected by a high average rate of attendance in patients who were prone to miss sessions due to illness or day

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sleeping hours of the child and other typical hazards of early motherhood. In addition, mothers expressed an overall high level of satisfaction with the group meetings and the therapy program. This stands in contrast to the experience of some other authors who found mothers to be reluctant to enter group therapy [24]. The nursery was very much appreciated by those mothers who had no other possibility to get baby-sitting for their child. On average, up to 50% of mothers made regular use of the nursery during group sessions. The limitations of the study were as follows: the sample was recruited in a clinical setting by consecutively admitting every referred patient who fulfilled inclusion criteria. Therefore, the sample could have been biased as mainly patients with adequate help-seeking behavior were included. Drop-outs concerned mainly patients with a different cultural and unskilled vocational background. Evaluation included only self-administered scales. Diagnosis was made by a clinical interview only and not by a standardized instrument. Randomization was not possible at the very beginning of the clinical implementation of the program. A control group using individual therapy as usual was, however, started after completion of five consecutive groups. The results of this control group will be reported in the near future.

Conclusions

Early motherhood is a period of increased vulnerability to develop mood disorders due to challenging positive and possibly negative life events. Until recently, only few studies have reported on specific psychotherapeutic interventions for mothers of infants and small children suffering from depression and anxiety. In general, psychotherapy seems to improve symptoms in this group of patients. Yet, little is known which interventions in particular are most helpful for these patients. Therefore, further investigations are needed to find out in more detail which strategies are most efficacious and effective. The Basle GMD is specific with regard to disorder, gender and life situation. The program proved to be efficacious and well accepted not only by reducing symptoms of depression in mothers but also by improving the relationship with the child as rated by the mothers themselves. The manual facilitates clinical implementation. The results of a post hoc control group with individual therapy as usual will be reported in the near future. In addition, a randomized study is planned with improved design and instruments for evaluation to compare individual therapy with group therapy in terms of symptom reduction as well as in terms of couple relationship and mother-child interaction.

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Hofecker-Fallahpour M, Zinkernagel-Burri C, Stoeckli B, Wüsten G, Stieglitz R-D, RiecherRössler A: Gruppentherapie bei Depression in der frühen Mutterschaft. Nervenarzt 2003;74: 767–774. Beck AT, Rush AJ, Shaw BF, Emery G: Cognitive Therapy of Depression. New York, Guilford Press, 1979. Lewinsohn M, Antonuccio DO, Steinmetz JL, Teri L: The Coping with Depression Course. A Psychoeducational Intervention for Unipolar Depression. Eugene, Castalia Publishing, 1984. Klerman GL, Weissman MM, Rounsaville BJ, Chevron ES: Interpersonal Psychotherapy of Depression. New York, Basic Books, 1984. Clark DM: Cognitive therapy for depression and anxiety: Is it better than drug treatment in the long term?; in Hawton K, Cowen P (eds): Dilemmas and Difficulties in the Management of Psychiatric Patients. New York, Oxford University Press, 1990, pp 55–64. Glick ID: Treating Depression. San Francisco, Jossey-Bass, 1995. O’Hara MW, Swain AM: Rates and risk of postpartum depression: A meta-analysis. Int Rev Psychiatry 1996;8:37–54. Fergusson DM, Horwood LJ, Thorpe K: Change in depression during and following pregnancy. ALSPAC Study Team. Study of pregnancy and children. Paediatr Perinat Epidemiol 1996;10: 279–293. Evans J, Heron J, Francomb H, Oke S, Golding J: Cohort study of depressed mood during pregnancy and after childbirth. BMJ 2001;323:257–260. Stuart S, Couser G, Schilder K, O’Hara MW, Gorman L: Postpartum anxiety and depression: Onset and comorbidity in a community sample. J Nerv Ment Dis 1998;186:420–424. Matthey S, Barnett B, Howie P, Kavanagh DJ: Diagnosing postpartum depression in mothers and fathers: Whatever happened to anxiety? J Affect Disord 2003;74:139–147. Wenzel A, Haugen EN, Jackson LC, Robinson K: Prevalence of generalized anxiety at eight weeks postpartum. Arch Women Ment Health 2003;6:43–49. Ballard CG, Davis R, Handy S, Mohan RN: Postpartum anxiety in mothers and fathers. Eur J Psychiatry 1993;7:117–121. Muzik M, Klier CM, Rosenblum KL: Are commonly used self-report inventories suitable for screening postpartum depression and anxiety disorders? Acta Psychiatr Scand 2000;102:71–73. Hofecker-Fallahpour M, Riecher-Rössler A: Depression in der frühen Mutterschaft: Erschöpft, gereizt, überängstlich. Neurotransmitter 2003;2:35–39. Dimsdale JE, Keefe FJ, Stein MR: Stress and psychiatry; in Sadock BJ, Sadock VA (eds): Comprehensive Textbook of Psychiatry. Philadelphia, Lippincott Williams & Wilkins, 2000, p 1837. Raskin VD, Richman JA, Gaines C: Patterns of depressive symptoms in expectant and new parents. Am J Psychiatry 1990;147:658–660. Matthey S, Barnett B, Ungerer J, Waters B: Paternal and maternal depressed mood during the transition to parenthood. J Affect Disord 2000;60:75–85. Pitt B: ‘Atypical’ depression following child birth. Br J Psychiatry 1968;114:1325–1335. Pitt B: Postpartum disorders; in Priest RG (ed): Psychological Disorders in Obstetrics and Gynaecology. London, Butterworths, 1985. Riecher-Rössler A, Hofecker-Fallahpour M: Postpartum depression: Do we still need this diagnostic term? Acta Psychiatr Scand 2003;108:51–56. Born L, Steiner M: Irritability: The forgotten dimension of female-specific mood disorders. Arch Women Ment Health 1999;2:153–167. Wisner KL, Peindl KS, Gigliotti T, Hanusa BH: Obsessions and compulsions in women with postpartum depression. J Clin Psychiatry 1999;60:176–180. Cooper P, Murray L, Wilson A, Romaniuk H: Controlled trial of short- and long-term effect of psychosocial treatment of postpartum depression. Br J Psychiatry 2003;182:412–419. O’Hara MW, Stuart S, Gorman L, Wenzel A: Efficacy of interpersonal therapy for postpartum depression. Arch Gen Psychiatry 2000;57:1039–1045.

