Nutrition and Health in Developing Countries (Nutrition and Health)

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Nutrition and Health in Developing Countries Edited by

Richard D. Semba, MD, MPH Martin W. Bloem, MD, PhD

HUMANA PRESS

NUTRITION AND HEALTH IN DEVELOPING COUNTRIES

NUTRITION 9

AND 9 HEALTH Adrianne Bendich, Series Editor

The Management of Eating Disorders and Obesity, edited by David J. Goldstein Vitamin D: Physiology, Molecular Biology, and Clinical Applications, edited by Michael F. Holick Preventive Nutrition: The Comprehensive Guide for Health Professionals, edited by Adrianne Bendich and Richard J. Deckelbaum

NUTRITION AND HEALTH IN DEVELOPING COUNTRIES Edited by

RICHARD D. SEMBA, MD, MPH Department of Ophthalmology, Division of Ocular Immunology, Johns Hopkins School of Medicine, Baltimore, MD

and

MARTIN W. BLOEM, MD, PHD Helen Keller International - Regional Headquarters, Jakarta, Indonesia

Foreword by NEVIN S. SCRIMSHAW, MD, PHD, MPH

HUMANA PRESS TOTOWA, NEW JERSEY

© 2001 Humana Press Inc. 999 Riverview Drive, Suite 208 Totowa, New Jersey 07512 All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise without written permission from the Publisher. All authored papers, comments, opinions, conclusions, or recommendations are those of the author(s), and do not necessarily reflect the views of the publisher. Production editor: Jason S. Runnion Cover design by Patricia F. Cleary. For additional copies, pricing for bulk purchases, and/or information about other Humana titles, contact Humana at the above address or at any of the following numbers: Tel.: 973-256-1699; Fax: 973-256-8341; E-mail: [email protected] or visit our website at http://humanapress.com This publication is printed on acid-free paper. ' ANSI Z39.48-1984 (American National Standards Institute) Permanence of Paper for Printed Library Materials. Photocopy Authorization Policy: Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Humana Press Inc., provided that the base fee of US $10.00 per copy, plus US $00.25 per page, is paid directly to the Copyright Clearance Center at 222 Rosewood Drive, Danvers, MA 01923. For those organizations that have been granted a photocopy license from the CCC, a separate system of payment has been arranged and is acceptable to Humana Press Inc. The fee code for users of the Transactional Reporting Service is: [0-89603-806-8/01 $10.00 + $00.25]. Printed in the United States of America. 10 9 8 7 6 5 4 3 2 1 Library of Congress Cataloging-in-Publication Data Nutrition and health in Developing countries / edited by Richard D. Semba and Martin W. Bloem. p.cm. Includes bibliograpical references and index. ISBN 0-89603-806-8 (alk. paper) 1. Malnutrition--Developing countries. 2.Nutrition--Developing countries. 3. Public health--Developing countries. I. Semba, Richard D. II. Bloem, Martin W. RA645.N87 N847 2001 613.2’09172’4--dc21

2001024072

DEDICATION To our parents, who struggled to bring a better life for the next generation: Hannah Semba and the late Thomas T. Semba, Japanese-Americans interned in the Tule Lake and Heart Mountain “relocation” camps, and Alexander and Jacqueline Bloem, Dutch-Indonesians and survivors of the Sumatra railway “work camp”, the Kramat camp, and the sinking of the Junyo Maru by the British submarine, HMS Tradewind, off the west coast of Sumatra.

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SERIES INTRODUCTION The Nutrition and Health series of books have, as an overriding mission, to provide health professionals with texts that are considered essential because each includes: 1) a synthesis of the state of the science, 2) timely, in-depth reviews by the leading researchers in their respective fields, 3) extensive, up-to-date fully annotated reference lists, 4) a detailed index, 5) relevant tables and figures, 6) identification of paradigm shifts and the consequences, 7) virtually no overlap of information between chapters, but targeted, inter-chapter referrals, 8) suggestions of areas for future research and 9) balanced, datadriven answers to patient /health professionals questions which are based upon the totality of evidence rather than the findings of any single study. The series volumes are not the outcome of a symposium. Rather, each editor has the potential to examine a chosen area with a broad perspective, both in subject matter as well as in the choice of chapter authors. The international perspective, especially with regard to public health initiatives, is emphasized where appropriate. The editors, whose trainings are both research and practice oriented, have the opportunity to develop a primary objective for their book; define the scope and focus, and then invite the leading authorities from around the world to be part of their initiative. The authors are encouraged to provide an overview of the field, discuss their own research and relate the research findings to potential human health consequences. Because each book is developed de novo, the chapters can be coordinated so that the resulting volume imparts greater knowledge than the sum of the information contained in the individual chapters. “Nutrition and Health in Developing Countries”, edited by Richard D. Semba and Martin W. Bloem represents, what I believe to be, the most comprehensive overview of the state of the field of international nutrition available to date. Both editors have extensive field as well as laboratory bench expertise; thus their in-depth knowledge of the interactions of nutritional status and its impact on global health provide them with the insights to biological as well as public health issues. Of equal importance, as leaders of this field, they have been able to include chapters by the world’s greatest experts. The editors have achieved their goal of providing readers with comprehensive chapters that are internally consistent in their style and format, that build upon the knowledge in prior chapters while educating the reader to better comprehend the information in subsequent chapters. Each author also provides an historic perspective as well as highlighting important areas for future research. This volume concentrates on five of the most critical questions in public health nutrition today. These questions include: who is affected and secondly what diseases are of greatest importance with regard to A) effects on nutritional status as well as B) effects of nutritional status on increasing the risk of disease acquisition? The editors have developed these sections so that readers, who are new to this area of nutrition, can begin with examination of the major health, and thus nutritionrelated problems seen in developing countries and the population groups most affected. These chapters include well-organized information on malaria, tuberculosis, HIV, measles, diarrhea, and lower respiratory tract infections and the populations at greatest risk for these adverse health conditions. Readers who are knowledgeable will also benefit from these and all other chapters because each contains well-organized tables and relevant figures and an extensive bibliography that helps to synthesize the complexities vii

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Series Introduction

inherent in the review of fifty or more years of research. Thirdly, what are the major nutritional deficits? Separate chapters are devoted to vitamin A, iron, iodine, zinc, multiple micronutrient deficiencies as well as overall macronutrient undernutrition. Next, there are critical reviews of the current and future scenarios that include the shifting importance between under and overnutrition (obesity), rural to urban shifts in populations, increased exposure to environmental hazards including pollution, food- and water borne contaminants and other factors that are affected by changes in socioeconomic factors. Finally, there are critical insights into the relevance of nutritional interventions in developing countries. The chapters include a systematic cost effectiveness analysis of intervention programs, two sensitive reviews of the difficulties of both implementing as well as then analyzing the effectiveness of nutrition programs. The concluding chapter places in perspective the multifaceted requirements to affect global policies, even in areas of agreement, such as the improvement of the nutritional status of individuals at greatest risk in developing countries. Nutrition and Health in Developing Countries, as the most comprehensive reference text in the field, provides health professionals at all levels of care as well as policy makers and program designers and implementers with balanced, referenced facts and data on which to base sound recommendations. This volume is of equal importance in the education of the next generation of health care professionals interested in improving global health, as nutrition remains the key to success. Adrianne Bendich, PhD GlaxoSmithKline, Parsippany, NJ

FOREWORD The most significant advance over the past two centuries has been the improvement in human health as judged by mortality rates, life expectancy and gains in height. Although this has been most dramatic in the industrialized countries, it has already extended to the more advanced developing countries and influenced even the most backward. Most of this improvement has been in mortality attributed to infectious diseases. It is not sufficiently recognized, however, that in Europe and other advanced regions in the past century most of the spectacular decreases in mortality from pneumonia, bronchitis, influenza, diphtheria and the other common communicable diseases of childhood occurred largely before the availability of vaccines and specific therapies. A thorough analysis of possible factors has led to the conclusion that improvements in nutrition were primarily responsible. In developing countries today most deaths attributed to diarrheal and respiratory disease would not have occurred in well nourished children. The classical nutritional deficiency diseases of scurvy, beri-beri, pellagra, and most recently kwashiorkor have also largely disappeared from the world. It is significant that these and other clinical nutritional disorders are usually precipitated by episodes of infectious disease superimposed on an already inadequate diet. This is a new kind of nutrition book. It not only examines all of the nutritional disorders prevalent in developing countries but also recognizes the synergistic interactions of nutrition and infections. It is quite appropriate that chapters deal with diarrheal diseases, acute respiratory infections, measles, malaria, tuberculosis, and human immunodeficiency virus infections. Other chapters explore major new problems for developing countries, that include the increase in chronic degenerative diseases, such as coronary heart disease, hypertension, and adult onset diabetes that are a consequences of growing affluence. These diseases will increasingly plague the developing countries in this century. Maternal, fetal, perinatal, and child nutrition issues are also well covered. A book is needed at the beginning of this new century that examines nutrition and health, past, present, and future in developing countries. This volume does so comprehensivel and authoritatively. It provides clear guidelines for improving nutrition and health in developing countries in the 21st century. It goes well beyond examining the epidemiology of acute and chronic nutrition-related disorders including infectious diseases. It also explores issues, urbanization, food, and nutrition security, the impact of nutrition and health programs, the economics of nutritional intervention, planning and policy development, and the nutritional and health significance of the epidemiological and demographic transition in developing countries. While improvements in health are to a major degree the result of social and economic development, they also contribute to further development by enabling populations to utilize better education and technology. Evidence is mounting that fetal and infant malnutrition can permanently affect cognitive performance and increase susceptibility to the chronic degenerative diseases of later life. Extending the improvements in nutrition, health and life expectancy in the industrialized countries during late 19th and 20th centuries to developing countries is a major challenge of the 21st century. Achieving peace within and among developing countries is another major challenge but as long as there are large differences in the health of populations, peace will continue to be elusive. ix

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Foreword

This volume is for all who are struggling with the nutrition and health problems of developing countries. At a time when their future generations are still being crippled by micronutrient deficiencies, by chronic undernutrition and by epidemic infections, these nations must also begin to deal with the consequences of nutritional excesses. The chapters of this book provide a better understanding of both the positive and negative changes in the determinants of health that these countries are experiencing in the 21st century. They represent a tour-de-force that contributes importantly to efforts to improve the nutrition and health of developing nations. Nevin S. Scrimshaw, PhD, MD, MPH Senior Advisor Food and Nutrition Program United Nations University Campton, NH

PREFACE Nutrition and Health in Developing Countries was written with the underlying conviction that nutrition is the main cornerstone of health in developing countries. Over three decades ago, an influential monograph by Nevin Scrimshaw, Carl Taylor, and John Gordon, entitled: Interactions of Nutrition and Infection, was published by the World Health Organization. The work highlighted the role of nutrition and immunity to infectious diseases and stimulated new investigation. Nutrition and Health in Developing Countries attempts to expand these lines of thought to integrate nutrition with health problems and infectious diseases in developing countries today. A further evolution has occurred in the conceptual framework of health and nutrition problems, and this includes an emphasis upon underlying factors, e.g., health services, environment conditions, and caring practices, and basic causes related to political and economic structures of society. These health and nutrition problems, in turn, impact the political and economic structures themselves, bringing the problem full circle. The objective of Nutrition and Health in Developing Countries is to provide policy makers, nutritionists, students, scientists, and professionals with the most recent and up-to-date knowledge regarding the major health and nutritional problems in developing countries. This specific knowledge is presented in order to facilitate an integrated approach to health research, programs, and policy. As such, the approach represents the tension inherent in combining diverse disciplines. This book is intended as a synthesis, and it is not meant as an exhaustive treatise of all infectious diseases or every nutrient deficiency in developing countries, as such information is generally accessible in tropical medicine and nutrition textbooks. The first part of this book emphasizes the major health problems in developing countries: maternal mortality, low birth weight, infant mortality, and child growth and development, diarrheal diseases, respiratory disease, measles, malaria, tuberculosis, and HIV/AIDS. These chapters include the epidemiology, prevention, and control of specific health problems, and they generally emphasize an integrated approach that includes nutrition. The second part of this book is concerned with specific nutritional topics and its role in different aspects of human health. There is a purposeful overlap between chapters on specific health problems and chapters on nutritional topics, for example, the role of zinc in diarrheal diseases. This approach was used to emphasize the different perspectives that may be taken, either from an infectious disease standpoint, for example, vs that from a specific nutrient. The third part of this book focuses upon the relationship of demographic changes with nutrition and approaches to solving nutrition and health problems on the policy level. Many individuals working in public health may be struck by conditions often found in developing countries today: high infant mortality rates, widespread malnutrition, tuberculosis, measles, and other health problems. However, similar conditions were faced by public health and policy makers about one hundred years ago in Europe and in the United States. The first chapter emphasizes a historical perspective on the approaches taken in the past to address specific problems of health and nutrition. For example, data in 1898 from Paris show that breast-feeding was strongly protective against diarrheal diseases compared with formula feeding (Chapter 1, Fig. 2). Would a greater awareness of such xi

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Preface

knowledge have prevented the scandalous debacle of formula feeding in Africa in the 1960s? This chapter traces the development of ideas and underlines the need to understand these past processes to avoid “reinventing the wheel,” a phenomenon apparent in some nutrition and health research in developing countries today. In 1987 in Nairobi, Kenya, the Safe Motherhood Initiative was launched, putting the much neglected problem of maternal mortality into the fore. Chapter 2 on maternal mortality emphasizes the quality of obstetrical care as its main underlying cause and calls for a convincing demonstration of the role of nutrition in maternal mortality. Maternal mortality remains one of the largest gaps in health between developing and developed countries. Low birth weight has been recognized as a major determinant of infant health, and maternal nutrition and the need for improved obstetrical care are highlighted (Chapter 3). Poverty, disease, and poor child growth and development are linked in a vicious cycle (Chapter 4). Diarrheal diseases and respiratory disease constitute a formidable challenge for infant and child health in developing countries, and a diversity of approaches is shown (Chapter 5 and 6). Nutrition is one important underlying factor to these problems, in addition to poverty, low education, crowding, and limited access to clean water and sanitation. Chapter 8 on malaria aims to dispel the misconception that nutrition plays little role in malaria infection. Recent data suggest that nutritional interventions may reduce the morbidity of malaria and enhance immunity to the parasite, and this is an active area of investigation. Despite a relatively effective vaccine, measles continues to affect an estimated 40 million children annually, and the importance of immunization, proper case management, and vitamin A supplementation are stressed (Chapter 7). Tuberculosis is undergoing a worldwide resurgence, and among the infectious diseases, tuberculosis is perhaps recognized as having a strong association with nutritional status (Chapter 9). The majority of individuals infected with human immunodeficiency virus live in developing countries, and addressing the HIV/AIDS epidemic remains one of the major problems in the setting of limited health resources (Chapter 10). Large advances have been made in our understanding of micronutrient malnutrition in the last two decades. Vitamin A deficiency is a major cause of childhood morbidity and mortality in many developing countries, and it is apparent that many diverse approaches will be needed to eliminate this problem (Chapter 11). New research suggests that zinc deficiency is widespread, and that zinc plays a major role in immunity to diarrheal and respiratory diseases (Chapter 12). Worldwide, iron deficiency is common among women and children (Chapter 13). The elimination of iodine deficiency disorders through the iodization of salt appears to be an attainable goal in the near future (Chapter 14). Many micronutrient deficiency disorders occur simultaneously, and the research and policy implications are discussed in Chapter 15. Malnutrition underlies a large proportion of childhood morbidity and mortality in developing countries, and approaches taken to this problem have evolved considerably in the last few decades (Chapter 16). With intermediate development, countries undergo what has been called the nutrition transition in which many nutritional deficiencies decline and other health problems, such as cardiovascular disease and diabetes, become more prominent (Chapter 17). Among these emerging health problems are obesity (Chapter 18). Among the pressing problems in many developing countries is that of rapid urbanization, e.g., Mexico City, Lagos, Dhaka, Jakarta, and Chapter 19 examines the challenges of obtaining food and nutrition security in these settings. Once nutrition and health programs have been designed,

Preface

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how would the impact of these programs be evaluated? Monitoring and evaluation of programs is an important tool to make programs more effective (Chapter 20). The cost effectiveness of nutritional interventions are presented in Chapter 21. A great challenge to policy makers in developing countries is that a multitude of competing needs usually exist simultaneously, and relative decisions must be made in the allocation of scarce resources. A broader view of health and nutrition policy and the complexities involved are discussed in Chapter 22. As editors, we are pleased to bring together this group of authors who come from diverse backgrounds of clinical nutrition, medicine, immunology, infectious disease, epidemiology, health policy, and economics. We hope that this book will stimulate further thought and research across disciplines in the goal of improving health and nutrition in developing countries. Richard D. Semba Martin W. Bloem

CONTENTS Dedication ...................................................................................................................... v Series Introduction ....................................................................................................... vii Foreword ....................................................................................................................... ix Preface ........................................................................................................................... xi Contributors ................................................................................................................ xvii 1

Nutrition and Development: A Historical Perspective .................... 1 Richard D. Semba

2

Maternal Mortality in Developing Countries ................................. 31 Carine Ronsmans

3

Low Birth Weight and Perinatal Mortality .................................... 57 Michael S. Kramer and Cesar G. Victoria

4

Child Growth and Development ..................................................... 71 Mercedes de Onis

5

Diarrheal Diseases .......................................................................... 93 Claudio F. Lanata and Robert E. Black

6

Acute Lower-Respiratory Infections ............................................ 131 Claudio F. Lanata and Robert E. Black

7

Measles .......................................................................................... 163 Gregory Hussey

8

Malaria ........................................................................................... 177 Anuraj H. Shankar

9

Tuberculosis .................................................................................. 209 Christopher Whalen and Richard D. Semba

10

Human Immunodeficiency Virus Infection .................................. 237 Richard D. Semba and Glenda E. Gray

11

Vitamin A Deficiency ................................................................... 267 Keith West, Jr. and Ian Darnton-Hill

12

Zinc Deficiency ............................................................................. 307 Roger Shrimpton

13

Iron Deficiency and Anemia ......................................................... 327 Ray Yip Iodine Deficiency Disorders ......................................................... 343 Richard D. Semba

14 15

Multiple Micronutrient Malnutrition: What Can Be Done? ........ 365 Usha Ramakrishnan and Sandra L. Huffman

16

Malnutrition .................................................................................. 393 Dirk G. Schroeder xv

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17

The Nutrition Transition and Its Relationship to Demographic Change ........................................................... 427 Barry M. Popkin

18

The Emerging Problem of Obesity in Developing Countries ...... 447 Colleen M. Doak and Barry M. Popkin

19

Rapid Urbanization and the Challenges of Obtaining Food and Nutrition Security .............................................................. 465 Marie T. Ruel, Lawrence Haddad, and James L. Garrett

20

Assessing and Communicating Impact of Nutrition and Health Programs ................................................................ 483 Saskia de Pee and Martin W. Bloem

21

The Economics of Nutritional Intervention ................................. 507 Susan Horton

22

Research and Policy Directions .................................................... 523 David Pelletier

Index ........................................................................................................................ 551

CONTRIBUTORS ROBERT E. BLACK, MD • School of Hygiene & Public Health, Johns Hopkins University, Baltimore, MD MARTIN W. BLOEM, MD, PHD • Helen Keller International, Jakarta, Indonesia IAN DARNTON-HILL, MD, MPH, MSC • Helen Keller International, New York, NY MERCEDES DE ONIS • World Health Organization, Department of Nutrition, Geneva, Switzerland SASKIA DE PEE, PHD • SPDC/NLNG Bonny Island - Nigeria, Den Haag, Netherlands COLLEEN M. DOAK • Department of Nutrition, University of North Carolina, Carolina Population Center, Chapel Hill, NC JAMES L. GARRETT, PHD • International Food Policy Research Institute, Washington, DC GLENDA GRAY, MBBCH , FCP • Perinatal HIV Research Unit, Maternity Hospital, Baragwanath Hospital, Soweto, South Africa LAWRENCE HADDAD, PHD • International Food Policy Research Institute, Washington, DC SUSAN HORTON, PHD • Department of Economics, University of Toronto, Toronto, Canada SANDRA HUFFMAN, SCD • Academy of Educational Development, Chevy Chase, MD GREG HUSSEY, MB, CHB, FFCH • Child Health Unit, Department of Pediatrics and Child Health, University of Cape Town, Rondebosch, Cape Town, South Africa MICHAEL S. KRAMER, MD • Department of Epidemiology & Biostatistics, Montreal, Quebec, Canada CLAUDIO F. LANATA, MD, MPH • Instituto de Investigacion Nutricional, Lima, Peru DAVID L. PELLETIER, PHD • Division of Nutritional Science, Cornell University, Ithaca, NY BARRY M. POPKIN, PHD • Department of Nutrition, Carolina Population Center, University of North Carolina, Chapel Hill, NC USHA RAMAKRISHNAN, PHD • Department of International Health, Rollins School of Public Health, Emory University, Atlanta, GA MARIE T. RUEL, PHD • International Food Policy Research Institute, Washington, DC CARINE RONSMANS, MD • London School of Hygiene & Tropical Medicine, Maternal & Child Epidemiology, London, UK DIRK SCHROEDER • Department of International Health, Rollins School of Public Health, Emory University, Atlanta, GA RICHARD D. SEMBA, MD, MPH • Johns Hopkins University School of Medicine, Baltimore, MD ANURAJ SHANKAR, PHD • Helen Keller International, Jakarta, Indonesia ROGER SHRIMPTON, PHD • UNICEF, New York, NY CESAR G. VICTORA, MD, PHD • Universidade Federal de Pelotas, Pelotas, Brasil CHRISTOPHER WHALEN, MD • Department of Epidemiology and Biostatistics, Case Western Reserve University, School of Medicine, Cleveland, OH KEITH WEST, JR., PHD • Division of Human Nutrition, Department of International Health, Johns Hopkins School of Hygiene & Public Health, Baltimore, MD RAY YIP, MD • UNICEF - China Office, Beijing, China

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Chapter 1 / Nutrition and Development: Historical Perspective

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Nutrition and Development A Historical Perspective

Richard D. Semba 1. INTRODUCTION In the last two centuries, there has been a general improvement in the health of people worldwide that has been attributed largely to changes in nutrition, hygiene, and public health. At the beginning of the 19th century, the burden of morbidity and mortality from infectious diseases such as malaria, cholera, measles, tuberculosis, and diarrheal disease, and nutritional deﬁciency diseases such as pellagra, rickets, and vitamin A deﬁciency, were relatively high in Europe, North America, and much of the rest of world. By the end of the 20th century, these diseases were largely eradicated from industrialized countries, but many of these diseases and their associated morbidity and mortality continue to be major problems in developing countries today. Mortality rates from infectious diseases have generally been declining in industrialized countries over the last 200 years, and improved nutrition and resistance to disease as well as better hygiene and sanitation have been cited as the main factors for a reduction in infectious disease mortality rather than technological advances in medicine (1–4). The purpose of this chapter is to provide a brief historical overview of major ideas and events that have shaped public health over the last two centuries, with an emphasis on developments related to nutrition and infectious disease. As a concise review, this chapter is limited to selected highlights from the last 200 years, and for a more detailed overview, the reader is referred to general texts on the history of public health (5–7), medicine (8), infectious disease (9,10), and geographical medicine (11), as well as to more specialized sources dealing with protein and energy (12), scurvy (13), pellagra (14), food (15–17), and hunger (18). Most of this review will focus on developments in Great Britain, the United States, and France, as these countries have drawn the most attention of historians of public health and nutrition.

2. THE IDEA OF PROGRESS IN PUBLIC HEALTH The idea of progress in public health largely rose during the Enlightenment in France among the philosophes such as Denis Diderot (1713–1784) and Jean le Rond From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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d’Alembert (1717–1783). Earlier antecedents were found in the methods of the French rationalist philosopher and mathematician René Descartes (1596–1650) (19). Diderot and d’Alembert edited the monumental Encyclopédie, ou Dictionnaire raisonné des sciences, des arts et des métiers, which was published between 1751 and 1772. The Encyclopédie, a major work of the Enlightenment, was meant to beneﬁt future generations with a compendium of human knowledge (20), and it included some issues relating to health, such as the duration of life, the health of infants, and growth of population. One of the greatest Encyclopedists was Marie-Jean-Antoine-Nicolas Caritat, Marquis de Condorcet (1743–1794), a French statesman, philosopher, and mathematician who wrote the Esquisse d’un tableau historique des progrès de l’esprit humain (Sketch for a History of the Progress of the Human Mind) (21). A critic of Robespierre and the Jacobins, Condorcet had been accused of treason and was sentenced in absentia to the guillotine. During a period of hiding in Paris in 1792, Condorcet wrote the remarkable Esquisse in which he argued for the inﬁnite perfectability of man. Condorcet predicted that there would be equality between men and women, the abolition of war, the end of colonialism and the slave trade, more equal distribution of wealth, and the eradication of disease through progress in medical science (21): “No one can doubt that, as preventive medicine improves and food and housing become healthier, as a way of life is established that develops our physical powers by exercise without ruining them by excess, as the two most virulent causes of deterioration, misery and excessive wealth, are eliminated, the average length of human life will be increased and a better health and a stronger physical constitution will be ensured. The improvement of medical practice, which will become more efﬁcacious with the progress of reason and of the social order, will mean the end of infectious and hereditary diseases and illnesses brought on by climate, food, or working conditions. It is reasonable to hope that all other diseases may likewise disappear as their distant causes are discovered” (22).

Condorcet’s work was published posthumously in 1795 and became a seminal work in the idea of progress in Western thought (19,23). The assumption that “the happiness of the human species is the most desirable object for human science to promote” was expressed by William Godwin (1756–1836) in An Enquiry Concerning Political Justice, and Its Inﬂuence on General Virtue and Happiness (24). Godwin noted the vast inequality in property and the role of political institutions in favoring these conditions, and he envisioned a future where intellectual and moral improvement and reform of government would reduce inequality, war, and injustice. According to Godwin, the perfectability of man was intrinsic to the human species, and political and intellectual state of man was presumed to be in a course of progressive improvement. Instead of indeﬁnite progress, Thomas Robert Malthus (1766–1834), a British economist, predicted overpopulation, misery, famine, and war, and his views ﬁrst appeared in an anonymous book, An Essay on the Principle of Population, as It Affects the Future Improvement of Society, with Remarks on the Speculations of Mr. Godwin, M. Condorcet, and Other Writers, which was published in 1798 (25). Malthus believed that the population was growing greater than the ability of the earth to provide subsistence. Preventive checks upon population included moral restraint, such as

Chapter 1 / Nutrition and Development: Historical Perspective

3

the postponement of marriage and avoidance of extramarital relationships. Later, Malthus was to concede that more personal and social action could prevent much of the grim scenario that he had predicted, and the debate about Malthus is frequently revived (26). A central idea of social medicine—an outgrowth of Enlightenment thought—was that government could use medical knowledge to improve the health of the people. A comprehensive social medicine approach was described by Johann Peter Frank (1745–1821), a German physician, in System einer vollständigen medicinischen Polizey (A System of Complete Medical Police) (27). Frank’s recommendations for sanitary, social, and economic reforms were broad, and based on the idea that medical police, a benevolent form of despotism, could provide for the health and protection of the people from cradle to grave. Frank was Director General of Public Health of Austrian Lombardy and Professor of Clinical Medicine at the University of Padua, and his social concerns are clearly stated in his graduation address De populorum miseria: morborum genitrice (The People’s Misery: Mother of Diseases) in 1790: “Starvation and sickness are pictured on the face of the entire laboring class. You recognize it at ﬁrst sight. And whoever has seen it will certainly not call any one of these people a free man. The word has become meaningless. Before sunrise, after having eaten a little and always the same unfermented bread that appeases his hunger only half- way, the farmer gets ready for hard work. With emaciated body under the hot rays of the sun he plows a soil that is not his and cultivates a vine that for him alone has no reward. His arms fall down, his dry tongue sticks to the palate, hunger is consuming him. The poor man can look forward to only a few grains of rice and a few beans soaked in water. And to this he can add only very sparingly the condiment with which nature has provided mankind in such a liberal way… Scarcity of food, however, and a quality of food that has no nutritional value make the citizens physically unﬁt for any sustained effort and predispose them for catching any matter of diseases. The weaker the organism and the more exhausted from troubles the human machine is, the sooner miasmas and contagions penetrate it like a dry sponge. Hence famine—sterility of the ﬁelds increased under an unfortunate constellation—is immediately followed by epidemics in the provinces” (28).

Among the myriad recommendations made by Frank in the System were that wells and springs used by the public should be examined regularly, and that rivers and ponds be kept clean and protected against sewage, industrial discharges, and refuse. The police were to be responsible for ensuring that an abundant and pure food supply was available, and observations were to be made whether certain kinds of foods eaten by different classes might predispose to serious ills or greater mortality. Frank also emphasized the importance of breastfeeding of infants. Although Frank’s work on “medical police” was considered somewhat outmoded by the time it was completely published, it was inﬂuential in setting a standard for broad approaches to public health (29). The underlying theme of this book—nutrition and health in developing countries—implies the prevailing model, which is inextricably tied to the parlance of “developing” and “developed” countries. This model for development implies that knowledge is cumulative and progress in nutrition and health generally proceeds in a linear fashion where the world is destined for improved nutrition, better health, more

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equity, and greater justice. Such precepts are implicit in the mission of large organizations such as the United Nations Children’s Fund, the World Health Organization, the United States Agency for International Development, the Overseas Development Agency, the World Bank, and the Food and Agricultural Organization.

3. THE RISE OF STATISTICS AND PROBABILITY The importance of keeping statistical records of health problems, including births, deaths, and other statistics relating to population, was emphasized by William Petty (1623–1687), an economist and physician, and John Graunt (1620–1674), a merchant, in England (30,31). In this early work on vital statistics, Graunt used detailed parish records to show the major causes of death, that mortality rates were higher in urban than rural areas, that more boys are born than girls, and that death rates varied by season (32). Early attempts to enumerate all births and deaths and determine total population were undertaken in Sweden in the middle of the 18th century, and other efforts were made in France and Holland (33). The use of “political arithmetic,” or “the art of reasoning by ﬁgures upon things relating to government” (34), continued into the 19th century. By 1836 the registration of births, marriages, and deaths had been made compulsory in England, and William Farr (1807–1883), a physician and compiler of abstracts in the Registrar General’s ofﬁce, became an advocate for social reform using statistics. Farr used life tables, an innovation introduced by the English astronomer Edmund Halley (1656–1742) (35), to show the relative health of districts, and infant mortality rates were used as a primary indicator of health (36). Better statistics would help improve health and assist in the efforts of preventive medicine, and Farr assigned a greater role in public health to physicians (37): “It has been shown that external agents have as great an inﬂuence on the frequency of sickness as on its fatality; the obvious corollary is, that man has as much power to prevent as to cure disease. That prevention is better than cure, is a proverb; that it is as easy, the facts we had advanced establish. Yet medical men, the guardians of public health, never have their attention called to the prevention of sickness; it forms no part of their education. To promote health is apparently contrary to their interests: the public do not seek the shield of medical art against disease, nor call the surgeon, till the arrows of death already rankle in the veins. This may be corrected by modifying the present system of medical education, and the manner of remunerating medical men. Public health may be promoted by placing the medical institutions of the country on a liberal scientiﬁc basis; by medical societies co-operating to collect statistical observations; and by medical writers renouncing the notion that a science can be founded upon the limited experience of an individual. Practical medicine cannot be taught in books; the science of medicine cannot be acquired in the sick room.”

Vital statistics were also examined by Adolphe Quetelet (1796–1874), a Belgian astronomer and mathematician, who showed that the distribution of observations around a mean could be expressed as the distribution of probabilities on a probability curve. In Sur l’homme et le développement de ses facultés, essai d’une physique sociale (On Man and the Development of his Faculties: An Essay on Social Physics), Quetelet investigated different aspects of “social physics,” such as birth and death, height and

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weight, health and disease. In this work he elaborated the important concept that the average man, or l’homme moyen, could be expressed mathematically (38). Statistics became the means to study the condition of the population, especially the working classes, and early Victorian Britain saw the formation of the Statistical Society of Manchester in 1833 and the Statistical Society of London in 1834 (39). Modern mathematical statistics arose largely from biometry in the late nineteenth century (40). Francis Galton (1822–1911), an English scientist and explorer of Africa, originated the concepts of regression and correlation, tools which were being developed to study heredity (41). Karl Pearson (1857–1936), a statistician at University College, London, continued to study the concepts of variation, correlation, and probability, and he introduced the term “standard deviation” in 1893 and deﬁned the correlation coefﬁcient mathematically in 1896 (42). Other important developments in statistics were the chi-square test in 1900, and the t-test and its distribution was deﬁned by W. S. Gosset (Student) in 1908 (43). Analysis of variance derives from a paper by Ronald A. Fisher (1890–1962), a British geneticist and statistician, in 1918. An important development in statistical methods was the integration of statistics with experimental design in The Design of Experiments by Fisher, in which the idea of randomization was promoted in experimental design (44). The idea of alternative hypotheses and two types of error was developed in the late 1920s (45) and was important in the determination of sample size and power calculations for experimental studies. The concepts of randomization, sample size and power, and placebo controls helped to reﬁne the controlled clinical trial as the basis for scientiﬁc evaluation of new therapies (46).

4. EARLY FOUNDATIONS OF PREVENTIVE MEDICINE The modern movement in preventive medicine and public health largely began in France in the ﬁrst half of the 19th century, largely inspired by the Enlightenment approach to health and disease (47,48). Louis René Villermé (1782–1863), used a numerical approach to show that there was a large gap in health between the rich and poor. Villermé was a former French army surgeon who was familiar with the psychological and social consequences of famine during the war (49). Shortly after leaving the military, Villermé showed in a large demographic study of Paris, Recherches statistiques sur la ville de Paris (Statistical Researches in the City of Paris), that mortality rates were highest in the poorest arrondissements, or districts, and lowest in the wealthy arrondissements (50). Thus, the differences between the rich and poor clearly extended far beyond ﬁnancial position into matters of life and death. Louis François Benoiston de Châteauneuf (1776–1862), a physician and contemporary of Villermé, showed that there were large differences in diet in Paris (51), and the differences in diet became incorporated into sociomedical investigations of mortality (52). According to Villermé (53), famine was followed by epidemics, and the poor were always hit the hardest by hunger and epidemics. He argued that a high state of civilization reduces epidemics and called for reforms so that people would be protected against the high price of food, which, for the poor, meant the same as famine. Some of Villermé’s and Benoiston’s work appeared in France’s ﬁrst journal of public health, Annales d’hygiène publique et de médecine légale, founded in 1829. In 1840, the appalling health conditions of textile workers were reported by Villermé (54), leading to a law the following year limiting child labor in France.

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In the kingdom of Naples, an important early survey was conducted in 1811 by the government of Joachim Murat (1767–1815) that addressed the relationship between nutrition and disease (55,56). In 1765, one year after a terrible famine killed thousands in the kingdom of Naples, Antonio Genovesi (1713–1769), a local leader of the Enlightenment, expressed the proto-Malthusian idea that an equilibrium exists between the population of the state and the availability of resources (57). An attempt was made to address such a relationship in a survey, which showed that there was widespread nutritional deprivation in the kingdom, especially in rural areas. In one area, famine was so common it was said that “tanto li contadini che li artieri pria degli occhi, aprono la bocca (upon awakening peasants and workers alike open their mouths before they open their eyes).” This survey was an early analysis of the mutual relationships among environmental, social variables, nutrition, and public health, and nutritional deprivation was identiﬁed as a main factor predisposing to disease (56).

5. THE SANITARY IDEA During the early industrialization of England, Jeremy Bentham (1748–1832), a writer on jurisprudence and utilitarian ethics, expressed the belief that laws should be socially useful and that actions should support “the happiness of the greatest number”(58). Edwin Chadwick (1800–1890), a follower of Bentham, became Secretary of the Royal Commission to investigate the Elizabethan Poor Laws, legislation from the early 17th century in which relief for the indigent was to be provided by the local parish, and employment of the poor was provided by workhouses. As the population grew, the problems of urban overcrowding and deterioration of food, sanitation, and housing became a major crisis by the 19th century. In 1842, Chadwick published Report on the Sanitary Condition of the Labouring Population of Great Britain which described the unsanitary living conditions among the poor (59). As in Villermé’s report, higher mortality was shown among the poorer classes than among the wealthy classes. The report recommended that the highest priority be given to practical measures such as drainage, removal of refuse, and improvement in the water supply, and it was emphasized that much disease among the poor could be prevented by public health measures. As Chadwick put it, “…all smell is disease” (60). Legislation followed in the wake of the report, including the British Public Health Act (1848), which established a general board of health, and legislation aimed at food adulteration, regulation of slaughterhouses and other trades, water supplies, and sewers. The sanitary movement in the United States largely echoed the efforts in France and England. In 1850 a major plan for public health, Report of the Sanitary Commission of Massachusetts, was presented to the government of Massachusetts state by Lemuel Shattuck (1793–1859), a teacher, bookseller, and genealogist (61). The report reviewed the sanitary movement abroad and in the United States, disease in the state of Massachusetts, and made recommendations for promotion of public health through creation of state and local boards of health, conduct of a regular census, better collection of vital statistics, improved sanitation, water, and housing, and other measures. The main basis for the report was that “…measures for prevention will effect inﬁnitely more, than remedies for the cure of disease.” Although Shattuck was unable to have many of the recommendations enacted into law immediately, the report was a harbinger for a comprehensive public health policy in the United States.

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The ﬁrst census in the United States by the federal government took place in 1790, and a nationwide census was decreed in the constitution to occur every 10 years (62). In Great Britain the ﬁrst nationwide census was undertaken in 1801, and periodic national censuses gained authority in France after 1840 (52). National registration systems and their vital statistics were used to bring attention to problems in public health in Europe, Great Britain, and the United States, and a greater need for accurate statistics was noted after the arrival of the worldwide cholera pandemics in the mid19th century (63).

6. CONTAGION VS MIASMA By the 19th century, epidemics of plague were gone from Europe, but other epidemic diseases such as scarlet fever, typhoid, typhus, and measles continued in outbreaks. Malaria was present in both Europe and the United States, and yellow fever was present in the south of the United States. Great pandemics of cholera swept large parts of the world in dates approximating 1817–1823, 1826–1837, 1846–1863, 1865–1875 (64), and later. The theory that epidemic disease was caused by miasmas rising from decaying organic matter was a dominant belief in the middle of the 19th century and a strong impetus behind the reforms of the sanitarians (6,9). Another major theory of epidemic disease was the contagionist theory in which an animate organism caused disease and was spread by person-to-person contact (65,66). Further credence to the contagionist theory was provided by epidemiological studies of measles, cholera, diphtheria, and typhoid fever. A measles epidemic affected the Faroe Islands in 1846, and a medical commission was sent by the Danish government to investigate. The commission included two Danish physicians who had just ﬁnished medical school, 26-year-old Peter Ludwig Panum (1820–1885) and 25-year-old August Henrik Manicus (1821–1850). In what is considered a classic study in epidemiology (9), Panum described the incubation period of measles and noted that transmission of measles was through person-to-person contact (67). He noted that measles attacked individuals of all ages, but those with a history of a previous attack of measles from a previous epidemic in 1781 were immune. Manicus observed that mortality was highest in a village that had the greatest poverty and poor diet, and he noted that diarrheal disease was mild among well-to-do islanders but was severe and persistent in the poorer villages (68). Both Panum and Manicus concluded that measles was contagious and not miasmatic in origin. Other studies that further may have changed perceptions about the contagiousness of disease was an investigation of cholera in London by John Snow (1813–1858), an English physician and anesthetist (69), and investigations of cholera by William Budd (1811–1880), a physician in Bristol. Budd thought that cholera was caused by a speciﬁc living organism that was found in the human intestinal tract and was spread through contaminated drinking water (70). During the cholera epidemic of 1854 in London, Snow demonstrated that the number of deaths from cholera was related to the amount of pollution from the Thames River among the different private companies supplying drinking water. Nearly all the victims had used water from the Broad Street pump in Soho. Snow concluded that cholera was carried in water contaminated by excreta of cholera patients, and that cholera was transmitted by ingestion of contaminated water and food and not through miasmata. Snow persuaded the local authorities to remove

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the handle from the Broad Street pump—presumably averting further deaths—but the epidemic was already in decline. The contamination of the Thames by sewage and industrial waste was acknowledged by a London Commission in 1828 and became the subject of satire (Fig. 1). The Metropolis Water Act of 1852 required London water companies to draw their water supplies from cleaner nontidal reaches of the Thames and to ﬁlter all water supplies for domestic use (71), and the cholera outbreak of 1854 occurred before all companies could comply with the 1852 act. The findings of Snow and Budd regarding the contagious nature of cholera did not lead to a sudden revolution in water science as has been generally believed (72,73), but these studies gave additional weight to the contagion theory. In the ensuing years, many international experts continued to hang on to the idea that miasmas were the cause of cholera (74). Other detailed investigations that reinforced the contagion theory of epidemic disease were those of diphtheria by Pierre Fidèle Bretonneau (1778–1862), a physician in Tours, France (75), and of typhoid fever by William Budd (76).

7. ADVANCES IN MICROBIOLOGY Further foundation for microbiological investigations were laid by Jacob Henle (1809–1885), a pathologist in Zurich, who thought that conclusive proof for an organism being responsible for a disease required three conditions: constant presence of the parasite, isolation from foreign admixtures, and reproduction of the disease with the isolated parasite (77). These postulates were further developed by his student, Robert Koch (1843–1910) (78). Louis Pasteur (1822–1895), a French chemist and microbiologist, further elaborated the germ theory of disease through broad studies that included the fermentation of beer and wine and diseases of silkworms. The last quarter of the 19th century was characterized by a rapid period of microbiological investigations, during which descriptions were made of the organisms responsible for anthrax (79), malaria (80), tuberculosis (81), and cholera (82). Other organisms including streptococcus, staphylococcus, Escherichia coli, leprosy, diphtheria, and Yersinia were described, and investigation was facilitated by the development of new staining techniques and culture media (5,65). Strategies to control infectious diseases by the turn of the century included reporting of cases, isolation of affected individuals, and disinfection of the premises. Compulsory notiﬁcation of infectious diseases was enacted in London, Berlin, and Paris within the last quarter of the 19th century (83). The ways in which diseases could be transmitted through contaminated water, ice, milk, and uncooked food was outlined by William Sedgwick (1855–1921), a biologist (84). In 1887, the ﬁrst systematic monitoring of the public water supply in the United States was conducted by Sedgwick for the Massachusetts Board of Health, and his techniques for measurement and ﬁltration of bacteria in the water supply became a standard for the country. In his inﬂuential treatise, The Sources of Modes of Infection (85), Charles V. Chapin (1856–1941), the Superintendent of Health in Providence, Rhode Island, emphasized the role of the carrier and further clariﬁed the idea that diseases could be transmitted through lack of hygiene, by direct and indirect contact, by fomites, through the air, in food and drink, and by insects.

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Fig. 1. A Monster Soup Commonly Called Thames Water, by William Heath (1795–1840), circa 1828. Philadelphia Museum of Art: Gift of Mrs. William H. Horstmann. Reproduced with permission.

8. NUTRITIONAL SCIENCE IN THE 19TH CENTURY Modern nutritional science has early roots in experimental physiology in France at the beginning of the 19th century, when ideas surrounding nutrition were subjected to examination by animal experimentation (86). François Magendie (1783–1855), professor of anatomy at the Collège de France, attempted to differentiate between various kinds of food and made a clear distinction between nitrogenous and nonnitrogenous foods (87). In an early experiment that hinted at the existence of vitamin A, Magendie found that dogs fed only sugar and distilled water developed corneal ulcers and died (88). The importance of nitrogenous foods was further recognized by Gerrit Jan Mulder (1802–1880), a Dutch physiological chemist, who coined the term “protein” to describe nitrogenous substances in plants and animal foods (89). The German chemist, Justus von Liebig (1803–1873) considered food to be divided into “plastic” foods (plant and animal proteins), and “respiratory” foods (carbohydrates and fat). Liebig’s main doctrine was that protein was used to build up the organism or repair tissues, whereas carbohydrates and fats served as fuels to facilitate the respiratory process (90). The deﬁnition of food was further reﬁned by Carl von Voit (1831–1908), a physiologist in Munich: “The foodstuffs are those substances which bring about the deposition of a substance essential to the composition of the body, or diminish and avert the loss thereof” (91). A former pupil of Voit’s, Wilbur Olin Atwater (1844–1907) conducted investigations into the caloric value of food using a bomb calorimeter and derived food and nutrient composition for an “average diet,” and the energy-yielding

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functions of food were emphasized (92). By the end of the 19th century, the prevailing notion was that food consisted of proteins, carbohydrates, fats, salts, and water. Improved nutrition was considered to strengthen resistance to disease, and Germain Sée (1818–1896), a French physician, made dietary recommendations for individuals with speciﬁc diseases (93). The inﬂuence of Liebig and Voit could be seen in some approaches; sufﬁcient nourishment was thought prevent “tissue waste” during a fever. Milk was given paramount importance as a dietary (94). Modern knowledge of nutrition was used to recommend diets for institutions such as schools, hospitals, prisons, and asylums. Special diets high in milk, whey, and egg yolk were recommended for certain diseases (95). In the early 20th century, inﬂuential textbooks in nutrition put heavy emphasis on the caloric value of food for human health (96,97).

9. INFANT MORTALITY AND SOCIAL REFORM In the late 18th century, infant mortality became the target of social reform in France, England, and the United States (98,99). A major cause of infant mortality was diarrheal disease, which often occurred in epidemic proportions during the summer in cities of England, Europe, and the United States. Using data from Paris (Fig. 2) and Finsbury, a poor area of Bedfordshire where he worked as medical ofﬁcer of health, George Newman (1870–1948), argued that breastfed infants suffered less from summer diarrhea than infants who were fed artiﬁcial formula or cow’s milk (100). The high infant mortality rate was considered to be mainly a problem of motherhood, and he emphasized proper training of mothers and promotion of breastfeeding. Newman argued that the infant mortality rate was gauge of health of a community, not the general death rate, and he considered it a sign of social degeneration that Great Britain should have a falling overall death rate but little change in the infant mortality rate over the proceeding 50 years. Arthur Newsholme (1857–1943), Newman, and others (101) implicated fecal contamination of food and milk in the epidemics of summer diarrhea (102). Similar concerns over infant mortality were voiced in Europe and the United States and led to the formation of national and international organizations devoted to the study and prevention of infant mortality, including the Ligue Française contre Mortalité Infantile (1902), the German Union for the Protection of Infants (1908), and the American Association for the Study and Prevention of Infant Mortality (1910). Among the measures sought by these groups were the education of mothers, the promotion of breastfeeding, improved prenatal care, and widespread gathering and compilation of vital statistics (98,99). Testing of the milk supply in large cities had revealed high bacterial counts in milk, and reform was aimed at providing a more pure milk supply through pasteurization (98).

10. THE EMERGENCE OF THE VITAMINS The late 19th and early 20th century was marked by the emergence of the vitamin theory and the characterization of the vitamins. Although descriptions of scurvy, beriberi, night blindness and keratomalacia, and rickets—manifestations of vitamin C, thiamin, vitamin A, and vitamin D deﬁciencies, respectively—and their empirical treatments are known in the older medical literature, it was not until the last quarter

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Fig. 2. Epidemics of diarrheal disease in Paris as described by Newman in 1906. Adapted from ref. (100).

of the 19th century that major progress commenced in the characterization of vitamins and vitamin-deﬁciency diseases. In the 19th century, beriberi was widespread in eastern and southeast Asia, and it was especially a problem for sailors on long voyages. In 1882, a Japanese naval vessel, Riujo, sailed from Japan to Honolulu via New Zealand and Chile, and after 272 days of navigation, 60% of the ship’s 276 crew members developed beriberi and 25 died (103). A Japanese naval surgeon, Kanehiro Takaki (1849–1920) (Fig. 3), conducted

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Fig. 3. Vessels involved in Navy research on beriberi by Kanehiro Takaki in the late 19th century.

epidemiological investigations of beriberi on different warships and examined clothing, living quarters, weather records, and rank. Takaki concluded that beriberi was related to the quality of food, particularly an insufﬁcient intake of nitrogenous foods. In 1884, he persuaded the Japanese government to provide additional meat and dry milk on a training ship, Tsukuba, which sailed the same route of the ill-fated Riujo. When the Tsukuba arrived in Japan 287 days later, there were a handful of cases of beriberi and no deaths. After Takaki’s dietary reforms were introduced, the cases of beriberi plummeted sharply in the Japanese navy (104,105).

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Fig. 4. Nicholai Lunin (1853–1937).

In 1886, Christiaan Eijkman (1858–1930), a Dutch army physician, was sent to the Dutch East Indies to investigate beriberi, which was generally thought at that time to be due to an unidentiﬁed bacterial infection. Eijkman demonstrated that chickens raised on polished rice alone developed a paralytic disorder similar to human beriberi and that this disorder could be corrected by a diet of unpolished rice. The bran portion of rice contained a substance which could prevent beriberi, and Eijkman originally thought that the polished rice contained a toxin that was neutralized by a substance in the bran portion (106). His colleague, Gerrit Grijns (1865–1944) believed that the disease affecting chickens and human beriberi were both due to an absence in the diet of a factor present in the rice polishings (107). From the time of the early experiments of Magendie, the contributions of several investigators over many decades helped to characterize vitamin A (108,109). Nicholai Ivanovich Lunin (1853–1937) (Fig. 4), working in the laboratory of Gustav von Bunge (1844–1920) at the University of Dorpat, determined that mice cannot survive on puriﬁed diet of fats, carbohydrates, proteins, and salts alone; however, he noted that mice could survive when milk was added. Lunin concluded “other substances indispensable for nutrition must be present in milk besides casein, fat, lactose, and salts” (110). Lunin’s conclusion was disseminated widely in von Bunge’s Lehrbuch

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der physiologischen und pathologischen Chemie (111). Another student performed experiments with simplified diets in mice and found that there was an unknown substance in egg yolk that was essential for life (112). At the University of Utrecht, Cornelius Pekelharing (1848–1922), conducted experiments that showed that mice are able to survive on diets in which small quantities of milk are added (113), and Wilhelm Stepp (1882–1964) showed that if the milk supplied to mice was extracted with alcohol-ether (thus removing the fat-soluble substance later known as vitamin A), the mice could not survive (114). The most explicit statement of the theory regarding the existence of vitamins came in 1906, when Frederick Gowland Hopkins (1861–1947), a biochemist at Cambridge University, who—on the basis of his own unpublished experiments and other observations—expressed the belief that there were “unsuspected dietetic factors” besides proteins, carbohydrates, fats, and minerals that were vital for health (115). In 1911, Casimir Funk (1884–1967) thought he had isolated the dietary factor involved in beriberi and coined the name “vitamine” for it (116). Further exposition of the vitamin theory came in 1912, when Funk presented that idea that beriberi, scurvy, and pellagra were all nutritional-deﬁciency diseases (117). Later in 1929, Eijkman and Hopkins jointly received the Nobel Prize for their early pioneering scientific research on vitamins (118). In the United States, Thomas Osborne (1859–1929) and Lafayette Mendel (1872–1935), working at Yale University, showed that a fat-soluble substance in butterfat was needed to support the growth of rats (119,120). After a period of illness, Hopkins published work he undertook in 1906–1907, which showed that mice could not survive on a puriﬁed diet without milk. Hopkins postulated the existence of what he called “accessory factors” in foods that were necessary for life (121). In studies with eggs and butter, Elmer McCollum (1879–1967), a biochemist at the University of Wisconsin, noted that their data “supports the belief that there are certain accessory articles in certain food-stuffs which are essential for normal growth for extended periods” (122). The “accessory factor” was later named “fat-soluble A” by McCollum, but it actually contained both vitamins A and D, leading to initial belief that “fat-soluble A” was responsible for rickets (123,124). In 1922, it was shown that cod-liver oil contained both vitamins A, an anti-xerophthalmic factor, and vitamin D, an anti-rachitic factor (125). Soon the term “fat-soluble A” was combined with Funk’s designation to become “vitamine A” and later “vitamin A.” The molecular structure of vitamin A was deduced in 1931 (126,127), and vitamin A was eventually crystallized in 1937 (128).

11. FURTHER RESEARCH ON NUTRITIONAL-DEFICIENCY DISEASES Pellagra, a syndrome characterized by dermatitis, diarrhea, dementia, and death, was described in Europe as early as the 18th century, and it was often ascribed to spoilt maize (129). With the rise of the germ theory of disease, it was thought that pellagra might also be attributable to an infection (130). In the early part of the 20th century, pellagra was increasingly recognized in the United States, especially in the South (131), and by 1916, it was second among the causes of death in South Carolina. Outbreaks of pellagra seemed to occur more commonly in asylums, jails, and poorhouses (132). The Pellagra Commission of the State of Illinois conducted investigations in 1911 and concluded that pellagra was attributable to an infection (133), and another investigation

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in South Carolina implicated poor sanitation (134). In 1914, Joseph Goldberger (1874–1929), a physician in the U.S. Public Health Service (135), conducted investigations of pellagra in South Carolina and showed that pellagra could be prevented by supplying milk, butter, and lean meat in the diet (136). Careful study showed that household ownership of a cow was protective against pellagra. Further investigations among prison volunteers revealed that pellagra could be produced by a restricted, mainly cereal diet (137). In later animal studies, niacin was implicated as the deﬁcient dietary factor involved in the etiology of pellagra (129). After World War II, a controversy erupted over whether protein deﬁciency was a major nutritional problem of developing countries (12). The syndrome of kwashiorkor—edema, wasting, diarrhea, and peeling of the skin—was described by Cicely Williams (1893—1992), an English physician, among children in the Gold Coast of West Africa (138). High mortality was noted among these children, and those affected appeared to be mostly one to four years old, weaned early, and fed entirely on white corn gruel. Initially it was thought that the condition related to a deﬁciency of B complex vitamins, but after the condition failed to respond to vitamins, it was considered a problem of protein deﬁciency. International efforts were focused upon closing the “protein gap” through high protein sources such as ﬁsh, soybean, and peanuts. Efforts to market an infant formula based on peanut ﬂour ended when it was discovered that under humid, tropical conditions, carcinogenic aﬂatoxins were produced by fungi growing in the ﬂour (139). The importance of calories was realized when children with kwashiorkor recovered upon eating foods with relatively low protein but high energy content (140), and the term “protein-calorie malnutrition” soon replaced “protein malnutrition” (141). Concern was raised that the problem of marasmus, which was more common owing to a decline in breastfeeding, was being relatively neglected (142). It was soon acknowledged that the “protein gap” was a myth; the chief problem in developing countries lay in a “food gap and an energy gap,” or an issue of “quantity rather than quality of food” (143).

12. NUTRITIONAL IMMUNOLOGY Nutritional immunology, the study of the relationship between nutrition and immunity, was a discipline that arose largely during the early 20th century. Although it had been observed over the centuries that famine would reduce an individual’s resistance to epidemic diseases, more speciﬁc clues were provided with the advent of animal experimentation using controlled diets. The recognition of speciﬁc vitamins and developments in immunology made it possible to study the effects of single or multiple vitamin deﬁciencies upon immune function. By the end of the 19th century, humoral antitoxic antibodies in the serum of immunized animals had been described, and this led to the development of serological tests involved in the diagnosis of infectious disease and measurement of immunological protection (144). Experimental infections were soon conducted in animals on controlled diets, and serological tests allowed assessment of the effect of dietary deprivation on immunity to infection. By the mid-1930s, animal studies suggested that deﬁciencies of some of the vitamins reduced resistance to infection (145–147). In the late 1920s, vitamin A was recognized to have an effect on immunity to infection, and vitamin A became known as the “anti-infective” vitamin (148). Largely

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Fig. 5. Edward Mellanby (1884–1955).

through the inﬂuence of Edward Mellanby (1884–1955), a professor of physiology at Shefﬁeld University (Fig. 5), vitamin A underwent a period of intense clinical investigation. Between 1920 and 1940, at least 30 trials were conducted to determine whether vitamin A could reduce the morbidity and mortality from infectious diseases, including respiratory disease, measles, puerperal sepsis, and tuberculosis (149). The paradigm that vitamin A could reduce morbidity and mortality was established by the 1930s. These trials were conducted prior to the time when many of the innovations known to the modern controlled clinical trial, such as randomization, sample size and power calculations, and placebo controls were widely known. The discovery of the sulfa antibiotics and their clinical applications soon overshadowed investigations of vitamin A as “antiinfective” therapy, and there was about a 50-year lull in clinical investigation of vitamin A as an intervention to reduce morbidity and mortality until the late 1980s (150). In 1950, a joint expert committee on nutrition of the Food and Agricultural Organization (FAO) and the World Health Organization (WHO) recommended that studies be made on the relationship of nutritional status to resistance against intestinal parasites. Further observations made in the ensuing decade suggested that many infectious diseases were associated with malnutrition. A WHO Expert Committee on Nutrition and Infection reviewed the issue of the interaction between nutrition and infection in

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1965, and a comprehensive monograph, Interactions of Nutrition and Infection, by Nevin Scrimshaw, Carl Taylor, and John Gordon appeared in 1968 (151). The effect of nutritional status on resistance to diarrheal and respiratory disease, viral, parasitic, and other infections was reviewed, and the present state of knowledge regarding the effects of speciﬁc micronutrient deﬁciencies on immune function was presented. The authors concluded: “Infections are likely to have more serious consequences among persons with clinical or subclinical malnutrition, and infectious diseases have the capacity to turn borderline nutritional deﬁciencies into severe malnutrition. In this way, malnutrition and infection can be mutually aggravating and produce more serious consequences for the patient than would be expected from a summation of the independent effects of the two.”

This seminal work served as the foundation for research on nutritional immunology in the last three decades of the 20th century. An important detailed review of the effects of single nutrients on immunity was made by William Beisel in 1982 (152). Tremendous advances in nutritional immunology have been made in the last 20 years, and many of these recent ﬁndings regarding the relationship between micronutrients and immunity to infection are presented elsewhere in this book.

13. GROWTH IN FOOD PRODUCTION In England, growth in food production from 1750 to 1880 was not seen not so much as owing to technological innovation as to increasing soil fertility and crop yield through manuring and sowing of legumes (153). Improved reaping machines appeared in the early 19th century, and cast iron replaced wrought iron and wood in many agricultural implements. Introduction of new fodder crops for winter feeding helped better animal husbandry. In France, railway construction considered to be a vital factor improving the agricultural economy in the mid-19th century, and animal breeding, crop rotation, and mechanization contributed to improve agricultural practice (154). In England, the better road transport increased the market for the dairy producer. Advances in the process by which ammonia could be produced from atmospheric nitrogen allowed more widespread use of fertilizers in the early 20th century (155). Increased mechanization with tractors, combined harvesters, automatic hay- balers, and seed and fertilizer drills has been noted between 1910 and 1950 in England, and advances in plant breeding brought new cereal and clover varieties (155). In the United States, technological advances in the plow, reaper, binder, and thresher aided the development of mechanized farming in the nineteenth century. Industrialized agriculture expanded in the beginning of the 20th century with the development of gasoline-powered tractors.

14. LONG TERM TRENDS IN DIET Available evidence suggests that the majority of the world’s population before 1800 consumed a diet that is below contemporary minimum standards of optimal nutrition (156). In France, the caloric intake of the average diet increased steadily during the 19th century, but the basic composition of the diet did not appear to change much until after about 1880 (157). Inspired by the French voluntary Caisses des Écoles, which

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fed hungry school children, charities were founded to feed children in England. The Victorian working-class diet was especially poor in quality and quantity (158). Near the end of the 19th century, over 1 in 10 children attending London schools were estimated to be habitually going hungry (159). Alarm was raised over the problem of inadequate nutrition when the report of the Inter-Departmental Committee on Physical Deterioration was published in 1904 (160). The committee showed that 40–60% of young men presenting for military service at the time of the South African War were rejected on medical grounds, and much of this physical inadequacy was attributed to malnutrition. This and other reports led to the Education (Provision of Meals) Act of 1906, which mandated national policy for feeding needy children at school. The number of London children receiving meals was about 27,000 in 1907 and by 1909 that number had doubled (161). When the Report on the Present State of Knowledge concerning Accessory Food Factors (Vitamines) appeared in 1919, it helped shape dietary recommendations based on newer knowledge of vitamins (162). The value of milk was emphasized by the report, and a study showed that provision of supplemental milk each day had better weight and height gain than those who were not supplemented (163). By 1945, about 40% of the school population was taking school meals and 46% were drinking school milk (161). An association between low socioeconomic level and inadequate diet was known in France (51) and England (164). In A Study of the Diet of the Labouring Classes in Edinburgh (1901), D. Noël Paton and his colleagues showed that many workers did not have the income to obtain a sufﬁcient supply of food and lacked the education to make correct choices of food (165). A discussion later followed in the British Medical Journal (166): Who is responsible for the conditions which lead to the state of poverty and bad nutrition disclosed by this report? Lies the fault with poor themselves—is it because they are thriftless, because they lack training in cooking and in the economical spending of such income as they possess? Or is it that the actual wages which they can command are so low that it is impossible for them to purchase the actual necessities of life?

Whether the problem lay with lack of education or inadequate income was unclear, and each side had its adherents (167). In 1936, John Boyd Orr (1880–1971) published Food Health and Income: Report on a Survey of Diet in Relation to Income, and this report created a sensation in England and was widely publicized around the world. This dietary survey suggested that the poorest of the poor, about four and one half million people, consumed a diet deﬁcient in all dietary constituents examined, and that the next poorest, about nine million people, had a diet adequate in protein, fat, and carbohydrates but deﬁcient in all vitamins and minerals (168). Only half the population surveyed had a diet that was adequate in all dietary constituents, including all vitamins and minerals. Although the per capita consumption of fruit, vegetables, and dairy products had greatly increased between 1909 and 1934 in Great Britain, there was clearly more that could be done to improve nutrition (168). Analysis of household budgets suggests that the average daily intakes of vitamin A, vitamin C, and thiamin were mostly inadequate in 1900 but increased to largely sufﬁcient intakes by 1944 among poor, working-class, and middle-class families in Great Britain (164). Long term analysis of nutritional status show that height grew in the United Kingdom between the mid-19th century through the years following World War II (169).

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In the United States, there have been large dietary changes over the last 200 years (17,170). In the early 19th century, many individuals did not consume adequate amounts of fruits, vegetables, and dairy products, and dietary deﬁciencies were not uncommon among rural and urban dwellers. From about 1830–1870, the mean stature of Americans had a prolonged decline, and this may possibly have been due to increased urbanization and poorer nutrition for urban workers during industrialization (171,172), and from the 1880s to the present, there has been a steady increase in stature. The apparent per capita consumption of dairy products increased in the United States between 1909 to 1930 (173,174). The discovery of the vitamins led to a greater awareness of nutrition, and the pharmaceutical and food industries promoted their products to mothers using a combination of fear, hope, and guilt (175). Fortiﬁcation of baker’s bread with thiamin, riboﬂavin, niacin, iron, and calcium became mandatory in 1943. When federal wartime legislation ended in 1946, many states continued to require the enrichment of bread (170). When George Newman, one of the primary architects of public health reform in Great Britain, wrote to a colleague in 1939, he reminisced about the “silent revolution” in Great Britain: [They]…who say I am an idealist and wild optimist do not know their history. How can one be otherwise who knew England and English medicine in 1895 and know it now? It is the greatest silent revolution in our time. The opportunity and the quality of human life has, as you truly say, been ‘transformed.’ They don’t know what ‘malnutrition’ means nowadays. Everybody is undernourished in some degree a way, but prevalent malnutrition is rare, whilst it used to be common (176).

In The Building of a Nation’s Health in 1939, Newman identiﬁed adequate nutrition as being one of the “most powerful instruments” of preventive medicine (177).

15. THE DECLINE OF MORTALITY In The Modern Rise of Population (1976), Thomas McKeown (1912–1988) showed that population grew in Europe since the mid-18th century, and he attributed the rise in population largely to a reduction in deaths from infectious diseases (1). The decline of infectious disease mortality was occurring prior to the identiﬁcation of speciﬁc pathogens, the widespread use of immunizations, the development of antibiotics, and the rise of sophisticated, technologically based clinical medicine (Fig. 6). Improved nutrition, greater food supplies, puriﬁcation of water, better sanitation, and improved housing are among the main factors cited in the reduction of infectious disease morbidity and mortality (2). A close interrelationship between nutrition, infection, and hygiene was acknowledged (2,3), and McKeown’s conclusions were primarily based upon observations of infectious disease mortality rates from the late 19th century and later. These views have become orthodox and inﬂuential in the debate regarding appropriate strategies for reducing mortality in developing countries, and scientiﬁc ﬁndings of the last 20 years from developing countries largely supports McKeown’s contention that nutritional status inﬂuences infectious disease morbidity and mortality. Others have disputed some of McKeown’s conclusions, citing evidence that the rise of population from the 16th century may have been primarily owing to an increase in fertility rather than decline in mortality (178), or that the relationship between nutrition and infection is “controversial” (179). There is little question that there has been a

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Fig. 6. Case fatality rates for measles, 1850–1970. Adapted with permission from McKeown (1).

general decline in mortality in Europe since the middle of the 17th century, but given the close relationship between socioeconomic level, education, housing, food, clean water, sanitation, and hygiene, it has been difﬁcult to separate out speciﬁc causal factors (180–182). During the same period there has been a probable reduction in exposure to pathogenic organisms through changes in man’s environment (4), and over the last 200 years, there has been a near disappearance of deﬁciency diseases that were once commonly reported in Europe, such as goiter, pellagra, rickets, and xerophthalmia (129,149,183). These deﬁciency diseases cause signiﬁcant morbidity and mortality but have been relatively neglected in historical demography.

16. GRADUATE EDUCATION IN PUBLIC HEALTH The early sanitary reform efforts in the 19th century were dominated by nonmedical personnel in the United States and Europe, as it was often seen as the responsibility of engineers, biologists, and chemists. The appointment of John Simon (1816–1904), a surgeon, to the head of the Medical Department of the Privy Council in 1854 was a visible sign of change where the public health system was dominated by the medical profession (184). New public health legislation created a need for qualiﬁed medical practitioners to serve as ofﬁcers of health, and programs offering a diploma in public health appeared in Dublin, Edinburgh, and Cambridge. In Vienna, the subjects of

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“Medical Police” and “Forensic Medicine” were combined under the designation of “State Medicine” at the Vienna Medical School (185). At ﬁrst, “Medical Police” was taught largely with emphasis on knowledge of ordinances and sanitary regulations in Austria, which were inﬂuenced by Frank’s Medicinische Polizey, but emphasis slowly changed to scientiﬁc investigation and sanitation after cholera and typhoid epidemics struck Vienna. Courses in public health were taught in some universities in the United States at the turn of the century, but schools of hygiene and public health were not created as a separate entity until the early 20th century. In 1916, the School of Hygiene and Public Health was established at the Johns Hopkins University with William H. Welch as its director (186) and the School of Public Health opened at Harvard University in 1922 (187). With endowment of the Rockefeller Foundation, the London School of Hygiene and Tropical Medicine opened in 1929. By 1925, the teaching of hygiene varied enormously, with institutes of hygiene established among medical faculty in Germany and Sweden, hygiene taught through bacteriology in France, and new schools of public health at Johns Hopkins, Harvard, and Pennsylvania in the United States (188). The number of universities with schools or programs of public health continued to grow in the United States, Great Britain, and Europe (189).

17. INTERNATIONAL ORGANIZATIONS Among the larger institutions involved in scientiﬁc research related to public health were the Institut Pasteur, the Lister Institute, the Rockefeller Institute, and the National Institutes of Health. The success of Pasteur in microbiological investigations and rabies immunization led to the establishment of the Institut Pasteur in Paris in 1888. The institute was a model for bacteriological research, and within a few years, other Pasteur Institutes were established in more than 40 places around the world. These institutes scattered around the globe were loosely knit and linked by ideology (190). The Institut Pasteur made major contributions to preventive medicine with new vaccines and therapies for infectious diseases (191). In 1891, the Lister Institute was established in London, and research on vitamins was a major part of the research program, with notable emphasis upon rickets (192). The Rockefeller Foundation established an International Health Commission in 1913, and the commission grew out of early efforts of the Rockefeller Sanitary Commission to eradicate hookworm in the southern United States (193). The International Health Division, or Health Commission, of the Rockefeller Foundation, expanded efforts to eradicate hookworm overseas, and during the 1920s the focus expanded to malaria, yellow fever, and tuberculosis (194,195). The Rockefeller Foundation helped to transform medical education in the United States and tended to emphasize a technological approach to medicine (196). The National Institutes of Health had its early roots in public health with the establishment of the Hygienic Laboratory of the Marine Hospital Service in 1887 (197). The laboratory was responsible for bacteriological work, including diagnosis of infectious diseases among immigrants. The scope of the laboratory increased with Progressive Era regulations such as the Biologics Control Act of 1902 and the Pure Food and Drugs Act of 1906. In 1912, the service became known as the U.S. Public Health Service, and among its activities were investigations of pellagra by Joseph

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Goldberger. The National Institute of Health was formally established by the U.S. Congress in 1930, and by 1948 it consisted of several institutes to become the National Institutes of Health (NIH) (198). Although the NIH had its roots in hygiene and public health, a shift occurred with the creation of the Communicable Disease Center (CDC) in Atlanta, Georgia in 1946. The CDC soon dealt with epidemics and other public health crises such as inﬂuenza outbreaks, polio surveillance, and measles eradication. International health organizations grew out of efforts to coordinate quarantines and control international epidemics such as cholera and plague. In 1907 the Ofﬁce International d’Hygiène Publique (International Ofﬁce of Public Health) was established in Rome, and the purpose of the organization was to collect and disseminate epidemiological information about smallpox, plague, cholera, and other diseases. The Health Organization of the League of Nations was created in 1923, and its activities included promotion of health, international standardization of biological tests and products, and control of disease. In 1948, the WHO was created after international ratiﬁcation, and it assumed the activities of the Health Organization of the League of Nations and other ofﬁces. The Pan American Sanitary Bureau became the regional ofﬁce of the WHO for Latin America in 1949, and in 1958 it changed its name to the Pan American Health Organization (PAHO). Treatment campaigns against yaws, smallpox eradication, oral rehydration therapy, and childhood immunizations were among the many achievements of the WHO since its inception. The United Nations International Children’s Emergency Fund (UNICEF) was created in 1946 by resolution of the United Nations General Assembly, and the purpose of UNICEF was to protect the well- being of children around the world. Early activities of UNICEF included shipments of powdered milk for children in Europe, vaccination efforts, support for vector control, and provision of equipment for maternal and child health centers (199). Milk powder—which required reconstitution through heating and rapid cooling reportedly had little impact on nutritional deﬁciency in rural Africa, because it proved too time-consuming for women to boil and cool milk in large cauldrons over a wood ﬁre in the face of other work in their ﬁelds (199). Most of UNICEF’s assistance in Africa in the 1950s went towards malaria eradication. By 1970, the focus of UNICEF moved away from milk and protein supplementation towards emphasis on improving community water supplies by installation of hand pumps and tube wells and an emphasis on primary health care. The Food and Agricultural Organization (FAO) was founded in 1945 in Quebec, Canada, with the purpose of raising the levels of nutrition and standards of living, securing improvements in the production and distribution of food and agricultural products, and improving the condition of rural populations (200). The ﬁrst director general of FAO was John Boyd Orr, who brought attention to the relationship between income and diet in England in the 1930s. The FAO, based in Rome, provides assistance for sustainable agriculture, promotes transfer of skills and technology in ﬁeld projects, offers advice on agricultural policy and planning, and fosters international cooperation on nutrition, biodiversity, and agricultural commodities. The World Bank originated with reconstruction efforts after World War II, when delegates from 44 nations met in Bretton Woods, New Hampshire, and drew up articles of agreement for the International Bank for Reconstruction and Development in 1944 (201,202). The mission of the World Bank shifted from reconstruction to development, especially for economically developing countries. World Bank loans to poor countries

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Table 1 Major Diseases in Europe, Great Britain, and the United States During the 19th Century Infectious diseases Diarrheal disease Cholera Malaria Yellow fever Tuberculosis Typhoid Typhus Measles

Nutrition deﬁciency disorders Rickets Pellagra Goiter/cretinism Nutritional blindness

in Africa and Asia increased under the tenure of the World Bank’s ﬁfth president, Robert McNamara. McNamara was aware of Alan Berg’s work on nutrition and health at the Brookings Institution, which later appeared in The Nutrition Factor (202,203), and a nutrition unit was created at the World Bank in 1972. The role of the Bank was to encourage development-oriented work rather than mass food distribution in developing countries, and such projects included identiﬁcation of populations at high risk for malnutrition, developing food subsidy programs, integrating nutrition assistance with primary care and family planning, nutrition education, promotion of home gardening, improving water and sanitation, and delivering micronutrient supplements (204).

18. CONCLUSIONS Over the last 200 years in most of Europe and the United States, there has been a major reduction in mortality rates, a virtual elimination of many infectious diseases, an improvement in diet, and virtual disappearance of nearly all nutritional deﬁciency disorders. Many of the so-called “tropical” diseases such as malaria, yellow fever, and cholera were once endemic or epidemic in industrialized countries and have now disappeared (Table 1). Case fatality rates for many infectious diseases dropped tremendously during the late 19th century and early 20th century. New knowledge of nutrition and the characterization of vitamins helped to improve the diet in the early 20th century, and innovations in agricultural practices helped to increase food production. After World War II, international organizations grew in strength and are addressing basic issues of nutrition, hygiene, and control of infectious diseases in developing countries. Nutrition has played a major role among the developments in public health during the last 200 years and is likely to remain as a major foundation for public health.

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96. Lusk G. The Elements of the Science of Nutrition. Philadelphia and London: W. B. Saunders, 1906. 97. Chittenden RH. The Nutrition of Man. New York, NY: Frederick A. Stokes, 1907. 98. Meckel RA. Save the Babies: American Public Health Reform and the Prevention of Infant Mortality, 1850–1929. Baltimore and London: Johns Hopkins University Press, 1990. 99. Klaus A. Every Child a Lion: the Origins of Maternal Infant and Health Policy in the United States and France, 1890–1920. Ithaca and London: Cornell University Press, 1993. 100. Newman G. Infant Mortality: A Social Problem. London: Methuen and Company, 1906. 101. Peters OH. Observations upon the Natural History of Epidemic Diarrhoea. Cambridge, UK: Cambridge University Press, 1911. 102. Eyler JM. Sir Arthur Newsholme and State Medicine, 1885–1943. Cambridge, UK: Cambridge University Press, 1997. 103. Shimazono N, Katsura E. Review of Japanese Literature on Beriberi and Thiamine. Kyoto: Vitamin B Research Committee of Japan, 1965. 104. Takaki K. Prevention of beriberi in the Japanese Navy. Se-i-kai Med J 1885; 4:29–37. 105. Takaki K. Three lectures on the preservation of health amongst the personnel of the Japanese Navy and Army. Lancet 1906; 1:1369–1374, 1451–1455, 1520–1523. 106. Eijkman C. Polyneuritis bij hoenderen. Geneesk Tijdschr nederl Indië 1890; 30:295–334; 1892; 32: 353–362; 1896; 36:214–269. 107. Grijns G. Over polyneuritis gallinarum. Geneesk Tijdschr nederl. Indië 1901; 41:3–110. 108. Steenbock H. A review of certain researches relating to the occurrence and chemical nature of vitamin A. Yale J Biol Med 1932; 4:563–578. 109. Wolf G, Carpenter KJ. Early research into the vitamins: the work of Wilhelm Stepp. J Nutr 1997; 127: 1255–1259. 110. Lunin N. Über die Bedeutung der anorganischen Salze für die Ernährung des Thieres. Zeitschr physiol Chem 1881; 5:31–39. 111. Bunge G von. Lehrbuch der physiologischen und pathologischen Chemie. Leipzig: FCW Vogel, 1887. 112. Socin CA. In welcher Form wird das Eisen resorbirt? Zeitschr physiol Chem 1891; 15:93–139. 113. Pekelharing CA. Over onze kennis van de waarde der voedingsmiddelen uit chemische fabrieken. Nederlandsch Tijdschr. Geneeskunde 1905; 41:111–124. 114. Stepp W. Experimentelle Untersuchungen über die Bedeutung der Lipoide für die Ernährung. Z Biol 1911; 57:136–170. 115. Hopkins FG. The analyst and the medical man. Analyst 1906; 31:385–404. 116. Funk C. On the chemical nature of the substance which cures polyneuritis in birds induced by a diet of polished rice. J Physiol 1911; 43:395–400. 117. Funk C. The etiology of the deﬁciency diseases. Beri-beri, polyneuritis in birds, epidemic dropsy, scuvy, experimental scurvy in animals, infantile scurvy, ship beri-beri, pellagra. J State Med 1912; 20: 341–368. 118. Needham J, Baldwin E, eds. Hopkins and Biochemistry, 1861–1947. Cambridge, UK: W. Hefner and Sons, 1949. 119. Osborne TB, Mendel LB. Feeding Experiments with Isolated Food-Substances. Washington, DC: Carnegie Institute of Washington, Publication 156, 1911 120. Osborne TB, Mendel LB. The relationship of growth to the chemical constituents of the diet. J Biol Chem 1913: 15:311–326. 121. Hopkins FG. Feeding experiments illustrating the importance of accessory factors in normal dietaries. J Physiol 1912; 44:425–460. 122. McCollum EV, Davis M. The necessity of certain lipins in the diet during growth. J Biol Chem 1913; 15:167–175. 123. Mellanby E. The part played by an “accessory factor” in the production of experimental rickets. J Physiol 1918–1919; 52:xi–xii. 124. Mellanby E. A further demonstration of the part played by accessory food factors in the aetiology of rickets. J Physiol 1918–1919; 52:liii–liv. 125. McCollum EV, Simmonds N, Becker JE, Shipley PG. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem 1922; 53:293–312. 126. Karrer P, Morf R, Schöpp K. Zur Kenntnis des Vitamins-A aus Fischtranen. Helv Chim Acta 1931; 14: 1036–1040.

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127. Karrer P, Morf R, Schöpp K. Zur Kenntnis des Vitamins-A aus Fischtranen II. Helv Chim Acta 1931; 14:1431–1436. 128. Holmes HN, Corbet RE. The isolation of crystalline vitamin A. J Am Chem Soc 1937; 59:2042–2047. 129. Carpenter KJ, ed. Pellagra. Benchmark Papers in Biochemistry, vol. 2. Stroudsburg: Hutchinson Ross, 1981. 130. Sambon LW. Progress report on the investigation of pellagra. J Trop Med Hyg 1910; 13:289–300. 131. Etheridge EW. The Butterﬂy Caste: A Social History of Pellagra in the South. Westport, CT: Greenwood, 1972. 132. Searcy GH. An epidemic of acute pellagra. Alabama Med J 1907; 20:387–392 133. Report of the Pellagra Commission of the State of Illinois, November, 1911. Springﬁeld, IL: State Journal Company, 1912. 134. Siler JF, Garrison PE, MacNeal WJ. The relation of methods of disposal of sewage to the spread of pellagra. Arch Intern Med 1914; 14:453–74. 135. Terris M, ed. Goldberger on Pellagra. Baton Rouge: Louisiana State University Press, 1964. 136. Goldberger J, Wheeler GA, Sydenstricker E. A study of the diet of nonpellagrous and of pellagrous households in textile mill communities in South Carolina in 1916. J Am Med Assoc 1918; 71: 944–949. 137. Goldberger J, Wheeler GA. Experimental pellagra in the human subject brought about by a restricted diet. Public Health Rep 1915; 30:3336–3339. 138. Williams CD. A nutritional disease of childhood associated with a maize diet. Arch Dis Child 1933; 8:423–433. 139. Orr E. The use of protein-rich foods for the relief of malnutrition in developing countries: an analysis of experience. London, Tropical Products Institute, 1972. 140. Pretorius PJ, Smith ZM. The effects of various skimmed milk formulae on the diarrhea, nitrogen retention and initiation of cure in kwashiorkor. J Trop Pediatr 1968; 4:50–60. 141. Jelliffe DB. Protein-calorie malnutrition in tropical preschool children. J Pediatr 1959; 54:227–256. 142. McLaren DS. The great protein ﬁasco. Lancet 1974; 2: 93–96. 143. Waterlow JC, Payne PR. The protein gap. Nature (London) 1975; 258:113–117. 144. Silverstein AM. A History of Immunology. San Diego: Academic Press, 1989. 145. Fox FW. Vitamin A and infection: a review of recent work. East Afr Med J 1933; 10:190–214. 146. Robertson EC. The vitamins and resistance to infection. Medicine 1934; 13:123–206. 147. Clausen SW. The influence of nutrition upon resistance to infection. Physiol Rev 1934; 14: 309–350. 148. Green HN, Mellanby E. Vitamin A as an anti-infective agent. BMJ 1929; 2:691–696. 149. Semba RD. Vitamin A as “anti-infective” therapy, 1920–1940. J Nutr 1999; 129:783–791. 150. Beaton GH, Martorell R, L’Abbe KA, Edmonston B, McCabe G, Ross AC, Harvey B. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries. ACC/SCN State-of-the-Art Nutrition Policy Discussion Paper No. 13, United Nations, New York, 1993. 151. Scrimshaw NS, Taylor CE, Gordon JE. Interactions of Nutrition and Infection. Geneva: WHO, 1968. 152. Beisel WR. Single nutrients and immunity. Am J Clin Nutr 1982; 35(suppl):417–468. 153. Chambers JD, Mingay GE. The Agricultural Revolution, 1750–1880. New York, NY: Schocken Books, 1966. 154. Price R. The Modernization of Rural France: Communications Networks and Agricultural Market Structures in Nineteenth-Century France. New York, NY: St. Martin’s Press, 1983. 155. Holmes CJ. Science and practice in English arable farming, 1910–1950. In: Diet and Health in Modern Britain. Oddy DJ, Miller DS, eds. London, Sydney, and Dover, New Hampshire: Croom Helm, 1985. 156. Aymard M. Toward the history of nutrition: some methodological remarks. In: Food and Drink in History. Forster R, Ranum O, eds. Selections from the Annales Economies, Sociétés, Civilisations, vol. 5. Baltimore and London: Johns Hopkins University Press, 1979, pp. 1–16. 157. Toutain JC. La consommation alimentaire en France de 1789 à 1964. Geneva: Droz, 1971. 158. Wohl AS. Endangered Lives: Public Health in Victorian Britain. Cambridge, MA: Harvard University Press, 1983.

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159. Buckley ME. The Feeding of School Children. London: G. Bell and Sons, 1914. 160. Great Britain. Inter-Departmental Committee on Physical Deterioration. Report of the InterDepartmental Committee on Physical Deterioration. 3 vols. London: Wyman and Sons, 1904. 161. Burnett J. The rise and decline of school meals in Britain, 1860–1990. In: The Origins and Development of Food Policies in Europe. Burnett J, Oddy DJ, eds. London and New York: Leicester University Press, 1994. 162. Medical Research Committee. Report on the Present State of Knowledge concerning Accessory Food Factors (Vitamines), Compiled by a Committee Appointed Jointly by the Lister Institute and Medical Research Committee. London: Her Majesty’s Stationery Ofﬁce, 1919. 163. Mann HCC. Diets for Boys during the School Age. Medical Research Council Special Report Series, No. 105. London: H. M. Stationery Ofﬁce, 1926. 164. Nelson M. Social-class trends in British diet, 1860–1980. In: Food, Diet and Economic Change Past and Present. Geissler C, Oddy DJ, eds. Leicester, London and New York: Leicester University Press, 1993; 101–120. 165. Paton DN, Dunlop JC, Inglis E. A Study of the Diet of the Labouring Classes in Edinburgh, Carried Out under the Auspices of the Town Council of the City of Edinburgh. Edinburgh: Otto Schulze, 1901. 166. Editorial. Diet of the labouring classes. BMJ 1913; 1:647. 167. Smith D, Nicolson M. Nutrition, education, ignorance and income: a twentieth-century debate. In: The Science and Culture of Nutrition, 1840–1940. Kamminga H, Cunningham A, eds. Amsterdam and Atlanta, Rodopi, 1995, pp. 288–318. 168. Orr JB. Food Health and Income: Report on a Survey of the Adequacy of Diet in Relation to Income. London: Macmillan, 1936. 169. Floud R, Wachter K, Gregory A. Height, Health and History: Nutritional Status in the United Kingdom, 1750–1980. Cambridge, UK: Cambridge University Press, 1990. 170. McIntosh EN. American Food Habits in Historical Perspective. Westport, CT and London: Praeger, 1995. 171. Fogel RW, Engerman SL, Trussell J. Exploring the uses of data on height. Soc Sci History 1982; 6: 401–421. 172. Lindhert PH, Williamson JG. Three centuries of inequality. In: Research in Economic History, vol. 1. Sedling P, ed. JAI, Greenwich, CT 1976; pp. 69–123. 173. U.S. Bureau of the Census. Historical Statistics of the United States, Colonial Times to 1970. Washington, DC: Government Printing Ofﬁce, 1975. 174. U.S. Department of Agriculture. Consumption of Foods in the United States, 1909–1952. Agricultural Handbook No. 62. Washington, DC: Government Printing Ofﬁce, 1953. 175. Apple RD. Vitamania: Vitamins in American Culture. New Brunswick, NJ: Rutgers University Press, 1996. 176. Newman G. Letter to Charles Flemming. July 28, 1939. [Collection of the author] 177. Newman G. The Building of a Nation’s Health. London: Macmillan, 1939. 178. Wrigley EA, Schoﬁeld RS. The Population History of England, 1541–1871. Cambridge, MA: Harvard University Press, 1981. 179. Livi-Bacci M. Population and Nutrition: An Essay on European Demographic History. Cambridge, UK: Cambridge University Press, 1986. 180. Tranter NL. Population and Society, 1750–1940: Contrasts in Population Growth. London and New York, NY: Longman, 1985. 181. Schoﬁeld R, Reher D, Bideau A, eds. The Decline of Mortality in Europe. Oxford: Claredon Press, 1991. 182. Corsini CA, Viazzo PP, eds. The Decline of Infant and Child Mortality. The European Experience: 1750–1990. The Hague: Kluwer Law International, 1997. 183. Hess AF. Rickets Including Osteomalacia and Tetany. Philadelphia: Lea and Febiger, 1929. 184. Fee E, Porter D. Public health, preventive medicine, and professionalization: Britain and the United States in the nineteenth century. In: A History of Education in Public Health. Health that Mocks the Doctors’ Rules. Fee E, Acheson RM, eds. Oxford and New York, NY: Oxford University Press, 1991, pp. 15–43. 185. Lesky E. The Vienna Medical School of the 19th century. Baltimore and London: Johns Hopkins University Press, 1976.

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186. Fee E. Disease and Discovery: A History of the Johns Hopkins School of Hygiene and Public Health, 1916–1939. Baltimore and London: Johns Hopkins University Press, 1987. 187. Curran JA. Founders of the Harvard School of Public Health, with Biographical Notes, 1909–1946. New York, NY: Josiah Macy, Jr. Foundation, 1970. 188. Flexner A. Medical Education: A Comparative Study. New York, NY: Macmillan, 1925. 189. Cottrell JD. The Teaching of Public Health in Europe. Geneva: WHO, 1969. 190. Moulin AM. The Pasteur Institutes between the two world wars. The transformation of the international sanitary order. In: International Health Organizations and Movements, 1918–1939. Weindling P, ed. Cambridge: Cambridge University Press, 1995, pp. 244–265. 191. Delaunay A. L’Institut Pasteur: des origines a aujourd’hui. Paris: Editions France-Empire, 1962. 192. Chick H, Hume M, Macfarlane M. War on Disease: A History of the Lister Institute. London: André Deutsch, 1971. 193. Ettling J. The Germ of Laziness: Rockefeller Philanthropy and Public Health in the New South. Cambridge, MA and London: Harvard University Press, 1981. 194. Farley J. The International Health Division of the Rockefeller Foundation: the Russell years, 1920–1934. In: International Health Organizations and Movements, 1918–1939. Weindling P, ed. Cambridge, UK: Cambridge University Press, 1995, pp. 203–221. 195. Cueto M. The cycles of eradication : the Rockefeller Foundation and Latin American public health, 1918–1940. In: International Health Organizations and Movements, 1918–1939. Weindling P, ed. Cambridge, UK: Cambridge University Press, 1995, pp. 222–243. 196. Brown ER. Rockefeller Medicine Men: Medicine and Capitalism in America. Berkeley: University of California Press, 1979. 197. Williams RC. The United States Public Health Service, 1798–1950. Washington, DC: Commissioned Ofﬁcers Association of the United States Public Health Service, 1951. 198. Harden VA. Inventing the NIH: Federal Biomedical Research Policy, 1887–1937. Baltimore and London: Johns Hopkins University Press, 1986. 199. Black M. The Children and the Nations: The Story of Unicef. Sydney: P.I.C. for Unicef, 1986. 200. Phillips RW. FAO: Its Origins, Formation and Evolution, 1945–1981. Rome: Food and Agricultural Organization of the United Nations, 1981. 201. Salda ACM. Historical Dictionary of the World Bank. Lanham, MD and London: Scarecrow Press, 1997. 202. Kapur D, Lewis JP, Webb R. The World Bank: Its First Half Century. Washington, DC: Brookings Institution Press, 1997. 203. Berg A. The Nutrition Factor: Its Role in National Development. Washington, DC: Brookings Institution, 1973. 204. Berg A. Malnutrition What Can be Done? Lessons from World Bank Experience. Baltimore: Johns Hopkins University Press, 1987.

Chapter 2 / Maternal Mortality

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Maternal Mortality in Developing Countries Carine Ronsmans

1. INTRODUCTION According to the latest estimates of the World Health Organization (WHO) and United Nations International Children’s Emergency Fund (UNICEF), 585,000 women still die every year from complications of their pregnancy, and nearly 90% of these deaths are in sub-Saharan Africa and Asia (1). Obstetric complications continue to represent the major cause among women of childbearing age, far ahead of tuberculosis, suicide, sexually transmitted diseases, or AIDS (2). Although developed countries have made enormous progress in bringing down the huge death rates associated with pregnancy, women in developing countries continue to face very high risks of death and disability as a result of pregnancy. The growing awareness of the continuing high rates of maternal mortality during the early 1980s led to the launch of the Safe Motherhood Initiative in Nairobi in 1987. After this “call for action,” governmental and nongovernmental organizations have joined forces to reduce the huge burden of maternal mortality in the world. Substantial progress has been made in documenting the extent of maternal ill health, and many of the groups involved have now embraced safer motherhood as among the highest priorities in public health practice. The recent Safe Motherhood Technical Consultation held in Sri Lanka in 1997 marked a decade of attention for Safe Motherhood and highlighted key strategies that may make pregnancy safer (2). The aim of this chapter is to review the evidence underlying the strategies that are proposed to reduce the huge burden of maternal mortality. It starts off by documenting the magnitude of maternal mortality while brieﬂy highlighting the problems associated with its measurement. After a review of the main factors known to contribute to maternal mortality, the strategies that have been proposed to reduce the high levels of maternal mortality in the world are discussed. This review explicitly focuses on the evidence linking maternal mortality with effective strategies, ignoring the fact that some of these strategies, although perhaps not proven effective to reduce maternal mortality, may have beneﬁcial effects on the health of the unborn child or the woman in general. In doing so, an incomplete picture of From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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intervention strategies to improve perinatal and women’s health in developing countries is presented. It is important, however, to separate the different entities, in order to gain a better understanding of what we can hope to achieve in reaching the goal of a reduction in maternal mortality in poor countries.

2. MAGNITUDE AND CAUSES OF MATERNAL MORTALITY 2.1. Measuring Maternal Mortality The measurement of maternal mortality is surprisingly complex. The factors that make maternal mortality difﬁcult to measure include: (1) the uncertainty about the precise time period during which pregnant women are at higher risk of adverse health effects, (2) the lack of insight into the causes of death that are indirectly attributable to the pregnancy, and (3) the under-reporting of pregnancy as a cause of death. In addition, the relative rarity of maternal deaths (in statistical terms) makes interpretation of trends in maternal mortality over time or between geographical areas very difﬁcult. Traditionally, a death is deﬁned as maternal if it occurs during pregnancy or within 42 d of its termination (3). The length of the postpartum period at risk has varied substantially however, and the 10th revision of the International Classiﬁcation of Diseases (ICD-10) now acknowledges the need for an extended time period referring to “late maternal deaths,” which occur after 42 d and up to 1 yr after delivery (4) (Table 1). Not all deaths during or shortly after pregnancy are owing to the pregnancy. Traditionally, deaths from direct and indirect obstetric causes have been included in the maternal mortality statistic, whereas deaths from accidental and incidental causes have not (Table 1). Deaths from direct obstetric causes such as eclampsia, hemorrhage, obstructed labor, or puerperal sepsis are undoubtedly attributable to the pregnancy, as such conditions can only occur in pregnant women. Far less certainty exists, however, with regard to indirect obstetric causes, particularly those owing to infectious diseases. The notion of “diseases aggravated by the pregnancy” is not straightforward, and some diseases may merely coincide with the pregnancy without being aggravated by it. In addition, the verbal autopsy methods on which most cause-of-death ascertainments are based may be unreliable, particularly for indirect causes of maternal death (5). In settings relying on verbal autopsy methods, all deaths in pregnant or recently delivered women are commonly included in the maternal mortality statistic (whether or not they are attributable to the pregnancy), except for deaths owing to unintentional and intentional injuries (5,6). The exclusion of deaths from accidents, homicides, or suicides from the maternal mortality statistic is a matter of controversy and there is a growing awareness that such deaths may, at least in part, be caused by the pregnancy (7,8). In Matlab, Bangladesh, 20% of deaths to pregnant unmarried women were owing to suicide compared to 5% for married women, and pregnant girls were nearly three times more likely to die from violent causes than nonpregnant girls (7,9). Studies in developed countries suggest that suicide may be precipitated by pregnancy and that some accidents may be pregnancy-related (8). Many pregnancy-related deaths still go unnoticed or unreported, and substantial errors in the estimates of maternal mortality persist (3,10). Correctly measuring maternal mortality not only requires a complete registration of deaths in women of

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Table 1 Deﬁnition of Maternal Mortality (ICD-10) Maternal death: The death of a woman while pregnant or within 42 d of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management, but not from accidental or incidental causes Late maternal deaths: The death of a woman from direct or indirect obstetric causes more than 42 d but less than one year after termination of pregnancy Pregnancy-related death: The death of a woman while pregnant or within 42 d of termination of pregnancy, irrespective of the cause of death. Direct obstetric deaths: Deaths resulting from obstetric complications of the pregnant state (pregnancy, labor, and puerperium), from interventions, omissions, incorrect treatment, or from a chain of events resulting from any of the above. They include conditions such as hypertensive diseases of pregnancy, hemorrhage, dystocia, genital tract sepsis, spontanuous or induced abortion. Indirect obstetric deaths: Death resulting from previous existing disease, or disease that developed during pregnancy and that was not owing to direct obstetric causes, but was aggravated by physiologic effects of pregnancy. Adapted with permission from ref. (4).

reproductive age, which in many countries may be lacking, but also the recognition that the woman was pregnant or recently delivered at the time of her death. Deaths during early pregnancy, such as those owing to abortion or ectopic pregnancy, are often not recognized or reported as pregnancy-related, and death certiﬁcates often omit the notion of pregnancy. The verbal autopsy techniques on which many cause of death assignments are based may have poor reliability (5). Maternal mortality is usually expressed in two different ways: the maternal mortality rate and the maternal mortality ratio. The rate is expressed as maternal deaths per 100,000 women of reproductive age. The maternal mortality ratio—sometimes erroneously called the maternal mortality rate—compared maternal deaths to the numbers of live births. The maternal mortality rate and ratio measure very different kinds of risks. The ratio measures the risk of death a woman faces with each pregnancy whereas the rate measures the risks to women, whether or not they are pregnant. The rate is in fact a compound measure of the level of fertility and the risks associated with each pregnancy. Any intervention lowering fertility will automatically lower the maternal mortality rate, but not necessarily the ratio (see Subheading 2.2.). As many assessments of progress in Safe Motherhood aim at separating the effects of lowering fertility from those directly aimed at improving the health of women once they are pregnant, the maternal mortality ratio has now become the preferred statistic (2). The problems in the measurement of maternal mortality are such that maternal mortality is not recommended anymore as an outcome measure against which to assess program successes (2). Although hopes were raised that morbidity would be a good alternative measure, it has proven very difﬁcult to measure the prevalence of maternal morbidity at the community level (11,12). In fact, very little is known about the incidence of obstetric complications in developing countries. The use of facilitybased data has now been suggested as alternative means to study program effectiveness, but experience with such indicators has so far been limited (13,14).