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Dr. Maria Hofecker-Fallahpour Psychiatrische Universitätspoliklinik Petersgraben 4 CH–4031 Basel (Switzerland) Tel. ⫹41 61 265 50 40, Fax ⫹41 61 265 45 88, E-Mail [email protected]

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Riecher-Rössler A, Steiner M (eds): Perinatal Stress, Mood and Anxiety Disorders. From Bench to Bedside. Bibl Psychiatr. Basel, Karger, 2005, No 173, pp 182–193

Alternative Treatment Strategies for Perinatal Depression and Anxiety Madeleine O’Higginsa, Vivette Glovera, Maria Corralb a

Institute of Reproductive and Developmental Biology, Imperial College London, London, UK; bReproductive Mental Health Programme, St. Paul’s and BC Women’s Hospitals, Vancouver, Canada

Complementary and alternative medicine (CAM) is the first choice for many people suffering from anxiety and depression. These are the only medical conditions for which the majority seek complementary or alternative treatments, rather than orthodox ones. Kessler et al. [1] reported that, in the USA, 53% of those with symptoms of anxiety had used alternative treatments compared with 41% who had sought conventional treatment. In the case of depression, the figures were 57 and 36%, respectively. It is possible that these percentages are even higher in the perinatal period when women are likely to be even more reluctant to take medication. Mood disturbances and anxiety problems are common at this time. Postnatal depression is present in 10–15% of mothers [2], and depression also affects at least this percentage antenatally [3, 4]. There is a strong comorbidity between anxiety and depression. Matthey et al. [5] note that anxiety may often be the presenting symptom of a mother with postnatal depression. While the symptoms of depression and anxiety appear to be the same in the perinatal period as at other times, there is a growing fetus and developing baby who must also be considered when deciding on treatment. Studies demonstrating the efficacy and safety of pharmacological treatments for perinatal depression, particularly those involving the use of tricyclic antidepressants and serotonin reuptake inhibitors, are only just starting [6, 7]. Women remain concerned about the possible effects these medications may have on the fetus and breast-fed baby. Recent research shows that most of these medications do not increase the risk of congenital malformations when used during pregnancy [8]. However, there have been few studies published that address the

issue of long-term safety of these medications [9, 10]. Following childbirth, most women choose to breast-feed their infants for at least several months. The research to date indicates that relatively low levels of antidepressant medication are excreted into breast milk, and similarly, infant serum levels of these medications have been shown to be low [11]. Despite the encouraging nature of these early data, many women continue to express a preference for non-pharmacological treatments of anxiety or depression occurring during pregnancy or in the postpartum period. In this paper, the current evidence for some non-pharmacological, ‘alternative treatment strategies’ is reviewed with reference to their potential use in the perinatal period.

What Is Meant by ‘Alternative Treatment Strategies’?

For the purpose of this review, the term ‘alternative treatment strategies’ is used to refer to treatments for anxiety or depression other than antidepressants or forms of counselling and psychotherapy. This encompasses a wide range, including homoeopathy, acupuncture, herbal remedies, exercise or relaxation and bright light therapy. Those discussed here will be yoga/relaxation/meditation, exercise, infant massage and bright light therapy, as these are the ones for which there is some evidence for efficacy in depression or anxiety [1, 12–14]. We will also discuss the little research there is that is specific to the perinatal period [15, 16]. There is a lack of good-quality research in the area of complementary therapies. There is still a debate about the most appropriate type of research to undertake and also a lack of consensus on terms and definitions. Much has been written about the feasibility and applicability of randomised controlled trials for investigating CAM. While this is considered the gold standard for research in orthodox medicine, some argue that relevance is sacrificed in favour of rigour when randomised controlled trials are used in this area [17]. Richardson [17] notes the importance of the therapeutic relationship, which may not be measured quantitatively. Vuckovic [18] mentions the incidental outcomes that may result from choosing a complementary treatment option. She cites lifestyle changes, such as stopping smoking, as possible incidental outcomes that may be important to the patient, but could go unrecorded in a randomised controlled trial. One other concern about research into CAM has been that randomised controlled trials do not fit well with the tailoring of treatments to individual patients that is important in many such treatments [19]. This is all true. However, the problem with these approaches is that they can be used to explain away negative results for such reasons: evidence that a particular treatment does not work is never accepted.

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Our approach is that with research into CAM, the first requirement should still be to establish with a trial, preferably a randomised controlled trial, whether a particular treatment has better results than no treatment. One can then try to unpick which components of the CAM are actually producing the benefit, and also tailor treatments for individual patients. This can be combined with qualitative or other hypothesis-generating research.

Exercise

Craft and Landers [20] have conducted a meta-analysis of studies that have looked at exercise as an intervention for clinically depressed patients or those that were seriously mentally ill and depressed as a result of that mental illness. It was found that all types of exercise investigated were effective in lowering depression scores. Larzelere and Wiseman [12] further note that changes in physical fitness are only weakly related to depression reduction. They emphasise the importance of long-term maintenance of exercise behaviour to ensure the reduction in depression persists. Results from the meta-analyses [21] show that the largest effect size has been found with programmes of exercise lasting 9–12 weeks. Craft and Landers [20] suggest that research should now focus on even longer programmes of exercise, as such protocols have not been examined. While both aerobic and non-aerobic activities are reported to be equally effective in the treatment of depression in the article by Larzelere and Wiseman [12], Craft and Landers [20] mention that running appeared to have the largest effect, although this was not statistically significant. One suggested mechanism for such effects is via the serotonin system in the brain. Acute physical exercise has been shown to increase levels in rats [22]. Exercise is generally agreed to be useful in producing a small to moderate reduction in both trait and state anxiety [23]. Research suggests that exercise duration should be of 40 min or more with a training period of 16 weeks or longer [24] in order to produce the largest decrease in trait anxiety. Larzelere and Wiseman [12] suggest the same guidelines for exercise to reduce depression should be followed here. This implies that exercise should be undertaken at a level and frequency that is comfortable for the patient. The effects of exercise on anxiety reduction are said to be equal to effects of treatments including meditation or relaxation [23]. One small randomised controlled trial has been conducted into exercise as an intervention for mothers with depressive symptoms [25]. In this study, mothers who participated in an exercise intervention showed a significant improvement in depressive symptomatology compared to a control group. The mothers in the exercise group also had improved physical fitness when compared to the