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Table 2 Estimates of Maternal Mortality by United Nations Regions (1990) Location

Maternal mortality ratio (maternal deaths per 100,000 live births)

Africa Asia Europe Latin America and the Caribbean Northern America Oceania

870 390 136 190 111 680

Adapted from ref. (4).

2.2. Medical Causes of Maternal Mortality In developing countries as a whole, maternal mortality ratios range from 190 per 100,000 live births in Latin America and the Caribbean to 870 per 100,000 in Africa (Table 2). In many countries of East, Central, and West Africa, maternal mortality exceeds 1,000 deaths per 100,000 live births. The main causes of maternal death have not changed over the last 20 years. The large majority of maternal deaths in developing countries are owing to ﬁve major direct obstetric complications: hemorrhage, infection, unsafe abortion, hypertensive disorders of pregnancy, and obstructed labor (2) (Fig. 1). Although huge variations are seen in the relative contribution of each of the direct obstetric causes to mortality, deaths from intra- or post-partum hemorrhage tend to be the leading cause of death, with about one-quarter of all deaths being attributed to severe bleeding. Estimates for deaths from unsafe abortion have varied substantially, but the consequences of illegal abortions may still be underestimated. Some authors have suggested that postpartum sepsis, a condition that carries a huge risk for the mother, may be declining in certain areas (5,15). Approximately 20% of maternal deaths worldwide are estimated to be owing to the so-called indirect obstetric causes, including anemia, cardiovascular diseases, and infections (2). Although there is no doubt that certain chronic diseases such as diabetes or cardiovascular disease or infections such as hepatitis are aggravated by the pregnancy, the common belief that the stresses of pregnancy lead to a breakdown of immune resistance, allowing infectious diseases to set in, is not always supported by strong epidemiological evidence (16). The widely acknowledged association between tuberculosis and pregnancy, for example, has been challenged recently and the authors conclude that tuberculosis is not associated with pregnancy (17). The association between HIV and pregnancy is under investigation, but a recent study suggests that pregnancy may not lead to HIV progression and death (18). Adverse effects of malaria during pregnancy on maternal health have been postulated, but the increased prevalence and density of malaria parasitemia in pregnant women are not necessarily associated with symptoms in the mother and their effect on maternal ill health is uncertain (19,20). In settings with low malaria transmission, on the other hand, severe malaria may be more common in pregnant than in nonpregnant women (21). Malaria may also increase the risk of maternal death through its effect on maternal anemia (22).

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Indirect causes (20%) Severe bleeding (25%) Infection (15%) Unsafe abortion (13%) Eclampsia (12%) Obstructed labour (8%) Other direct causes (8%)

Fig. 1. Main causes of maternal deaths.

Severe anemia is believed to be an important cause of maternal death in developing countries, although much of the evidence is circumstantial (23). Mild anemia in pregnancy may go unnoticed, but the potential adverse effects of pregnancy increase as hemoglobin levels fall. Very severe anemia with hemoglobin levels of less than 4 g/dL can lead to heart failure and death from shock (24). It has also been suggested that anemic mothers are less able to tolerate blood loss during childbirth, although this has never been empirically veriﬁed. Severe anemia in pregnancy has been reported as the main cause of 8–23% of maternal deaths in some hospitals and 11–16% in communitybased studies (25–27). In Tanzania, symptoms such as severe weakness, pallor, shortness of breath, and peripheral edema, which may be suggestive of anemia, were present in nearly half of maternal deaths (27). In a hospital study in Western Kenya, reproductive age women with hemoglobin levels below 6 g/dL were eight times more likely to die than women with a hemoglobin level of more than 6 g/dL (28). In a multivariate analysis, severe anemia and HIV status were signiﬁcant predictors of mortality, whereas pregnancy status was not. In other words, severe anemia carries a huge risk of death for women of reproductive age, but pregnancy may not aggravate that risk.

3. STRATEGIES TO REDUCE MATERNAL MORTALITY The strategies that have been promoted as potentially effective ways to overcome the high rates of maternal mortality have been multiple, and substantial changes have occurred over the last 30 years. Initial efforts since the 1950s have focused on prenatal clinics and maternal education, followed by an emphasis on family planning (13). In the 1970s, training and promotion of traditional birth attendants were introduced, whereas the 1990s were dominated by an emphasis on increased access to and quality of obstetric care. More recently, a new magic bullet has been introduced, namely, the nutritional supplementation of pregnant or reproductive-age women. Relatively few of the strategies proposed over the last 30 years have involved the medical profession directly, as interventions such as family planning or prenatal care were thought to be deliverable by community health workers. Many of the suggested strategies were modeled after the experience with child survival programs, and the

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desire for ﬁnding so-called cheap and community-based interventions has left many of the interventions unchallenged for long. Only in 1991, when Maine et al. (29) published their inﬂuential work using evidence from the Kasongo study, did the emphasis shift to the importance of professional delivery care. Ensuring skilled medical attendance at delivery has now become the leading goal for maternal health programs (2). In reviewing the evidence in support of certain strategies, it must be borne in mind that there is very little direct evidence linking maternal health interventions to maternal mortality. The absolute numbers of maternal deaths are generally small, and large populations are needed to investigate the determinants of maternal mortality. For this reason, evidence from randomized controlled trials, the gold standard in health care evaluations, is seldom available to those trying to understand the strategies underlying maternal-mortality reductions. Our knowledge so far is based largely on historical precedent in Western countries, and on so-called “thought experiments” (30).

4. SOCIOECONOMIC DEVELOPMENT, WOMEN’S EDUCATION, AND MATERNAL MORTALITY There is no doubt that the poorest countries suffer the highest burden of maternal mortality. The maternal mortality ratio is often quoted as the statistic that most clearly highlights the huge gap between developed and developing countries. The women’s life-time risk of maternal death is almost 40 times higher in the developing than in the developed world; and the highest maternal mortality ratios of 1,000 per 100,000 live births found in some regions of Eastern and Western Africa are as much as 100 times higher than those observed in some Western countries (2). Yet the relationship between high levels of maternal mortality and poverty is not straightforward. When De Brouwere and colleagues (13) mapped the maternal mortality ratios by gross national product (GNP) per capita for countries with a GNP per capita below US $1000 in 1993, the estimates ranged from 22 to 1,600 per 100,000 without any clear association with the level of economic development (Fig. 2). Countries with a similar GNP per capita such as Vietnam, Uganda, and Burundi (US $170–180), for example, had maternal mortality ratios of 160, 1,200, and 1,300, respectively. Similarly, Loudon (31) in his excellent review of historical trends in maternal mortality in western countries, could not explain the huge differences in the levels of maternal mortality between the U.S., England, and Wales, and the Netherlands in the earlier part of this century by differences in the social or economic context prevailing at that time in each of these countries (Fig. 3). In the 1920s, the United States experienced maternal mortality ratios as high as 689 per 100,000 live births, a ﬁgure not unlike many developing countries today. The Netherlands, in contrast, had already reached levels as low as 242 deaths per 100,00 live births, while England and Wales were at an intermediary level of 433. Loudon (31) remarks that, “Maternal mortality, unlike infant mortality, was remarkably insensitive to social and economic factors per se but remarkably sensitive to standards of obstetric care.” The relationship between women’s education and maternal mortality has also been called into question. Harrison (32,33) has repeatedly called on the international community to reinforce the importance of women’s education because of its possible effect on maternal health. In a review of 22,774 hospital births in Zaria, Northern Nigeria, Harrison (32) found that the levels of maternal mortality were lower in edu-

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Fig. 2. Maternal mortality ratios by gross national product (GNP) per capita for countries with GNP <$1000 US. Adopted with permission from (13).

Fig. 3. Maternal mortality in the Netherlands, England, and Wales, and USA, 1990–1950. Adapted with permission from ref. (31).

cated that in uneducated women, and he suggested that the relationship might be causal. However, as health facilities were under-used by the uneducated, a spurious relationship because of the underselection of normal deliveries among the uneducated

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cannot be ruled out. In China, maternal deaths belonged to families with lower monthly income, and were more likely to be illiterate, than pregnant controls (34). A study conducted in Addis Ababa, on the other hand, found no clear associations with either the level of education of the woman or her husband’s income, but the sample size was very small (35). In Matlab, Bangladesh, the absence of an association between maternal schooling and maternal mortality sharply contrasts with the strong associations found for child mortality (36). Women’s education is a human right, and the ﬁght against illiteracy remains one of the key priorities for improving the social and health situation of women. Education of mothers has been convincingly shown to increase the health of children (37), and the uptake of reproductive health interventions such as family planning is certainly enhanced if women are educated. Educating women, however, has not been shown to directly affect maternal health.

5. FAMILY PLANNING AND MATERNAL MORTALITY During the 1980s, family planning was presented as one of the key strategies for maternal mortality reduction in developing countries (24,38). If accepted by a large proportion of the population, and if used continuously for prolonged periods, contraceptive methods should, at least in theory, contribute to lowering the high levels of maternal mortality. Family planning may prevent unwanted pregnancy (and illegal abortion), redistribute births from high- to low-risk categories, reduce the total number of births, and have direct beneﬁts from the contraceptive methods themselves (39). Yet various reports examining the potential impact of family planning on the reduction of maternal mortality have suggested disappointing effects (39,40). There is no doubt that widespread use of contraceptives will reduce the total numbers of maternal deaths and hence lower the maternal-mortality rate, as fewer women will be exposed to the risks of pregnancy. However, the effects on the maternal-mortality ratio, that is, the risk of death once a woman is pregnant, are thought to be minimal (39–41). The vastly lower mortality ratios in the developed world when compared to developing countries cannot be attributed to changes in the demographic distribution of births (31,39). A study in Bangladesh has also convincingly shown that although increased use of contraceptives was associated with a steady decline in the maternal mortality rate, no such effects were observed for the maternal-mortality ratio (12,42). Declines in the maternal mortality ratio were thought to be associated with increased access to obstetric care (12,43). There is considerable evidence that the extremes of maternal age affect the risk of dying in pregnancy, and studies generally also conﬁrm the excess risk of ﬁrst births and births of higher order (39,44). What is less clear is whether age and parity act independently of one another, nor whether the effects persist after taking into account the possible confounding effect of socioeconomic status. At very young ages the growth of the bony pelvis is immature, and childbearing in girls less than 16 yr old has been shown to carry huge risks (32). Experiences from industrialized countries however suggest that pregnancies in very young girls may be only marginally more risky that in older women (45,46). In a review article, Zimicky (44) concludes that, “while the evidence is suggestive rather than conclusive, it seems that ages below 20 and above 30 enhance the simple parity-speciﬁc patterns.”

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Eliminating births to very young, old, or high-parity women will not have a major impact on the survival chances associated with pregnancy (39,40). Although the risks of maternal death tend to be highest in the extremes of reproductive performance, most births—and by consequence maternal deaths—occur in the low-risk groups. Moreover, ﬁrst births are generally at highest risk, and family-planning programs, by inducing a relative shift from high-parity, high-risk groups to ﬁrst-birth, high-risk groups, will have little effect on the overall level of maternal mortality. The widely held view that short birth intervals affect the risk of maternal death has never been empirically conﬁrmed (36,44). The results of a large, nested case-control study from Matlab, Bangladesh did not ﬁnd an association between the preceding birth-to-conception interval and the risk of maternal mortality (36). A detailed scrutiny into biologically plausible arguments in favor of such an association also failed to provide compelling evidence favouring an effect of birth-interval length on maternal mortality.

6. NUTRITION AND MATERNAL HEALTH During pregnancy, growth of the fetus and the uterus induce an increase in the demand for energy and many nutrients, including iron, folic acid, calcium, vitamin A, and zinc. In chronically malnourished populations, micronutrient supplementation appears attractive as a potential intervention to reduce maternal and fetal mortality because it is believed to be cheap, safe, and easier than the more fundamental changes in society that may be required. Widespread appeals for the promotion of micronutrient supplementation of pregnant or reproductive age women have been made, and some agencies have incorporated supplementation strategies in their policy agenda (47,48). This section analyses the evidence linking energy and micronutrient deﬁciencies with an increased risk of maternal mortality. As very few studies have been able to explore such direct links, efforts are made to explore the potential for energy and micronutrient deﬁciencies to reduce life threatening maternal complications.

6.1. Direct Effects of Energy or Micronutrient Deﬁciency on Maternal Mortality Recent reviews of evidence from randomized controlled trials provide very little support for a direct link between micronutrient deﬁciencies in the mother and her risks of dying in pregnancy (49–51). There is at present no evidence of beneﬁt from routine zinc, calcium, iron, or folate supplementation during pregnancy in reducing the mortality risks associated with pregnancy. The authors do point out however, that few studies were done in communities with micronutrient deﬁciencies, and that most trials were not sufﬁciently large to draw meaningful conclusions with regard to effects, beneﬁcial or harmful, on maternal mortality. Recently published results from a large randomised, double-blind placebo-controlled trial of vitamin A and `-carotene in Nepal suggest that vitamin A and/or `-carotene may be associated with a 40% reduction in maternal mortality (6). The trial was wellconducted and involved the supplementation of more than 40,000 women of reproductive age with weekly doses of either placebo, vitamin A (7000 µg retinol equivalents) or `-carotene (42 mg or 7000 µg retinol equivalents). Causes of death were ascertained using verbal autopsy methods. The investigators observed a reduction in mortality

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Fig. 4. Effect of vitamin A or `-carotene on maternal mortality. Adapted from ref. (6).

during pregnancy and within 12 wk after delivery from 704 deaths per 100,000 live births in women receiving placebo to 426 and 361 deaths per 100,000 live births in the vitamin A and `-carotene group respectively (Fig. 4). The authors suggest that, “raising the intake of preformed vitamin A or provitamin A carotenoids towards the values recommended for pregnancy or lactation, presumably by supplementation or by dietary means, can complement prenatal and essential obstetric services in lowering maternal mortality in rural South Asia.” An accompanying editorial suggests that further work is needed before putting the ﬁndings of this trial into practice (52). Methodological difﬁculties (particularly loss to follow-up), the fact that the effect was most pronounced in the group of causes least likely to respond to supplements (deaths from injuries), and the possible teratogenic effects of vitamin A supplementation lead the author to conclude that further evaluation of beneﬁts and possible hazards is needed before the ﬁndings can be translated into policy. In addition, the study leaves us uncertain whether the appropriate intervention is vitamin A or `-carotene, whether it should be delivered before conception or prenatally, and whether it is feasible for programs to administer supplementation weekly (53). Given these uncertainties, it is rather astonishing that certain agencies have already opted for the supplementation of pregnant women with vitamin A during prenatal care (48). Historical data from Western countries do not provide compelling evidence that the general health status of women affects their risk of dying in childbirth. Loudon (31) was puzzled by the paucity of evidence showing that an improvement in the health of the mothers reduced maternal mortality in Western countries. Although the standard

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Fig. 5. Infant and maternal mortality in England and Wales, 1900–1980. Partially based upon ref. (31).

of living rose throughout Britain after 1880, and although Loudon regarded the health of mothers as a key determinant of the level of maternal mortality, he could ﬁnd no evidence supporting such an association. The sharp contrast between the trends in infant and maternal mortality between 1900 and 1980 in England and Wales provide very useful insights (Fig. 5). Infant mortality rates, which were widely believed to be associated with increased living standards and improved nutrition, declined steadily throughout that period. The maternal-mortality ratios, on the other hand, remained high until 1940, and declined sharply thereafter. Pantin (54), on the other hand, suggested that the declines in maternal mortality on the Isle of Man before 1911 may have been attributable, at least in part to improved maternal health. In the absence of strong evidence of a direct link between nutritional deﬁciencies and maternal mortality, the next step is to search for evidence of a link between nutritional deﬁciencies and obstetric complications. The associations that merit attention include: (1) malnutrition and obstructed labor, (2) calcium deﬁciency and pre-eclampsia, (3) iron

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deﬁciency and anemia, (4) vitamin A deﬁciency and anemia or infection, and (4) zinc deﬁciency and hemorrhage or infection.

6.2. Malnutrition and the Risk of Obstructed Labor The association between short stature and an increased risk of cephalo-pelvic disproportion is well-established (55,56). In a review of 14 studies, WHO found that women in the lowest quartile of height had a 60% higher risk of assisted delivery than women in the top quartile, and the ﬁndings were consistent across study sites (56). Although assisted delivery does not always equate to cephalo-pelvic disproportion, it is probably a good marker for dystocia in settings where Caesarean sections are only done in extreme circumstances. The nature of the effect appears to be relative rather than absolute in that, whatever the average height of the population of women, the lowest tenth percentile is always at higher risk (55). The conventional cut-off for low height of 150 cm, for example, does not hold true in the Bangladeshi population, where half of the women are below that cut-off, yet only women shorter than 140 cm are at increased risk of prolonged labor (57). The WHO meta-analysis did not ﬁnd evidence for an association between poor anthropometric measurements such as mid-upper-arm circumference, pre-pregnancy weight or body mass index (BMI), attained weight or BMI during pregnancy and weight gain during pregnancy, and increased risks of assisted delivery (56). In fact, most of the anthropometric indicators had an inverse relationship with assisted delivery in that thinner women had a lower risk of assisted delivery than their better-nourished peers. This, according to the authors, is plausible “insofar as a low body mass index indicates a thin mother, probably with limited calorie intake, for whom fetal growth is likely to be constrained, thus reducing the likelihood of assisted delivery” (56). This adaptive mechanism, although adversely affecting fetal survival, may in fact protect the mother. It has been suggested that the low levels of maternal mortality among Scandinavian women before 1930 could be partly owing to the fact that they had a stronger build, a broader pelvis, and suffered less rickets. This hypothesis was invalidated by the observation that recent Scandinavian immigrants in the U.S. suffered as high risks of maternal death as their “native” peers (31). The high levels of maternal mortality in the U.S. at that time were in large part attributable to mismanagement of the delivery by doctors (31,58). Nutritional advice in pregnancy appears to increase the pregnant woman’s energy and protein intakes, but the implications for maternal health cannot be judged from the available trials (59). Kramer also states that “given the rather modest health beneﬁts demonstrated with actual protein/energy supplementation, the provision of such advice is unlikely to be of major importance.” The assertion that the increased fetal size that may accompany nutritional supplementation may lead to an increased risk of prolonged labor (60) has not been empirically tested. High-energy supplementation of pregnant women in The Gambia led to a signiﬁcant increase in the head circumference of babies (61). However, the small size of this increase and the impressive reduction in perinatal mortality suggest that the supplementation was unlikely to have increased the incidence of cephalo-pelvic disproportion. Although certain risk factors such as a small pelvis in a short woman or in growing teenage girls generally fall under the broad heading of “nutritional” factors, the

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strategies to either prevent or treat them are not necessarily nutritional. Stunting caused by early malnutrition cannot be reversed in adulthood. Although nutrional supplementation in childhood may enhance future height (62), it is uncertain what the small gains in average attained height mean in terms of preventing difﬁcult labor. Improved labor management is probably the most appropriate strategy for preventing adverse health effects in stunted women. The low risks associated with pregnancies in very young girls in Western countries do suggest that adequate labor management can ensure a safe delivery in these girls (45,46).

6.3. Calcium Deﬁciency and the Risk of Pre-Eclampsia The association between high calcium intake and a low incidence of hypertensive diseases in pregnancy was ﬁrst shown in a study among the Mayan Indians in Guatemala in 1980 (63). The traditional practice of soaking corn in lime before cooking was associated with an unusually high calcium intake and a low incidence of pre-eclampsia and eclampsia. A similar association between high calcium intake and a low prevalence of pre-eclampsia has also been reported from Ethiopia and was later conﬁrmed by further epidemiological and clinical studies (49). Low calcium intake may cause high blood pressure by stimulating parathyroid hormone or renin release, and inducing vasoconstriction by increasing intracellular calcium in vascular smooth muscle and intensifying smooth muscle reactivity (64). Calcium supplementation has been postulated to act on smooth-muscle reactivity by reducing parathyroid hormone release and intracellular calcium. By the same mechanism calcium supplementation has been suggested to reduce uterine smooth muscle reactivity and prevent preterm labor and delivery (65). Reviews of calcium supplementation trials during pregnancy provide strong support for the supplementation of pregnant women with calcium as a means of preventing pregnancy-induced hypertension and pre-eclampsia in communities with low calcium intake (49). Two meta-analyses of randomized controlled trials have consistently shown a protective effect of calcium supplementation on the incidence of pre-eclampsia (66,67). Supplementation of 1.5 or 2 g of calcium daily was associated with a halving in the risk of pregnancy-induced hypertension, and a reduction in the risk of pre-eclampsia of between 45% and 75%. The magnitude of the effect was considerably greater among women at high risk of developing hypertension and those with low baseline dietary calcium (49). Some reviewers warned that most trials were based on small samples and that further studies with larger sample sizes were needed to conﬁrm the impact of calcium on the mother and the fetus. The more recent Cochrane Review of randomized trials, on the other hand, concluded that sufﬁcient evidence is available to support calcium supplementation for pregnant women at high risk of pregnancy-induced hypertension and in communities with low dietary calcium intake (49). The absence of an effect of calcium on either the incidence or the severity of pre-eclampsia in nulliparous low-risk women in the largest study to date (68) does cast doubt on the potential beneﬁts of calcium supplementation in low-risk women with adequate dietary calcium intake. The ﬁndings of this study, however, do not call into question the potential role of calcium supplementation in populations with low dietary calcium intake (49). There is very little evidence linking poor nutritional status (expressed by anthropometric indicators) during pregnancy and pre-eclampsia (56). In fact, the WHO meta-

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analysis found a consistent pattern of poor maternal nutritional status associated with a reduced risk of pre-eclampsia (56). The odds ratios for the association between maternal height, arm circumference, and pre-pregnancy weight or BMI were all less than 1, suggesting that better-nourished women are at higher risk. It has been well-documented that obese women have a higher incidence of pregnancy-induced hypertension (69). Recently, pre-eclampsia has also been linked to oxidative stress and supplementation with antioxidants has been suggested as an effective way to improve vascular endothelial function and prevent pre-eclampsia. In a recent pilot study, supplementation of pregnant women at increased risk of pre-eclampsia with vitamins C and E substantially reduced the risk of pre-eclampsia (70). The sample size was small, however, and larger trials in different populations, with attention for safety, particularly for the infant, are needed before adopting such a strategy (71).

6.4. Iron Deﬁciency and Anemia During pregnancy, the demands for iron may increase because of the expansion of the red cell mass and the deposition of substantial amounts of iron in the fetus and the placenta (23). These increased demands are partially offset by the cessation of menses and the increased absorption of iron during pregnancy. During pregnancy, the hemoglobin and serum iron concentrations fall and the needs for additional iron increase as the pregnancy progresses (23). Iron supplementation in pregnancy has become routine practice throughout the world. In developing countries, anemia during pregnancy is very common. The WHO (72) estimates that more than half of pregnant women in developing countries may be anemic (deﬁned as hemoglobin below 11 g/dL). The prevalence of severe anemia (deﬁned as hemoglobin below 8 g/dL) is not well-documented, and it is not certain that the prevalence of mild anemia mirrors the prevalence of severe anemia. Stoltzfus (73) summarized data on the prevalence of anemia from six different populations (Table 3). Although the prevalence of overall anemia is similar in the six sites, the prevalence of moderate-to-severe anemia is markedly different. Because only very severely anemic women are at higher risk of dying, the prevalence of mild anemia may not be in itself a good marker of risk. There is little doubt that iron supplementation in pregnancy of around 100 mg elemental iron daily improves maternal iron status during pregnancy and immediately after delivery in both industrialized and developing countries (23,74). Increases in hemoglobin, hematocrit, serum ferritin, and serum iron are usually apparent within 3 mo. Routine iron supplementation results in a substantial reduction in the proportion of women with a hemoglobin level below 10 or 10.5 g/dL in late pregnancy. Whether iron supplementation reduces the incidence of severe anemia is uncertain. Most trials exclude severely anemic women and the assumption that the supplementation of the entire population of pregnant women would cause a shift in the distribution of anemia, such that the prevalence of very severe anemia would decrease has not been empirically tested. Despite the long-standing universal practice of iron supplementation in pregnancy, it is rather astonishing how little is known about its effects on pregnancy outcome. A review of randomized controlled trials of routine iron supplementation during pregnancy concluded that although the trials demonstrated a positive effect on hemoglobin levels

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Table 3 Prevalence of Mild, Moderate, and Severe Anemia in Various Populations Population Nepal, 3 mo postpartum Central Java, 3 mo postpartum Zanzibar, not pregnant Nepal, pregnant Shangai, pregnant Peru, pregnant

Sample size

Anemic* (%)

Hb <10 g/dL (%)

Hb <9 g

1,613 1,146 1,583 1,052 1,826 1,670

81.4 71.9 71.7 69.8 66.2 44.3

28.4 15.1 26.2 40.5 25.3 14.5

1 1 2

*Anemic, Hb <11 g/dL in pregnant women and <12 g/dL in nonpregnant women. Adapted with permission from ref. (73).

at delivery and at 6-wk postpartum, there was very little information on a possible effect on maternal or fetal outcomes (74). A trial of routine vs selective iron supplementation during pregnancy in Finland suggested that Caesarean sections and postpartum blood transfusions were more common among the selectively supplemented group, but the authors warned that such effects may have been owing to reactions of midwives and doctors to low hematocrit values (75). From the available evidence, no conclusions can be drawn on the effects of iron supplementation during pregnancy on its outcome for the mother. Limited compliance with iron supplementation is thought to be a major reason for the low effectiveness of anemia-prevention programs in developing countries (76,77). Reasons for noncompliance include inadequate program support, insufﬁcient service delivery (particularly unavailability of iron supplements), and patient factors such as fear for side effects (78). Weekly rather than daily supplementation with iron appears to be promising (79). In developing countries, anemia in pregnancy may only partly be owing to iron deﬁciency, and malaria and infections such as hookworm may be equally important causes. In a randomized controlled trial in Kenya, Shulman et al. (25) showed that intermittent treatment of primigravida with sulphadoxine-pyrimethamine reduced the prevalence of severe anemia (hemoglobin <8 g/dL) from 24% in the placebo group to 14% in the intervention group. In such settings, malaria prophylaxis may be a more important strategy for the prevention of severe anemia than iron supplementation.

6.5. Vitamin A Deﬁciency and the Risk of Anemia or Infection In children, vitamin A has been shown to be associated with sharp reductions in mortality and the severity of infections. The hypotheses underlying such an association have mainly centered on the immunity-impairing effects of vitamin A deﬁciency. During pregnancy, four pathways have been suggested through which vitamin A supplementation (or its precursors) may improve the maternal health status. First, vitamin A may decrease the risk of bacterial and viral infections during pregnancy through its beneﬁcial effects on maternal immunity. Second, vitamin A may improve the mother’s hematological status. Third, vitamin A may enhance the implantation and development of the placenta, and fourth, vitamin A deﬁciency has been associated with pregnancy-induced hypertension (80).

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Vitamin A deﬁciency has not often been shown to be associated with infections during or after pregnancy. Circumstantial evidence suggests that vitamin A or `-carotene deﬁciency may be associated with puerperal infection, bacteriuria, and vaginal candidosis (81–83). Christian et al. (80) found that Nepali women with night-blindness were twice as likely than normal pregnant controls to report symptoms such as lower abdominal pain, painful urination, vaginal discharge, convulsions, or swelling of the face and hands. Women’s reports of reproductive ill-health are unreliable, however, and should not be taken to represent medically deﬁned illness (11,84). Retinol is known to be decreased by the acute-phase response of infections, even in the presence of adequate liver stores of vitamin A (85). Therefore, vitamin A serum concentrations may be markers of infection rather than causally related to it. The randomized controlled trial of vitamin and `-carotene supplementation in women of reproductive age in Nepal failed to ﬁnd an effect of supplementation on mortality from sepsis or infection (6). There is so far no direct evidence supporting an association between vitamin A supplementation and the risks of severe infection during or after pregnancy in malnourished populations. Vitamin A deﬁciency may contribute to low hemoglobin levels (86). Low levels of hemoglobin have been found in xerophthalmic women in India and among women with night blindness in Nepal (80,87). Whether this association is causal remains to be seen, however, because most women with vitamin A deﬁciency also had a poor overall nutritional status, and the low vitamin A status may have been a mere marker of other deﬁciencies. Supplementation with vitamin A in pregnant women in Indonesia reduced the prevalence of nutritional anemia, suggesting a possible causal role of vitamin A (88). Pregnant women with hemoglobin levels between 8 and 11 g/dL were randomly allocated to four groups of daily supplements: vitamin A (2.4 mg retinol equivalents), iron (60 mg elemental iron), vitamin A and iron, and placebo. The proportions of nonanemic women increased substantially with either vitamin A or iron, and the effect was most pronounced in the group receiving both vitamin A and iron (Table 4). Supplementation of sole vitamin A alone did not have an effect on hemoglobin levels in HIV 1-infected women in Tanzania, however, whereas multivitamins caused a signiﬁcant increase (89). There is no direct evidence linking vitamin A deﬁciency to the risk of obstetric hemorrhage, nor are there plausible biological pathways underlying a potential association between vitamin A or `-carotene deﬁciency and uterine atony, the leading cause of postpartum hemorrhage. Vitamin A and its precursors may be essential for the placenta, as the placenta has been shown to have higher concentrations of retinolbinding protein and `-carotene than other body tissues (90). In HIV-1-infected women, supplementation of multivitamins, but not of vitamin A, has been shown to increase the weight of the placenta (89). Sharma et al. (91) reported a signiﬁcant reduction in serum antioxidants, including `-carotene, in pregnancies complicated by abruptio placentae compared to normal pregnancies. As with infections, however, the low concentrations of vitamin A and `-carotene may be the result of the stress of placental abruption rather than its cause. A number of observational studies have found a higher prevalence of vitamin A or `-carotene deﬁciency among women with pre-eclampsia (92–95). As already mentioned earlier, such observational evidence should not be interpreted as causal, because decreased retinol might be a consequence of acute-phase reaction or an decrease

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Table 4 Effects of Supplementation with Vitamin A, Iron, and Vitamin A and Iron on the Prevalence of Anemia in Pregnant Women in Indonesia Intervention Placebo Vitamin A Iron Vitamin A and Iron

Percent nonanemic (95% c.i.) 16 (7–29)1 35 (22–48) 68 (54–79) 97 (88–99)

Adapted with permission from ref. (88).

in circulating serum protein associated with the pre-eclampsia. Two randomized controlled trials of ﬁsh oil supplementation (which is rich in vitamin A) in pregnant women have found no signiﬁcant effects on pre-eclampsia (96,97). Unlike `-carotene, vitamin A may be highly toxic when taken in high doses and its teratogenicity is still a subject of debate (52,98,99). In a large cohort study, U.S. women consuming more than 10,000 IU of vitamin A per day were found to have a ﬁvefold increased risk of defects associated with cranial-neural crest tissue than women consuming 5,000 IU or less (99). However, a large case control study found no association between periconceptual vitamin A exposure of more than 10,000 IU and malformations (100). It is now generally accepted that the supplements suggested for malnourished women in developing countries are safe. The most compelling potential mechanisms of action of vitamin A and its precursors is through improvements of the immune and hematological status of the pregnant woman. Evidence in support of beneﬁcial effects of vitamin supplementation on either infection or anemia during pregnancy is scant, however, and much further work is needed before such supplementation can be proposed as a strategy for reducing maternal mortality.

6.6.

Zinc Deﬁciency and the Risk of Hemorrhage or Infection

Zinc supplementation in infants may reduce the incidence of diarrhea and acute respiratory infections (101,102), and it has been suggested that zinc may therefore also inﬂuence maternal health (2). Zinc plays an important role in many biological functions, including protein synthesis and nucleic acid metabolism. Certain reports have suggested an association between serum zinc deﬁciency and dysfunctional labor, placental ablation, and hemorrhage (103–106). Others have not found such associations (107,108). Observational studies have to be interpreted with caution, however, as zinc values vary signiﬁcantly by gestational age, and zinc deﬁciency may be a consequence rather than a cause of pregnancy complications (104). There is no evidence to date supporting a beneﬁcial effect of routine zinc supplementation during pregnancy on maternal health (51). A well-conducted randomized controlled trial in pregnant women in the United Kingdom found no effect of zinc supplementation on pregnancy complications such as pregnancy-induced hypertension, abnormal labor, postpartum hemorrhage, or postpartum infection (108). Hunt et al. (109) had found a signiﬁcantly lower risk of pregnancy-induced hypertension

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among Hispanic women living in the U.S. who had received zinc supplements during pregnancy, but found no effect on infections or bleeding during pregnancy. There are very few trials of zinc supplementation in pregnant women with a poor dietary intake. A study in Peru has shown that adding zinc to prenatal iron and folic acid supplements may increase maternal zinc status (110). Among African-American women with relatively low plasma zinc concentrations, daily zinc supplementation increased plasma zinc concentrations and birth-weight (111). The implications of improved maternal zinc status for maternal health, however, are unknown.

7. PRENATAL CARE Prenatal care has long been seen as the backbone of maternal health services. The primary rationale for the widespread introduction of prenatal care has been the belief that if a predominantly healthy population is screened, early signs of, or risk factors for, morbidity and mortality can be detected and intervened upon (112). Prenatal care has been widely seen as an intervention that could be introduced at the community level, and has been presented as among the most cost-effective strategies to improve women’s and child health (24,38). Reviews examining the effectiveness of formal risk assessment in pregnancy have concluded that the risk approach may not be effective in preventing maternal death nor in ensuring rational use of resources (2,29,112). The low predictability of some of the major causes of maternal death—postpartum hemorrhage, shock, and sepsis—had already been recognized as early as 1932 (113). Evaluations of the performance of risk-scoring systems in developing countries have also shown that complications such as dystocia and postpartum hemorrhage cannot be adequately predicted (55,57,114). The low predictability of such adverse maternal outcomes has led to a shift in the emphasis of safe motherhood strategies from universal prenatal care to universal access to professional delivery care (2). The narrow focus on the failure of sociodemographic factors, physical characteristics of women, or clinical signs during pregnancy to predict adequately obstructed labor or postpartum bleeding has led us to overlook the potential wider role of prenatal care. prenatal care clearly has its value for the detection and treatment of pregnancy-related complications (i.e., malaria, severe anemia, urinary infections, hypertensive diseases) and the prevention of potential problems (i.e., HIV, malaria). In addition, prenatal care offers an opportunity for informing the woman about the risks associated with the pregnancy and about her options for professional care during delivery. Women seeking prenatal care may also be more likely to seek professional care during delivery (57). Prenatal care may not be an efﬁcient strategy to identify those most in need for obstetric service delivery, but if promoted in concurrence with effective emergency obstetrical care (EOC), and delivered in skilled hands, it may become an effective instrument for better use of EOC services.

8. TRAINING OF TRADITIONAL BIRTH ATTENDANTS It has long been recognized that women should not give birth alone. Because it was not deemed feasible to provide access to professional medical care for all women, and because women throughout the developing world were already giving birth in the presence of traditional birth attendants (TBAs), the training of such attendants

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appeared to be an attractive option. The training of TBAs was also in accordance with empowerment of the community, a growing paradigm during the 1970s and 1980s, and that period saw the emergence of the training of hundreds of thousands of TBAs. TBAs were expected to screen women during prenatal clinics, and to provide a clean environment for giving birth. It was also hoped that they could be integrated into the health system and be recognized as ofﬁcial health personnel (58). Training of TBAs has not proven to be an effective strategy for reducing maternal mortality (2,58). In a quasi-experimental study from The Gambia, Greenwood et al. (115) showed that the use of traditional birth attendants may have a positive effect, but three years after the program began maternal mortality remained a high as 700 per 100,000 (115). In Bangladesh, training of TBAs had no effect on maternal mortality (116). It slowly emerged that TBAs would have little impact on maternal mortality, and that facilitating access to professional medical care would be a more effective strategy (29,117). The reasons for the failure of TBA training are multiple (58). There is a large variation in the skills and experience of TBAs and some may have little more skills than holding the woman in their arms during childbirth, whereas other TBAs master a good number of basic obstetric skills through years of experience. Resources to provide the necessary supervision and support have often been lacking (118). Traditional knowledge is rooted in the local culture and may be difﬁcult to change. Most importantly, it has never been clear what the content of the training program should have been (58).

9. ACCESS TO PROFESSIONAL DELIVERY CARE The last 10 years have seen a shift from community-based strategies to reduce maternal mortality to an increasing emphasis on the role of professional care at the time of delivery. Historical data provide the most compelling evidence for the crucial role of obstetric care in the decline of maternal mortality. There can be no doubt that the remarkably steep and sustained decline in maternal mortality in all Western countries from 1935 onwards is owing to increased access to high-quality obstetric care compounded by major advances in obstetric techniques (31). Factors such as the discovery of antibiotics in the 1940s, the use of blood transfusion and ergometrine during the Second World War, and safer methods for Caesarean section and induction of labor since the 1950s, all contributed to the extraordinary decline in maternal mortality in Western countries (31). Although in the 1920s some Western countries were still at levels of maternal mortality currently seen in developing countries, improved delivery care caused their levels to decline to as low as 20 deaths per 100,000 in a period as short as 30 years. Support for the crucial role of obstetric care is also provided from a current example in the United States. Members of a religious group who received no prenatal care and who delivered at home without trained attendance had a maternal mortality ratio about 100 times higher than the state-wide rates (119). Although the numbers of maternal deaths were small, the maternal mortality ratio of 872 deaths per 100,000 live births among Faith Assembly members was signiﬁcantly higher than the ratio of 9 deaths per 100,000 among the remainder of the population. These ﬁndings suggest that, even in the United States, absence of skilled obstetric care greatly increases the risk of maternal death.

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Table 5 Avoidable Factors for 718 Maternal Deaths in Egypt (1992–1993) Avoidable factors No or poor prenatal care Delay in seeking medical care Unwanted pregnancy Substandard care from general practitioner Substandard care from obstetricians Substandard care from traditional birth attendant Lack of drugs, supplies, and equipment Lack of blood bank Lack of transportation No avoidable factors

Number of deaths (%) 239 (33) 304 (42) 136 (5)1 187 (12) 334 (47) 184 (12) 115 (2)1 115 (2)1 128 (4)1 154 (8)1

Adapted from ref. (121).

How best to organize maternity services to ensure that all women have access to highly skilled care for childbirth remains a matter of debate. As the Netherlands have shown, hospital delivery for all women is not necessary to achieve very low levels of maternal mortality. Similarly, the Swedish success in the late 19th century was a result of the training of professional midwives in the systematic use of aseptic techniques; hospital births were uncommon (120). In fact, doctors have often been shown to be the cause of high levels of maternal mortality (31,54). In Egypt, where a large proportion of the women deliver in a hospital, more than half of the maternal deaths have been attributed to inappropriate management by obstetricians (Table 5) (121). Health-care systems have been said to contribute to, rather than to prevent, maternal mortality (122). Direct evidence from developing countries that increased access to obstetric care can reduce maternal mortality is scarce. The available evidence suggests that low mortality can be achieved with a variety of different models of health care. Rural China, for example, reached low levels of maternal mortality despite nonprofessional attendance at home births, whereas Malaysia reached low mortality by training a large body of professional midwives to attend home deliveries (123). Other countries such as Sri Lanka have reached low levels of mortality in the presence of nearly universal institutional delivery rates (2). The few quasi-experimental studies addressing the potential role of professional care in the reduction of maternal mortality in developing countries have not been able to provide conclusive evidence. The ﬁndings from a large community-based study in Matlab, Bangladesh, for example, which provided support for professional midwifery care in the community, have been questioned repeatedly (12,43). Other studies either had very low sample sizes or were poorly designed (115,124–126). One of the key messages emerging from the Safe Motherhood technical consultation held in Sri Lanka in 1997 was that maternal mortality reduction could not occur in the absence of a change in the political environment around women’s health (2). Reductions in maternal mortality in Western countries would also not have been possible without a political commitment to do so. This commitment involves the necessity to document the magnitude of the problem, the recognition that most maternal deaths are avoidable with

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the currently available technology, and most importantly, the active mobilization of qualiﬁed health professionals and the community (58). Without a willingness of decisionmakers to take up their responsibility and health providers to be held accountable for their actions, the decline could not have taken place. The WHO also emphasizes that national commitment at high level and by health care providers will be necessary to ensure that implementation of the actions required by the Mother-Baby package are feasible and sustainable.

10. SUMMARY AND CONCLUSIONS Maternal mortality is one of the statistics showing the largest degree of disparity between developed and developing countries. Poverty contributes to this disparity but does not explain it completely, as countries with similar levels of socioeconomic development have widely ranging levels of maternal mortality. Historical data from Western countries provides the most compelling evidence as to which strategies will most likely contribute to the decline of maternal mortality in less developed countries. Sustained reductions in maternal mortality will be possible if modern high-quality obstetric care will be made available to all women through a system of professional midwifery and referral hospital care in a context of political commitment and accountability of health providers. There is very little evidence from the industrialized world supporting the direct role of strategies involving women’s education, family planning, or nutrition in the improvement of the health of pregnant women. Nutritional supplementation of pregnant or reproductive age women has been proposed as a new strategy for the reduction of maternal mortality in developing countries. The suggestion for a possible role for nutritional supplementation has largely emanated from the beneﬁcial effects micronutrient supplementation may have on child survival. The evidence so far in support of such a strategy in pregnant women is scant, except for calcium supplementation, which has been convincingly shown to be associated with a reduction in the incidence of pre-eclampsia. Further research is needed before micronutrient supplementation can be introduced as a complementary strategy to increasing the access to and quality of professional obstetric care for all women.

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Low Birth Weight and Perinatal Mortality Michael S. Kramer and Cesar G. Victora

1. INTRODUCTION It is widely recognized that weight at birth is an important indicator of fetal and neonatal health for both individuals and populations. Birth weight in particular is strongly associated with fetal, neonatal, and postneonatal mortality; infant and childhood morbidity; and long-term growth and development (1,2). According to the World Bank/World Health Organization (WHO) study of the global burden of disease, low birth weight (LBW) and other perinatal causes are a leading cause of death and disability (3). Of the 2.44 million global deaths resulting from perinatal causes, 97% occur in developing country settings. Thus LBW and perinatal mortality are public health problems of crucial importance in such settings.

2. BACKGROUND AND DEFINITIONS 2.1. Low Birth Weight LBW is deﬁned by the WHO as a birth weight <2500 g (4). Birth weight, however, is determined by two processes: the duration of gestation and the rate of fetal growth. Thus, a fetus or newborn infant can have a birth weight <2500 g either because he/she is born early (preterm birth) or is born small for his/her gestational age (SGA), a proxy for intrauterine growth restriction (IUGR) (5). Preterm birth is deﬁned as delivery before 37 completed wk (259 d). Although some SGA infants are merely constitutionally small rather than truly growth-restricted, and some growth-restricted infants who would otherwise be constitutionally large do not meet standard criteria for SGA, SGA is often used as a proxy for IUGR. WHO deﬁnes SGA as a birth weight below the 10th percentile for gestational age based on the sex-speciﬁc reference by Williams et al. (2,6). LBW is a concept developed and promulgated by epidemiologists and public health practitioners. Its popularity can probably be attributed to two facts: (1) infant mortality (particularly neonatal mortality) increases exponentially at birth weights below 2500 g (7), and (2) birth weight (and hence LBW) can be measured with excellent precision. From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Fig. 1. Venn diagram illustrating relationships between low birth weight (LBW), intrauterine growth restriction (IUGR), and preterm birth (PTB).

Because of many differences between preterm birth and IUGR, however, the LBW concept has been a major hindrance to progress in perinatal epidemiology, in general, and to understanding the effects of maternal nutrition, in particular. As shown in Fig. 1, newborn infants may be growth-restricted or preterm without having LBW. For example, the SGA cut-off for males at 40 wk is 2944 g, whereas the median birth weight for males at 35 wk is 2562 g (6). From an etiologic perspective, the two different types of LBW are quite heterogeneous. It is now clear that the causal determinants of preterm birth and IUGR differ both qualitatively (i.e., they have different etiologic determinants) and quantitatively (the relative risks are different for common determinants) (5). Table 1 lists the most important determinants of preterm birth and IUGR in developing country settings. The distinction between preterm birth and IUGR is important for understanding the prevalence of LBW, which differs vastly between and within countries. For example, it has been clearly demonstrated that in developing countries where LBW rates are extremely high, most LBW infants are growth-restricted, rather than preterm (8,9). In inter-racial comparisons within the U.S., on the other hand, the increased LBW prevalence among Blacks is largely owing to an increase in preterm birth (10–12). IUGR and preterm birth also have important differences with respect to prognosis. Preterm infants are at increased risk of infant death; short- and long-term pulmonary, ophthalmologic, and neurologic morbidity; and delayed psychomotor development (13–15). In developed countries, preterm birth generates high health care costs, particularly for neonatal intensive care, which is often required for many months for infants born extremely preterm (<32 wk gestational age) (16). Severely growthrestricted infants are at increased risk of neonatal death and of signiﬁcant short-term morbidity from hypoglycemia, hypocalcemia, and polycythemia. Over the longer term, they tend to have small but permanent deﬁcits in growth and neurocognitive development. Recent epidemiologic studies by Barker and colleagues suggest that such infants may be at increased risk of Type 2 diabetes, hypertension, and coronary artery disease when they reach middle age many decades later (17). In developing country

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Table 1 Determinants of Preterm Births and IUGR in Rural Developing Country Settingsa Preterm birth Genital tract infection Multiple birth Pregnancy-induced hypertension Low prepregnancy BMI Incompetent cervix Prior preterm birth Abruptio placentae Heavy work Cigarette smokingc

IUGR Low energy intake/gestational weight gain Nonwhite racial/ethnic origin Low prepregnancy BMI Short stature Malariab Cigarette smokingc Primiparity Pregnancy-induced hypertension Congenital anomalies Other genetic factors

aListed

in decreasing order of importance. primiparae. cAssuming a 10–20% prevalence of maternal smoking during pregnancy. bFor

settings, the distinction between IUGR and preterm birth has been more difﬁcult to make because of the difﬁculty in obtaining valid estimates of gestational age. Because of late entry into prenatal care, poor recall of the last normal menstrual period, and absence of routine early ultrasound dating, gestational age is often based on examination of the newborn (18–20) in these settings, although such methods systematically overestimate the gestational age of extremely preterm infants (21–23). The available evidence, however, indicates that even mildly growth-restricted term infants from developing countries, are at increased risk of death (24,25) and morbidity from both diarrhea and respiratory infections in the ﬁrst two years of life (25,26).

2.2. Perinatal Mortality Perinatal deaths include both fetal deaths (i.e., deaths in utero among fetuses born without signs of life) *20 wk gestational age and deaths among live-born infants occurring in the ﬁrst week of life (the latter referred to as early neonatal deaths). The perinatal mortality rate is deﬁned as the number of fetal deaths plus the number of ﬁrst-week infant deaths, divided by total number of births (live births plus fetal deaths) *20 wk gestational age. Fetal deaths occurring prior to 20 wk are considered miscarriages (spontaneous abortions), whereas those occurring at *20 wk are commonly referred to as stillbirths. Fetal deaths may occur either antepartum (before the onset of labor) or intrapartum (during labor). Antepartum fetal death is strongly associated with IUGR (27,28), whereas intrapartum fetal death is usually independent of IUGR. In fact, intrapartum death is more likely to occur in the context of a macrosomic (large) fetus (29,30). This is particularly a problem in developing countries when access to emergency obstetric care and caesarean section is problematic (31–33). Early neonatal death is highly associated with preterm birth (12). In fact, the majority of deaths occurring in the ﬁrst week of life in developed countries nowadays occur among extremely preterm infants (<32 wk). In developing countries, lesser degrees of prematurity also carry a risk of early neonatal death, and IUGR is a more common cause of early neonatal death in developing countries that in developed ones (34–37).

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Table 2 Pregnancy Outcome Among Countries Participating in WHO Collaborative Study (38,39)

Country

LBW (% of live births)

IUGR (% of live (births)

6.3 4.2 16.1 8.1 12.1 12.5 28.2 10.5 5.6 11.6 17.8 14.3 18.4 9.6 6.2 10.6 4.8 6.0 5.2

9.7 9.4 17.8 14.7 13.5 25.3 54.2 19.8 6.9 26.1 30.4 36.3 34.0 17.0 12.3 11.2 5.8 6.9 18.2

Argentina China Colombia Cuba Gambia Guatemala India (Pune) Indonesia Ireland Malawi Myanmar Nepal (Rural) Sri Lanka Thailand United Kingdom U.S./CDC (Black) U.S./CDC (Hispanic) U.S./CDC (White) Vietnam a8

Preterm (% of live births) 7.2 7.5 15.7 7.2 13.5 15.8 9.7 18.5 6.2 8.2 24.6 15.8 14.0 21.3 4.6 16.6 10.2 9.3 13.6

Infant mortality (per 1,000 live births) 124 138 130 119 180 149 176 150 116 138 105 181 115 127 116 a a a

134

per 1000 for U.S. overall.

Other common causes of early neonatal death include congenital anomalies, infection (sepsis), and asphyxia.

3. DESCRIPTIVE EPIDEMIOLOGY Table 2 is based on country samples participating in the WHO Collaborative Study of Maternal Anthropometry and Pregnancy Outcome (38) (for LBW, IUGR, and preterm birth) and on United Nations International Children’s Emergency Fund’s (UNICEF) annual publication on the State of the World’s Children (for infant mortality) (39). As shown in the table, LBW rates vary widely among the listed countries, with prevalences of 4–6% of live births in China and some of the most highly developed countries, 10–15% in developing countries in Latin America and Africa, 15–20% in some areas of south Asia, and nearly 30% in India (38). The data shown in Table 2 should be interpreted with caution, however, because the country samples participating in the WHO Collaborative Study may not be generalizable to the entire birth cohorts of the respective countries. Table 2 also provides prevalence rates for preterm birth and IUGR, although caution is advised in interpreting the preterm data from developing countries, given the aforementioned problems in accurate estimation of gestational age in many such settings. Despite these problems, the data in Table 2 clearly underline the point made above, i.e., that the main determinant of variation in LBW rates is the IUGR rate, and

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Table 3 Maternal Anthropometric Measures (Means) Among Countries Participating in WHO Collaborative Study (38) Country Argentina Myanmar China Colombia Cuba Gambia Guatemala India (Pune) Indonesia Ireland Malawi Nepal (Rural) Sri Lanka Thailand UK U.S./CDC (Black) U.S./CDC (Hispanic) U.S./CDC (White) Vietnam

Height (cm)

Prepregnancy BMI

Weight gain (kg)

157 151 160 155 157 157 148 150 149 158 155 150 150 153 159 162 158 163 152

22.4 19.8 19.5 23.3 21.8 19.7 20.8 18.3 20.2 23.7 21.0 19.5 18.8 20.8 22.2 23.1 23.7 22.6 19.6

10.8 — 11.7 10.1 14.6 16.5 17.1 — — 11.0 14.7 — — 18.0 11.6 13.5 12.8 14.4 15.6

that the high LBW rates reported in some developing countries are largely attributable to high rates of IUGR. UNICEF’s data (39) on infant mortality also vary widely, with rates varying inversely with level of socioeconomic development. Developing countries other than Cuba report generally higher rates of both LBW and infant mortality than developed countries. Table 1 also demonstrates several notable exceptions, however. Argentina, China, and Vietnam all report high infant mortality despite low rates of LBW, whereas in Sri Lanka, the reverse pattern is seen. These results reﬂect large differences in birth-weight speciﬁc mortality owing to variations in access to and quality of high-risk obstetric and neonatal care. The extremely high infant mortality reported for Malawi and Myanmar also indicate high birth weight-speciﬁc mortality. Table 3 is also based on the WHO Collaborative Study (38). The table summarizes height, prepregnancy weight, prepregnancy body mass index (BMI, i.e., the weight in kg divided by the height2 in m2), and gestational weight gain in the participating country study samples. These data show considerably lower maternal height, prepregnancy BMI, and gestational weight gain in developing country settings. In many respects, the data parallel those shown in Table 2 for IUGR, which is concordant with the important effects of these anthropometric factors on fetal growth (5). A variety of deﬁciencies in micronutrient intake and/or status have been documented in developing country settings. These include a higher prevalence of anemia and of iron, folate, and zinc deﬁciencies (40–46).

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Table 4 Associations Between Low Values (Lowest Quartile) of Anthropometric Indicators and IUGR and Preterm Birth, from the WHO Collaborative Study Anthropometric indicator Short stature Low prepregnancy BMI Weight gain to mo 5 Weight gain to mo 7

IUGRa

Preterm Birtha

1.9 (1.8–2.0) 1.8 (1.7–2.0) 1.8 (1.4–2.4) 1.8 (1.5–2.2)

1.2 (1.1–1.2) 1.3 (1.1–1.4) 0.4 (0.3–0.6) 0.7 (0.6–0.9)

Adapted from ref. (38). aOdds ratios and 95% conﬁdence intervals.

4. ETIOLOGIC ROLE OF MATERNAL NUTRITION From a public health standpoint, the importance of an etiologic determinant is reﬂected by its etiologic fraction (also called the population attributable risk). The etiologic fraction, in turn, depends both on the determinant’s relative risk for the particular pregnancy outcome and on its prevalence in the population.

4.1. IUGR In developing countries, low gestational weight gain, prepregnancy BMI, and short stature are associated with large etiologic fractions for IUGR (5). The large etiologic fractions are the consequences not only of the high relative risk for individual women with these anthropometric risk factors, but also of their high prevalence in developing country settings. A summary of the relative risks for associations between maternal anthropometric indicators and IUGR is shown in Table 4, again based primarily on ﬁndings from the WHO Collaborative Study (38). Another important aspect of maternal nutrition concerns work and energy expenditure during pregnancy. This is particularly important in developing countries, where women often work in strenuous agricultural activities, in seeking and carrying water for the family, and in other physically demanding domestic tasks (47). Although few epidemiologic studies carried out in developing countries have examined the relationship between energy expenditure and pregnancy outcome, it seems reasonable to assume that in settings where energy intake is limited, either by availability or cost, heavy energy expenditure during pregnancy can lead to insufﬁciently positive (or even negative) maternal energy balance and thereby increase the risk of IUGR. Studies from the Gambia clearly demonstrate that the combination of reduced food availability and heavy agricultural work negatively impact on both maternal weight gain and fetal growth (48). The available evidence does not suggest an important etiologic role for micronutrients in preventing IUGR among infants of healthy mothers. Because of confounding by energy intake and energy expenditure, many of the observational studies reporting an association between micronutrient deﬁciencies and these pregnancy outcome are probably biased. The limited evidence available from randomized controlled trials and overviews of such trials contained in the Cochrane Database of Systematic Reviews does not provide strong evidence for the etiologic role of iron, folate, calcium, zinc, or omega-3 or omega-6 fatty acids, (49–55) although further trials in nutrient-deﬁcient

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populations seem justiﬁed for folate, zinc, and calcium. In HIV-infected women, however, multivitamin supplementation does appear effective in reducing the risk of IUGR (56).

4.2. Preterm Birth Anthropometric factors that appear etiologically important for IUGR are not nearly so important for preterm birth (5,38). As shown in Table 4, the WHO Collaborative Study found small increases in the relative risk for preterm birth associated with short stature and low prepregnancy BMI. Methodologic problems pervade studies relating gestational weight gain to preterm birth. Preterm pregnancies are associated with a lower total weight gain, merely because women have had a shorter period of time in which to gain weight. The evidence concerning the effects on preterm birth of rate of weight gain, or of weight gain in early pregnancy, is conﬂicting. In fact, the WHO Collaborative Study found that low weight gain was protective against preterm birth (38), although this ﬁnding is not consistent with other studies (57). As seen with IUGR, multivitamin supplementation appears to lower the risk of preterm birth in HIV-positive women (56). Additional randomized trials are required to evaluate the potential etiologic roles of low folic acid, zinc, and calcium and of heavy maternal work, particularly in otherwise healthy women, in developing countries where these factors are prevalent.

4.3. Fetal Death In developed countries (58–61) and one study from Brazil (62), antepartum fetal death is associated with high prepregnancy BMI (obesity), rather than with low prepregnancy BMI. Although fetal death has been poorly studied in developing countries, it may be true that the low prepregnancy BMI characteristic of clearly undernourished mothers in such countries would also be associated with an increased risk. Low gestational weight gain is also associated with antepartum fetal death, particularly when it results in a severely growth-restricted fetus. In a recently published randomized trial from the Gambia, balanced energy/protein supplementation resulted in an increase in gestational weight gain and a reduced risk of stillbirth, although the timing of the stillbirths (ante- vs intrapartum) was not speciﬁed (48). Nonetheless, antepartum fetal death is largely determined by non-nutritional factors, including inadequate prenatal care surveillance and delayed referral when fetal or maternal pathology is detected. These health care system factors are particularly important in some developing country settings, where the training of prenatal care providers and the availability of highlytrained specialists may be inadequate (31). In other developing countries, however, high-risk obstetrics may be all too accessible. Brazil, for example, has recently witnessed an epidemic of Caesarean section (63). In developed countries, prenatal care surveillance, diagnostic procedures, referral, and early intervention (induction or Caesarean section) have probably been responsible for the continued fall in antepartum stillbirths. Intrapartum stillbirths are often associated with obstructed labor. This is more likely to occur in women of short stature and thus constitutes a greater potential risk in women from developing countries (38), particularly when access to emergency obstetric care and caesarean section is a problem (31–33). Moreover, obesity is becoming more prevalent in many developing countries (64), and it is a known determinant of

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macrosomia (65–67). A large fetus can result in a difﬁcult delivery, and once again, if emergency obstetric facilities are not readily available, can greatly increase the risk of fetal death (29,30). The importance of well-trained birth attendants, and of prompt transfer and transport when problems arise, cannot be overemphasized in this regard.

4.4. Early Neonatal Death Because most early neonatal deaths in developed countries occur among extremely preterm infants, the etiologic determinants of early neonatal death are similar to those for preterm birth. Severely growth-restricted infants are also at risk for early neonatal death (68), but in most developed countries, such infants, if born alive, are likely to survive and to survive intact. As mentioned earlier, severely growth-restricted infants are known to have an increased risk of hypoglycemia and hypercalcemia and of stroke and other complications owing to polycythemia and high blood viscosity (68). In the context of modern neonatal intensive care, these complications of IUGR are treatable. Obviously, however, in developing countries where access to such care is difﬁcult or impossible, IUGR is likely to play a more important role in neonatal death, particularly from infection (24–26,69). The previously-cited trial from the Gambia, for example, reported a signiﬁcant reduction in early neonatal death for undernourished women who received a very large balanced energy/protein supplement (48). Finally, although neural tube defects comprise only a small minority of congenital anomalies, they are usually fatal in developing country settings and are largely preventable by periconceptual folate supplementation (70,71).

5. OPPORTUNITIES FOR NUTRITIONAL INTERVENTION 5.1. The Risk Approach: Selective Maternal Energy Supplementation The idea of using anthropometric screening to select women for nutritional intervention (in this case, maternal energy supplementation) has considerable appeal. Thus, the height and weight of women could be measured prior to or early in pregnancy, and their weight gain could be monitored. Women with low height, low prepregnancy weight or BMI, or low rate of gestational weight gain would then be referred for energy supplementation. Such a combined program of anthropometric screening and selective supplementation would theoretically be more efﬁcient in allocating a scarce and expensive resource (energy supplementation) to those women who are most in need. Unfortunately, however, available data suggest that the risk approach is not very effective (72). Based on a decision analysis using data from the WHO Collaborative Study, it seems clear that screening based on any of the anthropometric indicators mentioned earlier has both low sensitivity and low speciﬁcity (38,72). In other words, screening both fails to pick up many women with adverse pregnancy outcomes and identiﬁes many women as being at risk who have normal pregnancy outcomes. Also discouraging is the low efﬁcacy of the interventions themselves. Maternal energy supplementation has been shown to result in only a modest increase in energy intake, because much of the supplement appears to displace the normal diet (73). The consequence is little impact on fetal growth and no clear impact on the duration of gestation. Thus, many women would have to be screened and treated to prevent a few cases of IUGR or preterm birth. The combination of the low sensitivity of anthropometric screening and low efﬁcacy of the intervention indicates that such a risk approach would

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make only a small dent in the overall prevalence of adverse pregnancy outcomes, even in developing countries where they are quite common (72).

5.2. Universal Maternal Energy Supplementation As mentioned earlier, the best evidence available from controlled trials of supplementation shows a modest effect of maternal energy supplementation on fetal growth and little or no impact on gestational duration (73). Providing such supplementation to all pregnant women in a country or region is expensive, logistically difﬁcult, and therefore difficult to recommend on the basis of its efficacy. Universal maternal energy supplementation may well be justiﬁed, however, where the prevalence of maternal undernutrition is high, as demonstrated in a recent randomized trial from The Gambia, where many pregnant women are undernourished, particularly during the rainy, “hungry” season (48). The prevalence of low prepregnancy BMI and low weight gain in this type of setting is probably sufﬁcient to justify universal intervention. As emphasized by Rose for preventing cardiovascular disease (74,75), population-wide interventions in high-risk settings are likely to be a more effective preventive strategy than strategies based on identiﬁcation and treatment of high-risk individuals.

5.3. Periconceptual Folate Supplementation In developing country settings, food fortification is probably a more effective and more feasible public-health intervention than attempting to provide a dietary supplement in the periconceptual period. Adequate periconceptual folate status should succeed in reducing a high fraction of neural tube defects and their attributable neonatal deaths (71).

5.4. Reduction in Childhood Stunting Improved childhood nutrition, particularly in the ﬁrst 2–3 yr, would reduce the prevalence of childhood stunting and of consequent maternal short stature (76,77). In the long term this should help reduce the risks of intrapartum fetal death, IUGR and (to a lesser degree) preterm birth in developing countries (5,38).

5.5. Prevention of Maternal Obesity Maternal obesity is increasing in many developed countries (78–82) and is even becoming prevalent in some developing ones, especially in Latin America (64). Given its strong association with both antepartum and intrapartum fetal death, reduction in maternal obesity would help reduce these adverse pregnancy outcomes, although such reduction could theoretically increase the risk of IUGR. Unfortunately, however, data on the efﬁcacy of interventions to prevent or treat obesity are extremely discouraging. New preventive and therapeutic interventions are urgently required in both developed and developing countries to stem this worrisome epidemic.

6. CONCLUSIONS High perinatal mortality is a major public health problem in many developing countries. Although high IUGR rates may contribute to this high mortality, it is caused largely by high birth weight-speciﬁc (and gestational age-speciﬁc) mortality owing to inadequate access to trained birth attendants, high-risk obstetric care, and neonatal intensive care.

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The gestational age distribution also plays an important role. Even though data are sparse on prevalence of preterm birth in developing country settings, perinatal mortality is so much higher among preterm infants (particularly those born before 32 wk) that preterm birth prevention should become a high priority for developing countries as well. The fetal growth (birth weight-for-gestational age) distribution plays a less important role, although severely growth-restricted infants are at greatly increased risk of perinatal death in developing countries. Because maternal undernutrition is a major contributor to IUGR in developing country settings, it may play an important role in perinatal mortality. The etiologic contribution of IUGR is probably even more important in the suboptimal long-term growth and development of children in such settings. Maternal undernutrition, and particularly low prepregnancy BMI, is also likely to increase the risk of preterm birth and, therefore, of early neonatal death. One of the challenges for developing countries will be to reduce maternal undernutrition without encouraging a concomitant epidemic of maternal obesity. Maternal overnutrition has been demonstrated to have adverse consequences for both offspring and mother. These consequences may be even more important in settings without ready access to emergency obstetric care and Caesarean section. It would be unfortunate indeed if developing countries compounded their problems in perinatal health by experiencing the same epidemic in obesity now plaguing so many developed countries.

7. RECOMMENDATIONS • Clinical and public health interventions should focus on reducing perinatal mortality, among both low and normal-weight infants, rather than on preventing LBW. These interventions include institutional (hospital or clinic) delivery, access to Caesarean section and other aspects of emergency obstetric care, and training of local health workers to recognize and treat neonatal sepsis (infection). • Where maternal undernutrition is prevalent, universal balanced energy/protein supplementation should be offered. • Other successful nutritional interventions are likely to be limited to prevention of neural defects through folate fortiﬁcation of food and/or periconceptual supplementation. • Priorities for future research include additional randomized trials of zinc, folate, and calcium supplementation and observational studies of possible interactions between common nutritional deﬁciencies (iron, zinc, folate, and vitamin A) and the microbial agents causing neonatal sepsis.

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32. Ferraz EM, Gray RH. A case-control study of stillbirths in Northeast Brazil. Intl J Gynecol Obstet 1990; 34:13–19. 33. Escoffery C, Greenwood R, Ashley D, Coard K, Keeling J, Golding J. Deaths associated with intrapartum asphyxia in Jamaica. Paediatr Perinat Epidemiol 1994; 8(suppl1):119–142. 34. Perera T, Lwin KM. Perinatal mortality and morbidity including low birthweight: a South-East Asia regional proﬁle. SEARO Regional Health Papers No. 3. 1984. 35. Victora CG, Barros FC, Vaughan PJ, Texeira AMB. Birthweight and infant mortality: a longitudinal study of 5914 Brazilian children. Intl J Epidimiol 1987; 16(2):239–245. 36. Samms-Vaughan ME, McCaw-Binns AM, Ashley DC, Foster-Williams K. Neonatal mortality determinants in Jamaica. J Trop Pediatr 1990; 36:171–175. 37. Gray RH, Ferraz EM, Amorim MS, De Melo LF. Levels and determinants of early neonatal mortality in natal northeastern Brazil: results of a surveillance and case-control study. Intl J Epidemiol 1991; 20: 467–473. 38. WHO. Maternal anthropometry and pregnancy outcomes: WHO Collaborative Study. Bull WHO 1995; 73(suppl):1–98. 39. Govindasamy P, Stewart MK, Rutstein SO, Boerma JT, Sommerfelt AE. United Nations Children’s Fund. The State of the World’s Children 1997. Oxford: Oxford University Press, 1997. 40. Cook JD, Alvarado J, Gutnisky A, Jamra M, Labardini J, Layrisse M, et al. Nutritional deﬁciency and anemia in Latin America: a collaborative study. Blood 1971; 38:591–603. 41. Yusufji D, Mathan VI, Baker SJ. Iron, folate, and vitamin B12 nutrition in pregnancy: a study of 1000 women from southern India. Bull WHO 1973; 48:15–22. 42. Cavdar AO, Babacan E, Arcasoy A, Ertem U. Effect of nutrition on serum zinc concentration during pregnancy in Turkish women. Am J Clin Nutr 1980; 33:542–544. 43. Baker SJ. Nutritional Anaemias: Part 2: tropical Asia. Clin Haematol 1981; 10:843–871. 44. WHO. The Prevalence of Anaemia in Women: A Tabulation of Available Information, 2nd ed. WHO/MCH/MSM, 92.2. Geneva: WHO, 1992. 45. Kirksey A, Wachs TD, Yunis F, Srinath U, Rahmanifar A, McCabe G, et al. Relation of maternal zinc nutriture to pregnancy outcome and infant development in an Egyptian village. Am J Clin Nutr 1994; 60:782–792. 46. Gillespie S. Major issues in the control of iron deﬁciency. Ottawa: Micronutrient Initiative/UNICEF, 1998. 47. Subcommittee on Diet, Physical Activity, and Pregnancy Outcome, Food and Nutrition Board, U.S. Institute of Medicine/National Academy of Sciences. Diet and Activity During Pregnancy and Lactation. In: Nutrition Issues in Developing Countries. Washington, DC: National Academy Press, 1992. 48. Ceesay SM, Prentice AM, Cole TJ, Foord F, Weaver LT, Poskitt EME, et al. Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial. BMJ 1997; 315:786–790. 49. Mahomed K. Routine iron supplementation during pregnancy [Cochrane review]. In: Pregnancy and childbirth module of the Cochrane Database of Systematic Reviews. Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, eds. The Cochrane Library, Issue 4, Oxford: Update Software, 1999. 50. Mahomed K. Routine folate supplementation in pregnancy [Cochrane review]. In: Pregnancy and childbirth module of the Cochrane Database of Systematic Reviews. Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, eds. The Cochrane Library, Issue 4, Oxford: Update Software, 1999. 51. Mahomed K. Zinc supplementation in pregnancy [Cochrane review]. In: Pregnancy and childbirth module of the Cochrane Database of Systematic Reviews. Neilson JP, Crowther CA, Hodnett ED, Hofmeyr GJ, eds. The Cochrane Library, Issue 2, Oxford: Update Software, 1998. 52. Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997; 337:69–76. 53. Kesmodel U, Olsen SF, Salvig JD. Marine n-3 fatty acid and calcium intake in relation to pregnancy induced hypertension, intrauterine growth retardation, and preterm delivery. Acta Obstet Gynecol Scand 1997; 76:38–44. 54. Olsen SF, Hansen HS, Secher NJ, Jensen B, Sandstrom B. Gestation length and birth weight in relation to intake of marine n-3 fatty acids. Br J Nutrit 1995; 73:397–404. 55. Caulﬁeld LE, Zavaleta N, Figueroa A, Leon Z. Maternal zinc supplementation does not affect size at birth or pregnancy duration in Peru. J Nutr 1999; 129:1563–1568.

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56. Fawzi WW, Msamanga GI, Spiegelman D, Urassa EJ, McGrath N, Mwakagile D, et al. Randomized trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-infected women in Tanzania. Lancet 1998; 351:1477–1482. 57. Carmichael SL, Abrams B. A critical review of the relationship between gestational weight gain and preterm delivery. Obstet Gynecol 1997; 89:865–873. 58. Naeye RL. Maternal body weight and pregnancy outcome. Am J Clin Nutr 1990; 52:273–279. 59. Little RE, Weinberg CR. Risk factors for antepartum and intrapartum stillbirth. Am J Epidemiol 1993; 137:1177–1189. 60. Lucas A, Morley R, Cole TJ, et al. Maternal fatness and viability of preterm infants. BMJ 1988; 296: 1495–1497. 61. Cnattingius, S, Bergstrom R, Lipworth L, Kramer MS. Prepregnancy weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998; 338:147–152. 62. Barros FC, Victora CG, Vaughan JP, Estanislasu HJ. Perinatal mortality in southern Brazil: a population-based study of 7,392 births. Bull WHO 1987; 65:95–104. 63. Barros FC, Vaughan JP, Victora CG, Huttly SRA. An epidemic of caesarean sections in Brazil? The inﬂuence of tubal ligations and socioeconomic status. Lancet 1991; 338:167–169. 64. WHO. Obesity: Preventing and Managing the Global Epidemic. Geneva: WHO, 1998. 65. Udall, JN, Harrison GG, Vaucher Y, Walson PD, Morrow GIII. Interaction of maternal and neonatal obesity. Pediatrics 1978; 62:17–21. 66. Ounsted M, Scott A. Associations between maternal weight, height, weight-for-height, weight-gain and birth weight. In: Maternal Nutrition in Pregnancy Eating for Two? Dobbing J, ed. Academic, London, 1981 pp. 113–129. 67. Wolfe HM, Zador IE, Gross TL, Martier SS, Sokol RJ. The clinical utility of maternal body mass index in pregnancy. Am J Obstet Gynecol 1991; 164:1306–1310. 68. Kramer MS, Olivier M, McLean FH, Willis DM, Usher RH. The impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome. Pediatrics 1990; 85:707–713. 69. Bang AT, Bang RA, Baitule SB, Reddy MH, Deshmukh MD. Effect of home-based neonatal care and management of sepsis on neonatal mortality: ﬁeld trial in rural India. Lancet 1999; 354:1955–1961. 70. MRC Vitamin Study Research Group Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338:131–137. 71. Berry RJ, Li Z, Erickson JD, Li S, Moore CA, Wang H, et al. Prevention of neural-tube defects with folic acid in China. N Engl J Med 1999; 341:1485–1490. 72. Kramer MS, Haas J, Kelly A. Maternal anthropometry-based screening and pregnancy outcome: a decision analysis. Trop Med Intl Health 1998; 3:447–453. 73. Kramer MS. The effects of energy and protein intake on pregnancy outcome: an overview of the research evidence from controlled clinical trials. Am J Clin Nutr 1993; 58:627–635. 74. Rose G. Strategy of prevention: lessons from cardiovascular disease. BMJ 1981; 282:1847–1851. 75. Rose G. Sick individuals and sick populations. Intl J Epidemiol 1985; 14:32–38. 76. Haas JD, Murdoch S, Rivera J, Martorell R. Early nutrition and later physical work capacity. Nutr Rev 1996; 54 (2 Pt 2):S41–S48. 77. Martorell R, Ramakrishnan U, Schroeder DG, Ruel M. Reproductive performance and nutrition during childhood. Nutr Rev 1996; 54 (4 Pt 2): S15–S21. 78. Subcommittee on Nutritional Status and Weight Gain During Pregnancy, Food and Nutrition Board, U.S. Institute of Medicine/National Academy of Sciences. Nutrition During Pregnancy. Washington, DC: National Academy Press, 1990. 79. Galuska DA, Serdula M, Pamuk E, Siegel PZ, Byers T. Trends in overweight among US adults from 1987 to 1993. Am J Public Health 1996; 86:1729–1735. 80. Kuczmarski RJ, Flegal KM, Campbell SM, Johnson CL. Increasing prevalence of overweight among US adults. JAMA 1994; 272:205–211. 81. Kuskowska-Wolk A, Bergstrom R. Trends in body mass index and prevalence of obesity in Swedish women 1980–89. J Epidemiol Comm Health 1993; 47:195–199. 82. Skodova Z, Pisa Z, Emrova R, et al. Cardiovascular risk factors in the Czech population. Cor Vasa 1991; 33:114–122.

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1. INTRODUCTION In this new century, the quality of life of infants and young children, as opposed to mere survival, is becoming increasingly important. Most developing countries have experienced dramatic decreases in their infant and under-ﬁve mortality rates over the last three decades. As greater numbers of children survive, it becomes critical to pay closer attention to children’s ability to develop their full physical and mental potentials. This in turn will have important consequences in adult life. Child growth is internationally recognized as the best global indicator of physical well-being in children because poor feeding practices—both in quantity and quality— and infections, or more often a combination of the two, are major factors that affect physical growth and mental development in children (1). Poor child growth is the consequence of a range of factors that are closely linked to the overall standard of living and whether a population can meet its basic needs, such as access to food, housing, and health care. Child-growth assessment thus not only serves as a means for evaluating the health and nutritional status of children but also provides an excellent measurement of the inequalities in health faced by populations. Based on this principle, internationally set health goals for this century will be assessed on the basis of improvements on the rates of linear growth retardation or stunting (2). There is strong evidence that poor growth (i.e., low height-for-age or stunting) is usually associated with deﬁcient or delayed mental development (3), and a number of studies have demonstrated a relationship between growth status and school performance and intellectual achievement (4,5). The precise mechanism linking stunting and poor mental development is not known. The association cannot be regarded as a simple causal relationship because of the complex environmental factors that affect both growth and development; many socioeconomic disadvantages that coexist with stunting may also detrimentally affect mental development. It is possible that more than one mechanism act together. For example, nutritionally deprived children are often described as lethargic, possibly because they reduce their activity as a protective measure to conserve energy (6). This reduced activity limits the child’s ability for exploration and interaction and thus may have negative consequences for children’s

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motor and cognitive development. Children who do not practice their existing skills may be less likely to acquire new skills. At the same time, the apathy these children exhibit could lead adults to treat them differently from nonstunted children. Undernutrition could also have a direct effect on children’s central nervous system (CNS). These complex relationships make it difﬁcult to disentangle the exact mechanisms of the association between deﬁcits in growth and poor mental development. Impaired growth is ultimately a response to limited nutrient availability and/or utilization at the cellular level. Although in the past most of the attention has been directed toward the negative consequences associated with inadequate protein-energy intake, there is increasing recognition of the important role that micronutrient deﬁciencies plays in children’s growth and development. At severe levels of protein-energy deﬁciency, linear growth probably stops and body reserves are used as energy and protein sources to maintain vital functions. At less severe stages, however, it may be possible to cope by simply slowing the rate of linear growth and other compensatory mechanisms such as reduced activity. The negative consequences of micronutrient deﬁciencies range from altered immunity and increased risk of infectious diseases and death to reduced growth and mental development (7). Nutritional deficiencies in turn are deeply rooted in poverty and deprivation. Poverty breeds undernutrition, which, in turn, generates poverty in a vicious cycle that perpetuates across generations. The intrinsic links between poverty and nutrition have been reviewed in detail elsewhere (8). Based on national level data, Fig. 1 shows the effect of socioeconomic status on stunting for four countries in Asia and Latin America. These associations are consistent across those countries with similar dose-response relationship. Regardless of the origin, the consequences of impaired growth and development in children can be long-lasting and compromise academic performance and the ability to contribute to society. Most growth retardation occurs very early in life; the two periods of highest vulnerability are during intrauterine development and during the transition from reliance on breast milk to addition of other foods to the diet, generally beginning in the second 6 mo of life (9). In fact, almost all of the growth retardation documented in studies carried out in developing countries has its origin in the ﬁrst 2 or 3 yr of life (10). Once present, growth retardation usually remains for life as growth deﬁcits are generally not recuperated (11). This chapter reviews concepts and indicators for measuring impaired fetal and child growth; describes the magnitude and geographical distribution of growth retardation in developing countries; discusses the links between fetal- and child-growth retardation; outlines the main health and social consequences of impaired growth in terms of morbidity, mortality, child development, and adult-life consequences; and reviews interventions aimed at promoting healthy growth and development.

2. MEASURING IMPAIRED GROWTH: CONCEPTS AND INDICATORS 2.1. Fetal Growth Growth failure is a cumulative process that can begin in utero. Various criteria have been used to classify an infant as having experienced normal, subnormal, or supranormal growth in utero. Recently an expert committee from the World Health Organization (WHO) recommended the 10th percentile of a birth-weight-for-gestational-age, sex-

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Fig. 1. Variation of height-for-age according to educational level.

speciﬁc, single/twins risk curve for the classiﬁcation of small-for-gestational age (1). Strictly speaking, small-for-gestational-age infants are not synonymous to intrauterine growth retardation (IUGR); some small-for-gestational-age infants may merely represent the lower tail of the normal fetal growth distribution. In individual cases, however, it is usually very difﬁcult to determine whether an observed birth weight that is low for gestational age is the result of true in utero growth restriction or represents a “normally small” infant. Classiﬁcation of IUGR is therefore based on the established cut-off for small-for-gestational-age. The higher the prevalence of small-for-gestational-age in a given population, the greater the likelihood that smallfor-gestational-age is a result of IUGR (1). Historically, because valid assessment of gestational age is often not available in developing countries, the incidence of low birth weight (LBW) has been used as a proxy to quantify the magnitude of IUGR in these settings. This approach, however, underestimates considerably the true magnitude of IUGR because it does not take into account those infants whose weight at birth falls below the 10th percentile but who

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weigh more than 2500 g; many of these infants are likely to also have IUGR (12). It is thus important to improve the availability and quality of gestational age estimates on a population-wide basis in developing countries. This includes, where feasible, recording early in pregnancy the mother’s recall of the date her last normal menstrual period began and the training of birth attendants in the physical assessment of the newborn. In developed countries, early ultrasound examination has improved the validity and reliability of gestational-age assessment, although evidence from randomized trials does not demonstrate improvement in maternal or fetal/infant outcomes with routine early ultrasound (13). The issue of which reference curve to use in assessing growth at birth has been a cause of debate. Based on the observation that children of well-off populations in developing countries experience similar growth patterns as those of healthy, wellnourished children in developed countries, and that children of the same genetic background show differing growth performance depending on the environment in which they grow up, there is prevailing international consensus that children of all races have the same growth potential, and that country- or race-speciﬁc growth references are not advised (1). Growth curves should certainly not be adjusted for factors that may be a cause of growth retardation. For example, making adjustments for the height of stunted parents in deprived populations could reinforce the wrong impression that children from these populations are born small for genetic reasons and that not much can be done about this. On this basis, recently a group of international experts recommended that an international fetal growth reference curve should be developed based on pooled data from countries in different geographical regions where fetal growth is believed optimal (13). There remain outstanding research questions in the classiﬁcation and deﬁnition of IUGR. Although the use of a single, sex-speciﬁc international reference is justiﬁable, research is needed to assess whether infants of different genetic backgrounds born at a particular weight-for-gestational-age are at substantially different risks for mortality and morbidity. Similarly, it would be important to determine whether infants who are born small because their mothers are primiparous or living at high altitude are at the same risk for adverse outcomes as those of equivalent size who are small because, for instance, their mothers are stunted or have pre-eclampsia or are smokers. In addition, research is needed to based the criteria for deﬁning IUGR on evidence of increased risk for important health outcomes, such as perinatal mortality. Because proportionality at birth may be related to adverse health outcomes (13,14), an attempt should also be made to develop reference data and indicators for the classiﬁcation of newborns as “wasted” and “stunted,” and to quantify the morbidity and mortality risks associated with these two types of infants.

2.2. Child-Growth Indicators and Their Interpretation In children the three most commonly used indices to assess their growth status are weight-for-height, height-for-age, and weight-for-age. These anthropometric indices can be interpreted as follows: 2.2.1. LOW WEIGHT-FOR-HEIGHT Wasting or thinness indicates in most cases a recent and severe process of weight loss, which is often associated with acute starvation and/or severe disease. However, wasting

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may also be the result of a chronic unfavorable condition. Provided there is no severe food shortage, the prevalence of wasting is usually below 5%, even in poor countries (10). The Indian subcontinent, where higher prevalences are found, is an important exception. On the severity index, prevalences between 10–14% are regarded as serious, and 15% or above as critical (1). Typically, the prevalence of low weight-for-height shows a peak in the second year of life (10). Lack of evidence of wasting in a population does not imply the absence of current nutritional problems; stunting and other deﬁcits may be present (15). 2.2.2. LOW HEIGHT-FOR-AGE Stunted growth reﬂects a process of failure to reach linear growth potential as a result of suboptimal health and/or nutritional conditions. On a population basis, high levels of stunting are associated with poor socioeconomic conditions (Fig. 1) and increased risk of frequent and early exposure to adverse conditions such as illness and/or inappropriate feeding practices. Similarly, a decrease in the national stunting rate is usually indicative of improvements in overall socioeconomic conditions of a country (16). The worldwide variation of the prevalence of low height-for-age is considerable, ranging from 5–65% among the less-developed countries (10,17). In many such settings, prevalence starts to rise at the age of about 3 mo; the process of stunting slows down at around 3 yr of age, after which mean heights run parallel to the reference (10). Therefore, the age of the child modiﬁes the interpretation of the ﬁndings: for children in the age group below 2–3 yr, low height-for-age probably reﬂects a continuing process of “failing to grow” or “stunting;” for older children, it reﬂects a state of “having failed to grow” or “being stunted.” From the point of view of interventions, it is important to differentiate between these two groups. 2.2.3. LOW WEIGHT-FOR-AGE Weight-for-age reﬂects body mass relative to chronological age. It is inﬂuenced by both the height of the child (height-for-age) and his or her weight (weight-for-height), and its composite nature makes interpretation complex. For example, weight-for-age fails to distinguish between short children of adequate body weight and tall, thin children. However, in the absence of signiﬁcant wasting in a community, similar information is provided by weight-for-age and height-for-age, in that both reﬂect the longterm health and nutritional experience of the individual or population. Short-term change, especially reduction in weight-for-age, reveals change in weight-for-height. In general terms, the worldwide variation of low weight-for-age and its age distribution are similar to those of low height-for-age (10). Other available anthropometric indices that can be used to describe growth status during childhood include mid-upper arm circumference (MUAC), body mass index (BMI), skinfolds, and head circumference; however, few have achieved such widespread use as the height- and weight-based indices mentioned earlier. MUAC has been proposed as an alternative index for use where the collection of height and weight measurements is difﬁcult (e.g., refugee crises), however, its proper application requires the use of age-speciﬁc reference data to permit interpretation of ﬁndings as MUACfor-age (18). In addition to the inconvenience of having to refer to reference data, this also implies the need to determine age, an important drawback of using MUAC-for-age under difﬁcult ﬁeld conditions.

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2.3. The International Reference Population The designation of a child as having impaired growth implies some means of comparison with a “reference” child of the same age and sex. Thus, in practical terms, anthropometric values need to be compared across individuals or populations in relation to an acceptable set of reference values. This need has made the choice of a growth reference population an important issue that has received considerable attention in the last decades. The international reference growth curves, the so-called National Center for Health Statistics (NCHS)/World Health Organization (WHO) international reference population, were formulated in the 1970s by combining growth data from two distinct data sets. All samples consisted of healthy, well-nourished U.S. children as the curves were originally planned to serve as a reference for the U.S. A detailed account of the historical background of the NCHS/WHO growth charts can be found elsewhere (1,19). The WHO adopted the reference curves of the NCHS for international use in the late 1970s (20) based on the then growing evidence that the growth patterns of wellfed, healthy preschool children from diverse ethnic backgrounds are very similar (21). Differences of genetic origin are evident for some comparisons; however, these variations are relatively minor compared with the large worldwide variation in growth related to health and nutrition (22). The adoption by WHO of the NCHS-based growth curves resulted in their wide international dissemination. Throughout the 1980s, several microcomputer-based software versions of the NCHS/WHO international growth reference were developed and supported by the Centers for Disease Control and Prevention (CDC) and WHO. These software-based references have contributed to the wide acceptance of the concept of the international growth reference because they simpliﬁed the handling of anthropometric data from surveys, surveillance, and clinical studies. Although the NCHS/WHO international growth curves have served many useful purposes throughout these years, because of a number of serious drawbacks, the suitability of these curves for international purposes has recently been challenged (1,23). Work supported by WHO has demonstrated that the current international reference is sufﬁciently ﬂawed as to interfere with the sound health and nutritional management of infants and young children. These ﬂaws arise from both technical and biological considerations. In particular, the current reference may lead to the early introduction of complementary foods in exclusively breast-fed infants, which often has adverse consequences for the health and nutritional well-being of infants (24,25). As a result, an international effort is currently underway to develop a new international growth reference (26). Until the new reference is developed, the NCHS/WHO growth reference curves will remain the reference values recommended for international use.

2.4. Issues in the Interpretation of Growth Data One essential consideration is the appropriate use of the reference data. The way in which a reference is interpreted and the clinical and public health decisions that will be based upon it are often more important than the choice of reference. The reference should be used as a general guide for screening and monitoring and not as a ﬁxed standard that can be applied in a rigid fashion to individuals from different ethnic, socioeconomic, and nutritional and health backgrounds. For clinical or individual-based

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application, reference values should be used as a screening tool to detect individuals at greater risk of health or nutritional disorders; and they should not be viewed as a self-sufﬁcient diagnostic tool. For population-based application, the reference values should be used for comparison and monitoring purposes. In a given population, a high prevalence of anthropometric deficit will be indicative of significant health and nutritional problems; however, it is not only those individuals below the cut-off point who are at risk. The entire population is at risk, and the cut-off point should be used only to facilitate the application of the indicator. There are three different systems by which a child or a group of children can be compared to the reference population: Z-scores (standard deviation [SD] scores), percentiles, and percent of median. For population-based assessment—including surveys and nutritional surveillance—the Z-score is widely recognized as the best system for analysis and presentation of anthropometric data because of its advantages compared to the other methods (1). At the individual level, however, although there is substantial recognition that Z-score is the most appropriate descriptor of malnutrition, health and nutrition centers (e.g., supplementary feeding programs in refugee camps) have been in practice reluctant to adopt its use for individual assessment. A detailed description of the three systems, including a discussion of their strengths and weaknesses, can be found elsewhere (27). In clinical applications, children are commonly classiﬁed using a cut-off value, often <–2 and >+2 Z-scores. The rationale for this is the statistical deﬁnition of the central 95% of a distribution as the “normal” range, which is not necessarily based on the optimal point for predicting functional outcomes. A better approach to classifying individual children would be to base the cut-offs on the relationship between growth deﬁcits and health outcomes, such as mortality, morbidity, and child development. The difﬁculty of this approach is that these relationships differ according to the prevalence of health and nutritional disorders, and thus it would be more advisable to develop practical methods for identifying local cut-offs that take account of local circumstances. For population-based applications, a major advantage of the Z-score system is that a group of Z-scores can be subjected to summary statistics such as the mean and SD. The mean Z-score, though less commonly used, has the advantage of describing the nutritional status of the entire population directly without resorting to a subset of individuals below a set cut-off. A mean Z-score signiﬁcantly lower than zero—the expected value for the reference distribution—usually means that the entire distribution has shifted downward, suggesting that most, if not all, individuals have been affected. Using the mean Z-score as an index of severity for health and nutrition problems results in increased awareness that, if a condition is severe, an intervention is required for the entire community, not just those who are classiﬁed as “malnourished” by the cut-off criteria (28). In addition, the observed SD value of the Z-score distribution is very useful for assessing data quality (1). Lastly, experience with population surveillance has contributed to emphasizing the usefulness of identifying prevalence ranges to assess the severity of a situation as the basis for making public health decisions. For example, when 10% of a population is below the –2 SD cut-off for weight-for-height, is that too much, too little, or average? The intention of the so-called “trigger-levels” is to assist in answering this question by giving some kind of guideline for the purpose of establishing levels of public

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Table 1 Classiﬁcation for Assessing Severity of Growth Deﬁcits by Prevalence Ranges Among Children Under 5 Yr of Age Severity of growth deﬁcits by prevalence ranges (%) Indicator

Low

Medium

High

Very high

Stunting Underweight Wasting

<20 <10 <5

20–29 10–19 5–9

30–39 20–29 10–14

*40 *30 *15

Adapted with permission from ref. (1).

health importance of a situation. Such classiﬁcations are very helpful for summarizing prevalence data and can be used for targeting purposes when establishing intervention priorities. It is important to note that the “trigger-levels” vary according to the different anthropometric indicators. The prevalence ranges shown in Table 1 are those currently recommended (1) to classify levels of stunting, underweight, and wasting.

3. PREVALENCE OF GROWTH RETARDATION IN DEVELOPING COUNTRIES A recent analysis using data from the WHO Global Database on Low Birth Weight quantiﬁes the magnitude of IUGR in different countries and regions of the world (12). As summarized in Table 2, it is currently estimated that at least 13.7 million babies in developing countries are already malnourished at birth every year, representing 11% (ranging from 1.9–20.9%) of all newborns in these countries. This rate is considerably higher than that estimated for developed countries, which is approx 2%. Overall, the incidence of IUGR-LBW is about six times higher in developing than in developed countries (29). The estimates of IUGR-LBW, however, greatly underestimate the magnitude of fetal-growth retardation; the actual incidence of IUGR could be considerably higher. For example, if the rates of infants below the 10th percentile of the birth-weight-forgestational-age reference curve is considered, 23.8%, or approx 30 million newborns/yr, would be affected (Table 2). There are nevertheless some healthy infants with birth weights below the 10th percentile who represent the lower tail of a fetal growth distribution. However, in most developing countries, a large proportion of newborns suffers from some degree of IUGR, as illustrated by the overall downward shift of the birth-weight distribution. Unfortunately, a methodology to disentangle these two groups is not available. The risk of being born malnourished is highest in Asia, followed by Africa. Taking into consideration the number of total live births in each geographical region, nearly 75% of all affected newborns are born in Asia (mainly Southcentral Asia), 20% in Africa, and about 5% in Latin America (12). Although there are constraints to deriving these estimates, mainly related to the qualitative and quantitative limitations of the available data, they still represent a valid approximation for descriptive and epidemiological purposes. These estimates conﬁrm that IUGR is a major public health problem worldwide. In many countries, the high rates of impaired fetal growth exceed the recommended levels for triggering public health action (12). A prevalence of IUGR in excess of 20% has been recommended as the cut-off point;

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Table 2 Summary Estimates of Impaired Fetal Growth in Developing Countries

Indicator

Total number newborns affected per yeara

Source

Rate (%)

IUGR-LBW (<2500 g; *37 wk gestation)

Live births weighted average using LBW rates from WHO data bank and regression model

11.0 (1.9–20.9)b

13,699,000

LBW (<2500 g; all gestational ages)

Live births weighted average using LBW rates from WHO data bank

16.4 (5.8–28.3)

20,423,000

IUGR From WHO Collaborative Study on (<10th percentile; Maternal Anthropometry and all gestational ages) Pregnancy Outcomes

23.8 (9.4–54.2)

29,639,000

aTotal

live births for 1995 are based on the UN World Population Prospects.

bRange.

Adapted with permission from ref. (12).

in the absence of information on gestational age, a prevalence >15% of LBW may be used as a proxy cut-off (1). Population-wide interventions are urgently needed in these high-prevalence countries aimed at preventing fetal-growth retardation. The WHO Global Database on Child Growth and Malnutrition (10,17) compiles data on height-for-age, weight-for-age, and weight-for-height of preschool children worldwide to monitor global progress in combatting childhood malnutrition. The rigorous methodology and large coverage of the Global Database permits an accurate description of the magnitude and geographical distribution of child growth retardation in developing countries. At present, the Global Database covers over 95% of the total population of under-5-yr-olds (about 510 million children) living in developing countries, or 84% of this age group worldwide. Based on this vast amount of data, Fig. 2 displays the geographical distribution of countries according to their prevalence of stunting. Prevalences have been grouped according to the recommended “trigger” levels of public health importance (Table 1). The disaggregation by sex shows no consistent differences between male and female, however, prevalence rates are consistently higher in rural than in urban areas, and can vary considerably by age and region within countries. Detailed information on national surveys concerning data disaggregated by age, sex, urban/rural residence, and region, can be found elsewhere (10). Table 3 presents regional and global estimates for the prevalence and number of stunted under-5-yr-old children by UN regions for 1990 and 1995. It is estimated that about 38% of children under 5 yr of age in developing countries, or 206 million, were stunted in 1995. Asia being the most affected region. The number of under-5-yrolds living in each geographical area—54 million in Latin America, 122 million in Africa, and 363 million in Asia—renders the regional distribution even more unequal. Currently, over two-thirds (72%) of the world’s stunted children live in Asia (especially Southcentral Asia), whereas 23% are found in Africa and 5% in Latin America. Oceania, despite its high prevalence of stunting, contributes very little to the absolute number

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Fig. 2. Prevalence of stunted children in developing countries. Adapted with permission from ref. (10).

of stunted children, because there live fewer than 1 million under-5-yr-olds in the developing countries of this region. Estimates of stunting for all UN-subregions in Africa, Asia, and Latin America are also presented in Table 3. Southcentral Asia has by far the highest stunting levels, both in terms of prevalence and absolute numbers. In this subregion alone, about 50%, or 86 million under-ﬁves are stunted, accounting for 42% of the total number of stunted children in developing countries. Within Asia, the South-eastern subregion follows next, also with very high rates of stunting. Its contribution in terms of absolute numbers is considerably less, however, because there are much fewer under-5-yr-olds living in this subregion. In Africa, Eastern Africa ranks ﬁrst with 48% of stunted children, followed by Middle (40%) and Western (37%) Africa. About 40 million are stunted in these three subregions, accounting for about 20% of the total number of stunted children in developing countries. Lower levels are found in Latin America with an average prevalence level of 18% or around 10 million stunted children. Central America presents a considerably higher rate (27%) than that found in South America (14%). Table 3 also shows recent trends (1990–1995) in stunting. Global and regional historical trends (1975–1995) in prevalence and numbers of affected children are presented in Fig. 3 and 4. The prevalence of stunting has progressively fallen in developing countries from 1975 to 1995. However, the latest evidence shows a deceleration in improved child growth status, and in Africa the previous decreasing trend has been reversed. As a result, the total number of stunted children in Africa has increased from around 41 million in 1990 to 47 million in 1995 (Table 3 and Fig. 4). Progress towards reducing malnutrition varies widely across countries. Trend information for those countries with multiple national survey data are presented elsewhere (10). Overall, the data compiled by WHO’s Global Database conﬁrm the extent of stunting on a global

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Table 3 Trends Based on Regional Estimates for 1990 and 1995 in Prevalence and Numbers of Stunted Children (<–2 SD Height-for-Age) 1990 (UN regions and subregions Africa East Africa Middle Africa Northern Africa Southern Africa Western Africa Asiac Eastern Asiac Southcentral Asia Southeastern Asia Western Asia Latin America and Caribbean Caribbean Central America South America Oceaniad Developing countries Global

1995

%

Millionsa

%

Millions

36.8 48.3 NAb 25.4 NA 36.8 42.6 31.4 52.7 40.8 NA 21.9 22.2 30.4 18.1 36.4 39.4 34.6

240.6 1117.5 NA 115.3 NA 112.4 162.2 139.1 194.2 123.2 NA 211.9 110.8 114.7 116.4 210.3 215.0 216.0

38.6 48.0 40.2 26.6 23.7 37.1 41.0 31.4 49.6 39.7 24.9 17.9 17.3 26.7 13.8 31.4 38.1 34.0

247.0 119.4 116.3 115.6 111.6 114.2 149.1 134.5 186.5 122.6 115.5 229.7 110.6 114.3 114.7 220.3 206.2 208.1

aTotal

population under 5 yr of age based on the World Population Prospects—The 1996 Revision. available (insufﬁcient population coverage to derive estimates). cExcluding Japan. dExcluding Australia and New Zealand. Adapted with permission from ref. (10). bNA-Not

Fig. 3. Global trends in prevalences of stunting in children under 5 yr of age, 1975–1995. Adapted with permission from ref. (10).

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Fig. 4. Global trends in numbers of stunted children under 5 yr of age, 1975–1995. Adapted with permission from ref. (10).

scale, which continues to hamper the physical and mental development of infants and young children.

4. HEALTH AND SOCIAL CONSEQUENCES OF IMPAIRED GROWTH The health and social consequences of the current high prevalences of fetal- and child-growth retardation in developing countries are severe. Fetuses who suffer from growth retardation have higher perinatal morbidity and mortality (14,30,31), are at an increased risk of sudden infant death syndrome (SIDS) (32), and have higher infant mortality and childhood morbidity (33). During childhood they are more likely to have poor cognitive development (34,35) and neurologic impairment (36–38); in adulthood they are at increased risk of cardiovascular disease (39), high blood pressure (40), obstructive lung disease (41), diabetes (42), high cholesterol concentrations (43), and renal damage (44). Newborns with IUGR have lower levels of insuline-like growth factor I (IGF-1) and higher growth-hormone levels (45), indicating an endocrine process that could be related to these long-term impairments. The major outcomes of poor growth during childhood can be classiﬁed in terms of mortality, morbidity (incidence and severity), and psychological and intellectual development. There are also important consequences in adult life in terms of body size, work and reproductive performances, and risk of chronic diseases. A number of studies have demonstrated the association between increasing severity of anthropometric deﬁcits and mortality (46). It is now recognized that growth retardation has a far more powerful impact on child mortality than has been traditionally recognized, which, in turn, has important implications for policy and programs addressing child survival. In 1995, it was estimated that 54%, or about 6.3 million deaths among children under 5 yr of age in developing countries were associated with poor

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Fig. 5. Distribution of 11.6 million deaths among children less than 5 yr old in all developing countries, 1995. Adapted with permission from ref. (10).

growth (Fig. 5), the majority of which were owing to the potentiating effect of mildto-moderate growth retardation as opposed to severe retardation (46,47). Thus, strategies that focus only on severely retarded children will be insufﬁcient to improve child survival in a meaningful way. The most signiﬁcant impact can be expected when all grades of severity are targeted. Similarly, children suffering from impaired growth tend to have more severe diarrheal episodes and are more susceptible to several infectious diseases frequently seen in developing countries, such as malaria or meningitis (48,49) (Fig. 6). The risk of pneumonia is also increased in these children (50). There is strong evidence that poor growth is associated with impaired development (3,5), and a number of studies have demonstrated a relationship between growth status and school performance and intellectual achievement (4). Child stunting leads to signiﬁcant reduction in adult size (4); one of the main consequences of small adult size resulting from stunting during childhood is reduced work capacity (51), which in turn has an impact on economic productivity. For women, maternal size is associated with speciﬁc reproductive outcomes. Data from the Guatemalan Longitudinal Study (4) shows how the percentage of women with short stature varies strikingly according to the degree of stunting at 3 yr of age. As shown in Fig. 7, 65% of the girls severely stunted at age 3, had short stature when they became adults. Short women are at a greater risk for obstetric complications because of smaller pelvic size (1). There is also a strong association between maternal height and birth weight (52). This results in an intergenerational effect because LBW babies are themselves likely to have anthropometric deﬁcits at later ages (53,54). These LBW babies, born to stunted mothers, contribute to closing the intergenerational cycle by which low maternal size and anemia, predisposes to LBW babies, which in turn predisposes to growth failure on children, leading back to small adults (Fig. 8). Also the ocurrence of early pregnancy will contribute both in terms of LBW and inducing premature cessation of growth in the mother. The implications of this vicious cycle are enormous for the human and socioeconomic development of the affected populations.

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Fig. 6. Mortality of malaria, cerebral malaria, transfused malaria anemia, meningitis, bronchiolitis, pneumonia, gastroenteritis, malnutrition, and of all diseases combined by weight-for-age (WAZ) expressed as Z-score on admission. Adapted with permission from ref. (49).

In summary, the magnitude of the problem and the severity of the health and social consequences associated with impaired growth cannot be overemphasized. Child growth is a major determinant of human development. Thus there is an urgent need to develop and/or identify effective community-based interventions for improving child growth and development. Population-wide interventions aimed at preventing IUGR are also urgently required, given the strong association between pre- and post-natal growth (1,54) and the magnitude of fetal-growth retardation in developing countries.

5. INTERVENTIONS AIMED AT PROMOTING HEALTHY GROWTH AND DEVELOPMENT A comprehensive review of the evidence from 126 randomized controlled trials (RCTs) evaluating 36 prenatal interventions aimed at preventing or treating impaired fetal growth was recently carried out by Gülmezoglu et al. (55). The same authors provided an in-depth analysis of nutritional interventions evaluated in RCTs (56). RCTs are widely recognized to be the most objective and rigorous available method to evaluate the effectiveness of health-care interventions. Systematic reviews of RCTs provide an excellent tool for summarizing the results of interventions. By following a rigorous methodology they reduce bias; improve reliability and accuracy of conclusions; and can establish if trial results are consistent and generalizable across populations, settings, and treatment variations. The strategies evaluated by Gülmezoglu et al. (55) include care and advice during pregnancy (e.g., social support for women at risk, strategies to stop smoking, nutritional advice); nutrition supplementation (e.g.,

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Fig. 7. Prevalence of short stature (<149 cm) in Guatemalan women (> 18 yr) by degree of stunting at 3 yr of age. Adapted with permission from ref. (14).

Fig. 8. Intergenerational cycle of growth failure.

protein/energy, vitamin and minerals, antianemic supplements, ﬁsh-oil supplementation); and prevention/treatment of hypertensive disorders, fetal compromise, and infections. Based on this review, only 2 out of 24 non-nutritional interventions—strategies to reduce maternal smoking and antimalarial chemoprophylaxis in primigravidae—provide evidence of being beneﬁcial (Table 4). Strategies to reduce smoking during pregnancy are associated with increased birth weight and lower rate of term-LBW (typical odds ration: 0.80; 95% CI: 0.65–0.98). These effects have been greater in more compliant groups, and those groups who were more successful in stopping smoking showed the highest mean birth weight gains. The systematic review on the use of antimalarial drug chemoprophylaxis shows that malaria chemoprophylaxis is associated with higher maternal hemoglobin levels and birth weights. These effects were more prominent in primigravidae, who are known to be more susceptible.

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Table 4 Forms of Care Likely to be Beneﬁcial and Forms of Care of Unknown Effectiveness That Merit Further Research for the Prevention or Treatment of Impaired Fetal Growth Intervention

IFG Outcome

Effecta

Comments

Forms of care likely to be beneﬁcial Smoking cessation

Antimalarials— primigravidae Balanced protein/energy supplementation

Term-LBW

MBW SGA

0.80 (0.65–0.98)

Effect stronger in more compliant women; intervention in agreement with overall health advice 112 g (41–183 gm)b 4 trials of small sample size 0.76 (0.58–1.01)

Borderline signiﬁcance but does not include the new positive Gambia trial; lack of effective method to select women that will beneﬁt the most

Forms of care of unknown effectiveness that merit further research Routine zinc

Term-LBW

0.77 (0.54–1.11)

Routine folate

Term-LBW

0.60 (0.37–0.97)

Routine magnesium

Term-LBW

0.59 (0.37–0.93)

Abdominal decompression (for suspected IFG)

Term-LBW

0.21 (0.13–0.34)

Only the most recent trial showed positive effect Populations poorly deﬁned and limitations in randomization procedures Trials have high numbers of exclusions and limitations in the randomization procedures Possibility of selection, observer and analysis bias in the 2 RCTs; safety unknown; the large effect observed makes worthwhile to explore this technique further

aTypical odds ratios (OR) and 95% conﬁdence intervals (an OR <1 indicates that the intervention resulted in favorable outcomes). bWeighted mean difference between intervention and control groups. LBW, Low birth weight. MBW, Mean birth weight. SGA, Small for gestational age. IFG, Impaired fetal growth. Adapted with permission from ref. (55).

Only one of the 12 nutritional interventions—balanced protein/energy supplementation—shows a reduction in the incidence of IUGR (55,56). Supplementation was associated with increases in maternal weight gain and mean birth weight, and a decrease in the number of IUGR babies of borderline statistical signiﬁcance (Table 4). A new community-based trial in rural Gambia, recently made available and thus not included

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in the calculations of the typical odds ratio in Table 4, shows that supplementation signiﬁcantly increased birthweight by 136 g (57). The odds ratio for LBW babies in supplemented women was 0.61 (95% CI: 0.47–0.79), supporting the results of the systematic review (56). Overall, it is surprising how limited data are supporting the effectiveness of nutritional interventions during pregnancy, some of which are of widespread use even in women without nutritional deﬁciencies. However, it is obvious that women manifesting nutritional deﬁcits can only beneﬁt from reversing such situation. On this basis, efforts to improve women’s nutrition should be a priority, especially in developing countries, although the expected effect of maternal nutrition supplementation on birth weight may be modest (5100 g). Similarly, the average effect associated with some interventions suggests a potential effect of considerable magnitude (Table 4). Zinc, folate, and magnesium supplementation should be rigorously evaluated. Trials to evaluate these and other promising interventions should target populations at risk for IUGR; be based on sound epidemiological or basic science background information; and follow rigorous methods, including adequate sample sizes, to detect any impact on sustantial outcomes (55,56). In countries where multiple pathologies coexist, it may be difﬁcult to achieve beneﬁcial results by testing a single intervention. Malaria and other parasites, malnutrition, and anemia coexist in many developing countries and the presence of such a combination of conditions is probably worse than each one of them alone. Appropriate combinations of interventions (for example, a combination of antianemic (ironfolate) and antimicrobial/antiparasite agents tested in population-based trials) should be rigorously evaluated, because it is very unlikely that the intergenerational and intragenerational effect of deprivation and poverty on maternal and fetal health can be overcome by a single intervention or treatment. Simple solutions will not resolve the problem of fetal malnutrition and its associated outcomes (58). The WHO recently conducted a comprehensive review evaluating the effectiveness of interventions aimed at improving physical growth and/or psychological development during childhood (59). The review concluded: • Nutrition interventions signiﬁcantly improve physical growth in poor and malnourished populations. Balanced protein/energy supplementation during pregnancy improve birth weight and reduce the incidence of IUGR. Food supplementation for infants and young children has documented impacts on physical growth. Other types of effective nutrition interventions include care-giver education about feeding practices for young children, breast-feeding promotion, and zinc supplementation in zinc-deﬁcient areas. Programs that include education, food supplementation, and/or micronutrient supplementation can result in reductions in the prevalence of moderate and severe growth retardation. • Nutrition interventions signiﬁcantly improve psychological development in disadvantaged populations. Increased intake of nutrients and energy during the ﬁrst 2 yr of life, and prenatally through supplements to mothers, have signiﬁcant positive impacts on cognitive and motor development. For example, interventions to prevent iodine deﬁciency have dramatic effects on cognitive development, as well as preventing the physical stunting that accompanies iodine deﬁciency. • Psychosocial interventions signiﬁcantly improve psychological development. For example, children attending preschool center-based programs gain an average of about eight IQ points by the time they are ready to start school. They are also less likely to repeat primary school grades or be placed in special education classes.

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• Combined interventions to improve both physical growth and psychological development have even greater impact in disadvantaged populations at risk of malnutrition. The combination of supplementation and stimulation interventions appears to have a greater effect on cognitive development than either one alone. These combined nutrition and psychological interventions had signiﬁcant impacts on both growth and development in every study that tested this relationship.

There are a number of conditions under which the impact on growth and development is most likely to be seen. Interventions during the earliest periods of life—prenatally and during infancy and early childhood—are likely to have the greatest impact. The children at higher risk are generally the ones who show the greatest response to growth and development interventions. Growth and development programs that utilize several types of interventions and more than one delivery channel are more efﬁcacious than those that are more restricted in scope. Types of interventions include nutrition education on diet and feeding practices, providing supplementary food or micronutrient supplements, and demonstrating cognitive stimulation activities or other activities to improve parenting skills. Types of delivery channels are home visits, group counseling, child-care centers, and mass media. Program efﬁcacy and effectiveness appear to be greater when parents are more involved. When discussing combined interventions, a number of challenges arise. Many potential models for combined interventions to promote physical growth and psychological development of infants and young children have not yet been implemented. Others have been implemented but not systematically evaluated, which is essential. There is a need to develop and evaluate a model of combined interventions that could reach a large proportion of children who are at risk of growth and development faltering. An example could be a culturally adaptable counseling package that combines nutrition counseling on complementary feeding (with food supplementation if necessary) with counselling on psychosocial care (e.g., warmth, attentive listening, proactive stimulation, and support for exploration and autonomy). There is also an urgent need to evaluate the effectiveness of different content, program venues, and delivery channels. Poor growth is part of a vicious cycle that includes poverty and disease. These three factors are interlinked in such a way that each contributes to the presence and permanence of the others. Given the complexity of the underlying causes of the problem, new efforts must also be made to understand the speciﬁc economic, behavioral, dietary, and other factors affecting child growth and development. A good technical package has proved to be insufﬁcient by itself; a distinguishing feature of successful programs has been community involvement in identifying the problems and mobilizing action to resolve them. Future interventions should thus be strongly community-based. Special effort should be made to improve the situation of women—as primary child caregivers—with particular attention to their health and nutrition throughout the life cycle. Similarly, a focus on complementary feeding, combined with continued attention to the protection and promotion of breast feeding, remains a key component for tackling the problem. The future of human societies relies on children being able to achieve their optimal physical growth and mental development. Never before has there been so much knowledge to assist families and societies in their desire to raise children to reach their full potential. A fundamental need is to focus the attention of policy-makers on nutritional status as one of the main indicators of development, and as a precondition for

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the socioeconomic advancement of societies in any signiﬁcant long-term sense. A good start in life will pay off, in terms of both human capital and economic development.

REFERENCES 1. World Health Organization (WHO). Physical status: the use and interpretation of anthropometry. Technical Report Series No. 854. Geneva: WHO, 1995. 2. Visschedijk J, Siméant S. Targets for health for all in the 21st century. World Health Stat Q 1998; 51: 56–67. 3. Pollitt E, Gorman KS, Engle PL, Martorell R, Rivera J. Early supplementary feeding and cognition: effects over two decades. Monogr Soc Res Child Dev 1993; 58:1–99. 4. Martorell R, Rivera J, Kaplowitz H, Pollitt E. Long-term consequences of growth retardation during early childhood. In: Human Growth: Basic and Clinical Aspects. Hernandez M, Argente J, eds. Amsterdam: Elsevier, 1992, pp. 143–149. 5. Pan American Health Organization. (PAHO). Nutrition, health and child development. Scientiﬁc Publication No. 566. Washington, DC: PAHO, 1998. 6. Spurr GB. Physical activity and energy expenditure in undernutrition. Prog Food Nutr 1990; 14: 139–192. 7. Black RE, ed. Zinc for child health. Am J Clin Nutr 1998; 68(suppl): 414S–516S. 8. Administrative Committee on Coordination/Subcommittee on Nutrition (ACC/SCN). Nutrition and Poverty. Nutrition Policy Paper #16. Geneva: ACC/SCN, 1997. 9. Brown KH, Begin F. Malnutrition among weanlings of developing countries: Still a problem begging for solutions. J Pediatr Gastroenterol Nutr 1993; 17:132–138. 10. de Onis M, Blössner M. WHO Global Database on Child Growth and Malnutrition. Doc WHO/ NUT/97.4. Geneva: WHO, 1997. 11. Martorell R, Kettel Khan L, Schroeder DG. Reversibility of stunting: epidemiological ﬁndings in children from developing countries. Eur J Clin Nutr 1994; 48(suppl 1):S45–S57. 12. de Onis M, Blössner M, Villar J. Levels and patterns of intrauterine growth retardation in developing countries. Eur J Clin Nutr 1998; 52:S1,S5–S15. 13. Bakketeig LS, Butte N, de Onis M, Kramer M, O’Donnell A, Prada JA, Hoffman HJ. Report of the IDECG Working Group on deﬁnitions, classiﬁcations, causes, mechanisms and prevention of IUGR. Eur J Clin Nutr 1998; 52:S1,S94–S96. 14. Villar J, de Onis M, Kestler E, Bolaños F, Cerezo R, Bernedes H. The differential neonatal morbidity of the intrauterine growth retardation syndrome. Am J Obstet Gynecol 1990; 163:151–157. 15. Victora CG. The association between wasting and stunting: an international perspective. J Nutr 1992; 122:1105–1110. 16. Frongillo EA Jr, de Onis M, Hanson KM. Socioeconomic and demographic factors are associated with worldwide patterns of stunting and wasting of children. J Nutr 1997; 127:2302–2309. 17. de Onis M, Blössner M. Nutrition and child health: an overview from the WHO Global Database on Child Growth and Malnutrition. Scand J Nutr 1998; 42:136–139. 18. de Onis M, Yip R, Mei Z. The development of MUAC-for-age reference data recommended by a WHO Expert Committee. Bull WHO 1997; 75:11–18. 19. de Onis M, Yip R. The WHO growth chart: historical considerations and current scientiﬁc issues. Bibl Nutr Dieta 1996; 53:74–89. 20. Waterlow JC, Buzina R, Keller W, Lane JM, Nichaman MZ, Tanner JM. The presentation and use of height and weight data for comparing nutritional status of groups of children under the age of 10 years. Bull WHO 1977; 55:489–498. 21. Habicht JP, Martorell R, Yarbrough C, Malina RM, Klein RE. Height and weight standards for preschool children; how relevant are ethnic differences in growth potential. Lancet 1974; 1:611–614. 22. Martorell R. Child growth retardation: a discussion of its causes and its relationship to health. In: Nutritional Adaptation in Man. Blaxter KL, Waterlow JC, eds. London: John Libbey, 1985; pp. 13–30. 23. de Onis M, Habicht JP. Anthropometric reference data for international use: recommendations from a World Health Organization Expert Committee. Am J Clin Nutr 1996; 64:650–658. 24. WHO Working Group on Infant Growth. An evaluation of infant growth: the use and interpretation of anthropometry in infants. Bull WHO 1995; 73:165-–174.

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25. WHO Working Group on Infant Growth. An evaluation of infant growth. Doc WHO/NUT/94.8. Geneva: WHO, 1994. 26. de Onis M, Garza C, Habicht JP. Time for a new growth reference. Pediatrics 1997; 100(5):E8. 27. Gorstein J, Sullivan K, Yip R, de Onis M, Trowbridge F, Fajans P et al. Issues in the assessment of nutritional status using anthropometry. Bull WHO 1994; 72:273–283. 28. Yip R, Scanlon K. The burden of malnutrition: a population perspective. J Nutr 1994; 124: 2043S–2046S. 29. Villar J, Ezcurra EJ, Gurtner de la Fuente V, Campodonico L. Pre-term delivery syndrome: the unmet need. New Perspectives for the Effective Treatment of Pre-term Labor: An International Consensus. Res Clin Forums 1994; 16:9–38. 30. Williams RL, Creasy RK, Cunningham GC, Hawes WE, Norris FD, Tashiro M. Fetal growth and perinatal viability in California. Obstet Gynecol 1982; 59:624–632. 31. Balcazar H, Haas JD. Retarded fetal growth patterns and early neonatal mortality in a Mexico city population. Bull PAHO 1991; 25:55–63. 32. Øyen N, Skjaerven R, Little RE, Wilcot AT. Fetal growth retardation in Sudden Infant Death Syndrome (SIDS) babies and their siblings. Am J Epidemiol 1995; 142:84–90. 33. Ashworth A. Effects of intrauterine growth retardation on mortality and morbidity in infants and young children. Eur J Clin Nutr 1998; 52:S1, S34–S42. 34. Paz I, Gale R, Laor A, Danon YL, Stevenson DK, Seidman DS. The cognitive outcome of full term small for gestational age infants at late adolescence. Obstet Gynecol 1995; 85:452–456. 35. Low J, Handley-Derry M, Burke S, et al. Association of intrauterine fetal growth retardation and learning deﬁcits at age 9 to 11 years. Am J Obstet Gynecol 1992; 167:1499–1505. 36. Parkinson CE, Wallis S, Harvey D. School achievement and behaviour of children who are small-fordates at birth. Dev Med Child Neurol 1981; 23:41–50. 37. Taylor DJ, Howie PW. Fetal growth achievement and neurodevelopmental disability. Br J Obstet Gynaecol 1989; 96:789–794. 38. Villar J, Smeriglio V, Martorell R, Brown CH, Klein RE. Heterogenous growth and mental development of intrauterine growth-retarded infants during the ﬁrst 3 years of life. Pediatrics 1984; 74:783–791. 39. Osmond C, Barker DJ, Winter PD, Fall CH, Simmonds SJ. Early growth and death from cardiovascular disease in women. BMJ 1993; 307:1519–1524. 40. Williams S, St. George IM, Silva P. Intrauterine growth retardation and blood pressure at age seven and eighteen. J Clin Epidemiol 1992; 45:1257–1263. 41. Barker DJP. The intrauterine origins of cardiovascular and obstructive lung disease in adult life: The Mark Daniels lecture 1990. J R Coll Physicians Lond. 1991; 25:129–133. 42. Hales CN, Barker DJ, Clark PM, et al. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303:1019–1022. 43. Barker DJ, Martyn CN, Osmond C, Hales CN, Fall CH. Growth in utero and serum cholesterol concentrations in adult life. BMJ 1993; 307:1524–1527. 44. Hinchliffe SA, Lynch MR, Sargent PH, Howard CV, Van Velzen D. The effect of intrauterine growth retardation on the development of renal nephrons. Br J Obstet Gynaecol 1992; 99:296–301. 45. Nieto-Diaz A, Villar J, Matorras-Weinig R, Valenzuela-Ruiz P. Intrauterine growth retardation at term: association between anthropometric and endocrine parameters. Acta Obstet Gynecol Scand 1996; 75:127–131. 46. de Onis M. Measuring nutritional status in relation to mortality. Bull WHO 2000; 78:127–1274. 47. Pelletier D, Frongillo EA Jr, Habicht JP. Epidemiologic evidence for a potentiating effect of malnutrition on child mortality. Am J Public Health 1993; 83:1130–1133. 48. Tomkins A and Watson F: Malnutrition and infection: a review. ACC/SCN State-of-the-Art Series, Nutrition Policy Discussion Paper No. 5. Geneva: ACC/SCN, 1989. 49. Man WD, Weber M, Palmer A, Schneider G, Wadda R, Jaffar S, et al. Nutritional status of children admitted to hospital with different diseases and its relationship to outcome in The Gambia, West Africa. Trop Med Intl Health 1998; 3:678–686. 50. Victora CG, Fuchs SC, Flores A, Fonseca W, Kirkwood BR. Risk factors for pneumonia in a Brazilian metropolitan area. Pediatrics 1994; 93(6 Pt 1):977–985. 51. Spurr GB, Barac-Nieto M, Maksud MG. Productivity and maximal oxygen consumption in sugar cane cutters. Am J Clin Nutr 1977; 30:316–321. 52. Kramer MS. Determinants of low birth weight: methodological assessment and meta-analysis. Bull WHO 1987; 65:663–737.

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53. Klebanoff MA, Yip R. Inﬂuence of maternal birth weight on rate of fetal growth and duration of gestation. J Pediatr 1987; 111:287–292. 54. Binkin NJ, Yip R, Fleshood L, Trowbridge FL. Birthweight and childhood growth. Pediatrics 1988; 82:828–834. 55. Gülmezoglu M, de Onis M, Villar J. Effectiveness of interventions to prevent or treat impaired fetal growth. Obstet Gynecol Surv 1997; 52:139–149. 56. de Onis M, Villar J, Gülmezoglu M. Nutritional interventions to prevent intrauterine growth retardation: evidence from randomized controlled trials. Eur J Clin Nutr 1998; 52:S1,S83–S93. 57. Ceesay SM, Prentice AM, Cole TJ, Ford F, Weaver LT, Poskitt EME, Whitehead RG. Effects on birth weight and perinatal mortality of maternal dietary supplements in rural Gambia: 5 year randomised controlled trial. BMJ 1997; 315:786–790. 58. Ferro-Luzzi A, Ashworth A, Martorell R, Scrimshaw N. Report of the IDECG Working Group on effects of IUGR on infants, children and adolescents: immunocompetence, mortality, morbidity, body size, body composition, and physical performance. Eur J Clin Nutr 1998; 52:S1,S97–S99. 59. WHO A critical link: interventions for physical growth and psychological development. DOC WHO/CHS/CAH/99.3 Geneva: Division of Child Health and Development, WHO 1999.

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Chapter 5 / Diarrheal Diseases

5

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Diarrheal Diseases Claudio F. Lanata and Robert E. Black

1. INTRODUCTION Diarrheal diseases are a leading cause of childhood morbidity and mortality in developing countries. An important contributing factor to these deaths is malnutrition. Diarrhea is a condition characterized by stools of decreased consistency and increased number, and is usually owing to infection of the gastrointestinal tract by pathogenic viruses, bacteria, or parasites. There has been great variability in the literature regarding the deﬁnition of diarrhea, as stool consistency and number can be inﬂuenced by age and type of diet. For most epidemiological studies, diarrhea is deﬁned as a condition in which three or more liquid stools are passed within any 24-hr period (1,2). This deﬁnition may be less satisfactory for breast-feeding infants under 2 mo of age, who often pass frequent, loose, “pasty” stools that are not considered to be diarrhea. An episode of diarrhea is usually considered to be terminated when an individual has at least 2 d free of diarrhea, as deﬁned earlier. Dysentery is deﬁned as diarrheal disease in which blood is present in liquid stools. Persistent diarrhea is deﬁned as an episode of diarrhea that lasts for at least 14 d. In this chapter we will review the current knowledge on this important subject, reviewing the epidemiology, pathogenesis, the interactions between nutrition and diarrheal diseases, the dietary management of these conditions, and nutrition interventions that may prevent diarrheal diseases.

2. PUBLIC HEALTH IMPORTANCE The World Health Organization (WHO) estimates that diarrheal diseases cause 3.5 million deaths per year, and most of these deaths occur within the ﬁrst 2 yr of life (3,4). Repeated attacks of diarrhea in children can lead to undernutrition, poor growth, decreased immune competence, and death. Attacks of diarrhea in undernourished children tend to be more severe and of longer duration, suggesting a vicious cycle of diarrhea and undernutrition.

3. HISTORICAL BACKGROUND Diarrheal diseases are most commonly associated with poverty, poor sanitation and hygiene, inadequate water supplies, and limited education. In the 19th and early 20th From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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centuries, diarrheal diseases contributed substantially to the high infant and young child mortality rates in Europe and the United States (5,6). Summer epidemics of diarrhea were commonly observed among infants and young children in large cities such as Paris and London during the mid- and late 19th century (7). The conditions and problems with diarrheal disease in the United States and Europe up to the early 20th century were similar to those encountered in many developing countries today (8,9). With improvements in sanitation, hygiene, child feeding practices, and improved water supplies, the problems of diarrheal disease was greatly diminished in industrialized countries. With its dramatic clinical course, epidemic nature, and high mortality, cholera has been probably the most widely studied of the diarrheal diseases through history (10,11). Cholera was endemic in south Asia and the East Indies in the 19th century and underwent several pandemics in the 19th century and into the 20th century, following trade routes and human migration (12). Further discussion of cholera and public health are discussed in Chapter 1. The relationship between nutritional status and diarrheal diseases has been recognized since early 1960s, after an increased prevalence of diarrhea was observed in malnourished children (13). Since then, several carefully conducted epidemiological and clinical studies have documented clearly the relationship between nutrition and diarrheal diseases (14). A signiﬁcant development in the treatment of diarrheal diseases has been the increased use of oral rehydration therapy using a single fluid such as glucose, sodium chloride, trisodium citrate dihydrate, and potassium chloride, collectively known as oral rehydration salts (ORS) mixed in water to form ORS solution. Oral rehydration was recognized to be effective in the treatment of cholera in adults (15) and children (16) and also was shown to be effective in treating diarrhea caused by other pathogens (17,18).

4. EPIDEMIOLOGY The epidemiology of diarrheal diseases in developing countries is complex and has been reviewed in detail elsewhere (19).

4.1. Geographical Distribution Diarrheal diseases occur worldwide but are more common in developing countries where conditions of poverty, poor hygiene and sanitation, lack of access to clean water, and limited education are found. Diarrheal diseases are also more common in urban slums where crowding and inadequate housing may be common. The prevalence of diarrheal diseases may be more common in warmer climates, which facilitate the growth of pathogens in contaminated foods.

4.2. Risk Factors Whether an individual develops diarrheal disease is a consequence of exposure to pathogenic organisms and the susceptibility of the host to infection (age, nutritional status, immunity). Nearly all diarrheal diseases are transmitted by direct contact with feces or by contact with water, food, utensils, ﬁngers, ﬂies, or soil that has been contaminated with feces. Many different risk factors have been identiﬁed for diarrheal disease (Table 1). Low socioeconomic status (SES) (20–23), crowding (21,24,25),

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Table 1 Risk Factors for Diarrheal Diseases Limited access to clean water Poor sanitation Lack of latrine Low socioeconomic status Low maternal age Low maternal education Contaminated baby bottles Contaminated weaning foods Early introduction to solid foods Fecal contamination of hands Child defecation in common areas Improper food preparation Improper food storage Contaminated eating utensils Uncovered water reservoirs House ﬂies Micronutrient deﬁciencies Immunosuppression Post-measles attack

less access to clean water and sanitation (24,26,27), low maternal age (28), and low maternal education (29) have been described as risk factors for diarrhea. The lack of breast feeding or not doing it exclusively during the ﬁrst 6 mo of life has being clearly demonstrated to be a risk factor for the development of diarrhea and its duration. In a large longitudinal study done in the Philippines, children under 2 yr of age who did not breast feed had an increased risk (8- to 10-fold increased mortality rate) of both diarrheal morbidity and mortality, mostly during the ﬁrst 6 mo of life (30). Poor feeding patterns seem to be related to the development of diarrheal diseases. In a case-control study in Brazil, children completely weaned had 14-fold increased risk of mortality owing to diarrheal diseases and fourfold increased risk of mortality owing to respiratory infections, as compared with breast-fed children, controlling for confounding variables (31). Several mechanisms in addition to the nutritional ones, including transfer of immunity by breast milk and avoidance of pathogens from contaminated weaning foods, may be involved (32–34). Baby bottles are also known to be a risk factor for the development of acute otitis, diarrhea, and pneumonia (35). Early introduction of solid foods are also a risk factor for the development of acute diarrhea (33,36), likely through ingestion of enteropathogens with the foods. Fecal contamination of mother’s hands may occur at the time of defecation or when cleaning their children’s feces (37). An association between hand contamination with fecal coliform bacteria and the incidence of diarrhea has been observed in Bangladesh, with stronger association found in communities with unimproved water and sanitation (38). Bacterial contamination of food has been documented extensively in developing countries (39). The level of bacterial contamination is inﬂuenced by temperature of food

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preparation, the storage time between preparation and eating, and the use of refrigeration. Uncooked fruits and vegetables may be contaminated with fecal coliform bacteria, viruses, and other pathogens before reaching the home (40). Irrigation with sewagecontaminated water may increase contamination of fruits and vegetables with fecal bacteria. Baby bottles, baby-bottle nipples, cups and spoons, and food containers have been found to be frequently contaminated with fecal bacteria and diarrheal pathogens (41–43). Waterborne transmission has been well documented for most enteropathogens, especially Vibrio cholerae, Salmonella typhi, and Giardia lamblia, and the use of contaminated unboiled drinking water has been associated with diarrhea (44,45). Contaminated water vessels and uncovered water reservoirs are associated with increased risk of diarrheal disease (23). House ﬂies have been implicated by some studies as a mode of transmission for diarrheal disease (46). Exposure of children to animal feces, such as chicken feces, has been implicated in transmission of Campylobacter jejuni diarrhea (47). Host risk factors for diarrheal diseases include undernutrition, as reflected by low anthropometric status using a variety of indicators (25,48,49), micronutrient deﬁciencies (such as that of vitamin A and zinc), a previous episode of diarrhea (50), and hypochlorydria (51). Decreased immunity is also a risk factor for diarrheal disease. Malnutrition, micronutrient deﬁciencies, and immune status are discussed further in Subheading 5.6.

4.3. Incidence Diarrheal incidence has varied across studies, and this may be owing to methodological differences, including the deﬁnition of diarrhea and the surveillance techniques used, or may be owing to actual differences in the study populations. A summary of prospective, community-based studies found a median incidence of 2.6 diarrheal episodes/child/yr for children under 5 yr of age (3). In these studies, the highest incidence was found in studies in which there were smaller numbers of children who were visited frequently, suggesting that larger studies with infrequent surveillance may have found lower rates because of underreporting of diarrhea. The incidence of diarrhea in selected developing countries (48,52–56) by age is shown in Fig. 1. The high incidence of diarrhea is found in the ﬁrst 2 yr of life, with a peak incidence usually between 6 and 11 mo of age. Community-based studies suggest that the incidence of diarrhea is similar between girls and boys.

4.4. Seasonality In many developing countries, the incidence of diarrhea may have a peak during hot and/or wet months (20,57). Rotavirus infection may have little seasonality in tropical areas but often peaks in cool and/or dry season in temperate regions (58).

4.5. Duration In most settings, diarrheal episodes are self-limited and resolve within 1 wk, and a small fraction will take up to 2 wk to resolve. Persistent diarrhea (greater than 14 d duration) rarely constitutes more than one ﬁfth of all episodes in community-based studies, and the incidence of persistent diarrhea in children under 5 yr of age has ranged up to 60 episodes per 100 child-years in different studies, and the incidence of persistent diarrhea also declines with age (Fig. 2).

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Fig. 1. Incidence of diarrhea. Adapted from ref. (19).

Fig. 2. Incidence of persistent diarrhea. Adapted from ref. (19).

5. CLINICAL FEATURES/PATHOPHYSIOLOGY Diarrheal disease may be accompanied by other associated problems, including dehydration, fever, electrolyte disturbances, anorexia, convulsions, measles, micronutri-

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ent deﬁciencies, and severe protein energy malnutrition (PEM). The clinical case management of diarrheal disease can be found elsewhere (59).

5.1. Major Pathogens Involved in Diarrheal Diseases in Children The major pathogens involved in diarrheal disease has been studied in both communitybased and hospital-based studies. Enterotoxigenic Escherichia coli has been found to be the leading enteropathogen in analysis of 18 community-based studies, constituting about 14% of all episodes of diarrhea (19). G. lamblia has been identiﬁed as the next most common pathogen, but the prevalence of this protozoan appears to be highly variable. Other common enteropathogens include Campylobacter, rotavirus, Shigella, Cryptosporidium parvum, and Entamoeba histolytica. Community-based studies best represent the overall occurrence of diarrhea illness, regardless of severity of disease or care-seeking behavior. In clinic- or hospital-based studies, rotavirus has been the leading enteropathogen found, followed by bacterial pathogens such as enterotoxigenic E. coli, Campylobacter, and Shigella. V. cholerae, Salmonella, and Aeromonas may be frequent in some settings. In general, community-based studies have usually identiﬁed enteropathogens in about half the episodes of diarrhea studies, and facility-based studies have identiﬁed enteropathogens in 60–70%.

5.2. Pathophysiology Acute diarrheal disease has been separated into two groups according to the pathogenesis and site of disease in the intestinal tract (60). Enterotoxic and viral diarrheas are characterized by impaired absorption in the upper small intestine and a noninﬂammatory, often watery diarrhea. Enterotoxigenic E. coli has colonization factors, which allow the bacteria to adhere to the small bowel, and enterotoxins, which cause secretion of ﬂuid and electrolytes into the intestinal lumen. V. cholerae produces an enterotoxin that also causes loss of ﬂuid and electrolytes in the intestinal lumen. Rotavirus can cause patchy mucosal changes in the small intestine, blunting of villi, reduced activity of lactase and other disaccharidases, and reduced absorption of carbohydrates. Invasive bacterial diarrheas such as Shigella, Salmonella, Yersinia enterocolitica, C. jejuni, and enteroinvasive E. coli can invade intestinal epithelial cells and cause an inﬂammatory diarrhea (61). Invasive enteropathogens may also produce enterotoxins.

5.3. Effects on Mortality Early studies documented the increased risk of death owing to diarrheal diseases in malnourished children (62). Malnourished children who were discharged from a hospital after treatment for diarrheal illnesses had 14 times greater risk of dying as compared with better-nourished controls (63). In a community-based study in rural India, severely malnourished children had 24-fold higher diarrheal case fatality rate compared to normally nourished children (64). In a case-control study in Mexico, diarrhea cases with previous history of malnutrition had 7.5-fold greater chance of dying as compared with severe diarrhea cases who survived (65). The risk of dying from diarrheal diseases is proportional to the degree of malnutrition. In a review of six prospective studies, a consistent increased in mortality was observed with poorer nutritional status, as indicated by weight for age, with a synergistic effect of malnutrition and morbidity (66). In a large prospective study done in the Philippines, the

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risk of mortality increased 1.6 times for each one-unit decrease in weight-for-age Z-score (67). This study also documented a similar risk of increased mortality from diarrhea and acute respiratory illnesses, where mortality for diarrhea and lower respiratory illness increased 1.7 times, respectively, for each one-unit decrease in weight-for-age Z-score. The mortality associated with both, acute lower respiratory diseases and diarrhea combined was doubled for each one-unit decrease in weight-for-age Z-score (67). The mortality from diarrhea in malnourished children seems to be particularly higher in persistent diarrhea as compared with acute episodes. Persistent diarrhea per se is associated with greater mortality than acute diarrhea (64), but if persistent episodes (diarrheal episodes of *14 d duration) are associated with severe malnutrition, the risk of death increased 68-fold in Bangladesh (68). In conclusion, childhood malnutrition is consistently associated with an increased risk of death, both for diarrheal (persistent diarrhea in particular) and respiratory illnesses.

5.4. Effects of Malnutrition on Morbidity Early studies documented a relationship between malnutrition and the prevalence of diarrheal diseases (13,69–71). This relationship is stronger for an increased duration of diarrheal illnesses in undernourished children, especially those episodes owing to Shigella sp. and enterotoxigenic E. coli, than for an increased incidence (72,73). The duration of diarrheal episodes owing to these organisms or episodes generally increases threefold or more for less well nourished children. Undernutrition is also a risk factor for persistent diarrhea (74,75). Poorer nutritional status has been documented to be associated with an increased rate of stool output in children (76), leading to an increased risk of dehydration (77). These mechanisms probably explain the increased risk for hospitalization and length of hospital stay owing to diarrheal disease in the presence of malnutrition (78–80). Studies also show an increased risk for diarrhea incidence. Prior malnutrition has been associated with 1.5–2.0-fold increased risk of developing a diarrheal episode in several geographical areas (81–86). This increased risk of diarrhea may explain why some studies have found that prior episodes of diarrhea were a strong predictor for diarrhea in a subsequent period in undernourished children (87–89). Some organisms may be particularly selected as a cause of infection in malnourished children like C. parvum infections (90).

5.5. Effects on Growth of Children Several studies have clearly documented a negative effect of diarrhea on the weight and height gain of children during or after an episode of acute diarrhea (69,70,91–96). The effect seems to be more consistent in reducing weight gain than in reducing height or length gain. The growth faltering observed has varied from 10–20% in countries with lower prevalence of malnutrition in the Americas (69,71) to 70–80% in countries with high prevalence of malnutrition in Africa (70,93,97), suggesting that the negative effect of diarrheal diseases is greater in children with poorer nutritional status, most likely owing to their poorer diets. This negative effect can be reversed by 14–30 d after the episode if the child returns to his/her normal diet and remains healthy (91,98). As expected, the magnitude of the weight deﬁcit is inversely related to the duration of the diarrheal episode (99). Although the distribution of durations of diarrheal episodes is

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continuous and skewed toward the longer duration, episodes that last more than 14 d are a subgroup associated with higher risk of dying (68). Persistent diarrheal episodes, which account for about 3–20% of all diarrheal episodes (99), occur in children who also have higher burden of diarrhea in general, and both the persistent episodes and the high prevalence adversely affect growth (99–101). Both symptomatic and asymptomatic infections can cause an adverse effect on growth. A recent community-based study has indicated that both symptomatic and asymptomatic infections with C. parvum in Peruvian children were associated with a reduction of weight gain, controlling for other variables (102). Even though the effect size was less in asymptomatic infections, because its higher prevalence, asymptomatic infections played a greater role on the overall impact of C. parvum infection on growth than symptomatic infections. C. parvum infected-children, especially those infected when they were under 6 mo of age or when they were stunted at the time of infection, did not have catch-up growth, showing signiﬁcant differences in height even 1 yr after the infection, as compared with noninfected children, suggesting a long-lasting, adverse effect on linear growth (103). The effect of diarrhea on growth could be owing to a reduced appetite, altered feeding practices, decreased nutrient absorption, or increased metabolic needs. Recent studies have described a modifying effect of diet on the relationship between diarrhea and growth. Diarrhea has a lesser effect on growth of breast-fed infants (104), among those whose usual dietary intake is greater or of better quality (105), or among children who receive food supplements (106,107). Thus, an adequate diet can protect from the nutritional impact of diarrhea. Also, children with an adequate diet will grow faster after an illness, experiencing what it has been called catch-up growth, especially if they do not have recurrent infections (81,108,109).

5.4. EFFECT ON DIETARY INTAKE Several clinical and community-based studies have found that diarrheal diseases are associated with some reduction in the dietary intake during illness (110–116). Initial studies provided conﬂicting results because they did not distinguish between breast milk and other liquids and solids. Carefully conducted studies in children who were not breast feeding any longer have indicated that common illnesses including diarrhea have reduced energy consumption by 15–20% (112,113). This reduction is of a lesser magnitude in infants who receive more than 50% of their energy intake from breast milk, where the reduction in dietary intake during illness only occurs from non breastmilk sources (115). The reduction of energy intake during diarrhea seems greater in hospitalized children than at the community level (110,111) possibly owing to the greater severity of illness or to a difference in the acceptability of hospital vs home diets. It was postulated that the characteristics of the diet may inﬂuence the dietary intake during illness, although a study done in Peru did not show that dietary viscosity inﬂuenced the energy consumption of a potato-based diet (117).

5.5. Effects on Nutrient Absorption and Intestinal Function Diarrheal illnesses can reduce intestinal absorption as a result of several mechanisms: direct enterocyte and crypt cell destruction by the enteropathogen (or its toxins) or by the immune response of the individual; increased intestinal motility with a reduction

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of transit time; and reduced bile acids by increased fecal losses or bacterial hydrolysis (118). Owing to these mechanisms, malabsorption or abnormal digestion of protein, fat, and especially carbohydrates occur (119,120), potentially increasing the intraintestinal ﬂuid volume and fecal losses by its osmotic effect, and worsening the diarrheal episode, especially with rotavirus diarrhea (121). Diarrhea can also increase the intestinal permeability to test sugars, an effect that lasts after the end of the diarrheal episode and has been associated with reduced growth in a West African study (122). This increased permeability may also increase the risk of sensitization to dietary proteins and the development of food allergies (123). Finally, diarrhea also increases the fecal excretion of selected micronutrients, like zinc and copper (124) and some vitamins (125).

5.6. Relationship with Nutrition and Immunity 5.6.1. UNDERNUTRITION Severe malnutrition is associated with a depressed immune response, which is one of the mechanisms that may explain the increased incidence and severity of infections in undernourished children. As initially documented in a study done in Peru, delayed cutaneous hypersensitivity to several antigens, as an indicator of cell-mediated immunity, has proven to be a very good predictor of the incidence of diarrhea, controlling for anthropometric status (126). Studies done in Bangladesh (127) and Kenya (128) conﬁrmed these ﬁndings; anergic children had 20–50% increased incidence of diarrheal diseases, independent of their nutritional status. Cell-mediated immune status was also an important predictor of persistent diarrhea (129), as anergic children experienced twice the incidence of persistent diarrhea in the period after their assessment. This increased risk can vary over time, as children have been observed to change their delayed cutaneous hypersensitivity status when re-evaluated 6–12 mo later (Lanata, C.F., unpublished observations). 5.6.2. VITAMIN A Diarrheal disease has been associated with increased risk of developing vitamin A deﬁciency (130), and in turn, vitamin A deﬁciency has been associated with increased risk of developing diarrheal disease in preschool children (131). Several studies have shown that children with diarrhea (especially more severe diarrhea and persistent diarrhea) have a strong association with xerophthalmia or low vitamin A status assessed by several indicators, including serum retinol levels (132). The observation that serum retinol levels were lower in children with acute diarrhea seems to be explained, in part, by an increased urinary loss of vitamin A during acute diarrhea, especially those episodes associated with rotavirus or fever (133). This urinary loss of retinol, which seems to be transient (134) is owing to an impaired tubular reabsorption of low-molecular-weight proteins, including the binding protein transporting retinol, as documented in children with shigellosis (135). The relationship between vitamin A deﬁciency and diarrheal disease is also discussed elsewhere in this book (see Chapter 2). 5.6.3. ZINC In contrast to vitamin A supplementation, the studies done with zinc supplementation have shown more consistent results in the prevention of diarrheal and respiratory diseases. It is now clear that zinc has an important role not only in growth, but also in the immune capacity of children to ﬁght against diarrheal and respiratory diseases

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(136,137). Because zinc-containing foods with the highest bioavailability are animal proteins—a dietary source under-represented in the diet of children living in most developing countries—zinc deﬁciency may be one of the most important nutritional disorders in developing countries (136). The potential role of zinc in prevention of diarrhea is discussed further in Subheading 7.3. 5.6.4. OTHER MICRONUTRIENTS Other micronutrients may also play a role in the development of infectious diseases. Copper deﬁciency in children, a rare condition, is also associated with persistent diarrhea that disappears after supplementation (138,139). Selenium, another essential trace element, may have a more important role. Among several functions, it is needed in erythrocytes and granulocytes to metabolize H2O2, and together with vitamin E has anti-oxidant effects in tissues. Therefore it may have anti-proliferative and cancerprotecting effects (140). Selenium requirements are greater in infants and young children and its concentration in human milk is affected by maternal intake (140). In studies with pigs, selenium-deﬁcient diets have been observed to cause a marked suppression of lymphocyte response to mitogens as well as an increased burst respiratory response of stimulated granulocytes (141). In an experimental swine dysentery model, selenium supplementation was associated with improved clinical response as well as with greater weight gain in the recovery period (142). Studies are needed to evaluate the role of selenium in diarrhea in infants.

6. DIAGNOSIS Diarrhea, as mentioned previously, is deﬁned as a condition in which three or more liquid stools are passed within a 24-h period (1,2). On an individual level, the clinical concept of diarrhea can range from a subtle variation from normal to a rapidly fatal disease. Nausea, vomiting, fever, abdominal cramps, dehydration, and convulsions may also be present but are not necessary for the diagnosis of diarrhea. The clinical assessment of the patient and case management of diarrhea are beyond the scope of this chapter and can be found in a treatment manual of the WHO (59).

7. TREATMENT 7.1. Oral Rehydration Therapy Oral rehydration therapy (ORT) is the treatment of choice for patients with some dehydration. The purpose of ORT is to treat the deﬁcits in water and electrolytes that occurs with acute watery diarrhea. Approximately 95% of children who visit a health care facility for acute watery diarrhea can be successfully treated with ORT.

7.2. Nutritional Management One of the strategies that has been considered to reduce the negative impact of diarrheal diseases on the nutritional status of children has been the dietary management of children during illness or immediately after recovering. For years physicians have feared that food could be incompletely digested as a consequence of the malabsorption observed in diarrheal diseases, thereby increasing the stool output owing to osmotic effects, with an increase in the risk of dehydration and other diarrheal complications. This has caused many clinicians to be cautious with the introduction of foods during

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acute diarrheal diseases. Studies recently conducted in several developing countries have provided evidence of the importance of an adequate dietary intake during and after diarrhea. These studies have included the timing of when to introduce feeding and the amount of food that could be given, and the diet characteristics, including micronutrient contents, in both acute and persistent diarrhea. 7.2.1. TIMING OF FEEDING In a clinical trial conducted in Peru, children with acute diarrhea were randomized into four groups, with the objective of evaluating the consequences of introduction of a full-strength diet early in the course of an acute diarrheal episode on the clinical course of illness and the nutritional status of these children (143). One group received a full-strength, lactose-free diet immediately after being rehydrated. A second group received a half-strength, lactose-free diet for 2 d prior to the introduction of the fullstrength formulation. A third group received no diet and were kept on oral rehydration solutions for 2 d, followed by a half-strength diet for 2 d, and then the full-strength diet introduced 2 d later. The fourth group was similar to the third group, but received only intravenous ﬂuids for the ﬁrst 2 d before the half- and full-strength diet was introduced. The groups were comparable in their clinical and biological characteristics. The introduction of a full-strength diet after being rehydrated was not associated with any change in the stool output of these children. In contrast, children who received the full-strength diet gained weight continuously from the start of the study, whereas those who received the half-strength formula for 2 d gained weight only when they were given the full-strength formula, requiring 8 d to become similar in weight to the children receiving the full-strength formula earlier. Children who received no diet for the ﬁrst 2 d lost weight during that period. They only gained weight once they were given the full-strength formula; however, even after 2 wk of observation, they were still signiﬁcantly less well nourished that the children given full-strength diets earlier. Similar ﬁndings were also observed in children under 1 yr of age in Romania (144), and in a multi-center study conducted in several hospitals in Europe (145). These studies have prompted the WHO and pediatric societies to recommend continuing feedings with their usual diet in children with diarrhea, as well as rapid reintroduction of usual feedings immediately after rehydrating a child with more severe diarrhea in a hospital setting (146). 7.2.2. LACTOSE One of the major concerns related with the dietary management of children with diarrhea has been the lactose content of the diet. Because lactose malabsorption frequently occurs with diarrhea, there is a possibility that partially-absorbed lactose will pass into the colon and increase the ﬂuid volume in the lumen by osmotic pressure, leading to an increased stool output and dehydration. This was felt to be a strong reason to restrict lactose in the diet of children with diarrhea. Despite the fact that human milk contains more lactose than cow’s milk, it is much better absorbed and tolerated. In a randomized trial where continued or interrupted breast feeding were compared in children with diarrhea, children who continued breast feeding had a lower stool output than those who received only oral rehydration solution for the ﬁrst 24 h of hospitalization (147). Breast milk may also have a direct effect on diarrhea by providing speciﬁc secretory IgA against viral or bacterial pathogens, as well as by the presence of lactadherin, a mucin-associated glycoprotein, which binds speciﬁcally to rotavirus,

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inhibiting its replication (148). The evidence is strong that breast milk should be continued in children with diarrhea. Several clinical trials have focused on the safety of providing nonhuman milk to children with diarrhea, with conﬂicting results. In a recent meta-analysis of 13 clinical trials, children who were fed undiluted lactose-containing diets had a 22% rate of treatment failure compared with 12% treatment failure in children who were given lactose-free diets (149). The meta-analysis suggested that this effect was mainly seen among children who were moderately to severely dehydrated on admission. No signiﬁcant differences on treatment failure existed between children who had mild to no dehydration. Based on this analysis, the WHO recommends to continue with nondiluted, lactosecontaining, nonhuman milks in children with diarrhea. Moderate or severe dehydration is infrequent and these children require treatment in health facilities. Thus, they should be fed under close medical supervision. Some of these children who may not tolerate undiluted nonhuman milk may be infected with enteropathogenic E. coli (EPEC), as indicated by a study done in Brazil, where an increased stool output associated with a lactose-containing formula was mainly observed in children with EPEC infections (150). A better alternative than providing water-diluted, nonhuman milk to those children with more severe diarrhea seems to be the mixture of milk with other foods, like potato, rice, or noodles. 7.2.3. MIXED DIETS In a clinical trial in Peruvian children with acute diarrhea, a blend of toasted wheat and pea ﬂour and a mixture of potato and milk were compared with a commercially available lactose-free, soy-protein formula (151). No difference in stool output or treatment failure occurred during the ﬁrst 48 h of admission. Even more, when the median duration of excretion of liquid stools were compared, the common food group had less than half the duration of the formula group (60-h vs 144-h median duration, respectively). Similar studies comparing bean- (152), chicken- (153), maize- (154) and rice- (155) based diets have conﬁrmed these ﬁndings. Children with diarrhea who are fed with locally available mixtures of foods, even including nonhuman milk, had no adverse effects and had a reduction on the duration of diarrhea. In a prospective, community-based study in Peruvian children, the consumption of cereals during diarrhea was associated with shortening the duration of the episode by 1 d (156). One of these studies (155) demonstrated that treatment failures owing to recurring dehydration were signiﬁcantly less in children fed a mixture of rice or chicken and other common foods than with a soy-protein infant formula. (Maulen-Radovan (155) demonstrated that treatment failures due to recurring dehydration were signiﬁcantly less in children fed a mixture of rice or chicken and other common foods than with a soy-protein infant formula. In a study done in malnourished children recovering from a diarrheal episode owing to shigellosis in Bangladesh, providing a high-protein diet, as compared with a standard diet, during a 3-wk period was associated with a significant gain in height when assessed 6 mo later (157). When a milk-cereal formula was offered for 10 d to these malnourished children with shigellosis, giving a higher density diet (with the same proportion of protein) was associated with a signiﬁcant weight gain, even 1 mo after being discharged from the hospital with no subsequent dietary intervention at home (158).

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These studies highlight the importance of a good-quality diet, both in terms of energy density and of protein content, to be offered to children with diarrhea and in the convalescent period, even when these diets may not be available thereafter. One way of achieving this is to increase the energy density of staple foods by fermentation or germination. Amylase-rich ﬂour from germinated wheat can instantly liquefy a thick porridge, making it more acceptable to sick children and increase its energy density (159). Amylase-treated porridge obtained from germinated wheat has been shown to increase the energy intake of children with diarrhea (160,161). It may be particularly important to provide good quality diet with adequate protein during shigellosis, because this illness results in substantial loss of protein in the stool (162). 7.2.4. FIBER Because of the consistent observations of a reduced duration of diarrhea among children fed mixed diets, several investigators have studied the role of dietary ﬁber on the duration of diarrhea, because most of these staple foods have a high ﬁber content. Dietary ﬁber—noncellulose polysaccharides that form the indigestible portion of the plant cell wall—together with lignins, are not absorbed by the human intestinal tract. In the colon they are partially digested by fecal bacteria, increasing the total fecal bacterial mass. Dietary ﬁber also has hydrophilic sites that bind to water. These two effects may explain the changes in stool consistency observed with the ingestion of high-ﬁber diets. Not all types of dietary ﬁber may have an effect on diarrheal duration, as demonstrated in a human volunteer study, where only psyllium increased fecal consistency and stool viscosity and wheat bran or calcium polycarbophil did not (163). This effect depends on the ratio between the concentration of water-binding insoluble solids in the distal colon, like psyllium, and the amount of fecal water reaching the colon (164). The presence of ﬁber in the diet diminishes the intestinal transit time, even in the presence of a high ﬂow rate of enteral feedings in experimental dog models, by intensifying inhibitory feedback from the distal gut into the upper intestine (165), through a cholecystokinin-mediated mechanism. Some dietary soluble ﬁber, like partially hydrolyzed guar gum (Sunﬁber), not only reduces the duration of liquid stools during diarrhea, but increases ﬂatulence, as a result of fermentation of the soluble ﬁber in the colon. Concomitant production of short-chain fatty acids increases the intestinal absorption of water and sodium, as reviewed in Subheading 7.2.8. (166). The consumption of dietary ﬁber in children with diarrhea has, therefore, been associated with a reduction of the duration of diarrhea as documented in studies done in the U.S. (167) and Belgium (168). In a clinical trial done in Peruvian children with acute diarrhea, a group given a soy-protein infant formula was compared with a group that received the same formula with soy polysaccharide ﬁber (169). As expected, the group that received the ﬁber supplement had a substantial reduction in the median duration of diarrhea. This apparent reduction, however, was mainly owing to the characteristics of the stool, because stool wet or dry weight was similar between the groups. Also, there were no differences in the absorption of macronutrients from the diet or changes in the anthropometric status of the study children. This osmotic “cosmetic” effect on diarrheal stools in children may be important, even if not translated into a nutritional beneﬁt, by diminishing liquid stools, which are always a concern to mothers. If some dietary ﬁbers have the added effect of an increased water absorption in

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the distal gut by an increased production of short-chain fatty acids, this may be an important contribution to the management of children with diarrhea. Even if dietary ﬁbers by themselves do not have a strong justiﬁcation as supplements, the use during diarrhea of mixtures of locally available staple foods with high dietary ﬁber content in children with diarrhea are still recommended in light of these studies. 7.2.5. PROBIOTICS Other dietary components that have been considered to play a role in the management of diarrhea are probiotics—viable bacteria in the food. Although they are not really food or nutrients to humans, when added to foods they can beneﬁt humans by their action on some food components or by inhibiting the growth or function of pathogenic bacteria. Several such organisms have been studied as potential agents in the treatment or prevention of diarrhea. Organisms that are capable of fermenting lactose, like in yogurts, may diminish the lactose content of the diet, therefore increasing the digestibility of milk products in children with diarrhea. Because of this effect, yogurt may be better tolerated than nonhuman milk in children with diarrhea (170). However, when nonhuman milk is given as part of a mixed diet in children with diarrhea, no beneﬁts on the severity, duration, and treatment failure of diarrhea were seen when milk was substituted with yogurt, even in malnourished children (171). Speciﬁc probiotic agents have also being evaluated individually. Lactobacillus casei GG, an acid- and bile-resistant strain that colonizes the intestinal mucosa, has been found to reduce the duration and severity of rotavirus diarrhea (172) and other diarrhea (173,174). In rotavirus diarrhea, the supplementation with lactobacillus GG not only decreases the diarrheal duration, but also reduces the excretion of rotavirus in the stools (175). Furthermore, in a recently conducted community-based study done in Peruvian children, lactobacillus GG or placebo were given 6 d/wk for 15 mo to a large group of children in peri-urban Lima (176). Lactobacillus GG supplementation was associated with a signiﬁcant reduction in the incidence of acute diarrhea (13% reduction), especially in children who were not breast feeding (20% reduction in nonbreast-fed vs none in breastfed). Thus, supplementation with this organism not only reduces the duration and severity of an acute diarrheal episode, but also can prevent its development. Other single organisms have also being tested. Lactobacillus reuterii, an organism of human origin that is a natural colonizer of the gastrointestinal tract, had similar effects in children hospitalized with rotavirus diarrhea in Finland (177), showing a dose-response: 48% of children who received a dose of 1010 colony forming units (cfu) of the organisms had watery diarrhea by the second day of treatment compared with 70% in those who received a lower dose (10 7 cfu) and 80% in those who received placebo (178). Other bacteria like Biﬁdobacterium biﬁdum and Streptococcus thermophilus have been found to prevent the development of acute diarrhea and rotavirus shedding in infants admitted to a chronic medical-care hospital (179). The administration of enterococcus SF 68 strain during diarrhea in adults was also associated with a signiﬁcant reduction of the duration and severity of diarrhea (180). The fermentation of mixed diets with Lactobacillus acidophilus has being shown to prevent the development of diarrhea with enterotoxigenic E. coli in mice (181). In contrast, when adult volunteers were given a combination of L. acidophilus and Lactobacillus bulgaricus and then challenged with E. coli strains that produced heatstable or heat-labile enterotoxins or both, there were no differences in the attack

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rate, incubation period, duration, and severity of diarrhea compared with volunteers who were given placebo (182). Saccharomyces boulardii was able to prevent the development of diarrhea in critically ill tube-fed adults hospitalized in intensive care units (183). From all these studies, it could be concluded that probiotics are promising agents in the management and prevention of diarrhea, and deserve further evaluation in children in developing countries with different ﬁeld conditions and etiologic agents. Each of the most promising organisms should be tested to confirm their potential use in the treatment and prevention of diarrhea (184,185). If efﬁcacy is further demonstrated, studies of cost-effectiveness of these interventions will be needed to determine whether these approaches are useful. 7.2.6. PREBIOTICS Because probiotics are beneﬁcial to the host only when they are present in the gut, therefore requiring frequent oral administration to have a permanent effect, other mechanisms to manipulate the composition of the gut ﬂora potentially to increase the growth of bacterial groups like biﬁdobacteria or lactobacillus have been tried. Prebiotics, nondigestible food ingredients in humans, are capable of selectively stimulating the growth or activity of one or a limited group of bacterial species in the gut. This could prevent a negative health impact owing to another type of bacteria (186,187). Nondigestible oligosaccharides, in particular fructooligosaccharides, naturally exist in a variety of plants and are used as a natural endulcorant. They have been shown to stimulate the growth of bifidobacteria in the gut, enabling them to become the predominant species in human feces (188,189). Studies are needed to evaluate the beneﬁt of this approach in the prevention of diarrhea in children in developed and developing countries. 7.2.7. EPIDERMAL GROWTH FACTOR Oral administration of the epidermal growth factor, which is present in human milk, has stimulated the recovery of the small intestinal morphology and function after rotavirus infection in pigs (190), as well as improved weight gain, reduced small and large intestinal colonization with enteropathogenic E. coli, and improved the intestinal function in rabbits (191). Human studies are needed to conﬁrm these preliminary ﬁndings. 7.2.8. SHORT-CHAIN FATTY ACIDS In the large bowel, unabsorbed carbohydrates are fermented by the colonic ﬂora to short-chain fatty acids, also producing gas. Animal studies have documented that the production of short-chain fatty acids in the large bowel function as a compensatory response to diarrhea, because they are associated with an increase in the capacity to absorb ﬂuids from the large bowel (192). In small infants, owing to an immature fecal ﬂora, short chain fatty acids are not produced and unabsorbed carbohydrates are not fermented, passing through the colon unchanged, contributing to diarrheal losses by their osmotic effects. Whether unabsorbed carbohydrates cause diarrhea probably depends on the balance between the osmotic force of the carbohydrate and the colonic capacity to digest it by bacterial fermentation. Danish adult volunteers were given two nonabsorbable carbohydrates, one of which (lactulose) produced a high osmolar product in the gut after colonic fermentation compared with the other (fructo-oligosaccharide, Idolax) (193). Increasing doses of lactulose induced a higher fecal volume, indicating

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that the osmotic effect is the main mechanism of carbohydrate-induced diarrhea. Short-chain fatty acids may also have a direct pharmacologic effect. The consumption of short-chain fatty acids by patients with diarrhea has resulted in a net absorption of sodium and water from the large bowel lumen, improving the function of the colonic mucosa, as documented in a study in Indian adults (194). The mechanisms of the effect of short-chain fatty acids are not clearly understood. One short-chain fatty acid, butyrate, has been studied in some depth. It is absorbed from the colon via passive diffusion of the lipid-soluble form, and by active mechanisms linked to various ion-exchange transporters, which may be affected by neuroendocrine factors (195). Butyrate has been shown to regulate colonic motility, increase colonic blood ﬂow, and may enhance colonic healing, as seen after colonic anastomosis (195). Further studies in controlled, randomized, double-blind clinical trials are needed with short-chain fatty acids or with diets that manipulate their colonic production in children with diarrhea. 7.2.9. GLUTAMINE Glutamine, a nonessential amino acid, is absorbed in the intestinal tract coupled with sodium. It is an important nitrogen-carrying amino acid and is one of the principal metabolic substrates for enterocytes. Because of these effects, it has being suggested that its addition to oral rehydration solutions may improve ﬂuid and electrolyte absorption and may stimulate a more rapid healing process in the intestine, lessening the duration or severity of diarrhea. Glutamine-based oral rehydration solution was associated with an increased water and electrolyte absorption compared with standard WHO oral rehydration solution or with Ringer’s solution, used as a control in a perfused rabbit ileal loop model of secretory diarrhea induced by cholera toxin (196). Morphological changes in the colon were also stimulated with the use of glutamine-based oral rehydration solution in calves with diarrhea induced by enterotoxigenic E. coli (197). Diarrhea-induced changes in villus length and width, crypt depth and width, and villus surface area were prevented with the glutamine-based solution compared with WHO oral rehydration solution. In another animal model, however, this solution did not have any beneﬁcial effect on diarrhea. Several improved oral rehydration solutions, including glutamine-based solution, were tested in a model of piglet rotavirus enteritis (198). None of the solutions tested had any signiﬁcant effect in shortening the clinical illness or in stimulating the recovery of the mucosa. A randomized, double-blind, controlled trial of glutamine-based oral rehydration solution in infants showed that it had no additional therapeutic advantages compared to the standard WHO oral rehydration solution in noncholera diarrhea (199). Amino acid-containing oral rehydration solutions are not recommended by WHO (200). 7.2.10. NUCLEOTIDES Because some types of diarrhea (e.g., rotavirus) create extensive damage to the intestinal mucosa, there is a need to produce new villous cells in the recovery process. The intestinal mucosa has a limited capacity to synthesize nucleotides needed in the growth of tissue and obtains most of them either from the blood or the intestinal lumen (from the diet or sloughed mucosal cells) (201,202). The addition of nucleotides to the diet, therefore, could increase the recovery from diarrhea (203). In weanling rats after lactose-induced prolonged diarrhea, the use of a diet supplemented with nucleotides

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was associated with intestinal histologic and ultrastructural morphology closer to the normal tissue than in rats given a standard semipuriﬁed diet (204). There is a need to evaluate possible beneﬁts of nucleotide supplementation during acute or persistent diarrhea in children. 7.2.11. LECTINS Lectins are molecules that bind speciﬁcally to sugar moieties, e.g., glycoproteins or glycolipids, present in the surface of several mucosal cells as well as other organisms like bacteria or parasites. Several staple foods contain relatively high concentrations of lectins, like beans, wheat, and lentils, many of which are poorly absorbed in the gastrointestinal tract, as well as being resistant to heat and digestive enzymes (205). Dietary lectins have been hypothesized to facilitate the binding of bacteria to the intestinal mucosa, as well as to be cytotoxic to damaged mucosal cells, promoting the development of diarrhea or its prolongation (206–209). In rat studies, red kidney beans given to weanling rats caused diarrhea, increased fecal energy loss, and the translocation of indigenous intestinal bacteria (Citrobacter sp. and E. coli) to the mesenteric lymph nodes (210). In Bangladesh, the consumption of lentils was associated with a 14% increase in the prevalence of diarrhea (99), although this was not observed in Peruvian children (156). In contrast, other types of dietary lectins may be protective. In plants, lectins have antimicrobial activity and are thought to play a role in plant defense against bacteria (211). Some of these plant lectins can have anti-bacterial activity to human pathogens like E. coli (212), and may play a role in some human infections (213). Some types of feedings have the capacity to induce endogenous synthesis of lectins, which has been found to reduce the incidence of diarrhea and promote better weight gain in piglets (214). Several surface carbohydrates of G. lamblia (215) and C. parvum (216) are speciﬁcally agglutinated by lectins from seaweed, wheat germ, and other plant lectins. Antigenic constituents of sporulated C. parvum oocyst antigens that reacted with antisera from orally infected mice were speciﬁcally bound to plan lectins, including wheat germ agglutinin (217). In the mouse model of giardiasis, the administration of wheat germ agglutinin, inhibited the growth of G. lamblia trophozoites in vitro as well as the development of Giardia muris infections in adult mouse (218). It can be concluded that dietary lectins may increased the risk of developing bacterial diarrhea, as well as inhibit the development of protozoal infections in humans. Further randomized, placebo-controlled, double-blind clinical trials with dietary lectins are warranted, particularly in the treatment or prevention of G. lamblia and C. parvum infections.

7.3. Micronutrient Supplementation Speciﬁc micronutrients like zinc and vitamin A, have being evaluated as therapeutic agents in acute diarrheal diseases. 7.3.1. ZINC In an initial study done in a small group of Indian children with acute diarrhea, a small reduction (9%) of diarrhea was reported after zinc supplementation, especially in those children who had a low zinc concentration in the rectal mucosal biopsy specimens (219). In a controlled community-based study done also in India, children were randomized to receive a multivitamin preparation with or without 20 mg of

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elemental zinc provided as zinc gluconate during an acute diarrheal episode (220). Zinc-supplemented children had a 23% faster recovery from the episode as well as a 39% reduction of the probability of the episode lasting more than 7 d of duration if zinc supplementation was started within 3 d of the onset of the episode. Zinc supplementation was also associated with a reduction in the severity of diarrhea as indicated by a reduced mean number of watery stools per day. Another study done in Bangladesh (221) showed similar ﬁndings. In a recent pooled analysis of three of these trials, zinc supplements during an acute diarrheal episode was found to be associated with a 15% faster recovery and a 20% reduction of the probability of an episode lasting more than 7 d (222). No difference in the effect was seen by age, gender, and nutritional status of study children in the pooled analysis. Zinc supplementation during acute diarrhea improves the intestinal permeability, as indicated by the urinary lactulose⬊manitol excretion ratio, suggesting an increased healing of small bowel mucosal damage (223). Zinc supplementation also has a therapeutic effect in persistent diarrhea. In a study done in Bangladesh, zinc supplementation in children with persistent diarrhea was associated with a 33% reduction of diarrheal duration, an effect that was greater among malnourished children and in boys (224). Supplemented children also were able to maintain body weight during hospitalization as well as their serum zinc concentration, as compared with unsupplemented control children who lost weight and had a reduction on their serum zinc level. A study done in Peru had similar results but did not reach statistical signiﬁcance (225). In a pooled analysis of four clinical trials done in children with persistent diarrhea in Bangladesh, Peru, and Pakistan, zinc supplementation was associated with a 29% faster recovery and 49% lower rate of treatment failure or death than control children (223). Zinc supplementation may be an important therapeutic tool in children with acute and persistent diarrhea in developing countries. Effectiveness trials to evaluate the impact of supplementation or food fortiﬁcation in a public health context in developing countries are needed. 7.3.2. VITAMIN A Since vitamin A supplementation had a signiﬁcant impact in reducing diarrhearelated mortality in children, several investigators have evaluated the effects of vitamin A supplementation in the treatment of diarrhea cases. Clinical trials have failed to demonstrate any beneﬁt of vitamin A on the duration or severity of diarrhea where given as a treatment (226), unless the cases had clinical signs of vitamin A deﬁciency or malnutrition (227,228). In a large double-blind controlled trial in 900 Indian children with acute diarrhea, vitamin A supplementation had no beneﬁcial effects in all study children, but was associated with a reduction in diarrhea duration, mean number of stools or proportion of watery stools, and diarrheal episodes that became persistent in the subgroup of children who were not breast-fed (229). In contrast, another doubleblind controlled trial in 684 Bangladeshi children failed to demonstrate any beneﬁcial effect of vitamin A supplementation during acute diarrhea of any type (230), although another trial done in Bangladesh suggests that the clinical course of acute shigellosis may be beneﬁted by vitamin A supplementation (231). The potential beneﬁt of vitamin A supplementation in acute shigellosis needs to be conﬁrmed, especially in other areas with less malnutrition and vitamin A deﬁciency in the population.

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7.4. Dietary Management of Persistent Diarrhea In children with persistent diarrhea, many of whom may also be malnourished, the presence of lactose or carbohydrate malabsorption has been recognized as a reason for treatment failures (232). Inexpensive and widely available mixed diets have been proven to be effective in the management of these children. A chicken-based diet was similar to more expensive elemental or soy-based diets in malnourished children with persistent diarrhea in Mexico (233). In Croatia, a chicken-based diet not only was as good as a semi-elemental diet, but also was associated with a reduction on diarrheal duration (234). In children with persistent diarrhea in India, cow milk mixed with cereals was compared with a milk-free diet (235). Both diets had similar results in terms of diarrhea recovery and nutritional beneﬁts, indicating that milk mixed with other foods could be used in these children. In order to standardize the dietary management of children with persistent diarrhea, the WHO supported a multicenter study done in Bangladesh, India, Mexico, Pakistan, Peru, and Vietnam. All children were offered an initial diet with cereals, vegetable oil, animal milk, or yogurt, with vitamins and minerals added. If the patient did not improve on that initial diet, a lactose-free diet was then given to these children. Sixty-ﬁve percent of the children were successfully managed only with the initial diet, whereas 80% were successfully managed with the combination of both diets (236). As shown in other studies, treatment failures were mostly associated with the presence of associated illnesses that required speciﬁc antibiotics. This study proved that children with persistent diarrhea in developing countries can be managed with simple, cheap, and available foods.

8. PREVENTION 8.1. Breast Feeding Promotion of breast feeding is considered a high priority in the prevention of diarrheal diseases. Nonbreast-fed children have also up to twofold increase in diarrheal duration and up to sixfold increase risk of persistent diarrhea compared with partially or fully breast-fed children (147,237,238). Breast-fed children have a reduced mortality risk (239). Nonbreast-fed or partially breast-fed children have up to 25-fold increased risk of death (31,240,241). Breast-feeding promotion has been estimated to reduce diarrhea prevalence by 40% in infants aged 0–2 mo, 30% in those aged 3–5 mo, and 10% in those aged 6–11 mo (239). Intervention studies to promote the introduction of exclusive breast feeding in infants under 6 mo of age, however, have proven to be difficult to implement, which may explain the scarcity of published articles documenting the beneﬁts of such interventions in the prevention of diarrhea morbidity or mortality, although preliminary studies are encouraging (242). A recently published randomized, controlled trial of home-based peer counseling to promote exclusive breast feeding has reported an increased in the rate of exclusive breast feeding at 3 mo postpartum after a six visits (67% exclusive breast feeding) or three visits (50% exclusive breast feeding) counseling frequencies, compared with no counseling (12% exclusive breast feeding) (243). Duration of breast feeding was longer in the intervention groups and diarrhea was less frequent in the intervention groups (12%) compared

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with the control group (26%). These results, if conﬁrmed in studies done in other geographical areas, document the importance of breast-feeding promotion to improve infant health.

8.2. Improved Weaning Practices Several epidemiological studies have clearly documented that diarrhea increases at the time of introduction of weaning foods. Diarrheal rates are greater in infants not receiving breast milk compared with those receiving exclusive or partial breast feeding (239). In infants under 6 mo of age, the simple addition of water or infusions to breast milk are associated with two- or threefold increase in diarrhea rates (33,36). Bacterial contamination of weaning foods in developing countries has been documented (244–246). Food has been incriminated as a source of outbreaks of diarrheal diseases in developed countries (247) and as a source of traveler’s diarrhea (248,249), documenting its important role in the transmission of diarrhea. All major bacterial enteropathogens have been isolated from weaning food samples, in concentrations from 103–108 bacteria per gram or milliliter (245,246). Food seems to be more frequently contaminated and to have higher bacterial counts than drinking water in developing countries, presumably owing to multiplication of the bacteria in the food (246). The promotion of an adequate weaning food under hygienic conditions would have the dual advantage of improving nutrient content and decreasing microbial contamination, which should be effective in reducing diarrheal diseases (250–252). Randomized, controlled trials of improved weaning food practices to prevent diarrheal diseases are needed in developing countries.

8.3. Use of Safe Water Contaminated water plays an important role in the transmission of some pathogens that cause diarrhea. In many developing countries, a large proportion of the population does not have access to safe water (253). In spite of available potable water, further contamination with enteropathogens may occur in the home as a result of contaminated vessels and utensils. Thus, the provision of safe water must be accompanied by health education aimed at better hygiene and weaning practices.

8.4. Handwashing Hygiene education and handwashing may help to reduce the incidence of diarrheal diseases. The risk of diarrhea with lack of handwashing has been described in mothers after defecating or cleaning a child. The level of hand contamination with fecal coliforms is greater in communities with unimproved water and sanitation facilities, suggesting that the impact of handwashing may be greater in in such communities (254) Not only bacteria but viruses can adhere to hands, as documented with rotavirus in Bangladesh (255). Handwashing with soap is effective in eliminating fecal contamination (256–258), even for viruses (259). Handwashing does not necessarily need to be done with soap, since using ash, mud, or other agents may also facilitate the removal of bacteria, being more effective than using water alone (260). Handwashing education programs have been found to reduce diarrheal incidence by 14–48% (239).

8.5. Latrines and Proper Disposal of Human Waste Because the fecal-oral route is the main route of transmission for diarrheal pathogens, the safe disposal of human feces would be expected to reduce transmission of most

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pathogens. Sanitation schemes such as latrines generally require proper education and active involvement of the community in order to be effective. It also should be recognized that in many communities, young children may be allowed to defecate freely even though sanitation facilities such as latrines are available (261,262). Welldesigned programs that combine improvements in water supply, sanitation, and hygiene education are thought potentially to reduce diarrheal morbidity by 35–50% (263).

8.6. Measles Immunization Major complications of measles infection include diarrheal disease, immune suppression, and a period of increased susceptibility to infectious diseases following an attack (see Chapter 13). Widespread measles immunization coverage would be expected to have an impact upon diarrhea. It has been estimated that measles vaccination coverage of 60% would reduce diarrheal incidence by 2% and decrease diarrheal mortality by 13% (264).

8.7. Nutritional Interventions Improving the nutritional status of children should be effective in preventing diarrheal morbidity and mortality. In the study of the global burden of disease, communicable diseases, together with maternal, perinatal, and nutritional disorders, explained 44% of the disability-adjusted life-years (DALYs) worldwide, whereas childhood malnutrition alone accounted for 16% of all DALYs (265). However, randomized, controlled interventions that were able to document an improvement of the nutritional status of children, e.g., through food supplements, have not studied its effects in preventing diarrheal diseases. Preliminary results in nonrandomized studies, like the observed reduction in the incidence of diarrheal diseases following nutritional improvement through home-garden production and nutrition education in Vietnamese children (266), need to be conﬁrmed.

8.7.1. Zinc Low serum zinc levels have been found to be signiﬁcant predictors of the incidence of diarrhea in general and severe diarrhea in particular, as well as an increased risk for the development of acute lower-respiratory infections, especially in boys (267). In a community-based, double-blind, randomized trial done in India, zinc supplementation given daily for 6 mo was associated with a signiﬁcant reduction in diarrhea incidence (17–26% reduction) and prevalence (35% reduction), which was mainly seen in children older than 12 mo of age, in boys, and in children with low serum zinc levels (268). A similar effect was also observed in the prevention of persistent diarrhea and dysentery in this study. Zinc supplementation was associated with a 21% reduction of persistent diarrhea and 14% reduction of dysentery, which were not statistically signiﬁcant overall (269). Again the effect was more apparent in boys, and in children with low serum zinc levels prior to supplementation, and in children older than 11 mo of age. A similar study done in Guatemala also found a 22% reduction in the incidence of acute and persistent diarrhea, mainly among poorly nourished boys (270). Similar studies done in Mexico, Peru, and Vietnam were combined with the results observed in India and Guatemala in a pooled analysis. Zinc supplementation resulted in statistically signiﬁcant reductions of 18% in the incidence and 25% in the prevalence of diarrhea, and 41% in the incidence of pneumonia (271). A trend was found for the prevention of

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persistent diarrhea and dysentery, without reaching statistical signiﬁcance. The effect of zinc in the prevention of diarrhea or acute lower-respiratory infections seems to be owing, in part, to the improvement of the cellular immune function, as evaluated by multi-antigen CMI skin tests, as well as in the proportion of certain lymphocyte subsets in the blood (272). Low serum zinc levels in mothers either early or late in gestation have been associated with low birth weight (LBW): the lower the serum zinc level in the mother, the lower the birth weight (273). Zinc supplementation given daily during an 8-wk period to LBW full-term infants in Brazil was associated with a 28% reduction in the prevalence of diarrhea and 33% reduction in the prevalence of cough (274). In another study done in India, zinc supplementation given between 30 d and 9 mo of life to a large group of infants who were small for their gestational age, found that supplemented children had signiﬁcantly lower mortality (275). This study is the ﬁrst one to demonstrate a potential beneﬁt of zinc supplementation on mortality. Well-designed trial to evaluate the impact of zinc supplementation on infant and childhood mortality needs to be conducted. 8.7.2. VITAMIN A An association between xerophthalmia and childhood mortality was noted in Indonesia (276), leading to several controlled intervention trials of vitamin A supplementation in developing countries endemic for vitamin A deﬁciency. There was an overall 23% reduction in mortality in children 6–59 mo of age, as indicated in a meta-analysis of these studies (277). In those trials where cause-speciﬁc mortality data were obtained, vitamin A supplementation was associated with a 35–50% reduction in diarrheaassociated mortality (278–281). When this association was evaluated in prospective, community-based trials of vitamin A supplementation, there were conﬂicting results. In a large study done in Ghana, in an area with high prevalence of xerophthalmia, it was demonstrated that vitamin A supplementation reduces the severity of diarrheal diseases, rather than its incidence or prevalence (281,282). Supplemented children had a lower incidence of diarrheal episodes with high number of liquid stools per day or with dehydration, which resulted in signiﬁcant reductions in clinic visits (17% reduction) and hospitalizations (38% reduction) for diarrhea cases. In an additional trial done in nonxerophthalmic children in northeastern Brazil, vitamin A supplementation was associated with a reduced probability of having diarrheal episodes, especially those with high number of liquid stools per day (283). No impact was observed on dysenteric diarrheal episodes. On examining all of the studies of vitamin A supplementation, it was concluded, however, that there was no overall effect on diarrhea rates (277). The most likely conclusion is that vitamin A supplementation reduces the severity of diarrheal episodes and complications but does not reduces the incidence of all diarrhea. One possible mechanisms for this observation is that supplemented children are able to mount an acute-phase response after a diarrheal episode as compared with those who receive placebo (284). 8.7.3. NUCLEOTIDES A strategy that has been considered for the prevention of diarrheal diseases is the provision of a dietary supplement with nucleotides. This hypothesis was tested in a

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large multi-center study done in infants from Spain. A formula with nucleotide supplementation was given for the ﬁrst 6 mo of life and compared with unsupplemented formula (285). There was a 36% reduction on the incidence of diarrhea as noted by participating mothers, as well as cases detected in 340 pediatric clinics. The duration and severity of diarrhea was also less in the supplemented infants compared with control infants. No impact on anthropometric indicators were found in these infants living in a developed country. In a controlled community-based study in Chilean children who received an infant formula with or without supplemental nucleotides (286), children who received the supplemented formula had a signiﬁcant reduction in the incidence and prevalence of diarrhea, although no difference existed in the causes of diarrheal episodes or in their clinical characteristics. These studies need to be replicated in developing countries with poor socioeconomic conditions. Other ways of providing dietary nucleotides, such as by consumption of staple foods that contain animal proteins with adequate amounts of nucleotides, need further evaluation.

8.8. Vaccines Rotavirus may be responsible for 5% of all diarrheal episodes and for 20% of diarrheal deaths in children under 5 yr of age (287). A live rotavirus vaccine prepared from a rhesus rotavirus, to which speciﬁc antigens from human rotavirus were added by molecular techniques (rhesus-human, reassortant, tetravalent rotavirus vaccine), was proved to be effective in developed countries and was introduced into the U.S. in 1998 (288). The efﬁcacy of this vaccine in developing countries was initially considered not optimal, owing to its lower level of protection seen in ﬁeld trials done in Peru (289) and Brazil (290). However, a re-analysis of these two trials has suggested that the vaccine had similar vaccine efﬁcacy against moderate and severe rotavirus diarrhea than in trials conducted in Venezuela and U.S. (291). Because of an apparent association of intussusception with this rotavirus vaccine (292), the vaccine was put on hold (293) and withdrawn from the U.S. market by the manufacturer. There is a need of a safe and effective rotavirus vaccine to be used in both developed and developing countries (294). Other vaccines against cholera and typhoid fever are available in the market but seldom used in developing countries. New vaccines against shigellosis and enterotoxigenic E. coli are expected to become available in the near future.

8.9. Other Potential Interventions As reviewed in this chapter, other potential interventions that could have a preventive effect on diarrheal diseases have been identiﬁed. The prevention of diarrheal diseases by the administration of probiotics, particularly Lactobacillus GG, and prebiotics needs to be further documented, as well as the potential beneﬁt of the utilization of food-related products like epidermal growth factor or short-chain fatty acids.

9. FUTURE DIRECTIONS As highlighted in this chapter, there has been considerable progress in documenting the importance of nutrition and its relationship with diarrheal diseases in children in developing countries. However, there are several research activities that should be conducted to develop a package of effective interventions that could be implemented

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in an inexpensive way in developing countries. Many gaps of information still exist in some critical areas, as indicated in this review, which will be summarize only brieﬂy herein: • The effect of diarrhea on growth and nutrition has been well-documented. There is a further need to evaluate the nutritional cost of asymptomatic infections in children, as documented with C. parvum in Peru. This may cause an important burden owing to the high prevalence of asymptomatic infections. • In the area of dietary management of diarrheal diseases, signiﬁcant progress has occurred, with the identiﬁcation of a variety of potential elements that may be effective in the management or treatment of these diseases. The use of probiotics in the treatment and prevention of diarrheal diseases, particularly Lactobacillus GG, is very promising. Studies are needed to evaluate further other strains that may have similar potential, as well as effectiveness studies of these approaches in a public health context. It is also important to evaluate the beneﬁt of prebiotics, both in the treatment and prevention of diarrheal diseases, because this strategy may be more cost-effective than the use of probiotics. • Further studies are needed to elucidate the mechanisms of action of short-chain fatty acids in the gut. The direct effect of administering short-chain fatty acids to children with diarrhea, as anti-diarrheal agents promoting water and electrolyte absorption as documented with butyrate, needs further evaluation. Similar studies are also needed with other agents that may be beneﬁcial to children with diarrhea, like epidermal growth factor and nucleotides. • The use of lectins to prevent the development of diarrhea associated with G. lamblia and C. parvum needs to be evaluated in controlled clinical trials. • Several well-conducted clinical trials have documented the beneﬁt of zinc supplementation in the treatment and prevention of diarrheal diseases. There is a need now to evaluate the implementation of this effective intervention within the public health context, by doing effectiveness trials of zinc supplementation in children attending public health facilities with diarrheal diseases. • On the prevention side, there is sufﬁcient evidence to suggest that zinc supplementation may have a very important impact on child mortality in developing countries, not only with LBW babies. Properly conducted ﬁeld trials to evaluate the potential impact of zinc supplementation on mortality are needed. • Further investigation is needed into the means of increasing the dietary intake of readily absorbed zinc in children, such as food fortiﬁcation, taking into considerations the consumption of staple foods available for fortiﬁcation in developing countries. • Vitamin A supplementation deserves further evaluation as treatment for shigellosis. • In the area of nutrition, there is overwhelming evidence indicating the importance of better nutritional status in the prevention of diarrheal diseases and their complications. However, few studies have documented an impact on improving the nutritional status of children in developing countries, and the beneﬁts of these changes on the rates of diarrheal diseases. Further controlled trials evaluating the impact of intervention programs promoting exclusive breast feeding on diarrheal diseases, as well as an improved quality of weaning foods, are urgently needed. • An area of investigation that deserves particular attention is food hygiene, because it may be one of the most important, and yet neglected, mechanisms of transmission of enteropathogens in developing countries.

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10. CONCLUSIONS It can be concluded from this review that nutrition and diarrheal diseases are closely related. These infectious diseases have an important impact in the nutritional status of affected children, especially in developing countries where the consumption of a weaning diet of very low quality inhibits an adequate catch-up growth after recovery from these illnesses. Poorly nourished children, on the other hand, are at a greater risk of developing these illnesses as well as getting more severe episodes, including persistent diarrhea, with a significant increase on their risk of dying. Considerable knowledge exists today of adequate dietary management of diarrheal diseases, which should inhibit their negative effects on nutrition. However, in many developing countries, the unavailability of an adequate weaning food not only prevents adequate dietary management during illnesses but, more importantly, has a pronounced and permanent effect on the nutritional status of these children. Considerable progress has been made in identifying potential effective dietary interventions in the treatment, and in some cases, prevention of diarrheal diseases. The use of probiotics, prebiotics, epidermal growth factor, short-chain fatty acids, nucleotides, lectins, and micronutrients, particularly zinc, have opened whole new avenues for research in nutrition and disease control. It is likely that in the future, when studies will have clearly identiﬁed the cost-effectiveness of these potential interventions, public health ofﬁcers in developing countries may consider not only ways to improve the diet of their population, but also the interventions that will reduce morbidity and mortality. These advances may go beyond the immediate beneﬁt of reducing the burden of illness and improve the quality of life (e.g., through enhanced cognitive development) as well.

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273. Neggers YH, Cutter GR, Alvarez JO, Goldenberg RL, Acton R, Go RC., Roseman JM. The relationship between maternal serum zinc levels during pregnancy and birthweight. Early Hum Dev 1991; 25:75–85. 274. Lira PI, Ashworth A, Morris SS. Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full term infants in northeast Brazil. Am J Clin Nutr 1998; 68 (2 suppl):418S–424S. 275. Sazawal S, Black RE, Menon VP, Dhingra U, Dhingra P, Mazumder S, et al. Effect of zinc and mineral supplementation in small for gestational age infants on growth and mortality. FASEB J 1999; A309.7. 276. Sommer A, Tarwotjo I, Hussaini G, Susanto D. Increased mortality in children with mild vitamin A deﬁciency. Lancet 1983; 2:585–588. 277. Beaton GH, Martorell R, L’Abbe KA, Edmonston B, McCabe G, Ross AC, Harvey B, eds. Effectiveness of Vitamin A Supplementation in the Control of Young Child Morbidity and Mortality in Developing Countries. Final Report to CIDA. Toronto, Canada: University of Toronto, 1992. 278. Rahmathullah L, Underwood BA, Thulasiraj RD, Milton RC, Ramaswamy K, Rahmathullah R, Babu G. Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323:929–935. 279. West KP Jr, Pokhrel RP, Katz J, LeClerq SC, Khatry SK, Shrestha SR, et al. Efﬁcacy of vitamin A in reducing preschool child mortality in Nepal. Lancet 1991; 338:67–71. 280. Daulaire NMP, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. BMJ 1992; 304:207–210. 281. Ghana VAST Study Team. Vitamin A supplementation in northern Ghana: effects on clinic attendances, hospital admissions, and child mortality. Lancet 1993; 342:7–12. 282. Arthur P, Kirkwood B, Ross D, Morris S, Gyapong J, Tomkins A, Addy H. Impact of vitamin A supplementation on childhood morbidity in northern Ghana. Lancet 1992; 339:361–362. 283. Barreto ML, Santos LMP, Assis AMO, Araujo MPN, Farenzena GJ, Santos PAB, Fiaccone RL. Effect of vitamin A supplementation on diarrhoea and acute lower respiratory-tract infections in young children in Brazil. Lancet 1994; 344:228–231. 284. Filteau SM, Morris SS, Raynes JG, Arthur P, Ross DA, Kirkwood BR, et al. Vitamin A supplementation, morbidity, and serum acute-phase proteins in young Ghanaian children. Am J Clin Nutr 1995; 62: 434–438. 285. Lama More RA, Gil-Alberdi Gonzalez B. Effect of nucleotides as dietary supplement on diarrhea in healthy infants. An Esp Pediatr 1998; 48:371–375. 286. Brunser O, Espinoza J, Araya M, Cruchet S, Gil A. Effect of dietary nucleotide supplementation on diarrhoeal disease in infants. Acta Paediatr 1994; 83:188–191. 287. De Zoysa I, Feachem RG. Interventions for the control of diarrhoeal diseases among young children: rotavirus and cholera immunization. Bull WHO 1985; 63:569–583. 288. Committee on Infectious Diseases, American Academy of Pediatrics. Prevention of rotavirus disease: guidelines for use of rotavirus vaccine. Pediatrics 1998; 102:1483–1491. 289. Lanata CF, Midthum K, Black RE, Butron B, Huapaya A, Penny ME, et al. Safety, immunogenicity and protective efﬁcacy of one or three doses of the Rhesus tetravalent rotavirus vaccine in infants from Lima, Peru. J Infect Dis 1996; 174:268–275. 290. Linhares AC, Gabbay YB, Mascarenhas JPD, et al. Immunogenicity, safety and efﬁcacy of rhesushuman reassortant rotavirus vaccine in Belem, Brazil. Bull WHO 1996; 74:491–500. 291. Linhares AC, Lanata CF, Hausdorff WP, Gabbay YB, Black RE. Reappraisal of the Peruvian and Brazilian lower titer tetravalent rhesus-human reassortant rotavirus vaccine efﬁcacy trials: analysis by severity of diarrhea. Ped Infect Dis J 1999; 18:1001–1006. 292. CDC. Intussusception among recipients of rotavirus vaccine. United States, 1998–1999. Morb Mortal Weekly Rep 1999; 48:577–581. 293. Suzuki H, Katsushima N, Konno T. Rotavirus vaccine put on hold. Lancet 1999; 354:1390. 294. Cunliffe NA, Kilgore PE, Bresee JS, Steele AD, Luo N, Hart CA, Glass RI. Epidemiology of rotavirus diarrhoea in Africa: a review to assess the need for rotavirus immunization. Bull WHO 1998; 76:525–537.

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Acute Lower-Respiratory Infections Claudio F. Lanata and Robert E. Black

1. INTRODUCTION Acute respiratory infections are the leading cause of morbidity and mortality among infants and children in developing countries. It is estimated that acute respiratory infections cause up to 4.0 million deaths per year in children (1,2), and an important contributing factor to these deaths is malnutrition (3). Acute respiratory infections include both acute upper-respiratory infections and acute lower-respiratory infections. Acute lower-respiratory infections consist primarily of pneumonia, but also include croup, tracheobronchitis, and bronchiolitis. The speciﬁc aims of this chapter are to present current knowledge regarding the epidemiology, pathophysiology, diagnosis, and treatment of acute lower-respiratory infections, and the potential role of nutrition in treatment and prevention.

2. PUBLIC HEALTH IMPORTANCE The World Bank’s World Development Report 1993 reported that an estimated 12,443,000 deaths occurred in 1990 among children less than 5 yr of age (4). Of these deaths, acute lower-respiratory infections (not associated with measles, pertussis, or human immunodeﬁciency virus [HIV] infection) were estimated to account for 2,654,000 deaths, and acute upper-respiratory infections accounted for 58,000 deaths. Deaths from acute respiratory infections associated with measles, pertussis, and HIV infection in young children have been estimated to account for an additional 822,000 deaths, and perinatal deaths owing to acute lower-respiratory infections have been estimated to account for an additional 240,000 deaths. Thus, in 1990, a total of 3,774,000 deaths from acute respiratory infections were estimated to occur, accounting for 30.3% of all deaths in young children in developing countries (Fig. 1) (2).

3. HISTORICAL BACKGROUND Among the acute respiratory infections, inﬂuenza epidemics are well-described in historical accounts from at least the 12th century (5). Epidemics have been especially From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Fig. 1. Causes of acute lower-respiratory infection worldwide. Adapted with permission from ref. (2).

well-documented in Great Britain (6). Influenza is known to have occurred in many pandemics, with involvement of all areas of the globe and a characteristic geographical spread along the routes of human travel. The great pandemic of inﬂuenza in 1918–1919 is considered to have accounted for the most deaths from an epidemic disease since the Black Death of the 14th century, killing an estimated 21 million people worldwide (7,8). A common cause of pneumonia, pneumococcus (Diplococcus [Streptococcus] pneumoniae), was identiﬁed in 1881, and subsequent animal studies showed that it was involved in the causation of pneumonia (9). By the turn of the century in the United States, it was estimated that mortality from pneumonia affected 1 out of 500 individuals (10). Antipneumoccocal sera were developed for the treatment of pneumonia, however, typing of the many pneumococcal strains was needed to ensure that the proper pneumoccocal antisera were used. Sulfa antibiotics, which emerged in the late 1930s, were later shown to be more effective than serum therapy in the treatment of pneumococcal pneumonia (9). Identiﬁcation of many viral pathogens involved in acute respiratory infections, including respiratory syncytial virus (RSV), parainﬂuenza virus, and rhinoviruses occurred in the 1950s (9).

4. EPIDEMIOLOGY Several risk factors have been identiﬁed for acute lower-respiratory infections, that will be reviewed brieﬂy in this chapter (Table 1).