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control group. The exercise intervention consisted of 2 group pram-walking sessions a week with an additional pram-walking session to be done independently each week. The exercise was of moderate intensity for 30–40 min, which is consistent with the guidelines for exercise protocols for anxiety described above. The control group attended a support session once a week. The study period was 12 weeks, which falls within the intervention period that appeared to have maximum effects in the meta-analyses of exercise interventions for depression previously described. While this study cannot distinguish whether the reduction in depression was due to the exercise itself or other aspects of the intervention, the finding that the groups did not differ in their reported levels of social support before and after the study period of 12 weeks suggest that it is unlikely that the social aspect of the exercise intervention is responsible for the effects seen here. However, this was a small study (n ⫽ 19) and more research is needed to further investigate the benefits of exercise for postnatal depression. Its benefits for anxiety in the postnatal period should also be examined. Studies have not focused on the antenatal period and there are no specific recommendations as to what type of exercise might be most suitable for pregnant women. However, Da Costa et al. [26] looked at mothers’ reported physical activity during pregnancy and its relationship to depressed mood and state anxiety in addition to other measures of psychological well-being. They started collecting data on women in the third month of pregnancy. They found that in the first and second trimesters, mothers who exercised reported less depressed mood and state anxiety. Less state anxiety was reported by exercising mothers in the third trimester. The overall findings appear to indicate that exercise may be a useful means of increasing psychological well-being in mothers in the perinatal period, but more research is needed in this area. It will also be important to examine what type of exercise would be most suitable, particularly for mothers during pregnancy. Cortisol is elevated during stress, anxiety and depression, but it is also elevated in normal pregnancy. Bessinger et al. [27] report that moderate-intensity exercise increased circulating cortisol levels more in women who were pregnant than in women who had already delivered. This may indicate that moderateintensity exercise has a similar effect on pregnant women to intense exercise at other times, since data from Jacks et al. [28] found that in healthy males, cortisol only increased after exercise at high intensity for a long duration. Previously, McMurray et al. [29] reported that pregnancy significantly alters the metabolic responses to exercise in the water. They observed the usual increase in cortisol levels with pregnancy but levels of cortisol remained lower in the pregnant women during immersion and exercise. These findings emphasise the need for research into exercise as a treatment for anxiety and depression specifically in the perinatal period, and the need to look for long-term effects on both mood and biology.

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Touch and Massage in Anxiety and Depression

This has been the aspect of CAM which has been most studied in the perinatal period. Tiffany Field [30] has been a pioneer in generating interest in the area of touch and its therapeutic effects. She has reported that massage or touch therapy has benefits for depression and anxiety in addition to facilitating growth (for example, in premature infants) and enhancing immune function. Massage in pregnancy has been found to reduce levels of anxiety-, stress- and depression-related hormones, and has been reported to be superior in its effects to relaxation therapy [31]. Field et al. [32] studied teenage mothers and found massage to be an effective therapy for reducing their anxiety and depression. Studies of brain activity have shown that receiving massage therapy reduces frontal EEG symmetry in both mothers [33] and in infants of depressed mothers who were massaged by a researcher trained in the procedure [34]. Right frontal EEG asymmetry is a pattern associated with depression. More recent research has found that, not only is there a reduction in depression in mothers who are taught infant massage, but they also have improved interactions with their infants [13]. In this small study, mothers with postnatal depression were all assigned to a support group, with one group of mothers also attending baby massage classes. After the intervention, only those who attended the massage class had statistically significantly improved interactions with their babies; they improved into the normal range. Mothers who had attended the massage class also had a greater reduction in their depression scores than the controls, and their infants also scored more positively on the global interaction scale [35]. This could partly be a result of mothers learning to interpret their infants’ non-verbal cues in the massage classes. This is an important finding as children of mothers who have suffered from postnatal depression are reported to have impaired development [36, 37]; this is likely to be mediated, at least in part, by the poor interactions between some depressed mothers and their babies. An intervention, such as baby massage, that can improve the interaction, may help combat the long-term effects of postnatal depression on the child. The results in this area are supported by animal research. Meaney et al. [38] found lower levels of stress hormones in frequently handled rat pups, while the touch/growth relationship has also been shown in rats [39]. It is further suggested that massage may raise levels of oxytocin in both the mother and baby. Massage therapy is known to increase plasma oxytocin in healthy adult women [40], while tactile stimulation is reported to induce the release of oxytocin in young dogs and in calves [41]. Oxytocin has been shown to increase maternal behaviour in animal models [42] and it has been implicated in social bonding [43]. Thus, baby massage could be helping to release oxytocin in both mothers

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and babies and contribute to the development of a close mother-infant relationship in this way. Massage therapies, whether by the mother on her infant, or on the mother, do not appear to have any contra-indications in the perinatal period. Of course, the type of massage needs to be tailored to the recipient. In baby massage classes run by the International Association for Infant Massage [44], this is an important part of the teaching. Mothers are taught to be sensitive to their infant’s cues and not to force massage on them unless they are receptive. The oils used in massage also need to be considered. Aromatherapy has been supposed as having an evidence base by the House of Lords Select Committee on Science and Technology [16]. Amongst the suggested oils for massage in postnatal depression are bergamot, lavender and rose [45], but research is needed into their efficacy for helping women with postnatal depression. Research into what oils are appropriate in the antenatal period would also be useful. In baby massage, oils used include sesame oil and organic vegetable oils. At infant massage classes, a choice may be provided as some mothers, for example, prefer to avoid nut oils in case of nut allergies.