4.1. Risk Factors 4.1.1. LOW BIRTH WEIGHT (LBW) Low birth weight (LBW) (<2500 g) is associated with increased morbidity and mortality from acute lower-respiratory infections. Case-control studies from Brazil

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Table 1 Risk Factors for Acute Lower-Respiratory Infection Low birth weight Lack of breast-feeding Malnutrition Vitamin A deﬁciency Selenium deﬁciency Zinc deﬁciency Vitamin D or calcium deﬁciency Immunosuppression Attendance at day-care centers Crowding Exposure to cooking ﬁre Parental smoking Outdoor contaminants Low socioeconomic status, poor housing Household dampness Respiratory disease in the household Prior respiratory infections Young age Males Season Lack of immunization Human immunodeﬁciency virus (HIV) Sickle-cell disease

(11,12) and Sri Lanka (13) have documented that LBW was associated with an increased risk of acute lower-respiratory infection. LBW infants appeared to have a 50% greater risk of pneumonia compared with infants with birth weight *2500 g (11). These ﬁndings have been conﬁrmed by longitudinal studies done in Pelotas, Brazil (14), and in China (15), where LBW children had higher hospital admissions for respiratory disease. LBW has also been associated with repeated episodes of wheezing disorders during the ﬁrst year of life (16). Epidemiologic studies have also shown an association between LBW and increased mortality from acute lower-respiratory infections in Brazil (17,18), India (19), and the Philippines (20). Infants born at term weighing 2000–2499 g at birth have neonatal mortality 10 times greater than that of infants weighing 3000–3499 g (21). This increased risk of mortality owing to respiratory diseases seems to be greater among LBW infants who were stunted at birth (21). The incidence of LBW is greater in developing countries than in developed countries for several reasons (21), one of which is poor maternal weight gain during pregnancy. Maternal weight gain of less than 10 kg was associated with a 40% increased risk of hospitalization owing to pneumonia in Brazil (22). This increased risk of morbidity and mortality among LBW infants may be owing to impaired immunity and/or impaired lung function (3). The incidence of LBW, especially those infants small-for-gestational-age born at term, continues to be in developing countries, owing to poor diet, infections, adolescent pregnancies and other reasons. This constitutes an important public health problem for developing countries.

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4.1.2. LACK OF BREAST FEEDING Lack of breast feeding has been identiﬁed as a major risk factor for morbidity and mortality in children with acute lower-respiratory infections. Children in China who were not breast fed were twice as likely to be hospitalized than breast-fed children (15). Lack of breast feeding was found to be a risk factor for acute lower-respiratory infection, including radiologically conﬁrmed pneumonia, in case-control studies in Argentina (23) and Porto Alegre, Brazil (11). Nonbreast-fed children were 17 times more likely to be hospitalized for pneumonia than breast-fed children in Pelotas, Brazil; this risk increased to 61 times in infants under 3 mo of age (24). In an isolated Indian community in Manitoba, Canada, bottle-fed infants were more likely to be hospitalized for pneumonia than breast-fed infants (25). Epidemiologic studies are less clear as to whether lack of breast feeding also increases the risk of death in children with acute lower-respiratory infections. A case-control study in Pelotas, Brazil showed that risk of death from respiratory infections was higher in infants who were not breast fed (26). In The Gambia, a case-control study of children who died with acute lower-respiratory infections did not ﬁnd an association with lack of breast feeding (27). No signiﬁcant association was found between lack of breast feeding and mortality from acute lowerrespiratory infections in the Philippines, but an association was noted between lack of breast feeding and mortality owing to acute lower-respiratory infection and diarrhea combined among young infants (20). Breast feeding may be protective against acute respiratory infections because of transfer of immunity by breast milk, the presence of antibacterial and antiviral substances in breast milk, and avoidance of pathogens from contaminated weaning foods (28–30). Baby bottles are also known to be a risk factor for the development of acute otitis, diarrhea, and pneumonia (31). 4.1.3. MALNUTRITION The relationship between malnutrition and the incidence of respiratory diseases has only been evaluated critically since the 1990s (32). Two studies done under the support of the U.S. Board on Science and Technology for International Development (BOSTID) looked into this relationship. One study done in Guatemala did not ﬁnd an association between nutritional status and acute lower-respiratory infections (33), whereas the other done in the Philippines found an increased risk of acute respiratory infections in children with less than –3 Z-score in weight-for-age compared with the National Center for Health Statistics median reference population (34). This study found that undernourished children had a relative risk of 1.2 for an increased incidence of any acute respiratory illness and 1.9 for acute lower-respiratory infections (34). These initial ﬁndings have been conﬁrmed by subsequent studies done in Bangladesh (35,36), and India (31). These studies used a symptom-based deﬁnition of acute lower-respiratory infections without clinical or radiographic conﬁrmation of pneumonia. In addition, an association between undernutrition and an increased risk of developing pneumonia seems to exist, as indicated by hospital-based studies done in The Gambia (37), Brazil (14), and Chile (38), where undernutrition was identiﬁed as a risk factor for hospitalizations owing to pneumonia. In a case-control study done in The Gambia, the development of pneumococcal infections was associated with a history of poor weight gain prior to illness, as compared with community controls (39). Malnutrition seems to increase the severity of acute lower-respiratory infection (40), increasing its probability of having

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bacteraemia (in many cases with multiple microbial organisms), pleural effusion, and other complications (41). In a large study done in the Philippines, the risk of mortality increased 1.7 times for each one-unit decrease in weight-for-age Z-score (42). In this study the mortality associated with both acute lower-respiratory diseases and diarrhea combined was doubled for each one-unit decrease in weight-for-age Z-score. Another study in the Philippines had found a similar increased risk of death of severe malnutrition with acute lower-respiratory infections (34). In conclusion, poor nutritional status in children seems to be associated with a modest increased risk for developing any acute respiratory disease and a moderate risk for developing acute lower-respiratory infection or pneumonia. Malnutrition seems also to be a risk factor for the development of malaria attacks (43), a condition that is difﬁcult to differentiate from pneumonia in countries with endemic malaria. 4.1.4. MICRONUTRIENT STATUS Micronutrient status has been implicated as a risk factor in acute respiratory infections. Respiratory disease has been associated with increased risk of developing vitamin A deﬁciency (44), and in turn, vitamin A deﬁciency has been associated with increased risk of developing respiratory disease in preschool children (45,46). However, when respiratory diseases were assessed in carefully controlled prospective trials of vitamin A supplementation, no major reduction occurred in the mortality or morbidity associated with respiratory diseases, as indicated in a meta-analysis of all available studies (47). The initial association between low serum retinol levels and pneumonia may be explained by vitamin A that is lost in the urine during these infections (48), probably by mechanisms similar to those documented for diarrheal diseases (49). Children with low plasma zinc concentrations in an urban-slum setting were found to have a mean prevalence rate of acute lower-respiratory infections that was 3.5-fold higher than children with normal plasma zinc concentrations (50). As presented in Subheading 7.3.4., zinc supplementation has been associated with a 41% reduction in the incidence of pneumonia, in a pooled analysis of all available studies (51), indicating the importance of zinc deﬁciency as a risk factor for pneumonia. It is now clear that zinc is not only important in growth but also in the immune function of children, which is affected in zinc-deﬁcient children suffering diarrheal and respiratory diseases (52,53). Most children in developing countries consume very little amounts of animal proteins—the dietary source of zinc with the highest bioavailability—explaining why zinc deﬁciency may be one of the most important nutritional disorders in children from developing countries (52). Selenium deficiency may be a risk factor for the development of respiratory infections, particularly pneumonia, among critically ill patients and malnourished children. Premature infants may be particularly at risk. It is known that selenium serum concentration drops in premature infants after birth, especially in those who develop respiratory distress syndrome (54). In a prospective study in LBW infants, low plasma selenium levels were associated with chronic lung disease and bronchopulmonary dysplasia, as well as with the total days of oxygen requirement. For each drop of 0.1 µmol/L of selenium in plasma, there was a 58% increase in days of oxygendependency, controlling for gestational age and age when infants were fully fed orally (55). Premature infants, especially those treated with oxygen, may warrant selenium supplementation. In contrast with respiratory diseases, there seems not to

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be an association between acute or persistent diarrhea and selenium plasma levels in children (56). Other micronutrients may also play a role in susceptibility of children to pneumonia and other acute respiratory infections. In a case-control study done in Ethiopia, children with clinical or radiological evidence of rickets had a probability of pneumonia 13 times higher than did children without rickets, suggesting that vitamin D or calcium deﬁciency may also be important as a risk factor for pneumonia (57). 4.1.5. DECREASED IMMUNITY Some indicators of decreased immunity have been associated with the risk of acute respiratory diseases. Depressed cell-mediated immunity has been demonstrated to be an important predictor of both acute upper- (20% increased risk) (58), and lower(80% increased risk) (35) respiratory infections in Bangladeshi children, controlling for nutritional status. A study done in Kenya found a similar association with acute respiratory infections (34% increased risk) (59). This impaired immune capacity of children in developing countries seems to be related to micronutrient deﬁciencies (zinc in particular) and malnutrition. 4.1.6. ENVIRONMENTAL AND SOCIOECONOMIC FACTORS Several environmental and socioeconomic factors have been found to be associated with respiratory infections in children. Attendance at day-care centers has been identiﬁed as a strong risk factor for acute upper- and lower-respiratory tract infections in children in several studies, both in developed (60,61) and developing countries (11,12,62). Children in day-care centers have between 5–12 times greater risk of pneumonia than those cared for at home. This increased risk is not only for bacterial pneumonia, but also for other causes of pneumonia like Mycoplasma pneumoniae (63) and RSV (64). The very low rate of invasive pneumococcal disease observed in Switzerland between 1985 and 1994 has been attributed to the lower rate of day-care attendance of Swiss children compared to other European countries (65). Day-care centers increase the contact between young children, and facilitates the transmission of infections through respiratory droplets. Similar to attendance at day-care centers, crowding (number of persons in the household, number of persons sharing the bedroom, number of siblings under 5 yr of age, greater parity) also favors the transmission of respiratory infections, as documented in case-control (11–13,64) and longitudinal (66) studies. Even at the turn of this century, household crowding was associated with an increased risk of death owing to measles-associated pneumonia (67). Increased contact with other children or adults, whether at home or at institutions, is a strong risk factor for pneumonia and other respiratory diseases. Another mechanism by which crowding may affect the risk of respiratory diseases is the exposure to smoking and other indoor air pollutants. Exposure to smoke during cooking and parental smoking was associated with deaths owing to acute lowerrespiratory infections in a case-control study in The Gambia (27). Maternal smoking (greater or equal than 5 cigarettes/d) was associated with upper- and lower-respiratory diseases in a longitudinal study in Chile (66). In a large prospective study of 1459 children under 2 yr of age in periurban Lima, Peru, even the exposure of a child to a very low level of household members who smoke (mean consumption 11 cigarettes/wk,

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only 6% of mothers reported smoking) was consistently associated with an increased risk of cough and respiratory illnesses (68). Environmental exposure to tobacco smoke has been associated clearly with an increased risk of pneumonia, bronchitis, bronchiolitis, chronic middle ear effusion, and increased frequency and severity of attacks among asthmatics (69,70). Maternal smoking during pregnancy increases the risk of sudden infant death syndrome (SIDS) (71). In the U.S., questionnaire data between 1988 and 1994 has shown that environmental exposure to tobacco smoke was 38% in children under 5 yr of age, and was associated with wheezing disorders rather than pneumonia (72). Developing countries are rapidly increasing their rate of maternal and household smoking, the reduction of which should be considerd a public health priority. Breast feeding protects children from this increased risk of lower-respiratory diseases associated with exposure to environmental tobacco smoke (71,73), which is another reason for breast-feeding promotion. Many households in developing countries utilize biomass fuels (wood, manure, carbon, agricultural waste, etc.) mostly because more efﬁcient fossil fuels or electricity are either not available or not affordable (74). These fuels are usually burned in inefﬁcient stoves or openly within the family room without the use of a chimney, especially in rural areas in the highlands. Children exposed to these sources of indoor air pollution have increased risk of respiratory illnesses. In Nepal, the risk of severe respiratory diseases increased with the number of hours each infant spent near a stove (75,76). In The Gambia, carriage of a child on the mother’s back while cooking was associated with acute lower-respiratory infections (77), as was the use of wood-burning stoves in Native Americans (78). An increased incidence of acute lower-respiratory infection was reported associated with the use of kerosene stoves in India (79), but not in Peru (68). Among different combustion products, a high concentration of suspended particulates with 0.1–10 microm of diameter (PM10) has been linked with an increased risk of pneumonia. This effect seems to be mediated through an inhibition of the inﬂamatory response of alveolar macrophages by PM10 exposure, as documented with RSV infections (80). Not only may indoor sources of air contaminants be important, but environmental air pollution may also play a role as a risk factor for pneumonia, especially among atopic individuals (81). Because of all these reasons, the incidence of acute lower-respiratory diseases has been reported to be higher in crowded urban areas of low socioeconomic status, where most of these factors are combined (31). Lower social class (31,66,82,83), race (82,83), parental education (11,22,31,66), and poor housing (23,66) are variables associated with lower-respiratory infections through crowding, indoor air pollution, and environmental exposure to tobacco, as well as other nutritional factors. The presence of a pet animal at home (13) as well as household dampness (68,84) are particular risk factors for wheezing disorders and childhood asthma, most likely by favoring the growth of molds (85) and the presence of other household allergens. 4.1.7. PRIOR INFECTIONS Several studies have reported an increased risk of pneumonia or acute lowerrespiratory infections in children who have had a prior episode of pneumonia or wheezing (11–13,23). Viral infections, particularly RSV or influenza virus, also predispose to invasive pneumococcal disease in children for 4 weeks after the viral infection (86). In a case-control study in Brazil, wheezing disorders were associated

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with a sevenfold increased risk of pneumonia in children, controlling for other factors (87). On the other hand, prior acute lower-respiratory infections (croup, bronchitis, bronchiolitis, or pneumonia) were also a risk factor for wheezing in infancy (16). But prior infection does not always seems to be a risk factor. Infections in early life seem to be related with the chances of developing asthma and allergic disorders later in life. An initial report from Japan documented that children 12 yr old who had a positive tuberculin response predicted a lower incidence of asthma, lower serum IgE levels, and the predominance of a cytokine proﬁle not associated with atopy (88). This report was used to postulate that the reduction of early childhood infections, such as tuberculosis, owing to development and better living standards, may be one reason for the increase in asthma and atopy observed in developed societies in the last 20 years (89). Recently conducted studies, however, have shown controversial results. Atopy (a state of allergic response, mediated by IgE, to normally innocuous common environmental antigens—allergens like household dust, mites, or plant pollens—and asthma at school age was not associated with attendance at day-care from ages 1–3 in Finland, although having no siblings was associated with hay fever, atopic eczema, and asthma at school age (90). In Germany, repeat episodes of fever and antibiotic treatment in early life (as assessed by parental questionnaires) were strongly associated with asthma and current wheezing at school age and inversely related to atopy and bronquial hyperresponsiveness (91). Aeroallergen skin test reactivity by prick test was greater among school-aged children in Italy whose fathers were in the highest educational level and in those with no siblings, after adjusting for other factors (92). More studies are needed, especially in developing societies that are in a transient state from poor to better-off socioeconomic status, to understand better the relationship between early exposure to childhood infections and asthma or atopy in school-aged children and how this could be manipulated. 4.1.8. OTHER FACTORS Other factors have been associated with pneumonia or acute lower-respiratory infections, like young age, males, young maternal age, and so forth. Infants and children under 2 yr of age have the highest incidence of infections, particularly RSV (64). Mortality owing to lower-respiratory diseases is concentrated among infants under 6 mo of age (1). Males have higher incidence of wheezing disorders or RSV infections in infancy than females (13,64,68,93). Young maternal age (11) and adolescent mothers (22) have been reported to have an increased risk of pneumonia in their children. Lack of immunization has also been associated with increased risk of respiratory morbidity (12,31) and mortality (27). The increased incidence of HIV infections in the heterosexual population is changing the epidemiology of respiratory infections in children from developed and developing countries. As the prevalence of HIV increases in women, the number of newborns infected with HIV through vertical transmission (estimated at 20–30%) will also increase (94). As documented in Haiti, a large proportion of HIV-infected newborns (60% in this study) will die before reaching 6 mo of life, whether meningitis, sepsis, or pneumonia is the immediate cause of death (95). Other conditions prevalent in developing countries, like sickle cell disease, are also associated with an increased risk of invasive pneumococcal and Haemophilus inﬂuenzae infections (94). Finally, lack of maternal antibodies is a risk factor for the development of infections in early infancy,

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as documented for RSV (64). This association may offer the opportunity to protect newborns through maternal immunization, as discussed in Subheading 7.1.

4.2. Incidence Before reviewing the information available on incidence of acute lower-respiratory infections in children, it is important to discuss brieﬂy the deﬁnitions of pneumonia or ALRI used in these studies, because they have profound inﬂuence on the rates reported, as reviewed elsewhere (96). Studies done in developed countries generally report cases diagnosed by physicians on clinical grounds, sometimes complemented by chest X-rays. In contrast, studies conducted in developing countries usually are based on diagnosis from respiratory signs and symptoms reported by the mother or identiﬁed by ﬁeld workers. Even though the presence of cough, rapid respiratory rates, and other respiratory signs are highly suggestive of pneumonia, as promoted by the WHO casemanagement guidelines, it is difﬁcult to distinguish very clearly between pneumonia and other types of acute lower-respiratory infections, especially in community-based prospective studies (96,97). The methodology used in these studies is also critical. High variability exists on the normal respiratory-rate-by-age, which at some ages is very similar (within 1 standard deviation [SD]) of the cut-off value used by WHO to consider that a child has tachypnea (98). The technique used to measured the respiratory rate is also important (99). Physical signs on chest examination have important variations when repeat observations are done with one or multiple observers (100). Even chest X-rays may be negative in the presence of pneumonia proven by postmortem examination in children (101). To complicate the issue further, rates will change if cases are identiﬁed at health facilities when mothers decide to bring their children for care (passive surveillance), as compared with frequent home-visits by trained ﬁeld workers to identify respiratory infections (active surveillance). Because of these variables, studies using passive surveillance and chest X-ray to diagnose pneumonia report the lowest rates and studies using active surveillance and symptom-based diagnosis of acute lower-respiratory infections report the highest rates. Because of these reasons, the comparison of ALRI or pneumonia rates across studies and countries may not be valid and should be taken with caution if the methods used are not similar. The incidence of acute respiratory infections (mostly upper) in developing countries have been reported between 4–7 episodes/child/yr, being similar in America (102), Africa (103), and Asia (104). The incidence of pneumonia, as diagnosed by physicians with or without radiology, has been reported as 53 episodes per 100 child-years in children under 3 yr of age in Guatemala (102); 30 episodes per 100 child-years in infants and children under 2 yr of age in Peru (96,105); and 16.5 episodes per 100 child-years in children under 5 yr of age in The Gambia (106). The incidence of acute lower-respiratory infection, as diagnosed by the presence of cough with an increased respiratory rate and/or other respiratory signs like subcostal retraction, nasal ﬂaring, wheezing, or fever has varied from 7 episodes per 100 childyears in children under 5 yr of age in Thailand (107) to 296 episodes per 100 child-years in children under 5 yr of age in Uruguay (108). Interestingly, this huge variation in rates was also observed in studies promoted by BOSTID of the U.S. National Academy of Science, despite their attempts to standardize their methodology by appropriate training and supervision (109).

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The age-speciﬁc incidence rates for acute respiratory infections are generally highest in infants at 6–11 mo of age. However, for wheezing disorders, higher rates are observed in infants under 6 mo of age and among boys (Lanata CF, unpublished).

4.3. Seasonality Seasonal distribution for incidence rates of acute respiratory infections and acute lower-respiratory infections has been examined in several BOSTID studies (109). Patterns of acute respiratory infections appear to vary by location. The highest incidence of acute respiratory infections in Colombia and Thailand was observed from September through December. In Guatemala, the highest rates were noted from January through July. Two peaks were observed in the Philippines, one in January and one in October. Seasonality was also observed for acute lower-respiratory infections in different BOSTID sites, but that patterns did not necessarily coincide with that for acute respiratory infections overall (109). This variation is most likely owing to the mixture of pneumonia and wheezing disorders that are combined by the methodology used in the BOSTID studies. Wheezing disorders or infections by RSV are more seasonal than pneumococcal or Haemophilus inﬂuenzae infections in tropical developing countries, being more common in winter or cold months (66,82). Mortality owing to acute lowerrespiratory infections, more so in neonates, is also higher in winter months (110). These observations have led people to believe that exposure to cold weather or high humidity is associated with an increased risk of developing acute lower-respiratory infections or pneumonia. Volunteers studies with rhinoviruses after exposure to cold and to high humidity failed to demonstrate an increased risk of infection as compared to a warm and dry environment (111). Epidemiological studies done in England have also failed to demonstrate an association between indoor temperature and humidity and respiratory infections (112). Most likely, cold weather induces individuals to reduce ventilation indoors, and the crowding that results from remaining indoors increases the risk of respiratory infections, rather than the cold directly affecting the health. There is a need to better document this lack of association in order to clarify this issue.

4.4. Duration Most episodes of acute respiratory infections and acute lower-respiratory infections last less than 2 wk (109). In a prospective home surveillance study done in Peru of respiratory signs and symptoms by frequent (twice weekly) home visits by trained ﬁeld workers, it was shown that cough and phlegm started developing 10–12 days prior to the diagnosis of pneumonia by a physician or a positive chest X-ray. It was also found that patients took 10–12 d to recover after diagnosis (96). Rapid breathing, fever, loss of appetite, and ill-appearance, as reported by the mother, appears between 5–8 d prior to diagnosis and lasts 5–8 d after the diagnosis (except fever that disappears in 24 h after starting antibiotics) (96). Thus, the duration of symptoms are related to their severity, as well as to early treatment with antibiotics. Based on this study, it could be said that most respiratory signs and symptoms associated with pneumonia in the community usually would last no more than 15 d.

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4.5. Case-Fatality Ratios Case-fatality ratios for acute lower-respiratory infections in different hospital-based studies have ranged from 3.2% (109) to greater than 20% (113,114) in developing countries. Higher case fatality has been associated with age under 1 yr (115–117), malnutrition (115–118), increased respiratory rate (>70/min) (118), cyanosis and low oxygen saturation (115,116,118), rickets (116), loose stools (117), and late hospital admission (119). Females have been reported to have an increased case fatality in Papua New Guinea (115) and in the BOSTID studies (109). In malnourished children, pneumonia is a predictor of mortality (120). Gambian children who were hospitalized with severe pneumonia and survived were followed-up after discharge from the hospital (121). It was found that children who were malnourished while in the hospital had a three-fold greater risk of death after being sent home than that of children without malnutrition, indicating the importance of nutritional recovery in the hospital before a patient is sent home (121). Owing to the increase in the prevalence of penicillin-resistant strains of Streptococcus pneumoniae, concerns of greater case-fatality rates in infections with resistant strains has emerged (122). However, in several studies (123–126), the mortality associated with resistant strains did not increase even when penicillin or related drugs were used, owing to the high concentration these antibiotics achieved in the lung tissue, several levels above the minimal inhibitory concentration of the strains (126). On the contrary, resistant strains have higher mortality rates in meningitis owing to the lower antibiotic concentration in the cerebrospinal ﬂuid (125,126). As expected, appropriate case management can reduce a high level of case fatality, as documented in Zambia when the WHO protocol for case management of pneumonia was introduced in a rural hospital (114).

5. CLINICAL FEATURES/PATHOPHYSIOLOGY 5.1. Clinical Presentation Acute upper-respiratory infections are usually deﬁned based on signs of at least one of the following: runny nose, sore throat, cough, or earache or ear discharge, without any findings of acute lower-respiratory infections (109). Acute lower-respiratory infections are based on the presence of cough and at least one of the following signs: increased respiratory rate (>60/min in infants under 2 mo of age, >50/min in infants 2–11 mo old, and >40/min in children 12 mo and older), rales or crepitations, wheezing, stridor, or chest indrawing (109,127–129). The presence of cough and an increased respiratory rate or chest indrawing is about 70% sensitive and speciﬁc to identify pneumonia, especially in cases seen in an emergency room of a health facility (127–129). In areas that do not have malaria, the presence of fever may increase the speciﬁcity without much drop in the sensitivity (97,130), increasing its positive predictive value. The presence of chest indrawing, nasal ﬂaring, and cyanosis are signs of more severe disease (96). The presence of nasal mucus, of any color or consistency, was not associated with pneumonia in a longitudinal study in Peru (96), against the popular belief that purulent nasal discharge is associated with pneumonia. Bacteremic pneumococcal

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pneumonia is usually associated with high fever, increased white blood cell (WBC) counts, and ill appearance (131); in 80% of cases, they had a lobar pneumonia. In the laboratory, apart from a positive chest X-ray, children with pneumonia have an increased count of WBC during the ﬁrst 2 d of their clinical course, declining thereafter, reaching the lowest levels by day 4 (132). The erythrocyte sedimentation rate follows an opposite course, being normal or mildly elevated during the start of the clinical course and increasing steadily thereafter (132).

5.2. Major Pathogens Involved in Acute Lower-Respiratory Diseases in Children In both community- and hospital-based studies, viruses are more commonly isolated than bacteria from specimens taken from children with acute lower-respiratory infections, in part owing to the limitations of current methods to identify a bacterial cause of pneumonia. RSV is the leading viral pathogen involved in acute lower-respiratory infections in children, being isolated in 11–37% of patients (109,133–136). Thirty percent of children infected with RSV have pneumonia; bronchiolitis is the most common clinical presentation (137). Other important viral causes of acute lowerrespiratory infections are adenovirus, parainﬂuenza virus, and inﬂuenza virus (138,139). Identiﬁcation of the bacterial causes of pneumonia is limited by the low rate of isolation of bacteria in blood cultures and the impracticality and risk involved with needle aspiration of the lung for culture. Cultures taken from the trachea or throat are invalid because they are usually contaminated by bacteria that grows in those settings, not necessarily representing the cause of the pneumonia. In cultured specimens taken from sterile sites (blood or lung tissue) in children with acute lower-respiratory infections, the most commonly identiﬁed bacterial pathogen has generally been Streptococcus pneumoniae, followed by Hemophilus inﬂuenzae (109,134,136,140). Other important pathogens include Bordetella pertussis and Mycoplasma pneumoniae. Pneumonia in cases with pertussis has been reported in 9.4% of cases, the severity of the disease being greater among infants <6 mo of age (141), Pertussis in the very young infant or in individuals previously immunized can also occur. In very young infants, the disease is atypical and severe, requiring hospitalization (142). In previously immunized individuals, pertussis is mild, prolonged (>4 wk of symptoms) and atypical (143). In some endemic areas, Chlamydia trachomatis should also be considered in cases with pneumonia, especially if the individual has concurrent conjuntivitis (144). As with M. pneumoniae, Chlamydia pneumoniae is also a cause of pneumonia epidemics in school children and adults (145). Mixed infections with different pathogens may occur. Empyema can occur in S. pneumoniae pneumonia. However, Staphylococcus aureus is a common cause of empyema in developing countries, requiring thoracentesis and prolonged antibiotic therapy (146,147). Another complication of pneumococcal pneumonia is necrotizing pneumonia, usually associated with lung abcesses and cavitation, with better clinical course in children than in adults (148). Croup in children is associated with older children (mean age 21 mo), usually associated more with viral organisms than bacteria (149). An important sub-group of children that has been recently studied in developing countries are infants under 3 mo of age. In two studies done in Ethiopia (150) and Papua New Guinea (151), Streptococcus pyogenes and S. pneumoniae were the most common isolates, followed by S. aureus. RSV was the most common viral agent. Organisms

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frequently isolated in young infants in developed countries, like Salmonella group B and Streptococcus agalactiae, were rarely isolated. However, in a similar study done in the Philippines (152), Salmonella spp, Enterobacter spp. and Gram-negative organisms were more common than S. pneumoniae, indicating that the pattern observed in developed countries may also be present in some developing countries. Further studies on the etiology of severe infectious diseases in infants under 3 mo of age are needed. Because of the newly recognized need to rid Streptococcus pneumoniae from young infants, WHO is now evaluating the use of maternal immunization to protect neonates (153). Klebsiella pneumoniae (154), blastomycosis (155), Legionella pneumonia (156), and melioidosis (157) are some of the opportunistic infections that may occur in premature babies and persons who are immuno-compromised, have congenital diseases, or are given steroids. In some isolated rural areas with low immunization coverage, measles epidemics that are associated with up to 32% of pneumonia cases still occur (158).

5.3. Pathophysiology The pathophysiology of acute lower-respiratory infections may vary depending on the pathogen involved. In general, the immune defenses in the lung are provided by a cough reﬂex, action of cilia in the tracheobronchial tree, mucus secretion by goblet cells, and phagocytic activity by alveolar macrophages. Pneumonia occurs when pathogenic organisms overwhelm these host defenses and infection occurs in the lower respiratory tract. In the affected portion of the lung, polymorphonuclear leukocytes, erythrocytes, and proteinaceous secretions are present, and consolidation occurs, which may appear as a homogeneous density on chest radiograph. In general, consolidation occurs less among young infants. The affected individual may develop fever, tachycardia, and cyanosis, and sputum production may be present. Phagocytosis, antibody responses, and other immune mechanisms usually allow recovery from pneumonia within several days to a couple of weeks. A series of elegant experimental studies have clariﬁed the physiologic changes occurring in the lung with lobar pneumonia. Studies in dogs with pneumonia induced by inoculation with S. pneumoniae (159) or Pseudomona aeruginosa (160) revealed that the exudate produced in the site of infection reduces the gas exchanged by ﬁlling the alveoli, preventing them from being inﬂated. This causes a reduction in the total lung capacity as well as in the functional residual capacity, proportional to the magnitude of the lung involved. The lung reacts with hypoxia-induced pulmonary vasoconstriction in the affected area, initially thought to be an attempt to divert blood to ventilated lung tissues to maintain a high oxygen tension in the blood (161). This, however, is not effective, and blood goes through the pneumonic, unventilated tissue, creating an arterial-venous shunt, which explains the hypoxia seen in severe pneumonia (162). This pulmonary vasoconstriction induces pulmonary hypertension, which in severe pneumonia causes right ventricular cardiac failure, a condition that is associated with increased mortality and that does not respond to digoxin therapy (163). Very few children with right ventricular failure will manifest the typical clinical signs of hepatomegaly, tachycardia, raised jugular venous pressure, or peripheral edema. They usually only have dilatation of the right ventricle on ultrasound examination of the heart (163). Oxygen administration reduces the vasoconstriction and increases the blood’s oxygen tension through the preserved lung tissue, but the shunt remains unchanged

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because the pneumonic lung is not ventilated (164). Intrapulmonary blood shunt is not the only reason for hypoxia, because the pneumonic tissue increases its consumption of oxygen, and at the same time, fever and infection also increase the oxygen requirements in the rest of the body (165). The involvement of lung tissue by pneumonia also causes a reduction of lung compliance and an increase in the work of breathing. In the dog model, administration of intravenous ﬂuids that could increase the plasma volume and the pulmonary capillary wedge pressure is associated with large increases in lobar wet weights of the affected pneumonic lung, probably owing in part to transudation of plasma and crystalloid into alveolar spaces (166). The magnitude of the intrapulmonary shunt may be increased by endogenous vasodilator mediators, exogenous systemically administered vasodilator drugs, positioning the patient with the affected lung down, and increasing the positive airway pressure by mechanical ventilation (167). Factors that reduce shunt include effective hypoxic pulmonary vasoconstriction, inhaled locally acting vasodilators that act primarily on the ventilated lung, and positioning the patient with the affected lung up (167). The blood’s oxygen saturation is improved if the patient is in prone position rather than in supine position (168). The administration of aerosolized vasodilators may be beneﬁcial to patients by improving their ventilation in the ventilated lung, thereby improving the blood’s oxygen tension (169). The lung compliance of the remaining ventilated lung seems also to be reduced, possibly by a reduction in surfactant activity, further increasing the work of breathing (167). Pulmonary surfactant is a complex material composed of lipids and proteins that is found in the ﬂuid lining of the alveolar surface of the lungs. Surfactant prevents alveolar collapse at low lung volume, and preserves bronchiolar patency during normal and forced respiration (170). It is also involved in the protection of the lung from injuries and infections caused by inhaled particles or micro-organisms (170). Pulmonary surfactant is absent in prematurity, being one of the reasons for the respiratory distress syndrome and hyaline membrane disease in premature newborns (170). But surfactant abnormalities are also present at various degrees in asthma, bronchiolitis, pneumonia, cystic ﬁbrosis, and with HIV infections (170). It is possible that in the future, exogenous surfactant replacement may play a role in the treatment of these conditions. The recovery process in pneumonia is produced by clearing of ﬂuids and other materials from the air space, improving ventilation, and in part, to a reduction of perfusion of poorly ventilated areas of the lung (171). The reduction of blood ﬂow through the consolidated lung reduces the shunt and improves arterial oxygen concentration (167). However, the lung is not always able to recover completely. Long- term consequences after childhood pneumonia have been reported in pulmonary function test among adults, including a reduction of lung volume (172). There have been discussions whether the abnormal pulmonary function seen with some ALRI like wheezing disorders is a consequence or a risk factor of the initial attack. In an elegant prospective study done in Taiwan, respiratory function was assessed by single occlusion technique and rapid thoracic compression technique in a group of infants at a mean of 2 mo of age who were then followed for 2 yr (173). Infants who developed a subsequent attack of wheezing had low values of total respiratory compliance corrected for body weight, as compared with those infants who did not develop a wheezing attack. This study indicates that differences in lung function in early life, for reasons yet to be understood, predispose infants to ALRI with wheezing disorders in their ﬁrst 2 yr of life.

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5.4. Impact of Acute Respiratory Infections on Nutrition and Growth Few studies have focused on the impact of respiratory diseases on nutrition and growth. As compared with tuberculosis, which has a prolonged course of illness with pronounced impact on nutrition (174), the role of acute respiratory diseases on the nutritional status of children has been not well documented as compared with diarrheal diseases. In a prospective study on a small cohort of Gambian children, acute lowerrespiratory infections diagnosed by a pediatrician, were associated with a loss of 14.7 g of weight/d of illness, greater than the reduction observed with diarrheal diseases (175). Because their higher prevalence, however, diarrheal diseases explained one-half and acute lower-respiratory infections only accounted for 25% of observed weight deﬁcit. One study in the Philippines has documented the impact of febrile respiratory illness on weight gain (176). In Papua New Guinea, weight gain was reduced during episodes of acute lower-respiratory infections in young children (177). A large longitudinal study in Brazil suggests that hospitalization for pneumonia and subsequent height-for-age are signiﬁcantly associated (14), and acute respiratory infections had a negative impact on weight gain in Guatemala (33). Acute respiratory illnesses have being shown to be associated with 10–20% reduction in food intake (178). This could be owing to a reduction in the child’s appetite—as has been well-documented in a study in Peru (179)—the same mechanism that is postulated for the reduction of weight after a diarrheal episode or a febrile illness (180–183). As with these other illnesses, catabolism may also play a role. Based on these studies, we can conclude that acute lower respiratory illnesses, especially those associated with fever, have a negative impact on the nutritional status of children if the child’s appetite is reduced, and there is a subsequent reduction of dietary intake. Further studies are needed to quantify the magnitude of this negative relationship between acute lower-respiratory infection and growth.

6.0. TREATMENT 6.1. Case Management of Pneumonia A case management approach for pneumonia in children has been developed by the WHO and is based on the assumptions that the main causes of fatal pneumonia are caused by S. pneumoniae and Hemophilus inﬂuenzae (184) and that antibiotic treatment of pneumonia can reduce case-fatality rates (185). An algorithm based on clinical signs was developed to facilitate the recognition and management of acute respiratory infections by nonspecialist doctors working in small hospitals with limited facilities (186,187). Several intervention studies using a case-management strategy for pneumonia were conducted in Tanzania (188), India (19,189), Nepal (190,191), Pakistan (192), and Bangladesh (193). A meta-analysis of intervention trials on case management of pneumonia in community settings shows that the case-management strategy has a substantial effect on infant mortality rates and under-ﬁve mortality rates, at least in settings where infant-mortality rates are 90/1000 live births or greater (194). Despite differences in study populations (location, immunization coverage, diarrhea management, infant mortality rates) and antibiotic treatment in the different intervention trials that differed (penicillin, ampicillin, co-trimoxazole), there was a generally consistent impact of case management on pneumonia mortality in infants (Fig. 2), and in children 1–4 yr (Fig. 3). Case management of pneumonia appeared to reduce infant mortality

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Fig. 2. Case management and acute lower-respiratory infection mortality in infants. Adapted with permission from ref. (194).

Fig. 3. Case management and acute lower-respiratory infection mortality in young children, 1–4 yr. Adapted with permission from ref. (194).

by 20% (15.9 deaths/1000 live births, with a smaller reduction noted among children 1–4 yr. Overall, total reduction in mortality in under-ﬁve mortality was 25% (36 deaths/1000 live births) (194).

6.2. Nutritional Interventions for Treatment of Acute Respiratory Infections 6.2.1. ZINC Zinc supplementation as a prophylactic measure appears to have potential in reducing the morbidity and mortality of acute respiratory infections, as discussed in the section

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on prevention below (Subheading 7.3.1.), but little has been done to investigate the use of zinc as an adjunct therapy for children admitted for hospitalization with acute lower-respiratory infections. Zinc gluconate glycine lozenges have been suggested as a therapy for common cold (195). Some randomized, double-masked, placebo-controlled trials have shown significant reduction in the duration of symptoms of common cold (196,197), whereas others have not (198–200). Meta-analyses of randomized, controlled clinical trials have suggested that zinc lozenges may be effective in the reduction of cold symptoms in adults and children, but that the studies had many problems including zinc dose; inadequate placebo control; and formulation of the lozenge that may include citric acid, sorbitol, mannitol, or tartaric acid, which may bind free zinc ion in the mouth, reducing its therapeutic effect (201–203). Zinc lozenges are associated with adverse effects in general, with bad taste and nausea as prominent symptoms (204). 6.2.2. VITAMIN A A few studies have evaluated the beneﬁt of vitamin A supplementation in nonmeasles childhood pneumonia, and these trials have not shown any beneﬁt on the duration of illness or incidence of adverse outcomes (205), although there is some suggestion that it may diminish some severity indicators such as the occurrence of fever (206). In contrast, one recently published study indicated that high dose vitamin A administration to a small group of Peruvian children hospitalized with community-acquired pneumonia resulted in more severe disease compared with control children who received placebo (207). Children in the vitamin A group were more likely to require supplemental oxygen. These studies indicate that vitamin A supplementation has no role in the therapy of pneumonia. 6.2.3. SELENIUM Selenium may play a potentially important role in acute lower-respiratory infections, and this relationship has only been partly explored. In humans, it was recognized early that patients on total parenteral nutrition who developed selenium deﬁciency had a marked reduction on erythrocyte and granulocyte glutathione peroxidase activity, which inhibits its capacity to metabolize H2O2, abnormalities that returned to normal after selenium supplementation (208). In critically ill patients admitted to intensive care units, the frequency of ventilator-associated pneumonia, organ-system failure, and mortality (especially in those who developed a systemic inﬂammatory-response syndrome), was three times higher in patients with low plasma selenium concentration on admission (209). This fall in plasma concentration of selenium seems to occur mostly in patients with septicemia or pneumonia compared with those who develop viral infections (210,211). In a recent double-blind, controlled trial in Chinese children, selenium supplementation in children hospitalized with pneumonia or bronchiolitis associated with RSV resulted in a faster recovery rate of speciﬁc respiratory signs or symptoms (212).

7.0. PREVENTION Potential interventions for the reduction of morbidity and mortality of pneumonia in children under 5 yr old include immunization, improving nutrition, reducing environmental pollution, reducing transmission of pathogens, and improvement of childcare practices (2,3).

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7.1. Immunization Measles was estimated to account for 578,000, and pertussis was estimated to account for 230,000 acute respiratory infection-related deaths in 1990 in under 5-yr old children (2). Increasing immunization coverage with measles vaccine and with diphtheria-pertussis-tetanus vaccine would be expected to lower the deaths from these two vaccine-preventable causes of acute respiratory infections. Pneumococcal vaccines may potentially prevent childhood pneumonia, but more information is needed about serotypes in different countries for optimal coverage (213), and further work is needed to improve the immunogenicity of the polysaccharide pneumococcal vaccine in infants (214). The conjugate of 5, 7, 9, or 11 pneumococcal saccharides to either tetanus toxoid, diphtheria toxoid, or SRM197 has been able to produce a safe and immunogenic pneumococcal vaccine in children, as evaluated in the U.S. (215), Finland (216), Israel (217), The Gambia (218), and South Africa (219). Preliminary results of a controlled trial against invasive pneumococcal diseases in Californian children has been very optimistic (Hausdorf W, personal communication). These vaccine is currently under further evaluation or about to start to test its efﬁcacy against acute otitis in the U.S. and Europe; invasive disease and pneumonia in South Africa, The Gambia and Chile; and childhood mortality in The Gambia. This vaccine reduces the nasopharyngeal carriage of vaccine-related pneumococcal strains, suggesting that it may have a herd immunity effect, increasing its efficacy (217,219). However, the increased nasopharyngeal carriage rate of nonvaccine-related pneumococcal serotypes, as documented in South Africa (219), needs to be evaluated further to see if it may have any adverse effect in the long term. If the vaccine proves to be as successful as the H. inﬂuenzae type b (Hib) vaccine, its use, however, may be limited to developed countries, at least at the beginning, because it is expected that the introductory price may make it unavailable for developing countries. Other pneumococcal vaccines are under the horizon. Pneumococcal vaccines against pneumococcal proteins (common to several serotypes), and DNA vaccines that induce anti-pneumococcal antibodies have shown promising results in animal models (214). Further evaluation of these vaccines in humans is expected. Hib vaccine has been shown to be effective in reducing childhood pneumonia and meningitis in some industrialized countries, and a recent trial in The Gambia shows that a conjugate Hib vaccine was 95% protective against all invasive Hib disease and 100% against Hib pneumonia (220). Although Hib causes only a small proportion of pneumonia, the vaccine was able to be 21% protective against any type of radiologically deﬁned pneumonia in young children, indicating its potential to control diseases in children and infants from developing countries. This newly available vaccine has been rapidly introduced to developed countries, but to date only some developing countries in Latin America and The Gambia are using it; it is not clear when countries in Asia and Africa will begin using the vaccine. The protection of the fetus by transplacental transfer of maternal antibodies has allowed the protection of infants against tetanus by maternal immunization. Similar approaches are also being considered to protect neonates against pneumococcal diseases, pertussis, group B streptococcal infections, and Hib infections (153). Other vaccines against human parainﬂuenza virus type 3 and RSV are also under development and may became available in the near future (221).

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In the meantime, the use of the currently available pneumococcal polysaccharide vaccine should be considered in adults, because it has shown a high effectiveness (83%) in adults from developed countries (222). Inﬂuenza vaccine is rarely used in developing countries, and should also be considered.

7.3. Nutrition 7.3.1. BREAST FEEDING A hypothetical model was developed to determine the potential reduction in mortality from pneumonia in children with improvements in breast-feeding practices (3). The impact of increasing the prevalence of mother’s breast feeding was related to the pattern of breast feeding in different locations. The greatest impact on pneumonia mortality by increasing the prevalence of breast feeding would be expected in areas where the prevalence of breast feeding is low (3). In sub-Saharan Africa, where universal breast feeding to 12 mo of age is common, breast-feeding promotion efforts would have a limited effect, but in some countries in Latin America, the promotion of breast feeding would be expected theoretically to avert a large proportion of deaths from pneumonia. 7.3.2. PREVENTION OF LBW The prevention of LBW may hypothetically decrease pneumonia mortality in developing countries, depending on the prevalence of LBW and the magnitude of the reduction in LBW (3). There is a need to identify effective ways to reduce the prevalence of LBW in developing countries. Zinc supplementation has shown some promising results. 7.3.3. REDUCTION OF MALNUTRITION The reduction in malnutrition among infants and young children would be expected to reduce pneumonia deaths, especially in regions where the proportion of infants and children who are underweight is high, such as south Asia (3). The improvement of the weaning diet of children 6–24 mo of age is a public health priority. No effective interventions have been yet developed owing to the difﬁculties in behavioral changes and other factors that limit the availability of an adequate diet for these children. Food supplementation has been considered as an alternative approach by many developing countries, whereas food fortiﬁcation is used in very few countries in the developing world. 7.3.4. ZINC SUPPLEMENTATION Zinc supplementation shows potential for reducing the incidence of acute lower-respiratory disease. In a study involving growth-retarded children in Vietnam, zinc supplementation was associated with a 2.5-fold reduction in episodes of respiratory infections (223). A trial conducted in India showed that daily zinc supplementation, 10 mg, signiﬁcantly reduced the incidence of acute lower-respiratory infections in infants and preschool children during a 6-mo period (224). A pooled analysis of these two trials and other trials in Peru and Jamaica found a 41% reduction in pneumonia (51). A community-based trial in Guatemala did not show any signiﬁcant effect of zinc supplementation on the incidence of respiratory infection in young infants (225). Mexican preschool children receiving daily zinc supplementation had signiﬁcantly fewer episodes of diarrheal but not respiratory disease (226). There is a need to replicate

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this study in other sites, as well as to evaluate the impact of zinc supplementation on childhood mortality. Effective and sustainable ways to increase the dietary intake of bioavailable zinc in developing countries is also needed. 7.3.5. VITAMIN A SUPPLEMENTATION As reviewed in Subheading 4.1.4., vitamin A supplementation appears to have little impact upon acute respiratory diseases in preschool children. Initial studies found an association between xerophthalmia or lower retinol serum concentrations and respiratory diseases (45,46). However, when respiratory diseases were assessed in carefully controlled prospective trials of vitamin A supplementation, no major reduction occurred in the mortality or morbidity associated with respiratory diseases, as indicated in a meta-analysis of all available studies (47). Vitamin A does not have any role in the prevention of respiratory diseases in children. 7.3.6. SELENIUM SUPPLEMENTATION Selenium supplementation may have possible beneﬁt in reducing the morbidity and mortality of acute respiratory diseases in humans. Dietary supplementation with selenium for dairy cattle has become a standard practice, and has been associated with a reduction of calf losses owing to respiratory diseases (227). In patients with major burns, supplementation with selenium combined with copper and zinc was associated with fewer bronchopneumonia infections and with a shorter hospital stay in a doubleblind, placebo-controlled trial (228). Selenium has also been incriminated in the pathogenesis of asthma. It has been postulated that the combination of dietary, environmental, and genetic factors that decrease the cellular reducing capacity will increase tissue vulnerability to oxidant stress. This will result in inﬂammation and tissue damage in the respiratory system, and later in immune damage, leading to an increased risk to develop asthma (229). Severely malnourished children often have very low plasma selenium concentrations and low erythrocyte and plasma glutathione peroxidase activity, which may predispose them to the development of serious infections (230). Controlled, randomized, double-blind trials are needed with selenium supplementation, for treatment or prevention of respiratory illnesses in children; toxicity should be also closely monitored (231).

7.4. Other Measures Reducing indoor and outdoor air pollution, elimination of environmental tobacco smoke, and reduction of crowding are potential interventions that may prevent childhood pneumonia in developing countries (2). Modiﬁcations of child-care practices, including improvement of care-seeking, better maternal education, and increased child spacing are also potential areas that may have an impact on reducing pneumonia in children. All these potential interventions require evaluation in controlled studies in developing countries before they can be considered.

8. FUTURE DIRECTIONS As reviewed in this chapter, a series of studies are needed to be able to answer many of the questions raised. The most important ones are listed here.

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8.1. Risk Factors for Pneumonia and ALRI • The interactions between nutrition and acute respiratory diseases have been incompletely characterized. • The impact of acute lower-respiratory infections on subsequent nutritional status and growth needs further elucidation in developing countries. • There is a need to perform properly conducted studies to prove or disprove the relationship between cold and/or high-humidity exposure and pneumonia and other ALRI. • Further studies are needed to clarify if abnormal lung function proceeds, or is a consequence of, pneumonia or acute lower-respiratory infection or both. • Studies to clarify whether or not the changes in early life exposure to common childhood infections as seen in developed countries are related to atopy and asthma in school-aged children or adults, and how this relationship could be modiﬁed. • There is a need to understand better the pathophysiology of intrauterine growth and how LBW could be avoided. • The relationship between maternal immune status and the protection of neonates by transplacental immune mechanisms needs further study. • Only zinc and vitamin A have been evaluated in relation to pneumonia and acute lower-respiratory infection. Other micronutrients, like selenium, vitamin D, calcium, and iron, deserve further studies. There is a need to study further the relationship between indoor air pollutants and acute lower-respiratory infection, identifying the combustion products that are more closely related to these diseases, and describing its pathophysiology.

8.2. Clinical Aspects • There is a need to standardize the methodology and deﬁnitions of pneumonia and acute lower-respiratory infection for the conduct of longitudinal prospective studies on acute lower-respiratory infection epidemiology. Guidelines should be published to guide investigators how to do such studies in order to facilitate the comparability of results across studies. • There is a need to improve the diagnostic capabilities of bacterial pathogens as causes of pneumonia and invasive diseases in infants and children in order to facilitate the clinical management of patients and the conduct of epidemiological studies. • The results of the WHO-sponsored studies on the etiology of severe infections of infants under 3 mo of age have indicated the need to re-evaluate the clinical management of these cases in developing countries. • The increased prevalence of antibiotic resistant bacteria strains is worrisome. There is a need to monitor this trend, and at the same time try to diminish the inappropriate use of antibiotics. Alternative methods for the treatment of these infections may be needed in the near future.

8.3. Prevention • There is a need to develop effective interventions that could improve the nutritional status of children in developing countries and to study their impact on the incidence and severity of pneumonia and other acute lower-respiratory infections. • The protective efﬁcacy of breast-feeding promotion on pneumonia and other acute lower-respiratory infection needs further evaluation and documentation.

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• Although zinc supplementation has been proven to reduce the incidence of pneumonia and acute lower-respiratory infection, there is a need to document its impact on mortality, which should facilitate the development of a sustainable approach to improve the zinc status of children in developing countries. • The studies on the impact of zinc lonzenges on upper respiratory infections are still inconclusive. A properly designed study, controlling for all confounding variables and the presentation and formulation of the lozenge, needs to be done to answer in a deﬁnitive way whether or not it is beneﬁcial to children. • Prospective studies as well as double-blind, placebo-controlled clinical trials with selenium as a treatment or prevention of respiratory diseases in children, particularly in premature or LBW infants, are needed. • Maternal immunization seems to be a promising intervention for the control of infections in the neonatal period. Proposed vaccine candidates should be evaluated, in properly designed studies. • The search for effective and affordable vaccines for children in the developing world against the most prevalent childhood illnesses should continue. • Ways to reduce the risk of transmission of respiratory pathogens in crowded areas and in day-care centers are urgently needed. Effective interventions should be developed and tested in developing countries. • The exposure of children in developing countries to indoor air pollutants, including environmental tobacco smoke, needs further evaluation. Appropriate interventions (such as improving stoves) should be developed and tested for their efﬁcacy to prevent pneumonia and other ALRI.

9. CONCLUSIONS Acute lower-respiratory diseases are some of the most important diseases of infants and young children in developing countries and are closely associated with high morbidity and mortality. A series of factors that increase the risk of developing pneumonia and other types of acute lower-respiratory infections have been identiﬁed, whereas others require further studies. Although a considerable number of studies have been conducted to measure the incidence and clinical characteristics of these illnesses, there is still a need to standardize the methodology to be used in the ﬁeld. Physician-based diagnostic methodologies seems to be preferable to symptom-based deﬁnitions of pneumonia, which are not capable of adequately separating pneumonia from wheezing disorders and other acute lower-respiratory infections; this explains the great variability of the rates reported in studies using that methodology. Recently conducted studies on the etiology of severe infections in infants under 3 mo of age have identify the increased rate of pneumococcal diseases even from the neonatal period. Maternal immunization may be an important public health tool to reduce severe infections during the neonatal and early postneonatal period of infants. Despite the considerable knowledge on risk factors for pneumonia and other ALRI, there are relatively few proven interventions to prevent them. The most promising ones are vaccines. The new pneumococcal conjugates vaccines, combined with the Hib vaccine, may be important interventions to control severe invasive diseases caused by these bacteria. However, the likelihood of using these new vaccines in countries most at need is very low, at least in the near future, because of economic reasons. The

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international community needs to explore ways to bring these effective interventions to the poorer countries of the world. While new vaccines are developed, tested, and implemented, other interventions are also needed that will focus on nutrition and the control of micronutrient deﬁciencies. Further studies are needed to identify sustainable interventions to improve the general nutritional status of children in developing countries, as well as their families. The deﬁciencies of zinc, selenium, calcium, and vitamin D in children are also important and should be controlled. These studies also need to document their impact on pneumonia and other acute lower-respiratory infections in the affected population. Finally, new evidence suggests that frequent respiratory infections in early life may be associated with the development of atopy and asthma later on in life. This hypothesis requires further evaluation, controlling for several confounding variables that may affect this relationship.

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160. Hanly P, Light RB. Lung mechanics, gas exchange, pulmonary perfusion, and hemodynamics in canine model of acute Pseudomona pneumonia. Lung 1987; 165:305–322. 161. Hiser W, Pennan RW, Reeves JT. Preservation of hypoxic pulmonary pressor response in canine pneumococcal pneumonia. Am Rev Respir Dis 1975; 112:817–822. 162. Light RB, Mink SN, Wood LD. Pathophysiology of gas exchange and pulmonary perfusion in pneumococcal lobar pneumonia in dogs. J Appl Physiol 1981; 50:524–530. 163. Shann F, MacGregor D, Richens J, Coakley J. Cardiac failure in children with pneumonia in Papua New Guinea. Pediatr Infect Dis J 1998; 17:1141–1143. 164. Gea J, Roca J, Torres A, Agusti AG, Wagner PD, Rodriguez-Roisin R. Mechanisms of abnormal gas exchange in patients with pneumonia. Anesthesiology 1991; 75:782–789. 165. Light RB. Intrapulmonary oxygen consumption in experimental pneumococcal pneumonia. J Appl Physiol 1988; 64:2490–2495. 166. Cooligan T, Light RB, Wood LD, Mink SN. Plasma volume expansion in canine pneumococcal pneumonia: its effects on respiratory gas exchange and pneumonia size. Am Rev Respir Dis 1982; 126: 86–91. 167. Light RB. Pulmonary pathophysiology of pneumococcal pneumonia. Semin Respir Infect 1999; 14: 218–226. 168. Chaisupamongkollarp T, Preuthipan , Vaicheeta S, Chantarojanasiri T, Kongvivekkajornkij W, Suwanjutha S. Prone position in spontaneously breathing infants with pneumonia. Acta Paediatr 1999; 88:1033–1034. 169. Rodriguez-Roisin R, Roca J. Update ‘96 on pulmonary gas exchange pathophysiology in pneumonia. Semin Respir Infect 1996; 11:3–12. 170. Griese M. Pulmonary surfactant in health and human lung diseases: state of the art. Eur Respir J 1999; 13:1455–1476. 171. Light RB, Mink SN, Cooligan RG, Wood LD. The physiology of recovery in experimental pneumococcal pneumonia. Clin Invest Med 1983; 6:147–151. 172. Johnston ID. Effect of pneumonia in childhood on adult lung function. J Pediatr 1999; 135:33–37. 173. Yau KI, Fang LJ, Shieh KH. Factors predisposing infants to lower respiratory infection with wheezing in the ﬁrst two years of life. Ann Allergy Asthma Immunol 1999; 82:165–170. 174. Hussey G, Chisholm T, Kibel M. Miliary tuberculosis in children: a review of 94 cases. Pediatr Infect Dis J 1991; 10:832–836. 175. Rowland MGM., Rowland SGJ., Cole TJ. Impact of infection on the growth of children from 0 to 2 years in an urban West African community. Am J Clin Nutr 1988; 47:134–138. 176. Adair L, Popkin BM, Van Derslice J, Akin J, Guilkey D, Black R, et al. Growth dynamics during the ﬁrst two years of life: a prospective study in the Philippines. Eur J Clin Nutr 1993; 47:42–51. 177. Smith TA, Lehman D, Coakley C, Spooner V, Alpers MP. Relationships between growth and acute lower-respiratory infections in children <5 y in a highland population of Papua New Guinea. Am J Clin Nutr 1991; 53:963–970. 178. Pereira SM, Begum A. The influence of illnesses on the food intake of young children. Intl J Epidemiol 1987; 16:445–450. 179. Brown KH, Peerson JM, Lopez de Romaña G, Creed de Kanashiro H, Black RE. Validity and epidemiology of reported poor appetite among Peruvian infants from a low-income, periurban community. Am J Clin Nutr 1995; 61:26–32. 180. Bhandari N, Sazawal S, Clemens JD, Kashyap DK, Dhingra U, Bhan MK. Association between diarrheal duration and nutrition decline: implications for an empirically validated deﬁnition of persistent diarrhea. Indian J Pediatr 1994; 61:559–566. 181. Brown KH, Stallings RY, Creed de Kanashiro CH., Lopez de Romaña G, Black RE. Effects of common illnesses on infants_ energy intakes from breast milk and other foods during longitudinal community-based studies in Huascar (Lima), Peru. Am J Clin Nutr 1990; 52:1005–1013. 182. Becker S, Black RE, Brown KH. Relative effects of diarrhea, fever, and dietary energy intake on weight gain in rural Bangladeshi children. Am J Clin Nutr 1991; 53:1499–1503. 183. Franks AJ, Jurgensen C. Nutrition and health in the ﬁrst year of life on a Paciﬁc atoll. Observations on Abemama Atoll, Central Paciﬁc. Trans R Soc Trop Med Hyg 1985; 79:681–684. 184. Shann F. Etiology of severe pneumonia in children in developing countries. Pediatr Infect Dis J 1986; 5:247–252. 185. McCord C, Keilmann AA. A successful programme for medical auxiliaries in treating childhood diarrhea and pneumonia. Trop Doct 1978; 8:220–225.

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186. Shann F, Hart K, Thomas D. Acute lower respiratory tract infection in children: possible criteria for selection of patients for antibiotic therapy and hospital admissions. Bull WHO 1984; 62:749–753. 187. World Health Organization. Respiratory Infections in Children: Management in Small Hospitals. A Manual for Doctors. Geneva: WHO, 1988. 188. Mtango FDE, Neuvians D. Acute respiratory infections in children under ﬁve years. Control project in Bagamoyo District, Tanzania. Trans R Soc Trop Med Hyg 1986; 80:851–858. 189. Bang AT, Bang RA, Tale O, Sontakke P, Solanki J, Wargantiwar R, Kelzarkar P. Reduction in pneumonia mortality and total childhood mortality by means of community-based intervention trial in Gadchiroli, India. Lancet 1990; 336:201–206. 190. Pandey MR, Sharma PR, Gubhaju BB, Shakya GM, Neupane RP, Gautam A, Shrestha IB. Impact of a pilot acute respiratory infection (ARI) control programme in a rural community of the hill region of Nepal. Ann Trop Paediatr 1989b; 9:212–220. 191. Pandey MR, Daulaire NMP, Starbuck ES, Houston RM, McPherson K. Reduction in total under-ﬁve mortality in western Nepal through community-based antimicrobial treatment of pneumonia. Lancet 1991; 338:993–997. 192. Khan AJ, Khan JA, Akbar M, Addiss DG. Acute respiratory infections in children: a case management intervention in Abbottabad District, Pakistan. Bull WHO, 1990; 68:577–585. 193. Fauveau V, Stewart MK, Chakraborty J, Khan SA. Impact on mortality of a community-based programme to control acute lower respiratory tract infections. Bull WHO, 1992; 70:109–116. 194. Sazawal S, Black RE. Meta-analysis of intervention trials on case-management of pneumonia in community settings. Lancet 1992; 340:528–533. 195. Macknin ML. Zinc lozenges for the common cold. Cleveland Clin J Med 1999; 66:27–32. 196. Eby GA, Davis DR, Halcomb WW. Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study. Antimicrob Agents Chemother 1984; 25:20–24. 197. Mossad SB, Macknin ML, Medendorp SV, Mason P. Zinc gluconate lozenges for treating the common cold. A randomized, double-blind, placebo-controlled study. Ann Intern Med 1996;125: 81–88. 198. Douglas RM, Miles HB, Moore BW, Ryan P, Pinnock CB. Failure of effervescent zinc acetate lozenges to alter the course of upper respiratory tract infections in Australian adults. Antimicrob Agents Chemother 1987; 31:1263–1265. 199. Farr BM, Conner EM, Betts RF, Oleske J, Minnefor A, Gwaltney JM Jr. Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds. Antimicrob Agents Chemother 1987; 31:1183–1187. 200. Smith DS, Helzner EC, Nuttall CE.Jr, Collins M, Rofman BA, Ginsberg D, et al. Failure of zinc gluconate in treatment of acute upper respiratory tract infections. Antimicrob Agents Chemother 1989;33:646-648. 201. Garland ML, Hagmeyer KO. The role of zinc lozenges in treatment of common cold. Ann Pharmacother 1998; 32:63–69. 202. Marshall S. Zinc gluconate and the common cold. Review of randomized controlled trials. Can Fam Physician 1998; 44:1037–1042. 203. Jackson JL, Peterson C, Lesho E. A meta-analysis of zinc salts lozenges and the common cold. Arch Intern Med 1997; 157:2373–2376. 204. Macknin ML, Piedmonte M, Calendine C, Janosky J, Wald E. Zinc gluconate lozenges for treating the common cold in children: a randomized controlled trial. JAMA 1998; 279:1962–1967. 205. Donnen P, Dramaix M, Brasseur D, Bitwe R, Vertongen F, Hennart P. Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low dose of vitamin A on the morbidity of hospitalized, malnourished children. Am J Clin Nutr 1998; 68:1254–1260. 206. Nacul LC, Kirkwood BR, Arthur P, Morris SS, Magalhaes M, Fink MC. Randomized, double blind, placebo controlled clinical trial of efﬁcacy of vitamin A treatment in non-measles childhood pneumonia. BMJ 1997; 315:505–510. 207. Stephensen CB, Franchi LM, Hernandez H, Campos M, Gilman RH, Alvarez JO. Adverse effects of high-dose vitamin A supplements in children hospitalized with pneumonia. Pediatrics 1998; 101:3. 208. Baker SS, Lerman RH, Krey SH, Crocker KA, Hirsh EF, Cohen H. Selenium deﬁciency with total parenteral nutrition: reversal of biochemical and functional abnormalities by selenium supplementation: a case report. Am J Clin Nutr 1983; 38:769–774. 209. Forceville X, Vitoux D, Gauzit R, Combes A, Lahilaire P, Chappuis P. Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients. Crit Care Med 1998; 26:1536–1544.

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210. Srinivas U, Braconier JH, Jeppsson B, Abdulla M, Akesson B, Ockerman PA. Trace element alterations in infectious diseases. Scand J Clin Lab Invest 1988; 48:495–500. 211. Chen JR, Anderson JM. Legionnaires disease: concentrations of selenium and other elements. Science 1979; 206:1426–1427. 212. Liu X, Yin S, Li G. Effects of selenium supplement on acute lower respiratory tract infection caused by respiratory syncytial virus. Chung Hua Yu Fang I Hsueh Tsa Chih. 1997; 31:358–361. 213. Sniadack DH, Schwartz B, Lipman H, Bogaerts J, Butler JC, Dagan R, et al. Potential interventions for the prevention of childhood pneumonia: geographic and temporal differences in serotype and serogroup distribution of sterile site pneumococcal isolates from children implications for vaccine strategies. Pediatr Infect Dis J 1995; 14:503–510. 214. Butler JC, Shapiro ED, Carlone GM. Pneumococcal vaccines: history, current status, and future directions. Am J Med 1999; 107(1A):69S–76S. 215. Rennels MB, Edwards KM, Keyserling HL, Reisinger KS, Hogerman DA, Madore DV, et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to CRM197 in United Sates infants. Pediatrics 1998; 101:604–611. 216. Ahman H, Kayhty H, Lehtonen H, Leroy O, Froeschle J, Eskola J. Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory. Pediatr Infect Dis J 1998; 17:211–216. 217. Dagan R, Muallem M, Melamed R, Leroy O, Yagupsky P. Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J 1997; 16:1060–1064. 218. Leach A, Ceesay SJ, Banya WA, Greenwood BM. Pilot trial of a pentavalent pneumococcal polysaccharide/protein conjugate vaccine in Gambian infants. Pediatr Infect Dis J 1996; 15: 333–339. 219. Mbelle N, Huebner RE, Wasas AD, Kimura A, Chang I, Klugman KP. Immunogenicity and impact of nasopharyngeal carrige of a nonavalent pneumococcal conjugate vaccine. J Infect Dis 1999; 180: 1171–1176. 220. Mulholland K, Hilton S, Adegbola R, Usen S, Opraugo A, Omosigho C, et al. Randomised trial of Haemophilus inﬂuenzae type-b tetanus protein conjugate vaccine for prevention of pneumonia and meningitis in Gambian infants. Lancet 1997; 349:1191–1197. 221. World Health Organization. Global Programme for Vaccines and Immunization, Vaccine Research and Development. Report of the Technical Review Group Meeting, 7–8 June 1998. Achievements and plan of activities, July 1998–June 1999. WHO/VRD/GEN/98.02. Geneva: WHO, 1998b. 222. Hutchison BG, Oxman AD, Shannon HS, Lloyd S, Altmayer CA, Thomas K. Clinical effectiveness of pneumococcal vaccine. Meta-analysis. Can Fam Physician 1999; 45:2381–2393. 223. Ninh NX, Thissen JP, Collette L, Gerard G, Khoi HH, Ketelslegers JM. Zinc supplementation increases growth and circulating insulin-like growth factor I (IFG-I) in growth-retarded Vietnamese children. Am J Clin Nutr 1996; 63:514–519. 224. Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan MK. Zinc supplementation reduces the incidence of acute lower-respiratory infection in infants and preschool children: a double-blind controlled trial. Pediatrics 1998; 102:1–5. 225. Ruel MT, Rivera JA, Santizo MC, Lönnerdal B, Brown KH. Impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics 1997; 99:808–813. 226. Rosado JL, López P, Muñoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr 1997; 65:13–19. 227. Gerloff BJ. Effect of selenium supplementation on dairy cattle. J Anim Sci 1992; 70:3934–3940. 228. Berger MM, Spertini F, Shenkin A, Wardle C, Wiesner L, Schindler C, Chiolero RL. Trace element supplementation modulates pulmonary infection rates after major burns: a double-blind, placebocontrolled trial. Am J Clin Nutr 1998; 68:365–371. 229. Greene LS. Asthma and oxidant stress: nutritional, environmental, and genetic risk factors. J Am Coll Nutr 1995; 14:317–324. 230. Thomas AG, Miller V, Shenkin A, Fell GS, Taylor F. Selenium and glutathione peroxidase status in paediatric health and gastrointestinal disease. J Pediatr Gastroenterol Nutr 1994; 19:213–219. 231. Pentel P, Fletcher D, Jentzen J. Fatal acute selenium toxicity. J Forensic Sci 1985; 30:556–562.

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Measles Gregory Hussey

1. INTRODUCTION Despite the availability of a cheap and effective vaccine, measles remains a problem in developing countries. It is a leading childhood killer, accounting for more deaths than any other vaccine-preventable disease. This chapter discusses important epidemiological, clinical, and management issues that are relevant in developing countries. The association between measles and nutrition, particularly vitamin A is stressed. The need to reduce the disease burden through effective case management and immunization is highlighted.

2. DEFINITION Measles is an acute infectious disease caused by an RNA paramyxovirus. The disease is characterized by a generalized maculo-papular eythematous rash, high fever and coryza, conjunctivitis, cough, or stomatitis. Measles virus is related to other morbilliviruses such as rinderpest virus, peste des petits ruminants virus, and canine distemper virus. Experimental animal models involving some of these other morbilliviruses have been used to gain insight into measles infection in humans.

3. PUBLIC HEALTH IMPORTANCE Measles is a major cause of childhood morbidity and mortality. The World Health Organization (WHO) has estimated that over 40 million measles cases and approx one million deaths occur annually in developing countries (1). Measles accounts for approx 10% of the global all-cause mortality among children <5 yr, with half of the deaths occurring in infancy (2). Most deaths are a consequence of complications such as pneumonia, diarrhea, and malnutrition. In addition, countless thousands are disabled as a consequence of chronic lung disease, malnutrition, blindness, deafness, and recurrent infections (3).

4. HISTORICAL BACKGROUND Measles as a clinical entity has been known for centuries. A distinction between measles and smallpox was made as early as the 10th century by Rhazes (4). In 1676, From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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a detailed clinical description of measles was made by Thomas Sydenham (5). During the 18th century, measles epidemics occurred in England in about 1 out of 3 yr (6) and in Germany about every 4–5 yr (7). In contrast, with the more isolated island population of Japan, measles epidemics occurred less frequently, at intervals of about 20–30 yr during the Tokugawa period (1600–1868) (8). One of the ﬁrst detailed epidemiological descriptions of measles was by Peter Panum in 1846. In his study of the epidemic on the Faroe Islands he deﬁned the incubation period, mode of transmission, i.e., personto-person via droplet infection, and showed that infection resulted in lifelong immunity (9). Buccal spots, an early diagnostic sign in measles, were described by Henry Koplik, an American physician, in 1896 (9). David Morley’s studies in Nigeria in the 1950s and 1960s highlighted the importance of measles as a signiﬁcant cause of childhood morbidity and mortality in developing countries (11). In particular, he emphasized the important interaction between measles and malnutrition (12). Until recently the nutritional status of the child was generally believed to be one of the major determinants of disease severity in measles. However, Peter Aaby, in a number of studies in West Africa in the 1980s, showed that overcrowding and viral dose was probably the most signiﬁcant predictor of mortality (13). There is no speciﬁc treatment for measles. However, high dose vitamin A therapy reduces the rate of complications and mortality (14,15). The WHO recommends vitamin A as part of the standard case management for measles (16). The measles virus was isolated in 1954 by Enders and Peebles and a serological test was developed (17). Work on a vaccine against measles subsequently commenced and in 1963 the ﬁrst vaccine was licensed in the U.S. (18). Despite the availability of a safe and effective vaccine, measles remained a signiﬁcant problem in developing countries. One of the reasons for this was the inability to immunize successfully young infants because of passively derived maternal antibodies (19). To overcome this problem the high-dose Edmonston-Zagreb vaccine was recommended for use in developing countries for infants between 4 and 6 mo of age (20). However, it was found subsequently to be associated with increased child mortality in the months following immunization (21,22). The hypothesis was that the excess mortality was a consequence of immune suppression following exposure to the high viral titer (23). This vaccine is no longer recommended for use in infants (24).

5. EPIDEMIOLOGY Measles is a highly communicable disease and spreads from person to person via droplet infection. The probability of an exposed susceptible person contracting the disease on exposure is very high. The infectious period is from the onset of the illness until 4–5 d after the appearance of the rash. Humans are the only natural host. Measles is endemic in most developing countries and cases occur predominantly in children aged less than 5 yr old. The improvement of measles vaccine coverage in some countries has led to a changing epidemiology with outbreaks affecting predominantly older children and adolescents (25). In developed countries, measles is uncommon and is a disease of older children and young adults who have not been immunized or in whom primary immunization has failed (26). Areas where measles transmission is likely to occur include areas with high population density, poor socioeconomic status (SES), very low immunization coverage, and

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high numbers of measles cases and/or deaths from measles (27). Overcrowded living conditions have been identiﬁed as an important determinant of intensity of exposure and subsequent disease outcome (28). Secondary cases (children who contract measles from another case in a household or health center) has a higher case fatality rate than primary cases. This is probably owing to increased exposure to a higher viral dose (29). Other children at particular risk for developing severe disease include children less than 1 yr old, those who are vitamin A deﬁcient, the severely malnourished, the immunocompromised (including HIV-infected children), children who live in zones of armed conﬂict or in refugee camps, and children who are migrants (27). The widespread use of measles immunization since the 1960s has raised a potentially important issue regarding the timing of measles immunization. The level of protective antibodies against measles is lower in individuals who were immunized in childhood compared with individuals who originally had a wild-type measles infection. The level of protective antibodies becomes especially important during pregancy, as the level of passively transferred maternal antibodies against measles in infants is related maternal levels of antibodies. Infants who have lower levels of maternal antibodies have a shorter period of protection against wild-type measles infection. It is unclear whether the timing of measles vaccines will need to be revised for infants born to mothers who were immunized against measles compared to infants born to mothers who experienced wild-type measles infection.

6. PATHOPHYSIOLOGY The clinical expression of infection and consequently the complications of measles are governed by the extent of the virus-induced epithelial damage, by the degree of immune suppression (30), and by the patient’s vitamin A status (31). The pathologic effects of measles virus infection and vitamin A deﬁciency are remarkably similar, in that both are responsible for epithelial damage and immune suppression. The epithelia of the respiratory and gastrointestinal tracts and the conjunctiva are particularly vulnerable. The reason for the dramatic decline in serum vitamin A levels during acute measles and other infections is not known. Contributing factors include reduced intake as a consequence of infection-induced anorexia; increased catabolism, utilization, and urinary excretion; and problems with retinol-binding protein homeostasis (32,33). The clinical signiﬁcance of measles virus immunosuppression has been documented by ﬁndings indicating that lymphopenia owing to lower T- and B-cell levels, impaired antibody response, and reduced C3 levels were signiﬁcant predictors of the clinical severity of measles (34). In addition, persistent immune suppression may account for the increased morbidity and mortality associated with measles in the ensuing months after the acute infection (35). The importance of vitamin A as a predictor of disease severity has been documented in a number of studies. In Zaire, children with measles, especially those under 2 yr of age, who had a vitamin A level below 5 ug/dl had a three times greater risk of dying compared to children with higher levels (36). In the U.S., where clinical vitamin A deﬁciency does not occur, low serum vitamin A levels have been associated with an increased risk of hospitalization and severe disease (37,38).

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7. INTERACTION WITH NUTRITION 7.1. Effect of Measles on Nutrition An acute attack of measles can have a signiﬁcant adverse effect on the nutritional status of children (12,39). The mechanisms include infection-induced anorexia, refusal to take food because of the associated stomatitis or mouth ulceration, catabolic effects of infection, associated diarrhea and vomiting, and protein-losing enteropathy (40–43). Energy balance studies in children with measles indicate signiﬁcant increased fecal and urine losses and reduced intake (41). Acute diarrhea is a common problem in children with measles and contributes to negative nitrogen balance and increased mortality (44–46). Prolonged or persistent diarrhea has a major impact on nutritional status and may follow the acute episode in about 30% of cases (47). Diarrhea in measles is a consequence of a number of interrelated factors (48). The measles virus causes epithelial damage, which is compounded by the hyporetinaemia that invariable occurs in the acute phase. In addition, both measles and vitamin A deﬁciency reduce immune competence, resulting in increased susceptibility to gastrointestinal pathogens. The net effect of the gastrointestinal damage is diarrheal disease and protein-losing enteropathy (40). Measles is thus a common precipitating cause of kwashiokor (11,39). Severe stomatitis and mouth ulcers, which are frequently owing to Herpes simplex or Candida infections, are common complications of measles (49). Superadded secondary bacterial infections may develop, especially if oral hygiene is poor. This may cause difﬁculty with feeding, and result in dehydration, and aggravate malnutrition.

7.2. Effect of Malnutrition on Measles Malnutrition is generally thought to be an important determinant of disease severity. A number of hospital based studies have indicated that malnourished children with measles have a higher morbidity and mortality rate (50–53). This, however, does not necessarily imply a causal relationship. Measles is an acute catabolic event associated with reduced intake, increased gastrointestinal losses, and rapid weight loss. Lower weight, therefore, may be a reﬂection of more severe disease. Malnourished children with measles have also been shown to have prolonged excretion of virus, impaired immunity and increased susceptibility to secondary infection compared to wellnourished children (53). This assumption has been challenged recently by the ﬁndings in several community studies that have found no relation between nutritional status and risk of severe or fatal measles. It has been argued that overcrowding and intensive exposure (i.e., virus dose) are more important determinants of disease severity and mortality (13,28,29).

8. CLINICAL FEATURES The incubation period of measles is 8–12 d. The illness starts with a prodrome characterized by fever, cough, and coryza, which lasts for 2–3 d. Koplik spots are visible on the buccal mucosa during this period. The maculopapular erythematious rash then appears, starting in the neck, then spreading to the face and the rest of the body. The child has a high fever; is irritable; photophobic; and usually has a conjunctivitis,

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Fig. 1. Clinical course of measles.

cough, and stomatitis (see Fig. 1). The illness lasts for about 4–5 d. The rash then fades or discolors. Desquamation occurs frequently and may persist for weeks. Signiﬁcant complications occur in 15–25% of all cases and include pneumonia, diarrhea, malnutrition, otitis media, severe mouth ulcers, and severe conjunctivitis (3). The case fatality rate of children hospitalized with measles varies between 5 and 15%. Measles is a signiﬁcant risk factor for the development of keratomatacia in developing countries and, if not recognized and treated early, will result in blindness (54). Uncommon complications include encephalitis, myocarditis, nephritis, and pneumothorax (55,56). Subacute sclerosing panencephalitis is an extremely uncommon long-term complication of measles (57). A number of studies have indicated that children who had measles have signiﬁcantly increased morbidity and mortality in the ensuing months when compared with community controls (35,58). This is characterized by failure to thrive, recurrent infections, persistent pneumonia, and diarrhea. If present, vitamin A deﬁciency will aggravate these problems. Measles can be severe, atypical, and prolonged in immunocompromised HIV-infected children (59,60).

9. DIAGNOSIS The diagnosis of measles is usually based on the prodrome, Koplik’s spots, and characteristic rash, and the diagnosis is seldom difﬁcult. If necessary, serological diagnosis may be required. The diagnosis can also be conﬁrmed by ﬁnding typical multinucleate giant cells in a buccal smear. The rash of measles can be confused with rubella, infectious mononucleosis, scarlet fever, Rocky Mountain spotted fever, and enteroviral infections.

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10. TREATMENT Although there is no speciﬁc therapy for measles, the adverse consequences can be reduced by treatment with vitamin A (14,15,61–65), providing good supportive medical care and through the treatment of complications (66). The basic principles of management are shown in Table 1. Children with speciﬁc complications of measles such as pneumonia, diarrhea, and malnutrition must be treated in accordance with current WHO recommendations for the speciﬁc problem (66). Antibiotics should only be given if there is a speciﬁc indication such as pneumonia, otitis media, or dysentery. There is little evidence that prophylactic antibiotics are of beneﬁt in children with measles (67). They may be useful in children who are at an additional risk for secondary bacterial infections, such as those with severe malnutrition, AIDS, and xerophthalmia. The indiscriminate use of antibiotics may result in unnecessary complications such as antibiotic-associated diarrhea, severe drug reactions, and the emergence of drug-resistant organisms.

10.1. Nutritional Support Because measles virus infection is a major catabolic event and associated with signiﬁcant weight loss, careful attention must be paid to the nutritional needs of these children (68). Mothers must be encouraged to feed the child even if diarrhea is present. Breast feeding must be maintained. In the children who are not breast fed, the energy content of the food must be increased by adding a teaspoon of vegetable oil and a teaspoon of sugar to the milk or cereal. The child must be given more ﬂuids than usual to prevent dehydration. If dehydration is present, additional ﬂuids must be provided in the form of oral or intravenous rehydration solution. Where available, additional vitamins and minerals such as multi-vitamin syrup must be provided. If a hospitalized child refuses to take feeds, then a nasogastric tube must be inserted and liquid feeds and ﬂuids given through the tube. In many cultures, there is the mistaken custom to stop feeding or to reduce feeds in children with measles. Mothers and caregivers must be informed of the importance of maintaining adequate feeding during the acute and convalescent stage. Because failure to thrive and recurrent infections are common in the months following measles (35,58), it is therefore essential that children are closely monitored and regular clinic attendance is recommended for at least 6 mo following recovery from acute measles.

10.2. Vitamin A Therapy Seven published clinical trials (six inpatient and one outpatient study), have evaluated the effect of vitamin A supplementation on morbidity and mortality (14,15,61–65). The studies differed in terms of their designs and the dose of vitamin A given. In Cape Town, South Africa (15), Tanzania (14), and India (64), the children received 200,000 IU on 2 successive days; in Kenya (63) a single dose, which varied with age, was given; in Zambia (65), they received a single dose of 200,000 IU; in Durban, South Africa (52), they received 100,000 IU (<1 yr of age) or 200,000 IU (>1 yr) on day 1, 2, and 8; and in England (61) they received approx 20,000 IU daily in the form of cod-liver oil for 1–3 wk (estimated dose of 140,000–400,000 IU altogether). All the studies were done on inpatients except for the Zambian study, which was done on outpatients.

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Table 1 Basic Principles of Measles Case Management Treat the whole child. Anticipate complications in high-risk groups. Admit severely ill children to hospital. Treat fever with paracetamol if the temperature is above 39°C. Give vitamin A according to WHO recommendations. Encourage breast feeding. Provide nutritional support to all children. Act promptly to treat eye lesions. Use antibiotics only when there are clear indications. Give oral rehydration solution for diarrhea.

In the UK trial, the case-fatality rate in the treated group was 3.7% compared to 8.7% in the untreated group (61). The relative risk (RR) of dying from measles following supplementation with vitamin A was 0.46 (95% C.I. 0.26–0.81; p = 0.018) compared to those not supplemented. The effect was most noticeable with respect to deaths owing to pneumonia. In the Tanzanian clinical trial, 6 (7%) of the 88 vitamin A-supplemented children who were admitted to a rural hospital died, whereas there were 12/92 (13%) deaths in the control group. Although there were twice as many deaths in the placebo group, the difference was not signiﬁcant, (RR 0.52, 95% C.I. 0.21–1.33; p = 0.25). There was, however, a signiﬁcant difference in mortality in children less than 2 yr, RR 0.15 ( p = 0.03) and for the cases who were complicated by croup (14). In the Cape Town study done on children with severe measles who were admitted to an urban regional hospital, vitamin A therapy had a signiﬁcant effect on mortality with 10/97 (10%) deaths occurring in the placebo group and only 2/92 (2%) deaths in the vitamin A treated group (relative risk 0.21, 95% C.I. 0.05–0.94; p = 0.046) (15). The Durban study consisted of a small sample size (n = 60) and only one death was reported in the placebo group (62). A recent meta-analysis of the four studies in the UK, South Africa, and Tanzania showed that vitamin A therapy reduced mortality by an impressive 67% ( p = 0.004) (69). In the Kenyan study, the overall case fatality was 2.7% and did not differ among treated (n = 146) and untreated (n = 148) children (63). The study from India, which evaluated the impact of vitamin A therapy in children with postmeasles complications (the average time of hospitalization following onset of rash was about 8 d), reported a case fatality rate of 16% in the vitamin A-treated group compared to 32% in the group that did not receive vitamin A ( p < 0.02) (64). Mortality rates in these trials are summarized in Fig. 2. Three African (15,62,63) trials speciﬁcally studied the impact of vitamin A on morbidity. In Cape Town, the treated children had a signiﬁcantly shorter hospital stay, recovered more rapidly from pneumonia and diarrhea, and fewer children developed croup, persistent pneumonia, or persistent diarrhea (15). In Durban, the vitamin A-treated children also recovered more rapidly overall and speciﬁcally from pneumonia. In addition, the integrated morbidity scores (determined by clinical ﬁndings and chest radiograph) at 1, 6, and 26 wk following infection were reduced by 82, 61, and 85%,

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Fig. 2. Clinical trials of vitamin A therapy in acute measles. Based upon refs. (8,9,55,57).

respectively, in the supplemented group (62). In Kenya, children given vitamin A had a signiﬁcantly lower risk of developing otitis media and recovered more rapidly from diarrhoea (63). Furthermore, three large scale community intervention trials, one in South India (70) and two in Nepal (71,72) have evaluated the effect of prophylactic vitamin A supplements on childhood mortality and have included in their analysis the effect on measles-related mortality. A meta-analysis of these studies showed a 36% reduction in mortality with a RR 0.74 (95% C.I. 0.53–1.04; p = 0.08) (73). These ﬁndings are consistent with those from the hospital-based studies. The beneﬁcial effects of vitamin A therapy reported in the aforementioned clinical trials have been conﬁrmed in an evaluation of a vitamin A supplementation program implemented as part of the routine case management of all children hospitalized with measles in Cape Town (74). The morbidity (hospital stay and intensive-care admissions) and mortality in children hospitalized during 1989 and 1990, after the implementation of the program were signiﬁcantly less than that in the children admitted during 1985 and 1986, the period prior to the implementation of vitamin A therapy. The signiﬁcance of these ﬁndings is that vitamin A therapy provides protection against the complications of measles infection in everyday hospital practice. All the clinical trials on vitamin A therapy in acute measles have been done in a hospital setting. One study from Zambia evaluated the effect of vitamin A therapy in an outpatient setting (65). In a blinded placebo-controlled trial, children were given a single high dose of vitamin A in oil. At baseline, 63 and 68% of treated and placebo treated children had pneumonia. After 4 wk pneumonia was absent in the treated group, but occurred in 12% of controls.

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Table 2 Vitamin A Dosage Age Infants <6 mo Infants 6–11 mo Children *12 mo

Immediately on diagnosis

Next day

150,000 IU 100,000 IU 200,000 IU

150,000 IU 100,000 IU 200,000 IU

10.3. Vitamin A Dosage The dosage schedule of vitamin A for children with measles is shown in Table 2. Note that if the child has any eye signs of vitamin A deﬁciency, then a third dose must be given at least 2 wk after the second dose.

11. PREVENTION 11.1. Measles Vaccine Most of the current live attenuated vaccines (including Schwarz, Moraten, Edmonston Zagreb, and AIK-C) in use throughout the world were derived from the original virus isolated and cultured by Enders and Peebles in 1954 (17). Measles vaccine is safe and very effective. The vaccine may cause a minor febrile or measles-like illness 7–10 d after injection. When administered to children over the age of 12 mo, as is the case in most developed countries, seroconversion is over 95% (75). Under the age of 12 months seroconversion is lower because of the interference of maternally derived antibodies (19). However because of the high probability of exposure to measles before the age of 1 yr in many developing countries, and because disease is usually more severe in infants, WHO has advocated vaccination at 9 mo of age (76). In special circumstances, WHO recommends that a ﬁrst dose be given at 6 mo in addition to the 9-mo dose. Such circumstances are during measles outbreaks, for infants hospitalized with any illness, and in areas where more than 15% of cases are known to occur in infants under 9 mo of age. In developed countries, it is recommended that a child receive at least two measles vaccines after the age of 1 yr (77). In these countries the measles vaccine is frequently administered together with mumps and rubella vaccine. Measles vaccine is recommended for children with HIV infection (60,78). Some authorities advise against its use in severely immunocompromised HIV-infected children (77). By 1985, virtually all countries had incorporated measles vaccine into their national expanded programme on immunization (EPI). Since then, the global coverage of children less than 1 yr of age with one dose of measles vaccine has increased signiﬁcantly and it is now estimated to be over 80% (1). The worldwide use of measles vaccine has also resulted in a dramatic decline in reported measles cases (Fig. 3). In many countries (even some developing countries), measles is now under control, i.e., the measles morbidity and mortality rate has been reduced to a small fraction of preimmunization levels, and plans for the elimination of the disease are being implemented. These include strengthening the national EPI activities, conducting mass campaigns, and developing an effective measles surveillance strategy (79).

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Fig. 3. Reported measles cases and vaccine coverage worldwide, 1983–1996. Based upon www. who.int/vaccines-surveillance.

11.2. Improving Vitamin A Status of Children Population-based studies indicate that vitamin A reduces childhood morbidity and mortality (69,73). WHO and United Nations International Children’s Emergency Fund (UNICEF’s) strategies for control and eventual elimination of vitamin A deﬁciency include the provision of vitamin A to children through a combination of strategies such as breast feeding, vitamin A supplementation, food fortiﬁcation, and dietary diversiﬁcation (80). WHO has also published guidelines for the simultaneous administration of vitamin A and measles vaccine as part of the routine EPI schedule (81). EPI is being viewed as the gateway to elimination of vitamin A deﬁciency. The program provides a greater number of opportunities for delivery of vitamin A to mothers and children than any other health program, reaching about 80% of the world’s children in their ﬁrst year of life, as well as their mothers. Vitamin A can safely be administered at 9 mo of age or older without having any effect on the production of antibodies to concurrently administered measles vaccine (82,83).

12. RESEARCH NEEDS One of the major impediments to measles control and elimination is the high rate of transmission among young children and infants coupled with the reduced efﬁcacy of the vaccine in children less than 1 yr old. WHO is exploring alternative strategies for immunization as well as evaluating new vaccines (84). In the context of the measles eradication strategy, simple diagnostic tests that can be utilized under ﬁeld conditions are being assessed, as is the development and strengthening of measles surveillance systems. In addition alternative routes of immunization, including the mucosal route, are being explored (79). One of the biggest challenges facing developing countries

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is to develop strategies to reach the “hard-to-reach children,” i.e., children living in remote and often inaccessible geographical areas as well as the poor living in the large periurban slums. A recent WHO consultative meeting has highlighted the paucity of data on optimal case-management and the need to do studies that would inform our current and future practice (85). Of particular note was the need to research the interaction between measles and malnutrition, to identify the optimal method of providing nutritional support for children hospitalized with measles, to determine the impact of stomatitis on nutrition and to identify the most effective therapy, and to document the natural history of complications and the phenomenon of long-term delayed mortality.

13. CONCLUSIONS Measles has long been a leading childhood killer, but major progress has been made in the last two decades in preventing measles through immunization and improving survival of affected children through effective case management. Although there is no speciﬁc therapy for measles, disease severity and mortality can be reduced by vitamin A therapy and the provision of good supportive care. Particular attention should be paid to the nutritional requirements of affected children. Measles is a preventable disease. The goal should be to work towards the elimination and ultimately the eradication of measles by ensuring universal immunization; a goal that is attainable. However, it requires an injection of signiﬁcant resources, particular in developing countries where there is a poor primary health care infrastructure and where measles is endemic.

REFERENCES 1. Centers for Disease Control and Prevention (CDC). Progress toward global measles control and elimination, 1990–1996. MMWR 1997; 46:893–897. 2. World Health Organization (WHO). Division of Diarrhoeal and Acute Respiratory Disease Control. Integrated management of the sick child. Bull WHO 1995; 73:735–740. 3. Hussey GD, Clements CJ. Clinical problems in measles. Ann Trop Paed 1996; 16:307–317. 4. Rhazes [Abu Bakr Muhammad ibn Zakariya al-Razi]. A treatise on the smallpox and measles. Translated from the Arabic by William Alexander Greenhil. London: Sydenham Society, 1848. 5. Sydenham T. Observationes medicae circa morborum acutorum historiam et curationem. Londini: G. Kettilby, 1676. 6. Creighton C. A history of epidemics in Britain, 2 vols. Cambridge, UK: Cambridge University Press, 1894. 7. Hirsch A. Handbook of Geographical and Historical Pathology, 3 vols. London: New Sydenham Society, 1883. 8. Jannetta AB. Epidemics and mortality in early modern Japan. Princeton, NJ: Princeton University Press, 1987. 9. Panum PL. Observations made during the epidemic of measles in the Faroe Islands in the year 1846. Med Classics 1929; 3:829–886. 10. Koplik H. The diagnosis of the invasion of measles from a study of the exanthema as it appears on the buccal mucous membrane. Arch Pediatr 1896; 13:918–922. 11. Morley D, Woodland M, Martin WJ. Measles in Nigerian children: a study of the disease in West Africa, and its manifestations in England and other countries during different epochs. J Hyg Camb 1963; 61:115–134. 12. Morley D. Severe measles in the tropics-1. BMJ 1969; 1:297–300, 363–365. 13. Aaby P. Malnutrition and overcrowding/intensive exposure in severe measles infection: review of community studies. Rev Infect Dis 1988; 10:478–491.

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44. Coomey JOO, Richardson JE. Measles in Ghana. Ann Trop Paediatr 1984; 4:189–194. 45. Varavithya W, Charuvantji A, Tarounotai T, et al. Diarrhoea in measles. J Med Assoc Thai 1985; 68: 298–301. 46. Greenberg BL, Sack RB, Salazar-Lindo E, et al. Measles-associated diarrhea in hospitalized children in Lima, Peru: pathogenic agents and impact on growth. J Infect Dis 1991; 163:495–502. 47. Koster FT, Curlin GC, Aziz KMA, Haque A. Synergistic impact of measles and diarrhoea on nutrition and mortality in Bangladesh. Bull WHO 1981; 59:901–908. 48. Hussey GD, Klein M. Measles. Child Hosp Q 2:301–305. 49. Orren A, Kipps A, Moodie JW, et al. Increased susceptibility to herpes simplex virus infections in children with acute measles. Infect Immunol 1981; 31:1–6. 50. Burgess W, Mduma B, Josephson GV. Measles in Mbeya, Tanzania, 1981–1983. J Trop Pediatr 1986; 32:148–153. 51. Samsi TK, Ruspandji T, Susanto I, Gunawan K. Risk factors for severe measles. Southeast Asian J Trop Med Public Health 1992; 23:497–503. 52. Alwar AJE. The effect of protein energy malnutrition on morbidity and mortality due to measles at Kenyatta National Hospital, Nairobi, Kenya. East Afr Med J 1992; 69:415–418. 53. Dossetor J, Whittle HC, Greenwood BM. Persistent measles infection in malnourished children. BMJ 1977; 1:1633–1635. 54. Foster A, Sommer A. Corneal ulceration, measles, and childhood blindness in Tanzania. Br J Ophthal 1987; 71:331–343. 55. Tidstrom B. Complications in measles with special reference to encephalitis. Acta Med Scand 1968; 184: 411–415. 56. Miller DL. Frequency of complications of measles. BMJ 1964; 2:75–78. 57. Zilber N, Rannon L, Alter M, Kahana E. Measles, measles vaccination, and risk of subacute sclerosing panencephalitis (SSPE). Neurology 1983; 33:1558–1564. 58. Burstrom B, Aaby P, Mutie DM, Kimani G, Bjerregaard P. Severe measles outbreak in Western Kenya. E Afr Med J 1992; 69:419–423. 59. Markowitz LE, Chandler FW, Roldan EO, et al. Fatal measles pneumonia without a rash: in a child with AIDS. J Infect Dis 1988; 158:480–483. 60. Palumbo P, Hoyt L, Demasio K, Oleske J, Connor E. Population-based study of measles and measles immunization in human immunodeﬁciency virus-infected children. Pediatr Infect Dis J 1992; 11: 1008–1114. 61. Ellison JB. Intensive vitamin therapy in measles. Br M J 1932; 2:708–711. 62. Coutsoudis A, Broughton M, Coovadia HM. Vitamin A supplementation reduces measles morbidity in young African children: a randomised, placebo-controlled, double-blind trial. Am J Clin Nutr 1991; 54:890–895. 63. Ogaro FO, Orinda VA Onyango F, Black RE. Effect of vitamin A on diarrhoeal and respiratory complications of measles. Trop Geogr Med 1993; 45:283–286. 64. Madhulika, Kabra SK, Talati A. Vitamin A supplementation in post-measles complications. J Trop Pediatr 1994; 40:305–307. 65. Rosales FJ, Kjolhede C, Goodman L. Efﬁcacy of a single oral dose of 200,000 IU of oil-soluble vitamin A in measles-associated morbidity. Am J Epidemiol 1996; 143:413–422. 66. WHO. Case management of measles: a policy document. Geneva: WHO, 1996. 67. Shann F. Meta-analysis of trials of prophylactic antibiotics for children with measles: inadequate evidence. BMJ 1997; 314:334–336. 68. Hussey GD. Managing measles. Integrated management reduces disease severity. BMJ 1997; 314: 316–317. 69. Glasziou PP, Mackerras DEM. Vitamin A supplementation in infectious diseases: a meta-analysis. BMJ 1993; 306:366–370. 70. Rahmathullah L, Underwood B, Thulasiraj RD, et al. Reduced mortality among children in Southern India receiving a small weekly dose of vitamin A. N Engl J Med 1990; 323:929–935. 71. West KP Jr., Pokhrel RP, Katz J, et al. Efﬁcacy of vitamin A in reducing pre-school child mortality in Nepal. Lancet 1991; 338:67–71. 72. Daulaire NM, Starbuck ES, Houston RM, Church MS, Stukel TA, Pandey MR. Childhood mortality after a high dose of vitamin A in a high risk population. BMJ 1992; 304:207–210.