Relaxation

Meditation/Yoga and Depression A study conducted into the antidepressant effects of Sudarshan Kriya yoga [46] has suggested that its effectiveness may be comparable to drug treatment (imipramine) in severe hospitalised depressives. This form of yoga involves rhythmic hyperventilation interspersed with normal breathing and concluding with 10–15 min of a ‘tranquil state’ in a supine position. This type of breathing has demonstrable effects on brain function, ‘normalising’ an event-related potential (P300) that is low in patients with severe endogenous depression [47]. This type of pattern has also been reported for antidepressant medications and for electroconvulsive therapy [48, 49]. Relaxation has been shown to lower salivary cortisol levels in addition to self-report measures of anxiety and perceived stress [50]. Practising yoga has been shown to decrease serum cortisol levels in yoga instructors [51]. These results, showing a biological effect of relaxation therapies, should encourage more research into their effects as stand-alone interventions for anxiety. Baby yoga is becoming increasingly popular, as shown by the number of books and classes that are available. Baby yoga involves mothers handling their babies and helping them stretch out. They may be put into certain poses and it often incorporates a massage as a warm-up [52]. Babies who do baby yoga are said anecdotally to be less likely to suffer from digestive problems such as

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constipation and tend to be more relaxed. A happier, more relaxed baby is likely to be easier for a mother to look after and this could help the relationship with a depressed mother. However, there is no research in this area and this is needed to establish and clarify any benefits it may have. Relaxation and Anxiety Research comparing relaxation with other therapies for anxiety is scarce, possibly because relaxation is often seen as a technique to be used in conjunction rather than in its own right [12]. Relaxation training has been shown to be effective as part of a treatment package for posttraumatic stress disorder or generalised anxiety disorder [53, 54]. Research looking at the perinatal period is necessary. If this is positive, these strategies, perhaps baby yoga in particular, could be most useful for mothers and mothers-to-be suffering at this time. Including the baby in the intervention seems practical and may make it easier for mothers to take part. The research relating to the effects of touch are likely to be relevant in research into baby yoga and it would also be interesting to look at any effects on motherinfant interaction with this intervention.

Bright Light Therapy

Rosenthal et al. [55] at the National Institutes of Mental Health first described seasonal affective disorder (SAD) and its treatment with bright light therapy in 1984. Since then, bright light therapy has not only become established as an evidence-based first-line treatment for SAD, but it has also been used to treat various forms of non-seasonal depression with success [56]. Light is usually administered using light boxes, which emit specific intensities of light. Most currently used standard light boxes emit light intensities of 5,000–10,000 lx, with minimal (less than 1%) ultraviolet emission. Patients place the device on a table or desk and sit in front of the light box, with the device approximately 25–35 cm from eye level. Patients are instructed to sit in front of the light for a prescribed period of time, usually ranging from 20 min to 1 h, depending on the intensity of light exposure. The treatment is effective and well tolerated, with few side-effects reported [57]. Ophthalmologic examinations are recommended in individuals with a history of pre-existing ocular problems. Some experts recommend that every new patient beginning treatment with bright light therapy should have an eye exam [58]. The exact mechanism of action for bright light therapy is still unknown. Bright light therapy induces phase shifts through its suppression of melatonin, and this may account for some of its efficacy in treatment. Another mechanism

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likely involves changes in the levels of various neurotransmitters in the hypothalamic region of the brain. Serotonin has been most widely studied in this regard, although dopamine has also been implicated [59]. Bright Light Therapy in the Treatment of Depression during Pregnancy One open study has reported on the use of bright light therapy in depressed pregnant women [60]. In that study, Oren et al. [60] treated 16 pregnant women with 60 min of daily morning bright light therapy for 3 weeks. The treatment was well tolerated, except in 2 patients, who experienced nausea during the treatment. The nausea improved after light exposure was reduced from 60 min to 45 min daily. Seven of the 16 patients were offered extended treatment with bright light for 5 weeks. Patients were followed weekly during the course of treatment and the main outcome measure was the SIGH-SAD score, a 29-item modified Hamilton Depression Scale frequently used in treatment studies of seasonal depression. In this cohort of pregnant women, improvement from baseline was 49% after 3 weeks of treatment and 59% after 5 weeks of treatment. The authors concluded that bright light therapy has an antidepressant effect in pregnant women with depression. The improvement was more gradual than that seen in the treatment of winter depression with bright light, but was comparable with the time course for improvement generally seen when psychopharmacological agents are used. Bright Light Therapy in the Treatment of Postpartum Depression There has only been one case report in the literature describing the use of bright light therapy in postpartum depression [14]. Two women were treated with 10,000 lx of morning bright light for 4 weeks. Both women responded to treatment without side-effects and showed a 60% reduction in symptoms during the course of treatment. One of the 2 women was nursing her infant. A second small study investigating the use of bright light therapy in postpartum women has recently been completed. This study was a double-blind, randomised control study, comparing morning bright light (10,000 lx) with morning dim red light (600 lx) as the control condition [Corral et al., unpubl. data]. Eighteen women were randomised into the study after a diagnosis of postpartum depression was established and after meeting inclusion criteria and consenting to participate. Ten women received bright light and 8 the red light for a total of 5 weeks of treatment. Women used the light boxes at home for 30 min in the morning, between 07.00 and 09.00 h. The results are shown in figure 1; two patients in the bright light group and 1 patient in the red light group were excluded from the analysis because of missing data points.