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73. Beaton GH, Martorell R, Aronson KJ, et al. Effectiveness of vitamin A supplementation in the control of young child morbidity and mortality in developing countries. Discussion paper no. 13. Geneva: Administrative Committee on Coordination/Subcommittee on Nutrition (ACC/SCN), 1993. 74. Hussey GD, Klein M. Routine high dose vitamin A therapy for children hospitalized with measles. J Trop Paeds 1993; 39:342–345. 75. Preblud SR, Katz SL. Measles vaccine. In: Vaccines. Plotkin SA, Mortimer EA, eds. Philadelphia, WB Saunders: 1988, pp. 182–211. 76. World Health Organization: Global programme for vaccines and immunization. Immunization policy. WHO/EPI/GEN/95.03 REV.1. Geneva, WHO, 1995. 77. Watson JC, Hadler SC, Dykewicz CA, Reef S, Phillips L. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1998; 47(RR-8):1–57. 78. Arpadi SM, Markowitz LE, Baughman AL, et al. Measles antibody in vaccinated human immunodeﬁciency virus type 1-infected children. Pediatrics 1996; 97:653–657. 79. CDC. Advances in global measles control and elimination: summary of the 1997 international meeting. MMWR 1998; 47(RR-11):1–23. 80. World Summit for Children–Mid-decade goal: VAD. JCHPSS/94/2.8. Geneva: UNICEF-WHO Joint Committee on Health Policy Special Session, 27–28 January, 1994. 81. WHO. Using immunization contacts as the gateway to eliminating vitamin A deﬁciency. WHO/EPI/ GEN/94.9. Geneva: WHO, 1994. 82. Semba RD, Akib A, Beeler J, et al. Effect of vitamin A supplementation on measles vaccination in nine-month-old infants. Public Health 1997; 111:245–247. 83. Benn CS, Aaby P, Bale C, et al. Randomised trial of effect of vitamin A supplementation on antibody response to measles vaccine in Guinea-Bissau, West Africa. Lancet 1997; 350:101–105. 84. WHO and United Nations International Children’s Emergency Fund (UNICEF). Measles in state of the world’s vaccines and immunization. Geneva: WHO, 1996, pp. 39–44. 85. WHO. Clinical research on treatment of measles: report of a meeting. WHO/CDR/95.15. Geneva: WHO, 1995.

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Malaria Anuraj H. Shankar

1. INTRODUCTION Malaria is the most signiﬁcant parasitic disease of human beings and remains a major cause of morbidity, anemia, and mortality worldwide. Malaria currently accounts for approximately 200 million morbid episodes and 2–3 million deaths each year, estimates that have been increasing over the last 3 decades (1). The disease is caused by protozoan organisms of the genus Plasmodium, which invade and replicate within red blood cells, a process resulting in the manifestations of disease including cyclical fevers, anemia, convulsions, and death. The parasite is transmitted from person to person by biting anopholine mosquitoes. There are four malaria species that infect humans, Plasmodium falciparum, P. vivax, P. malariae, and P. ovale. They are distributed in varying degrees throughout the tropical world, and in some more temperate areas, wherever ecological and sociological conditions favor sufﬁcient interactions between humans, mosquitoes, and parasites to maintain transmission. It is, however, important to acknowledge that the majority of acute morbidity and mortality is caused by P. falciparum, and that nearly 90% of all cases and fatalities occur in sub-Saharan Africa. Although all persons are at risk for malaria, in many settings the burden of disease is carried primarily by children below the age of 5 and by pregnant women. Malaria is a treatable infection, and a variety of antimalarial drugs are available. However, drug resistance has become a major problem and new effective compounds are needed. Prevention of malaria has focused on reduction of man–mosquito contact by application of insecticides, use of bednets, and environmental management to reduce mosquito-breeding areas. The development of a malaria vaccine is currently a major focus of research. Clearly, additional low cost and effective means to assist in the prevention and treatment of malaria are needed. It has long been acknowledged that populations residing in malarious areas generally live under conditions leading to poor nutritional status. The groups at highest risk for the adverse effects of malaria, children and pregnant women, are also most affected by poor nutrition. Although it has been suspected that nutrition might inﬂuence susceptibility to infection by the malaria parasite or modify the course of disease, there have been comparatively few efforts to examine such interactions. Among the studies that have

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been done, some suggest that poor nutritional status may actually be protective, whereas others suggest an exacerbative effect. Most recently, however, ﬁeld trials of nutritional supplementation indicate that certain nutrients can signiﬁcantly reduce the burden of malarial disease. What is clear is that nutrition strongly inﬂuences the disease burden of malaria, and that malaria itself has a profound effect on host nutritional status. This chapter describes the history and current state of knowledge of malaria and nutrition, and develop a rational paradigm for the development of targeted, nutrient-based interventions as adjuncts to current methods of malaria treatment and prevention.

2. HISTORICAL BACKGROUND 2.1. Historical Overview of Malaria Human beings have long been afﬂicted with malaria. Medical writings dating from 2700 BC in China and India describe what is most likely malaria, and the disease is described in writings of Homer (2). Indeed, the Greeks had known the relation of fever to swamps and low-lying water since the 6th century BC, and Roman efforts to drain large areas of swampland were partially motivated by the desire to reduce malaria. Effective treatment for malaria was not recognized in the West until the early 1600s, after Jesuit priests in Peru observed Amerindians treating cyclical fevers with a tea made from the bark of the Cinchona tree. By 1820, the active ingredient from the bark, quinine, had been isolated and its use for cyclic fevers became widespread. The malaria parasite itself was discovered in the blood of humans by Laveran in 1880. In 1898, Ross, working in India, and Grassi and colleagues, working in Italy, independently described the life cycle of malaria in birds and man, respectively. Recognition of the role of mosquitoes in transmission lead to efforts to reduce mosquito breeding through drainage and environmental control, and reduction in human-mosquito contact through clothing, repellents, and bednets.

2.2. Attempts to Eradicate Malaria As mentioned, malaria control had initially been limited to reduction of mosquitobreeding habitat, use of bednets, and treatment of cases with quinine. However, two developments changed the strategies used to combat malaria. First, in the 1930s, chloroquine was developed as a derivative of quinine that was cheaper, more effective, and had fewer side effects. Second, in 1940, DDT was synthesized and realized to be the most potent insecticide available to man, remaining active for several months after application. In 1955, the World Health Organization (WHO), in response to the optimism engendered by the potential of these discoveries, formulated a plan for worldwide malaria eradication. By the late 1950s, one of the most ambitious health campaigns in history had been launched (3). Early efforts were enormously successful in some countries such as the U.S., Italy, Malta, and Sri Lanka, but met with limited success in others. Unfortunately, implementation was minimal in Africa, where disease burden was greatest. By the late-1960s, it was clear that eradication operations were untenable in many countries, and further compounding problems was the emergence of anopheline resistance to insecticides and parasite resistance to anti-malarials (4,5). A rapid resurgence of malaria and widespread emergence of chloroquine-resistant malaria followed the subsequent decline of the eradication effort.

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2.3. Modern Approaches to Malaria Control By the mid-1970s, the focus of combating malaria had shifted to control rather than eradication. There was also a gradual resurgence in malaria research that was fueled by developments in molecular biology and immunology. Despite major advances in understanding the biology of the parasite, diagnostic techniques, vector control methods, and antimalarial drugs, malaria has steadily increased over the last three decades. The current WHO Global Malaria Control strategy is focused on four goals: (1) provide early diagnosis and prompt treatment; (2) plan and implement selective and sustainable preventive measures, including vector control; (3) early detection to contain or prevent epidemics; and (4) strengthen local capacities in basic/applied research to permit the regular assessment of a country’s malaria situation, in particular the ecological, social, and economic determinants of the disease. The recently initiated WHO “Roll Back Malaria” Program exempliﬁes the renewed interest in controlling malaria and—determined not to repeat past mistakes—has genuinely prioritized on malaria in Africa. The WHO goals are being pursued through a variety of means including provision of malaria-treatment kits to village-based health workers or pharmacists, and focused training and capacity building through networking. The most signiﬁcant developments have, however, been the resurrection and improvement of an older technology, the bednet, and a focused effort on malaria vaccine development. 2.3.1. INSECTICIDE-TREATED BEDNETS The use of curtains or fabric to shield sleeping persons from mosquitoes has been practiced since ancient times. Indeed, the use of mosquito nets was strongly advocated after Ross and Grassi had discovered that mosquitoes did indeed transmit malaria. Though useful if maintained and used properly, bednets were easily rendered ineffective if holes developed in the netting or if it was improperly hung. In 1950 researchers observed that if bednets were dipped in residual insecticides, mosquitoes ﬂying against or landing on the net were exposed to lethal doses and died within minutes. Improved development has led to renewed interest in bednets, speciﬁcally insecticide-treated nets (ITN). Several trials (6–8) demonstrated that ITN’s were very effective in reducing morbidity and mortality. Meta-analysis of these trials indicated overall reductions in malaria morbidity by 48% and mortality by 20–40% (9). 2.3.2. VACCINE DEVELOPMENT Rationale for the belief that a malaria vaccine could be developed was based on the clear epidemiological evidence that humans develop protective immunity against malaria when repeatedly exposed to the infection. In addition, the maturation of molecular biology and modern immunology provided novel tools and hope that malaria vaccines were feasible. Initial studies focused heavily on the sporozoite, the stage inoculated to humans by the mosquito. Emphasis on the sporozoite as an immunological target for protection was motivated by observations made in the 1950s that humans could be protected against a challenge infection after exposure to the bite of irradiated malaria-infected mosquitos (10,11). By the early 1980s, researchers at New York University had cloned the circumsporozoite protein (CSP), the predominant protein on the surface

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of the sporozoite and the ﬁrst gene to be cloned from a human parasite. Following demonstration that rodents could be immunized with recombinant CSP, there was considerable optimism that a vaccine would soon be available. Unfortunately, phase II trials in humans, including experimental challenge infections (12), failed to demonstrate adequate protection. However, research continued and initial results with newer vaccine formulations based on the CSP have been promising (13). By the late 1980s, the attention of malaria vaccine development had begun to shift to the blood stage of the parasite, with the rationale being that the erythrocytic phase was responsible for clinical disease and mortality. Further impetus for this approach came from experiments in 1963 (14), demonstrating that infusion of antibody from resistant adults into children suffering acute clinical malaria resulted in rapid clearance of parasitemia. By the late 1980s, Pattaroyo and colleagues in Colombia developed a synthetic vaccine known as SPf66, which was based on several different blood stage antigens shown to be protective against experimental P. falciparum infection of monkeys (15). SPf66 became the ﬁrst vaccine to be tested in large-scale ﬁeld trials. Although initial results of 30–70% efﬁcacy in South America (16) and Tanzania (17) were promising, additional ﬁeld trials in The Gambia (18), Thailand (19), and Tanzania (20) failed to demonstrate efﬁcacy. Nevertheless, vaccine development has continued and several vaccine candidates are undergoing ﬁeld-testing in Africa and Papua New Guinea.

3. EPIDEMIOLOGY The starting point for understanding malaria as a disease, and the rationale behind control programs, must be an in-depth understanding of the intricate and often villagespeciﬁc aspects of ecology, biology, and epidemiology of malaria. Such knowledge is also the basis for understanding nutritional modulation of malaria morbidity and mortality.

3.1. Geographic Distribution and Disease Burden The relative importance of malaria varies greatly in different geographical areas of the world. As mentioned, nearly 90% of life-threatening P. falciparum-related disease continues to be in Africa, with the remaining 10% occurring primarily in Southeast Asia and India, followed by South America (1). Both incidence and seriousness of disease deﬁne its public health signiﬁcance. P. falciparum causes a variety of pathophysiological and potentially lethal conditions such as cerebral malaria and severe malaria anemia. Additional complications include splenomegaly, and renal and pulmonary pathology. In much of tropical Africa, malaria is the leading disease burden on the population. In Ghana, for example, P. falciparum accounts for nearly 10% of all healthy life-years lost (21,22), making it the greatest single health threat to the population. In many cases, malaria is a contributing factor to death even though the ﬁnal cause may be attributed to another disease such as diarrhea or pneumonia. Community-based intervention studies (23,24) indicate that malaria may account for nearly half the under-5 mortality. When malaria is controlled, reductions in nonmalaria mortality also decrease. P. vivax, though not as overtly pathogenic as P. falciparum, continues to be a major cause of morbidity in parts of China, India, Southeast Asia, Polynesia, and South

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Fig. 1. Life cycle of Plasmodium.

America. It is a signiﬁcant cause of morbidity and anemia, and these effects may indirectly contribute to all-cause mortality. Likewise, P. malariae is not as pathogenic as P. falciparum, although an unusual and highly lethal nephrosis can occur. P. ovale is a relatively uncommon infection and its contribution to overall malaria morbidity is not substantial. In addition to the proximate effects of morbidity and death, malaria results in chronic effects of persistent anemia, long-term disability, poor educational and work performance, and the cost of coping with illness and death within the family and community. In many cases, severe anemia from malaria requires blood transfusion and this in turn has been closely associated with transmission of HIV and with hepatitis B virus. Lastly, malaria during pregnancy, particularly with the ﬁrst pregnancy, places the woman at special risk for severe anemia and death from malaria (25). In addition, prenatal malaria can result in intrauterine growth retardation, low birth weight (LBW), premature delivery, fetal death, and miscarriage.

3.2. Life Cycle of the Malaria Parasite The complex life cycle of Plasmodium spp. is given in Fig. 1. The parasite undergoes two developmental stages in the human host resulting in asexual reproduction, and three in the mosquito resulting from sexual reproduction. The parasite is transmitted to humans as a sporozoite in the saliva of an infected female anopheline mosquito taking a blood meal. Sporozoites enter the venous circulation through the capillary beds and invade liver cells within minutes. Over the next 5–15 d, the sporozoite replicates to produce ~40,000 daughter parasites, called merozoites. In the case of P. vivax and P. ovale, dormant forms known as hypnozoites sometimes develop in the liver cells, remaining viable for up to 50 yr (26). When released from liver cells, merozoites invade erythrocytes. These intra-erythrocytic merozoites differentiate into trophozoites, which consume the intracellular hemoglobin and give rise to 6–24 daughter merozoites. The red cell eventually ruptures, releasing these merozoites to invade new erythrocytes and perpetuate the cycle. Each erythrocytic cycle requires 48 h for P. falciparum, P. vivax, and P. ovale, but 72 h for P. malariae (27,28). The different species of parasites also have different

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preferences for certain erythrocytes. P. vivax and P. ovale prefer younger nucleated red cells known as reticulocytes, whereas P. malariae prefers older red cells. P. falciparum has a marginal preference for younger cells but will readily infect all erythrocytes (27,28). In addition, P. falciparum-infected erythrocytes develop knob-like structures on their surface, which, along with several protein structures, lead to adherence of infected erythrocytes to the postcapillary venous endothelium (5,29). This results in sequestration of infected erythrocytes in the capillary beds, thereby preventing circulation of infected erythrocytes to the spleen, which is a major site of parasite removal. Moreover, rupture of infected erythrocytes occurs in an environment of tightly packed cells that facilitates re-invasion by daughter merozoites. For these reasons, as well as others, P. falciparum achieves the highest levels of erythrocytic infection, and results in the greatest degree of pathology. Within the erythrocyte some merozoites differentiate into sexual forms known as macrogametocytes (female) and microgametocytes (male). When taken up in a blood meal, gametocytes emerge in the mosquito gut and begin sexual reproduction leading to sporogonic development. The male and female gametes fuse, providing for genetic recombination, to form a zygote that transforms to the ookinete, which penetrates the gut wall and attaches to the epithelium. Over the next 7–12 d, the oocyst enlarges, forming ~10,000 sporozoites, and ruptures into the coelomic cavity. The sporozoites then migrate to the salivary glands and are ready be transmitted to the human host, thus completing the cycle. The actual time required for replication in the mosquito depends on the species of parasite, mosquito, and particularly on the ambient temperature. Under optimal conditions at 30°C, P. falciparum requires 9 d, but at 20°C it takes 23 d (5). With an average life span for most anophelines less than 3 wk, ambient temperature is critical to transmission. Once infected, the mosquito transmits sporozoites with each blood meal (5). Fifty to sixty species of the genus Anopheles are known to be capable of transmitting malaria to humans. There is great variation in different species in their host feeding preferences and ability to support malaria replication. An. gambiae is the most important vector in Africa, and among the most efﬁcient for malaria.

3.4. Classiﬁcation Schemes of Malaria Endemnicity The frequency of inoculation of the sporozoite into the human host is, of course, a primary determinant of infection. This is measured by determining the biting rate of anophline mosquitoes and the proportion of mosquitoes that are infected with the parasite. The entomological inoculation rate (EIR) is the product of these numbers and represents the frequency with the typical person is directly exposed to infection. The EIR ranges from a few bites a year to over 300 in high-transmission areas. Malaria endemnicity has been classiﬁed into four broad categories based on percentages of children, age 1–10, with enlarged spleens and the prevalence of circulating malaria parasites (30,31): (1) Holo-endemic refers to areas with constantly high EIR and with prevalence and spleen rates exceeding 75%. Immunity typically develops rapidly such that by age 10, acute malaria morbidity and mortality is low. (2) Hyperendemic includes regions with regular, often seasonal transmission, with spleen and parasite rates from 50–75%. Immunity is less developed and adults also experience signiﬁcant illness. (3) Meso-endemic areas have malaria transmission fairly regularly

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but at much lower levels, and spleen and parasite rates range from 10–50%. Such areas are prone to occasional epidemics involving those with little immunity, which may result in fairly high mortality. (4) Hypo-endemic areas are with limited malaria transmission. The population will have little or no immunity, and severe malaria epidemics involving all age groups can develop.

3.5. Clinical Disease Disease processes in malaria result from the erythrocytic cycle of invasion and hemolysis. Along with the liberation of the merozoites, hemolysis releases several pyrogenic compounds from infected red cells that stimulate the clinical paroxysms of fever and chills. In some patients, the erythrocytic cycle becomes synchronized so that virtually all merozoites are released every 48 or 72 h. This accounts for the periodicity of these symptoms and is the basis for the older classiﬁcation of malaria into tertian (every 3rd d) and quartan (every 4th d) disease. However, clinical manifestations of infection, particularly in children, can range from the totally asymptomatic to severe disease and rapid death. Children may present with symptoms including listlessness, pyrexia, abdominal cramping, difﬁculty breathing, mental disorientation, or convulsions. The distinction between infection and disease is particularly important in malaria. Infection with the malaria parasite does not necessarily result in disease. In highly endemic areas childhood prevalence rates exceed 50% but few will have acute symptoms. Typically, in hyperendemic areas the prevalence and density of infection with P. falciparum peak in early childhood and decline thereafter, with density receding prior to prevalence. The density of infection at which symptoms appear is also greater in early life and becomes lower with age (32). This indicates that separate immunological effectors modulate infection, parasite density, and febrile responses to the parasites. It is also of interest that, even in areas of perennial transmission, the incidence of malarial disease is substantially greater with seasonal increases in transmission, suggesting that recent inoculation more frequently leads to disease (33). Indeed, it appears that many individuals who become symptomatic have encountered a new parasite variant (34). In the case of P. vivax and P. ovale, reactivation of dormant hypnozoites can result in long-term relapses. Although P. falciparum and P. malariae do not produce hypnozoites, untreated or inadequately treated infections may result in persistent low-grade parasitemia leading to recrudescent disease (35).

3.6. Epidemiology of Severe Malaria As the intensity of transmission increases, the proportion of severe malaria cases and mortality is concentrated in lower age groups. In high-transmission areas, severe malaria and death is generally restricted to those below 5 yr of age, and most clinical disease occurs below 15 yr of age (36,37). Severe malaria can include a variety of life threatening manifestations, but usually refers to either severe anemia or conditions with cerebral or neurological involvement (23,36,38,39). These are distinct clinical sequelae with different epidemiological patterns that are altered by transmission intensity. In high-transmission areas (e.g., EIR > 100/yr), severe anemia predominates in the youngest children from 6–24 mo of age, whereas cerebral malaria is more common in older children from 36–48 mo of age. In lower transmission areas (e.g., EIR < 10), severe disease is predominantly cerebral malaria in older children. Interestingly, despite

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the different manifestations, the number of children experiencing severe disease is similar (37,40,41). These age-speciﬁc effects may be related to a combination of increased exposure as well as age-dependent maturation of the immune system (42). In addition, constancy of transmission appears to inﬂuence severe disease. Areas of intense perennial transmission tend toward severe anemia, with cerebral malaria being more frequent in areas of seasonal transmission (43). There is also space-time clustering of severe malaria (44,45), suggesting that severe malaria occurs in localized micro-epidemics.

3.7. Diagnosis and Drug Treatment of Malaria 3.7.1. DIAGNOSIS Diagnosis of malaria infection is generally made by microscopic detection of the parasite in a Geimsa-stained ﬁnger-prick blood sample smeared on a glass slide. A thick smear is usually viewed to detect and enumerate parasites, and the thin smear is used for speciation. The ability to detect low-grade infections depends on the number of ﬁelds examined and the experience of the technician viewing the slide. Although technologically simple, microscope-based diagnosis requires a trained technician to obtain reliable results. Additional, though often more expensive, techniques have been developed that allow detection of the parasite by unskilled personnel (46). Several of these tests, such as the ParaSight-F test, detect circulating malaria antigen in the blood and are available as a dipstick (47). Others, such as the QBC column, concentrate parasites into a thin band in a centrifuged capillary tube, which is then viewed under a microscope. 3.7.2. DRUG TREATMENTS In non-Western countries, the history of herbal drug use goes back hundreds of years before any effective drugs were available in Europe. In China, derivatives of the plant Qing-hao-su have been in use for centuries, and pre-Columbian Peruvian healers used tea made from the bark of the Cinchona tree. The active ingredient of the Cinchona bark, quinine, was extracted in 1820 in Europe. Chloroquine, a quinine derivative, was invented in the late 1930s and is active against asexual stages of all human malaria except drug-resistant strains of P. falciparum. It is well-tolerated, even when taken chronically for long periods, and is safe for young children and pregnant women. It has a prolonged half-life of 33 d, which facilitates its use as a prophylactic drug. The most important side effect is pruritis reported almost uniquely but frequently by Black Africans. Owing to its low toxicity and cost, and high effectiveness, chloroquine remains the ﬁrst-line drug of choice in many areas. Additional drugs described below offer various advantages and disadvantages over chloroquine. Quinine continues to be an important therapeutic agent, especially for drug-resistant P. falciparum malaria, but it has a relatively short shelf-life and has more adverse reactions than chloroquine. Artemisinin and related compounds, derived from Qinghao-su, have demonstrated a high degree of effectiveness with relatively low rates of adverse reactions. A rapidly absorbed suppository formulation for young children is also available. Pyrimethamine and proguanil are effective drugs, but resistance generally occurs relatively quickly. Sulfadoxine-pyrimethamine (Fansidar), originally developed for

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efﬁcacy against chloroquine-resistant P. falciparum, is widely used in areas of drugresistance. However, prophylactic use has been associated with severe and often fatal adverse reactions. Increasing reports of fansidar-resistant P. falciparum is further limiting usefulness (1). Meﬂoquine, another quinine derivative, is widely used for prophylaxis in areas with chloroquine resistance. It is more expensive and has more adverse reactions than chloroquine. Primaquine is unique in that it has activity against all forms of the malaria parasite occurring in humans. Because of its effect on sporozoites and the hepatic forms, it can be used to prevent the establishment of infection in the liver. However, Primaquine also causes hemolysis in those with glucose-6-phosphate dehydrogenase (G6PD) deﬁciency, a common trait in Africans.

3.8. Host-Parasite Interactions and Immunity Malaria is a very intense stimulator of the human immune system. Many biological defense systems are activated in response to malaria infections including the reticuloendothelial system with great enhancement of phagocytic activities in the spleen, lymph nodes, and liver to remove altered RBCs and other debris, an intense activation of humoral defenses. Indeed, humans can develop several grams per liter of immunoglobulin directed against malaria, and a great range of cellular immune and cytokine cascade defenses. Some of these responses are protective and others may contribute to the pathology. As previously mentioned, P. falciparum infected red cells undergo complex changes including the expression of protein knobs on the red cell surface (5,29). These proteins are highly variable in their antigenic expression and are the products of highly variable “var” genes. Up to 150 different var genes have been identiﬁed, which occupy up to 5% of the malaria genome (5). This commitment to antigenic diversity of the knobs reﬂects the key role they play in the survival of P. falciparum. The var gene proteins also confer adherence to noninfected red cells, a phenomenon known as rosetting. These processes facilitate sequestration of the parasite in the microvasculature, and may facilitate maturation by keeping parasites in their preferred less-oxygenated blood. Proteins expressed on vascular endothelium serve as receptors for attachment of infected erythrocytes. Immune mediators such as tumor necrosis factor-α (TNF-α) released during infection may activate some of these. Much work has gone into efforts to relate speciﬁc phenotypic parasitic characteristics—such as the capacity to stimulate the release of cytokines including TNF-α, the production of nitric oxide, and the cytoadherence and rosetting phenotypes (and their underlying genotypes)—to the diversity of clinical events provoked by P. falciparum that lead to severe disease (48–51). Although the rosetting phenotype has been reported to be associated with cerebral malaria, no clear association so far has been found between any particular cytoadherance phenotype and cerebral malaria or other forms of severe malaria (37,52). There is also evidence that parasites stimulate TNF-α, but thus far no pattern has been consistently discerned. What is clear is that great antigenic diversity exists within any given P. falciparum population within humans or within vectors (53–55).

3.9. Modulating Factors of Malaria Morbidity and Mortality The formation of small towns arising in concert with agricultural development in much of Africa, Asia, and South America has facilitated malaria transmission by concentrating populations in relatively conﬁned areas near water supplies. The

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development of small dams and irrigation schemes has also added to anopheline breeding. Additionally, the agricultural use of pesticides has been a factor in the development and spread of insecticide-resistant vectors. From the biomedical perspective, the heavy morbidity and mortality caused by malaria has led to the selection of multiple genetic traits, which confer some degree of protection. Most of these involve the red cell and include structural variants in hemoglobin. Variants in the β-globin chain of hemoglobin include hemoglobin S (sicklecell trait), and hemoglobins C and E. Altered α- and β-chain production results in α and β thalassemias. Others traits include erythrocyte enzyme deﬁciency of glucose6-phosphate dehydrogenase (G6PD), red-cell cyto-skeletal abnormalities such as ovalocytosis, and loss of red-cell membrane proteins such as Duffy blood group factor (56–58). In some cases, selection for polymorhisms of immunological effectors, such as TNF-α, has occured (55). Most all of these genetic polymorphisms are somewhat deleterious to overall health, but provide survival advantage in malarious areas.

4. EFFECTS OF NUTRITION ON MALARIA 4.1. Early Perceptions of the Impact of Nutrition on Malaria Prior to 1950, it was widely accepted that malnutrition led to greater susceptibility to malaria. The Indian Famine Commission in 1898 reported that malaria was more frequent and fatal in those suffering from poor diets (59). Likewise, historical accounts from the late 19th and early 20th centuries indicated that famines and poor economic conditions in north India and Sri Lanka tended to precipitate malaria epidemics, and that the poorer classes experienced greater mortality (60,61). Several reports from 1920–1940 in Corsica (62), Algeria (62), Vietnam (63), Turkey (64), and Ghana (65) stated that malaria was more frequent and severe among groups and individuals who were undernourished. In 1954, Garnham, a prominent malariologist of his time, stated that in Africa the clinical effects and mortality of malaria were more severe when superimposed on malnourished children (66). Still, there were reports to the contrary. In 1897, an Italian industrialist unsuccessfully attempted to exploit the fertile but malaria-infested Pontine marshes near Rome by protecting farmers with generous provisions of food and quinine (67). Some claimed there was no association between nutritional status and malaria morbidity (68), whereas others recounted that increases in food consumption following famines actually exacerbated malaria (69). Unfortunately, most of these reports were based on qualitative clinical and epidemiological observations or even anecdotal information. Little, if any, quantitative data or methodological information was published to substantiate the conclusions. By the early 1950s, however, clinicians and malariologists began making attempts to quantify more carefully interactions between nutrition and malaria. Three studies from Ghana and Nigeria published between 1954 and 1971 (70–72) were particularly inﬂuential, and strongly promoted the notion that malnutrition was in fact protective for malaria. This idea was reinforced by a series of studies by Murray et al. (73–76) from 1975–1980 on re-feeding and malaria in famine victims from Niger and Sudan. Animal studies appeared to support these reported malaria suppressive effects of a poor diet, leading to the current perception that malnourished children are less susceptible to malaria infection, morbidity, and mortality (77–80). This section of the chapter will review

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these studies and more recent data from humans, and re-examine data from the animal studies.

4.2. Malnutrition and Malaria: Synergism or Antagonism? 4.2.1. MALNOURISHED INDIVIDUALS AND MALARIA MORBIDITY AND MORTALITY Several studies have examined the association between malnutrition, usually proteinenergy malnutrition (PEM), and malaria morbidity and mortality. These are presented in Tables 1 and 2. Some studies were based on clinic outpatients, whereas others were hospital admissions or community-based cross-sectional studies. Most were case-control studies but some were longitudinal surveillance of cohorts. 4.2.1.1. Clinic-Based Studies. Among the ﬁrst was a large scale clinic based study in Uganda (81,82) (Table 1), which concluded that no association existed between nutritional status and malaria mortality. This study was less than ideal as nutritional status was based on qualitative and subjective indicators such as thin or pale hair or being “very” thin, and malaria diagnosis was based only on spleen enlargement, whereas mortality risk was estimated by presence or absence of sibling mortality. Another smaller clinic-based study in India reported progressively increasing parasite density with improved nutritional status (83), suggesting that malnutrition was protective. However, two additional studies, one in Brazil (84) and one done on Soviet army personnel (85), reported greater frequency or more severe malaria in those who were malnourished. 4.2.1.2. Early Studies of Hospital Admissions for Severe Malaria. As mentioned, early hospital-based studies strongly inﬂuenced current perceptions of malaria and malnutrition. First, in 1954, an autopsy report by Edington (70) indicated that 4 Ghanaian children who died from cerebral malaria were all well nourished. Other accounts from South Africa in 1960 (86) reported that malaria was rarely seen in malnourished children. This was followed by another qualitative report from Edington (1967) (87) in Nigeria stating that children dying of cerebral malaria were usually well nourished, and that cerebral malaria was rare in children suffering from kwashiorkor. Case-control studies from Nigeria by Hendrickse in 1967 (71) and 1971 (72) concluded that children suffering from malaria were less likely to be malnourished or have convulsions. Hendrickse also re-afﬁrmed the apparent protection owing to kwashiorkor (71). A subsequent autopsy report from Nigeria of 25 malnourished children indicated that only 2 had died of malaria (88). 4.2.1.3. Critical Analysis of the Early Hospital-Based Studies. Although these reports appeared convincing of a protective effect of malnutrition on malaria, several characteristics of the studies weaken such conclusions. Most importantly, the study populations were comprised of clinic cases or malnourished children and comparisons were made between those with or without malaria. In the absence of healthy community controls, one can only conclude that malaria is less exacerbated by malnutrition than other conditions. The overall prevalence of malnutrition among malaria cases in these studies was remarkably high, suggesting possible synergy with malnutrition. A more informative analysis would have included the relationship between the degree of (Text continued on page 190)

Table 1 Interaction Between Malnutrition and Plasmodium falciparum: Clinic and Hospital-Based Studies Country

Study design

Number of subjects

Age group

Gongora (81)

Uganda

Clinic out-patients

22,000

< 6 yr

Ahmad et al. (83)

India

Clinic out-patients

75

birth–12 yr

Pereira et al. (84)

Brazil

120

17–72 yr

Liashenko (85)

Afghanistan, Vietnam, Cambodia

1342

Soviet army males ~20–28 yr

Hendrickse (71)

Nigeria

Clinic out-patients: Pf patients vs healthy controls Clinical malaria out-patients: underweight vs normal weight Hospital admissions

333

children

Hendrickse (72)

Nigeria

Hospital admissions: Pf patients vs febrile cases

295

Birth–10 yr

Hospital admissions: all admissions

1549

Birth–14 yr

Hospital admissions: cerebral malaria vs other causes

376

1–5 yr

Razanamparany Madagascar et al. (91) Randriamiharisoa et al. (92) Olumese Nigeria et al. (93) Chad

Hospital admissions: all admissions

1050

1 mo–5 yr

Man et al. (95)

The Gambia

Hospital admissions

13,579

Birth–5 yr

Higher reported sibling mortality associated with patients with spleen enlargement or malnutrition but no stronger association if both were present. Patients with progressively greater malnutrition (based on weight for height Z-score) have increased Pf parasitemia.* P. falciparum cases weighed 13% less than healthy controls. Malnourished P. falciparum patients had lower antibody response to infection, which was associated with greater acute morbidity. Heavy infections are more frequently seen in well-nourished children. Among malnourished children the cause of death is rarely malaria. Malaria patients are 0.82 times as likely to be malnourished, malnutrition in patients ~6 times more frequent than population; malnourished children 0.64 times as likely to have convulsions. Malnourished malaria patients were 2.5* times more likely to die. 73% of all malaria cases were malnourished. Cerebral malaria patients are 0.40* times as likely to be malnourished, but malnourished cerebral malaria patients are 3.5* times more likely to die or suffer neurological deﬁcits. Malaria patients are 0.57* times as likely to be malnourished, malnourished malaria patients were 1.5* times more likely to die. Malnourished by WAZ score: malaria patients are 0.67 times as likely to be malnourished but weigh ~0.35 kg less than control children; overall, children with malaria are 1.30 times more likely to die.

Interaction Neutral

Antagonistic Synergistic Synergistic

Antagonistic Antagonostic synergistic

Synergistic

Synergistic

Synergistic Synergistic

Shankar

Renaudin (94)

Description of observations

188

Reference

Number of Study design

subjects

Age group

Monjour et al. (105) Burkina Faso

Cross-sectional survey

165

6 mo–3 yr

Burgess et al. (97)

Malawi

Cross-sectional survey

445

Birth–5 yr

Wenlock (98)

Zambia

Cross-sectional survey

6,938

Sharp and Papua New Harvey (99) Guinea Carswell et al. (104) Tanzania

Cross-sectional survey

166

Birth–5 yr

Cross-sectional survey

244

El Samani (100)

Sudan

Cross-sectional survey

445

School-age children Birth–5 yr

DominguezVasquez and Alzate Sanchez (103) Renaudin & Lombart (101) Tshikuka et al. (102) Sturchler et al. (194) Williams et al. (107)

Colombia

Cross-sectional survey

124

Birth–6 yr

Chad

Cross-sectional survey

144

Birth–1 yr

Zaire

Cross-sectional survey

558

4 mo–10 yr

Longitudinal surveillance 170 (multiple cross-sectional) Vanuatu Longitudinal surveillance 1511 of malaria attacks for 1 yr Papua Longitudinal surveillance 136 New Guinea of malaria attacks for 1 yr

1 mo–15 yr

Reference

Genton et al. (108)

Country

Tanzania

All ages

Birth–10 yr 10 mo–5 yr

Description of observations Underweight children are 0.90 times as likely to be infected. Underweight children had greater prevalence of malaria.* Underweight children were 1.27 times more likely to be infected.* Stunted children were 1.9 times more likely to have an enlarged spleen.* No association between underweight children and antibody levels to malaria antigens. Stunted children were 1.4 times more likely to have recent malaria illness (not slide-conﬁrmed malaria).* Underweight children have decreased antibody responses to malaria antigens.* Malnourished children were 1.54 times more likely to be infected.* Malnourished children were 1.23 times more likely to be infected.* Children with low growth tended to be more freqently infected.* Underweight children were more likely to have an attack of P. vivax* and a tendency toward more attacks by P. falciparum. Stunted children have lower risk for malaria attacks;* anti-malaria cell-mediated immunity higher in stunted children,* but antibody responses to malaria are lower in underweight children.*

Interaction Neutral

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Table 2 Interaction Between Malnutrition and Plasmodium falciparum: Cross-sectional and Longitudinal Studies

Synergistic Synergistic Synergistic Neutral Synergistic Synergistic or antagonistic Synergistic Synergistic Synergistic Synergistic Antagonistic with some synergistic

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malnutrition among malaria cases and the risk of malaria mortality. Unfortunately, such analyses were not done, partly because relatively nonstandardized qualitative descriptors rather than quantitative assessment were used to categorize malnutrition. In some studies, incomplete analyses of the existing data were made. For example, Hendrickse reported decreased risk of convulsions in malnourished malaria patients, but the same decline in convulsion risk was also observed for malnourished nonmalaria patients. Additional caveats reside in the lack of information on socioeconomic status (SES) or residence of the cases. Well-nourished cases may tend to come from the urban areas and have less acquired immunity, whereas malnourished cases could come from outlying higher transmission areas leading to greater immunity. Indeed, Edington reported that the children suffering from cerebral malaria tended to have less hookworm (87), an observation possibly related to SES. Lastly, the conclusions based on patients suffering from kwashiorkor may not be generalizable to overall malnutrition because aﬂatoxins, a causative agent of kwashiorkor, are toxic to malaria parasites in vitro and in vivo (89,90). 4.2.1.4. Recent Studies of Hospital Admissions for Severe Malaria. In the last 10 years, additional studies have been completed on the relationship between malnutrition and malaria. These larger studies more carefully documented nutritional status by reference standards using height, weight, and age, and have evaluated malnutrition as a risk factor for malaria mortality among hospital admissions. Four studies (Table 1) conducted in Madagascar (91,92), Nigeria (93), Chad (94), and The Gambia (95) indicate that malnourished patients are 1.3–3.5 times more likely to die or suffer permanent neurological sequelae compared to normally nourished malaria patients. In addition, the study from The Gambia indicated that malaria patients typically weighed 350 g less than healthy control children (95). It is also important to note that in all studies, as seen by Hendrickse, malnourished hospital patients were less likely to have malaria, suggesting that although malaria may be exacerbated by malnutrition, other diseases may are more adversely affected. Indeed, additional analyses in The Gambia study (95) conﬁrm the greater impact of malnutrition on risk of death from diarrhea and pneumonia. In contrast to these reports, one study of 60 hospital patients in India indicated that parasitemia tended to increase with improving nutritional status; however, no data on clinical outcomes were presented (96). 4.2.1.5. Cross-Sectional Studies of Malariometric Indicators. Several crosssectional surveys (Table 2) also favor a synergistic relationship between malnutrition and malaria. Studies carried out in Malawi (97), Zambia (98), Papua New Guinea (99), Sudan (100), Chad (101), and Zaire (102) indicate greater risk for infection (97,98,101,102), malaria illness (100), or spleen enlargement (99), among malnourished children. A study in Colombia indicated that malnourished children had lower antimalaria antibody levels (103). This could be interpreted as a synergistic effect if malnutrition suppresses antibody response to malaria, or possibly antagonistic if malnutrition protects against infection such that antibodies are not produced. In Tanzania (104) there was no effect of nutritional status on anti-parasite antibody levels(104), and a study in Burkina Faso (105) found no association between prevalence and nutritional status. 4.2.1.6. Longitudinal Cohort Studies and Effects of Nutrition on Drug-Resistant Malaria. Lastly, longitudinal cohort studies in Tanzania (106) and Vanuatu (107) indicate that malnutrition predisposes children to malaria illness. In contrast, one

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report from Papua New Guinea suggests that stunted children may be more resistant to malaria attacks (108). However, this protection was not seen in underweight children. It is of interest that the stunted children also exhibited increased immune responses to malaria antigens, whereas the wasted children had suppressed responses. Additional evidence of an exacerbative role of malnutrition on malaria can be seen in several drug-resistance studies. Malnourished Rwandan refugees had slower parasite clearance, higher parasite titers at presentation, and more severe drug resistance (109). Likewise, in the Solomon islands, malnourished children were 3.6 times more likely to have drug-resistant malaria (110,111). 4.2.2. STUDIES IN FAMINE RELIEF The Murray family examined the presence of malaria in famine victims during nutritional rehabilitation in a series of studies. During the Sahelian famine in Niger, victims were admitted to a hospital for re-feeding and it was observed that P. falciparum malaria developed in many of these individuals within a few days (74), often resulting in cerebral pathology. Because there was no transmission of malaria at the hospital, it was believed that feeding had provided essential nutrients for sequestered parasites, leading to recrudescent infection (73,74). In another study, famine victims were given either grain or milk for rehabilitation and it was observed that those given grain were more likely to experience recrudescent cerebral malaria (75). These studies suggested that quality as well as quantity of the diet is an important determinant of malaria morbidity. The previously mentioned 1945 report of the Bengal Famine Commission also stated that re-feeding tended to precipitate malaria disease in those carrying lowgrade infections (69). The Murrays concluded that the interaction between poor diet and malaria is part of an ecological balance between humans and malaria, which was interpreted as a beneﬁcial aspect of malnutrition. 4.2.3. STUDIES IN ANIMALS A variety of animal experiments have also contributed to the idea that PEM reduces malaria morbidity. Early work showed that monkeys maintained on a low-protein diet did indeed have lower parasitemia (112–115). However, the animals either were unable to clear the infection, resulting in multiple recrudescences (113), or parasitemia appeared earlier and lasted longer (115). Immune responses were also suppressed (115). However, for monkeys suffering from cerebral malaria, protein-deprived animals had fewer parasitized erythrocytes in the cerebral capillaries and did not develop the disrupted endothelium seen in normally fed monkeys. Still, cerebral and pulmonary edema was present in all animals irrespective of dietary regimen (116). The primate experiments were complemented by a variety of informative data from studies of rodent malaria. A comprehensive series of investigations by Ramakrishnan et al. in the early 1950s indicated that malaria parasitemia was less severe in protein deprived rats and that survival was enhanced (117–122). He also showed that methionine and para-amino benzoic acid (PABA) promoted infection in starving rats (117). Importantly, it was also clear that protein deprived animals were unable to clear the infection (122), and that protein restriction in young rats exacerbated malaria parasitemia and mortality (119). Moreover, parasite densities were higher and more lethal during relapses in protein deprived animals (122). Lastly, starved animals experienced strong relapse infections when food was given (119).

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Additional studies by Edirisinghe et al. (79,123–126) documented that acute and chronic protein deprivation depressed peak parasitemia more than 75% and prevented death. However, as shown in previous work, the animals were unable to clear the infection (125), and antibodies preventing parasite growth did not adequately develop. Elegant work by Fern et al. (126) then demonstrated that re-addition of threonine to a low protein diet restored susceptibility, and that this effect was enhanced by valine, isoleucine, and methionine. However, phenylalanine, tyrosine, lysine, histidine, and tryptophan did not appear to have this promoting effect. Subsequent studies in rats and mice conﬁrmed that low-protein diets suppressed parasitemia (127–131) and inhibited cell mediated immunity (127,128), and that effects were reversible by addition of PABA (128). Effects on mortality were, however, less consistent. In some cases, low-protein diets suppressed parasitemia but mortality was higher, albeit delayed (132). Addition of threonine and methionine to the low-protein diet decreased mortality (132), although methionine and threonine alone had no effect when added to the deﬁcient diet. Others observed no effect on mortality in moderately malnourished mice, but increased death was seen in severely malnourished animals (133). Protein-deﬁcient diets were, however, consistently protective for rodent cerebral malaria (130,131,134). 4.2.6. SYNTHESIS OF DATA CONCERNING EFFECTS OF PROTEIN-ENERGY MALNUTRITION ON MALARIA The considerable body of data from humans and animals, though complex, provides ample evidence to draw some conclusions regarding the interaction between malnutrition and malaria. Although it is frequently mentioned that malnutrition is protective for malaria (77–80), more recent data and careful re-examination of the human studies and data from animals indicates that malnutrition does exacerbate malaria, and considerably increases the likelihood of mortality. The human hospital-based studies suggesting a protective effect of malnutrition are inconclusive owing to the many methodological and design issues mentioned previously. Similarly, the animal-based data, often cited as supportive evidence that malnutrition is protective, is not so clear when carefully examined. Closer inspection reveals that although parasitemia tends to be lower in poorly fed animals, they are unable to clear the infection, and immune responses to the parasite are suppressed. This leads to more chronic infections and more severe relapses. Also, the observation that malnutrition is particularly deleterious for malaria in younger animals is important. In cerebral malaria, poor diets appear protective for animals, but human data indicates that malnourished children are more likely to die from cerebral malaria. This discrepancy may be rooted in differences in the etiology of cerebral pathology in animals and humans. The famine or starvation situation is, however, a special case and it is consistently observed in humans and animals that refeeding an infected starved host re-activates low-grade infections. The implication is that anti-malarial measures should be included during nutritional rehabilitation of famine victims.

4.3. Impact of Malaria on Child Growth Although malnutrition appears to exacerbate malaria, it is also true that malaria itself results in growth failure and is a contributing factor to malnutrition. Several reports from Africa have noted a transient weight loss in young African children following a

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malaria attack (135–137). In The Gambia, two longitudinal cohort studies indicated that P. falciparum malaria was signiﬁcantly related to lower weight gain and growth faltering, particularly in children below 36 mo of age (138,139). Other studies have attempted to compare weights in different communities with different levels of malaria. In El Salvador, no differences in weight or height were observed in areas with low or high transmission of P. vivax (140). In contrast, researchers in Papua New Guinea found signiﬁcantly greater malnourished individuals in villages with high P. falciparum transmission intensity compared to control villages with lower transmission (99). Additional studies of chemoprophylaxis provided more deﬁnitive evidence for the effects of malaria on growth. A 1-yr placebo-controlled trial of pyrimethamine prophylaxis in 176 Ghanaian 7-yr old children resulted in a nonsigniﬁcant 78 g excess weight gain in those taking pyrimethanine (141). In a small 2-yr study in The Gambia (142) of 52 children randomized to chloroquine prophylaxis or placebo at birth, unprotected children weighed signiﬁcantly less between 6 and 24 mo. Another 2-yr study in Nigeria that followed 198 children given chloroquine prophylaxis or a placebo shortly after birth found that protected children tended to have greater height, weight, mid-upper-arm circumference (MUAC), and mean serum albumin levels, although the differences were relatively small (143). Interestingly only 1 child given chloroquine died from malnutrition, compared to 6 such deaths in the control group. Moderate effects on nutritional status were also observed following other malaria interventions. The Garki Project (1980) examined the effects of prolonged and largescale insecticide spraying and chemoprophylaxis on nutritional parameters in a northern Nigerian community, and observed small but signiﬁcant changes in weight gain and MUAC (144). However, similar interventions in Tanzania found no effect in 2–18 mo old children after malaria control (145) Snow et al. (1997) in Kenya followed 1500 children 1–11 mo of age, half of whom slept under insecticide-treated bed nets (146). The number of children classiﬁed as malnourished was 25% less in those using ITNs, and MUAC were also increased. A similar study of bed nets and treatment-on-demand in Tanzania found that protected children gained more weight, with the strongest effects seen in those less than 18 mo of age (147).

4.4. Inﬂuence of Speciﬁc Nutrients on Malaria Morbidity 4.4.1. IRON Iron deficiency affects nearly two billion people worldwide resulting in over 500 million cases of anemia (148). Additional sequelae include poor neurological development, lower work capacity, LBW, and increased maternal and infant mortality (149,150). The burden of both iron deﬁciency and malaria falls primarily on preschool children and pregnant women (151,152), and iron supplementation of these groups is the primary means of prevention and treatment of anemia. Multiple studies have attempted to evaluate the beneﬁt of iron supplementation in malaria endemic areas (76,153–172). Some of these studies reported that iron supplementation increased the risk of developing or reactivating malarial illness (76,153,156), whereas others reported no signiﬁcant adverse effects (161,164,173). To resolve this issue, a systematic review and meta-analysis of controlled trials of iron supplementation was recently completed (174) A search produced 13 trials, 9 published (76,153–156,158,161,163,164) and 4 unpublished (157,159,160,162). Data from the 13 trials, totaling 5230 subjects, were pooled to obtain composite effects of iron supplements on malaria attack rates,

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parasite prevalence, parasite density, prevalence of enlarged spleens, hemoglobin levels, and anemia. Iron supplementation resulted in a nonsigniﬁcant 9% (RR = 1.09, 95% CI 0.92–1.30, n = 8) increase in the risk of a malaria attack. End-of-trial cross-sectional data indicated a 17% (RR = 1.17, 95% CI 1.08–1.25, n = 13) greater risk of infection in those given iron. For trials providing baseline data, the absolute increase in infection rates was 5.7% (95% CI –1.2–8.5, n = 9), which was nonsigniﬁcant. Iron supplements were also associated with a nonsigniﬁcant 12% (RR = 1.12, 95% CI 0.99–1.26, n = 6) increase in risk of spleen enlargement. Qualitative assessment of parasite density suggested a tendency toward higher levels in those receiving iron. A subanalysis of trials implementing iron regimens in accord with international recommendations revealed no evidence for increased infection or morbidity. Overall, hemoglobin levels improved by 1.2 g/dL (95% CI 1.2–1.3, n = 11) following iron supplementation and the risk of anemia was reduced by 50% (RR = 0.50, 95% CI 0.45–0.54, n = 4). The data indicate that prophylactic iron supplementation was associated with increases in certain malariometric indices. However, these tended to be relatively small effects and were often nonsigniﬁcant. In contrast, improvements in hematological status following iron supplementation were substantial and have clear public health beneﬁt. Based on the present evidence, iron supplementation in malaria endemic areas should be pursued in accord with international guidelines, and co-implementation with anti-malaria activities would be recommended. 4.4.2. ZINC Zinc is essential for normal immune function (175) and has been shown to reduce the incidence of diarrhea and pneumonia (176). Indeed, zinc is essential for a variety of lymphocyte functions implicated in resistance to malaria, including production of immunoglobulin (IgG), interferon-γ (IFN-γ), TNF-α, and microbicidal activity of macrophages (175,177). Cross-sectional studies among school-aged children in Papua New Guinea (175) and pregnant women in Malawi (178) have reported inverse associations between measures of zinc status and P. falciparum parasitemia. In addition, a placebo-controlled trial of zinc supplementation in preschool children in The Gambia documented a 30% reduction in health-center attendance owing to P. falciparum (179), although this was not statistically signiﬁcant. Lastly, mildly zinc-deﬁcient mice experienced mortality from a normally nonlethal strain of P. yoelii (180), and zinc supplements decreased markers of oxidative stress during infection with P. berghei (181). Additional murine studies indicated that moderate zinc deﬁciency resulted in 40% mortality from the normally nonlethal rodent malaria P. yoelii 17X-NL (180). A recently completed placebo-controlled trial of zinc supplementation of preschool children in Papua New Guinea provides additional evidence for the role of zinc in malaria. The study indicated that zinc supplementation reduced by 38% the frequency of health-center attendance owing to P. falciparum malaria. Moreover, a 69% reduction was observed for malaria episodes accompanied by high levels of parasitemia (i.e., ≥100,000 parasites/µL), suggesting that zinc may preferentially protect against more severe malaria episodes. Although the 38% reduction in clinic-based P. falciparum-episodes reported here is encouraging, and the 69% reduction in episodes with heavy infections portends an

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effect on severe malaria, additional information is needed to document the geographic regions and conditions of malaria transmission in which zinc might be effective. 4.4.3. VITAMIN A Vitamin A is essential for normal immune function (182) and several studies suggest it could play a role in potentiating resistance to malaria. Early studies in vitamin A-deﬁcient rats and mice showed an increased susceptibility to malaria that was readily reversed by supplementation (183,184). More recently, a genetic locus, which includes cellular retinol binding protein 1, has been shown to modulate malaria mortality and parasitaemia in mice (185). In vitro, addition of free retinol to P. falciparum cultures reduced parasite replication in one study (186), but not in another (187). In humans, the evidence for a protective role of vitamin A has been suggestive but equivocal. Although cross-sectional studies in preschool children and in adults have reported inverse associations between plasma vitamin A levels and P. falciparum parasitaemia (188–193), this may have been owing to an acute-phase response (188,191,191,193). One study observed that low baseline vitamin A status was associated with increased risk of parasitaemia, but confounding by age could not be excluded (194). Lastly, a substudy of a vitamin A trial in preschool children in Ghana reported no statistically signiﬁcant effects of vitamin A on P. falciparum morbidity or mortality (195). However, longitudinal surveillance of slide-conﬁrmed malaria morbidity was not conducted (196). The most deﬁnitive study to date of the effects of vitamin A on malaria was recently completed in Papua New Guinea (197). The study, a double-blind placebo-controlled trial, indicated that vitamin A supplementation reduced the frequency of P. falciparum episodes by 30% (95% CI 14–43, p = 0.0013) among preschool children. At the end of the study, geometric mean parasite density was 36% lower in the vitamin A than the placebo and the proportion of children with spleen enlargement was reduced by 11%, although neither difference was signiﬁcant. However, it was clear that children aged 12–36 mo beneﬁted most, having 35% (95% CI 14–50, p = 0.0023) fewer malaria attacks, 26% fewer enlarged spleens, and a 68% reduction in parasite density. 4.4.4. B VITAMINS 4.4.4.1. Folate. Folate deﬁciency can enhance susceptibility to avian malaria (198). In contrast, primate malaria species were unable to survive in severely folate-deﬁcient rhesus monkeys (199). In humans, low infection rates have been reported in pregnant women who were consuming a diet high in folates (200), and greater infection rates have also been reported in those suffering from megaloblastic anemia (201). However, malaria itself may induce folate deﬁciency (201–203), and some evidence exists suggesting improper red cell utilization of folates during malaria infection (204). A trial of prophylactic folate supplementation in preschool children in The Gambia (205) showed no adverse effects for malaria. And a trial of folate supplements in pregnant women (206) showed no adverse effect on parasitemia, even though reticulocyte counts did increase. Two separate trials reported that development of P. falciparum in vivo was not affected by folate supplements given with pyrimethamine (207,208). In one case, the folates were even given in doses sufﬁcient to reverse the side effects of high-dose primethamine (208). The routine use of folate supplements in malarious areas has, in fact, been advocated in the past (201,209). However, a

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more recent trial indicated greater treatment failure for pyrimethamine when folate supplements were given (210). 4.4.4.2. Riboﬂavin. Riboﬂavin status also inﬂuences malaria morbidity. The relationship appears to be one of antagonism such that deﬁciency confers a degree of protection. Reports from Papua New Guinea (211,212) indicated that riboﬂavin deﬁcient infants were less likely to be infected. Similar observation were made in India (213,214), and The Gambia (215). In India, clinical malaria was also less severe in riboﬂavin-deﬁcient individuals (216). Because riboﬂavin in an essential factor for the glutathione peroxidase, an anti-oxidative enzyme, it has been proposed that deﬁciency promotes an oxidative environment leading to destruction of the parasite. Indeed, lipid peroxidation was increased in riboﬂavin-deﬁcient children with malaria infection (217), and reduced glutathione peroxidase activity was observed in red cells from riboﬂavin-deﬁcient infected individuals (218). Consistent with this notion is the observation that reduced glutathione activity persists in some populations residing in malarious areas despite adequate riboﬂavin intake (219), suggesting that isoforms with reduced activity confer resistance to malaria. There is evidence for other mechanisms as well. P. falciparum-infected erythrocytes have an increased requirement for riboﬂavin (220). Moreover, riboﬂavin analogs inhibit the growth of parasites in vitro (221,222), and in vivo in experimental murine malaria (221). In some cases these activities also correlated with reduced activity of glutathione reductase (221). Riboﬂavin-deﬁcient rats are also more resistant to malaria (223). However, riboﬂavin-deﬁcient chicks are more susceptible (224). Interestingly, additional work in rats suggests that the protective effect was not owing to increased susceptibility of erythrocytes to oxidative damage, hemolysis, or erythropoesis (225). 4.4.4.1. Thiamin. Recent reports from Thailand indicate that poor thiamin status is associated with greater risk of severe malaria, and also simple clinical malaria (226). This is consistent with early experiments in which thiamin-deﬁcient ducks were more susceptible to avian malaria (227). There are also reports that acute cerebral ataxia following malaria can be treated with thiamin (228). 4.4.5. VITAMIN E AND OTHER ANTIOXIDANTS Several reports indicate that deﬁciencies of vitamin E and other antioxidants tend to protect against malaria infection (229). As discussed earlier, the absence of antioxidants makes the parasite more vulnerable to damage by oxygen radical produced by the immune system. In humans, it was initially proposed that the exacerbative effects on cerebral malaria following re-feeding of famine victims (75) with grain was owing to the vitamin E content of the grain that would be absent in the diet of those who received milk (230,231). The exacerbative effect of vitamin E on malaria was ﬁrst described by Godfrey (1957), who demonstrated that the anti-malaria effects of cod-liver oil in mice were reversible by giving vitamin E (232). Multiple studies in rodent systems conﬁrmed the protective effects of vitamin E deﬁciency (233–237) and the ability of vitamin E to abrogate the protective effects of pro-oxidant compounds, such as per-oxidizable fatty acids, on malaria (234–237). Interesting, however, was the observation that vitamin E deﬁciency was also protective against murine cerebral malaria (238), in which oxidative damage plays a signiﬁcant role. Studies of avian malaria in the duck also observed a protective effect of vitamin E deﬁciency (239).

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With regard to selenium, there are no human studies addressing the role of selenium in malaria. A few animal studies have been published and indicate that selenium has little role in modulating rodent malaria (240,241). However, selenium-deﬁcient ducks were more susceptible to avian malaria (239). Vitamin C also has been studied in animals, but little has been done in humans. Experiments in monkeys indicated that vitamin C deﬁciency exacerbated malaria (242). In mice, however, results have been mixed. Godfrey (1957) indicated that large doses of vitamin C, as with vitamin E, could abrogate the protective effect of cod-liver oil. This was not the case, however, when lower doses were used in conjunction with vitamin E-deﬁcient mice (229), nor did vitamin C supplements modify the course of parasitemia in normal mice. These data indicate that although anti-oxidant vitamins may have an exacerbative role under some conditions, it is difﬁcult to predict the effect of a nutrient on malaria based on its anti-oxidant properties alone. In addition, data are lacking for the effects of anti-oxidant nutrients in humans.

4. CONCLUSIONS AND RECOMMENDATIONS Malaria remains a very signiﬁcant public health problem throughout the tropical world. The future success of malaria control lies in the ability to implement multiple, effective interventions that are technologically and economically sustainable. The current focus on early detection and treatment, insecticide-treated bed nets, and vector control through environmental management are useful tools. There is also reason for optimism that a malaria vaccine with at least partially efﬁcacy will be available for endemic areas within the coming decade. This chapter has attempted to elucidate the strong role that nutrition plays in modulating malaria morbidity and mortality, and the potential that nutrient-based interventions might have in combating malaria. Indeed, given the clearly deleterious effects of poor nutritional status on malaria mortality, general improvements in dietary intake through improved childhood nutrition and economic development are likely to have a very large impact on reducing the disease burden of malaria. The observation that selective nutrient supplementation with vitamin A or zinc can substantially lower malaria attack rates suggest that targeted nutrient-based interventions can serve as useful adjuncts to malaria-control programs. At US $0.12 for a 1-yr supply (243), vitamin A supplementation would rank among the more cost-effective interventions for malaria (244). Moreover, both vitamin A and zinc supplementation have been demonstrated in several settings to reduce substantially morbidity from other infectious diseases (176,245,246). The effects of other nutrients also require examination as indicated by the recently reported predisposition to severe and uncomplicated malaria owing to thiamin deﬁciency (226). In general, low-cost, high-safety, and potential efﬁcacy of targeted nutritional supplementation or fortiﬁcation suggest that a rational approach to development of such interventions might prove useful for prevention or as adjunctive therapy for P. falciparum malaria. Other beneﬁts may also be gained. For example, nutrient supplementation may mitigate the delay in acquired immunity associated with bed nets (247) and chemoprophylaxis (154).

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Although there is reason for concern over an exacerbative effect of some nutrients on malaria morbidity, such as iron and certain anti-oxidants, available data do not justify withholding of supplementation from populations in need. Rather, an integrated approach to malaria control and nutritional improvement should be adopted. In addition, more detailed investigations should be undertaken to clarify the effects of speciﬁc nutrients on malaria morbidity. Efforts should be made to more carefully assess the role of nutrition and selective nutrients on malaria morbidity and also mortality. Although these should focus primarily on P. falciparum in Africa, other geographic areas should not be neglected. It is likely that investigations of the role of nutrition in P. vivax malaria will also prove informative. Speciﬁcally, there is a need for well-designed longitudinal and clinicbased studies to determine the mechanistic basis of how nutrients inﬂuence malaria immunity and pathology. Additional public health issues include examination of different nutritional requirements for adults and children with respect to malaria, and the speciﬁc physiology of malnutrition and malaria in severely malnourished individuals such as those encountered under famine conditions. It would also be useful to understand how malaria affects dietary intake, dietary patterns, and food beliefs surrounding malaria illness. Lastly, nutritional modulation of malaria morbidity and mortality highlights the complex nature of resistance to malaria. It is clear that different nutrients such as vitamin A, zinc, and iron selectively modify different aspects of malaria immunity and pathology. Study of these effects and their underlying mechanisms may yield important insight to host-parasite interactions, possibly leading to new therapies or vaccines.

REFERENCES 1. Krogstad DJ. Malaria as a re-emerging disease. Epidemiol Rev 1996; 18:77–79. 2. Bruce-Chwatt LJ. History of malaria from prehistory to eradication. In: Malaria: Principles and Practice of Malariology. Wernsdorfer WH, McGregor IA, eds. Edinburgh: Churchill Livingstone, 1988, pp. 1–69. 3. World Health Organization Expert Committee on Malaria. WHO Technical Report Series No. 357. Geneva: WHO, 1967. 4. WHO. Re-examination of the global strategy of malaria eradication. A report by the director general to the 22nd World Health Assembly. Geneva: WHO, 1969. 5. Krishna S. Science, medicine, and the future. Malaria. BMJ 1997; 315:730–732. 6. Binka FN, Kubaje A, Adjuik M, Williams LA, Lengeler C, Maude GH, et al. Impact of permethrin impregnated bednets on child mortality in Kassena-Nankana district, Ghana: a randomized controlled trial. Trop Med Intl Health 1996; 1:147–154. 7. Nevill CG, Some ES, Mung’ala VO, Mutemi W, New L, Marsh K, Lengeler C, Snow RW. Insecticidetreated bednets reduce mortality and severe morbidity from malaria among children on the Kenyan coast Trop Med Intl Health 1996; 1:139–146. 8. D’Alessandro U, Olaleye B, Langerock P, Bennett S, Cham K, Cham B, Greenwood BM. The Gambian National Impregnated Bednet Programme: evaluation of effectiveness by means of case-control studies. Trans R Soc Trop Med Hyg 1997;91:638–642. 9. Lengeler C. Insecticide treated bednets and curtains for malaria control. Cochrane Review. In: The Cochrane Library, Issue 4. Oxford: Update Software, 1998. 10. Clyde DF, Most H, McCarthy VC, Vanderberg JP. Immunization of man against sporozoite-induced falciparum malaria. Am J Med Sci 1973; 266:169–177. 11. Clyde DF. Immunization of man against falciparum and vivax malaria by use of attenuated sporozoites. Am J Trop Med Hyg 1975; 24:397–401. 12. Hoffman SL, Sherwood JA, Hollingdale MR, et al. Safety and efﬁcacy of a recombinant DNA Plasmodium falciparum sporozoite vaccine. Lancet 1987; 1: 1277–1281.

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174. Shankar AH, Fishman S, Goodman S, Stoltzfus RJ. The inﬂuence of iron supplementation on malaria morbidity: a meta-analysis of controlled trials. BMJ (in press). 175. Shankar AH, Prasad AS. Zinc and immune function: the biological basis of altered resistance to infection. Am J Clin Nutr 1998; 68:447S–463S. 176. Black RE. Therapeutic and preventive effects of zinc on serious childhood infectious diseases in developing countries. Am J Clin Nutr 1998; 68:476S–479S. 177. Good MF, Kaslow DC, Miller LH. Pathways and strategies for developing a malaria blood-stage vaccine. Ann Rev Immunol 1998; 16:57–87. 178. Gibson RS, Huddle JM. Suboptimal zinc status in pregnant Malawian women: its association with low intakes of poorly available zinc, frequent reproductive cycling, and malaria. Am J Clin Nutr 1998; 67:702–709. 179. Bates CJ, Evans PH, Dardenne M, et al. A trial of zinc supplementation in young rural Gambian children. Br J Nutr 1993; 69:243–255. 180. Shankar AH, Kumar N, Scott AL. Zinc-deﬁciency exacerbates experimental malaria infection in mice. FASEB J 1995; 9:A4269. 181. Arif AJ, Mathur PD, Chandra S, Singh C, Sen AB. Effect of zinc diet on xanthine oxidase activity of liver of mice infected with Plasmodium berghei. Indian J Malariol 1987; 24:59–63. 182. Semba RD. The role of vitamin A and related retinoids in immune function. Nutr Rev 1998; 56:S38–S48. 183. Krishnan S, Krishnan AD, Mustafa AS, Talwar GP, Ramalingaswami V. Effect of vitamin A and undernutrition on the susceptibility of rodents to a malarial parasite Plasmodium berghei. J Nutr 1976; 106:784–791. 184. Stoltzfus RJ, Jalal F, Harvey PWJ, Nesheim MC. Interactions between vitamin A deﬁciency and Plasmodium berghei infection in the rat. J Nutr 1989; 119:2030–2037. 185. Foote SJ, Burt RA, Baldwin TM, et al. Mouse loci for malaria-induced mortality and the control of parasitaemia. Nature Genet 1997; 17:380–381. 186. Davis TME, Skinner-Adam TS, Beilby J. In vitro growth inhibition of Plasmodium falciparum by retinol at concentrations present in normal human serum. Acta Trop 1998; 69:111–119. 187. Samba DC, Basco LK, Bleiberg-Daniel F, Lemmonier D, Le Bras J. Absence of effect of retinol on the in vitro development of Plasmodium falciparum. Intl J Vit Nutr Res 1992; 62:99–100. 188. Thurnham DI, Singkamani R. The acute phase response and vitamin A status in malaria. Trans R Soc Trop Med Hyg 1991; 85:194–199. 189. Galan P, Samba C, Luzeau R, Amedee-Manesme O. Vitamin A deficiency in pre-school age Congolese children during malarial attacks Part 2: impact of parasitic disease on vitamin A status. Intl J Vit Nutr Res 1990; 60:224–228. 190. Samba D, Luzeau R, Mourey MS, Amedee-Manesme O. Consequences de l’acces palustre sur les reserves vitaminiques A. Gastroenterol Clin Biol 1989; 13:A288. 191. Tabone MD, Muanza K, Lyagoubi M, et al. The role of interleukin-6 in vitamin A deﬁciency during Plasmodium falciparum malaria and possible consequences for vitamin A supplementation. Immunology 1992; 75:553–554. 192. Filteau SM, Morris SS, Abbott RA, et al. Inﬂuence of morbidity on serum retinol of children in a community-based study in northern Ghana. Am J Clin Nutr 1993; 58:192–197. 193. Friis H, Mwaniki D, Omondi B, et al. Serum retinol concentrations and Schistosoma mansoni, intestinal helminths, and malarial parasitemia: a cross-sectional study in Kenyan preschool and primary school children. Am J Clin Nutr 1997; 66:665–671. 194. Sturchler D, Tanner M, Hanck A, et al. A longitudinal study on relations of retinol with parasitic infections and the immune response in children of Kikwawila village, Tanzania. Acta Trop 1987; 44: 213–227. 195. Binka FN, Ross DA, Morris SS, et al. Vitamin A supplementation and childhood malaria in northern Ghana. Am J Clin Nutr 1995; 61:853–859. 196. Shankar AH. Vitamin A and malaria. Am J Clin Nutr 1995; 62:842–843. 197. Shankar AH, Genton B, Semba RD, et al. Effect of vitamin A supplementation on morbidity due to Plasmodium falciparum in young children in Papua New Guinea: a randomised trial. Lancet 1999; 354:203–209. 198. Seeler AO, Ott WH. Studies on nutrition and avian malaria. III. Deﬁciency of ‘folic acid’ and other unidentiﬁed factors. J Infect Dis 1945; 77:82–84.

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199. Das KC, Virdi JS, Herbert V. Survival of the dietarily deprived: folate deﬁciency protects against malaria in primates. Blood 1992; 80:281a. 200. Hamilton PJ, Gebbie DA, Wilks NE, Lothe F. The role of malaria, folic acid deficiency and haemoglobin AS in pregnancy at Mulago hospital. Trans R Soc Trop Med Hyg 1972; 66:594–602. 201. Fleming AF, Werblinska B. Anaemia in childhood in the quinea savanna of Nigeria. Ann Trop Paediatr 1982; 2:161–173. 202. Strickland GT, Kostinas JE. Folic acid deﬁciency complicating malaria. Am J Trop Med Hyg 1970; 19: 910–915. 203. Fleming AF, Hendrickse JP, Allan NC. The prevention of megaloblastic anaemia in pregnancy in Nigeria. J Obstet Gynaecol Br Commonwealth 1968; 75:425–432. 204. Brabin BJ, van den Berg H, Nijmeyer F. Folacin, cobalamin, and hematological status during pregnancy in rural Kenya: the inﬂuence of parity, gestation, and Plasmodium falciparum malaria. Am J Clin Nutr 1986; 43:803–815. 205. Fuller NJ, Bates CJ, Hayes RJ, et al. The effects of antimalarials and folate supplements on haematological indices and red cell folate levels in Gambian children. Ann Trop Paediatr 1988; 8: 61–67. 206. Gail K, Herms V. Inﬂuence of pteroylglutamic acid (folic acid) on parasite density (Plasmodium falciparum) in pregnant women in West Africa. Zeitschrift Tropenmed Parasitol 1969; 20:440–450. 207. Hurley MGD. Administration of pyrimenthamine with folic and folinic acids in human malaria. Trans R Soc Trop Med Hyg 1959; 53:410–411. 208. Tong MJ, Strickland GT, Votteri BA, Gunning J. Supplemental folates in the therapy of Plasmodium falciparum malaria. J Am Med Assoc 1970; 214:2330–2333. 209. Topley E. Anaemia where malaria is endemic. Trop Doctor 1975; 5:18–22. 210. van Hensbroek MB, Morris-Jones S, Meisner S, et al. Iron, but not folic acid, combined with effective antimalarial therapy promotes haematological recovery in African children after acute falciparum malaria. Trans R Soc Trop Med Hyg 1995; 89:672–676. 211. Oppenheimer SJ, Bull R, Thurnham DI. Riboﬂavin deﬁciency in Madang infants. Papua New Guinea Med J 1983; 26:17–20. 212. Thurnham DI, Oppenheimer SJ, Bull R. Riboﬂavin status and malaria in infants in Papua New Guinea. Trans R Soc Trop Med Hyg 1983; 77:423–424. 213. Dutta P, Pinto J, Rivlin R. Antimalarial effects of riboﬂavin deﬁciency. Lancet 1985; 2:1040–1043. 214. Thurnham DI. Antimalarial effects of riboﬂavin deﬁciency. Lancet 1985; 2:1310–1311. 215. Bates CJ, Powers HJ, Lamb WH, Anderson BB, Perry GM, Vullo C. Antimalarial effects of riboﬂavin deﬁciency. Lancet 1986; 1:329–330. 216. Das BS, Das DB, Satpathy RN, Patnaik JK, Bose TK. Riboﬂavin deﬁciency and severity of malaria. Eur J Clin Nutr 1988; 42:277–283. 217. Das BS, Thurnham DI, Patnaik JK, Das DB, Satpathy R, Bose TK. Increased plasma lipid peroxidation in riboﬂavin-deﬁcient, malaria-infected children. Am J Clin Nutr 1990; 51:859–863. 218. Barraviera B, Machado PE, Meira DA. Glutathione reductase activity and its relation with riboﬂavin levels measured by methemoglobin reduction by cystamine in patients with malaria (preliminary report). Rev Instit Med Trop Sao Paulo 1988; 30:107–108. 219. Anderson BB, Giuberti M, Perry GM, Salsini G, Casadio I, Vullo C. Low red blood cell glutathione reductase and pyridoxine phosphate oxidase activities not related to dietary riboﬂavin: selection by malaria? Am J Clin Nutr 1993; 57:666–672. 220. Dutta P. Enhanced uptake and metabolism of riboﬂavin in erythrocytes infected with Plasmodium falciparum. J Protozool 1991; 38:479–483. 221. Cowden WB, Clark IA. Antimalarial activity of synthetic riboﬂavin antagonists. Trans R Soc Trop Med Hyg 1987; 81:533. 222. Cowden WB, Butcher GA, Hunt NH, Clark IA, Yoneda F. Antimalarial activity of a riboﬂavin analog against Plasmodium vinckei in vivo and Plasmodium falciparum in vitro. Am J Trop Med Hyg 1987; 37:495–500. 223. Kaikai P, Thurnham DI. The inﬂuence of riboﬂavin deﬁciency on Plasmodium berghei infection in rats. Trans R Soc Trop Med Hyg 1983; 77:680–686. 224. Seeler AO, Ott WH. Effect of riboﬂavin deﬁciency on the course of Plasmodium Lophurae infection in chicks. J Infect Dis 1944; 75:175–178. 225. Dutta P, Gee M, Rivlin RS, Pinto J. Riboﬂavin deﬁciency and glutathione metabolism in rats: possible mechanisms underlying altered responses to hemolytic stimuli. J Nutr 1988; 118:1149–1157.

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226. Krishna S, Taylor AM, Supanaranond W, et al. Thiamine deﬁciency and malaria in adults from southeast Asia. Lancet 1999; 353:546–549. 227. Ramo Rao R, Sirsi N. Avian malaria and B complex vitamins. I. Thiamine. J Indian Instit Sci 1956; 38:108. 228. Adamolekun B, Eniola A. Thiamine-responsive acute cerebellar ataxia following febrile illness. Cent Afr J Med 1993; 39:40–41. 229. Levander OA, Ager JrAL. Malarial parasites and antioxidant nutrients. Parasitology 1993; 107: S95–S106. 230. Kretschmar W. The importance of p-aminobenzoic acid to the course and immunity of malaria in animals (Plasmodium berghei) and in man (Plasmodium falciparum). 2. Studies on naturally fed small children. Zeitschrift Tropenmedizin und Parasitologie 1966; 17:369–374. 231. Eaton JW, Eckman JR, Berger E, Jacob HS. Suppression of malaria infection by oxidant-sensitive host erythrocytes. Nature 1976; 264:758–760. 232. Godfrey DG. Antiparasitic action of dietary cod liver oil upon Plasmodium berghei and its reversal by vitamin E. Exp Parasitol 1957; 6:555–565. 233. Eckman JR, Eaton JW, Berger E, Jacob HS. Role of vitamin E in regulating malaria expression. Trans Assoc Am Physicians 1976; 89:105–115. 234. Levander OA, Ager Jr. AL, Morris VC, May RG. Menhaden-ﬁsh oil in a vitamin E-deﬁcient diet: protection against chloroquine-resistant malaria in mice. Am J Clin Nutr 1989; 50:1237–1239. 235. Levander OA, Ager Jr. AL, Morris VC, May RG. Plasmodium yoelii: comparative antimalarial activities of dietary ﬁsh oils and ﬁsh oil concentrates in vitamin E-deﬁcient mice. Exp Parasitol 1990; 70:323–329. 236. Levander OA, Ager Jr. AL, Morris VC, May RG. Protective effect of ground ﬂaxseed or ethyl linolenate in a vitamin E-deﬁcient diet against murine malaria. Nutr Res 1991; 11:941–948. 237. Taylor DW, Levander OA, Krishna VR, Evans CB, Morris VC, Barta JR. Vitamin E-deﬁcient diets enriched with ﬁsh oil suppress lethal Plasmodium yoelii infections in athymic and scid/bg mice. Infect Immun 1997; 65:197–202. 238. Levander OA, Fontela R, Morris VC, Ager JrAL. Protection against murine cerebral malaria by dietary-induced oxidative stress. J Parasitol 1995; 81:99–103. 239. Yarrington JT, Whitehair CK, Corwin RM. Vitamin E - selenium deﬁciency and its inﬂuence on avian malarial infection in the duck. J Nutr 1973; 103:231–241. 240. Levander OA. Selenium and sulfur in antioxidant protective systems: relationships with vitamin E and malaria. Proc Soc Exp Biol Med 1992; 200:255–259. 241. Levander OA, Ager Jr. AL, Morris VC, May RG. Qinghaosu, dietary vitamin E, selenium, and cod-liver oil: effect on the susceptibility of mice to the malarial parasite Plasmodium yoelii. Am J Clin Nutr 1989; 50:346–352. 242. McKee RW, Geiman QM. Studies on malarial parasites. V. Effects of ascorbic acid on malaria (Plasmodium knowlesi) in monkeys. Proc Soc Exp Biol Med 1946; 63:313–315. 243. West KPJr. Vitamin A deﬁciency: its epidemiology and relation to child mortality and morbidity. In: Blomhoff R (ed.) Vitamin A in Health and Disease. New York, Marcel Dekker, 1994; pp. 585–614. 244. Graves PM. Comparison of the cost-effectiveness of vaccines and insecticide impregnation of mosquito nets for the prevention of malaria. Ann Trop Med Parasitol 1998; 92:399–410. 245. Sazawal S, Black R, Jalla S, Bhan MK, Bhandari N, Sinha A. Zinc supplementation in young children with acute diarrhea in India. New Engl J Med 1995; 333:839–844. 246. Sazawal S, Black R, Jalla S, Mazumdar S, Sinha A, Bhan MK. Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind controlled trial. Pediatrics 1998; 102:1–5. 247. Snow RW, Omumbo JA, Lowe B, et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349:1650–1654.

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Tuberculosis Christopher Whalen and Richard D. Semba

1. INTRODUCTION 1.1. Deﬁnitions Tuberculosis is an infection caused by Mycobacterium tuberculosis or related organisms such as Mycobacterium bovis. M. tuberculosis, a slow-growing, acid-faststaining bacillus, is the most common cause of tuberculosis in man and will be the focus of this chapter. Tuberculosis is most commonly transmitted from person to person via the aerial route, and most individuals who are infected do not develop clinical disease. About 5% of those infected may develop clinical manifestations such as pulmonary or miliary disease, and disease may occur at the time of primary infection or may occur years later. Malnutrition and other immunosuppressive disorders such as human immunodeﬁciency virus (HIV) infection increase the risk of developing clinical disease (Fig. 1). In the absence of effective chemotherapy, tuberculosis is characterized by wasting and high mortality. The association of poor nutrition with tuberculosis is evident in older terms for tuberculosis such as the Greek term “phthisis” or “to waste away” and “consumption.”

1.2. Public Health Importance Worldwide, tuberculosis is the leading infectious cause of death, accounting for 3 million deaths annually. About one-third of the world’s population, or 1.8 billion individuals, are infected with M. tuberculosis, representing an enormous pool of individuals at risk for development of future disease (1). In sub-Saharan Africa, the Indian subcontinent, and southeast Asia, half or more of adults have latent tuberculosis infection. Each year, between 7 and 8 million people throughout the world develop active tuberculosis, and the vast majority of cases occur in sub-Saharan Africa and Asia. Tuberculosis is responsible for about one-quarter of all preventable deaths in developing countries, and many of these deaths are associated with underlying HIV infection. The current global situation of tuberculosis is complicated by three factors: the evolving pandemic of HIV type 1, the emergence of multi-drug resistant tuberculosis, and the increased mobility of populations. The epidemics of tuberculosis and HIV overlap in many regions of the world, especially in sub-Saharan Africa, and the potential From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Fig. 1. General model for tuberculosis infection and common risk factors.

of the disease to spread is enormous, especially in Asia where the HIV epidemic is growing rapidly (2). Multidrug-resistant tuberculosis represents a major threat to the global control of tuberculosis, and a recent global survey indicates that drug-resistant strains are being transmitted in every continent (3). On both local and global levels, the mixing of potential or infectious cases of tuberculosis within populations of susceptible individuals has increased because of greater mobility in a modern world (4,5). War, political strife, famine, poverty, and refugee crises render the control of tuberculosis even more intractable.

2. HISTORICAL BACKGROUND 2.1. Antiquity Tuberculosis has been described from the mummiﬁed remains of a priest who lived 3,000 years ago in the Twenty-First Dynasty of ancient Egypt (6,7), and the disease has also been found in mummiﬁed remains of a child from pre-Columbian Peru (8). A clinical description consistent with pulmonary tuberculosis appears in Epidemics III of the Hippocratic corpus from the 5th century, BC (9). The terms “phthisis,” “tabes,” and “marasmus” were used to describe diseases characterized by emaciation, including tuberculosis, and in Greek derivation these terms are close in signifying wasting

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away, weakness, and decay. Tuberculosis is mentioned by many medical writers from antiquity. Aretaeus the Cappadocian (81–?138 AD) provided a detailed description of advanced tuberculosis, and he recommended a generous diet of fresh eggs and milk as treatment (10). In classical Rome, Galen (130–200 AD) suggested that patients take ass’ milk as a treatment for tuberculosis (11).

2.2. Early Ideas About Tuberculosis During the middle ages, scrofula (tuberculosis of the lymph glands of the neck) became known as “the King’s Evil,” because kings were thought to have the power to cure the condition by touching afﬂicted individuals (12,13). Scrofula and pulmonary tuberculosis were generally considered to be separate illnesses. Different forms of consumption were described by Richard Morton (1635–1698) in Phthisiologia: or a Treatise of Consumptions, and pulmonary consumption was considered a distinct entity, characterized by wasting, fever, and a dry, nonproductive cough that later became purulent. “Exulceration” was a process of coughing up material that resulted in cavities in the lung (14). In the 18th century, the nosology, or classiﬁcation of disease, emerged as an important approach, and it was largely inﬂuenced by the Linnaean system for the taxonomy of plants. Thus, diseases could be classiﬁed according to their symptoms. William Cullen (1710–1790), a physician in Scotland, devised a well-known classiﬁcation of diseases in which “phthisis” was deﬁned as a hectic fever accompanied by the expectoration of purulent matter from the lungs (15). Wasting was not part of Cullen’s deﬁnition of phthisis. Phthisis could arise from “acrimony” in the blood, which could produce tubercles and then ulceration; symptoms followed. An interpretation of clinical observations of tuberculosis by Morton and Cullen have been presented in detail elsewhere (16). The Paris Medical School was pre-eminent in Europe during the early half of the 19th century, when medical knowledge became based on an integration of direct clinical observation of large numbers of patients with detailed postmortem examinations of those who had died (17,18). Instead of viewing phthisis as a rather sudden presentation of illness, Gaspard-Laurent Bayle (1774–1816) considered phthisis to be a process in which different stages led to destruction of the lungs (19). The invention of the stethoscope by René-Théophile-Hyacinthe Laennec (1781–1826) allowed inference about abnormalities inside the chest and correlation with other clinical ﬁndings. In Traité de l’auscultation médiate of 1819, Laennec used the term phthisis to refer to destructive diseases of the lung that were associated with the tubercle (20). Towards the mid-19th century, a dominant idea in cell theory was that cells, with nucleus and outer membrane, could grow out of blastema, or morbid secretions (21). Thus, blastema gave rise to tubercle formation. Advances in microscopy and more precise observations led Rudolf Virchow (1821–1902), a German pathologist, to refute the blastema theory and to conclude that exudation did not give rise to new cells, but that cells arose out of preexisting cells, or “omnis cellula e cellula” (each cell from a cell). Virchow considered that caseation, or formation of cheese-like masses, i.e. the tubercle, was the result of cellular transformation, and that it was not speciﬁc for phthisis alone, occurring in cancer and suppuration as well. In Virchow’s view, scrofula resulted from a weakness of the mother tissue—a constitutional predisposition—where cells went to pieces more easily.

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2.3. Tuberculosis as an Infectious Disease The idea that tuberculosis could be caused by a speciﬁc infectious agent was pursued by Jean-Antoine Villemin (1827–1892). Other diseases such as syphilis, smallpox, and glanders appeared to be caused by speciﬁc infectious agents. Villemin demonstrated that caseous material and tubercles from human could cause tuberculosis in rabbits. He performed other experiments showing that sputum and bronchial secretions were also infectious in nature (22), and he concluded that tuberculosis was a transmissible disease. Robert Koch (1843–1910), a German physician, conducted microscopic studies that led to the description of the tubercle bacillus (23). Koch devised a new staining technique that allowed the detection of rod-shaped bacteria in affected tissues, and he was able to grow the bacteria in artiﬁcial culture media. The pure culture, when injected into an animal host, resulted in tuberculosis. Koch later described a phenomenon in which an extract of tuberculosis injected in the skin could differentiate between a previously infected and uninfected animal, leading eventually to the development of the tuberculin skin test (24). Koch’s reputation suffered greatly when he claimed that tuberculin, an extract of tubercle bacilli, could cure tuberculosis. Therapies for the treatment of tuberculosis in the 18th century included fresh air, which was thought to aid the healing and closing of cavities and ulcers in the lungs (25). Moving to warmer climates and long sea voyages were sought by some afﬂicted with tuberculosis (26). In Europe, the Swiss Alps became a popular destination for those seeking a cure in the latter half of the 19th century. The sanatorium became a prominent approach to tuberculosis treatment, and this institutionalized care, usually in sunny, rural locations, included fresh air, rest, regulated exercise, and supervised diet (26,27). Sunlight exposure, sea bathing, and radiation with ultraviolet light were also advocated for treatment of tuberculosis (28). Collapse therapy of the lung (artiﬁcial pneumothorax) was used to treat pulmonary tuberculosis (29).

2.4. COD-LIVER OIL THERAPY The use of cod-liver oil deserves special mention in regard to nutrition and tuberculosis. In the 18th and 19th centuries in European cities, tuberculosis was widespread and the cause of 25% of all adult deaths (30). During the early 19th century, the survival in adults with pulmonary tuberculosis was 2 yr from the time of diagnosis, and no therapy was effective (31). The therapy for tuberculosis was considered to have changed dramatically with the introduction of cod-liver oil (32). Cod-liver oil is a rich source of vitamins A and D and was long known as having medicinal properties in fishing villages along the North Sea and in Norway. The use of cod-liver oil as a treatment for tuberculosis spread to Germany (33) and France (34). After the introduction of cod-liver oil at Brompton Hospital, the main hospital for tuberculosis in London, using historical controls, the survival rate increased fourfold from an average two years to eight years after diagnosis (31). Cod-liver oil consumption at Brompton Hospital alone reached 1,500 gallons per year (35), and in addition to a decrease in mortality, weight gain was typically observed among those treated with cod-liver oil (36). From 1820 until 1920, there are numerous reports of clinical improvement in pulmonary and lymphatic tuberculosis with cod-liver oil therapy (37). In an early trial of cod-liver oil for adults with pulmonary tuberculosis complicated by intestinal

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involvement, 28 cases received symptomatic treatment only and 50 cases were treated with cod-liver oil. Adults treated with cod-liver oil had a steady gain in weight, whereas adults in the control group had a continual loss of weight in 50 wk of follow-up, with 10% mortality reported in the cod-liver oil treatment group vs 71% mortality in those receiving symptomatic treatment (38). During the tuberculosis sanitarium movement in the United States in the early part of this century, cod-liver oil was often used as treatment. Cod-liver oil therapy for tuberculosis was largely superceded by antibiotic treatment in the 1940s, and in general, scientiﬁc interest in nutritional status and tuberculosis waned. Dietetic management of tuberculosis continued to include an “eggs and milk” approach in the 1940s and 1950s (39) and later an emphasis on high protein intake (40). Because of the later emphasis on tuberculosis chemotherapy, most reports on the relationship between nutritional status and tuberculosis largely antedate 1950.

2.5. Bacilli Calmette-Guérin Vaccine and Tuberculosis Chemotherapy At the Pasteur Institute, efforts were made by Léon Charles Albert Calmette (1863–1933) and Camille Guérin (1872–1961) to develop a vaccine against tuberculosis. An attenuated strain of bovine tubercle bacilli, Bacilli Calmette-Guérin (BCG), was found to have a protective effect in calves, and later this vaccine, known as BCG, was tried in infants (41). BCG vaccine was eventually accepted by many countries around the world and was recommended by the World Health Organization (WHO) as part of tuberculosis control (42), however, the vaccine was not adopted in the United States, despite evidence for efﬁcacy of the vaccine (43,44). The United States remains one of the few countries where BCG vaccine is not given to people as the standard of care for tuberculosis control. Streptomycin was isolated in the laboratory of Selman Waksman (1888–1973), a Russian soil microbiologist who had migrated to the United States. A preliminary trial suggested that it could be effective against tuberculosis (45), and a large controlled, clinical trial was conducted by the British Medical Research Council, which provided definitive evidence that streptomycin was an effective treatment for pulmonary tuberculosis (46). A similar effort to evaluate streptomycin through a clinical trial at the Veteran’s Administration in the United States failed to provide persuasive therapeutic evidence because investigators abandoned the use of an untreated control group for comparison, delaying recommendations for more widespread use of the drug (47). In the 1950s, isonicotinic acid hydrazide, or isoniazid, emerged as a new treatment for tuberculosis (48), and soon multiple therapy was initiated to treat tuberculosis and reduce the chance of drug resistance.

2.6. THE DECLINE OF TUBERCULOSIS IN INDUSTRIALIZED COUNTRIES In the latter half of the 19th century and through the ﬁrst half of the 20th century, mortality rates from pulmonary tuberculosis were steadily declining in England and Wales (Fig. 2). Thomas McKeown (1912–1988) hypothesized that the decline in tuberculosis mortality was largely the result of improvements in standards of living and nutrition, rather than advances in medicine, such as antibiotics (49,50). Others have argued that government sanitary reforms and isolation of individuals with tuberculosis

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Fig. 2. Case-fatality rates for tuberculosis. Adapted with permission from McKeown (49).

accounted for the decline in the disease. Tuberculosis often affects populations where poverty, inadequate housing, crowding, alcoholism, poor diet, and bad hygiene are present, and the decline of tuberculosis probably occurred because of a combination of factors, many of which are difﬁcult to disentangle from historical epidemiology (51). For further reading, general histories of tuberculosis can be found in older, standard texts, most of which have a medical orientation and celebrate medical men and scientiﬁc progress through great discoveries (52–55), and in other texts which are more accessible to the general reader (56,57). The social history of tuberculosis in the United States (58,59), France (51), Great Britain (27), and Japan (60) are discussed in other texts.

3. EPIDEMIOLOGY 3.1. Geographic Distribution Tuberculosis is distributed throughout the world, but the main burden of tuberculosis infection and disease in found in developing countries. During the 1990s, Africa and Asia had the highest prevalence of both tuberculous infection and active tuberculosis. The prevalence of tuberculosis ranges from 26% in the Americas to 44% in the Western Paciﬁc. The annual risk of infection, a marker of M. tuberculosis transmission (61) is estimated at 1–2%/yr (62). Similarly for active tuberculosis, the annual global incidence has increased from 62 cases/100,000 population in the 1980s to 75 cases/100,000 population in the 1990s (1). The greatest increase in incidence has occurred in Asia, where the annual incidence has changed from 115 cases/100,000 population to 148 cases/100,000 population between 1985 and 1995, an increase of 25%. Africa had the second highest increase in tuberculosis incidence in this period, rising 19% with an average incidence of 80 cases/100,000 population. Asia and Africa now account for 75% of the tuberculosis cases worldwide (1).

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3.2. High-Risk Groups and Risk Factors In considering the epidemiology of tuberculosis, it is useful to separate the risk of acquiring infection from the risk of developing active disease. The risks for infection relate to the probability of contact with an infected case, whereas the risk for developing disease once infected relate to the success of the host immune response in containing the infection. Groups at high risk for infection include close contacts of infectious cases (63), individuals living in congregate settings such as prisons (64), homeless (65), nursing homes (66), recent immigrants from countries where the prevalence of tuberculosis is high, and medically underserved or marginalized populations. In addition, individuals with a recent tuberculin skin test conversion from negative to positive are at risk for early progression of disease. Once infected, an individual has about a 10% lifetime risk of developing active tuberculosis. Some recently infected individuals fail to contain the initial infection and progress to develop active tuberculosis, a situation known as progressive primary disease. Other individuals successfully contain the initial infection, become latently infected for a prolonged period of time, and then develop active disease years to decades after the infection (67,68). Common conditions associated with the risk of developing active tuberculosis are diseases associated with immunosuppression such as HIV infection, measles, and malnutrition. Other conditions associated with the reactivation of tuberculosis include ﬁbrotic lung lesions consistent with previous untreated pulmonary tuberculosis, lymphoma, prolonged immunosuppressive therapy (e.g., corticosteroids), head and neck cancers, insulin-dependent diabetes mellitus, and end-stage renal disease. Host nutritional status may inﬂuence the risk of an infected individual developing active tuberculosis, as discussed in a following section.

3.4. Incidence and Prevalence of Tuberculosis in Vulnerable Populations 3.4.1. HIV INFECTION HIV infection confers the greatest known risk for the development of both progressive primary disease and reactivation tuberculosis. Among patients with advanced HIV disease, recent infection progresses to disease within 6 mo in 30–40% of patients (68). Among individuals with a reactive tuberculin skin test, deﬁned as 5 mm or greater induration, the risk of disease depends on the population involved. In cohort studies of injection drug users, the risk is high, about 7–12%/yr (69). In Africa, the risk ranges from 3–8 cases per 100 person-years of observation (70,71). The risk of tuberculosis among tuberculin negative persons in lower. Among HIV-infected individuals with cutaneous anergy to tuberculin and other skin-test antigens (e.g., candida, mumps, tetanus), there appears to be an increased risk for developing active tuberculosis (72). In sub-Saharan Africa, the seroprevalence rates of HIV infection in adults with tuberculosis range from 20–67% (2), and higher seroprevalence rates of HIV occur among children (73,74). 3.4.2. CHILDREN Children younger than 5 yr of age are particularly susceptible to tuberculosis, particularly disseminated forms of disease. In most instances, children are exposed to an infectious parent or relative through household contact. This exposure leads to an initial tuberculous infection in over one-half of contacts. The attack rate for active tuberculosis in children who are contacts is high, estimated to be 25% within 5 yr of

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the exposure (75) or 400 cases/100,000 population for children less than 5 yr old (67). The risk for developing tuberculosis declines to minimal levels among adolescents until puberty, when the risk again increases. 3.4.3. OLDER ADULTS Older adults represent another group at risk for the development of tuberculosis. Active tuberculosis in this population most likely represents reactivation of remote tuberculous infetions. In the United States, the average rates of tuberculosis are about three times higher in older adults compared to the national average (21.5 vs 7.4 cases/100,000 population, respectively). Moreoever, even today in the United States, tuberculosis among persons older than 65 yr of age accounts for 24% of the total cases of tuberculosis. Older age has also been associated with increased mortality. Tuberculosis in the elderly is an important problem because of the potential for transmission in nursing homes. Tuberculosis incidence rates are 39 cases/100,000 population in nursing homes vs 21 cases/100,00 population in the community. It is likely that nursing homes represent sites for ongoing transmission, not only to other residents of the home but to health-care providers. Another high risk situation for the transmission of tuberculosis occurs where older grandparents live together with young children under age 5 in extended family households. 3.4.4. OTHER POPULATIONS AT RISK Other populations at high risk for tuberculosis include some minority groups, the homeless, foreign-born immigrants from countries where the prevalence of tuberculosis is high, and prisoners. At-risk minority populations comprise 70% of the tuberculosis cases in the United States. Compared to the rate in non-Hispanic Whites, the incidence rates in Asians is 10 times greater, in non-Hispanic Blacks 8 times greater, and in Hispanics and Native Americans 5 times greater (76). The homeless are a difﬁcult group to track and make accurate estimates of incidence, however, the prevalence of tuberculosis in these individuals is high. In a study from New York city, 43% of men in a homeless shelter over a 5-yr period had latent tuberculous infection and 6% had active tuberculosis (77). Prisoners have an incidence rate for tuberculosis that is 10 times the general population, with rates that range from 90 cases/100,000 inmates to 184 cases/100,000 inmates (78). Foreign-born individuals residing in the United States comprise a disproportionate number of tuberculosis cases in the United States and accounted for 60% of the excess tuberculosis cases observed between 1985 and 1995 (79). The incidence rates among foreign-born in the United States depend on the country of origin and range from 12 cases to 177 cases/100,000 population (80), with countries of origin with the highest rates from Asia, Haiti, and sub-Saharan Africa.

3.5. Drug-Resistant Tuberculosis Within months of the ﬁrst use of streptomycin for the treatment of tuberculosis, drug-resistant strains of M. tuberculosis emerged. The development of drug resistance to a single drug was a harbinger of events to come as new antituberculous drugs were introduced into practice. The use of multiple drugs in the treatment regimen for tuberculosis prevented the emergence of drug-resistant strains (81) and has become the standard practice in treated active disease. Despite the standard multidrug treatment regimens, multidrug resistant strains of M. tuberculosis have emerged, best documented

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in well-studied outbreaks of tuberculosis in the United States during the early 1990s. The emergence of drug resistance is directly related to previous treatment for tuberculosis, whether through improper regimens, inadequate treatment, and incomplete adherence (82). A nationwide survey in the United States in indicated that resistance to one or more antituberculous drugs was present in 14% of cases and resistance to both isoniazid and rifampin, the two most potent antituberculous drugs currently available, was present in 3.5% of specimens tests (83). The problem of drug-resistant tuberculosis is a global problem, as a recent survey conducted by the WHO of 35 countries throughout the world indicated that all countries reported cases of resistant tuberculosis (3). Approximately 10% of strains tested were resistant to one or more antituberculous medications. The treatment and management of drug-resistant tuberculosis is one of the greatest challenges of the future facing tuberculosis-control programs.

4. CLINICAL FEATURES/PATHOPHYSIOLOGY 4.1. Clinical Features of Tuberculosis Tuberculosis is a disease produced by chronic infection with M. tuberculosis. The spectrum of disease ranges from asymptomatic latent tuberculous infection to disseminated disease. The most common form of tuberculosis is latent infection. The only way to make the diagnosis of latent tuberculous infection is through tuberculin skin testing. An individual with latent tuberculous infection will generally have a positive tuberculin skin test. Active tuberculosis, the form of disease that disrupts normal host physiology to produce symptoms, is generally classiﬁed as pulmonary or extrapulmonary disease. Pulmonary disease is the most common form of active tuberculosis, accounting for about 80% of cases. Cough is the most common symptom associated with pulmonary tuberculosis, occurring in over 95% of cases. The cough is usually chronic, lasting more than 1 mo, and it is most often productive of sputum. Occasionally hemoptysis (coughing up blood), dyspnea (shortness of breath), and chest pain develop. Other constitutional symptoms include fevers, night sweats, and weight loss. The physical examination for tuberculosis is nonspeciﬁc, but common ﬁndings include inanition and abnormal breath sounds in the affected parts of the lung. The chest radiograph is often used to conﬁrm the presence and assess the extent of disease. Inﬁltrates are nearly universal and cavitary lesions, usually in the upper lung segments, are often found, particularly in reactivation of latent infection. Extrapulmonary disease accounts for about 20% of active tuberculosis cases. Although almost any site can be affected by tuberculosis, the most common extrapulmomary sites are the lymph nodes (most often the cervical lymph nodes), pleura, kidneys, meninges, and bone or joints. The diagnosis of tuberculosis at these sites requires a high level of clinical suspicion and proper diagnostic specimens taken for acid-fast staining, mycobacterial culture, and histopathology. Even as the incidence of pulmonary tuberculosis was declining in the United States, the rate of extrapulmonary disease remained constant. With the HIV epidemic, the proportion of extrapulmonary tuberculosis increased, as HIV-infected individuals are more susceptible to extrapulmonary disease.

4.2. Pathophysiology M. tuberculosis is transmitted through the airborne route from infectious cases to susceptible contacts. An infected individual will cough and produce an aerosol of tiny

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droplet particles that contain live M. tuberculosis. When these particles are inhaled by a susceptible contact, they impact deep in the lung parenchyma in the alveoli. The initial interaction between the host immune system and M. tuberculosis occurs in the alveoli where pulmonary macrophages engulf, process, and present mycobacterial antigens in conjunction with MHC class II molecules. When the complex of mycobacterial antigen and MHC molecule is recognized by antigen-speciﬁc CD4 lymphocytes, the CD4 lymphocytes release interferon-a (IFN-a) and interleukin-2 (IL-2). The INF-a serves to activate macrophages and enhance their ability to contain mycobacteria. This response is regulated, in part, by IL-12, which induces differentiation of Th-1 cells and augments the release of INF-a from the T lymphocytes (84). The activated macrophages release a number of cytokines including tumor necrosis factor-_ (TNF-_) (85), IL-1 (86), and IL-6 (87) that are responsible for the recruitment of cells to the site of infection, formation of granuloma, and development of the delayed-type hypersensitivity response. This process is downregulated by effects of monocytederived transforming growth factor-` (TGF-`) and IL-10 on CD4 lymphocytes (88,89). Within this network of cytokines, TNF-_ appears to play a more central role in the pathogenesis of tuberculosis. TNF-_ is essential for granuloma formation (90) and activates macrophage clearance of the organism. Further, proteins and polysaccharides of M. tuberculosis stimulate mononuclear phagocytes to express TNF-_ as well as other cytokines (91). Overexpression of TNF-_ also appears to be responsible for many of the systemic signs and morbidity of tuberculosis, such as fever, night sweats, and cachexia.

4.3. Role of Nutrition 4.3.1 PROTEIN AND ENERGY STATUS Malnutrition is well known among adults with tuberculosis. In adults with pulmonary tuberculosis in Malawi, weight, mid-upper arm circumference (MUAC), and serum albumin were lower than controls upon admission to the hospital, and these nutritional indices improved during treatment with effective chemotherapy, irrespective of clinical, nutritional, and radiographic features of tuberculosis upon admission (92,93). A study of nutritional status in 148 adults with smear-positive pulmonary tuberculosis in Tanzania showed that 77% of males and 58% of females had a body mass index (BMI) <18.5 upon admission (94). In general, adults gained weight during 6 mo of treatment with chemotherapy, but weight was lost after treatment had ﬁnished. The length of stay in the hospital was the primary determinant of weight gain in patients on chemotherapy, suggesting that nutritional intake in the hospital was better than could be achieved at home. Progressive nutritional recovery generally occurs during tuberculosis chemotherapy, however, serum albumin levels and mean arm muscle circumference have been reported as subnormal after 12 mo, suggesting that body protein reserves may not be fully recovered during treatment (95). Measurements of [13C]leucine ﬂux suggest that there is altered amino-acid metabolism in adults with tuberculosis, and this abnormality, or “anabolic block,” may contribute to wasting in tuberculosis despite nutritional support (96). In adults with pulmonary tuberculosis who developed respiratory failure, serum albumin and hemoglobin were strong predictors of survival (97). Body-composition studies suggest that body cell mass is relatively depleted in adults with tuberculosis and HIV infection (98).

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Less is known about nutritional status in children with tuberculosis. Children with severe protein energy malnutrition (PEM) are at a higher risk of developing tuberculosis (99). A study of children with pneumonia in The Gambia suggests that M. tuberculosis is not an uncommon cause of pneumonia, especially among children who are malnourished (100). In Bulawayo, Zimbabwe, an autopsy series of 184 children under age 5 who died at home showed that tuberculosis was present in 4%, and all of the children who died with tuberculosis had marasmus (101). Experimental animal studies show that protein-calorie malnutrition (PCM) has a marked effect on resistance to tuberculosis. Malnourished mice infected with M. tuberculosis had a fatal course of infection, and immunological abnormalities included tissue-speciﬁc decreases in expression of interferon a (INF-a), TNF-_, and nitric oxide synthetase (NOS) (102). Restoration of a full protein diet could reverse the fatal course of tuberculosis in malnourished mice. Skin sensitivity to puriﬁed protein derivative (PPD) and lymphocyte proliferation was not affected by protein and calorie restriction in cattle infected with M. bovis, however, alterations in the number of circulating CD2+, CD8+, and ab T cells was noted in the malnourished cattle (103). In a guinea-pig model, animals on a protein-restricted diet were vaccinated with M. bovis BCG vaccine and then infected via the respiratory route with virulent M. tuberculosis. Protein deﬁciency was associated with loss of tuberculin skin sensitivity, reduced lymphocyte proliferation responses to mycobacterial antigens, decreased IL-2 production, and reduced CD2+ lymphocytes in the thymus and peripheral blood (104,105). 4.3.2. VITAMIN A Clinic-based studies using different indicators of vitamin A status suggest that vitamin A deﬁciency is not uncommon among adults and children with tuberculosis. Low circulating vitamin A levels (106–109), depleted hepatic stores of vitamin A (110,111), and night blindness (112,113) have been described in adults with tuberculosis. In a large study of children from Cebu Island in the Philippines, xerophthalmia was associated with tuberculosis (114). Factors that may contribute to the development of vitamin A deﬁciency during tuberculosis include decreased dietary intake of vitamin A, impaired absorption of vitamin A (115), increased utilization of vitamin A during infection, and abnormal losses of vitamin A in the urine. Low serum vitamin A levels have been described in adults with tuberculosis and HIV infection in Rwanda (116). Animal studies suggest that vitamin A deﬁciency decreases resistance to experimental infection with M. tuberculosis. Early studies demonstrated that cod-liver oil had some impact on experimental tuberculosis in animals, such as dissemination of disease (117–119). Among animal inoculated with virulent tubercle bacilli, mortality was higher among vitamin A-deﬁcient rats than rats on a normal diet (120); more severe infection and extensive lesions have been noted in such animals on histopathology compared with control rats (121). In addition, rats given adequate vitamin A but restricted in protein or calories were not more susceptible to experimental tuberculosis infection, suggesting that increased susceptibility to tuberculosis was attributable to lack of vitamin A rather than PEM. An accelerated course of tuberculosis has been reported in vitamin A-deﬁcient rats (122). Vitamin A-deﬁcient mice have a more severe infection with M. bovis compared with mice supplemented with dietary `-carotene (123). Chicks on a high vitamin A diet had 26% increased survival compared with chicks on a normal diet following experimental infection with M. tuberculosis (124).

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In pigs experimentally infected with tuberculosis, those receiving cod-liver oil had greater weight gain and more limited tuberculous histopathology compared with pigs not receiving cod-liver oil (125). In vitro studies with cell lines and animal studies suggest that vitamin A and its active metabolites may inﬂuence immunological responses to tuberculosis. Dietary vitamin A enhances T-cell proliferation responses and antibody responses to M. tuberculosis antigen in the chick model (126). All-trans retinoic acid inhibits the multiplication of virulent M. tuberculosis in cultured human macrophages (127). Defective production of IL-2 has been implicated in anergy to PPD and disseminated tuberculosis (84). Vitamin A has been shown to enhance IL-2 production by activated T-cells (128,129), and vitamin A-supplemented mice challenged with M. bovis and treated with IL-2 have stronger delayed type hypersensitivity (DTH) responses and proliferation responses to PPD compared with control mice without supplementary vitamin A (130). 4.3.3. VITAMIN D It has been postulated that vitamin D deﬁciency is associated with tuberculosis (131). Unlike other respiratory diseases, the seasonality of tuberculosis in the United Kingdom shows a peak incidence in the summer, a time that follows low sunlight exposure and the low winter levels of vitamin D (132). Hypovitaminosis D might increase the risk of tuberculosis because of the effects of vitamin D upon immune function (133), and in vitro studies suggest that vitamin D status may inﬂuence resistance to tuberculosis. Cultured human monocytes and macrophages were protected against virulent tubercle bacilli by 1,25(OH2)-vitamin D3, an active metabolite of vitamin D (134–137). 1,25(OH2)-vitamin D3 may enhance the effects of pyrazinamide against tuberculosis (138). Studies in vitamin D-deﬁcient guinea pigs suggest that dietary vitamin D levels inﬂuence immunity to virulent M. tuberculosis (139). Abnormalities in calcium homeostasis have been reported in patients with tuberculosis, and the relationship of these abnormalities to vitamin D status is unclear. In untreated pulmonary tuberculosis, calcium levels have been reported to be decreased (140), increased (141,142), or normal (143) compared with healthy controls, and vitamin D levels are reported to be normal (144,145) during tuberculosis. It has been suggested that plentiful sunlight may cause high levels of vitamin D and calcium in patients in Africa (146). Isoniazid and rifampicin treatment for tuberculosis has been reported to depress (147) or have no effect (148) on vitamin D levels. Similarly, chemotherapy for tuberculosis has been reported to increase (149), decrease (150), or have no effect (151) on calcium levels. 4.3.4. B COMPLEX VITAMINS There is limited data regarding the status of B complex vitamins in individuals with tuberculosis. Low serum folate levels are common in adults with tuberculosis both before and during tuberculosis chemotherapy (109,152,153). In a study of adults with tuberculosis in Nigeria, serum vitamin B12 levels were not signiﬁcantly different from asymptomatic controls (154), and normal serum vitamin B12 levels were also described in Finland among adults with tuberculosis (152). 4.3.5. VITAMIN C A longitudinal study of 1,100 men was conducted in a low-income area of Philadelphia in the 1940s to determine whether nutritional deﬁciencies increased the risk

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of developing tuberculosis (155). At baseline, vitamins A, C, hemoglobin, albumin, calcium, and phosphorus were measured, and all subjects had chest roentgenographic examination to exclude those with evidence of tuberculosis. The subjects were followed for 7 yr, and 28 men subsequently developed tuberculosis. Low plasma levels of both vitamins A and C at baseline signiﬁcantly increased risk of developing tuberculosis. There is some evidence from animal models that vitamin deﬁciency may inﬂuence susceptibility to intestinal tuberculosis (156), and the evidence for vitamin A has been discussed previously. 4.3.5. OTHER NUTRITIONAL PROBLEMS Epidemiologic studies of tuberculosis among Asian immigrants in south London associate a vegetarian diet with tuberculosis (157,158). A case-control study was conducted among Asian immigrants to London from the Indian subcontinent and East Africa, and the single most important risk factor identiﬁed was vegetarianism, with the highest risk of tuberculosis among lactovegetarians (avoidance of meat or ﬁsh) (158). In most of the cases, tuberculosis developed more than 5 yr after arrival in the United Kingdom, suggesting that tuberculosis in these immigrant Asians was owing to reactivation secondary to decreased immunity associated with micronutrient malnutrition. The vegetarian Asian diet is known to increase the risk of deﬁciencies of iron, vitamin B12, and vitamin D (159), and probably zinc as well. The effect of zinc deﬁciency on immunity to tuberculosis has been studied in a guinea pig model, and these studies show that zinc-deﬁcient animals had reduced tuberculin sensitivity and fewer circulating T lymphocytes but no apparent altered resistance to virulent M. tuberculosis (139). Deﬁciencies of dietary protein and/or zinc interfere with immunological responses of guinea pigs to M. bovis BCG vaccination (160). Anemia is common during tuberculosis (161), and it is probable that the anemia of chronic inﬂammation accounts for a large proportion of anemia (162,163).

4.5. Strength of Evidence Regarding Role of Nutrition Although the association between malnutrition and tuberculosis is well known, there have been few controlled clinical trials conducted to investigate whether improved nutrition will reduce the risk of developing active disease or will improve the clinical outcome of tuberculosis. These issues have tremendous public health importance, but there are signiﬁcant challenges in attempts to answer such questions. The incidence rates of active tuberculosis are low enough to require extremely large sample sizes, i.e., thousands of subjects, in order to determine with adequate statistical power whether a nutritional intervention would have an impact on the incidence of tuberculosis. The measurement of outcomes following clinical disease, i.e., sputum-positive disease, radiographic evidence, and relapse of disease, are difﬁcult to measure in nutritional studies of patients with tuberculosis. Smaller intervention trials have been conducted that provide insight into the relationship between nutrition and tuberculosis, but none of these studies are deﬁnitive. One study conducted in Madras, India was particularly inﬂuential in shaping healthcare programs, because it showed that tuberculosis chemotherapy could be conducted on an outpatient basis rather than in a sanatorium (164). One hundred and sixty-three patients with tuberculosis were treated either in a sanatorium with a well-balanced diet or at home on a markedly poorer diet. Weight gain was greater in the patients

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treated in the sanatorium compared with patients treated at home. A higher proportion of sanatorium patients attained negative sputum cultures before the home patients, but the overall response to treatment was considered to be similar in both groups. In Harlem, New York city, a trial was conducted in the 1940s to determine whether a vitamin and mineral supplement could reduce the incidence of tuberculosis in families who had an active case of tuberculosis. One hundred and ninety-four families received either a vitamin and mineral supplement or no supplement. The attack rate of tuberculosis was 0.16/100 person-years in families who took the vitamins and minerals and 0.91/100 person years among families in the control group (165). The impact of vitamin A supplementation has been examined in small trials, but these studies have been limited by small sample size and insufﬁcient statistical power to examine major outcomes. In a study from the 1950s, 78 adults with moderately advanced tuberculosis were divided into three treatment groups: control, different forms of synthetic vitamin A, and cod-liver oil therapy. Cod- liver oil had a signiﬁcant impact on clinical outcome, with the most clinical failures noted in the control group (166). In the synthetic vitamin A group, some patients were given intramuscular injections of vitamin A palmitate in which vitamin A is absorbed irregularly. A controlled clinical trial involving 85 children with pulmonary tuberculosis in Cape Town suggested that two consecutive doses of vitamin A, 200,000 IU, at the commencement of tuberculosis chemotherapy, had no apparent impact on serum vitamin A levels, hemoglobin, roentgenographic ﬁndings, or weight Z-scores at 6 wk and 3 mo later (167).

5. DIAGNOSIS 5.1. Clinical and Laboratory Diagnosis The diagnosis of tuberculosis is based on the clinical syndrome and the identiﬁcation of M. tuberculosis in appropriate specimens taken from the patient. The identiﬁcation of M. tuberculosis relies on four complementary methods: staining techniques, mycobacterial culture, histopathology, and molecular methods. 5.1.1. STAINING TECHNIQUES Staining techniques are the most widely used methods for the identiﬁcation and diagnosis of M. tuberculosis infection. Two staining methods are currently in widespread use: the Ziehl-Neelsen procedure and the auramine-rhodamine method. Both techniques depend on the ability of the mycobacterium to retain the dye even after treatment with an acid solution, hence the term acid-fast (168). Diagnostic specimens treated with theses stains are viewed with the light microscope for the presence of organisms and graded according to standard deﬁnitions (169). The auramine-rhodamine method requires a ﬂuorescence microscope. The sensitivity of staining techniques is about 50–75%, yet the speciﬁcity is uniformly high, about 95–99%. The advantage to this technique is that it is inexpensive, readily available, and easily performed. The disadvantage is that the stains do not identify the species of mycobacteria. 5.1.2. MYOBACTERIAL CULTURE Mycobacterial culture represents the “gold standard” for the diagnosis of tuberculosis and should supplement the staining methods when possible. Culture increases the sensitivity above the staining techniques and allows the identiﬁcation of species

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involved. Sensitivity and speciﬁcity of culture has been reported at 82 and 98%, respectively (170). Typically, cultures for Mycobacterium take about 2–8 wk, and radiometric techniques have been used to detect bacterial growth within 2 wk. 5.1.3. MOLECULAR METHODS Diagnostic tests have been developed in which polymerase chain reaction (PCR) is used to amplify the DNA of Mycobacterium tuberculosis in sputum and other ﬂuids. Theoretically, PCR can detect even one strand of DNA. The sensitivity of this technique has been reported at 90% or greater (171), but the use of these techniques in sputum smear-negative tuberculosis remains to be established. 5.1.4. HISTOPATHOLOGY In the setting of extrapulmonary tuberculosis, the diagnosis may be suggested by the characteristic caseating granuloma seen in biopsied tissue. Fluorochrome staining with the auramine- rhodamine stain is useful in identifying acid-fast organisms within the granuloma, and raises suspicion of active tuberculosis. 5.1.5. SPECIMEN COLLECTION AND LABORATORY SAFETY Specimens for diagnostic testing are collected from involved sites. Expectorated sputum is used in the case of pulmonary tuberculosis. When cavitary lesions are present on the chest radiograph, the yield of acid-fast staining is high. When cavitary lesions are not present, sputum induction using nebulized saline often increases the yield. Diagnostic specimens may include urine, cerebrospinal ﬂuid, pleural ﬂuid, synovial ﬂuid, or gastric lavage ﬂuids. Biopsies are often taken of involved sites, including lymph nodes, pleura, synovium, bone, or other affected organs to increase the yield of diagnosis. In some cases, surgical procedures or bronchoscopy are required to obtain the appropriate specimens for diagnosis. Because M. tuberculosis is a contagious microorganism, special precautions are needed to ensure the safety of medical and laboratory personnel during the collection and processing of samples. Biosafety guidelines are published for the handling of mycobacterial specimens (172).

5.2. Differential Diagnosis The differential diagnosis for tuberculosis is extensive and includes other infectious etiologies, malignancy, development abnormalities, and inﬂammatory conditions. Other infectious diseases to be considered in the differential diagnosis of tuberculosis include necrotizing pneumonias caused by staphylococci or gram-negative bacteria and chronic lung abscess caused by anaerobic organisms. Fungal diseases such as histoplasmosis, blastomycosis, coccidiodomycosis, and aspergillosis can imitate tuberculosis. Lymphoma, bronochogenic carcinoma, and metastatic disease can produce a clinical picture that resemble tuberculosis. Rheumatoid nodules, sarcoidosis, Wegener’s granulomatosis, and lymphocytic granulomatosis are also included in the differential diagnosis.

6. TREATMENT AND PREVENTION 6.1. General Considerations The control of tuberculosis is founded on four general interventions: (1) passive case detection and appropriate treatment of infectious cases, (2) treatment of tuberculous

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infection, (3) BCG vaccination, and (4) environmental measures to interrupt transmission. A summary of each measure is given here. In the natural history of tuberculosis, there are two points that can be targeted for treatment: active tuberculosis and latent infection. The goal of treating active tuberculosis is twofold: to cure the patient of the disease and to reduce the risk of further transmission of infection to contacts in the community. Thus, treatment of active disease provides individual beneﬁt to the patient and accrues public health beneﬁt by curtailing the transmission of infection. The goal of treating latent tuberculous infection has been referred to as “preventive therapy” or “chemoprophylaxis” for tuberculosis. These terms are ambiguous as regards the primary prevention of tuberculous infection or prevention of disease in infected persons. A more accurate description of the intervention is to refer to the treatment of latent tuberculous infection.

6.2. Treatment of Active Tuberculosis 6.2.1. GENERAL TREATMENT REGIMENS Three regimens are currently recommended for the treatment of active tuberculosis (173) (Table 1). Standard short-course therapy, option one, is the most widely recommended regimen. This regimen uses daily isoniazid, rifampin, pyrazinamide, and ethambutol during the ﬁrst 2 mo of treatment, often referred to as the intensive phase of therapy, followed by 4 mo of isoniazid and rifampin given 2–3 times/wk. Ethambutol, or streptomycin, is usually included in the initial regimen until the results of the drug-susceptibility testing are available or in areas where primary drug resistance to isoniazid is less than 4%. An alternative regimen that is based on directly observed therapy, option two, consists of isoniazid, rifampin, pyrazinamide, and ethambutol 3 times/wk for 6 mo. All drugs are given according to body weight. Pulmonary and extrapulmonary tuberculosis are treated in the same manner except when extrapulmonary disease occurs in children when 12 mo of therapy is recommended. Other regimens with isoniazid and rifampin given for 9–12 mo have been used successfully to treat tuberculosis, but in this era, these are considered second-line regimens. Treatment of active tuberculosis is always indicated as the risk of mortality is approx 30% in untreated cases. Successful treatment of tuberculosis depends on regular dosing of multiple drugs to which the organism is susceptible for a sufﬁcient length of time (174). Because these drugs need to be given for 6 mo, adherence with therapy is a major determinant of treatment outcome. Poor adherence has been associated with treatment failures, relapse cases, and the emergence of multiple-drug resistance. The problem of poor adherence becomes ampliﬁed when drug-resistant strains are transmitted to susceptible contacts. To address the problem of nonadherence in tuberculosis treatment, directly observed therapy has been used (175,176) and has shown be cost-effective (177). In directly observed therapy, health-care workers observe the ingestion of each dose of medication to assure compliance. Intermittent regimens were developed to facilitate the use of directly observed therapy. When used, directly observed therapy can lead to treatment completion proportions as high as 90% when multiple enablers and enhancers are used in a patient-centered approach (178). In areas where directly observed therapy has been used, incidence rates of tuberculosis have declined as well as the rates of multidrug-resistant tuberculosis (176) and relapse cases (179). It should be noted that the only randomized clinical trial of directly observed therapy failed to

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Table 1 Regimens for the Treatment of Active Tuberculosis.a,b Option 1 Option 2 Option 3

Daily isoniazid, rifampin, and pyrazinamide × 8 wk, then isoniazid and rifampin daily or 2–3 ×/wk × 16 wkc Daily isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol × 2 wk, then same drugs × 6 wk by DOT, then isoniazid and rifampin × 16 wk by DOT Daily isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol 3 ×/wk × 6 mo by DOT

aOptions

2 and 3 include directly observed therapy (DOT). all three options, consult a tuberculosis medical expert if the patient is symptomatic or smear or culture positive after 3 mo. cIn areas where the isoniazid resistance rate is not documented to <4%, ethambutol or streptomycin should be added to the initial regimen until susceptibility to isoniazid and rifampin is demonstrated. Adapted with permission from ref. 173. bOn

show a difference in completion rate when compared with self-administration therapy (180). This study makes the point that supportive patient–provider relations may accomplish the same goals as directly observed therapy. Because of the success of directly observed therapy and the urgent need to control tuberculosis, the WHO has developed an entire strategy around directly observed therapy, also known as “DOTS” for Directly Observed Therapy, Short-course. This strategy is a comprehensive program that promotes case detection, direct observation of each dose of treatment, counseling, monitoring for cure, and reporting to local and international authorities. In high-burden countries where DOTS has been implemented, the average treatment completion proportion was 82% in 1996, although only 12% of tuberculosis cases were treated by directly observed therapy. 6.2.2. SPECIAL CIRCUMSTANCES In general, HIV-infected persons with active tuberculosis, children with pulmonary disease, and adults with extrapulmonary disease are all treated with the standard shortcourse regimen with good effect. Extrapulmonary disease in children is treated with 12 mo of therapy. In pregnant women, the risk of active tuberculosis poses a greater threat to the mother and fetus than do the medications, so treatment is recommended. In pregnant women, isoniazid, rifampin, and ethambutol are recommended for treatment. Pyrazinamide is not currently recommended because possible teratogenic effects are unknown. Treatment failure, relapse, and primary or secondary drug resistance pose special problems in the treatment and management of tuberculosis (173). In these settings, one cannot assume that the organism is susceptible to the standard treatment regimens. Therefore, additional drugs to which the organism is susceptible must be added to the regimen. Until the drug-susceptibility proﬁle is known, it is recommended that at least two new drugs be added to the standard regimen. Once the drug-susceptibility pattern is known, a tailored drug regimen can be chosen. Because of the complexity and potential toxicity of these drug regimens, treatment failures, relapses, and potential drug-resistant cases should be referred to experts in the ﬁeld for management.

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6.3. Treatment of Latent Infection Most individuals infected with M. tuberculosis manifest no signs of symptoms of disease. In fact, the only evidence of latent infection is a reactive tuberculin skin test. Yet, these latently infected individuals represent a large pool of people who are at risk for progression to active tuberculosis. Beginning in the 1970s, clinical trials were performed to determine whether treatment with isoniazid alone would reduce the risk of developing tuberculosis. The results of these trials indicate that isoniazid given for between 6 and 12 mo reduces the risk of tuberculosis by 75% (181). The widespread use of isoniazid therapy for latent infection has been limited because of its toxicity proﬁle and the adherence issues of long-term therapy, especially in individuals without symptoms of active disease. In recent years, a series of clinical trials have evaluated the use of 2–3-mo regimens in latent tuberculous infection (70,71,182–185). With the completion of these trials, there are new options for the treatment of latent infection. The choice of therapy will depend on the clinical and social circumstances. The recommendations for the treatment of latent tuberculous infection underwent extensive revisions in 1999 in light of new information regarding the short-course therapy for latent infection. Five regimens are currently recommended for the treatment of latent infection (Table 2). Two regimens are based on treatment with isoniazid and are similar to previous recommendations. Three new short- course, rifampin-based regimens are now recommended. Treatment with isoniazid requires a minimum of 6 mo of therapy. Although no clinical trial of 9-mo therapy has been performed, there is strong evidence from secondary analyses of several independent trials that 9 mo of isoniazid provides better protection against tuberculosis than does 6 mo. These analyses form the basis for the preferred use of 9 mo of therapy. In some local settings, however, 6 mo of therapy may be more cost-effective than 9 mo and would be the preferred regimen. The short-course rifampin-based regimens provide protection that is comparable to a 12-mo course of isoniazid therapy in HIV-infected adults with reactive tuberculin skin tests, and the results of these trials have been extrapolated to HIV-negative individuals in the absence of any formal efﬁcacy trials. Although toxicity remains a concern with these shorter regimens, adherence with treatment is expected to be considerably improved with the shorter regimen. In some instances the treatment of latent infection may be given twice weekly, but it is strongly advised that it be given in a supervised setting.

6.4. BCG Vaccination BCG is the mostly widely used vaccination throughout the world, yet it is one of the most controversial. The controversy stems from the variable protection it affords against active pulmonary disease. Since World War II, a vast literature has developed around the use of BCG vaccination including clinical trials and observational studies. Meta-analysis of these studies leads to some conclusions, although it does not resolve the controversies (43,186). There is general agreement that BCG vaccination provides uniform protection against the disseminated forms of tuberculosis often seen in children, such as meningeal and miliary tuberculosis. There is no question that BCG is effective in reducing not only the risk of tuberculosis in children but also mortality from tuberculosis. In regard to pulmonary disease, the protective efﬁcacy varies from –10 to 80% (43). Because pulmonary disease is responsible for the majority of M. tuber-

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culosis transmission, an accurate assessment of protection against this form of disease is critical in basing public policy toward BCG vaccination on scientiﬁc grounds. The reasons for the variability in protection are unknown, although the type of BCG used, the population studies, the study design used, the geographic location, and genetic heterogeneity may all contribute to the variability (44). In the end, one fact is clear: despite its worldwide use, BCG vaccination has not prevented the worldwide resurgence of tuberculosis observed in the last decade of this century.

6.5. Environmental Measures Outbreaks of tuberculosis in hospitals, nursing homes, and other health-care facilities indicate that M. tuberculosis is readily transmitted in the health-care setting. A number of environmental and personal measures can be taken to prevent the transmission of M. tuberculosis in these settings. In guidelines of the Centers for Disease Control and Prevention (CDC) (187), the primary emphasis of tuberculosis infection-control practice is based on three hierarchical levels of activity. First, administration measures must be in place to reduce the risk of exposure to an infectious case. This includes a strategy for the prompt diagnosis, isolation, and treatment of suspected cases of tuberculosis. Health care worker education, counseling, and screening form the cornerstone of tuberculosis surveillance and control in health-care settings. Second, engineering controls should be in place to reduce the concentration of droplet nuclei in the air, thereby reducing the risk of transmission (188). These measures include adequate ventilation, directional air ﬂow, ﬁltration of air, and the use of germicidal ultraviolet (UV) irradiation. Third, personal protective devices such as HEPA ﬁlter face masks may offer protection from exposure when worn properly by health-care personnel.

7. SUMMARY AND CONCLUSIONS Tuberculosis is a common infectious disease that accounts for major morbidity and mortality worldwide. One third of the world’s population is infected with M. tuberculosis, and this represents a large proportion of the population who are at risk for development of future clinical disease. The evolving HIV/AIDS pandemic and the increased mobility of populations have contributed to a large resurgence of tuberculosis, especially in Africa and Asia. Populations at high risk for acquiring tuberculosis infection include close contacts of infected individuals, people in institutionalized settings (prisons, nursing homes, homeless shelters), and those living in poverty. Once infected, most people have latent disease, and, in general, there is a 10% lifetime risk of developing clinical disease. The risk of developing clinical disease is higher in children, in individuals with immunosuppression (i.e., HIV infection, cancer, malnutrition), and in the elderly. Effective treatment regimens exist for both latent tuberculosis infection and active tuberculosis, but multidrug-resistant strains have emerged in different parts of the world.

8. RECOMMENDATIONS Aggressive application of programs for the control and treatment of tuberculosis are urgently needed to contain the resurgence of tuberculosis in developing countries. Implementation of directly observed therapy may reduce incidence rates of tuberculosis,

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rates of multidrug-resistant tuberculosis, and relapse rates. The association between malnutrition and tuberculosis is well-known, but there are three major gaps in knowledge that are of public health importance: • Although nutritional status seems to be related to the risk of developing active tuberculosis in individuals who have latent tuberculous infection, it is unclear whether any type of nutritional intervention will help prevent infected individuals from developing active disease. • Despite adequate chemotherapy for tuberculosis, morbidity and mortality can be high, especially among people who are co-infected with HIV. Whether adjunct nutritional support, in the form of micronutrient supplementation or other intervention, will improve clinical outcomes, such as morbidity, mortality, and relapse rates in those undergoing chemotherapy for tuberculosis, is not known. • In individuals who have multidrug-resistant tuberculosis, host factors may play the most important role in resistance to M. tuberculosis. Whether nutritional interventions will help improve clinical outcomes for these individuals is unknown.

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155. Getz HR, Long ER, Henderson HJ. A study of the relation of nutrition to the development of tuberculosis. Inﬂuence of ascorbic acid and vitamin A. Am Rev Tuberc 1951; 64:381–393. 156. McConkey M, Smith DT. The relation of vitamin C deﬁciency to intestinal tuberculosis in the guinea pig. J Exp Med 1933; 58:503–512. 157. Finch PJ, Millard FJC, Maxwell JD. Risk of tuberculosis in immigrant Asians: culturally acquired immunodeﬁciency? Thorax 1991; 46:1–5. 158. Strachan DP, Powell KJ, Thaker A, Millard FJC, Maxwell JD. Vegetarian diet as a risk factor for tuberculosis in immigrant south London Asians. Thorax 1995; 50:175–180. 159. Chanarin I, Stephenson E. Vegetarian diet and cobalamin deficiency: their association with tuberculosis. J Clin Pathol 1988; 41:759–762. 160. McMurray DN, Yetley EA. Response to Mycobacterium bovis BCG vaccination in protein- and zinc-deﬁcient guinea pigs. Infect Immun 1983; 39:755–761. 161. Corr WP Jr, Kyle RA, Bowie EJW. Hematologic changes in tuberculosis. Am J Med Sci 1964; 248: 709–714. 162. Baynes BD, Flax H, Bothwell TH, Bezwoda WR, MacPhail AP, Atkinson P, Lewis D. Haematological and iron-related measurements in active pulmonary tuberculosis. Scand J Haematol 1986; 36: 280–287. 163. Morris CDW, Bird AR, Nell H. The haematological and biochemical changes in severe pulmonary tuberculosis. Q J Med 1989; 272:1151–1159. 164. Ramakrishnan CV, Rajendran K, Jacob PG, Fox W, Radhakrishna S. The role of diet in the treatment of pulmonary tuberculosis. An evaluation in a controlled chemotherapy study in home and sanatorium patients in south India. Bull WHO 1961; 25:339–359. 165. Downes J. An experiment in the control of tuberculosis among Negroes. Milbank Mem Fund Q 1950; 28:127–159. 166. Getz HR. A physiologic and clinical study of failures in vitamin A metabolism in tuberculous patients. Am Rev Tuberc Pulm Dis 1955; 72:218–227. 167. Hanekom WA, Potgieter S, Hughes EJ, Malan H, Kessow G, Hussey GD. Vitamin A status and therapy in childhood pulmonary tuberculosis. J Pediatr 1997; 131:925–927. 168. Kent PT, Kubica GP. Public Health Mycobacteriology: A Guide for the Level III Laboratory. U.S. Department of Public Health and Human Services, Public Health Service. Atlanta: Centers for Disease Control, 1985. 169. International Union Against Tuberculosis and Lung Disease. Technical guide for sputum examination for tuberculosis by direct microscopy. Bull Intl Union Against Tuber Lung Dis 1986; 61:1–16. 170. Levy H, Feldman C, Sacho H, van der Meulen H, Kallenbach J, Koornhof H. Reevaluation of sputum microscopy and culture in the diagnosis of pulmonary tuberculosis. Chest 1989; 95:1193–1197. 171. Eisenach KD, Cave MD, Bates JH, Crawford JT. Polymerase chain reaction ampliﬁcation of a repetitive DNA sequence speciﬁc for Mycobacterium tuberculosis. J Infect Dis 1990; 161:977–981. 172. Anonymous. Biosafety in Microbiology and Biomedical Laboratories. Washington, DC: U.S. Government Printing Ofﬁce, 1993. 173. Bass JB, Farer LS, Hopewell PC, O’Brien R, Jacobs RF, Ruben F, Snider DE Jr, Thornton G. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Resp Crit Care Med 1994; 149:1359–1374. 174. American Thoracic Society. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Resp Crit Care Med 1994; 149:1359–1374. 175. McDonald RJ, Memon AM, Reichman LB. Successful supervised ambulatory management of tuberculosis treatment failure. Ann Intern Med 1982; 96:297–302. 176. Chaulk CP, Moore-Rice K, Rizzo R, Chaisson RE. Eleven years of community-based directly observed therapy for tuberculosis. JAMA 1995; 274:945–951. 177. Moore RD, Chaulk CP, Grifﬁths R, Cavalcante S, Chaisson RE. Cost-effectiveness of directly observed versus self-administered therapy for tuberculosis. Am J Resp Crit Care Med 1996; 154: 1013–1019. 178. Caulk CP, Kazandjian VA. Directly observed therapy for treatment completion of pulmonary tuberculosis. Consensus statement of the Public Health Tuberculosis Guidelines Panel. JAMA 1998; 279:943–948. 179. Weis SE, Slocum PC, Blais FX, King B, Nunn M, Matney GB, Gomez E, Foresman BH. The effect of directly observed therapy on the rates of drug resistance and relapse in tuberculosis. N Engl J Med 1994; 330:1179–1184.

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180. Zwarenstein M, Schoeman JH, Vundule C, Lombard CJ, Tatley M. Randomised controlled trial of self-supervised and directly observed treatment for tuberculosis. Lancet 1998; 352:1340–1343. 181. Ferebee SH. Controlled chemoprophylaxis trials in tuberculosis: a general review. Adv Tuberc Res 1970; 17:28–106. 182. Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993; 342:268–272. 183. Gordin FM, Matts JP, Miller C, Brown LS, Hafner R, John SL, et al. A controlled trial of isoniazid in persons with anergy and human immunodeﬁciency virus infection who are at high risk for tuberculosis. N Engl J Med 1997; 337:315–320. 184. Chaisson RE, Gordin F, Matts J, Garcia L, Hafner R, Obrien R. A randomized trial of rifampin/ pyrazinamide for 2 months vs. INH for 12 months in HIV+ tuberculin+ adults. Abstract 447/22126. Geneva: 12th World AIDS Conference, June 28–July3, 1998, Conference Record, p. 287. 185. Halsey NA, Coberly JS, Desormeaux J, Losikoff P, Atkinson J, Moulton LH, et al. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998; 351:786–792. 186. Rodrigues LA, Diwan VK, Wheeler JG. Protective effect of BCG against tuberculous meningitis and miliary tuberculosis: a meta-analysis. Intl J Epidemiol 1993; 22:1154–1158. 187. Centers for Disease Control and Prevention. Guidelines for the prevention of the transmission of Mycobacterium tuberculosis in health-care facilities. MMWR 1994; 43:1–111. 188. Segal-Maurer S, Kalkut GE. Environmental control of tuberculosis: continuing controversy. Clin Infect Dis 1994; 19:299–308.

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Human Immunodeﬁciency Virus Infection Richard D. Semba and Glenda E. Gray

1. INTRODUCTION 1.1. Deﬁnitions Infection with human immunodeﬁciency virus type 1 (HIV-1) causes a progressive decline in immunity that can lead to the acquired immunodeﬁciency syndrome (AIDS). The rate of disease progression can vary considerably, depending on host, environment, and viral factors. HIV-1 belongs to the lentivirus subfamily of retroviruses, which also includes HIV-2. This chapter will focus primarily on the problem of HIV-1 infection as it relates to developing countries and will emphasize the relationship between host nutritional status and the pathogenesis of HIV infection. In this chapter, HIV/AIDS will be used as a general term to refer to people who are infected with HIV who may or may not have the clinical diagnosis of AIDS.

1.2. PUBLIC HEALTH IMPORTANCE HIV/AIDS is now the single leading infectious cause of death in developing countries and, on a global scale, is primarily a problem affecting millions of people in developing countries. Since the beginning of the epidemic, an estimated 47 million people have become infected and 13.9 million people have died with HIV/AIDS. In 1998 alone, an estimated 2.5 million individuals died with AIDS worldwide (1). It is estimated that by the end of 1998 there were 33.4 million people infected with HIV, and the epidemic continues to grow, especially in sub-Saharan Africa and South and Southeast Asia. Regional statistics and features of the HIV/AIDS epidemic are shown in Fig. 1. The AIDS epidemic is having a major demographic impact on many countries were the prevalence of HIV is high, and these effects include an overall reduction in life expectancy, a decline in child survival, and an increase in orphans. Two major challenges for developing countries are the prevention of heterosexual transmission of HIV and the prevention of mother-to-child transmission of HIV.

From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Fig. 1. Global distribution of HIV/AIDS. Total: 33.4 million. Adapted from ref. (1).

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2. HISTORICAL BACKGROUND In the early 1980s, a new acquired immunodeﬁciency syndrome was described among homosexual men (2–4), injection drug users (5), hemophiliacs (6), and infants (7). Epidemiological observations suggested that there was an infectious agent transmitted from person to person by sexual intercourse, through blood transfusions, and from mother to infant (8). A retrovirus was isolated from patients with AIDS (9–11), and antibodies to the retrovirus were described (12,13). AIDS research progressed rapidly from the initial observations in the 1980s to include more complete descriptions of the spectrum of disease, sequencing and cloning of HIV-1, and elucidation of the infectious cycle of HIV-1. In 1985, AIDS wasting syndrome, or “slim disease,” was described in Uganda (14). Placebo-controlled clinical trials showed that zidovudine could prolong life (15) and that oral trimethoprim-sulfamethoxazole could be used as prophylaxis against Pneumocystis pneumonia (16). In the 1990s, highly active anti-retroviral therapy (HAART) was developed, and relatively effective viral suppression was observed with expensive combination therapies involving protease inhibitors. Where these complex drug regimens are used in the United States and Europe, there has been a promising reduction in the morbidity and mortality of HIV/AIDS. A large placebo-controlled trial showed that a complex regimen known as the ACTG 076 regimen consisting of oral zidovudine therapy to the mother during the second and third trimester, intravenous zidovudine to the mother at delivery, zidovudine to the infant for 6 wk, and formula feeding from birth, could reduce mother-to-child transmission of HIV (17). Despite the major advances in diagnosis, monitoring, and treatment of HIV/AIDS for those who live in wealthy industrialized countries, the major challenge is that over 90% of HIV-infected people live in the developing world where most of these expensive, technological advances are not affordable or available (18).

3. EPIDEMIOLOGY 3.1. Highest-Risk Groups The pattern of the HIV epidemic in developing countries contrasts with the overall pattern found in industrialized countries. In general, the two largest risk groups for HIV infection in developing countries include sexually active adults, and infants born to HIV-infected women, whereas in industrialized countries, homosexual men and injection drug users comprise the two largest risk groups. Sex workers are high-risk groups found in both industrialized and developing countries, and populations of injection drug users are found in some developing countries such as Thailand and Brazil.

3.2. Geographic Distribution The vast majority of individuals infected with HIV live in developing countries (19). Sub-Saharan Africa has been hardest hit by the AIDS epidemic, with an estimated 22.5 million, or about 70% of all individuals infected worldwide. In South and Southeast Asia, there are an estimated 6.7 million adults and children living with HIV/AIDS, and Latin America has an estimated 1.4 infected individuals (Fig. 1). Others areas which are affected include the Caribbean, Eastern Europe, Central Asia, Northern Africa, the Middle East, and East Asia and the Paciﬁc (1).

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3.3. Risk Factors 3.3.1. TRANSMISSION OF HIV The three major modes of transmission of HIV are through sexual contact, through mother-to-child transmission, and through transmission by blood products. Factors that increase the risk of transmission of HIV through sexual contact include unprotected receptive anal intercourse (20), unprotected vaginal intercourse (21), and the presence of other concurrent sexually transmitted diseases (STDs) such as genital ulcers, chancroid, syphilis, gonorrhea, and genital herpes infection (22,23). Uncircumcised men (24) and women who use traditional vaginal dessicants (25) may be at higher risk for becoming infected with HIV during sexual intercourse. Sexual intercourse during menses may increase the risk of HIV transmission (26). High plasma HIV load is associated with higher HIV load in seminal ﬂuid in men (27), and higher vaginal shedding of HIV in women (28). Risk factors for mother-to-child transmission of HIV include preterm birth, birth order, premature rupture of membranes, low maternal CD4 lymphocyte counts, high maternal HIV load, and breast-feeding (29–35). Maternal nutritional factors such as anemia and low plasma levels of vitamin A have been associated with mother-to-child transmission of HIV (36,37), but it is unclear whether nutritional deﬁciencies play a role in the etiology of HIV transmission. Among HIV-infected breast-feeding women, high HIV load in breast milk and subclinical mastitis are both associated with higher mother-to-child transmission of HIV (38). Transmission by blood products usually occurs through the sharing of needles and syringes by individuals engaged in intravenous drug use. Nosocomial spread of HIV has been noted in outbreaks in eastern Europe attributed to contaminated needles and syringes. Screening of blood products has largely eliminated HIV transmission through blood transfusion, although sporadic reports suggest that transmission is still occurring through contaminated blood products when there are breakdowns in laboratory screening and in the health-care system in general. 3.3.2. PROGRESSION OF HIV DISEASE The main indicators of disease progression during HIV infection are plasma HIV load (39) and circulating CD4 lymphocyte counts (40). In many industrialized countries, it has become standard clinical practice to monitor these laboratory indicators. In the case of individuals on long-term antiretroviral therapy, it has become imperative to measure plasma HIV load in order to monitor periodically for resistance of the virus to treatment. The measurement of either CD4 lymphocyte count or plasma HIV load requires sophisticated and expensive laboratory instrumentation and facilities, trained personnel, and sustained support, and costs for a single CD4 lymphocyte count (U.S. $20–30) and plasma HIV load (U.S. $80–100) are prohibitive for most developing countries. Monitoring of HIV disease progression in less technologically developed settings usually depends on the monitoring of complications that accompany different stages of HIV disease.

3.4. Incidence and Prevalence of HIV 3.4.1. INCIDENCE There is a paucity of data on the incidence of HIV infection measured directly in different populations, and most incidence rates are estimated from serial prevalence

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data of selected groups (41). Among young military conscripts in northern Thailand, the HIV incidence was about 2.5 per 100 person-years from 1991–1993 (42). HIV incidence was reported at 18.6 per 100 person-years among patients attending an inpatient drug treatment program in northern Thailand between 1993 and 1995 (43). In a study of male factory workers in Harare, Zimbabwe, HIV incidence was estimated to be 2.0 per 100 person-years (44). The overall HIV incidence was reported as 3.4 per 100 person-years among women attending family-planning clinics in Dar es Salaam, Tanzania (45). In a large population-based cohort in the rural Rakai District of Uganda, HIV incidence was about 2.0 per 100 person-years from 1990–1992. During the same period, the HIV prevalence declined owing to mortality and net out-migration, demonstrating that there are limitations on the analysis of trends in prevalence to estimate trends in incidence in mature HIV epidemics (46). 3.4.2. PREVALENCE In developing countries, most data regarding the prevalence of HIV comes from seroprevalence rates reported from women attending antenatal clinics. In Africa, HIV prevalence rates are highest in East and Southern Africa, with current estimates that about one quarter to one third of adults are infected with HIV. The HIV seroprevalence rates among pregnant women has increased steadily in many urban centers in Africa from 1985–1997 (1). 3.4.3. RATES OF MOTHER-TO-CHILD TRANSMISSION OF HIV Natural history studies have shown that the rates of mother-to-child transmission of HIV among women who do not breast feed are about 15–25% and that among women who breast feed, the rates are about 25–45% (47). In breast-feeding populations, about one third of the total mother-to-child transmission is thought to occur through breast milk. Different studies suggest that there is an additional 5–15% of mother-to-child transmission of HIV through breast feeding (48–50). An estimated 1,600 infants are infected with HIV each day through mother-to-child transmission of HIV (51). With the use of short-course antiretoviral therapy, transmission rates in the developed world can be reduced by 51% in nonbreast-feeding populations and by almost 40% in breast-feeding populations (52–55).

4. CLINICAL FEATURES/PATHOPHYSIOLOGY 4.1. Clinical Features The clinical course of HIV infection may be highly variable. Primary HIV infection is generally followed by a period in which the individual is asymptomatic. Over months to years, there is usually a slow decline in CD4 lymphocyte count and an increase in HIV load, and certain illnesses such as bacterial pneumonia, Herpes zoster, and oral candidiasis may occur. With further decline of CD4 lymphocyte count, AIDS-deﬁning illnesses, such as Kaposi’s sarcoma, Mycobacterium tuberculosis, and esophageal candidiasis may occur. There are three staging classiﬁcations for HIV infection in use: the Centers for Disease Control and Prevention (CDC) classiﬁcation, which is descriptive and intended for surveillance (56); the Walter Reed classiﬁcation, which relies on laboratory markers that are unavailable in many developing countries (57); and a proposed World Health Organization (WHO) classiﬁcation, which is intended

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Table 1 World Health Organization Classiﬁcation of HIV Disease Clinical stage 1 1. Asymptomatic infection 2. Persistent generalized lymphadenopathy 3. Acute retroviral infection Clinical stage 2 4. Unintentional weight loss, <10% of body weight 5. Minor cutaneous manifestations (e.g., seborrheic dermatitis, prurigo, fungal nail infections, oropharyngeal ulcerations, angular cheilitis) 6. Herpes zoster within the previous 5 yr 7. Recurrent upper-respiratory tract infections (e.g., bacterial sinusitis) Clinical stage 3 8. Unintentional weight loss, >10% of body weight 9. Chronic diarrhea, > 1 mo 10. Prolonged fever (intermittent or constant) > 1 mo 11. Oral candidiasis 12. Oral hairy leukoplakia 13. Pulmonary tuberculosis (typical or atypical) within the previous year 14. Severe bacterial infections (e.g., pneumonia, pyomyositis) 15. Vulvovaginal candidiasis, chronic (> 1 mo) or poorly responsive to therapy Clinical stage 4 16. HIV wasting syndrome 17. Pneumocystis carinii pneumonia 18. Toxoplasmosis of the brain 19. Cryptosporidiosis with diarrhea, > 1 mo 20. Isosporiasis with diarrhea, > 1 mo 21. Cryptococcosis, extrapulmonary 22. Cytomegalovirus disease of an organ other than liver, spleen, or lymph node 23. Herpes simplex virus infection, mucocutaneous (> 1 mo) or visceral (any duration) 24. Progressive multifocal leukoencephalopathy 25. Any disseminated endemic mycosis (e.g., histoplasmosis, coccidioidomycosis) 26. Candidiasis of the oesophagus, trachea, bronchi, or lungs 27. Atypical mycobacteriosis, disseminated 28. Nontyphoid Salmonella septicemia 29. Extrapulmonary tuberculosis 30. Lymphoma 31. Kaposi’s sarcoma 32. HIV encephalopathy

to be universally applicable (58). The WHO staging system for HIV infection and disease is shown in Table 1. 4.1.1. PRIMARY HIV INFECTION Acute primary HIV infection is characterized by a high viremia and decrease in CD4 lymphocyte count within 2–6 wk of initial infection. Within weeks, seroconversion to HIV occurs with the appearance of antibodies in the peripheral circulation to HIV.

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Table 2 AIDS-deﬁning Illnesses CD4 count <200 cells/µL Candidiasis, pulmonary or esophageal Cervical cancer Coccidioidomycosis Cryptococcosis, extrapulmonary Cryptosporidiosis Cytomegalovirus Encephalopathy, HIV Herpes simplex, chronic (>1 mo), esophogeal Histoplasmosis

Isosporiasis Kaposi’s sarcoma Lymphoma Mycobacterium avium Mycobacterium kansasii Pneumocystis carinii Pneumonia, recurrent Progressive multifocal leukemia Salmonellosis

Adapted from ref. (56).

Symptoms of acute HIV infection include fever, joint pain, and night sweats, although some individuals may be asymptomatic (59). The level of viremia during primary HIV infection is considered to be a predictor of long-term outcome after seroconversion (60). During primary HIV infection, individuals may be highly infectious and are at higher risk of transmitting HIV to others during sexual intercourse (61). 4.1.2. ASYMPTOMATIC HIV INFECTION After primary HIV infection, plasma HIV load usually drops to the undetectable level (<200 copies/mL). During the asymptomatic phase of HIV infection, the CD4 lymphocyte count may slowly decline at a rate of 50–100 cells/µL per yr (62), and there may be considerable variability in the rate of decline. HIV is not latent during this period but is actively replicating in lymphoid tissue. Other laboratory abnormalities, such as anemia and lymphopenia may be detected. The infected individual may have lymphadenopathy but no other symptoms or signs. Asymptomatic HIV infection can last for many years. 4.1.3. SYMPTOMATIC HIV INFECTION In early symptomatic HIV infection, fever, night sweats, fatigue, and headaches are common, and diarrhea and anorexia contribute to weight loss. Mucocutaneous disorders such as oral candidiasis, oral hairy leukoplakia, molluscum contagiosum, and seborrheic dermatitis are relatively common (63). Varicella-zoster infection may be common in early symptomatic HIV infection. Late symptomatic HIV infection is usually associated with the appearance of one or more AIDS-deﬁning illnesses. Oral candidiasis and lymphadenopathy were identiﬁed as the best predictors of HIV infection among adults in Tanzania (64). 4.1.4. ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) According to the widely used CDC criteria, the deﬁnition of AIDS is based on a CD4 lymphocyte count <200 cells/µL and/or one or more of several different conditions (Table 2). The pattern of AIDS-associated illnesses appears to differ greatly between developing countries in Africa, for example, and North America and Europe. In developing countries, a major AIDS-deﬁning illness is Mycobacterium tuberculosis,

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and tuberculosis is covered in detail in chapter 15 of this book. Cryptococcal meningitis is one of the major initial AIDS-deﬁning illnesses in adults in South Africa (65). Prior to HAART in North America and Europe, about one-third of HIV-infected patients would develop cytomegalovirus (CMV) infection. Although CMV infection occurs in developing countries, it is not a leading AIDS-associated opportunistic infection, perhaps because of geographical differences in the epidemiology of CMV infection, differences in approaches to diagnosis, and/or different rates of survival among HIVinfected adults. The WHO clinical case deﬁnition for AIDS had a sensitivity of 72.2%, speciﬁcity of 78.3%, and positive predictive value of 61.6% in a study in northern Zaire (66), and another study from Tanzania found lower sensitivity but higher speciﬁcity and positive predictive value of the WHO clinical case deﬁnition for AIDS (64).

4.2. Pediatric HIV Infection Nearly all cases of HIV infection in children are acquired through mother-to-child transmission of HIV. The natural history of HIV infection in children is variable and tends to be more rapidly progressive when compared to adults. In the developed world, before the widespread use of antiretroviral therapy, 30% of infected infants presented before 6 mo of age and 17–25% died within the ﬁrst 18 mo of life. By 6 yr of age, up to 75% of children were alive, with 50% still alive by 9 yr of age (67). In 1996, in the U.S. the median age of children with AIDS was 8 yr. Survival of children with AIDS appears to be bimodal with approx 10–20% of infected children being “rapid progressors,” usually dying of AIDS before 4 yr of age, whereas the remaining 80–90% of children have survival patterns more typical of adults with AIDS, with a mean survival of approx 9–10 yr (67). Survival of children infected with HIV in Africa appears to be much shorter than that seen in Europe and the United States. In Uganda, the infant mortality rate for children with laboratory diagnosis of HIV infection was 336/1000. Median survival of children in the Ugandan cohort was 21 mo with 66.2% of children dying by 36 mo of age (68). In a cohort in Malawi, the mortality rate per 1000 person-years of observation in HIV-infected children was 339.3, vs 46.3 among HIV-uninfected children born to HIV-infected women vs 35.7 among HIV-negative children born to HIV-uninfected women. Among HIV-infected children, the cumulative proportion surviving to age 24 mo was 70%, and to 36 mo the cumulative proportion surviving was 55% (69). In Zimbabwe, HIV-infected women had a perinatal mortality rate 2.1 times greater, a stillbirth rate 1.6 times greater, and a neonatal mortality rate 2.7 times greater than HIV uninfected women (70). Neonates born to HIV-infected women had an increased mortality rate (133/1000) compared to neonates born to HIV-uninfected women (40/1000) in Abidjan (71) and decreased 12-mo survival (61 vs 97%) in Brazzaville (72). In Haiti, Halsey et al. found that infants born to HIV-infected women had a signiﬁcantly lower mean birth weight (2944 g vs 3111g; p = 0.001), were more likely to weigh less than 2500 g at birth and were more likely to be less than 37 wk gestation than were infants born to HIV-uninfected women (73). In Asia, follow-up of children infected with HIV in the Bangkok perinatal HIV-transmission study measured mortality rates of 18% at 12 mo and 30% at 24 mo. In this cohort, most of the pediatric deaths were caused by pneumonia (74).

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4.2.1. FACTORS AFFECTING DISEASE PROGRESSION IN CHILDREN Progression of HIV infection in children may depend on the timing of transmission, the inoculum of virus, the phenotype of the virus, and immune functioning. The timing of viral detection in the newborn period may serve as a prognostic indicator of subsequent clinical course. Several prospective cohorts have observed signiﬁcant associations between early viral detection (in utero infection) and rapid disease progression in infancy. Kuhn et al. evaluated 432 infants born to mothers infected with HIV (75). HIV was detected by polymerase chain reaction (PCR) or culture within the ﬁrst 2 d of life in 28% of infants with a calculated relative risk for progression to AIDS or death of 2.6 (CI 1.5–4.6). In children with virus detectable 48 h after birth, 29% had died or developed AIDS by 1 yr of age (75). A threefold increased risk for early disease progression among infants with early viral detection was reported by Mayaux (76). In this study, infants who were determined to be infected in the intrapartum period also appeared to have rapid increases in HIV RNA with peak levels occurring between 4–6 wk of age and some of these infants being classiﬁed as developing a rapid progression of HIV disease (76). Currently there is no demonstrable RNA threshold that can differentiate rapid from slow progressors in the ﬁrst few months of life. Risk of disease progression has been shown to be related to high viral loads (>100,000 copies/mL), especially if CD4 counts are low (77). Two related properties of HIV are syncytium induction and macrophage tropism. In adults and children, macrophage tropism has been associated with a nonprogressive clinical state. In contrast, the syncytium-inducing and CD4 lymphocyte tropic phenotypes have been observed with the development of symptomatic progressive disease (78). There is an association between the human leukocyte antigen (HLA) system and genetic susceptibility to HIV. The discovery of the co-receptors CXCR4, CCR5, CCR2, and CCR3 and the effects of their mutants has led to clear evidence of genetic variability in host susceptibility. Homozygosity to the CCR5 gene confers protection against nonsyncytium-inducing or macrophage-tropic HIV strains, and that heterozygosity is associated with a slower disease progression in children and adults (79–81). 4.2.2. CLASSIFICATION OF HIV INFECTION IN CHILDREN The CDC has developed a classiﬁcation system for HIV-infected children that is based on immunologic criteria such as CD4 lymphocyte counts and clinical criteria, some of which require sophisticated laboratory support and diagnostic instrumentation (Table 3) (82). Thus, the CDC classiﬁcation is of limited use in many developing countries. The WHO has a simpliﬁed case deﬁnition for AIDS in children (83), but this deﬁnition has been shown to have poor sensitivity and good speciﬁcity (84,85). Early clinical signs and symptoms that are suggestive of HIV infection in an infant include weight loss or failure to thrive, delayed milestones, persistent diarrhea, persistent fever, and severe or repeated pneumonia. In a large cohort study in Zaire, the incidence rates of acute diarrhea were 170 per 100 child-years in HIV-infected infants compared with 100 episodes per 100 child-years in uninfected infants (86). The incidence of recurrent diarrhea was about twice as high and incidence of persistent diarrhea was about four times higher in HIV-infected infants compared with uninfected infants. Infants with HIV infection were shown to have an 11-fold increased risk of death from diarrhea (86).

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Table 3 1994 Revised Human Immunodeﬁciency Virus Pediatric Classiﬁcation System: Clinical Categories Category N: Not symptomatic Children who have no signs or symptoms considered to be the result of HIV infection or who have only one of the conditions listed in category A. Category A: Mildly symptomatic Children with two or more of the following conditions but none of the conditions listed in categories B and C. 1. Lymphadenopathy (greater or equal to 0.5 cm at more than two sites; bilateral = one site) 2. Hepatomegaly 3. Splenomegaly 4. Dermatitis 5. Parotitis 6. Recurrent or persistent upper-respiratory infection, sinusitis, or otitis medis Category B: Moderately symptomatic Children who have symptomatic conditions other than those listed for Category A or category C that are attributed to HIV infection. Examples of conditions in clinical category B include but are not limited to the following: 1. Anemia (<8 gm/dL), neutropenia (<1,000 mm3) or thrombocytopenia (<100,000/mm3) persisting for 30 d or more 2. Bacterial meningitis, pneumonia, or sepsis (single episode) 3. Candidias, oropharyngeal (i.e., thrush) persisting for 2 or more mo in children aged 6 mo 4. Cardiomyopathy 5. Cytomegalovirus infection with onset before age 1 mo 6. Diarrhea, recurrent or chronic 7. Hepatitis 8. Herpes Simplex Virus (HSV) stomatitis, recurrent (i.e., more than two episodes within 1 yr) 9. HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 mo 10. Herpes zoster (i.e., shingles) involving at least two distinct episodes or more than one dermatome 11. Leiomyosarcoma 12. Lymphoid Interstitial Pneumonia (LIP) or pulmonary hyperplasia complex 13. Nephropathy 14. Nocardiosis 15. Fever lasting more than 1 mo 16. Toxoplasmosis with onset before age 1 mo 17. Varicella, disseminated (i.e., complicated chickenpox) Category C: Severely Symptomatic Children who have early condition listed in the 1987 surveillance case deﬁnition for acquired immunodeﬁciency syndrome with the exception of LIP (which is a category B condition). Adapted from ref. (83).

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4.3. Pathophysiology 4.3.1. PATHOGENESIS The pathogenesis of HIV infection depends on both virologic and host factors. The main cellular targets for HIV are human cells that express the CD4 differentiation antigen on cell surface, such as CD4+ T lymphocytes, CD4+ monocytes and macrophages, and CD4+ dendritic cells. The outer envelope of HIV is covered with a surface glycoprotein known as gp120, and this glycoprotein speciﬁcally binds to the CD4 molecule. Various coreceptors, such as CCR5 and CXCR4, appear to be necessary for binding and HIV entry into the host cell (87). After fusion of viral and target cell membranes, viral RNA and proteins are deposited in the cytoplasm of the host cell. Uncoating results in the deposition of a reverse transcription complex in the cytoplasm, and this high molecular-weight complex then translocates into the host cell nucleus. Through reverse transcription, viral complementary DNA (cDNA) is synthesized and this proviral DNA is integrated into host cell DNA. Transcription of proviral DNA produces proteins such as Tat, Rev, and Nef, and important gene products such as gag, gag/pol, and other accessory gene products are expressed. Viral RNA is enclosed in an envelope glycoprotein and further maturation steps occur before mature virions bud off from the host cell. Lymphoid tissues serve as the primary site of viral replication and are the main reservoir for the virus. During acute HIV syndrome, the virus is disseminated widely in lymphoid tissues, plasma HIV load is high, and the infected individual responds with a speciﬁc immune response against HIV. After the appearance of an immune response, within 6 mo to 1 yr, the plasma HIV load decreases and then stabilizes to what has been termed a “set-point.” This set-point is of considerable importance, as it appears to correlate directly with the rate of HIV disease progression (60). The initial immune response to the virus during acute HIV syndrome may thus be a major determinate of the set-point. The immune response to HIV consists of nonspeciﬁc immune responses, HIV-speciﬁc antibody responses, and an HIV-speciﬁc cytotoxic T-lymphocyte responses by CD8+ lymphocytes. Among these immune responses, the cytotoxic T-lymphocyte response may be the most important (88). A period of clinical latency may last for years in which immune activation and viral replication occur without any obvious signs of symptoms of HIV infection. During this period, CD4 lymphocyte counts in peripheral blood may slowly decline until eventually the immune compromise results in the appearance of clinical disease. The loss of CD4 lymphocytes is the main immunologic abnormality of HIV infection. The rate of progression from primary HIV infection to AIDS may be 2–3 years in some individuals, who have been termed “rapid progressors” or may be 20 years or more in other individuals, who have been termed “long-term survivors” (89). The possible reasons for the large differences in AIDS-free survival include host immune responses, host genetic factors, and viral strain and phenotype. Individuals with a mutant allele for the coreceptor CCR5 have signiﬁcantly slower HIV disease progression (90). 4.3.2. HOST MICRONUTRIENT STATUS Among the host factors that may be involved in the pathogenesis of HIV infection is nutritional status. The rationale that micronutrient deﬁciencies are involved in the pathogenesis of HIV infection is rooted in two related theories: the free radical theory and the nutritional immunologic theory. Activated macrophages and neutrophils have

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important roles in the killing of microorganisms through the generation of reactive oxygen intermediates such as superoxide radicals (O2–), hydrogen peroxides (H2O2), and hydroxyl radicals (HO). These reactive oxygen intermediates (ROI) can oxidize nucleic acids; cause chromosomal breaks; elicit peroxidation of lipids in cell membranes; and can damage collagen, proteins, and enzymes. Thus, reactive oxygen intermediates can damage bystander cells and induce pathology. The generation of reactive oxygen intermediates by immune-effector cells or injured tissue is balanced by the antioxidant defense system. Oxidative stress refers to the condition when the balance between pro-oxidants and anti-oxidants is upset and there is overproduction of reactive oxygen intermediates and resulting pathology (91). Nuclear factor gB (NF-gB) is a transcriptional promotor of proteins that are involved in the inﬂammatory response and the acute phase reaction. NF-gB is bound to factor I gB in the cytoplasm in its inactive form, but various factors, such as tumor necrosis factor-_ (TNF-_) and ROI can cause the release of NF-gB from IgB, and NF-gB translocates to the nucleus and binds to DNA (92,93). Glutathione is a major intracellular thiol, which acts as a free-radical scavenger and inhibits activation of NF-gB (94,95). NF-gB is involved in the transcription of HIV-1, and free radicals may have interact with NF-gB and inﬂuence activation of HIV replication. HIV-infected adults with low levels of glutathione in their CD4+ lymphocytes have been shown to have decreased survival (96), providing some rationale for use of N-acetylcysteine (an oral prodrug form of glutathione) during HIV infection. Some micronutrients, such as vitamins A and E, and zinc, are involved in normal immune function. Micronutrient deﬁciencies may compromise host immunity to HIV and associated infections and thereby hasten clinical progression of disease. Vitamin A plays a central role in the growth and function of T and B cells, antibody responses, and maintenance of mucosal epithelia, including that of the respiratory, gastrointestinal, and genitourinary tracts (97). Zinc plays an important role in the growth, development, and function of neutrophils, macrophages, natural killer cells, and T and B lymphocytes (98). Vitamin E inﬂuences the function of T cells, B cells, and phagocytic cells and may protect immune effector cells against oxidative stress (99). Vitamin B6, selenium, and folate may inﬂuence immune function (100–102), but further work is needed regarding these micronutrients.

4.4. Role of Nutrition 4.4.1. FACTORS CONTRIBUTING TO POOR NUTRITIONAL STATUS Insufﬁcient dietary intake, malabsorption, diarrhea, and impaired storage and altered metabolism of nutrients can lead to both wasting and micronutrient malnutrition during HIV infection (103). Loss of appetite, aversion to food, dysphagia, nausea, and vomiting may be common in HIV-infected adults (104–107). Dietary assessment studies show that many HIV-infected individuals do not consume at least the recommended dietary allowance (RDA) for many micronutrients (108–112). The RDA is the level of intake of an essential nutrient that, on the basis of scientiﬁc knowledge, is considered to be adequate to meet the known nutrient needs of practically all healthy persons (113). The RDA is deﬁned at a level that is two standard deviations (SD) above what is considered to be the average level of requirement for a nutrient; thus, it is possible to consume less than the RDA and still have an adequate intake. It is unclear that the RDA can be applied to the nutrient needs of individuals with HIV infection, because studies show

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that intakes at the level of one RDA or higher are still associated with low serum or plasma levels of micronutrients (114). Diarrhea and malabsorption of fats, carbohydrates, and vitamin B12 appear to be common during HIV infection. Cryptosporidia, Microsporidia, cytomegalovirus, and Mycobacterium avium-intracellulare, are major causes of diarrhoea in patients with AIDS, and many pathogens are resistant to treatment and lead to severe weight loss and death (115). Fat malabsorption is common in all stages of infection (116,117), and malabsorption of fat probably adversely affects the absorption of fat-soluble vitamins such as vitamins A and E. About one-third of HIV-infected symptomatic children were shown to have carbohydrate malabsorption (118,119), and carbohydrate malabsorption is not uncommon among adults with pathogen-negative diarrhea and weight loss (120). Abnormal absorption of vitamin B12 may be common during HIV infection (121–123). Abnormal pathological changes in the jejunum and duodenum have been described in all stages of HIV disease (124–128). Increased intestinal permeability has been described in one quarter of asymptomatic HIV-infected adults (127). The liver is a site for accumulation of many micronutrients, including vitamins A, E, and iron. Hepatitis B and C are extremely common in HIV-infected adults and are associated with more rapid progression to cirrhosis and decreased survival (129,130). HIV-infected patients are at higher risk of developing renal disease, including acute renal failure, ﬂuid-electrolyte and acid-base disturbances, HIV-associated nephropathy and other glomerulopathies (131). A low molecular-weight proteinuria appears to be common during HIV infection and contributes to losses of retinol-binding protein and albumin (132). Signiﬁcant urinary losses of retinol and retinol-binding protein (RBP) have been described in patients with AIDS (133). Elevated urinary excretion of vitamin E may occur in adults with HIV infection (134). 4.4.2. PREVALENCE OF MICRONUTRIENT DEFICIENCIES Most studies of micronutrient status in HIV-infected individuals have relied on serum or plasma levels of micronutrients, and there are some limitations to the use of such laboratory indicators (103). However, there is sufﬁcient information from existing studies to make some general statements about micronutrient deﬁciencies during HIV infection. The prevalence of micronutrient deﬁciencies during HIV infection seems to vary widely, depending on the study population and stage of disease. In general, homosexual men and heterosexual adults in industrialized countries have the lowest prevalence of micronutrient deﬁciencies. Injection drug users from large inner cities, pregnant women, and children seem to be at the highest risk for having micronutrient deﬁciencies. There is still a paucity of data from developing countries regarding micronutrient status during HIV infection, although some reasonable extrapolation might be made from existing data from industrialized countries. Low vitamin A levels consistent with deﬁciency have been reported in about twothirds of lactating women in Cite Soleil, Port Au Prince, Haiti, in one-third of HIVinfected adults in an outpatient clinic in Kampala, Uganda (135), and in 40–60% of pregnant women studied in Malawi and Thailand (37,136). Abnormally low circulating provitamin A carotenoids occur in about 30–80% of HIV-infected individuals (136–139). HIV-infected children in Italy had lower `-carotene and vitamin E levels than healthy control children (140). Low serum levels of 1,25-dihydroxyvitamin D3, the biologically active form of vitamin D, have been described in HIV-infected adults

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with normal levels of 25-hydroxyvitamin D (141). Low vitamin E levels have been reported in 4% of heterosexual adults and in 10–20% of homosexual men and injection drug users (137,142,143). Most of these studies involving measurements of vitamin E levels have not measured the vitamin E:lipid ratio, which is considered to be a more accurate method for assessment of vitamin E status (144). During HIV infection, abnormally low plasma or serum vitamin C levels have been reported in 7–27% of homosexual men and injection drug users (137,139,142,145) and 20% of heterosexual adults (139). Normal blood thiamin and riboﬂavin levels have been reported during HIV infection, but blood levels of thiamin and riboﬂavin may be insensitive indicators of status. Abnormally low blood niacin levels have been reported in about 5% of HIV-infected adults (137,139). Abnormally low vitamin B6 levels have been reported in 10–30% of homosexual men and injection drug users (142,146). About 20–30% of homosexual men with AIDS have serum vitamin B12 levels below normal (121,147,148). Folate deﬁciency has been reported in about 0–8% of HIV-infected injection drug users and homosexual men (137,139,145,146), but one study reports that among HIV-infected adults who were not receiving folate supplements, about 60% had evidence of folate deﬁciency (149). In contrast, others have reported that serum or erythrocyte folate levels are increased during early HIV infection (150,151). Hematopoietic abnormalities are common during HIV infection. Malabsorption of iron, HIV infection itself, cytomegalovirus, and Mycobacterium avium intracellulare have been implicated as factors contributing to abnormal hematopoiesis (152). Bonemarrow biopsies and serum studies showed that over one-third of symptomatic, HIVinfected children had iron deﬁciency (152). Iron deﬁciency in HIV-infected children is associated with intestinal iron malabsorption and anemia (119). During HIV infection, serum copper levels consistent with deﬁciency were not found in heterosexual adults (139), but were noted in 3–11% of homosexual men and injection drug users (137,142). Higher serum copper levels were found in HIV-infected homosexual men, and these high levels may reﬂect an increase in serum caeruloplasmin levels during the acutephase response (153). Serum magnesium levels consistent with deﬁciency have been described in about 20–50% of HIV-infected adults (137,142), but the signiﬁcance of magnesium deﬁciency during HIV infection is unknown. Zinc deﬁciency, as measured by low serum or plasma levels, has been reported in about one quarter of asymptomatic homosexual men (142) and hospitalized patients with AIDS (154). Whole blood, red blood cell, and plasma selenium levels are lower in adults with AIDS (155). Low serum or plasma levels of selenium consistent with deﬁciency (156,157) and low cardiac selenium levels (158) have been described in HIV-infected adults. 4.4.3. WASTING SYNDROME Wasting syndrome is a condition that was originally deﬁned by the CDC as loss of more than 10% of body weight associated with more than 30 d of fever or diarrhea in an HIV-positive individual. Many epidemiological studies of wasting in HIV infection have used a less strict deﬁnition of wasting syndrome based on unintentional loss of more than 10% of body weight. Body cell mass, the nonadipose cell mass, is a more precise in measuring the extent of wasting, but it requires more complex instrumentation than a simple measurement of weight. Factors that contribute to wasting syndrome include hypermetabolism, or increased resting energy expenditure (159,160), opportunistic infections and associated anorexia (161), increased protein catabo-

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lism, gastrointestinal disease (162), malabsorption, and circulating cytokines. With the advent of HAART, wasting syndrome has become much less common in the United States and Europe, but it still remains a major problem in developing countries. Wasting syndrome is associated with higher risk of mortality (163,164).

4.5. Strength of Evidence Regarding Role of Nutrition 4.5.1. NATURAL HISTORY STUDIES Longitudinal studies suggest that deﬁciencies in certain micronutrients may be associated with increased morbidity and mortality during HIV infection. Low plasma or serum vitamin A levels are associated with accelerated HIV progression (143), increased mortality (165), higher vertical transmission of HIV (37), child growth failure (37), and increased HIV load in breast milk and in the birth canal (166–168). In HIV-infected homosexual men, high serum vitamin E levels were associated with a 30% decrease in risk of progression to AIDS (169). Low plasma vitamin B6 levels are not linked with HIV disease progression (146,170), but high intake of vitamin B6 supplements was associated with improved survival (171). The risk of progression to AIDS was twofold higher in homosexual men with vitamin B12 deﬁciency (146). The pathogenesis of anemia during HIV infection is poorly understood, and low hemoglobin levels have been associated with increased immune activation, low transferrin, and high ferritin levels (172). Low serum zinc levels are associated with impaired thymic function (173) and HIV disease progression in homosexual men (143,153). Although selenium deﬁciency is rare in humans, low selenium levels were common during HIV infection and linked with increased mortality (174). 4.5.2. MICRONUTRIENT SUPPLEMENTATION TRIALS Deﬁnitive evidence regarding the role of micronutrients in the pathogenesis of HIV infection will need to come from clinical trials, and there have been few clinical trials to date. Most of the existing studies consist of pilot interventions with single micronutrients. The available pilot studies have been conducted in populations that are at different risk for micronutrient deﬁciencies, thus, it is difﬁcult to make extrapolations to other populations from these ﬁndings. High-dose vitamin A supplementation seems to reduce diarrheal morbidity in HIV-infected infants in an underpriviledged population in Durban, South Africa (175). A clinical trial in children with AIDS in Cape Town showed that 200,000 IU (60 mg RE) vitamin A given on two consecutive days could increase circulating CD4 and NK cell counts (176). In HIV-infected injection drug users in inner-city Baltimore, a single high oral dose of vitamin A (200,000 IU; 60 mg RE) did not seem to inﬂuence HIV load but may possibly help stabilize the decline in circulating CD4+ lymphocytes (177). Megadose `-carotene does not appear to have additional beneﬁt for HIV-infected adults who are already on multivitamins in Portland, Oregon (178). Daily zinc supplementation (200 mg/d) for 30 d reduced infectious disease morbidity in adults with AIDS in Italy (179). A reduction in oxidative stress and an apparent decrease in viral load was noted in a clinical trial of vitamins E (800 mg/d) and C (1 gm/d) in HIV-infected adults in Toronto (180). A daily multivitamin supplement that was high in zinc and vitamin C had no inﬂuence on the morbidity of diarrheal disease in adults with wasting syndrome in Zambia (181). A large study from Tanzania suggests that micronutrient supplementation to HIVinfected pregnant women will reduce fetal deaths and improve birth outcomes (182).

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Women who received daily multivitamin supplementation from the second trimester until delivery had about a 40% decrease in fetal deaths and low birthweight. The study involved a 2 × 2 factorial design in which mothers received either (1) a multivitamin (vitamins C, E, B6, B12, folate, thiamin, riboﬂavin, niacin); (2) vitamin A (5000 IU; 1.5 mg RE) plus `-carotene (30 mg); (3) both a multivitamin, vitamin A, and `-carotene; or (4) placebo. All women in the study received daily iron and folate. Vitamin A and `-carotene supplementation had no apparent effect on fetal deaths and low birth weight (LBW). Multivitamins were associated with a signiﬁcant increase in CD3+, CD4+, and CD8+ lymphocyte counts. To date, this is the largest micronutrient clinical trial to be conducted among HIV-infected individuals, and shows that there may be great promise in using micronutrients to improve maternal and child health in developing countries.

5. DIAGNOSIS 5.1. Laboratory Diagnosis The laboratory diagnosis of HIV infection in adults and children over the age of 15 mo is usually made on the basis of two positive tests for antibody to HIV using two different enzyme-linked immunosorbent assays (ELISA) on a single serum or plasma sample (183). If the results of the two different HIV ELISAs are not concordant, a Western blot may be used to conﬁrm the diagnosis. Infants born to HIV-infected mothers represent a special case for diagnosis of HIV infection, because passively acquired maternal antibodies to HIV can yield positive HIV antibody testing even though the infant may not be HIV-infected. In many developing countries, passively acquired maternal antibodies usually have disappeared by the time the infant is 15 mo of age. Qualitative HIV DNA PCR (184) or quantitative HIV RNA PCR have the highest sensitivity and speciﬁcity for diagnosis of HIV infection in infants, however, these tests are of limited usefulness in many developing countries because of the cost, about $25–50/test and $75–100/test, respectively. In individuals who have recently been exposed to HIV, there is a serological window between exposure to the virus and the development of antibodies, and seroconversion usually occurs within 6 mo of exposure (185). There are a variety of HIV “rapid tests” that are commercially available, and some of these tests do not require refrigeration or laboratory instrumentation.

6. TREATMENT 6.1. Drugs and Supportive Care 6.1.1. ADULT HIV INFECTION The approaches to management of adults with HIV infection vary widely in developing countries and are often dependent on local conditions and socioeconomic factors. Much of the disparity in care is owing to the problem that many drugs, especially antiretroviral medications, are prohibitively expensive and that HIV infection optimally requires highly sophisticated technological medicine, i.e., diagnostic methods such as magnetic resonance imaging (MRI) scanners, sophisticated laboratory support, and so forth. Many countries in Africa that have been hit hard by the AIDS epidemic are still dealing with basic issues of clean water, sanitation, hygiene, nutrition, and primary care, and in this setting of limited health care resources, expensive AIDS care must compete with other priorities in health care.

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A major component of clinical care in developing countries is the diagnosis and treatment of tuberculosis in HIV-infected adults, an issue covered in another chapter in this book. Prophylaxis against Pneumocystis carinii pneumonia and toxoplasmosis by trimethoprin-sulfa is practiced in some settings in developing countries, but the issue of drug resistance needs evaluation. 6.1.2. PEDIATRIC HIV INFECTION Guidelines for the management of children with HIV infection can be found under a larger child health program called the Integrated Management of Childhood Illness (IMCI) developed by the WHO and UNICEF (186). The approach emphasizes diagnosis and appropriate treatment of major childhood illnesses, with emphasis on immunization, vitamin A supplementation, and improved infant feeding. Routine immunizations should be administered to all children at risk for or infected with HIV to ensure protection against all childhood diseases. The American Academy of Pediatrics, following a single report of a death in an adult with AIDS owing to pneumonia attributable to vaccine type-measles virus, has recommended that HIVinfected children, adolescents, and young adults who are severely immunocompromised (based on CD4+ lymphocyte enumeration) should not receive measles-mumps rubella vaccine (MMR). HIV-infected children, adolescents, and adults without evidence of severe immunosuppression should still receive the MMR vaccine. The ﬁrst dose should be administered at 12 mo of age. The second dose may be given as soon as 28 d after the ﬁrst dose. In the event of an outbreak in the community, vaccination with the monavalent or MMR vaccine is recommended for infants as young as 6 mo of age. Children who have been vaccinated before their ﬁrst birthday should be revaccinated at 12 mo of age, and an additional dose may be given as soon as 28 d later. It has also been recommended that upon exposure to wild-type measles, immune globulin prophylaxis should be adminstered to all HIV-infected children or children of unknown HIV status and HIV-infected adolescents, regardless of degree of immunosuppression or measles immunization status (187). Approximately 20% of AIDS-deﬁning illnesses reported in children to the CDC have been caused by serious recurrent bacterial infections (188). Of these, the greatest proportion is attributable to pneumococcal infection (188). Because of the susceptability of HIV-infected children to developing invasive pneumococcal disease, access to the polyvalent pneumoccal polysaccharide vaccine after 2 yr of age is recommended. For infants under 2 yr of age, efﬁcacy trials of conjugate pneumococcal trials are in progress that will establish the role of early immunization with conjugate pneumococcal vaccine in HIV-infected children. Pneumocystis carinii pneumonia (PCP) is the most commonly reported AIDSdeﬁning condition in children and is estimated to occur at a rate of 7–20% in the ﬁrst year of life in children not receiving PCP prophylactic therapy. It is now recommended that all infants and children at risk for or infected with HIV commence primary PCP prophylaxis at 4–6 wk of age and this should be continued until HIV infection can be reasonably excluded. For HIV-infected infants that are older than 1 yr of age, the use prophylaxis should be guided by CD4 counts. Lifelong prophylaxis should occur in all HIV infected infants and children who have had an episode of PCP (189). M. tuberculosis has become a major health problem for HIV-infected infants both in the developed and developing world. Vigorous screening for tuberculosis should occur

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in infants who are HIV-infected or at risk of being HIV-infected. The value of tuberculin skin testing for diagnosing tuberculosis in HIV-infected children is controversial. In a recent study from Soweto, South Africa, tuberculin reactivity was lower in HIV-infected children at all cutoff levels than in HIV uninfected children ( p < 0.0001) and was found to be of limited value as an adjunct in diagnosing tuberculosis in HIV-infected children (190). Despite the high incidence of tuberculosis co-infection with HIV, there is no data on the efﬁcacy of isoniazid (INH) prophylaxis for the prevention of tuberculosis in HIV-infected children. However, some clinicians in the U.S. may initiate INH prophylaxis in HIV-infected infants following a positive tuberculin skin test and a negative chest radiograph. Malnutrition is prevalent in pediatric HIV infection. In Soweto, South Africa, a hospital-based study found that 45% of all admitted HIV-positive children were malnourished compared to 22.2% of negative and untested children (p<0.001, OR 2.8 95% CI 2.6–3.1) (191). In the Ivory Coast, a study of pediatric hospital admissions showed that malnutrition occurred in 25% of HIV-infected children (192). Selenium deﬁciency has been found to be associated with rapid HIV progression and with a high risk of mortality (RR = 5.96, 95% CI, 1.32–26.81) that was independent of CD4 cell count (193). A prospective randomized clinical trial will determine whether selenim supplementation can alter disease progression. It has been proposed that the use of nutritional interventions in HIV-infected children, particularly in populations that do not have access to antiretroviral therapy, may help prevent malnutrition and wasting (194). In addition to the supportive care that includes the prevention and treatment of infectious diseases, the provision of nutritional supplementation, and psychosocial support, one must consider the use of antiretoviral therapy to manage effectively HIV disease in children. Treatment guidelines involving the use of antitretroviral therapy are evolving based on the results of recently conducted trials (Table 4). To date, there is limited data regarding the efﬁcacy of antiretroviral therapy in asymptomatic children or the long-term tolerability and efﬁcacy of triple therapy in children. The decision to commence therapy in infants and children may be based on the age of the infant, clinical symptomatology, CD4 counts (or percentages), plasma, or HIV RNA levels. The current recommendations by the Working Group on Antiretroviral Therapy and Medical Management of HIV-infected children is to start therapy in all infected children regardless of clinical, immunologic, or virologic parameters. This is based on the assumption that early intervention is preferable (195).

6.2. Role of Nutritional Interventions Currently, there is limited evidence to support any programmatic recommendations for micronutrient supplementation for HIV-infected individuals in developing countries. Multivitamin supplementation should be considered as part of a package of care for HIV-infected pregnant women, given the demonstrated impact on infant outcomes in Tanzania (182).

7. PREVENTION 7.1. Sexual Transmission of HIV Strategies to reduce the sexual transmission of HIV include the use of condoms; treatment of STDs; and HIV counseling, testing, and education. Latex condoms are

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Table 4 Indications for Initiation of Antiretroviral Therapy in Children With Immunodeﬁciency Virus (HIV) Infection I. Clinical symptoms associated with HIV infection [i.e., clinical categories A, B, or C (see table 2)] II. Evidence of immune suppression, indicated by CD4+T-lymphocyte absolute number or percentage [i.e., immune category 2 or 3 (see Table 1)] III. Age <12 mo, regardless of clinical, immunologic, or virologic status IV. For asymptomatic children aged 1 yr or older with normal immune status, two options can be considered: A. Preferred approach Initiate therapy-regardless of age or symptom status B. Alternative approach Defer treatment in situations in which the risk for clinical disease progression is low and other factors (e.g., concern for the durability of response, safety, and adherence) favor postponing treatment. In such cases, the health-care provider should regularly monitor virologic, immunologic, and clinical status. Factors to be considered in deciding to initiate therapy include the following: 1. High or increasing HIV RNA copy number 2. Rapidly declining CD4+T-lymphocyte number or percentage to values approaching those indicative of moderate immune suppression (i.e., immune category 2) (see Table 3) 3. Development of clinical symptoms

highly effective in reducing HIV transmission and STDs (196–199). Female condoms, vaginal microbicides, and spermicides are currently under evaluation. Control of STDs such as syphilis, trichomoniasis, and gonorrhea reduces the rate of HIV transmission (199,200). Treatment of STDs was shown to reduce HIV transmission in Tanzania by about 40% (201). In Uganda, community-level control of STDs had a major impact on reducing the prevalence of STDs, but no apparent impact on the incidence of HIV infection (202).

7.2. Mother-to-Child Transmission of HIV The best proven therapeutic method for preventing mother-to-child transmission of HIV is a combination of the ACTG 076 regimen, formula feeding, and Cesarean section, which can reduce mother-to-child transmission of HIV to about 1% (203). A long course of zidovudine is extremely expensive (US $800), and its cost is prohibitive for many developing countries (51). Universal Cesarean section would be nearly impossible in many developing country settings, given lack of manpower, resources, hygiene, and facilities to institute this intervention safely for all HIV-positive pregnant women. A shorter course of zidovudine during pregnancy has been shown to reduce mother-to-child transmission of HIV by 50% in nonbreast-feeding women in Thailand (52). Among women who were breast feeding, a shorter course of zidovudine reduced mother-to-child transmission of HIV by 37% to 3 mo after delivery in Côte d’Ivoire (53) and 38% to 6 mo in a multicenter study in Côte d’Ivoire and Burkina Faso (54). In addition, the use of an ultrashort regimen of nevirapine has been shown to reduce vertical transmission of HIV in Uganda. In this study, nevirapine administered in the

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intrapartum period and a single dose to the infant reduced transmission by 47% at 14–16 wk of age as compared to oral zidovudine administered during labor and given to the infant for 1-wk post-delivery (55). Other interventions that are being evaluated to reduce mother-to-child transmission of HIV include passive immunization, prophylaxis for chorioamnionitis, vaginal virucidal cleansing during labor, and multivitamin supplementation during pregnancy. Vaginal cleansing during labor has been shown to reduce maternal and infant mortality (204) although it does not appear to reduce mother-to-child transmission of HIV (205). As noted earlier in this chapter, multivitamin supplementation during pregnancy has been shown to improve birth outcomes (182). Various strategies that are in development to prevent postpartum transmission through breast milk include early weaning, low dose antiretroviral therapy to the infant while breast feeding, early and/or late administration of passive or active immune agents (206).

7.3. HIV Vaccines The ideal preventive measure against HIV infection would be an inexpensive, safe, and effective vaccine. The complex biology of HIV-1 infection raise many challenges to the development of a successful vaccine. Candidate HIV vaccines include those that involve envelope proteins, synthetic peptides, DNA, and poxvirus recombinants (207).

8. SUMMARY AND CONCLUSIONS HIV/AIDS is the single leading infectious cause of death in developing countries. Over 90% of infected individuals live in developing countries. The HIV/AIDS pandemic continues to spread with major demographic impact in sub-Saharan Africa and South and Southeast Asia. Two major challenges to controlling the epidemic are the prevention of sexual transmission of HIV through counseling, testing, education, and condom use, and the prevention of mother-to-child transmission of HIV through short-course anti-retroviral regimens and other low cost interventions. The pathogenesis of HIV infection may depend on both virologic factors (viral strain and phenotype) and host factors (genetic and nutritional). Nutritional deﬁciencies may play a role in the pathogenesis of HIV infection because of the role of some micronutrients as anti-oxidants and in immune function. Because of anorexia, diarrhea, malabsorption, and altered storage and metabolism, micronutrient abnormalities may be common during HIV infection. In many developing countries, the primary health-care infrastructure needs to be strengthened to include better access to HIV testing, counseling, and AIDS education, and measures must be taken so that such infrastructure can be sustained. These measurements include adequate clinic and hospital facilities to deal with epidemic, improved infrastructure to deal with the orphan crisis, adoption of pediatric guidelines on the use of prophylaxis for opportunistic infections, the establishment of voluntary counseling and testing depots based outside the hospital setting, adequate access to STD treatment and condoms/barrier methods, drug security and distribution infrastructure, and access to lower cost antiretroviral therapy to prevent vertical transmission of HIV-1.

9. RECOMMENDATIONS There are many basic issues regarding HIV/AIDS in developing countries that represent major gaps in knowledge.

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• The micronutrient status of infants, children, pregnant and lactating women, and adult men and women with HIV infection has not been described, except for a few studies concentrating on one or two micronutrients. Little to nothing is known about iron-deﬁciency anemia during HIV infection, and no studies have addressed iodine deficiency, a common problem in developing countries where HIV is prevalent. Selenium deﬁciency has not been deﬁned in high-risk populations for HIV infection in developing countries. The relationship between micronutrient status and morbidity and mortality during HIV infection is not well-known. • It is unknown whether nutritional interventions (supplementation, dietary education, fortiﬁcation) will improve morbidity and mortality during HIV infection. • Although zinc supplementation has been shown to reduce diarrheal disease morbidity, it is unclear whether or not it would be useful for diarrhea associated with HIV infection. • Little is known about the natural history of HIV infection in children beyond 2 yr of age, because most studies have focused on mother-to-child transmission of HIV. In some populations, the majority of HIV-infected children may survive beyond 3 yr of age, yet little is known about factors that are beneﬁcial for survival. Little is known about the natural history of HIV infection in children who become infected through breast feeding. • It is not known whether long-term clotrimoxazole prophylactic therapy safe and effective for infants and children in developing countries. • The efﬁcacy of INH prophylaxis for the prevention of tuberculosis in HIV-infected children needs to be determined. • The relationship between some common infectious diseases, i.e., malaria, ﬁlariasis, schistomiasis, and HIV, needs further elucidation. • Measles immunization schedules for the developing world may need re-evaluation in light of the HIV pandemic. • The role of screening, treatment, and prevention of mastitis in mother-to-child transmission of HIV in breast feeding populations, needs further elucidation (208).

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134. Jordão AA Jr, Silveira S, de Castro Figueiredo JF, Vannucchi H. Urinary excretion and plasma vitamin E levels in patients with AIDS. Nutrition 1998; 14:423–426. 135. Semba RD. Vitamin A and human immunodeﬁciency virus infection. Proc Nutr Soc 1997; 56: 459–469. 136. Phuapradit W, Chaturachinda K, Taneepanichskul S, Sirivarasry J, Khupulsup K, Lerdvuthisopon N. Serum vitamin A and beta-carotene levels in pregnant women infected with human immunodeﬁciency virus-1. Obstet Gynecol 1996; 87:564–567. 137. Bogden JD, Baker H, Frank O, et al. Micronutrient status and human immunodeﬁciency virus (HIV) infection. Ann NY Acad Sci 1990; 587:189–195. 138. Ullrich R, Schneider T, Heise W, et al. Serum carotene deﬁciency in HIV-infected patients. AIDS 1994; 8: 661–665. 139. Skurnick JH, Bogden JD, Baker H, et al. Micronutrient proﬁles in HIV-1-infected heterosexual adults. J Acquired Immune Deﬁc Syndr Hum Retrovirol 1996;12:75–83. 140. Mastroiacovo P, Ajassa C, Berardelli G, et al. Antioxidant vitamins and immunodeﬁciency. Intl J Vit Nutr Res 1996; 66:141–145. 141. Haug C, Müller F, Aukrust P, Freland SS. Subnormal serum concentration of 1,25-vitamin D in human immunodeﬁciency virus infection: correlation with degree of immune deﬁciency and survival. J Infect Dis 1994; 169:889–893. 142. Beach RS, Mantero-Atienza E, Shor-Posner G, et al. Speciﬁc nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 1992; 6:701–708. 143. Baum MK, Shor-Posner G, Lu Y, et al. Micronutrients and HIV-1 disease progression. AIDS 1995; 9: 1051–1056. 144. Thurnham DI, Davies JA, Crump BJ, Situnayake RD, Davis M. The use of different lipids to express serum tocopherol: lipid ratios for the measurement of vitamin E status. Ann Clin Biochem 1986; 23: 514–520. 145. Coodley G, Girard DE. Vitamins and minerals in HIV infection. J Gen Intern Med 1991; 6: 472–479. 146. Tang AM, Graham NMH, Chandra RK, Saah, AJ. Relation between serum vitamin B6, B12, and folate levels and human immunodeﬁciency virus type 1 (HIV-1) disease progression. J Nutr 1997; 127: 345–351. 147. Burkes RL, Cohen H, Krailo M, Sinow RM, Carmel R. Low serum cobalamin levels occur frequently in the acquired immune deﬁciency syndrome and related disorders. Eur J Haematol 1987; 38:141–147. 148. Paltiel O, Falutz J, Veilleux M, Rosenblatt DS, Gordon K. Clinical correlates of subnormal vitamin B12 levels in patients infected with the human immunodeﬁciency virus. Am J Hematol 1995; 49: 318–322. 149. Boudes P, Zittoun J, Sobel A. Folate, vitamin B12, and HIV infection. Lancet 1990; 335:1401–1402. 150. Beach RS, Mantero-Atienza E, Eisdorfer C, Fordyce-Baum MK. Altered folate metabolism in early HIV infection. JAMA 1988; 259:518. 151. Tilkian SM, Lefevre G, Coyle C. Altered folate metabolism in early HIV infection. JAMA 1988; 259: 3128–3129. 152. Mueller BU, Tannenbaum S, Pizzo PA. Bone marrow aspirates and biopsies in children with human immunodeﬁciency virus infection. J Pediatr Hemat Oncol 1996; 18:266–271. 153. Graham NMH, Sorensen D, Odaka N, et al. Relationship of serum copper and zinc levels to HIV-1 seropositivity and progression to AIDS. J Acquir Immune Deﬁc Syndr 1991; 4:976–980. 154. Koch J, Neal EA, Schlott MJ, et al. Zinc levels and infections in hospitalized patients with AIDS. Nutrition 1996; 12:515–518. 155. Dworkin BM, Rosenthal WS, Wormser GP, Weiss L. Selenium deﬁciency in the acquired immunodeﬁciency syndrome. J Parent Enteral Nutr 1986; 10:405–407. 156. Mantero-Atienza E, Sotomayor MG, Shor-Posner G, et al. Selenium status and immune function in asymptomatic HIV-1 seropositive men. Nutr Res 1991; 11:1237–1250. 157. Cirelli A, Ciardi M, de Simone C, et al. Serum selenium concentration and disease progress in patients with HIV infection. Clin Biochem 1991; 24:211–214. 158. Dworkin BM. Selenium deﬁciency HIV infection and the acquired immunodeﬁciency syndrome (AIDS). Chem Biol Interact 1994; 91:181–186.