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HAM-D 29 after 1 week of light therapy HAM-D 29 after 2 weeks of light therapy

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Fig. 1. Hamilton Depression Scale-29 items (HAM-D 29) scores in women with postnatal depression exposed either to bright light (n ⫽ 8) or red light (n ⫽ 7).

The depression scores for the women treated with bright light dropped by 44%, whereas the women treated with red light had an improvement of 33%. The improvement in the bright light group was much more consistent on a week-by-week basis compared with the changes seen in the red light group, which were more variable (fig. 1). There were no significant treatment differences between the two groups, but this was not unexpected given the small sample size. Overall, the women tolerated the treatment well and were pleased with the results. This small pilot study demonstrates that morning bright light therapy shows promise in the treatment of postpartum depression and it warrants further investigation in this patient population. It may well be that bright light therapy is suitable for a specific subgroup of women with postnatal depression. SAD has many features of atypical depression such as oversleeping and carbohydrate craving, and it may be women with these features who benefit. Conclusion

There is some evidence for the efficacy of exercise, touch/massage, yoga/meditation and bright light to treat anxiety and depression in general. In the perinatal period, there is evidence for the benefit of touch therapies, especially massage, both for the mother and the baby as well as for their interaction.

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Evidence is also starting to show some benefit of the use of bright light therapy for depression at this time. Pregnancy and the time postpartum are periods during which depression and anxiety are often present, and these disorders may also have an effect on the fetus [61] and the baby [35]. CAM therapies are likely to be a popular choice for women at this time. Clinicians and researchers working with these women need to continue to explore novel and alternative treatments in a scientific and controlled way.

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Madeleine O’Higgins Institute of Reproductive and Developmental Biology, Imperial College London Du Cane Road London W12 0NN (UK) Tel. ⫹44 207 594 2136, Fax ⫹44 207 594 2138, E-Mail [email protected]

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Author Index

Ahokas, A. 100 Aito, M. 100 Beach, A.J. 70 Brockington, I. 1

Hofecker-Fallahpour, M. 167 Kaukoranta, J. 100 Matthews, S.G. 28 Meaney, M.J. 28

Corral, M. 182 Newport, D.J. 70, 137 Glover, V. 182 Gunasekera, S. 112 Henry, A.L. 70

O’Hara, M.W. 150 O’Higgins, M. 182 Ragan, K. 137

Riecher-Rössler, A. VII, 6, 167 Rohde, A. 6 Ross, L.E. 112 Rowland, M. 112 Spinelli, M.G. 85 Steiner, M. VII, 112 Stowe, Z.N. 70, 137 Stuart, S. 150 Wadhwa, P.D. 50 Wahlbeck, K. 100

194

Subject Index

Anxiety disorders benzodiazepine management in pregnancy 119, 120 cognitive behavioral therapy 162, 164 complementary and alternative medicine, see Complementary and alternative medicine demands of early motherhood 168, 169 exercise effects 184, 185 interpersonal psychotherapy, see Interpersonal psychotherapy postpartum 19, 20 pregnancy 21 relaxation therapy 188 Aromatherapy, anxiety and depression studies 187 Attention deficit disorder (ADD) dopamine system gene polymorphisms 34, 35 familial risks 39 intrauterine growth restriction risks 29, 34 Baby blues definition 7 frequency 7 Basel group therapy for mothers with depression, see Group therapy for mothers with depression Behavioral perinatology maternal-placental-fetal neuroendocrine axis 57 prenatal stress and fetal outcomes

biobehavioral model 52–55 epidemiological findings 55, 56 placental corticotropin-releasing hormone role fetal growth 58 fetal neurodevelopment 60–62 immune-inflammatory processes in pregnancy 58–60 preterm labor effects 57 stress sensitivity 62 prospects for study 62–65 scope 50, 51 Benzodiazepines long-term neurodevelopment effects of prenatal exposure 129, 130 neonatal complications 120, 121 teratogenic effects 120 Bipolar disorder, management in pregnancy 123, 124 Bonding, mother and infants 15 Breast-feeding advantages 138 hormonal changes 138 postpartum depression management antidepressants adverse effects 142, 144, 145 clinical decision-making 142, 143, 145 infant exposure quantification 139–142 studies 139, 140 concerns 137 Bright light therapy, see Light therapy