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159. Hommes M, Romijn JA, Godfried MH, et al. Increased resting energy expenditure in the human immunodeﬁciency virus-infected men. Metabolism 1990; 39:1186–1190. 160. Melchior JD, Salmon D, Rigaud D. et al. Resting energy expenditure is increased in stable, malnourished HIV-infected patients. Am J Clin Nutr 1991; 53:437–441. 161. Grunfeld C, Pang M, Shimizu L, et al. Resting energy expenditure, caloric intake and short-term weight change in human immunodeﬁciency virus infection and the acquired immunodeﬁciency syndrome. Am J Clin Nutr 1992; 55:455–460. 162. Nahlen BL, Chu SY, Nwanyanwu OC, Berkelman RL, Martinez SA, Rullan JV. HIV wasting syndrome in the United States. AIDS 1993; 7:183–188. 163. Guenter P, Muurahainen N, Simons G, et al. Relatinoships among nutritional status, disease progression and survival in HIV infection. J Acquir Immune Deﬁc Syndr 1993; 6:1130–1138. 164. Palenicek JG, Graham NMH, He YD, et al. Weight loss prior to clinical AIDS as a predictor of survival. J Acquir Immune Deﬁc Syndr Hum Retrovirol 1995; 10:366–373. 165. Semba RD, Graham NM., Caiaffa WT, Margolick JB, Clement L, Vlahov D. Increased mortality associated with vitamin A deﬁciency during human immunodeﬁciency virus type 1 infection. Arch Intern Med 1993; 153:2149–2154. 166. Nduati RW, John GC, Richardson BA, Overbaugh J, Welch M, Ndinya-Achola J, et al. Human immunodeﬁciency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deﬁciency. J Infect Dis 1995; 172:1461–1468. 167. John GC, Nduati RW, Mbori-Ngacha D, Overbaugh J, Welch M, Richardson BA., et al. Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deﬁciency. J Infect Dis 1997; 175:57–62. 168. Mostad SB, Overbaugh J, De Vange DM, Welch MJ, Chohan B, Mandaliya K, et al. Hormonal contraception, vitamin A deﬁciency, and other risk factors for shedding of HIV-1 infected cells from the cervix and vagina. Lancet 1997; 350:922–927. 169. Tang AM, Graham NM, Semba RD, Saah AJ. Association between serum vitamin A and E levels and HIV-1 disease progression. AIDS 1997c; 11:613–620. 170. Baum MK, Mantero-Atienza E, Shor-Posner G, Fletcher MA, Morgan R, Eisdorfer C, et al. Association of vitamin B6 status with parameters of immune function in early HIV-1 infection. J Acquired Immune Deﬁc Syndr 1991; 4:1122–1132. 171. Tang AM, Graham NM, Saah AJ. Effects of micronutrient intakeon survival in human immunodeﬁciency virus type 1 infection. Am J Epidemiol 1997b;143: 1244–1256. 172. Fuchs D, Zangerle R, Artner-Dworzak E, Weiss G, Fritsch P, Tilz GP, et al. Association between imunne activation, changes of iron metabolism and anaemia in patients with HIV infection. Euro J Haemat 1993; 50:90–94. 173. Falutz J, Tsoukas C, Gold P. Zinc as a cofactor in human immunodeficiency virus-induced immunosuppression. JAMA 1988; 259:2850–2851. 174. Baum MK, Shor-Posner G, Lai S, Zhang G, Fletcher MA, Sauberlich H, Page JB. High risk of mortality in HIV infection is associated with selenium deﬁciency. J Acquired Immun Deﬁc Syndr Hum Retrovirol 1997; 15:70–374. 175. Coutsoudis A, Bobat RA, Coovadia HM, Kuhn L, Tsai WY, Stein ZA. The effects of vitamin A supplementation on the morbidity of children born to HIV-infected women. Am J Public Health 1995; 85:1076–1081. 176. Hussey G, Hughes J, Potgieter S, et al. Vitamin A status and supplementation and its effects on immunity in children with AIDS. Abstracts of the XVII International Vitamin A Consultative Group Meeting, Guatemala City. Washington, DC, International Life Sciences Institute, 1996, p. 6. 177. Semba RD, Lyles C, Margolick J, et al. Vitamin A supplementation and human immunodeﬁciency virus load in injection drug users. J Infect Dis 1998; 177:611–616. 178. Coodley GO, Coodley MK, Lusk R, et al. Beta-carotene in HIV infection: an extended evaluation. AIDS 1996; 10:967–973. 179. Mocchegiani E, Veccia S, Ancarani F, Scalise G, Fabris N. Beneﬁt of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS. Intl J Immunopharm 1995; 17:719–727. 180. Allard JP, Aghdassi E, Chau J, et al. Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects. AIDS 1998; 12:1653–1659.

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181. Kelly P, Musonda R, Kafwembe E, Kaetano L, Keane E, Farthing M. Micronutrient supplementation in the AIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial. AIDS 1999; 13: 495–500. 182. Fawzi WW, Msamanga GI, Spiegelman D, et al. Randomised trial of effects of vitamin supplements on pregnancy outcomes and T cell counts in HIV-1-infected women in Tanzania. Lancet 1998; 351: 1477–1482. 183. Sloand E, Pitt E, Chiarello RJ, Nemo GJ. HIV testing state of the art. JAMA 1991; 266:2861–2866. 184. Biggar RJ, Miley W, Miotti P, et al. Blood collection on ﬁlter paper: a practical approach to sample collection for studies of perinatal HIV transmission. J Acquired Immune Deﬁc Hum Retrovirol 1997; 14:368–373. 185. Horsburgh CR, Jason J, Longini IM, et al. Duration of human immunodeﬁciency virus infection before detection of antibody. Lancet 1989; 637–640. 186. Program on communicable diseases. IMCI Bibliography. Integrated management of childhood illness bibliography. Washington, D.C. Pan America Health Organization, 1997. 187. American Academy of Pediatrics. Committee on Infectious Diseases and Committee on Pediatric AIDS. Measles immunization in HIV-infected children. Pediatrics 1999; 103:1057–1060. 188. Hoernle EH, Reid TE. Human immunodeﬁciency virus inferior to children. Am J Health Syst Pharm 1995; 52:961–979. 189. National Pediatric and Family Resource Center and National Center for Infectious Diseases, Centers for Disease Control and Prevention. 1995 Revised guidelines for prophylaxis against Pneumocystis carinii pneumonia for children infected with or perinatally exposed to human immunodeﬁciency virus. MMWR Morb Mortal Wkly Report 1995; 44:1–11. 190. Madhi SA, Gray GE, Huebner RE, Sherman G, McKinnon D, Pettifor JM.Correlation between CD4+lymphocyte counts, concurrent antigrn skin test and tuberculin skin test reactivity in human immunodeﬁciency virus type 1-infected and -uninfected children with tuberculosis. Pediatr Infect Dis J 1999: 9:800–805. 191. Kwi KJ, Peetifor JM,Soderlund N. Paediatric hospital admissions at a South African urban regional hospital:the impact of HIV, 1992-1997 Ann Trop Paed 1999; 19:135–142. 192. Mutombo T, Keusse J, Sagare A. AIDS and malnutrition in a paediatric semi-rural mile of Ivory Coast. Med Trop Mars 1995; 55:357. 193. Campa A, Shor-Posner G, Indacochea F et al. Mortality risk in selenium-deﬁcient HIV-positive children. J Acquir Immune Deﬁc Syndr Hum Retrovirol 1999; 20:508–513. 194. Periquet BA, Jammes NM, Lambert WE et al. Micronutrient levels in HIV infected children. AIDS 1995; 9:887–893. 195. The Working Group on Antiretroviral Therapy on Antiretroviral Therapy and Medical Management of HIV Infected Children. Convened by the National Pediatric and Family HIV Resource Center NPHRC, Newark, NJ. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV infection. April 15, 1999. 196. Saracco A, Musicco M, Nicolosi A, et al. Man-to-woman sexual transmission of HIV: longitudinal study of 343 steady partners of infected men. J Acquired Immune Deﬁc Syndr Hum Retroviol 1993; 6:497–502. 197. Hanenberg RS, Rojanapithayakorn W, Kunasol P, et al. Impact of Thailand’s HIV-control programme as indicated by the decline of sexually transmitted diseases. Lancet 1994; 344: 243–245. 198. De Vicenzi I. A longitudinal study of human immunodeﬁciency virus transmission by heterosexual partners: European Study Group on Heterosexual Transmission of HIV. N Engl J Med 1994; 331: 341–346. 199. Laga M, Alary M, Nzila N, et al. Condom promotion, STD treatment leading to a declining incidence of HIV-1 infection in female Zairean sex workers. Lancet 1994; 344:246–248. 200. Ghys PD, Fransen K, Diallo MO, et al. The associations between cervicovaginal HIV shedding, sexually transmitted diseases and immunosuppression in female sex workers in female sex workers in Abidjan, Côte d’Ivoire. AIDS 1997; 11:F85–F93. 201. Grosskurth H, Mosha F, Todd J, Mwijarubi E, Klokke A, Senkoro K, et al. Impact of improved treatment of sexually transmitted diseases on HIV infection in rural Tanzania: randomised controlled trial. Lancet 1995; 346:530–536. 202. Wawer MJ, Sewankambo NK, Serwadda D, et al. Control of sexually transmitted diseases for AIDS prevention in Uganda: a randomised community trial. Lancet 1999; 353:525–535.

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203. Mandelbrot L, Le Chenadec J, Berrebi A, Bongain A, Beniﬂa JL, Delfraissy JF, et al. Perinatal HIV-1 transmission: interaction between zidovudine prophylaxis and mode of delivery I the French Perinatal Cohort. JAMA, 1998; 280:55–60. 204. Taha TE, Biggar RJ, Broadhead RL, et al. Effect of cleansing the birth canal with antiseptic solution on maternal and newborn morbidity and mortality in Malawi: clinical trial. BMJ 1997; 315: 216–219. 205. Biggar RJ, Miotti PG, Taha TE, et al. Perinatal intervention trial in Africa: effect of a birth canal cleansing intervention to prevent HIV-1 transmission. Lancet 1996; 347:1647–1650. 206. Burns DN, Mofenson LM: Paediatric HIV-1 infection. Lancet 1999; 354(suppl II):1–6. 207. Graham BS, Karzon DT. AIDS vaccine development. In: Textbook of AIDS medicine. 2nd ed. Merigan TC, Bartlett JG, Bolognesi D, eds. Baltimore: Williams and Wilkins, 1999. 208. Semba RD, Neville MC. Breast-feeding, mastitis, and HIV transmission: nutritional implications. Nutr Rev 1999; 57:146–153.

Chapter 11 / Vitamin A Deﬁciency

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Vitamin A Deﬁciency Keith P. West, Jr. and Ian Darnton-Hill

1. INTRODUCTION Vitamin A deﬁciency affects up to 250 million children (1), is responsible for over a million child deaths annually, and is the leading cause of preventable pediatric blindness in the developing world (2). It is an increasingly recognized problem among rural women in many countries and may be a major underlying cause of maternal mortality (3). International recognition of its public health importance (4) and emphasis on its control (5) has brought about substantial political (6–7) and resource commitments, coupled with increased program action (8–12) that provides global momentum to control this nutritional scourge. In recent years, there appears to have been a general decline in the prevalence of severe vitamin A deﬁciency (xerophthalmia) (13), which may reﬂect combined effects of effective programming and socio-economic development. At the same time, sensitive assessment tools have revealed the enormous magnitude of subclinical vitamin A deﬁciency over much of the developing world (1), leaving a clear public-health mandate for its prevention (13). This chapter provides a brief orientation to the vitamin itself, including its chemical structure and dietary sources, followed by discussions of the ocular, health and survival consequences of vitamin A deﬁciency, its epidemiology, clinicopathologic features, diagnosis, treatment, and prevention.

2. THE NUTRIENT: VITAMIN A Vitamin A is involved in regulating numerous key biologic processes in the body, including morphogenesis, growth, vision, reproduction, and cellular differentiation and proliferation. Neither humans nor animals can survive without vitamin A. As an essential nutrient, it cannot be synthesized in primates and, therefore, must be provided from the diet in adequate amounts to meet physiologic needs. A deﬁciency state may arise with prolonged inadequate intake, often coupled with the high, normal demands imposed by rapid growth during childhood, pregnancy or lactation, or by excessive utilization and loss during infection (2).

From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Fig. 1. Chemical structure of vitamin A-active compounds (all-trans retinol, retinyl palmitate, retinal, and all-trans retinoic acid) and `-carotene. Adapted with permission from ref. (22).

2.1. Structure and Nomenclature The term vitamin A is a generic descriptor that refers to fat-soluble compounds with a chemical structure of retinoids and biologic activity comparable to retinol (14). These molecules include retinol, retinyl esters (the dominant form in food), retinaldehyde, retinoic-acid species, and other vitamin A-active metabolic intermediates such as retinoyl glucuronides (15). Retinoic acids (all-trans and 9-cis) are irreversible metabolites of retinol that can fulﬁll some functions of vitamin A, such as controlling cellular differentiation, but not other functions, such as maintaining rod or cone vision. Vitamin A-active compounds are a subset of a much larger family of “retinoids” (16) that share a common, monocyclic chemical structure (Fig. 1). The vast majority of retinoids, however, are synthetic compounds (mostly still under investigation) that are not found in the diet and do not possess vitamin A activity.

2.2. Dietary Sources Vitamin A in the diet derives from preformed vitamin A in animal foods, and carotenoids (provitamin A), mainly from plant sources. Dietary sources of preformed

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vitamin A (mostly as esters) include animal foods such as liver, ﬁsh-liver oils, butter, cheese, milk fat, egg, and, increasingly, a large number of processed, vitamin A-fortiﬁed foods such as ready-to-eat cereal, snack foods, beverages, and nonfat dairy products. Approximately 50 of some 600 known carotenoid pigments are fat-soluble, yelloworange “provitamin A” compounds that can be bioconverted to retinol and other vitamin A compounds following uptake and absorption in the intestinal mucosa. Provitamin A carotenoids are found in yellow fruits and vegetables, such as ripe papaya and mango, carrot and yellow sweet potato, dark green leafy vegetables (embedded in green chloroplasts) and egg. Vitamin A content in food, as found in standard food composition tables, is usually expressed as micrograms of retinol equivalents (RE), which represents the biologic activity of 1 µg of all-trans retinol (17). `-Carotene (Fig. 1) is the most ubiquitous and efﬁciently converted provitamin A carotenoid in food. It has long been held that `-carotene in food is converted to retinol at a ratio of ~6⬊1, representing 1 RE per 6 µg of `-carotene (17). However, recent research suggests that this ratio may be much larger and variable, on the order of ~12⬊1 for `-carotene derived from ripe, yellow fruit and ~26⬊1 for `-carotene derived from vegetables such as green leaves and carrots (19–21). Other common provitamin A carotenoids, that are estimated to be half as efﬁcient as `-carotene in their conversion to vitamin A (17), include _-carotene, `-cryptoxanthin, and zeaxanthin.

3. PUBLIC HEALTH SIGNIFICANCE OF VITAMIN A DEFICIENCY The public health consequences of vitamin A deﬁciency take into consideration its blinding sequelae and its apparent causal role in child mortality. Its speciﬁcity and importance as a problem is evident by the extent, severity, chronicity, and associated health consequences of vitamin A deﬁciency.

3.1. Prevalence Between 125 (23) and 250 (1) million preschool-aged children are likely to be vitamin A-deﬁcient, with high-risk populations located mostly in the periequatorial regions of the world (Fig. 2). The geographic distribution roughly parallels ecological indices of poverty and malnutrition. Although most deﬁciency is “subclinical,” apparent only by biochemical (e.g., serum retinol concentrations), histopathologic (e.g., abnormal conjunctival cytology), or functional (e.g., dark adaptation) test data, this level of deﬁcit can still represent an important threat to child health and survival. Based on serum retinol measurement, a population prevalence of a deﬁcient concentration () 0.35 µmol/L) of * 5% among preschool-aged children identiﬁes vitamin A deﬁciency as a public health problem (Table 1) (24). More sensitive criteria can be also applied to classify a country or region (e.g., using a prevalence cutoff of 10% for serum retinol ) 0.70 µmol/L) or 20% for abnormal conjunctival impression cytology. Vitamin A deﬁciency can also be deﬁned in terms of clinical eye signs, representing moderate-to-severe deﬁciency. At least 3 million young children globally have xerophthalmia (Gr. xeros = drying; ophthalmia = of the eye) (1), the ocular consequences of vitamin A deficiency that include night blindness (XN), conjunctival xerosis (X1A), “Bitot’s spots” (X1B), corneal xerosis (X2), ulceration or necrosis, also called “keratomalacia” (X3) (Table 1). Previously, it was estimated that a half-million children develop corneal xerophthalmia each year in South and Southeast Asia alone (25).

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Fig. 2. Global distribution of vitamin A deﬁciency as a public health problem. Adapted from ref. (1).

Table 1 WHO Classiﬁcation and Minimum Prevalence Criteria for Xerophthalmia and Vitamin A Deﬁciency as a Public Health Program Deﬁnition (code)

Minimum prevalence

Highest-risk groups

Night blindness (XN)

1.0%a

Children 2–5 yr; pregnant/lactating women

Conjunctival xerosis (XIA) Bitot’s spots (X1B) Cornea xerosis (X2) Corneal ulceration keratomalacia (X3) Xerophthalmic corneal scar (XS) Serum retinol <0.35 mol/L <0.70 mol/L Abnormal CIC/RDR/MRDR

— 0.5%a

aProvisional

0.01%a

Children 1–3 yr

0.05%a 25.0%a 10.0%a 20.0%a

Cumulative >1 yr

cut-offs above which community interventions may be warranted. Adapted from ref. 24.

Approximately half of all corneal cases lead to blindness. Mortality among cases of corneal disease has been observed to range from 3–26%, with greater risk associated with concurrent wasting malnutrition (26). Based on decreasing trends in the incidence of corneal xerophthalmia over the past two decades in some historically high-risk regions of the world (Fig. 3) (27), this estimate may more closely approximate global rather than regional occurrence of corneal disease. Even so, vitamin A deﬁciency remains the most common, preventable cause of childhood blindness in the world.

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Fig. 3. Number of admissions (total, all pediatric and cases of xerophthalmia) at the Cicendo Eye Hospital, Bandung, Indonesia between 1981 to 1992. Adapted with permission from ref. (27). A dramatic decline in xerophthalmia admissions likely reﬂects a true decrease given rising pediatric admissions and stable total admissions over the same time period.

3.2. Effects on Child Morbidity and Mortality Vitamin A deﬁciency has long been known as an “anti-infective” vitamin (28). Decades of animal experiments have shown that progressive vitamin A depletion leads to poor growth, weight loss, infection, and death, often before eye signs develop (2,29). The regulatory roles of vitamin A in maintaining epithelial cell differentiation and function and immune competence provide biologic plausibility to its importance in decreasing severity and mortality of infectious diseases (30,31). A modern era of epidemiologic investigation into the role of vitamin A deﬁciency in child mortality began was launched with community-based observations by Sommer and colleagues in the early 1980s that Indonesian children having mild xerophthalmia (XN or X1B), with no other obvious nutritional stress, were 2–3 times more likely to develop diarrhea or respiratory infection (32), and more likely, in a dose-responsive fashion in relation to eye signs, to die (33) over the ensuing 4 mo than children without any xerophthalmic eye signs (Fig. 4). Subsequent studies in India (35) and Thailand (36) corroborated the increased risk of incident respiratory infection with mild xerophthalmia and hyporetinolemia, respectively, although they were unable to conﬁrm an increased incidence of diarrhea among vitamin A-deﬁcient children. Since 1986, eight population-based, vitamin A-child mortality intervention trials, enrolling more than 165,000 children, have been conducted in Southeast (37,38) and South Asia (39–42) and Africa (43,44) (Fig. 5). Results of meta-analyses based on these trials show that, in areas of endemic vitamin A deﬁciency, mortality of children

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Fig. 4. Mortality rates of Indonesian preschool children without xerophthalmia (normal) and by severity of “mild” xerophthalmia (XN < X1B < XN + X1B) (34).

Fig. 5. Percent changes in mortality rates of children between ~6 or 12 mo to <84 mo of age receiving vitamin A compared to children receiving control supplements while participating in community intervention trials in Southeast Asia (Aceh [37] and Java [38], Indonesia); South Asia (Tamil Nadu [39] and Andhra Pradesh [40], India and Sarlahi [41], and Jumla [42], Nepal); and Africa (Ghana [43] and Sudan [44]).Total number of enrolled children >165,000 (2). Adapted with permission.

6–71 mo of age can be reduced, on average, by 23% to 34% following vitamin A supplementation (45–48), depending on studies included and analytic approaches taken in each meta-analysis. This remarkable effect can be partly explained by an ability of vitamin A to lower case fatality from measles by ~50%, as observed in ﬁeld trials and hospital-based measles trials (2,34,49–51) (Fig. 6), mortality from severe diarrhea and dysentery, by ~40% (39,41,42,52) and, based on morbidity ﬁndings from a recent supplementation trial, possibly falciparum malaria (53). Combining mortality effects with regional estimates of both the prevalence of vitamin A deficiency and size of population at risk, it has been estimated that 1.3–2.5 million preventable, early childhood deaths occur each year as a result of underlying vitamin A deﬁciency (23). Amidst the consistent overall effects on child mortality, two seemingly incongruent observations exist: In contrast to evidence relating vitamin A deﬁciency to respiratorytract compromise and infection (1), vitamin A supplementation has not had a consistent

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Fig. 6. Fatality rates of children hospitalized with severe measles who participated in clinical vitamin A trials in England (49), Tanzania (50), and South Africa (51). Risks of mortality of vitamin A recipients relative to controls is *50% in each study (from ref. 34). Adapted with permission.

effect in reducing the incidence, severity, or mortality of acute lower-respiratory infection in children (54). Secondly, vitamin A supplementation of infants under 6 mo of age, either provided directly (42,55,56) or indirectly through maternal provision (57), has generally not been shown to beneﬁt early infant survival, which concurs with a lack of effect on the prevalence of early infant diarrheal and respiratory morbidity (56). The exception to date has been a 64% reduction in infant mortality, with corresponding reductions in sick clinic visits, observed among Indonesian infants randomized to receive 50,000 IU of vitamin A within 24 h after birth (58). The ﬁndings suggest that timing of supplement receipt in early infancy may affect efﬁcacy. An upper limit may also exist with respect to dosage (55), with 50,000 IU or less being preferred to larger amounts. Although apparently safe at this level (56,59,60), the impact of vitamin A intervention on early infant mortality remains an unresolved priority at present.

3.3. Maternal Health and Survival The inﬂuence of vitamin A on survival has recently been extended to the reproductive years of women. An estimated 10–20% of women living in rural, malnourished populations of South Asia experience night blindness during pregnancy or lactation (61–64). Beyond being symptomatic of vitamin A deﬁciency, its occurrence during pregnancy appears to reﬂect a state of chronic vitamin A deﬁciency, anemia and wasting undernutrition (65), increased risk of infection and reproductive morbidity, (65,66) and lower maternal survival during the ﬁrst 1–2 yr following delivery (67). In such (non-HIV positive) populations, as in rural Nepal, improved vitamin A intake, through supplementary or presumably dietary means, at recommended levels, has been shown to substantially reduce risk of mortality related to pregnancy through three months after delivery (Table 2) (3). Among women with night blindness during pregnancy, the survival beneﬁt of an adequate vitamin A intake extended well into the second year post-partum, appearing especially to protect women from fatal infection (67). The evident high prevalence in women, and its associated health consequences, encourages new thinking and efforts to prevent and control vitamin A deﬁciency throughout the life cycle (68).

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Table 2 Impact of Supplementation on Mortality Related to Pregnancy up to 12 wk PostPartum

No. of pregnanciesa No. of deaths Mortality (per 100,000 pregnancies) Relative risk (95% CI) p value

Placebo

Vitamin A

`-carotene

Vitamin A or `-carotene

7241 7651 6704

7747 6633 6426

7201 6626 6361

14,948 666,59 66,395

1.00

0.60(0.37–0.97) 0.51(0.30–0.86) <0.04 <0.01

0.56(0.37–0.84) <0.005

aIncludes 157 pregnancies that were lost to follow-up (43, 70, and 44 in placebo, vitamin A, and `-carotene groups respectively). Adapted from ref. (3).

In HIV-positive populations, a strong, dose-risk gradient has been demonstrated between maternal serum retinol and vertical transmission of HIV (69) and cervicovaginal shedding of HIV DNA (70), suggesting that maternal vitamin A deﬁciency may affect pregnancy outcomes in these high-risk groups. To date, however, vitamin A supplementation of HIV+ pregnant women, beginning in the third trimester, has shown little effect on outcomes such as low birth weight or perinatal mortality (71), or in interrupting transmission of HIV from mother to infant (72,73).

4. HISTORICAL BACKGROUND Vitamin A deﬁciency, as xerophthalmia, has been known to plague humankind over the past 3500 years (Table 3). Night blindness, and its treatment with foods now known to be rich in preformed vitamin A esters such as roasted ox, ass, or beef liver, was reported from ancient Egypt, Greece, and Assyria (74). Medical treatises from Europe, the Middle East, China, and Southeast Asia throughout the ﬁrst and second millennia documented the occurrence of night blindness and therapeutic value of animal liver (74). Clinical descriptions of corneal xerophthalmia ﬁrst appeared in England in the 18th century, followed by additional reports in the 19th and early 20th centuries of its occurrence, in association with infection and poor growth, and cure with animal and ﬁsh liver and oil products (74). Characterization of conjunctival xerosis with superﬁcial accumulation of keratinized cells and bacilli organisms, named “Bitot’s Spot,” was ﬁrst described by von Hubbenet and then by its namesake, Bitot, in France in 1860. The need for, and existence of, indispensable, accessory nutritional factors emerged in the scientiﬁc community in the late 19th century. In Japan in 1904, Mori drew attention to the inadequacy of rice and barley-based diets of children with “Hikan” (a disease that included keratomalacia), and the condition’s rapid clinical response to cod-liver oil (75). Interestingly, the therapeutic or preventive value of dark green leaves (rich dietary `-carotene source) against xerophthalmia was not reported in the early literature. Indeed, Westhoff working in Indonesia in 1911 drew attention to more frequent occurrence of xerophthalmia in areas where green vegetables and animal foods were often and infrequently consumed, respectively (76). The dawning of modern, experimental animal nutrition in the early 20th century, led by ﬁgures such as Hopkins, Frank, Osborne, and McCollum, led to the discovery of “vitamines.” Rat experiments conducted by McCollum and Davis (77) and, at nearly

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Table 3 Historical Benchmarks Regarding Human Vitamin A Deﬁciency Antiquity

Night blindness recognized in Egypt, Greece, Assyria. Fish and animal liver and oil reported as cure. 19th Century Magendie reports corneal xerophthalmia in dogs following dietary manipulation. von Hubbenet and Bitot describe conjunctival xerosis with “Bitot’s Spots.” Budd, in England, describes corneal xerophthalmia in East Indians. Guggenheim reports night blindness with keratomalacia in Russian children during Great Lenten Fast. Lunin concludes an unknown substance in milk is indispensible. 20th Century 1904 Mori reports “Hikan” in Japanese children that responds to cod-liver oil and liver (75). 1912 Hopkins postulates “accessory factors” necessary for life. Funk names these factors “vitamines.” 1913 McCollum and Davis (77), and Osborne and Mendel (78), discover “fat soluble A” (77). 1919 Bloch ﬁnds xerophthalmia in Danish orphans subsisting on milk-fat free oatmeal diet (79). 1928 Green and Mellanby coin term “anti-infective” for vitamin A (81). 1931 Green and Mellanby show cod-liver oil reduces puerperal fever (87). 1932 Ellison reports vitamin reduces measles fatality (49). 1948 Ramalingaswami relates “nutritional diarrhea” to vitamin A deﬁciency (83). 1959 McLaren publishes detailed photo accounts of xerophthalmia (88). 1959–1969 Gopalan and colleagues draw global attention to vitamin A deﬁciency in India (89). 1964 Oomen, McLaren, and Escapini publish the Epidemiology and Public Health Aspects of Hypovitaminosis A (90). 1974 The International Vitamin A Consultative Group is established. 1983–1984 Sommer and colleagues in Indonesia report mild xerophthalmia is associated with increased risk of incident infection (32) and child mortality (33). 1986 Sommer and colleagues report that vitamin A can reduce child mortality in Indonesia (37). 1989 UNICEF World Summit for Children considers vitamin A essential for child survival (91). 1992 At the International Conference on Nutrition in Rome, countries commit to preventing vitamin A deﬁciency (92). 1995 Bioavailability of provitamin A carotenoids in vegetables quantitatively challenged by de Pee and coworkers in Indonesia (18–21). 1998 Christian and colleagues reveal maternal night blindness as a common risk factor for maternal health in Nepal (65–67). 1999 West and coworkers in Nepal report vitamin A or `-carotene supplementation can lower maternal mortality (3). Based partly on refs. (26,28,74); sources for events through 1940s.

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the same time, Osborne and Mendel (78) showed that the additions of small amounts of an ether soluble extract from butter, egg yolk, or milk to the diets could promote growth, reduce morbidity and enhance survival. McCollum called this extract “fat soluble A,” which was shortly thereafter renamed “Vitamine A.” The clinical relevance of the animal ﬁndings quickly became apparent. Bloch, a Danish pediatrician during World War I, observed how orphans subsisting on a fat-free milk, oatmeal, and barleysoup diet were at greater risk of keratomalacia, infection, and poor growth, similar to McCollum’s vitamin A-deﬁcient animals, compared to children whose diet included a modest amount of whole milk (79). He surmised vitamin A deﬁciency to be the underlying cause of “Dystrophia Alipogenetica.” With Wolbach and Howe’s classic description in 1923 (80) of widespread metaplasia and keratinization of epithelial linings of the respiratory and genito-urinary tracts and glandular ducts in vitamin A-depleted animals, loss of the “barrier function” of epithelial linings became one plausible explanation for the associated decreased resistance to infection. While animal experimentation continued (81), clinical studies in humans from the 1920s through the 1940s continued to reveal associations between vitamin A deﬁciency or xerophthalmia and infectious diseases (82,83). The inverse relationship between febrile illness and plasma vitamin A concentration (84), now understood as part of the acute-phase response to infection (85,86), and the potential therapeutic effect of vitamin A in reducing childhood measles fatality (49), puerperal fever in women (87), and other clinically relevant conditions (28) began to be revealed. Epidemiologic studies since the 1950s have guided our understanding of the public health consequences of, and beneﬁts of preventing, vitamin A deﬁciency in human populations in the developing world. Clinical investigations by McLaren in Jordan (88) and Gopalan and colleagues in India (89) provided photographic and clinical detail of conjunctival and corneal xerophthalmia and its interaction with proteinenergy malnutrition. In 1964, Oomen, McLaren, and Escapini’s 46-country/Food and Agricultural Organization World Health Organization (FAO/WHO) “survey” of national health and nutrition institutions for extant reports and data on xerophthalmia indicated the global signiﬁcance of this problem throughout the developing world (90). Lack of population-based data and biases inherent in this type of data collection were appreciated. Nonetheless, the study mobilized further surveys, research, and commitment to prevent vitamin A deﬁciency and served as the forerunner of the current WHO classiﬁcation of countries at risk of vitamin A deﬁciency as a public health problem (1). A combination of a national survey, a longitudinal population study, and several hospital-based clinical studies of xerophthalmia among Indonesian children by Sommer and colleagues in the late 1970s provided the groundwork for our modern understanding of the causation, progression, risk factors, and health consequences of childhood xerophthalmia and vitamin A deﬁciency. Most notable were reports from this work, in the early 1980s, showing that that nonblinding, mild xerophthalmia (night blindness and Bitot’s spots) was associated with high risks of preschool child mortality (33), diarrhea, and respiratory infections (32), which motivated intervention trials that revealed consistent reductions in child mortality with vitamin A (Fig. 5).

5. EPIDEMIOLOGY The epidemiology of vitamin A deﬁciency derives largely from studies of xerophthalmia, the ocular consequences of vitamin A deﬁciency, especially its milder and

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Fig. 7. Availability of vitamin A in the food supply as provitamin A carotenoids (black segments) and preformed retinol (white segments) by region of the world between 1979–1981. Adapted with permission from ref. (93).

more prevalent stages of night blindness (XN) and Bitot’s spots (X1B). It relates to the distribution of deﬁciency by location, person, and time, and identiﬁes risk factors that may be proximal and causal (e.g., diet, care, and morbidity), and less proximal or indirect (e.g., socioeconomic status [SES]). Knowledge of causal exposures can inﬂuence the design and targeting of interventions, whereas the latter often provide the “context” within which vitamin A deﬁciency exists as well as information to target individuals, communities, or larger populations.

5.1. Location Vitamin A deﬁciency is a major public health problem in approx 78 developing countries (1) largely spanning peri-equatorial regions of the world (Fig. 2), where vast numbers of rural and peri-urban poor are exposed to inadequate dietary vitamin A and frequent infections. The extent and severity of deﬁciency appears most widespread where diets generally lack preformed vitamin A (93); for example, across large areas of South and Southeast Asia and Sahelian and sub-Saharan Africa (Fig. 7). This ecologic relationship, reinforced by recent trial-based evidence (18–20), provokes intriguing questions about the ability, and conditions under which, provitamin A carotenoids can fully meet population requirements for vitamin A (21). Based on compiled surveys, the WHO estimates that over 200 million preschool-aged children are vitamin A-deﬁcient in these high-risk regions (1). Current estimates of magnitude do not include older age groups, including women of reproductive age, among whom vitamin A deﬁciency appears to be an important problem (3,61–67,94,95), and so grossly underestimates the size of the problem. Still, geographic patterns of vitamin A deﬁciency help to prioritize regions and countries for assessment and prevention. Vitamin A deficiency tends to cluster within countries, providing insight into causation and groups for targeting. Where national survey or surveillance data exist (96–98), regions with a high prevalence of xerophthalmia, which often share common dietary patterns and other ecologic exposures (e.g., poor development and health infrastructures, strong seasonal ﬂuctuation in food availability, low SES), can be identified (Fig. 8). Importantly, the clustering intensifies within smaller groups. Population-based surveys in Africa (Malawi and Zambia), South Asia (Bangladesh and

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Fig. 8. Clustering of risk of xerophthalmia in Bangladeshi children according to prevalence by district, based on a national xerophthalmia survey. Adapted with permission from ref. (96).

Nepal) and Southeast Asia (Indonesia) reveal a consistent 1.5–2.0-fold risk of xerophthalmia among children in villages where other children have the condition (99–100). More striking is a 7–13-fold higher risk of having, or developing xerophthalmia, among children whose siblings have the condition, compared to children whose siblings are nonxerophthalmic (100) (Table 4). Additionally, similar to children with mild xerophthalmia, siblings of xerophthalmic children are exposed to the same poor diet, child-care, and neglect that may have led to xerophthalmia in the ﬁrst instance (101–102) and have been shown to incur a twofold higher risk of early childhood death (103) compared to children in nonxerophthalmic households. Thus, children with

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Table 4 Crude and Age-Adjusted Village and Household Pairwise Odds Ratios for Risk of Xerophthalmia Among Preschool Childrena Malawi Odds Ratio Crude Village Household Age-adjusted Village Household

ORb

n 2250

1.2 (1.0–1.4) c 2899 4.4 (2.2–8.8) 1.2 (1.0–1.5) 7.3 (3.2–16.7)

Zambia n

OR

2110

1.7 (0.9–3.1) 2449 7.4 (3.0–17.9) 1.7 (0.9–3.2) 7.9 (3.5–17.8)

Indonesia n

OR

22460

1.7 (1.4–2.2) 16337 9.7 (6.6–14.2) 1.8 (1.4–2.2) 10.5 (7.0–15.7)

Nepal n

OR

2240

2.2 (1.5–3.2) 2909 7.7 (4.5–13.2) 2.3 (1.6–3.4) 13.2 (6.0–29.0)

aNumbers of children <6 yr of age in each country: Malawi (n = 5441), Zambia (n = 4316), Indonesia (n = 28,586), and Nepal (n = 4764). bPairwise odds ratio based on alternating logistic regression. c95% conﬁdence intervals in parentheses. Adapted with permission from ref. (100).

xerophthalmia provide not only a rationale for treatment (24), but inform with respect to sibling, household, and community risk.

5.2. Persons at Risk 5.2.1. AGE Xerophthalmia (vitamin A deficiency) presents rather consistent patterns with respect to age, gender, and socioeconomic factors. Based on hospital admissions data from Indonesia (26) and Nepal (104), the incidence of corneal xerophthalmia, which rarely affects more than 0.1% of a population even in high-risk areas (25,26), appears to peak at 2–3 yr of age (Fig. 9). Acute onset of corneal disease may follow any combination of recent weaning from the breast with sole dependence on a poor household diet, an episode of severe measles, persistent diarrhea, other severe febrile illness, or wasting malnutrition, coupled with poor child-care (26). Although the incidence of corneal disease declines beyond age 3, the prevalence of healed, corneal scarring (XS), which represents permanent, potentially blinding sequella, continues to rise among survivors (2,26). The prevalence of mild xerophthalmia (XN and X1B) typically, though not always (105), rises with age through the ﬁfth year of life and often beyond, irrespective of area of the world or age-speciﬁc rates of deﬁciency (96,106–114) (Fig. 10). This pattern may be reﬂecting a rise seen over time as children in high-risk populations continue to be exposed to a poor diet, lacking breast milk (115,117) and insufﬁcient vegetables, fruits, and animal products with adequate vitamin A content (118–121). A similar increase in subclinical vitamin A deﬁciency (e.g., assessed by conjunctival impression cytology or serum retinol) with age might be expected to occur during the preschool years, but this has not been well-established (122,123). However, evidence is accumulating to show that vitamin A deﬁciency persists into adolescence (124)

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Fig. 9. Percent distribution of consecutive cases of corneal xerosis (X2) and ulceration/keratomalacia (X3) by age admitted to eye hospitals in Indonesia (n = 162) (26) and Nepal (n = 295) (104). Adapted with permission.

Fig. 10. Prevalence of xerophthalmia by age from population-based eye surveys in ﬁve countries. Adapted with persmission from refs. (107–109,111,112).

and adulthood, particularly among females of reproductive age (61,65,125–128). This risk becomes most apparent during pregnancy when, in rural South Asia, 10–20% of women report being night blind (61–67). Early reports from Africa suggest similar, high risks of night blindness among women of reproductive age (129).

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5.2.2. GENDER Boys tend to show a higher prevalence of mild xerophthalmia than girls throughout the preschool and early school-aged years (2,26,113,114,130–132). Similarly, experimental studies reveal increased vulnerability of male vs female animals to vitamin A depletion with respect to growth, vitamin A status, and survival (133), suggesting there may be a genetic basis to this risk difference. The gender bias is less apparent for subclinical (biochemical) deﬁciency (122) and has not been observed with respect to severe, corneal xerophthalmia (26). Variation in how boys and girls tend to be fed across cultures is likely to be the dominate cause of gender differences in risk (106,134). 5.2.3. SOCIOECONOMIC STATUS (SES) In general, socioeconomic well-being covaries with the risk of vitamin A deﬁciency, presumably by inﬂuencing adequacy of diet, hygiene, and care among children. Studies across cultures reveal low socioeconomic status of households in which xerophthalmic children reside compared to nonxerophthalmic households, reﬂected by poor parental education (26,96,103,119,123,132,135–137), landholding (26,96,103,135,138), housing quality (26,103,119,138), and hygiene (26,103,136), ownership of small assets (103,135,136,138) and draft animals (103,135), and history of child mortality (26,103,119). Not surprisingly, women with maternal night blindness also emerge from socioeconomically disadvantaged families (65). Typically, odds ratios for xerophthalmia lie between 1.5 and 2.5 when comparing risks among families with low vs higher SES. Socioeconomic inﬂuence on variation in serum retinol has been less consistently observed, with a clear, positive association among Bangladeshi school-aged children (5–12 yr) (139), but neither among adolescent girls in Dhaka (127) nor Indonesian preschoolers (122). Homeostatic mechanisms that maintain serum retinol across wide variation in vitamin A intake may make this association more difﬁcult to observe when serum retinol is expressed as a continuous variable. At the community level, high-risk villages, marked by the presence of * 1 child with xerophthalmia, tend to be poorer than those where no children have xerophthalmia (119). Differentials in SES cannot be relied on to predict risk of vitamin A deﬁciency, but do provide the context in which vitamin A deﬁciency persists and, in part, a basis for understanding how vitamin A deﬁciency may cluster within households and communities (2).

5.3. Periodicity Periodicity in risk of vitamin A deﬁciency is captured mostly by the inﬂuence of season and long-term trends on incidence or prevalence. Spring peaks in xerophthalmia were widely noted in early 20th century China, Europe, and Japan, variably coinciding with the spring growth spurt, changes in diet, and the diarrhea season (2). Drought increases risk of xerophthalmia (140,141). In rural South Asia, the incidence of xerophthalmia follows a predictable seasonality, waxing during the hot, dry season (March–June) and waning during the monsoon period (July–August) to a low level that is sustained beyond the major rice-harvest months of November and December (142). This annual cycle is best depicted by Sinha, who clinically examined 300 preschool children in the Village of Ichag, West Bengal, each month for over 2 yr (Fig. 11) (143). The seasonal peak of night blindness and Bitot’s spots is preceded by a period of high growth that follows the major harvest, which presumably draws down vitamin A

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Fig. 11. Seasonality of prevalence of mild xerophthalmia in Ichag Village, West Bengal, India over a 2-yr period. Data to right of arrow represent control group only among children who participated in a placebo-controlled vitamin A trial (143).

reserves, and coincides with a period of low intake of fruits and vegetables and high incidence of diarrhea and measles (142–144). Appearance of the mango season coupled with slower growth related to reduced food availability may partly explain the decrease in xerophthalmia late in the monsoon period. Seasonal patterns provide insight into the timing and nature of interventions, which should aim to mute the seasonal peak (e.g., distributing high-potency vitamin A prior to the highest-risk season) and, wherever feasible, address dietary and morbidity-related causes (e.g., promoting gardens or vegetable marketing, assuring high measles-vaccine coverage of vitamin A deﬁciency), wherever feasible (24,68,144–145). Risk of vitamin A deﬁciency can also shift over long periods of time that likely reﬂect gradual improvements in economic development, food consumption, health services, and environment (146). Though time-trend data are absent, the past century has witnessed the virtual disappearance of xerophthalmia from industrialized Western Europe, North America, and Japan. More recently, in Indonesia, the risk of potentially blinding vitamin A deﬁciency markedly decreased from the late 1970s to the early 1990s, reﬂected by a 75% reduction in the national prevalence of xerophthalmia (112) and a well-documented decline in xerophthalmia admissions to the Cicendo Eye Hospital in Bandung (Fig. 3) (27). Such progress, however, can be reversed in the presence of political and economic turmoil, as when xerophthalmia began to reappear in Indonesia following its economic collapse in the late 1990s (146,147).

5.4. Proximal Causes Vitamin A deﬁciency, as a public health problem, results from a chronic, dietary insufﬁciency of vitamin A, either preformed or from precursor carotenoids. It often occurs in association with protein-energy malnutrition, other micronutrient deﬁciencies and, as part of a “vicious cycle” with infection, in which one exacerbates and increases vulnerability to the other.

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5.4.1. BREAST FEEDING In afﬂuent populations, newborns are normally born with low liver stores of vitamin A that increase rapidly after ~3 mo of age throughout the preschool years (148–150), presumably reﬂecting dietary sufﬁciency from breast milk and complementary foods that promote storage of vitamin A in relation to normal requirements for growth and other needs. In malnourished societies, liver vitamin A stores may fail to accumulate beyond early infancy (150). This may be owing, in part, to a combination of low breast-milk vitamin A concentration, which is often half that of breast milk from wellnourished populations of women (150–151). Still, breast milk provides a critical dietary source of vitamin A (79,150–152) that may protect children from xerophthalmia. In many populations, breast feeding through the third and even fourth year of life is associated with age-adjusted odds ratios of 0.1–0.5, representing 50–90% reductions in the probability of developing xerophthalmia compared to children who have ceased breast feeding (26,115–117,153–156). In Malawi, accelerated weaning, involving both premature introduction of complementary foods (at 3 vs 4 mo of age) and early cessation of breast-feeding was associated with increased risk of preschool xerophthalmia (116). A dose-response association was observed in Nepal: children who were breast fed up to 10 or more times/d were 68 and 88%, respectively, less likely to have xerophthalmia than children of the same age who had ceased breast feeding (103) (Fig. 12A). Infectious illnesses, such as protracted diarrhea, measles, or severe respiratory infection may weaken the protection that is apparent with breast feeding. (115) 5.4.2. HOUSEHOLD DIET The mix of complementary foods offered to weanlings can modify or even eliminate the excess risk of xerophthalmia associated with the loss of breast milk from the diet. In Indonesia, where no association existed between breast feeding and xerophthalmia in the preschool years (Fig. 12B), children not routinely given milk, egg, yellow fruits and vegetables, dark green leaves, or meat/ﬁsh in the ﬁrst 12 mo of weaning were ~3 times more likely to be xerophthalmic than matched-control children given these foods (119). Similarly, in Nepal, protective odds ratios against xerophthalmia in the preschool years ranged from 0.09–0.41 for regular (* 3 ×/wk) consumption of meat, ﬁsh, egg, and mango in the ﬁrst two yr of life (103). Feeding histories of younger siblings in the ﬁrst two years of life were similar to the cases and controls in the study (Table 5) (101), reﬂecting a chronically poor diet in high-risk households. Numerous epidemiologic studies provide the basis for a progression of complementary feeding that appears to guard children from xerophthalmia through the preschool years. Intake of sweet, yellow fruit (mango and papaya) are strongly protective in the second and third years of life, denoted by a solid line in Fig. 13. As the inﬂuence of breast milk weakens, dark green leafy vegetables appear strongly protective from the third year onward. Finally, after infancy routine consumption of animal foods with preformed vitamin A (egg, dairy products, ﬁsh, and liver) appear to be highly protective (2,26,119,153,155–162). How and with whom children eat their meals may affect their risk of vitamin A deﬁciency. Detailed ethnographic studies in Nepal have shown that rural children are twice as likely to consume vegetables, fruits, pulses, meat or ﬁsh, and dairy products when they share a plate with another relative during meals than when left to eat alone (163). Among plate sharers, however, chronically vitamin A-deﬁcient children (i.e.,

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Fig. 12. (A) Percent of rural Nepalese children breast feeding by age among cases of xerophthalmia (dashed line) and age-sex matched nonxerophthalmic controls (solid line). OR, odds of breast feeding among cases relative to controls. * denotes that 95% conﬁdence interval excludes the value 1.0 (103). (B) Percent of rural Indonesian children breastfeeding by age among cases of xerophthalmia (dotted line) and their age-sex matched nonxerophthalmic controls (solid line). Both distributions are virtually superimposed (119). Adapted with permission.

those with a known history of xerophthalmia 1–2 yr before) were 1.7 times more likely to share a plate at meal time with an adult male (OR, 95% CI: 1.0–2.8) than lower risk children residing in nonxerophthalmic households (163). Sharing a plate at mealtime with a female of any age, on the other hand, was “protective” in its association with childhood xerophthalmia (OR = 0.6; 95% CI: 0.4–0.9). Paradoxically, this suggestive pattern of women assuring dietary adequacy for children, in some cultures, may predispose mothers themselves to vitamin A deﬁciency. In Nepal, for example, pregnant

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Table 5 Correlations in Siblings’ Feeding Patterns and Reported Frequency of Consumption of Selected Food Items (n = 67 Focus Child and Younger Sibling Pairsa) Correlation between siblings Speciﬁc food items Preformed vitamin A sources Meat Fish Traditional tonic Animal milk Other breast milk Eggs Carotenoid sources Mango Dark green leafy vegetables (DGLVs) Papaya

Spearman’s rank correlation

p value

0.38 0.39 0.38 0.66 0.50 0.53

<0.002 <0.002 <0.002 <0.001 <0.001 <0.001

0.54 0.33 0.14

<0.001 <0.007 0.27

aOnly younger siblings age >24 mo at time of interview used. Adapted with permission from ref. ref. (101).

Fig. 13. Composite depiction of age-speciﬁc protection against xerophthalmia conferred by food sources of vitamin A based on numerous epidemiologic studies in Southeast and South Asia and Africa. Solid bar denotes strong, consistent evidence of protective association; dash indicates weaker epidemiologic evidence. Adapted with permission from ref. (26).

women with night blindness were ~50% as likely as lower risk women to consume vitamin A-rich foods, especially in the food-scarce hot, dry, and monsoon seasons (65), and following the Indonesian economic crisis, mothers appeared to sacriﬁce their egg intake for their children (164). 5.4.3. INFECTIOUS MORBIDITY Vitamin A deﬁciency and infection interact within a “vicious cycle” (29), whereby one exacerbates and increases vulnerability to the other. The bi-directional relationship complicates frequent cross-sectional evidence of depressed plasma retinol levels with diarrhea, acute respiratory infections, measles, malaria, HIV/AIDS, and other

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infectious illnesses (2,36,66,85,165,166). However, prospective studies show that infection can induce vitamin A deﬁciency through a variety of ways, depending on the cause, duration, and severity of infection and vitamin A status of the host at onset. Serum retinol may be depressed because of decreased dietary intake or absorption owing to diarrhea or intestinal pathogens (167–169), impaired or accelerated hepatic depletion of retinol reserves (170), increased retinol utilization by target tissues, or increased urinary losses (171–174), and is associated with the acute-phase response (66,85,174). Hyporetinolemia may adversely affect immune competence, which could exacerbate or predispose children to infection (30). Urinary retinol loss, reﬂecting losses in body stores, can vary greatly by type and severity of infection. In a Bangladesh study, 6, 19, 17, and 65% of children hospitalized with dysentery, watery diarrhea, pneumonia, or sepsis excreted more than 0.07 µmol (20 ug) of retinol in urine/d, corresponding to 10% of a preschool child’s estimated metabolic requirement. Total urinary excretion of retinol per episode of sepsis was 6.0 µmol, amounting to ~20% of an average young child’s (3-mo) liver reserve of 35 µmol, or 75% of a marginally vitamin A-nourished child’s much lower liver reserve (e.g., 8 µmol) (173). This suggests that severe infection could acutely decompensate vitamin A nutriture and precipitate xerophthalmia. Indeed, in a prospective study in Indonesia, preschoolers with either diarrhea or acute respiratory disease were twice as likely to have developed xerophthalmia in a subsequent 3-mo period than healthier children (175). Severe diarrhea, dysentery, measles, and other severe, febrile illnesses are frequently reported to precede corneal xerophthalmia (2).

6. CLINICO-PATHOLOGICAL FEATURES 6.1. Xerophthalmia Anterior segment changes in the eye, consisting of conjunctival and corneal xerosis, and corneal ulceration and necrosis, and retinal dysfunction leading to poor dark adaptation and night blindness, comprise the ocular consequences of vitamin A deﬁciency. Active “xerophthalmia” includes all of these ocular stages of deﬁciency, plus less studied and understood lesions in the retinal pigment epithelium, described as “xerophthalmic fundus” (26,176). These fundal changes are not considered further here. Healed corneal scars resulting from corneal xerophthalmia are not considered “active” but represent the potentially blinding sequelae of xerophthalmia (24,26). 6.1.1. NIGHT BLINDNESS (XN) Night blindness is the earliest, speciﬁc clinical manifestation of vitamin A deﬁciency and is usually the most prevalent stage of xerophthalmia. Its occurrence reﬂects a failure in rod photoreceptor cells in the retina to maintain peripheral vision under scoptopic (or dimly lit) conditions. Rod outer segments contain large amounts of a protein, opsin, which binds covalently with 11-cis-retinal, acting as a chromophore, to form rhodopsin (“visual purple”). Light exposure, even at very low levels, to the back of the eye “bleaches” rhodopsin, causing 11-cis-retinal to isomerize (change its conﬁguration), yielding all-trans-retinal and a return to opsin. This reaction initiates an electrochemical impulse that travels along the optic nerve to the brain that results in vision. The “visual cycle” is completed as all-trans-retinal is reduced to vitamin A alcohol (all-trans-retinol), which is carried to the pigment epithelium where it

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Table 6 Serum Retinol in Night Blind and Non-night Blind Preschool Children and Pregnant Women Preschool children Indonesia

Number Serum retinol (umol/L) Mean SD Below 0.70 (umol/L) % Odds ratio (95% CI) “Sensitivity”a “Speciﬁcity”b Reference

Pregnant women

Bangladesh

Nepal

Cases

Controls

Cases

Controls

Cases

Controls

268

222

87

97

90

85

0.47 0.21

0.70 —

0.65 0.37

0.78 0.33

0.72 0.41

1.03 0.39

82 5.59

45

61 2.13

42

52 4.68

21

(3.84–8.60) 82% 55% (178)

(1.08–2.05) 61% 58% (137)

(2.31–9.56) 52% 91% (65)

aPercentage

of night-blind cases with serum retinol <0.70 umol/L. of (non-night blind) controls with serum retinol *0.70 umol/L. Adapted from refs. (65,137,178).

bPercentage

undergoes esteriﬁcation, isomerization, and oxidation to 11-cis-retinal. Vitamin A aldehyde is then returned to the rod outer segment to again form rhodopsin (177). Lack of vitamin A disables the visual cycle, resulting in poor vision in dim light that, if sufﬁciently severe, results in night blindness. Typically, a history of night blindness can be elicited using a local term for the condition, often translated as “chicken eyes” (which lack rods and, thus, night vision) or “twilight” or “evening” blindness (2,24,26). A history of night blindness is associated with low-to-deficient serum retinol concentrations in preschool-aged children (2,26,137,178,179) and pregnant women (65), compared to area-age/gestational age-matched controls. However, the odds of having low serum retinol (< 0.70 µmol/L) by night-blind status seems to vary across population groups (Table 6). The proportion of cases of XN with low serum retinol (“sensitivity,” or co-positivity) was higher in Indonesian children (82%) than in either Bangladeshi children (61%) or Nepalese pregnant women (52%), whose sensitivity was similar and low. Nutritional and disease conditions that could contribute to night blindness and be more prevalent in South Asia (e.g., zinc deﬁciency, wasting, anemia, infection), could partially blur its relationship with serum retinol (65–67,162) relative to less malnourished populations in Southeast Asia (26). On the other hand, “speciﬁcity” (or co-negativity) was excellent among Nepalese women (91%), suggesting that the condition may be more clearly ascertained in women than children. 6.1.2. CONJUNCTIVAL XEROSIS WITH BITOT’S SPOTS (X1B) Vitamin A deﬁciency leads to a keratinizing metaplasia of mucosal surfaces of the body, including the bulbar conjunctiva. In chronic deficiency, xerosis of the

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Fig. 14. Bitot’s spot (X1B). Adapted with permission from refs. (24,26).

conjunctiva appears as a dry, nonwettable, rough or granular surface, best seen on oblique illumination from a hand-light (2,24,26,176). On the ocular surface, the tear ﬁlm breaks up, revealing a xerotic surface that has been likened to “sandbanks at the receding tide” (180). Histologically, the lesions represent a transformation of normal, surface, columnar epithelium, with abundant mucous-secreting goblet cells, to a stratiﬁed, squamous epithelium that lacks goblet cells (24,176). In advanced xerosis, grey-yellow patches of keratinized cells and saprophytic bacilli called “Bitot’s spots” may aggregate on the surface, temporal to the limbus and, in more severe cases, on nasal surfaces as well (Fig. 14). The lesions may be bubbly, foamy, or cheese-like in appearance (176). 6.1.3. CORNEAL XEROSIS (X2), ULCERATION, AND NECROSIS (X3) Corneal xerophthalmia represents acute decompensation of the cornea, representing a sight-threatening medical emergency (2,24,26,176) that is also associated with high case fatality (26). Mild xerosis (“drying”) presents as superﬁcial punctate erosions that lend a hazy, nonwettable, and irregular appearance to the cornea on handlight examination. Usually both eyes are involved. With increased severity the cornea becomes edematous and takes on a dry, granular appearance, described like the “peel of an orange” (26). Vitamin A therapy successfully treats corneal xerosis, though in advanced disease, thick plaques of corniﬁed epithelium form that may slough off. Ulceration can be round or oval in appearance, shallow or deep to the stroma, usually

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Fig. 15. Corneal xerophthalmia/keratomalacia (X3) (24,26).

sharply demarcated and often peripheral to the visual axis. Usually, only one ulcer forms in the affected eye. Vitamin A treatment will heal the tissue leaving a opaque stromal scar, or leukoma. Iris may plug a perforated cornea, forming an adherent leukoma on healing. Keratomalacia (“corneal melting or softening”) refers to necrosis of cornea, forming initially opaque localized lesions that can expand rapidly to cover and blind the cornea (Fig. 15). Therapy with vitamin A leaves a densely scarred cornea, often with resultant phthisis (shrunken globe) or staphyloma (protuding cornea) (176).

6.2. Infection Vitamin A deﬁciency predisposes individuals to severe infection (32) and a higher risk of mortality in children (2,4,33,37–46) and women, at least during nutritionally stressing periods of pregnancy and lactation (3,67). Multiple roles of vitamin A in maintaining epithelial barrier function and regulating cellular and antibody-mediated immunity (30,31) provide biologic plausibility for vitamin A deﬁciency as a cause of morbidity.

6.3. Poor Growth Experimental vitamin A depletion in animals causes a deceleration in weight gain to a “plateau,” as hepatic retinol reserves become exhausted, and eventual weight loss (77,78,133). This dynamic is difﬁcult to observe, however, in children. Corneal xerophthalmia is associated with severe linear growth stunting and acute wasting

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Fig. 16. Mean height by age by xerophthalmia status and age of rural Indonesian children surveyed in 1978–1979. Corneal cases were shorter than children with X1B who, in turn, were shorter than matched controls without xerophthalmia. The latter were similar in height to a larger, nonxerophthalmic surveyed population. Adapted with permission from ref. (2).

malnutrition, likely owing to a combination of protein-energy malnutrition, infection, and multiple micronutrient deﬁciencies (2,26). Mild xerophthalmia (XN or X1B) is associated with moderate stunting (Fig. 16) and mild wasting (2,26,119,162). Spontaneous recovery from xerophthalmia, likely owing to dietary improvement, has been associated with gain in weight but less noticeable catch-up in linear growth over a 6-mo period (181). In general, vitamin A supplementation can not be expected to improve measurably weight or height gain in a population (182–187), although it may lead to measurable increases in lean body mass reﬂected by incremental upper-arm muscle area (185,188) and there may be growth responses in subsets of the population (188) or perhaps on a seasonal basis (185,189). In some settings, vitamin A may result in accelerated linear growth (38,60,190–192), particularly among children who are moderately to severely vitamin A deﬁcient and for whom the deﬁciency may be growth-limiting (185,191,192), though intercurrent infection may blunt the growth response (193). Moderately ill (e.g., children recovering from severe measles), wasted, or clinically vitamin A deﬁcient children may show marked ponderal and apparent lean body gains following vitamin A supplementation (185,194,195).

7. TREATMENT Children with any stage of xerophthalmia should be treated with vitamin A according to WHO treatment guidelines; i.e., with a high dose of vitamin A at presentation, the

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Table 7 Vitamin A Treatment and Prevention Schedules Preventionb Age <6 mo 6–11 mo *1 yr Women

Treatment at diagnosis

Dosage

Frequency

150,000 IUa 100,000 IUa 200,000 IUa 200,000 IUc

150,000 IUc 100,000 IUc 200,000 IUc 400,000 IUb

At 6, 10, 14 wks Every 4–6 mo Every 4–6 mo )8 wk after delivery

aTreat all cases of xerophthalmia and measles with the same age-speciﬁc dosage the next day and again 1–4 wk later. bProvisional recommendations of the International Vitamin A Consultative Group (IVACG), Annecy, France, 30 Oct.–2 Nov., 2000. cFor women of reproductive age, give 200,000 IU only for corneal xerophthalmia; for milder eye signs (night blindness or Bitot’s spots), give women 5,000–10,000 IU/d or )25,000 IU/wk for *4 wk. Adapted with permission from refs. (24,196).

next day, and 1–4 wk later (Table 7) (24,176,196). Supportive nutritional and antibiotic therapy should be considered, as indicated by the patient’s condition. Night blindness responds within 24–48 h of high-potency vitamin A treatment leading to a return to normal scotopic (night-time) vision (24,178,196). However, the efﬁcacy of the WHO guidelines to treat pregnant night-blind women with either 25,000 IU each week or 10,000 IU daily for at least 4 wk is presumed. A randomized trial in Nepal recently reported that long-term, weekly supplementation with ~23,000 IU only prevented about two-thirds of maternal night-blindness cases (63), suggesting that a higher, more frequent, or sustained dosage may be needed to achieve optimal efﬁcacy. Bitot’s spots (X1B) in pre-school children generally respond to high-potency vitamin A within 2–5 d, becoming smaller in size and disappearing within 2 wk. A small percentage of lesions may persist as smaller aggregates on the conjunctival surface for months (24,26). In older children, X1B may be more refractory to vitamin A. Although similar in clinical appearance, factors associated with responsive and nonresponsive X1B differ: the latter are more frequent with increased age, associated with localized vs more generalized metaplasia and goblet-cell loss, less often associated with night blindness, and observed at higher serum retinol concentration than responsive X1B (197–199). Corneal xerophthalmia can rapidly lead to blindness without immediate vitamin A treatment. Corneal xerosis quickly responds to vitamin A, usually within 2–5 d of therapy, with the cornea returning to normal without permanent sequellae within 1–2 wk (24,26). Shallow, small corneal ulcers, that usually form peripheral to the visual axis, heal with minimal structural damage or risk of visual loss. Ulcers will form an opaque stromal scar or leukoma. Ulcers that perforate the entire cornea (through Descemet’s membrane) and are plugged with iris will, on healing, form an adherent leukoma. These are often at the periphery of the cornea, and leave central vision of the healed eye intact (24,176). Corneal necrosis (keratomalacia) must be treated immediately with standard vitamin A therapy, coupled with topical antibiotics and other nutritional measures (24,26). Healing may induce large lesions to slough, forming decemetoceles (176).

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Children with severe measles are likely to beneﬁt from vitamin A therapy. Cases should be treated the same as children with xerophthalmia. Such treatment is likely, under most conditions, to reduce the severity of complications, accelerate recovery, and lower case fatality (2,24,26,196).

8. PREVENTION The main cause of vitamin A deﬁciency is an insufﬁcient dietary intake of vitamin A, probably compounded by poor bioavailability of provitamin A carotenoids from vegetable-based diets (18–21) that dominate the developing world (Fig. 2). Other important contributing factors include the increased requirements for vitamin A at certain stages in the life cycle (i.e., during periods of high growth, pregnancy, and lactation) and following episodes of infection (especially measles). Sociocultural factors such as intra-household distribution and gender preference (1,68) and other economic constraints to achieving an adequate diet and health provide the context within which deﬁciency occurs and prevention must take place (200). However, control of vitamin A deﬁciency need not await correction of “root” causes of poverty that, in the long run, would be expected to relieve most poor populations of the burden of malnutrition, including vitamin A deﬁciency. Effective prevention should ﬁrst and foremost increase vitamin A intake to adequate levels alongside efforts to reduce infectious diseases. Prevention, for purposes of implementation and estimating resource needs, can be categorized into three partly overlapping and complementary approaches (2,5): 1. Dietary diversiﬁcation: increasing vitamin A intake from locally available foods, achieved through nutrition education and social marketing, home or community garden programs, and other measures to improve food security; 2. Fortiﬁcation: taking advantage of existing consumption patterns of fortiﬁable foods to carry vitamin A into the diets of populations; and 3. Supplementation: encompassing community-based efforts to provide vitamin A supplements to high-risk groups, typically preschool-aged children and mothers within 6–8 wk after childbirth.

8.1. Dietary Diversiﬁcation Improving dietary intake of high-risk groups requires an adequate, affordable, and diverse supply of food sources of vitamin A, that preferably includes preformed sources of vitamin A throughout the year, and their sufﬁcient consumption, especially by those at highest risk: infants, young children, adolescent girls, and women of reproductive age. A ﬁrst-line, dietary intervention to protect infants and young children from vitamin A deﬁciency is prolonged breastfeeding, which consistently exhibits a protective association with respect to mild xerophthalmia through the fourth year of life (2,115–117,153–155), although data are lacking to show change in vitamin A status that can occur in children from breastfeeding promotion. With weaning, routine provision of soft yellow fruits and vegetables, dark green leaves, eggs, and other food sources of vitamin A should be provided (2,5,10,11,26,119,127,153) that, in controlled studies, have been shown to raise low serum retinol concentrations in children (reviewed in ref. 2). Where supply of food sources of vitamin A has been deemed inadequate, homestead gardening that combines appropriate horticultural, credit and nutrition education or

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social marketing services, (201–203) has shown promise in raising vitamin A intakes (145) and improving household economic returns and, therefore, food security (204). Further, food-based interventions that promote participation of women and rally community support through creative social marketing approaches appear capable of changing behavior and enhancing vitamin A intake (10,145,200,205–208) and, in some instances, have been shown to improve vitamin A status (200,209). Given evidence of poorer bioavailability of green leaf provitamin A carotenoid than previously thought (18–21,210), food-based approaches that promote a variety of carotenoid-containing foods to enhance vitamin A status are more likely to succeed in raising both vitamin A intake and status (145,157,211) than efforts that focus on one food (2). An exception to date has been a social marketing program that promoted the intake of egg, an important source of preformed vitamin A, in Indonesia that was able to modestly raise vitamin A intake and status (200). Still, evidence of impact on status and health, sustainability and cost, as borne by different participants, of long-term food-based interventions are generally lacking (5).

8.2. Fortiﬁcation Fortiﬁcation of food represents an increasingly important food-based approach to control vitamin A and other micronutrient deﬁciencies as fortiﬁable foods (“vehicles”) gain entry into markets of the developing world (9) and as fortiﬁcation of food-aid products becomes more common (213,214). Numerous foods have long been fortiﬁed in economies where food production and marketing systems are highly industrialized, integrated, and readily reach the consumer (212,215). Fortiﬁcation is likely to be most effective when one or more food “vehicles” are widely consumed by high-risk groups and their intake is reasonably narrow across other segments of a population (to minimize risk of overconsumption), processing and distribution are centralized (in a limited number of facilities to maintain quality control), organoleptic change from addition of vitamin A is imperceptible over time under ambient conditions, and costs of fortiﬁcation are small relative to the product itself, and capable of being absorbed, ultimately by the consumer (2,212). Fortiﬁcation has been slow in effectively scaling up in developing countries compared with experiences in the industrialized world. This has been owing largely to a lack of availability and market potential for fortiﬁable foods in most food economies where vitamin A deﬁciency remains a public health problem. Some notable successes exist, however, especially with respect to vitamin A fortiﬁcation of sugar in Guatemala and other Central American countries. Over a period of two decades, effectiveness studies demonstrated improved vitamin A status, and vigorous and persistent efforts were made by government and the food industry to ﬁnd economically sound solutions to recoup costs, develop enabling legislation, and market successfully vitamin A-fortiﬁed sugar in these countries (216–219). Vitamin A-fortiﬁed monsodium glutamate, a product that is widely consumed throughout Southeast Asia as a meal ﬂavor-enhancer, improved breast milk and serum retinol concentrations (190,220,221) as well as the growth and survival of preschool-aged children (38) in the Philippines and Indonesia, but product discoloration, problems with stability and packaging under highly humid conditions, difﬁculties in product pricing, and loss of manufacturer conﬁdence (2,222,223) led to failure in scaling up this potentially effective fortiﬁed product. Recently, fortiﬁcation of unrefrigerated margarine (224) and wheat flour (225), both consumed by the

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rural poor in the Philippines, has been shown to improve vitamin A status of children. These results, added to acceptable retention of vitamin A in such products under tropical, humid conditions (224,226), add to a growing variety of foods that can be fortiﬁed with vitamin A. Further, a staple such as wheat ﬂour offers the opportunity for multi-nutrient fortiﬁcation that could lead to the prevention of several micronutrient deﬁciencies (227). Cost-analysis data is sparse but ﬁndings, for example, from Guatemala suggest that, where the critical targeting and central-processing conditions are met, fortiﬁcation can be 2–4 times more cost-effective in reaching beneﬁciaries with adequate amounts of vitamin A than vitamin A capsule distribution or dietary diversiﬁcation efforts (228). Encouraging ﬁndings related to impact and costs, expanding product potential and an enhanced global momentum suggest that the time is ripe for expanding fortiﬁcation to prevent micronutrient malnutrition (212,229). Besides food items mentioned earlier, other vehicles for vitamin A fortiﬁcation include fats and oils, tea, milk/milk powder, cereals, other ﬂours, instant noodles, whole wheat, rice, salt, soybean oil, and infant formulas (2,215,229). In addition, naturally high sources of vitamin A can be protected during processing or used to fortify other products. For example, in India, red palm oil is added to other edible oils and Malaysia has done much work with retaining the `-carotene content of palm oil during processing (230). This kind of innovation will be required to advance fortiﬁcation as an effective and practical measure of control in the developing world.

8.3. Supplementation Periodic, high-dose vitamin A supplementation remains the most widely practiced, direct means to prevent deﬁciency by governments throughout the world (231,232). Each year UNICEF procures and distributes over 400 million vitamin A supplements to nearly 80 countries. This number excludes supplements distributed in several other countries of high vitamin A deﬁciency endemicity (i.e., India, Indonesia, Vietnam and China) (N. Dalmiya, UNICEF, personal communication, 1999). The rationale for supplementation with a high dose of vitamin A rests on the assumption that, as a fat-soluble nutrient, it is stored in the body, principally in the liver, and released in association with transport proteins to meet demands of body tissues, as required. The same physical form of oral supplement (i.e., typically a gelatinous capsule or oily syrup delivered with a spoon or squirter), used for treatment is also used for prophylaxis, varying only the dosage (fraction or multiples of a standard dose) according to purpose and age of recipients (24,196). This facilitates greatly the logistics of supplying supplements for programs. Thus, a theoretical 4–6 mo supply (usually 100–200,000 IU or ~30–60 mg retinol equivalents, or RE) (Table 7) provided at one time can establish a nutritional reserve for use during periods of reduced dietary intake or increased need (69,196). The efﬁcacy of high-dose vitamin A prophylaxis appears to be ~90% in preventing children from developing xerophthalmia over a 6-mo period (2), despite likely dosage absorption of only 30–50% under prevalent conditions of morbidity and malnutrition often found in developing countries (2,233), seasonal relapse that can occur during supplement intervals (117,234,235), and intercurrent infection that can reduce the period of protection afforded against low serum retinol and liver-store depletion (236). Program effectiveness, however, is lower. Assuming sufﬁcient, albeit nearly always incomplete, coverage (e.g., >65% of targeted children) and a degree of dosage inadequacy,

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community-based periodic vitamin A delivery can be expected to be ~75% effective in preventing children from developing xerophthalmia in high-risk populations (2,96,231,232). Protection against hyporetinolemia (i.e., serum retinol < 20 ug/dl or < 0.7 umol/L may be less well-sustained as serum retinol remains elevated for only up to ~2 mo following high-potency vitamin A receipt (2). Similar levels of protection against maternal night blindness (67%) and low postpartum serum-retinol concentration (69%) 6 mo following delivery have been reported with weekly low-dose vitamin A supplementation (63) and high-potency vitamin A receipt at delivery (128), respectively. High-potency vitamin A is well-tolerated by children, although up to ~10% of preschoolers may experience a transient side effect (nausea, vomiting, headache, diarrhea, or fever have been reported) following receipt of 200,000 IU (237); up to ~2% of young infants () 6 mo) may show a bulging fontanel following a single dose of 50,000 or more IU (60,238–240), although a larger proportion (4–8%) may experience such an effect following repeated dosing during the ﬁrst 6 mo of life (241). A bulging fontanel following receipt of 50,000 IU has not been accompanied by an increase in intracranial pressure (59); returns to normal usually within 48 h (59,239), and has not been associated with long-term developmental abnormalities (60). Administration of 100,000 IU as a single dose to infants under 6 mo of age may be excessive (55) and, therefore, should be reserved for treatment (24,26,196). High-potency vitamin A supplements can be delivered to high-risk populations in several ways. One approach is to restrict vitamin A use to health-care settings for the treatment of xerophthalmia, and case management of severe infections such as measles (49–51,194,242), malaria (53), severe malnutrition, diarrhea, and respiratory disease. This approach incorporates both elements of what has been termed “therapeutic” or “targeted” (24,231,196,243). Its advantage lies in its effort to reach the most vitamin A-deﬁcient, and thus the most responsive individuals, and being cost-efﬁcient as few new resources are required beyond the supplements themselves, minimal health-personnel training, and existing delivery capabilities (231,244). However, coverage may be poor as it depends fully on access of vulnerable groups to health and other “carrier” services and attributed costs may not be trivial if a supplement program requires additional assessment procedures or nutrition education services to be added (245). Secondly, vitamin A may be delivered for primary prevention in an “opportunistic” way, i.e., one that maximizes vitamin A receipt, once, intermittently, or periodically, through multiple, existing service programs (not initially motivated or designed for vitamin A distribution) that reach large proportions of target groups. Examples include the Expanded Programme for Immunization and National Immunization Days (NID) (246), and routine growth-monitoring clinics (231,247). Integrating vitamin A delivery with immunization services provides an excellent opportunity to provide infants with 25,000 or 50,000 IU during each of three routine contacts in the ﬁrst 6 mo of life, and 200,000 IU to their mothers if within 6 wk postpartum, 100,000 IU to infants in late infancy at the time of measles vaccination and a 200,000 IU supplement to older children who may be accessible on the day of community contact (246). Initial concerns about concurrent vitamin A dosing potentially interfering with seroconversion to vaccine have largely been dispelled (248,249). Growth-monitoring clinics provide regular access to children for vitamin A receipt, although coverage is affected by routinely observed low rates of participation, particularly by older preschool-aged children (247).

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Universal coverage represents the third, broadest coverage approach to vitamin A prophylaxis. Supplement distribution may be combined with other national or regional community programs (such as a NID) or stand alone as a “vertical” activity, sweeping through communities in high-risk regions to dose target-aged children (6 mo to 4 or 5 yr) on a planned timetable, usually every 4–6 mo (232). Universal coverage should always be a program aim in malnourished refugee populations (250). Historically poor coverage rates, typically under 50% (96,117,231,232), have been improved to rates in excess of 80% in recent years through campaign approaches that focus all distribution activities on 2 set days, 6 mo apart, each year (251,252). Key to success appears to be a strong social marketing approach to secure active and sustained community involvement in distribution activities (252), though as with many public programs, goals of sustainability are best met in times of political and economic stability (146). Community and household factors associated with adequate coverage tend to vary by country setting (96,117,231,232,253). Cost data for universal vitamin A distribution is lacking (5,231), making it difﬁcult to estimate program efﬁciency. It has been estimated that universal vitamin A distribution costs roughly ~US$ 0.25 per delivered dose, of which the capsule (if from UNICEF) costs US $0.02 (231), though costs of delivery may rise sharply in reaching remote populations (254). The feasibility and degree to which each approach can be pursued simultaneously depends on local needs, resources, capabilities, commitment, and evidence of beneﬁt. The need to change behavior of groups—families, communities, industry, government—remains an essential part of each strategy. Beyond cultural factors, adoption of each approach should be guided, to the extent possible, by evidence of need for targeting, impact potential, costs, and potential sustainability. For example, in some areas of the world, considerable epidemiologic evidence has accumulated to highlight (a) food-consumption patterns, including both food sources of vitamin A (153–162) and feeding behaviors (101,102,163) that appear highly protective against xerophthalmia and, presumably, subclinical vitamin A deﬁciency that could be improved in young children (Fig. 15) and women of reproductive age (145); (b) seasons when populations may be at greatest risk of deﬁciency and its consequences (Fig. 13), which can serve as a means to plan the timing of interventions (232); and (c) population groups, locales (Fig. 10), and even types of households (Table 4) (99,100,138) that would likely beneﬁt the most from increased vitamin A intake. Evidence from scientiﬁc trials, although variable by outcome and type of intervention, provides evidence of impact, or lack thereof, on status (2,18–20,63,114,125,131,143), safety (56,59,237–241), growth and development (60,182–193), health (2,30,43,52–54,58,71,182,194), and survival (2,3,37–49,51,55,57,58,67,71) that can form the basis for rational program decisions and expectations of beneﬁt. Cost data, however, across all interventions remains scant, reﬂecting an urgent priority. Still, more information and political commitment to prevent vitamin A deﬁciency (4–13) exist than ever before at the turn of this millenium, serving to motivate achievement of global preventive goals.

REFERENCES 1. World Health Organization/United Nations International Children’s Emergency Fund/International Vitamin A Consultive Group. (WHO/UNICEF/IVACG). The global prevalence of vitamin A deﬁciency. MDIS working paper #2, WHO/NUT/95.3. Geneva: WHO, 1995.

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2. Sommer A, West KP, Jr. Vitamin A Deﬁciency: Health, Survival, and Vision. New York, NY: Oxford University Press, 1996. 3. West KP Jr, Katz J, Khatry SK, LeClerq SC, Pradhan EK, Shrestha SR, et al. Double blind, cluster randomised trial of low dose supplementation with vitamin A or `-carotene on mortality related to pregnancy in Nepal. BMJ 1999; 318:570–575. 4. Vitamin A deﬁciency and childhood mortality. In: Helen Keller International, ed. Bellagio Meeting on Vitamin A Deﬁciency & Childhood Mortality. Proceedings of Public Health Signiﬁcance of Vitamin A Deﬁciency and its Control. New York, NY: Bellagio Study and Conference Center of the Rockefeller Foundation, 1992. 5. Gillespie S, Mason J. Controlling vitamin A deﬁciency. ACC/SCN State-of-the-Art Series. Nutrition Policy Discussion Paper no.14. Geneva: ACC/SCN of the United Nations, 1994. 6. World Declaration of Plan of Action for Nutrition. International Conference on Nutrition. Rome: Food and Agriculture Organization of the United Nations and the World Health Organization, 1992. 7. Ending Hidden Hunger. A Policy Conference on Micronutrient Malnutrition. Montreal, Canada. Task Force for Child Survival and Development, Atlanta, GA 1991. 8. Saving Lives Today and Tomorrow. A Decade Report on USAID’S Child Survival Program. Washington, DC: U.S. Agency for International Development, 1996. 9. McGuire J, Galloway R. Enriching Lives. Overcoming vitamin and mineral malnutrition in developing countries. Washington, DC: World Bank, 1994. 10. Seidel RE. Strategies for Promoting Vitamin A Production, Consumption, & Supplementation. Four Case Studies. Washington, DC: Academy for Educational Development, 1996. 11. Cervinskas J, Lotﬁ M. Vitamin A Deﬁciency: Key Resources in its Prevention and Elimination. 2nd ed. Ontario: The Micronutrient Initiative, 1996. 12. Joint Food and Agriculture Organization of the United Nations and World Health Organization (FAO/WHO) Progress Report on the Implementation of the ICN World Declaration and Plan of Action for Nutrition. Rome: FAO/WHO, 1996. 13. United Nations Administrative Committee on Coordination/Subcommittee on Nutrition: (ACC/SCN). Ending malnutrition by 2020: an agenda for change in the Millennium. Final report to the ACC/SCN by the Commission on the nutrition challenges of the 21st century. Geneva: ACC/SCN, 1999. 14. American Institute of Nutrition. Nomenclature policy: generic descriptors and trivial names for vitamin A and related compounds. J Nutr 1984; 114:643–644. 15. Kaul S, Olson JA. Effect of vitamin A deﬁciency on the hydrolysis of retinoyl -glucuronide to retinoic acid by rat tissue organelles in vitro. Intl J Vitr Nutr Res 1998; 68:232–236. 16. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). FASEB J 1976; 35:1332–1338. 17. National Research Council. Recommended Dietary Allowances. Washington, DC: National Academy Press, 1989. 18. de Pee S, West CE, Muhilal, Karyadi D, Hautvast JGAJ. Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables. Lancet 1995; 346:75–81. 19. de Pee S, West CE, Permaesih D, Martuti S, Muhilal, Hautvast J. Orange fruit is more effective than are dark-green, leafy vegetables in increasing serum concentrations of retinol and `-carotene in schoolchildren in Indonesia. Am J Clin Nutr 1998; 68:1058–1067. 20. de Pee S, Bloem MW, Gorstein J, et al. Reappraisal of the role of vegetables in the vitamin A status of mothers in Central Java, Indonesia. Am J Clin Nutr 1998; 68:1068–1074. 21. West CE, Castenmiller JJJM. Quantiﬁcation of the “SLAMENGHI” factors for carotenoid bioavailability and bioconversion. Intl J Vit Nutr 1998; 68:371–377. 22. Blomhoff R. Introduction: overview of vitamin A metabolism and function. In: Vitamin A in Health and Disease, Blomhoff R, ed. New York, NY: Marcel Dekker, 1994, pp. 1–35. 23. Humphrey JH, West KP, Jr., Sommer A. Vitamin A deﬁciency and attributable mortality among under-5-year-olds. Bull WHO 1992; 70:225–232. 24. Sommer A. Vitamin A Deﬁciency and its Consequences: A Field Guide to Their Detection and Control. 3rd ed. Geneva: WHO, 1995. 25. Sommer A, Tarwotjo I, Hussaini G, Susanto D, Soegiharto T. Incidence, prevalence and scale of blinding malnutrition. Lancet 1981; 1:1407–1408. 26. Sommer A. Nutritional Blindness, Xerophthalmia and Keratomalacia. New York, NY: Oxford University Press, 1982.

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184. Kirkwood BR, Ross DA, Arthur P, et al. Effect of vitamin A supplementation on the growth of young children in northern Ghana. Am J Clin Nutr 1996; 63:773–781. 185. West KP Jr, LeClerq SC, Shrestha SR, Wu LSF, Pradhan EK, Khatry SK, et al. Effects of vitamin A on growth of vitamin A-deﬁcient children: ﬁeld studies in Nepal. J Nutr 1997; 127:1957–1965. 186. Lie C, Ying C, En-Lin W, Brun T, Geissler C. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. Eur J Clin Nutr 1993; 47:88–96. 187. Ramakrishnan U, Latham MC, Abel R. Vitamin A supplementation does not improve growth of preschool children: a randomized, double-blind ﬁeld trial in South India. J Nutr 1995; 125:202–211. 188. West KP Jr, Djunaedi E, Pandji A, Kusdiono, Tarwotjo I, Sommer A, the Aceh Study Group. Vitamin A supplementation and growth: a randomized community trial. Am J Clin Nutr 1988; 48:1257–1264. 189. Bahl R, Bhandari N, Taneja S, Bhan MK. The impact of vitamin A supplementation on physical growth of children is dependent on season. Eur J Clin Nutr 1997; 51:26–29. 190. Muhilal, Murdiana A, Azis I, Saidin S, Jahari AB, Karyadi D. Vitamin A-fortiﬁed monosodium glutamate and vitamin A status: a controlled ﬁeld trial. Am J Clin Nutr 1988; 48:1265–1270. 191. Donnen P, Brasseur D, Dramaix M, et al. Vitamin A supplementation but not deworming improves growth of malnourished preschool children in Eastern Zaire. J Nutr 1998; 128:1320–1327. 192. Hadi H, Stoltzfus RJ, Dibley MJ, et al. Vitamin A supplementation selectively improves linear growth of Indonesian preschool children: a randomized controlled trial. Am J Clin Nutr 2000; 71: 507–513. 193. Hadi H, Stoltzfus RJ, Moulton LH, Dibley MJ, West KP Jr. Respiratory infections reduce the growth response to vitamin A supplementation in a randomized controlled trial. Intl J Epidemiol 1999; 28:874–881. 194. Coutsoudis A, Broughton M, Coovadia HM. Vitamin A supplementation reduces measles morbidity in young African children: a randomized, placebo-controlled, double-blind trial. Am J Clin Nutr 1991; 54:890–895. 195. Donnen P, Dramaix M, Brasseur D, Bitwe R, Vertongen F, Hennart P. Randomized placebo-controlled clinical trial of the effect of a single high dose or daily low doses of vitamin A on the morbidity of hospitalized, malnourished children. Am J Clin Nutr 1998; 68:1254–1260. 196. WHO/UNICEF/IVACG. Vitamin A supplements: a guide to their use in the treatment and prevention of vitamin A deﬁciency and xerophthalmia, 2nd ed. Geneva: WHO, 1997. 197. Sommer A, Emran N, Tjakrasudjatma S. Clinical characteristics of vitamin A responsive and nonresponsive Bitot’s spots. Am J Ophthalmol 1980; 90:160–171. 198. Semba RD, Wirasasmita S, Natadisastra G, Muhilal, Sommer A. Response of Bitot’s spots in preschool children to vitamin A treatment. Am J Ophthalmol 1990;110:416–420. 199. Sovani I, Humphrey JH, Kuntinalibronto DR, Natadisastra G, Muhilal, Tielsch JM. Response of Bitot’s spots to a single oral 100,000- or 200,000-IU dose of vitamin A. Am J Ophthalmol 1994; 118:792–796. 200. de Pee S, Bloem MW, Satoto, Yip R, Sukaton A, Tjiong R, et al. Impact of a social marketing campaign promoting dark-green leafy vegetables and eggs in Central Java, Indonesia. Intl J Vit Nutr Res 1998; 68:389–398. 201. Talukder A, Bloem MW. Home Gardening Activities in Bangladesh. Dhaka: Helen Keller International, 1992. 202. Talukder A, Khan TA, Baker SK, Zakaria AKM, Bloem MW, Kiess LK. Home Gardening Activities in Bangladesh. Mapping Report and Inventory. Dhaka: Helen Keller International, 1997. 203. Talukder A, Islam N, Klemm R, Bloem M. Home Gardening in South Asia. The Complete Handbook. Dhaka: Helen Keller International, 1993. 204. Marsh R. Building on traditional gardening to improve household food security. FAO Food Nutr Agricul 1998; 22:4–14. 205. Solon MA. Control of vitamin A deﬁciency by education and the public health approach. In: Vitamin A Deﬁciency and its Control. Bauernfeind JC, ed. Orlando: Academic, 1986, pp. 285–318. 206. Hagenimana V, Oyunga MA, Low J, Njoroge SM, Gichuki ST, Kabira J. The Effects of Women Farmers’ Adoption of Orange-Fleshed Sweet Potatoes: Raising Vitamin A Intake in Kenya. International Center for Research on Women, 1999. 207. Ayalew W, Wolde Gebriel Z, Kassa H. Reducing Vitamin A Deﬁciency in Ethiopia: Linkages With a Women-Focused Dairy Goat Farming Project. International Center for Research on Women, Washington, D.C. 1999.

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208. Smitasiri S, Attig GA, Dhanamitta S. Participatory action for nutrition education: social marketing vitamin A-rich foods in Thailand. Ecol Food Nutr 1992; 28:199–210. 209. Johnson-Welch C. Focusing on Women Works: Research on Improving Micronutrient Status Through Food-Based Interventions. International Center for Research on Women, Washington, D.C. 1999. 210. Van het Hof K. Dietary Factors That Affect Carotenoid Bioavailability. Wageningen: Graﬁsch Bedrijf Ponsen & Looijen BV, 1999. 211. Devadas RP, Saroja S, Murthy NK. Availability of `-carotene from papaya fruit and amaranth in preschool children. Indian J Nutr Dietet 1989; 17:41–44. 212. Darnton-Hill I. Overview: rationale and elements of a successful food fortiﬁcation program. Food Nutr Bull (In Press). 213. United States Department of Agriculture (USDA). Commodity speciﬁcations for various products procured for title II PL480 program. Kansas City, MO: USDA Kansas City Commodity Ofﬁce, 1994. 214. Fortiﬁcation of PL-480 foods. Arlington, VA: OMNI, 1994. 215. Bauernfeind JC, Arroyave G. Control of vitamin A deﬁciency by the nutriﬁcation of food approach. In: Vitamin A Deﬁciency and its Control. Bauernfeind, JC ed. Orlando: Academic, 1986, pp. 359–388. 216. Arroyave G, Aguilar JR, Flores M, Guzman MA. Evaluation of sugar fortiﬁcation with vitamin A at the national level. Washington DC: Pan American Health Organization, 1979, pp. 1–82. 217. Arroyave G. Vitamin A deﬁciency control in Central America. In: Vitamin A Deﬁciency and its Control. Bauernfeind JC, ed. Orlando: Academic, 1986, pp. 405–424. 218. Dary O. Avances en el proceso de fortiﬁcacion de azucar con vitamina A en Centro America. Boletin de la Oﬁcina Sanitaria Pan Americana 1994; 117:529–536. 219. Raphael A. Sugar Fortiﬁcation in Guatemala. Guatemala City: UNICEF, 1994–1995. 220. Solon FS, Fernandez TL, Latham MC, Popkin BM. An evaluation of strategies to control vitamin A deﬁciency in the Philippines. Am J Clin Nutr 1979; 32:1445–1453. 221. Latham MC, Solon FS. Vitamin A deﬁciency control in the Philippines. In: Vitamin A Deﬁciency and its Control. Bauernfeind JC, ed. Orlando: Academic, 1986, pp. 425–443. 222. Solon FS, Latham MC, Guirriec R, Florentino R, Williamson DF, Aguilar J. Fortiﬁcation of MSG with vitamin A: the Philippines experience. Food Technol. 1985; 39:71–79. 223. Hall HS. Vitamin A fortiﬁcation in a high stress environment. Unpublished report. Chicago: ACS National Meeting, 1993. 224. Solon FS, Solon MS, Mehansho H, West KP Jr, Sarol J, Perfecto C, et al. Evaluation of the effect of vitamin A-fortiﬁed margarine on the vitamin A status of preschool Filipino children. Eur J Clin Nutr 1996; 50:720–723. 225. Solon FS, Klemm RDW, Sanchez L, Darnton-Hill I, Craft NE, Christian P, West KP Jr. Evaluation of the efﬁcacy of vitamin A-fortiﬁed wheat-ﬂour bun on the vitamin A status of Filipino school children. Am J Clin Nutr 2000; 72:738–744. 226. Solon FS, Solon MA, Nano TA, Limson ERP, Mendoza O, Sanchez LE, Wambangco LS. Wheat Flour Fortiﬁcation with Vitamin A. Final report. Nutrition Center of the Philippines, Manilla 1998. 227. Nalubola R, Nestel P, Dexter P, Alnwick D. Fortiﬁcation of Wheat Flour with Vitamin A. An Update. Arlington, VA: OMNI Project/John Snow Inc, 1998. 228. Phillips M, Sanghvi T, Suarez R, McKigney J, Fiedler J. The costs and effectiveness of three vitamin A interventions in Guatemala. Soc Sci Med 1996; 42:1661–1668. 229. Lotﬁ M, Mannar MGV, Merx RJHM, Naber-van den Heuvel P. Micronutrient fortiﬁcation of foods: current practices, research, and opportunities. Ottawa: The Micronutrient Initiative/International Agricultural Centre, 1996. 230. Ong ASH. Nutritional aspects of palm oil: an introductory review. Asia Paciﬁc J Clin Nutr 1994; 3:201–206. 231. West KP Jr, Sommer A. Delivery of Oral Doses of Vitamin A to Prevent Vitamin A Deﬁciency and Nutritional Blindness. A State-of-the-Art Series, Nutrition Policy Discussion Paper No. 2 (second printing). Rome: ACC/SCN, 1993. 232. Darnton-Hill I, Sibanda F, Mitra M, Ali MM, Drexler AE, Rahman H, Samad Khan MA. Distribution of vitamin A capsules for the prevention and control of vitamin-A deﬁciency in Bangladesh. Food Nutr Bull 1988; 10:60–70. 233. Vitamin A deﬁciency and xerophthalmia. Report of a Joint WHO/USAID Meeting. WHO Technical Report Series, no 590. Geneva: WHO 1976, pp. 1–83.

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234. Sinha DP, Bang FB. The effect of massive doses of vitamin A on the signs of vitamin A deﬁciency in preschool children. Am J Clin Nutr 1976; 29:110–115. 235. Humphrey JH, West KP Jr, Muhilal, See LC, Natadisastra G, Sommer A. A priming dose of oral vitamin A given to preschool children may extend protection conferred by a subsequent large dose of vitamin A. J Nutr 1993; 123:1363–1369. 236. Campos FACS, Flores H, Underwood BA. Effect of an infection on vitamin A status of children as measured by the relative dose response (RDR). Am J Clin Nutr 1987; 46:91–94. 237. Florentino RF, Tanchoco CC, Ramos AC, Mendoza TS, Natividad EP, Tangco JBM, Sommer A.. Tolerance of preschoolers to two dosage strengths of vitamin A preparation. Am J Clin Nutr 1990; 52:694–700. 238. West KP Jr, Khatry SK, LeClerq SC, Adhikari R, See L, Katz J, Shrestha SR, Pradhan EK, Pokhrel RP, Sommer A. Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal. Bull WHO 1992; 70:733–739. 239. Stabell C, Bale C, da Silva AP, Olsen J, Aaby P. No evidence of fontanelle-bulging episodes after vitamin A supplementation of 6- and 9-month-old infants in Guinea Bissau. Eur J Clin Nutr 1995; 49:73–74. 240. Iliff PJ, Humphrey JH, Mahomva AI, Zvandasara P, Bonduelle M, Malaba L, Nathoo KJ. Tolerance of large doses of vitamin A given to mothers and their babies shortly after delivery. Nutr Res 1999; 19: 1437–1446. 241. Baqui AH, de Francisco A, Arifeen SE, Siddique AK, Sack RB. Bulging fontanelle after supplementation with 25 000 IU of vitamin A in infancy using immunization contacts. Acta Paediatr 1995; 84:863–866. 242. Coutsoudis A, Kiepiela P, Coovadia HM, Broughton M. Vitamin A supplementation enhances speciﬁc IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. Pediatr Infect Dis J 1992; 11:203–209. 243. World Health Organization. Vitamin A supplements dosage. Paper NUT/97.1. Geneva: WHO, 1997. 244. Arhin DC, Ross DA, Kufour F. Costs of vitamin A supplementation: the opportunity for integration with immunization in Ghana. Health Policy Plan 1993; 8:339–348. 245. Loevinsohn BP, Sutter RW, Costales MO. Using cost-effectiveness analysis to evaluate targeting strategies: the case of vitamin A supplementation. Health Policy Plan 1997; 12:29–37. 246. Global Programme for Vaccines and Immunization/Expanded Programme on Immunization. Integration of Vitamin A Supplementation with Immunization: Policy and Programme Implications. Report of a meeting, 12–13 January 1998. New York: UNICEF. Geneva: WHO, 1998. 247. Berger RA, Courtright P, Barrows J. Vitamin A capsule supplementation in Malawi villages: missed opportunities and possible interventions. Am J Public Health 1995; 85:718–719. 248. Semba RD, Muhilal, Mohgaddam NEG, Munasir Z, Akib A, Permaesih D, Muherdiyantiningsih, Osterhaus A. Integration of vitamin A supplementation with the expanded program on immunization does not affect seroconversion to oral poliovirus vaccine in infants. J Nutr 1999; 129:2203–2205. 249. Rahman MM, Mahalanabis D, Hossain S, Wahed MA, Alvarez JO, Siber GR, et al. Simultaneous vitamin A administration at routine immunization contact enhances antibody response to diphtheria vaccine in infants younger than six months. J Nutr 1999; 129:2192–2195. 250. Nieburg P, Waldman RJ, Leavell R, Sommer A, DeMaeyer EM. Vitamin A supplementation for refugees and famine victims. Bull WHO 1988; 66:689–697. 251. Helen Keller International. Vitamin A capsule distribution. Trends in Bangladesh. Dhaka: HKI, 1996. 252. Houston R. The Nepal National Vitamin A Program. Elements of Success. Nepal: NTAG/John Snow Inc/USAID, 1999. 253. Tarwotjo I, West KP Jr, Mele L, Nur S, Nendrawati H, Kraushaar D, Tilden RL, Aceh Study Group. Determinants of community-based coverage: periodic vitamin A supplementation. Am J Public Health 1989; 79:847–849. 254. West KP Jr, Pokhrel RP, Khatry SK. Estimating the relative efﬁciency of a vitamin A intervention from population-based data. J Nep Med Assoc 1992; 30:159–162.