195

Carbamazepine neonatal complications 122, 123 teratogenic effects 122 Chlorpromazine neonatal complications 126 teratogenic effects 124, 125 Clozapine, safety in pregnancy 126, 128, 129 Cognitive behavioral therapy (CBT) anxiety management 162, 164 group therapy in perinatal depression 171, 172 postpartum depression management 160, 161, 167 Complementary and alternative medicine (CAM) aromatherapy 187 definition 183 exercise 184, 185 light therapy 188–190 massage 186, 187 pharmacotherapy attitudes in postpartum period 182, 183 popularity in treatment of maternal depression and anxiety 182 prospects 190, 191 relaxation therapy 187, 188 research concerns 183, 184 Corticotropin-releasing factor (CRF), intrauterine growth retardation infants cord blood levels 30 fetal adversity and neural development 31, 32 postnatal programming of neural development 37, 38 stress response mediation 31 Corticotropin-releasing hormone (CRH), prenatal stress and fetal outcome role of placental hormone course of expression 54 fetal growth 58 fetal neurodevelopment 60–62 immune-inflammatory processes in pregnancy 58–60 overview 52, 53 parturition role 57, 58 preterm labor effects 58 stress sensitivity 62

Subject Index

Cortisol exercise response in pregnant women 185 relaxation effects 187 Depression, postpartum animal offspring studies of postpartum stress exposure 75, 76, 78, 79 demands of early motherhood 168, 169 diagnostic classification depression versus psychosis 16, 17, 22, 23 DSM-IV 8, 9 ICD-10 8 limitations 137 methodological problems 6, 7 specificity requirements consequences 13, 14 course 13 etiology 11–13 therapeutic needs 14–16 symptomatology 9, 10 frequency 7, 11, 72, 100, 168 historical perspective 2, 3 infant effects 74, 75 management cognitive behavioral therapy 160, 161, 167, 171, 172 complementary and alternative medicine, see Complementary and alternative medicine delay 14, 23 estrogen formulations and regimens 104–107 overview 16, 104 group psychotherapy, see Group therapy for mothers with depression interpersonal psychotherapy, see Interpersonal psychotherapy nursing women, see Breast-feeding pharmacotherapy 119, 120, 171 ‘pathoplastic’ influence of early motherhood 170 suicide, see Suicide, perinatal Depression, pregnancy fetal effects 72–74 interpersonal psychotherapy 163 light therapy 189 pharmacotherapy safety, see specific drugs

196

Diathesis/stress model of illness maternal depression incorporation 76, 77 overview 70, 71 Dopamine, estradiol effects 103 Electroencephalography (EEG) child studies following prenatal depression 73, 74 massage studies 186 Estrogen central nervous system effects 102, 103 changes in female reproduction 12, 101 mental effects during breast-feeding 138 postpartum depression management formulations and regimens 104–107 overview 16, 104 psychoprotectant effect 12 receptors 102, 103 Exercise anxiety effects 184, 185 depression effects 184, 185 Family environment environmental adversity and parental care 40, 41 maternal depression and stress, see Depression, postpartum postnatal programming of neural development 35–39 Filicide, features 94, 95 Gabapentin, teratogenic effects 123 Genetic susceptibility, peripartum disorders 11, 12 Group therapy for mothers with depression (GMD) contents of sessions 173 development 172 evaluation study instruments 175 limitations 178 outcomes 176–178 patient inclusion and exclusion criteria 174 sample 173–175 setting 174 statistics 175, 176

Subject Index

rationale 167, 168 therapeutic techniques 172, 173 Haldol (haloperidol) neonatal complications 126 teratogenic effects 124, 125 Hippocampus, stress effects on volume 32, 33 Hospitalization, indications 16 Hypothalamic-pituitary-adrenal (HPA) axis animal studies of stress and developmental effects 37–39 behavioral perinatology, see Behavioral perinatology environmental adversity and parental care 40, 41 intrauterine growth restriction fetal programming of gene expression 30, 31 glucocorticoid role 29, 30 neural development and fetal adversity 31–34 ovarian axis interactions 102 postnatal programming of neural development 35–39 pregnancy changes 102 reversibility of developmental effects of fetal adversity 41–43 Infanticide, perinatal filicide 94, 95 frequency 85 historical perspective 1–3, 85–87 infanticide-suicide 94–97 legal issues gender influences 91–93 insanity law in United States 88, 89 overview 86, 87 research-based information needs 91–93 United Kingdom 89, 90 Yates’ case 87, 88, 92–94 Insanity, law in United States 88, 89 Interpersonal psychotherapy (IPT) depression treatment efficacy 154, 155 group therapy 171 overview and principles 152–154

197

Interpersonal psychotherapy (IPT) (continued) perinatal psychiatric disorder trials postpartum depression acute treatment 158–162, 167, 170, 171 prevention 155–158 prepartum depression 163 prospects 164 perinatal social support impact on depression and anxiety 150–152 Intrauterine growth restriction (IUGR) attention deficit disorder risks 29, 34 behavioral disorder risks 34, 35 fetal programming of gene expression 30, 31 glucocorticoid role 29, 30 hippocampal effects 32–34 metabolic syndrome risks 28 neural development and fetal adversity 31–34 outcomes and variability 44 risk factors 28 Lactation, see Breast-feeding Lamotrigine, teratogenic effects 123 Light therapy depression management postpartum depression 189, 190 prepartum depression 189 seasonal affective disorder 188 principles 188 Lithium neonatal complications 122 teratogenic effects 121 Manualized group therapy for mothers with depression, see Group therapy for mothers with depression Massage anxiety and depression studies 186, 187 baby massage 186, 187 Metabolic syndrome, intrauterine growth restriction risks 28 Model Penal Code (MPC), insanity law 88, 89 Monoamine oxidase

Subject Index

estradiol effects 103 inhibitor safety in pregnancy 118, 119 progesterone effects 104 Mood disorders management in pregnancy 124–129 pregnancy 20, 21 Nefazodone, safety in pregnancy 119 Noradrenaline, estradiol effects 103 Obsessive-compulsive disorder (OCD) clinical features 19 ‘pathoplastic’ influence of early motherhood 170 Olanzapine, safety in pregnancy 126, 127 Oxytocin baby massage effects 186, 187 mental effects during breast-feeding 138 Panic disorder postpartum 19, 20 pregnancy 21 Posttraumatic stress disorder (PTSD), postpartum diagnostic classification 18, 19 frequency 18 hippocampal volume effects 33 historical perspective 2 predisposing factors 18, 19, 33 symptoms 18 treatment 19 Progesterone central nervous system effects 104 changes in pregnancy 101 Prolactin, mental effects during breast-feeding 138 Psychosis, postpartum diagnostic classification depression versus psychosis 16, 17, 22, 23 ICD-10 8 methodological problems 6, 7 specificity requirements consequences 13, 14 course 13 etiology 11–13 therapeutic needs 14–16

198

symptomatology 10 treatment delay 14 frequency 7, 10, 11 historical perspective 1 Psychosis, pregnancy 21 Psychosocial stressors, postpartum period 13, 168, 169 Psychotherapy, approaches 15 Quetiapine, safety in pregnancy 126, 128 Risperidone, safety in pregnancy 126, 127 Schizophrenia, management in pregnancy 124–129 Seasonal affective disorder (SAD), light therapy 188 Selective serotonin reuptake inhibitors (SSRIs) birth outcomes 113, 114 long-term neurodevelopment effects of prenatal exposure 129 neonatal complications 114–117 postpartum depression management in nursing women adverse effects 142, 144, 145 clinical decision-making 142, 143, 145 infant exposure quantification 139–142 studies 139, 140 spontaneous abortion risk 114 teratogenic effects 113, 119 Serotonin estradiol effects 103 exercise effects 184 transporter gene variants and infant behavior 35

Subject Index

Social support, perinatal support impact on depression and anxiety 150–152 Stress, see Behavioral perinatology; Hypothalamic-pituitary-adrenal axis Suicide, perinatal filicide 94, 95 frequency 94, 96, 97 infanticide-suicide 94–97 motivation 94, 95 risk factors 96 Topiramate, teratogenic effects 123 Touch therapy, anxiety and depression studies 186, 187 Trazodone, safety in pregnancy 119 Tricyclic antidepressants (TCAs) long-term neurodevelopment effects of prenatal exposure 129 neonatal complications 118 teratogenic effects 117, 118 Uncertainty principle, ethical question of antenatal clinical research 78 Valproic acid neonatal complications 122, 123 teratogenic effects 122 Venlafaxine, safety in pregnancy 119 Vulnerability-stress model, postpartum disorders 12, 14 Yates, Andrea 87, 88, 92–94 Yoga baby yoga 187, 188 depression studies 187

199