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307

Zinc Deﬁciency Roger Shrimpton

1. INTRODUCTION Zinc deﬁciency appears to be a common but overlooked problem in developing countries (1). The unique chemical properties of this transition element confer on zinc an important role in a wide variety of biological processes. Zinc occurs in the divalent state (Zn++) and does not exhibit redox chemistry in living organisms. It has a high afﬁnity for electrons and typically binds to proteins, amino acids, peptides, and nucleotides, permitting both catalytic and structural functions. Intakes of zinc in populations are commonly lower than recommended levels, but adaption mechanisms preclude the development of severe deﬁciency states. There is increasing evidence, however, that adaption to low zinc intakes is not without consequence. Recent studies have shown that zinc supplementation reduces the morbidity and mortality from common childhood infectious diseases such as diarrhea, acute lower-respiratory infections, and malaria (2). A large and growing literature on zinc and immune function also emphasizes the importance of mild zinc deﬁciency in reducing resistance to infection (3).

2. PUBLIC HEALTH SIGNIFICANCE The extent of zinc deﬁciency worldwide is undetermined, but probably similar to that of iron deﬁciency. It is thus likely that zinc deﬁciency is a public health problem in many countries (4,5). A recent series of clinical trials of zinc supplementation, conducted among children with mild degrees of undernutrition but not known to have zinc deﬁciency, suggest that the problem of zinc deﬁciency may indeed be widespread (2). A comparison of dietary intakes of zinc with requirements also suggests that zinc deﬁciency is a common public health problem, especially among women and children in developing countries (6). The difﬁculties of acquiring foodstuffs rich in zinc that do not have a high phytate content, which interferes with zinc absorption, together with increased losses owing to environmental conditions common in the tropics, are major contributing factors for zinc deﬁciency in developing countries. The consequences of such deﬁciency in terms of morbidity and mortality, although still to be properly quantiﬁed, are likely to be considerable. From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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3. HISTORICAL BACKGROUND Zinc was recognized as an essential factor for the growth of Aspergillus niger in 1869 (7), and amounts common in foodstuffs determined in early part of the century (8). Early attempts to demonstrate the essentiality of zinc were unsuccessful, largely because of problems of contamination. Reversible zinc deﬁciency was ﬁnally successfully produced in the rat for the ﬁrst time in the early 1930s (9). Studies in humans showed that the hair and toenails of Chinese subjects with beri-beri were very low in zinc, suggesting that zinc deﬁciency might be concomitant of thiamin deﬁciency, stated to be widespread in the poor Chinese communities of Taiwan (10,11). Balance studies in school children led to the conclusion that zinc had a much higher requirement than was previously thought, and was certainly not needed just as a “trace.” An average intake of 16 mg, of which 5 mg was retained, put zinc on a similar footing to iron in quantitative terms (12). Despite the variations in the concentrations of zinc in tissues, however, no characteristic manifestations of a suspected zinc deﬁciency were identiﬁed (13). The universal distribution of zinc in nature, the extreme difﬁculty with which zinc deﬁciency had been produced in rats, and the small supplements that prevented symptoms convinced most authorities that zinc deﬁciency as a practical problem in animals or humans was improbable (14–16). It came as a surprise, therefore, when parakeratosis, an endemic disease of swine, was shown to be owing to inadequate dietary zinc (17), especially because the ration contained 10 times the recognized requirement of the rat. The paradox was resolved when it was demonstrated that phytate, the phosphorus storage compound of plant seeds, decreased zinc availability in the soybean-based diet (18). The original attempts to produce zinc deﬁciency in the rat had used synthetic diets based on casein or eggwhite protein. In 1961, Prasad and colleagues described a syndrome of iron-deﬁciency anemia, hepato- splenomegaly, hypogonadism, and dwarﬁsm among young males in Iran who ate little animal protein, subsisted on unleavened wheat bread, and practiced geophagia (19). After zinc supplementation, the subjects grew pubic hair and their genitalia size increased (20). Further studies showed that zinc supplementation was effective in increasing growth in these subjects (21). Subsequent studies among 19- and 20-yr-old hypogonadal males rejected by Iranian Army because of “malnutrition” demonstrated that zinc supplementation increased sexual maturation faster than a well-balanced diet (22). In 1974, the recommended dietary allowance for zinc was established by the Food and Nutrition Board of the National Research Council of the National Academy of Sciences (23).

4. EPIDEMIOLOGY The incidence and prevalence of zinc deﬁciency around the world have not been deﬁned. Three factors appear to be contributing to this large gap in knowledge. First, since there is a lack of a sensitive, practical, and accepted indicator for zinc deﬁciency, population-based surveys have not been done. Second, marginal zinc deﬁciency is not characterized by a highly speciﬁc deﬁciency syndrome. Third, severe clinical deﬁciency in humans is not seen owing either to adaption to low intakes or death. It

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Table 1 Risk Factors for Zinc Deﬁciency Insufﬁcient dietary intake of zinc (low-protein diet) High phytate and/or ﬁber content of food (vegetarian diet) Diarrheal disease Malabsorption syndromes Parasitosis Hot, humid climate Lactation Rapid multiplicative cell growth (pregnancy, infancy, adolescence) Genetic diseases (acrodermatitis enteropatica, sickle cell anemia)

is only recently that the importance of zinc nutrition for public health has become more widely recognized. The risk of zinc deﬁciency is now realized to be highest among infants, young children, pregnant women, and lactating women, when needs are comparatively higher owing to the extra demands of multiplicative cell growth. Risk factors for zinc deﬁciency include factors that contribute to insufﬁcient dietary intake, including poverty, food taboos, and special diets (including vegetarian diets that are high in phytate and ﬁber). Increased demands owing to growth also put the pregnant and lactating mother and infants at risk. Individuals with speciﬁc disease states may also be at higher risk, including those with malabsorption syndromes, diarrhea, and parasitic diseases. Individuals with genetic diseases such acrodermatitis enteropathica, sicklecell disease, and cystic ﬁbrosis are also at special risk of deﬁciency (Table 1). Dietary zinc intake of young children appear to be inadequate in many developing countries (24). Women of child-bearing age also have insufﬁcient dietary zinc intake in many populations (25). Eighty percent of women globally, and 100% of women in developing countries, have usual intakes of zinc inadequate to meet the normative needs of pregnancy (26).

5. METABOLISM OF ZINC 5.1. Zinc Absorption Zinc apparently can be absorbed at all levels of the small intestine. Dietary zinc is digested free of its protein matrixes before becoming available for absorption. Pancreatic secretions that help digest food deliver an amount of zinc into the duodenum equivalent to that provided by most meals. The intestine must therefore recover appropriate amounts of zinc from both dietary and endogenous sources to maintain a favourable zinc balance. The total body zinc content of adults may be maintained with the absorption of about 5 mg/d of zinc (27). Zinc is absorbed both by passive diffusion and through a carrier-mediated process on the brush border of enterocytes (28,29). Zinc absorbed from the intestinal lumen is bound to many different molecules within the enterocytes, and metallothionein and cysteine-rich intestinal protein play a role in transmucosal transport (30,31). The absorption of zinc depends on both zinc status and the dietary intake of zinc. During periods of high intake, zinc absorption decreases

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and excretion of endogenous zinc into the gastrointestinal lumen is enhanced. In contrast, during periods of low intake absorption of zinc is enhanced and secretion of endogenous zinc into the gastrointestinal lumen is suppressed. During pregnancy and lactation women increase their zinc absorption rates. Californian women consuming 50% of the recommended dietary intake increased absorption rates from 15% preconceptually to 25% during lactation (32). Lactating women in the Amazon region, consuming a diet providing only 34% of the recommended intake, showed absorption rates of between 60 and 80% of dietary zinc (33).

5.2. Zinc Transport Zinc released into the mesenteric capillaries and the portal circulation is bound initially to albumin, and two thirds of portal zinc is taken up by the liver (34). Peripheral circulating zinc is ﬁrmly bound to _2-macroglobulin (30–40%), loosely bound to albumin (60–70%), and 7% chelated by amino acids (35,36). The latter pool is involved in nutritionaly relevant transport and distribution. There does not appear to be any homeostatic mechanisms for regulating circulating zinc levels and keeping them constant. Limited experimental studies in humans on low-zinc, high-energy diets show that signiﬁcant reductions in serum zinc levels take from 3–6 wk (37,38). Consumption of a low-zinc, low-energy diet causes amino acids to be mobilized from muscle for gluconeogenesis in the liver, liberating zinc into circulation and maintaining serum zinc levels even in the face of depletion.

5.3. Zinc Storage The total zinc content of the human body is estimated to be 60 mg in newborns (39) or 20 µg zinc/g, increasing to 30 µg zinc/g during growth and maturation; by adulthood, the total body zinc content is estimated to be about 1.5 g in women and 2.5 g in men. Zinc is found in all tissues and ﬂuids in the body, but it is primarily an intracellular ion. There is no speciﬁc storage organ for zinc. It is estimated that 60% of total body zinc is in striated muscle, 20% in bone, 5% in blood and liver, and 3% in the skin and gastrointestinal tract. The highest concentrations of zinc are found in the choroid of the eye and prostatic ﬂuids. Kinetic studies suggest that there are two major zinc pools in the body, one with a short half-life and another with a long half-life. The rapid turnover in zinc appears to occur in the liver, pancreas, kidney, and spleen. In lactating women in the Amazon region consuming low-zinc diets, the short-term pool size was reduced to about a half of expected values. Although the total body zinc turnover rates seemed normal, plasma zinc turnover rates were double what was expected (33).

5.4. Zinc Excretion Zinc is excreted mostly in the feces. Fecal losses of zinc are a combination of unabsorbed dietary zinc and endogenous secretions of zinc from the pancreas, gallbladder, stomach, and duodenum. Zinc loss from enterocytes appears to be, in part, under homeostatic control. Urinary losses although normally low can be high in catabolic states. During starvation when amino acids are mobilized from muscle to the liver for gluconeogenesis, much of the zinc liberated is lost through the urine (40). Zinc loss also occurs through turnover of skin, hair, nails, through sweat, menstrual blood loss, and semen. In tropical countries sweat losses can be considerable. An ejaculation contains about 1 mg of zinc, because of the high zinc content of seminal ﬂuid (41).

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Lactation is a form of zinc excretion in which about 2–3 mg of zinc are excreted per day in the ﬁrst several weeks postpartum, decreasing to 1 mg/d by 2–3 mo postpartum, and declining dramatically beyond this period (42).

6. BIOLOGICAL FUNCTIONS OF ZINC Zinc is essential for many important biological functions, including immunity, growth, neurological transmission, and reproduction (43). Zinc is the most abundant trace element inside most cells, the exception being red blood cells with iron, and bone cells with calcium. Zinc is not limited, as are calcium and iron, to a few functional roles.

6.1. Zinc Metalloenzymes Zinc is needed for the function of about 300 zinc metalloenzymes (44), and among the classes of enzymes with zinc metalloenzymes are oxidoreductases, transferases, hydrolases, lyases, isomerases, and ligases. These zinc metalloenzymes are broadly involved in structural, regulatory, catalytic, and noncatalytic functions. Presumably these enzymes are inﬂuenced by zinc status, but direct evidence of a link between zinc status and impaired function of a zinc- requiring enzyme in higher organisms is limited (27).

6.2. Zinc Fingers The binding of regulatory proteins to speciﬁc recognition sequences of genes is important to gene expression and regulation. Zinc fingers are protein complexes that form a tetrahedral complex with zinc and provide structural stability for small polypeptides (45). The region of the protein containing the zinc-binding domains is essential for binding to DNA and also plays a role in protein-protein interaction. Zincﬁnger domains are found in regulatory proteins in the nucleus and the cytoplasm, and are found among signal transduction factors.

6.3. Zinc and Biomembranes Zinc is a common divalent ion within the cytoplasm of cells, and zinc may play an important role in the structure and function of biomembranes because of its ability to stabilize thiol groups and phospholipids and to quench free radicals (46).

6.4. Zinc and Immune Function The importance of zinc in normal immune function is reﬂected in the increased susceptibility to infection seen in zinc deﬁciency (3). Zinc plays a role in nonspeciﬁc immunity, such as the barrier function of skin and mucosae, as well as function of polymorphonuclear leukocytes, natural killer cells, and complement. Zinc deﬁciency is associated with impaired T- and B-lymphocyte function and the generation of antibody responses. Zinc may also have an important role in immunity because of its function as an antioxidant and its role in apoptosis.

6.5. Other Functions of Zinc Zinc has been implicated as playing a potential role in many other important biological functions, including synaptic transmission, the activity of growth hormone, the polymerization of tubulin, and signal transduction (43).

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Table 2 Zinc Content of Some Common Foods Zinc Category (mg/1000 kcal) Very poor (0–2) Poor (1–5) Rich (4–12) Very rich (12–882)

Foods Fats, oils, butter, cream cheese, sweets, chocolates, soft drinks, alcoholic drinks, preserves Fish, fruits, reﬁned cereal products, pastries, biscuits, cakes, puddings, tubers, plantains, sausages, chips Whole grains, pork, poultry, milk, low-fat cheese, yogurt, eggs, nuts Lamb, leaf and root vegetables, crustacea, beef, kidney, liver, heart, mollusks

Adapted with permission from ref. (48).

7. PATHOPHYSIOLOGY OF ZINC DEFICIENCY Zinc deﬁciency may generally occur owing to one or more mechanisms, including inadequate intake of zinc; interference with absorption and bioavailability of dietary zinc; increased losses of zinc; impaired utilization of zinc; and increased requirement for zinc, as during pregnancy, lactation, and periods of rapid growth. Constitutive zinc metalloenzymes are part of the basic cellular structure and are relatively stable. Moreover, loss of 10–20% of a nonrate-limiting enzyme may not severely compromise metabolic function and cellular survival. If, however, a small pool of free zinc must provide ions for receptors and other transcription factors as needed for the immediate induction of fresh supplies of new enzymes, then even modest deﬁcits of free zinc might seriously erode homeostatic adaptability and growth and development (47).

7.1. Dietary Sources and Intake of Zinc The zinc content of foods is closely correlated with the protein content. The richest dietary sources of zinc are animal products such as shellﬁsh, red meat, liver, and poultry. Dark meat has twice the zinc content of white meat. The plant protein sources such as beans, lentils, chickpeas, and peas are also relatively rich in zinc. In whole cereal grains, zinc is contained in the bran and germ portions, which are normally lost through milling. Consequently, little zinc is found in white rice or white breads. Dairy products contain only moderate amounts of zinc, and drinking water is a minor source of zinc in most populations. The zinc content of some common foods are shown in Table 2, classiﬁed according to their zinc energy densities (48). Foods that will ensure that zinc needs are met if energy needs are met are classiﬁed as rich. Even in developed countries, zinc intakes are commonly sub-optimal because of the excessive consumption of very poor zinc sources such as soft drinks, reﬁned breads, cakes and sweets, and french fries. In many populations in developing countries, the consumption of meat and animal products is low, such that sub-optimal zinc intakes are also very common. Food taboos in Asia, especially, commonly contribute to preventing pregnant and lactating women and young children getting “hot” zinc and protein-rich foods. A comprehensive analysis and review of the complementary feeding of young children

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in developing countries concluded that meeting the micronutrient needs from complementary foods was the biggest challenge. Adequate amounts of iron and zinc can only be met if animal products are consumed in quantities unlikely to be feasible (49). Of complementary foods fed during the second semester of life to infants in the Amazon, none met recommended zinc to energy levels, and 88% were below 70% of the recommended level (50).

7.2. Absorption and Bioavailability of Zinc There are several important factors in foods that can interfere with absorption of dietary zinc. Zinc in animal foods is generally more available than the zinc in vegetable foods. Animal and human studies have shown that the phytate (inositol hexaphosphate) content of plant foods can inhibit zinc absorption (18,51), and the ﬁber, oxalate, tannin, and lignin content of plant foods can also reduce the absorption of zinc (52). Whole grains, legumes, and leafy vegetables contain high amounts of these factors. Zinc forms insoluble complexes with phytate at alkaline pH (53) and at pH values usually found in foods. Soaking and fermentation of plant foods are among some strategies that can be used to reduce intake of phytic acid (54), as phytate is partially hydrolyzed to other analogous metabolites that have a lower capacity to bind zinc. The populations of the Middle East, where zinc deﬁciency was originally described, had high zinc intakes, but the zinc source was an unleavened whole-wheat bread rich in phytate. The leavening of bread through the action of yeast reduces phytate content. Soy protein-based infant formulas may have a phytate content that reduces the absorption of zinc (55,56). Diarrheal disease also interfere with the absorption of zinc and contribute to accelerated fecal losses of both dietary and endogenous zinc.

7.3. Zinc Dietary Requirements The World Health Organization (WHO) established provisional standards for recommended intakes of zinc based on availability of zinc in the diet (57). Breast-fed infants are considered to absorb up to 80% of the zinc in breast milk. Three general categories of diets have been proposed according to the availability of zinc (57). Diets with a high availability of zinc are characterized by a low cereal ﬁber content, low phytate content, and adequate protein content of meats and ﬁsh. Also included in this category are semisynthetic formula diets based on animal proteins. Diets with a moderate availability of zinc include mixed diets containing animal or ﬁsh protein, lacto-ovo, ovovegetarian, or vegan diets that are not primarily based on unreﬁned cereals, and diets with a moderately high phytate/zinc molar ratio. Diets with a low availability of zinc include diets high in unreﬁned, unfermented, and ungerminated cereal grain, diets with a high phytate/zinc ratio, diets in which high phytate, soya protein constitute the primarily source of protein, diets high in energy intake from high phytate foods, and diets high in inorganic calcium salts (57). Zinc requirements are higher during pregnancy, lactation, and in infants and children during periods of rapid growth (Table 3).

8. CLINICAL MANIFESTATIONS OF ZINC DEFICIENCY The clinical manifestations of zinc deﬁciency are generally nonspeciﬁc, vary widely, and depend on the severity of deﬁciency (Table 4). Severe zinc deﬁciency, noted in

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Table 3 Recommended Zinc Intakes World Health Organization estimatesb Age (yrs)

Sex

RDAa

High

Moderate

Low

0.20–0.25

F M F, M F, M F, M F, M F, M F F F F M M M M F

5 5 5 5 10 10 10 15 15 15 15 15 15 15 15

— — — — 3.3 3.9 4.5 5.0 6.1 6.2 4.0 5.6 7.3 7.8 5.6

— — — — 5.6 6.5 7.5 8.4 10.3 10.2 6.5 9.3 12.1 13.1 9.4

— — — — 11.1 12.9 15.0 16.8 20.6 20.6 13.1 18.7 24.3 26.2 18.7

15 15 15

4.4 5.6 8.0

7.3 9.3 13.3

14.7 18.7 26.7

19 19 16

7.6 7.0 5.8

12.7 11.7 9.6

25.3 23.3 19.2

0.25–0.50 0.50–1 0.21–3 0.23–6 0.26–10 0.10–12 0.12–15 0.15–18 0.18–60+ 0.10–12 0.12–15 0.15–18 0.18–60+ Pregnancy First trimester Second trimester Third trimester Lactation .0–3 mo .3–6 mo .6–12 mo

F

aAdapted with permission from Food and Nutrition Board, National Research Council (Food and Nutrition Board, 1974). bBased on World Health Organization, by zinc availability in three general types of diet (57).

conditions such as acrodermatitis enteropathica and among patients fed total parenteral nutrition without zinc, is characterized by alopecia, diarrhea, skin lesions in the extremities and perioral area, and anorexia. Such patients, if not fed zinc, die from common infections such as diarrhea. Zinc deficiency is a nutritionally acquired immunodeﬁciency disorder, and is associated with greater morbidity and mortality from infectious diseases (3). In the original clinical observations in Iran, hypogonadism, delayed sexual maturation, and severe growth retardation were noted (19). Marginal zinc deﬁciency may be associated with nonspeciﬁc clinical manifestations such as growth retardation, failure to thrive, and impaired taste (hypogeusia). Zinc deﬁciency is common in the elderly, and associated with poor wound healing. Severe protein energy malnutrition has been shown to be associated with zinc deﬁciency. Zinc supplementation of such malnourished infants was shown to rapidly increase the size of the thymus, suggesting that zinc deﬁciency may play a part in the thymic atrophy and infections associated with malnutrition (58). In the recovery of malnourished children, it has been shown that if the zinc-to-energy ratio of the diet was not sufﬁcient, it could limit the rate of weight gain. The weight being gained could also

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Table 4 Clinical Manifestations of Zinc Deﬁciency Growth retardation Hypogonadism Delayed sexual maturation Immunodeﬁciency Increased infections Delayed wound healing Skin lesions Alopecia Hypospermia Night blindness Diarrhea Behavioral disturbances Anorexia Hypogeusia

be of different sorts of tissues. On low zinc-to-energy diets, less lean tissue is deposited and more adipose tissue is created. (59). Zinc deﬁciency during pregnancy is associated with adverse maternal and fetal outcomes (26). Severe maternal zinc deﬁciency has been associated with birth defects and spontaneous abortion. Fetal growth retardation, low birth weight, preterm delivery, and increased complications during delivery have been associated with marginal zinc deﬁciency (60). Zinc deﬁciency impairs oestrogen dependent gene expression in the uterus, via the receptor for the hormone, which contains a zinc-ﬁnger protein. This lack of effect of oestrogen impairs the conversion of the uterus from its passive state, to one capable of concerted contractions with sufﬁcient force to expel a fetus (61). Maternal and early infant zinc deﬁciencies may have an adverse inﬂuence on infant neurodevelopment, including motor development, cognition, and activity (62).

9. ASSESSMENT OF ZINC STATUS The determination of zinc status can be made on the population level, which is of importance for large epidemiological studies and public health, and at the individual level, which may be relevant for clinical management of individual patients. The diagnosis of zinc deﬁciency is hampered by the lack of a single, sensitive, and speciﬁc low-cost indicator of zinc status (63).

9.1. Plasma or Serum Zinc Concentrations Plasma or serum zinc concentrations are the most widely used indicator for zinc status. In general, during zinc deﬁciency, plasma or serum zinc concentrations will decrease. The amount of zinc circulating in plasma is <0.2% of the total body zinc content, as most of the total body content of zinc is contained in muscle and liver. Thus, small changes in the uptake or release of zinc in tissues can have a large effect on plasma or serum zinc concentrations (63). There are several factors that may confound the use of plasma or serum zinc concentrations, including infection (64), inﬂammation, chronic disease, liver disease, pregnancy (65), and malnutrition (66).

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Serum zinc concentrations have been determined in a large population of apparently healthy individuals in the United States, and age- and sex-related trends in zinc concentrations were noted (67). The usual cut-off point generally used to assess the risk of zinc deﬁciency using plasma or serum zinc concentrations is <10.71 µmol/L (<70 µg/dL) for morning-fasting blood samples, and <9.95 µmol/L (<65 µg/dL) for nonfasting blood samples (68). A display of the frequency distribution of plasma or serum zinc concentrations in populations may help facilitate comparisons between different studies and populations. For the assessment of zinc status of children in developing countries, plasma or serum zinc concentrations appear to be a useful indicator. Brown (69) recently compared three cross- sectional, community-based studies conducted among young children in Peru (70), Guatemala (71), and Zimbabwe (72), and none of these studies detected signiﬁcant relations between the presence of infection and the plasma or serum zinc concentrations of children in the community. Although zinc concentrations may decrease during an acute-phase response, these effects do not appear to limit the use of plasma zinc concentrations as an indicator of zinc status in community-based studies of children in developing countries. Among hospitalized individuals, or among adults, the effects of infection, inﬂammation, or other processes as mentioned earlier may limit the usefulness of plasma zinc concentrations as an indicator of zinc status. The most reliable method for diagnosis of zinc deﬁciency may be the response of plasma or serum zinc concentrations to zinc supplementation (68). In several studies, low plasma or serum zinc concentrations of young children were noted to increase after zinc supplementation (69). Zinc plasma or serum concentrations can be measured by ﬂame atomic absorption spectroscopy (73), and more recent methods include ashing small volume samples in a graphite furnace followed by ﬂameless atomic absorption spectroscopy. Several practical considerations must be made in collecting plasma or serum samples for the assessment of zinc concentrations. Ideally, the setting for the collection of blood samples should be standardized as much as possible in relation to meals, exercise, or other stress (69). Plasma or serum should be separated as quickly as possible, as zinc concentrations may change if the plasma or serum has not been separated from the blood within 1 h (74). In this regard, plasma may be preferable to serum in ﬁeld studies. Hemolyzed samples should not be used, as zinc concentrations are higher in erythrocytes than in plasma. Trace element-free syringes, pipet tips, and storage tubes are widely available from major laboratory supply houses and should be used for the collection of plasma or serum samples for zinc determinations, as zinc contamination may occur with use of regular blood-drawing equipment and supplies (75).

9.2. Dietary Assessment The assessment of dietary zinc intake in a population requires a complex approach: food-intake distributions of a population, analysis of local staple foods, and a comparison of zinc intake from these foods with estimates of the requirements for adequate intake of zinc (76). Dietary assessment can be based on the recall of an individual for food consumed or based on weighed food records compiled by research assistants. A 24-h dietary recall has been developed for assessment of the adequacy of tracemineral intakes in illiterate populations (77). In many developing countries, local food-composition tables may be unavailable, and the investigator must develop such a

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table by collecting foods for analysis and measuring trace-mineral content by atomic absorption spectroscopy (78). Other dietary components may limit the dietary availability of zinc, including phytates, calcium, and dietary ﬁber, and these must be considered in the food analyses (76). The observed or reported zinc intakes for a population can be used to derive a distribution of usual zinc intakes. The estimated bioavailability of zinc must be taken into account, as estimates of zinc absorption can vary widely, depending on phytates and other factors in the food. For developing countries, the requirement estimates for zinc have been established by the WHO based on the availability of zinc in the diet, as discussed previously in Subheading 7.3. (Table 3) (57).

9.3. Other Methods Hair zinc concentrations have been used as an indicator of zinc status in children, but this method may be confounded by effects of malnutrition (79). Erythrocyte zinc concentrations are insensitive indicators for zinc deﬁciency. Leukocytes contain high concentrations of zinc and have been examined as a indicator of zinc deﬁciency (80), however, the laboratory technique is difficult and laborious, and contamination of leukocyte samples with erythrocytes and platelets is problematic. Diminished taste acuity (hypogeusia) is one feature of marginal zinc deﬁciency in children and has been used as a basis for a functional test of zinc status (81). Stable isotope techniques may help provide further insight into zinc deﬁciency and the effects of zinc interventions (82).

10. ZINC SUPPLEMENTATION AS A PUBLIC HEALTH INTERVENTION Zinc supplementation has been shown to have both preventive and therapeutic beneﬁt in reducing the morbidity and mortality of a variety of childhood infectious diseases (Table 5). Zinc supplementation also has a positive effect on child growth. Zinc appears to have potential for improving maternal health and pregnancy outcomes, although the results of different studies have not been consistent.

10.1. Diarrheal Disease in Children Several studies suggest that zinc supplementation can reduce the incidence and severity of diarrheal disease in children, and the effects of zinc appear to be strongest among children who were considered to have low zinc status. In an early study in India, daily oral zinc supplementation was used for 50 infants and young children who were hospitalized with acute diarrhea. Although there was not a signiﬁcant reduction in the duration of diarrhea, investigators found that among children with low rectal mucosal zinc, there was a one-third reduction of diarrheal duration and stool frequency (83). Another study conducted by the same group of investigators showed that daily oral zinc supplementation reduced the duration of persistent diarrhea, but the results did not reach statistical signiﬁcance (84). A community-based trial of oral zinc supplementation was conducted in India involving 937 children, 6–35 mo of age, who presented with acute diarrhea (85). All children received daily multivitamins, and about half the children received daily oral zinc, 20 mg/d. Children receiving zinc had a 23% reduction in diarrheal duration and reduced severity of diarrhea. In the second phase of the study, 579 of the 937 children

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Table 5 Summary of Some Zinc Supplementation Studies in Children in Developing Countries Location

n

Subjects

Effects of zinc supplementation Reference

India

50

Infants with dehydrating diarrhea

India

937

Infants, 6–35 mo, with acute diarrhea, with community-based follow-up of children 579–609

Vietnam

146

Growth-retarded children, 4–36 mo

Overall nonsigniﬁcant reduction (69) in diarrheal duration and frequency, but signiﬁcant reduction among zinc-depleted infants. 23% reduction in duration of (71,73,78) diarrhea, reduction in severity of diarrhea on initial episode; overall nonsigniﬁcant reduction in incidence of persistent diarrhea and dysentery; overall nonsigniﬁcant reduction in incidence of acute diarrhea, but stratiﬁed analyses suggest some effects based on zinc status, age, and gender; 45% reduction in incidence of acute lowerrespiratory infections Signiﬁcant reductions in episodes (77) of diarrhea and respiratory infection. 22% reduction in diarrheal (76,82) incidence, 67% reduction in persistent diarrhea, change in activity patterns. Signiﬁcant reductions in episodes (75) of diarrheal disease Signiﬁcant reduction in diarrheal (81) prevalence and nonsigniﬁcant one-third reduction of cough

Guatemala

89

Mexico

219

Brazil

134

Infants, 6–9 mo, in community Preschool children in community Low birth-weight infants

continued in a follow-up trial to determine whether continued zinc supplementation, 10 mg/d, would reduce the incidence of acute diarrhea, persistent diarrhea, and dysentery. There was an 8% reduction in the incidence of diarrhea in children during 180 d of follow-up, and these results did not reach statistical signiﬁcance. In a stratiﬁed analysis, among children old than 11 mo of age who had low plasma zinc levels, zinc supplementation signiﬁcantly reduced the incidence of diarrhea by 17% (86). Overall, zinc supplementation reduced the incidence of persistent diarrhea by 21% and dysentery by 14%, but these effects did not reach statistical signiﬁcance (87). A stratiﬁed analysis showed that zinc supplementation signiﬁcantly reduced dysentery among boys by 38%. In a hospital-based trial in Bangladesh, all children with acute diarrhea were given multivitamins, and half were given an additional daily oral zinc, 20 mg (88). Zinc supplementation reduced the duration of diarrhea by 14% but the results did not reach statistical signiﬁcance. A stratiﬁed analysis showed that children with lower plasma zinc concentrations had a signiﬁcant 22% reduction in diarrheal duration. Among growth-

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retarded children in Vietnam, those receiving daily zinc supplementation, 10 mg, had a three-fold reduction in diarrheal episodes compared with children receiving placebo (89). Other studies conducted in Bangladesh and Indonesia have shown that zinc supplementation reduces diarrheal duration (63). Several community-based trials from Latin America also suggest that zinc supplementation reduces the incidence of diarrhea. Children in Mexico received zinc or placebo supplementation daily for 12 mo, and children receiving zinc had a signiﬁcant reduction in episodes of diarrheal disease (90). In Guatemala, children receiving daily zinc supplementation, 10 mg, had significantly lower incidence of diarrhea than children who did not receive supplements (91). Among low birth weight infants in northeast Brazil, a nonrandomized trial of zinc supplementation, 5 mg/d, was noted to reduce the prevalence of diarrhea by 28% over a 6-mo period (92).

10.2. Respiratory Disease in Children Zinc supplementation shows potential for the reduction of acute lower-respiratory disease. In the same study involving growth-retarded children in Vietnam, zinc supplementation was associated with a 2.5 reduction in episodes of respiratory infections (89). A trial conducted in India showed that daily zinc supplementation, 10 mg, signiﬁcantly reduced the incidence of acute lower respiratory infections in infants and preschool children during a 6-mo period (93).

10.3. Malaria in Children Zinc supplementation has been shown to have potential in reducing the morbidity of malaria. A community-based trial in the Gambia showed that young children supplemented with zinc had 32% fewer clinic visits for malaria (94). A recent trial in Papua New Guinea showed that children receiving 10 mg zinc/d had a signiﬁcant reduction in malaria parasitemia, malaria-attributed fevers, and reduced health-center visits (95).

10.4. Growth and Development of Children A recent meta-analysis of the effects of zinc supplementation on child growth found there was a small but highly signiﬁcant impact of zinc supplementation on children’s height increments. The greatest effect of supplementation were observable in the more stunted children (63). As has been noted previously, most zinc supplementation trials looking at growth outcomes have not focused on the age group of 6–12 mo of age when growth faltering is occurring (1). In India, zinc supplementation was noted to affect high movement activities among infants and young children (96). Zinc supplementation, 10 mg/d, was noted to affect the activity patterns of infants in rural Guatemala (97).

10.5. Maternal Health Zinc supplementation during pregnancy may play a role in improving maternal and child health (26). In industrialized countries, studies have been conducted to determine whether zinc supplementation will improve birth weight and the results have been mixed, but many of the studies were conducted in well-nourished populations. A large trial conducted among low-income women in Alabama showed that daily antenatal zinc supplementation, 25 mg/d, signiﬁcantly increased birth weight (98). A recent large trial conducted among 1295 pregnant women in Lima, Peru, showed that zinc supple-

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mentation, 15 mg/d, had no signiﬁcant impact on birth weight or prematurity (99). They did, however, ﬁnd evidence of more advanced neurological development of the fetus. They were also able to document increased transfer of immunoglobulins to the fetus, especially IgG, and were able to show reduced levels of ARI and diarrheal morbididty in the ﬁrst year of life (100) . Postpartum zinc supplementation appears to have no effect on the breast milk zinc content (42). Zinc supplementation of women during lactation in the Amazon, although not inﬂuencing the milk zinc levels, did inﬂuence the milk retinol levels. At 4 mo postpartum, the milk zinc retinol levels were double in the supplemented mothers as compared to the placebo control group (101). There were also growth effects, such that infants of zinc-supplemented mothers gained half a kilogram more than controls by 5 mo postpartum. The infants of zinc-supplemented mothers also had diarrhea three times more frequently (102). There appears to be a relationship between maternal zinc status and the levels of secretory immunoglobulin A in breast milk (103). The effects of zinc supplementation were more pronounced in the mothers of boys than girls.

10.6. Human Immunodeﬁciency Virus Infection Low serum or plasma zinc levels have been reported in 26% of asymptomatic homosexual men (104) and 29% of hospitalized patients with AIDS (105). Low serum zinc levels were associated with reduced secretory function of the thymus (106) and HIV disease progression in homosexual men (107,108). Zinc levels can decrease during the acute-phase response, and it has been suggested that these low zinc levels may reﬂect HIV replication (107). Daily zinc supplementation, 200 mg/d for 30 d reduced infectious disease morbidity in adults with AIDS in Italy (109).

11. PREVENTION OF ZINC DEFICIENCY Strategies to prevent zinc deﬁciency should consider the immediate, underlying, and basic causes of the deﬁciency. Immediate causality can be addressed by supplementation. The underlying causes include the control of disease, dietary diversiﬁcation, food fortiﬁcation, and improving zinc availability in plant sources. The promotion of exclusive breastfeeding for about 6 mo is one important preventive measure. Increasing the intake of foods with a high content of zinc such as meat and animal products may be an economic challenge in many settings in developing countries. Promoting their consumption preferentially by women and children instead of by men may be more feasible. Other dietary approaches include increasing the intakes of foods which enhance zinc absorption, modifying foods through fermentation, soaking, or other measures to reduce phytic-acid content (76). A potential complementary strategy to reduce zinc deﬁciency is that of breeding plants that are low in phytic acid and high in sulfur-containing amino acids, which promote zinc absorption (110). Zinc supplementation is a possible means of preventing zinc deﬁciency, but it is thought that supplementation must be given often, i.e., daily, and there may be programmatic impediments towards daily supplementation. However, zinc supplementation may have a role in high-risk situations, such as pregnancy, lactation, and early childhood (42,111). Where supplementation and fortiﬁcation are to be employed, the ideal situation would be to combine zinc with other nutrients, such as iron for example, because the target populations are also likely to be deﬁcient in iron as well as other nutrients.

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12. CONCLUSIONS Zinc is essential for many important biological processes, including gene expression, immune function, growth, and reproduction. The available data suggest that zinc deﬁciency is a major public health problem worldwide, with the most vulnerable groups being infants and young children, and pregnant and lactating women. Considerable capacity exists to adapt to inadequate zinc intake, such that overt clinical deﬁciency is rare. These adaptive mechanisms are not without consequence, however. Recent clinical trials show that zinc supplementation in children reduces the morbidity of diarrheal disease, respiratory disease, and malaria. It is less clear to what extent maternal zinc supplementation has a beneﬁt in improving maternal and child health outcomes. Zinc interventions during infancy, and for women during pregnancy and lactation, need to be further tested in a programmatic setting.

13. RECOMMENDATIONS • The study of zinc deﬁciency in developing countries has been hampered by a lack of a good indicator for zinc status. Further investigation is needed to develop an inexpensive, sensitive, and speciﬁc indicator for zinc status in individuals. • A recent review suggests that plasma or serum zinc concentrations may be more useful for indicating zinc status in populations than previously believed. Further work is needed to validate the concept of using plasma or serum zinc concentrations as an indicator for zinc deﬁciency in populations in developing countries. • The potential value of zinc supplementation in pregnant and lactating women needs to be explored further in a programmatic setting, in populations in developing countries. • Dietary-based interventions to improve zinc nutriture need further evaluation, especially for complementary foods. • Further epidemiological investigation is needed to identify risk factors for zinc deﬁciency among infants, young children, pregnant, and lactating women. • The effect of zinc deﬁciency and supplementation on various aspects of immune function need further evaluation. • The potential mortality reduction effects of improving zinc nutrition in women and infants should be measured in populations likely to have extensive marginal deﬁciency. • Further corroborative data is needed to demonstrate the efﬁcacy of zinc supplementation in reducing the morbidity of Plasmodium falciparum malaria in developing countries. • The potential use of zinc for fortiﬁcation of foodstuffs needs to be explored. • The possibility of improving zinc nutriture through plant breeding needs to be addressed.

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35. Prasad AS, Oberleas D. Binding of zinc to amino acids and serum proteins “in vitro.” J Lab Clin Med 1970; 76:416–425. 36. Giroux EL, Henkin RI. Competition for zinc among serum albumin and amino acids. Biochem et Biophys Acta 1972; 273:64–72. 37. Hess FM, King JC, Margen, S. Zinc excretion in young women on low zinc intakes and oral contraceptive agents. J. Nutr. 1977; 107:1610–1620. 38. Prasad AS, Rabbani P, Abbassi A, Bowersox E, Fox MRS. Experimental zinc deﬁciency in humans. Ann Int Med 1978; 89:483–490. 39. Swanson CA, King JC. Zinc and pregnancy outcome. Am J Clin Nutr 1987; 46:763–771. 40. Spencer H, Osis D, Kramer L, Norris C. Intake, excretion and retention of zinc in man. In: Trace Elements in Human Health and Disease, vol 1. Prasad AS, ed. New York, NY: Academic, 1976, pp. 345–361. 41. Baer MT, King JC. Tissue zinc levels and zinc excretion during experimental zinc depletion in young men. Am J Clin Nutr 1984; 39:556–570. 42. Krebs NF, Reidinger CJ, Hartley S, Robertson AD, Hambidge KM. Zinc supplementation during lactation: effects on maternal status and milk concentrations. Am J Clin Nutr 1995; 61:1030–1036. 43. Walsh CT, Sandstead HH, Prasad AS, Newberne PM, Fraker PJ. Zinc: health effects and research priorities for the 1990s. Environ Health Perspect 1994; 102(Suppl 2):5–46. 44. Vallee BL, Auld DS. Zinc coordination, function, and structure of zinc enzymes and other proteins. Biochemistry 1990; 29:5647–5659. 45. Berg JM, Shi Y. The galvanization of biology: a growing appreciation for the roles of zinc. Science 1996; 271:1081–1085. 46. Bettger WJ, O’Dell BL. Minireview: a critical physiological role of zinc in the structure and function of biomembranes. Life Sci 1981; 28:1425–1438. 47. Bunce GE. Interactions between zinc, vitamins A and D and hormones in the regulation of growth. In: Nutrient Regulation During Pregnancy, Lactation and Infant Growth. Allen L, King J, Lonnerdal B, eds. New York, NY: Plenum, 1994, pp. 257–264. 48. Solomons NW, Shrimpton R. Zinc. In: Tropical and Geographical Medicine. Warren K, Mahmoud AF, eds. New York, NY: McGraw-Hill, 1983, pp. 1059–1063. 49. WHO Complementary Feeding of Young Children in Developing Countries: a review of current scientiﬁc knowledge. Geneva: WHO, 1998. 50. Shrimpton R. Zinc intake from non-breast milk sources in the ﬁrst year of life in a poor urban slum in Manaus, Amazonas Brazil. Proc Nut Soc. 1997; 56:19A. 51. Turnlund JR, King JC, Keyes WR, Gong B, Michel MC. A stable isotope study of zinc absorption in young men: effects of phytate and _-cellulose. Am J Clin Nutr 1984; 40:1071–1077. 52. Solomons NW, Jacob RA, Pineda O, Viteri FE. Studies on the bioavailability of zinc in man. II. Absorption of zinc from organic and inorganic sources. J Lab Clin Med 1979; 94:335–343. 53. Mills CF. Dietary interactions involving trace elements. Ann Rev Nutr 1985; 5:173–193. 54. Gibson RS, Yeudall F, Drost N, Mtitimuni B, Cullinan T. Dietary interventions to prevent zinc deﬁciency. Am J Clin Nutr 1998; 68(suppl):484S–487S. 55. Lönnderdal B, Cederblad Å, Davidsson L, Sandström B. The effect of individual components of soy formula and cows’ milk formula on zinc bioavailability. Am J Clin Nutr 1984; 1064–1070. 56. Sandström B, Cederblad Å, Lönnderdal B. Zinc absorption from human milk, cow’s milk, and infant formulas. Am J Dis Child 1983; 137:726–729. 57. World Health Organization. Trace elements in human nutrition and health. Geneva: WHO, 1996. 57a. National Research Council. Subcommittee on the 10th edition of the RDAs. Recommended Dietary Allowances. 10th Edition. Washington, D.C.: National Academy, 1989. 58. Golden MH, Jackson AA, Golden BE. Effect of zinc on thymus of recently malnourished children. Lancet 1997; 2(8047):1057–1059. 59. Golden BE, Golden MH. Plasma zinc, rate of weight gain, and the energy cost of tissue deposition in children recovering from sever malnutrition on a cow’s milk or soya protein based diet. Am J Clin Nutr 1981; 34:892–899. 60. Jameson S. Zinc status in pregnancy: the effect of zinc therapy on perinatal mortality, prematurity, and placental ablation. Ann NY Acad Sci 1993; 678:178–192. 61. Bunce GE, Lytton F, Gunesekera B, Vessal M, Kim C. Molecular basis for abnormal parturition in zinc deﬁciency in rats. In: Nutrient Regulation during Pregnancy, Lactation and Infant Growth. Allen L, King J, Lonnerdal B, New York, NY: Plenum, 1994, pp. 209–234.

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62. Black MM. Zinc deﬁciency and child development. Am J Clin Nutr 1998; 68:464S–469S. 63. Brown KH. Effect of infections on plasma zinc concentrations and implications for zinc status assessment in low-income countries. Am J Clin Nutr 1998; 68 (suppl):425S–429S. 64. Beisel WR, Pekarek RS, Wannemacher RW Jr. Homeostatic mechanisms affecting plasma zinc levels in acute stress. In: Trace Elements in Human Health and Disease, vol. 1, Zinc and Copper. Prasad AS, ed. New York, NY: Academic, pp. 87–106. 65. Swanson CA, King JC. Reduced serum zinc concentration during pregnancy. Obstet Gynecol 1983; 62: 313–318. 66. Solomons NW. On the assessment of zinc and copper nutriture in man. Am J Clin Nutr 1979; 32: 856–871. 67. Pilch SM, Senti FR. Analysis of zinc data from the second national health and nutrition examination survey (NHANES II). J Nutr 1985; 115:1393–1397. 68. Gibson RS. Principles of Nutritional Assessment. New York and Oxford: Oxford University Press, 1990. 69. Brown KH, Peerson JM, Allen LH. Effect of zinc supplementation on children’s growth: a metaanalysis of intervention trials. Bibl Nutr Dieta 1998; 54:76–83. 70. Brown KH, Lanata CF, Yuen ML, Peerson JM, Butron B, Lönnerdal B. Potential magnitude of the misclassiﬁcation of a population’s trace element status due to infection: example from a survey of young Peruvian children. Am J Clin Nutr 1993; 58: 549–554. 71. Ruz M, Solomons NW, Mejia LA, Chew F. Alterations of circulating micronutrients with overt and occult infections in anaemic Guatemalan preschool children. Intl J Food Sci Nutr 1995; 46:257–265. 72. Friis H, Ndhlovu P, Kaondera K, Sandstrom B, Michaelsen KF, Vennervald BJ, Christensen NO. Serum concentration of micronutrients in relation to schistosomiasis and indicators of infection: a cross-sectional study among rural Zimbabwean school children. Eur J Clin Nutr 1996; 50:386–391. 73. Smith JC Jr, Butrimovitz GP, Purdy WC. Direct measurement of zinc in plasma by atomic absorption spectroscopy. Clin Chem 1979; 25:1487–1491. 74. English JL, Hambidge KM. Plasma and serum zinc concentrations: effect of time between collection and separation. Clin Chim Acta 1988; 175: 211–216. 75. Smith JC, Holbrook JT, Danford DE. Analysis and evaluation of zinc and copper in human plasma and serum. J Am Coll Nutr 1985; 4:627–638. 76. Gibson RS, Ferguson EL. Assessment of dietary zinc in population. Am J Clin Nutr 1998; 68(suppl):430S–434S. 77. Ferguson EL, Gadowsky SL, Huddle JM, Cullinan TR, Gibson RS. An interactive 24-h recall technique for assessing the adequacy of trace mineral intakes of rural Malawian women: its advantages and limitations. Eur J Clin Nutr 1995; 49:565–578. 78. Ferguson EL, Gibson RS, Opare-Obisaw C, et al. The phytate, nonstarch polysaccharide, zinc, calcium, copper, and manganese contents of 78 locally grown and prepared African foods. J Food Comp Anal 1993; 6:87–99. 79. Hambidge KM. Hair analyses: worthless for vitamins, limited for minerals. Am J Clin Nutr 1982; 36: 943–949. 80. Jones RB, Keeling PW, Hilton PJ, Thompson RP. The relationship between leukocyte and muscle zinc in health and disease. Clin Sci 1981; 60:237–239. 81. Hambidge KM, Hambidge C, Jacobs M, Baum JD. Low levels of zinc in hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 1972; 6:868–874. 82. Hambidge KM, Krebs NF, Miller L. Evaluation of zinc metabolism with use of stable-isotope techniques: implications for the assessment of zinc status. Am J Clin Nutr 1998; 68:410S–413S. 83. Sachdev HPS, Mittal NK, Mittal SK, Yadav HS. A controlled trial on utility of oral zinc supplementation in acute dehydrating diarrhea in infants. J Pediatr Gastroenterol Nutr 1988; 7:877–881. 84. Sachdev HPS, Mittal NK, Yadav HS. Oral zinc supplementation in persistent diarrhoea in infants. Ann Trop Pediatr 1990; 10:63–69. 85. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A, Jalla S. Zinc supplementation in young children with acute diarrhea in India. N Engl J Med 1995; 333:839–844. 86. Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A, Bhandari N. Efﬁcacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea: a community-based, double-blind, controlled trial. Am J Clin Nutr 1997; 66:413–418.

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87. Sazawal S, Black RE, Bhan MK, Jalla S, Bhandari N, Sinha A, Majumdar S. Zinc supplementation reduces the incidence of persistent diarrhea and dysentery among low socioeconomic children in India. J Nutr 1996; 126:443–450. 88. International Centre for Diarrhoeal Disease Research, Dhaka, Bangladesh. Zinc supplementation in the treatment of childhood diarrhoea. Indian J Pediatr 1995; 62:181–193. 89. Ninh NX, Thissen JP, Collette L, Gerard G, Khoi HH, Ketelslegers JM. Zinc supplementation increases growth and circulating insulin-like growth factor I (IFG-I) in growth-retarded Vietnamese children. Am J Clin Nutr 1996; 63:514–519. 90. Rosado JL, López P, Muñoz E, Martinez H, Allen LH. Zinc supplementation reduced morbidity, but neither zinc nor iron supplementation affected growth or body composition of Mexican preschoolers. Am J Clin Nutr 1997; 65:13–19. 91. Ruel MT, Rivera JA, Santizo MC, Lönnerdal B, Brown KH. Impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural Guatemalan children. Pediatrics 1997; 99:808–813. 92. Lira PIC, Ashworth A, Morris SS. Effect of zinc supplementation on the morbidity, immune function, and growth of low-birth-weight, full-term infants in northeast Brazil. Am J Clin Nutr 1998; 68(suppl):418S–424S. 93. Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan MK. Zinc supplementation reduces the incidence of acute lower respiratory infection in infants and preschool children: a double-blind controlled trial. Pediatrics 1998; 102:1–5. 94. Bates CJ, Evans PH, Dardenne M, et al. A trial of zinc supplementation in young rural Gambian children. Br J Nutr 1993; 69:243–255. 95. Genton B, Baisor M, et al. Zinc supplementation reduces morbidity due to plasmodium falicparum: a randomized trial in pre-school children in Papua, New Guinea. Am J Trop Med Hyg (In press). 96. Sazawal S, Bentley M, Black RE, Dhingra P, George S, Bhan MK. Effect of zinc supplementation among observed activity in preschool children in an urban slum population. Pediatrics 1996; 98:1132–1137. 97. Bentley ME, Caulﬁeld LE, Ram M, Santizo MC, Hurtado E, Rivera JA, Ruel MT, Brown KH. Zinc supplementation affects the activity patterns of rural Guatemalan infants. J Nutr 1997; 127: 1333–1338. 98. Goldenberg RL, Tamura T, Neggers Y, Copper RL, Johnston KE, DuBard MB, Hauth JC. The effect of zinc supplementation on pregnancy outcome. JAMA 1995; 274:463–468. 99. Caulﬁeld LE, Zavaleta N, Figueroa A, Leon A. Maternal zinc supplementation does not affect size at birth or pregnancy duration in Peru. J Nutr 1999; 129:1563–1568. 100. Merialdi M, Caulﬁeld LE, Zavaleta N, Figueroa A, DiPietro JA. Adding zinc to prenatal iron and folate tablets improves fetal neurobehavioural development. Am J Obstet Gynecol 1999; 180(2 Pt 1): 483–490. 101. Shrimpton R, Franca TS, Rocha YS, Alencar FH. Zinc supplementation in urban Amazonian mothers: concentrations of zinc and retinol in maternal serum and milk. Proc Nut Soc 1983; 42:122A 102. Shrimpton R, Allencar, FH, Vasconcellos JC, Rocha YR. Effects of maternal zinc supplementation on growth and diarrhoeal status of breastfed infants. Nutr Res 1985; Supp 1: 338–342. 103. Shrimpton R, Lehti K. Inﬂuence of zinc supplementation on breastmilk SigA levels. In: Trace Elements on Man and Animals TEMA 5. Mill CF, Bremner I, Chester JK, eds. UK: Commonwealth Agricultural Bureaux, 1985, pp. 90–93. 104. Beach RS, Mantero-Atienza E, Shor-Posner G, Javvier JJ, Szapocznik J, Morgan R, et al. Speciﬁc nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 1992; 6:701–708. 105. Koch J, Neal EA, Schlott MJ, Garcia-Shelton YL, Chan MF, Weaver KE, Cello JP. Zinc levels and infections in hospitalized patients with AIDS. Nutrition 1996; 12:515–518. 106. Falutz J, Tsoukas C, Gold P. Zinc as a cofactor in human immunodeficiency virus-induced immunosuppression. JAMA 1988; 259:2850–2851. 107. Graham NMH, Sorensen D, Odaka N, Brookmeyer R, Chan D, Willett WC, et al. Relationship of serum copper and zinc levels to HIV-1 seropositivity and progression to AIDS. J Acquir Immune Deﬁc Syndr 1991; 4:976–980. 108. Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, et al. Micronutrients and HIV-1 disease progression. AIDS 1995; 9:1051–1056.

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109. Mocchegiani E, Veccia S, Ancarani F, Scalise G, Fabris N. Beneﬁt of oral zinc supplementation as an adjunct to zidovudine (AZT) therapy against opportunistic infections in AIDS. Intl J Immunopharm 1995; 17:719–727. 110. Ruel MT, Bouis HE. Plant breeding: a long-term strategy for the control of zinc deﬁciency in vulnerable populations. Am J Clin Nutr 1998; 68:488S–494S. 111. Allen LH. Zinc and micronutrient supplements for children. Am J Clin Nutr 1998; 68:495S–498S.

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Iron Deﬁciency and Anemia Ray Yip

1. INTRODUCTION Iron deﬁciency is one of the most common nutrition disorders worldwide, affecting a large proportion of children and women in the developing world. In addition, iron deﬁciency is probably the only nutrient deﬁciency of signiﬁcant prevalence in virtually all developed countries. Iron is element 26 in the periodic table and has an atomic weight of 55.85. In aqueous solution, iron exists in two oxidation states, either Fe2+, the ferrous form, or Fe3+, the ferric form. Iron changes between these forms, enabling it to serve as a catalyst in redox reactions by donating or accepting electrons. Ironcontaining compounds play key roles in oxygen and energy metabolism. Iron is one of the most extensively investigated and understood nutrients. Although the burden and causes of iron deﬁciency are well-established, the challenge remains for the adequate prevention and control of iron deﬁciency. This will require greater effort in embarking on public-health measures that are feasible and cost-effective (1).

2. DEFINING ANEMIA AND IRON DEFICIENCY Anemia is a commonly used indicator to screen for iron deﬁciency in clinical settings, or to define the burden of iron deficiency in population-based surveys. Although anemia in itself is not speciﬁc for iron deﬁciency, especially in areas where other conditions such as malaria are common, there is a close association between anemia and iron deﬁciency. Iron deﬁciency, as deﬁned by speciﬁc biochemical tests, is the most common cause of anemia in most parts of the world. Iron-deﬁciency anemia represents the severe end of the spectrum of iron deﬁciency and requires the fulﬁllment of both the deﬁnition of anemia and iron deﬁciency (2). Iron deﬁciency without anemia represents a moderate form of iron deﬁciency where iron-dependent function is impaired but anemia is not present. Depleted iron stores represent the mildest form of iron deﬁciency when there is no functional impairments or anemia. Anemia is deﬁned as hemoglobin concentration below –2 standard deviations (SD) of the age- and sexspeciﬁc normal reference. The most commonly used cut-off for anemia is hemoglobin <110 gm/L for under ﬁve children and pregnant women, <120 gm/L for nonpregnant women, and <130 gm/L for men. From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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3. HISTORICAL BACKGROUND An early study on the composition of blood was conducted by Robert Boyle (1627–1691) in 1684. Various chemical analyses were conducted, and ashing of blood produced a brick-red substance (3). Vincenzo Menghini (1704–1759), a chemist and physician in Italy, demonstrated that particles of dried, powdered blood were attracted to a lodestone in 1747, suggesting the existence of iron in blood (4). Based on experimental studies, Jean Baptiste Boussingault (1802–1887), a French agricultural chemist, determined that iron was an essential nutrient for animals (5). Iron tablets were used in the 19th century for treatment of chlorosis, an early term for anemia in young women. Gustav von Bunge (1844–1920), a professor at the University of Dorpat in Estonia, showed that milk was a poor source of iron, thus, infants largely depended on prenatal iron reserves (6). Helen Mackay (1891–1965) demonstrated that anemia could be alleviated in infants in East London by provision of iron-fortiﬁed milk (7).

4. EPIDEMIOLOGY 4.1. Prevalence of Iron Deﬁciency and Anemia Using anemia as an indicator and data collected from multiple countries, the World Health Organization (WHO) estimates that half of children and women and up to a quarter of men are iron-deﬁcient in developing countries (8). In contrast, an estimated 7–12% of children and women are iron-deﬁcient in developed countries (9,10). Although not all anemia is caused by iron deficiency, in areas where the prevalence of anemia exceeds 30–40%, most anemia is caused in part or in total by iron deﬁciency. Because the presence of anemia reﬂects a more severe form of iron deﬁciency, it is safe to assume that the actual presence of iron deﬁciency is about two to three times that of the prevalence of iron-deﬁciency anemia. For example, if a survey found that 30% of young children were anemic, and further testing using an iron-speciﬁc test found that two out of three children had clear evidence of iron deﬁciency, then 20% of the children would have iron-deﬁciency anemia. The estimated prevalence of iron deﬁciency for this childhood population would be 40–60%.

4.2. Risk Factors for Iron Deﬁciency The highest risk groups for iron deﬁciency are preterm and low birth-weight infants, infants, and children during periods of rapid growth, children consuming milk who have a sensitivity to cow’s milk, premenopausal women, pregnant women, and individuals with nematode infections in the gastrointestinal tract (Table 1). Low consumption of iron-containing foods and consumption of foods that interfere with iron absorption, such as phytates, also increase the risk of iron deﬁciency. These individual risk factors will be discussed throughout the following sections.

5. METABOLISM OF IRON The average total body iron is about 3.8 gm in men and 2.3 gm in women. The iron-containing compounds in the body are grouped into functional iron, in which iron serves a metabolic or enzymatic function, and storage iron in which iron is transported or stored. Most functional iron is in the form of heme proteins, i.e., proteins which contain an iron-porphyrin prosthetic group. The basic structure of heme is a

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Table 1 Some Risk Factors for Iron Deﬁciency Pregnancy Prematurity Low birth weight Rapid growth Sensitivity to cow’s milk Low consumption of meat High consumption of phytates Menstruation Nematode infection in gastrointestinal tract

protoporphyrin-9 molecule with one iron atom. About two-thirds of the iron in the body is functional iron, mostly in the form of hemoglobin within erythrocytes. Hemoglobin has a molecular weight of 68,000 and is composed of four heme units. Other functional iron includes myoglobin and iron-containing enzymes. In men, about one-third of the total body iron is in the form of iron stores, whereas in women, storage iron accounts for about one-eighth of total body iron.

5.1. Absorption of Iron Iron absorption is inﬂuenced by several factors, including dietary iron content, the bioavailability of dietary iron, the amount of storage iron in the body, and the rate of erythrocyte production. Dietary iron consists primarily of either nonheme iron and heme iron, and these are absorbed by different mechanisms (11). Nonheme iron accounts for approx 85% or more of the diet, and it consists primarily of iron salts found in plant and dairy products. The absorption of nonheme iron depends on how the entire meal affects iron solubility. Heme iron comes primarily from hemoglobin and myoglobin found in meat, poultry, and ﬁsh. Although heme iron comprises a smaller proportion of iron in the diet, the absorption of heme iron is two to three times greater than nonheme iron and is less affected by the overall composition of the diet. Women absorb approx 13% of total dietary iron compared with men, who absorb about 6% of total dietary iron, and these differences may relate to the lower iron stores in women and the increased absorption of iron, which helps to compensate for menstrual losses of iron. The absorption of iron appears to be regulated by mucosal cells of the small intestine and is related to body iron stores. Thus, individuals with low hemoglobin absorb a greater fraction of nonheme iron from the diet.

5.2. Transport of Iron Heme iron and nonheme iron are transported from the intestine to the tissues by a plasma transport protein, transferrin. Transferrin delivers iron to tissues through surface receptors speciﬁc for transferrin, or transferrin receptor (12). The receptors bind to the transferrin-iron complex at the cell surface and carry the complex into the cell, where iron is released. The iron supply of the body is reﬂected in the iron saturation of transferrin. A low transferrin saturation indicates undersupply of iron or deﬁciency, and a high transferrin saturation indicates oversupply of iron. Transferrin saturation can also be altered during inﬂammatory conditions such as a febrile response. Transferrin

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receptors are found in high concentrations on tissues that have a high uptake of iron, including erythroid precursors, placenta, and liver. The expression of transferrin receptors on tissues is highly regulated in response to the availability of iron. In an iron-rich environment, the number of transferrin receptors decreases. In an iron-poor environment or when iron demand increases, the number of transferrin receptors increases. The concentration of circulating plasma or serum transferrin receptors is proportional to the expression of transferrin receptors on cell surfaces, and this is the basis for the use of circulating transferrin receptors as an indicator of iron status.

5.3. Storage of Iron The major iron-storage compounds are ferritin and hemosiderin, which are found primarily in the liver, spleen, reticuloendothelial cells, and bone marrow. In the liver, iron is stored mainly in parenchymal cells or hepatocytes, and iron is also stored in reticuloendothelial cells or Kupffer cells. In the bone marrow and spleen, iron is stored mainly in reticuloendothelial cells. Stored iron is used primarily for the production of hemoglobin and for meeting other cellular needs for iron. Wide variations in the amount of storage iron can occur without any apparent effect on body functions. Storage iron is usually almost entirely depleted before the development of iron-deﬁciency anemia. Full-term infants are born with a substantial store of iron, which usually can meet the infant’s iron needs until 6 mo of age (13). Preterm and low birth-weight (LBW) infants generally have less storage iron than full-term infants, and as a consequence, these infants may deplete their iron stores as early as 2–3 mo of age. Once infants have exhausted their body stores of iron, it is difﬁcult to build up substantial iron stores because of the rapid growth and high iron requirement that occurs up to 24 mo of age. After 24 mo of age, the growth rate slows and iron stores usually begin to accumulate (14).

5.4. Iron Turnover and Loss The production and destruction of erythrocytes accounts for most of the turnover of iron in the body. The average life-span of erythrocytes is about 120 d, and in an adult, the daily iron turnover is about 20 mg. Most of the iron from degraded erythrocytes is recaptured for the synthesis of hemoglobin. Iron losses in the feces are about 0.6 mg/d from bile, desquamated mucosal cells, and minute amounts of blood (15). Other routes of iron loss include desquamated skin and sweat (0.2–0.3 mg/d), urine (<0.1 mg/d). The average daily iron loss from adult men is 1.0 mg/d (range 0.5–2.0 mg/d). Premenopausal women need to replace the iron in menstrual blood loss, which accounts for 0.4–0.5 mg/d, combined with other iron losses for a total average iron loss of 1.3 mg/d (16).

6. ROLE OF IRON IN BIOLOGICAL FUNCTIONS 6.1. Hemoglobin Hemoglobin plays an essential role in the transfer of oxygen from the lungs to tissues in erythrocytes. Hemoglobin combines with oxygen in the pulmonary circulation and becomes largely deoxygenated in the capillary circulation of tissues. In severe anemia, the hemoglobin content of erythrocytes is reduced, decreasing oxygen delivery to tissues and leading to chronic tissue hypoxia.

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6.2. Myoglobin Myoglobin is found in muscle where it transports and stores oxygen needed for muscle contraction. The structure of myoglobin is a single heme group with a single globin chain. Myoglobin accounts for about 10% of the total body iron.

6.3. Cytochromes Cytochromes contain heme and are essential to respiration and energy metabolism. Cytochromes a, b, and c are involved in oxidative phosphorylation and the production of cellular energy. Cytochromes serve as electron carriers in transforming adenosine disphosphate (ADP) to adenosine triphosphate (ATP), the primary energy storage compound. Cytochrome P450 is found in microsomal membranes of liver and intestinal mucosal cells.

6.4. Other Iron-Containing Enzymes NADH dehydrogenase and succinate dehydrogenase are two nonheme, ironcontaining enzymes involved in energy metabolism. Hydrogen peroxidases also contain iron and protect against the accumulation of hydrogen peroxide. Catalase and peroxidase are two heme-containing enzymes that convert hydrogen peroxide to water and oxygen. Other iron-containing enzymes include aconitase, phosphoenolpyruvate carboxykinase, and ribonucleotide reductase.

6.5. Iron and Immune Function Although animal studies suggests that some immune compartments may be affected adversely by iron deﬁciency, there still is not convincing evidence from human studies that iron deﬁciency has an adverse effect on immunity (17). Some studies suggest that better iron status may beneﬁt certain microorganisms during infection; however, the relationship between iron status and immunity is complex and has often been greatly oversimpliﬁed. A recent meta-analysis suggests that iron supplementation may slightly worsen the clinical course of malaria infection (18).

7. PATHOGENESIS OF IRON DEFICIENCY AND ANEMIA 7.1. Increased Requirement for Iron In general, the etiology of iron deﬁciency can be viewed as a negative balance between iron intake and iron loss. Whenever there is rapid growth, as occurs during infancy, early childhood, adolescence, and pregnancy, iron requirement is much higher, and hence, a positive iron balance is difﬁcult to maintain. The blood volume expands in parallel with growth, with a corresponding increase in iron requirement (19). Iron loss, related to monthly menstrual blood loss as well as iron transfer to the fetus during pregnancy, is a major factor in the increased risk of iron deﬁciency for women of childbearing age (20). Table 2 compares the iron requirement of infants, women, and men. It is clear that infancy and pregnancy are times when requirement is high, increasing the risk for iron deﬁciency.

7.2. Poor Dietary Intake Worldwide, the majority of iron deﬁciency is the direct result of low dietary iron content, especially of bio-available iron. The dietary source of iron strongly inﬂuences

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Table 2 Iron Requirements in Infants, Women, and Men Group Infants Children Females Nonpregnant Pregnant Postmenopausal Males

Age

Recommended intake (mg/d)

20–3 mo 13–6 mo 26–12 mo 11–10 yr

— 16.6 18.8 10.8

10–45 yr

15.8 45.8 10.8 12.8 10.8

10–18 yr >18 yr

the efﬁciency of the absorption. For infants, the iron content of milk consumed is a major determinant of iron status. The iron content of breast milk is low, in comparison to that of cow’s milk. However, 50% of the iron in breast milk can be absorbed, in contrast to less than 10% from cow’s milk. The higher absorption efﬁciency of human breast milk does not entirely make up for the low iron content. After 6 mo of age, breast-fed infants require an additional source of iron from the diet to meet their iron requirement. Unfortunately, in most settings, complementary food is low in iron content and availability. The amount of iron absorption from a variety of foods ranges from less than 1% to more than 20%. Foods of vegetable origin are at the lower end of the range, dairy products are in the middle, and meat is at the upper end. Meat is a good source of iron, because most iron is in the form of heme iron, which has an absorption efﬁciency of 10–20%, which is two to three times greater than that for nonheme iron (2–7%). Nonheme iron found in plant foods and fortiﬁed food products is not only less well absorbed, the absorption is strongly inﬂuenced by the other foods ingested at the same meal. Ascorbic acid and meat protein are among the most potent enhancers of nonheme iron absorption. Tannin in tea and phytic acid in grain ﬁbers are among the better known inhibitors of nonheme iron absorption.

7.3. Abnormal Iron Loss The normal turnover of intestinal mucosa with some blood loss can be regarded as physiological blood, which is accounted for in the daily requirement. Normal menstrual blood loss is also an obligatory or physiological loss. The most common reason for abnormal blood loss in infants and younger children is the sensitivity of some children to the protein in cow’s milk, resulting in increased gastrointestinal occult blood loss. In many tropical communities where hygienic conditions are inadequate, hookworm infection is a major cause of gastrointestinal blood loss for older children and adults. Hookworms cause bleeding in the upper intestine, and the severity of blood loss as measured by the hemoglobin content of feces is proportional to the intensity of the hookworm infestation. Recent studies show that in endemic areas, upwards of 40% of the iron deﬁciency anemia and majority of the severe anemia can be attributed to hookworm infections. There are two common forms of hookworm Necator americanus and Ancyclostoma duodenale, and for the same worm load, N. americanus causes

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a greater level of bleeding. Tricurius, found in the colon, has also been shown to contribute to blood loss, but to a much lesser extent than hookworm.

8. CLINICAL MANIFESTATIONS OF IRON DEFICIENCY Hemoglobin contains the majority of functional iron in the body, and in addition, there are a number of other iron-dependent enzymes that can be adversely affected by iron deﬁciency (21). The functional consequences of iron deﬁciency, which are of major public health importance, are brieﬂy reviewed here.

8.1. Anemia and Mortality Although mild anemia (10–20 gm/L below the cut-off) is not accompanied by health impairment, at a moderate level of anemia, reduced oxygen-carrying capacity begins to interfere with aerobic function (22). In areas where severe anemia (hemoglobin <80 gm/L) is common, iron deﬁciency is usually one of multiple causes of anemia (23). Very severe anemia (hemoglobin < 50 gm/L) is associated with increased childhood and maternal mortality, and is often regarded as the underlying cause of death (24,25). Deaths associated with severe anemia generally occur in time of increased physiological stress, for example, during an acute febrile illness for a young child, or during the peripartum period, when oxygen delivery and cardiovascular function are further compromised by worsening hemoglobin concentrations (26).

8.2. Child Behavior and Development In recent years, the relationship between iron nutritional status and the cognitive development of younger children has been an area of active investigation. Consistently, children with iron deficiency anemia test less well in psychomotor development compared with iron-sufﬁcient children (27). When various developmental test scores are standardized, the magnitude of the deﬁcient associated with iron deﬁciency is approx 1 SD, a deﬁcit greater than that observed for mild childhood lead poisoning. However, some deﬁcit may be associated with iron deﬁciency without anemia (28,29). Although short-term iron treatment has been shown to reverse some aspects of the cognitive effect, the few long-term studies suggest that moderately severe iron deﬁciency in early childhood can lead to irreversible developmental disadvantage (30). For this reason, control of childhood iron-deﬁciency anemia should be based on primary prevention, rather than relying on the detection of anemia children after signiﬁcant iron deﬁciency has occurred.

8.3. Work Performance and Productivity It is well-established that signiﬁcant anemia related to iron deﬁciency will reduce work performance. The classic study by Viteri demonstrated a linear dose-response relationship between hemoglobin concentration and Harvard step-test performance (31). The adverse effect of iron deﬁciency on work or energy output appears to be mediated through a combination of decreased oxygen-carrying capacity from anemia and the effect of iron deﬁciency on muscle function. In animal studies, it has been shown that both aerobic and anaerobic functions are reduced (32). In developing countries, where a large proportion of the economic output is based on physical labor, a major reduction in work capacity can be of great economic

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consequence. Iron-supplementation studies among rubber tappers in Indonesia and tea pickers in Sri Lanka have clearly shown that gain in productivity secondary to treatment of signiﬁcant anemia (33,34). If the average reduction in productivity is 20% for an anemic individual, in a country where 50% of the women and 20% of the men are affected, the impact of iron deﬁciency anemia equals a total loss of 5–7% of the national economic output. Therefore, the economic consequence of iron deﬁciency for some poor countries may be substantial.

8.4. Heavy Metal Absorption In developed countries such as the United States and in some situations in developing countries, an important consequence of iron deﬁciency is an increased risk of lead poisoning. In the United States, young children who have iron deﬁciency have a three to four times higher prevalence of lead poisoning than children who are not iron-deﬁcient (35). This association is partly socioeconomic: poor children are more likely to have nutritional disorders and are also more likely to live in inadequate housing where risk to lead exposure is greater (35). However, there is strong evidence of a direct association between iron deﬁciency and lead toxicity, related to the fact that iron-deﬁcient individuals have increased efﬁciency of lead absorption (36). This increased absorptive capacity is not speciﬁc for iron, and the absorption of other divalent metals, including toxic heavy metals such as lead and cadmium, is also increased (37). The microcytic anemia thought in the past to be owing to lead poisoning is in fact iron-deﬁciency anemia, which is frequently observed among children with lead poisoning (38). Prevention of iron deﬁciency would reduce the number of children who are susceptible to lead poisoning through greater lead absorption, and one study suggests that iron treatment of children with lead poisoning may also help reduce their lead burden (39).

9. ASSESSMENT OF IRON NUTRITION STATUS 9.1. Tests for Iron Deﬁciency A number of hematologic and biochemical tests enable the characterization of iron status. Often, iron deﬁciency is deﬁned by one or more abnormal iron biochemical tests: serum ferritin, transferrin saturation, transferrin receptor, and erythryocyte protoporphyrin. Iron-deﬁciency anemia is deﬁned as meeting the criteria for both iron deﬁciency and anemia based on hemoglobin testing. Low serum ferritin per se is regarded as low or depleted iron stores. Even though all iron-related tests respond to changes in iron status, each test reﬂects different aspects of iron metabolism. For this reason, various tests are therefore of different utility, and results may not always agree between tests.

9.2. The Meaning of Anemia Anemia as measured by low hemoglobin concentration or low hematocrit is by far the most commonly used indicator for detecting iron deﬁciency. Common causes of anemia other than iron deﬁciency include malaria, hereditary hemoglobinopathies or red cell production defects such as thalassemia minor, recent or current infections including human immunodeﬁciency virus (HIV) infection, and any chronic conditions with an inﬂammatory response. On an individual basis, anemia cannot be used to detect those with milder forms of iron deﬁciency (iron deﬁciency without anemia). Because it

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Table 3 Relationship of Iron Status to Hematological Tests Laboratory Indicator

Depleted stores

Iron deﬁciency

Overload

Normal

N

N

N

?

N

N N N N

? ? B

N N

N N

N N

Hemoglobin Serum ferritin Transferrin saturation Erythrocyte Protoporphyrin MCV Serum transferrin Receptor

B BB

N N

N B

Iron deﬁciency anemia ? ?? ? BB ? B

Adapted from refs. (2,42).

is not generally feasible to perform iron biochemistry tests in many settings, hemoglobin response to iron treatment is a common approach in diagnosing iron deﬁciency. An increase in hemoglobin concentration of 10 or more g/L with a course of oral iron for those with anemia is indicative of iron deﬁciency. For population-based assessment or monitoring, prevalence of anemia is a useful indicator to deﬁne the severity of iron deﬁciency. One common reason for the misdiagnosis of anemia is inadequate laboratory procedures for hemoglobin determination related to capillary blood sampling or owing to inaccurate laboratory methods or procedures.

9.3. Detection of Anemia by Clinical Examination In resource-poor settings where it is not feasible to detect anemia by measurement of hemoglobin or hematocrit, clinical examination has been widely used to detect those with severe anemia. Clinical evidence regarding pallor of skin, conjunctiva, tongue, and palms are used to formulate an impression. In one study, the detection of severe anemia (hemoglobin <70 g/L), the sensitivity of clinical detection was reported to reach the range of 50–60%, and 90% for speciﬁcity (40).

9.4. Use of Frequency Distributions of Hemoglobin in Assessing Iron Status When iron nutrition is included as a component of a nutrition survey, the traditional method of measurement is hemoglobin values among children, whereas a speciﬁc anemia survey usually examines a sample of children and women. The prevalence of anemia then serves as the index of severity of iron deﬁciency in the population. This approach is useful in areas where iron deﬁciency is the predominant cause of anemia, as is generally the case in developed countries. When poor iron intake is the main etiologic factor present in the population, children and women are disproportionately affected, and the hemoglobin concentration of adult men is virtually unaffected. If conditions other than poor dietary iron intake also present at a signiﬁcant level, men can also have a high prevalence of anemia. For this reason, inclusion of a sample of men for anemia surveys can be useful in deﬁning the nature of a high prevalence of anemia among children and women. If the prevalence of anemia for men is low, poor dietary iron intake is almost certain to be the cause of anemia in children and women.

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If men also have a high prevalence of anemia, factors other than poor dietary iron intake are usually present. This can include severe hookworm infection causing iron deﬁciency owing to blood loss.

9.5. The Diagnosis of Multiple Conditions Contributing to Anemia If other conditions are suspected to be contributing to anemia, proper evaluation of multiple factors using biochemical testing is often difﬁcult. For example, both infections and vitamin A deﬁciency can cause depression of transferrin saturation and elevation of erythrocyte protoporphyrin measurements, which might lead to an incorrect interpretation that only iron deﬁciency is present (41). Measurement of serum or plasma transferrin receptor has been considered to be helpful in distinguishing the anemia of chronic infection from iron-deﬁciency anemia (42), but the sensitivity and speciﬁcity of serum or plasma transferrin receptor need further evaluation in different settings and among different risk groups. Areas with high rates of severe anemia are often found in developing countries where laboratory resources are limited. One method for the evaluation of different causes of anemia is the measurement of hemoglobin concentrations in the ﬁeld before and after different interventions. For example, Suharno and colleagues (43) investigated anemia among pregnant women in rural Indonesia where vitamin A deﬁciency was also present. Treatment of anemia with a combination of iron and vitamin A resulted in a much better response of hemoglobin concentrations than either iron or vitamin A alone, demonstrating that virtually all the anemia in this population was attributed to vitamin A and iron deﬁciency.

9.6. Field Testing for Hemoglobin A portable photometer, the HemoCue system (Anglholm, Sweden) has been used in many different ﬁeld surveys for the evaluation of anemia (44). This system consists of a battery-operated photometer and a disposable cuvet, which is coated with the dried reagent (sodium azide) and serves as the blood collection device. This one-step blood collection, using a cuvet without a wet reagent, makes the system uniquely suited for rapid ﬁeld surveys. Nonlaboratory personnel can be quickly and easily trained to operate the device, which is not dependent on electricity. In addition to these operational features, laboratory evaluation using standard methods found the HemoCue system to have satisfactory accuracy and precision (45). Long-term field experience also demonstrates that the instrument is stable and durable. These features make the HemoCue system suitable for the inclusion of hemoglobin measurements in nutrition surveys.

10. CONTROL OF IRON DEFICIENCY Despite the fact that the general strategy for improving iron nutrition is similar for infants and adult women (i.e., increasing dietary iron intake), the lack of overlap between infant and adult diet requires that separate approaches for intervention are considered. The three general strategies are: (1) supplementation through the primary health care system, (2) nutrition education and promotion (dietary selection), and (3) iron fortiﬁcation through industry-based food processing. These major approaches are not mutually exclusive, and in various settings, different approaches would be of greater importance.

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10.1. Primary Health Care-Based Approaches 10.1.1. IRON SUPPLEMENTATION There are two general approaches to iron supplementation through the primary health-care system. One approach is appropriate for areas where the prevalence of irondeﬁciency anemia is relatively low, i.e., less than 10–15%, and this approach involves screening for anemia and providing iron supplements only to those found to be anemic. The dosage of iron treatment is 3 mg/kg of elemental iron for children under 5, or 60 mg elemental iron daily for adults for 3 mo. The approach is to provide universal supplementation where the prevalence of iron-deﬁciency anemia is high and where the majority of the population is affected by iron deﬁciency. For practical purposes, the former approach is suitable in developed areas, and the latter approach is suitable for most developing countries. In most developing countries there is a general lack of adequate iron in the infant diet, and as a result, the prevalence of anemia exceeds 50% by 1 yr of age, indicating that the majority of children are iron- deﬁcient. Currently, UNICEF recommends a daily dose of 12.5 mg of elemental iron for infant 6–12 mo for such a purpose. Because there is a lack of low-cost preparation or drops for distribution in developing countries and lack of experience for large-scale supplementation, further evaluation of the feasibility of this approach is needed. The formulation of iron supplements must take into consideration other nutrients such as zinc and vitamin A, which are also likely to be deﬁcient in many developing country settings. Routine iron supplementation is the current cornerstone of efforts to reduce irondeﬁciency anemia during pregnancy. One major limitation of the iron-supplementation strategy is the need to establish a system for supply and distribution of iron tablets through the primary health-care system, and such supply and distribution is not always reliable in a resource-constrained setting. As with any system where there are multiple steps in getting supplies to a target population, it is not uncommon to have breakdowns in the supply chain. Poor compliance is another common problem for any medication required over a long period of time by asymptomatic individuals. At higher doses of iron (>60 mg elemental iron), the gastrointestinal side effects are common and may contribute to a lack of compliance. To overcome these problems, proper education on the importance of the supplement and potential side- effects need to be provided as part of the distribution program. Although routine iron/folate supplementation is common practice in many countries, the prevalence of maternal anemia often remains high, suggesting that the effectiveness of such a program is not high. Efforts to improve the effectiveness of the program include assuring the supply and distribution, commutation towards primary health-care workers and women on the beneﬁts of supplementation. One potential reason for lack of substantial anemia reduction could be the presence of other limiting factors such as vitamin A deﬁciency, or infections such as malaria or HIV infection. Thus far, the evidence indicates that greater effort is still needed to improve the effectiveness of such programs. One effort has been to test weekly instead of daily iron supplementation as an alternative to control maternal anemia. During the school age, weekly iron supplementation has shown to be useful in correcting iron-deﬁciency anemia. Under supervised conditions, weekly iron administration has the potential to improve iron status of women of childbearing age and in turn, prevent severe anemia during a subsequent pregnancy.

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10.1.2. CONTROL OF INTESTINAL HELMINTH INFECTION Recent studies from Zanzibar and Vietnam found that hookworm infestation can account for up to 40% of the iron deﬁciency anemia in highly endemic areas. In such settings, the potential impact of deworming can be justiﬁed as part of the anemia control program. Current evidence suggests that it is safe to deworm women after the ﬁrst trimester of pregnancy, and the decision of deworming all children and women can be based on the local prevalence, because screening and treatment on the individual level may be less feasible.

10.2. Nutrition Education and Promotion Among various micronutrients of interest, more is known about the bioavailability of iron in dietary sources than perhaps any other micronutrient. Factors that can either enhance or inhibit iron absorption have been well-studied. To date, there is limited evidence from developing countries that suggests that dietary selection is an effective approach to improving iron status. This might be attributed to the fact that the main iron-rich foods are animal sources, which are relatively expensive. There is some encouraging evidence from developed countries that nutrition education can lead to improved feeding patterns and iron status among infants and younger children, because iron-fortiﬁed foodstuffs such as infant cereal are commonly used. In most developing country settings, however, complementary foods are mainly local items with both low iron content and low iron bioavailability, which can also interfere with the absorption of iron in breast milk. Promotion of exclusive breast-feeding may help protect the higher absorption of iron from breast milk. Promoting the earlier introduction of meat-based complementary foods may be helpful. In the Middle East and northern Africa, tea is often introduced during infancy. Education efforts to delay the age at which tea is introduced and avoiding tea near meal times can be considered to be part of the education-based approach.

10.3. Iron Supplementation Iron can be supplied in the form of tablets or liquid, and commonly used preparations are ferrous sulfate, ferrous gluconate, and ferrous fumarate. The absorption of iron from a supplement is affected by the iron status of the individual and how the supplement is taken. Iron-deﬁcient individuals tend to have greater iron absorption, and iron is absorbed more readily if the supplement is taken between meals and with water or juice. Taking iron supplements with meals or with tea, coffee, or milk will lower the absorption of iron. Iron is usually absorbed better when given in a supplement alone, as calcium carbonate and magnesium oxide in some multivitamin preparations can inhibit iron absorption (46,47).

10.4. Fortiﬁcation Iron fortiﬁcation of commonly consumed foods (in settings where it is feasible) is likely the most cost-effective option. Ferrous sulfate, a highly soluble form of iron, is usually used to fortify infant formula and bread. In foods that are stored for a long period of time in air-permeable packages, ferrous sulfate and other highly soluble forms of iron may increase fat oxidation and rancidity, thus, less soluble forms of iron such as ferric orthophosphate and ferric pyrophosphate are often used to fortify these types of foods.

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One of the best examples of the effectiveness of fortiﬁcation in the prevention of iron-deﬁciency anemia was seen in a project to fortify milk powder with iron and vitamin C for low income families in Chile (48). Another project demonstrated that iron status of school-age children could be improved through provision of heme-ironfortiﬁed cookies in schools (49). Iron fortiﬁcation of common food items such as wheat ﬂour will affect the iron intake of all segments of the population except for infants. Women of childbearing age may potentially gain the most from this nontargeted approach. Experience to date indicates that it is highly feasible to fortify wheat ﬂour with iron and other micronutrients. The additional cost of fortiﬁcation is approx 0.5% of the overall cost of the processed ﬂour. This is a small margin that can reasonably be passed on to the consumer without undue burden. One argument against iron fortiﬁcation is that it is only suitable for areas with a high consumption of wheat ﬂour (>80–100 kg/person/yr). In reality, even at lower consumption levels, iron fortiﬁcation of ﬂour can be of great value in improving iron status. For example, in a population with an average per capita consumption of 30 kg/yr, if the ﬂour is fortiﬁed at 60 parts per million, the total amount of extra iron consumed will be 1800 mgs/yr or about 5 mg/d. This amount is about one-third of the daily intake requirement of a nonpregnant woman, or equivalent of a weekly intake of 30 mg as a supplement. At this level of consumption, iron deﬁciency anemia can be corrected over a year or can help build iron stores substantially. Based on the current experience, the fortiﬁcation of wheat ﬂour with iron should be considered in an areas with at least a moderate consumption of wheat ﬂour. Other food items that have been shown to be useful for iron fortiﬁcation include curry powder, soy sauces, salt and ﬁsh sauce, and milk powder. With the exception of milk powder, most other items have yet to become large-scale programs.

10.5. Iron Overload Concerns have been raised that iron fortiﬁcation may potentially harm the few individuals who may be at risk for iron overload owing to various diseases that cause excess iron accumulation, such as hereditary hemochromatosis, a genetic condition in which iron absorption is enhanced. Hereditary hemochromatosis is an autosomal recessive disorder with a homozygote frequency of 100–500 per 100,000 in North America and Europe (50). It is possible to screen for affected individuals and treat these individuals with prophylactic phlebotomy in order to prevent clinical disease (51). In developing countries, incidence of hereditary hemochromatosis is lower because it is a genetic disorder that is generally associated with northern European ancestry. In Asia and Africa, rare and severe hereditary anemias such as thalassemia major are more common, and these affected individuals often become iron-overloaded because of repeated transfusion. For the most part, these individuals have been identiﬁed, and speciﬁc measures can be taken to protect these individuals from iron overload. Other concerns have been raised regarding the possible contribution of high iron levels to the development of chronic diseases. The evidence for this association is contradictory (52,53), and it is possible that chronic disease may alter iron metabolism, giving rise to an apparent association that is not causal in nature. However, there is no advantage to higher iron stores as long as the body’s iron requirement is met. The association between higher iron status and chronic diseases should be viewed as hypothetical, requiring more reﬁned conﬁrmatory studies. Because chronic diseases are the leading cause of mortality in many countries, these studies have generated a

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great deal of concern and have affected efforts to improve iron nutrition even in areas with severe iron deﬁciency.

11. CONCLUSIONS The challenge of reducing iron deﬁciency and anemia worldwide depends upon the development of sound approaches to intervention. The most promising approach is dietary improvement by iron fortiﬁcation of common staples, while for selected groups at risk such as infants, young children, and pregnant women, iron supplementation will also be needed. Unfortunately, increasing consumption of animal products is not always a practical solution because of economic barriers. The programmatic approaches to improving iron nutrition among adult women and among infants must be developed separately, because there is little overlap between the diet consumed by the two groups. Prevention of iron-deﬁciency anemia among younger children should be considered a high-priority issue, because of the clear evidence that iron-deﬁciency anemia impairs childhood development. Assessing iron status for monitoring program impact does not always require the full compendium of iron laboratory tests. Rather, comparison of hemoglobin distribution curves and hemoglobin response to treatment are methods that can be implemented easily even in settings with limited resources.

12. RECOMMENDATIONS Although iron deﬁciency is perhaps the best characterized of all nutritional deﬁciency disorders, there are several areas that need to be characterized further through scientiﬁc investigation. • Further investigation is needed to determine the sensitivity and speciﬁcity of serum or plasma transferrin receptor as a laboratory indicator for iron-deﬁciency anemia in populations that have a high prevalence of anemia of chronic disease, i.e., malaria and HIV infection. • Further investigation is needed to determine the validity of serum or plasma transferrin receptor as a laboratory indicator of iron-deﬁciency anemia in children. • Further studies are needed to characterize the effect(s) of iron supplementation on immune responses to different infectious diseases. • Large-scale community trials are needed to examine the efﬁcacy of iron supplementation for the prevention of anemia in infancy and early childhood. • Further investigation is needed to determine whether nutrition promotion and an education-based approach will improve iron status in various settings in developing countries. • The association between chronic diseases and iron status needs further elucidation.

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Iodine Deﬁciency Disorders Richard D. Semba

1. INTRODUCTION Iodine, a nonmetallic solid in the halogen family, is an essential constituent of the thyroid hormones thyroxine (T4) and triiodothyronine (T3). Thyroid hormones are involved in a wide range of biological functions and modulate gene expression through speciﬁc nuclear receptors. Iodine is present in small amounts in soil, water, plants, and animals, and insufﬁcient dietary intake of iodine is generally related to lack of iodine in the soil. The iodine-deﬁciency disorders consist of a wide spectrum of disorders including mental retardation, impaired physical development, increased perinatal and infant mortality, hypothyroidism, cretinism, and goiter. Goiter is deﬁned as an enlargement of the thyroid gland, and cretinism is a term used for a severe form of iodine deﬁciency characterized by severe mental retardation. The effects of iodine deﬁciency are most pronounced during periods of rapid growth, that is, in the fetus, neonate, infant, and young children, and this may have a major effect on brain development. The ongoing global effort to eliminate iodine-deficiency disorders through iodization of salt represents one of the largest public health efforts of the 20th century.

2. PUBLIC HEALTH SIGNIFICANCE An estimated 1.6 billion people worldwide may consume inadequate amounts of iodine and are at risk for iodine deﬁciency disorders (1,2). Iodine deﬁciency is the leading cause of preventable mental retardation in the world (3). The prevalence of iodine deﬁciency is related to the local availability of iodine in water and iodine in plants and foods, and the problem of iodine deﬁciency is global, with mountainous regions and large river deltas being the most well-known areas for endemic iodinedeﬁciency disorders.

3. HISTORICAL BACKGROUND Descriptions of goiter and cretinism have been found in written records and iconography since antiquity, and seaweed or thyroid extracts were empirically known to be effective treatments for goiter (4). Iodine was discovered by a saltpeter manufacturer From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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near Paris, Bernard Courtois (5) (1777–1838), in 1811. Seaweed ash from Normandy was used in the production of saltpeter, and Courtois observed violet vapors and formation of black crystals when an extract of this burned seaweed was heated (4,6). This substance was named iodine by the French chemist Joseph Louis Gay-Lussac (1778–1850), after the Greek word for “violet.” Further investigations by chemists showed that iodine was found in various seaweeds, algae, and marine sponges but was present only in trace quantities in other sources in nature. The qualitative estimation of iodine was facilitated by the discovery of the iodine-starch reaction in which free iodine formed a blue color when combined with starch. Jean-François Coindet (1774–1834), a physician in Geneva, found that pure iodine was a remedy for goiter (7). While working in Bogota, Colombia, the French agricultural chemist Jean Baptiste Boussingault (1802–1887) noted that goiter was not endemic in communities that utilized iodinecontaining salt from certain salinas, and before his return to France in 1831 he advised the Colombian government to provide for distribution of this naturally iodized salt for the health of the community (8). During the mid-19th century, Gaspard Adolphe Chatin (1813–1901), a professor in the School of Pharmacy of Paris, conducted investigations of iodine in plants, water, and animals, and he concluded that lack of iodine in the drinking water could be the cause of goiter and cretinism (9). Public health authorities in three provinces (Bas-Rhin, Seine-Inférieure, Haute-Savoie) started prophylactic measures of giving schoolchildren daily iodine tablets, and a large reduction in goiter was noted (10). The French program of iodine prophylaxis used high doses of 0.1–0.5 mg/kg for iodization of salt and daily iodine tablets containing 0.01 g potassium iodide. Although schoolchildren seemed to have tolerated the doses well, some adults with goiter may have experienced iodineinduced hyperthyroidism (Jodbase-Basedow reaction), and consequently the iodine prophylaxis program was abandoned (4). The French Goitre Commission was also skeptical about Chatin’s theory that iodine deﬁciency caused goiter and cretinism, noting that some of the 420,000 individuals with goiter in France lived in places where the air and soil contain iodine, and instead, the Commission implicated toxins in the water and food as the cause of goiter (11). By the late 19th century, the geographical distribution of endemic goiter and cretinism was recognized to extend around the world, with detailed accounts available from many countries in Europe (12). In detailed studies in northwest India, Robert McCarrison (1878–1960) distinguished neurological, or nervous cretinism from hypothyroid, or myxoedematous cretinism (13). In the United States, a large-scale trial of iodine for goiter prophylaxis was conducted by David Marine (1880–1976) and O. P. Kimball among school girls in Akron, Ohio between 1916 and 1920 (14–17). Sodium iodide was found to be effective in preventing goiter and in treating existing goiter, and by 1924, iodized salt was introduced in Michigan for general prophylaxis (18). Iodized salt for prophylaxis of goiter was implemented in various cantons in Switzerland in the early 1920s, an effort that had to overcome many difﬁculties, including disagreement among scientists and local opposition (4). With more widespread use of iodized salt, there was a decline in goiter and cretinism in parts of Europe. Goiter and cretinism gained renewed attention in pioneering studies conducted in Papua New Guinea in the 1950s and 1960s. These studies showed that injections of iodized oil could prevent goiter and cretinism in isolated mountain villages (19,20). Although various international organizations called for the eradication of iodine deﬁciency from 1974 to 1983, little action took place

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Table 1 The Spectrum of Iodine Deﬁciency Disorders Fetus

Neonate Child and adolescent Adult

Abortions Stillbirths Congenital anomalies Increased perinatal mortality Increased infant mortality Neurological cretinism: mental deﬁciency, deaf mutism, spastic diplegia, squint Myxoedematous cretinism: dwarﬁsm, mental deﬁciency Psychomotor defects Neonatal goiter Neonatal hypothyroidism Goiter Juvenile hypothyroidism Retarded physical development Goiter with its complications Hypothyroidism Impaired mental function Iodine-induced hyperthyroidism

Adapted with permission from ref. (22).

during this decade (21). The term “iodine-deﬁciency disorders” was introduced in 1983 to encompass the wide spectrum of the effects of iodine deﬁciency on health, including physical impairment and mental retardation (Table 1) (22). A report by a special committee of the European Thyroid Association showed that iodine-deﬁciency disorders were still a serious problem in many European countries in the 1980s, contrary to the general impression that the problem had largely been eradicated in Europe (23). The International Council for Control of Iodine Deﬁciency Disorders (ICCIDD) was established in 1985 with support of United Nations International Children’s Emergency Fund (UNICEF) and World Health Organization (WHO) (21), and this expert council remains a driving force behind the global elimination of iodine-deﬁciency disorders (24). The ICCIDD is an independent group of more than 500 professionals with backgrounds in public health, medicine, nutrition, technology, and health planning, and this group has been drawn from more than 92 countries. In 1990 the World Health Assembly and the World Summit for Children agreed on the goal that iodine-deﬁciency disorders be eliminated as a public health problem by the year 2000. Regional meetings of WHO, UNICEF, and ICCIDD have been held to assist countries with their national programs for the elimination of IDD in the last decade, and great progress has been made in providing access to iodized salt worldwide (24).

4. EPIDEMIOLOGY 4.1. Geographical Distribution There is a natural cycle of iodine in nature between the ocean, the atmosphere, rainfall, and runoff of rainfall into streams and rivers (Fig. 1) (21). The ocean contains

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Fig. 1. Natural cycle of iodine.

most of the iodine on the earth’s surface, with a concentration of iodide of 50–60 µg/L. Sunlight oxidizes iodide in seawater to elemental iodine, which is volatile and evaporates from the surface of the ocean. The concentration of iodine in the air is about 0.7 µg/m3. Iodine in the atmosphere is returned to surface of the earth by rain, which has concentrations of iodine of 1.8–8.5 µg/L. Iodine is leached from the soil by rain, ﬂooding, deforestation, and glaciation. Crops and animals raised on iodine-poor soils will have low iodine content. Thus, iodine-deﬁciency disorders tend to occur most commonly in areas where the soil is poor in iodine, especially mountainous regions such as the Alps, Andes, and Himalayas, and large river ﬂoodplains and deltas, such as that of the Ganges and Irawaddy. The iodine content of the soil is usually reﬂected in the concentration of iodine in drinking water. For example, in India the iodine content of drinking water in iodine deﬁcient areas is 0.1–1.2 µg/L and in the city of New Delhi, which is not iodine-deﬁcient, is 9.0 µg/L (21).

4.2. Prevalence The largest populations at risk of iodine deﬁciency disorders are in Asia and southeast Asia, followed by Africa and Latin America (Table 2). It is estimated that there are 740 million individuals in the world with goiter. In Asia, goiter prevalence is highest in China, Indonesia, and countries along the Himalayan mountains such as India, Bhutan, Nepal, and Pakistan. Among countries with a high prevalence of goiter in Africa are Zaire, Tanzania, Sudan, and Cameroon. Goiter remains a major problem in countries along the Andean chain such as Peru, Bolivia, Colombia, and Ecuador. Long-term iodine prophylaxis has contributed to the decline of goiter in some parts of Europe (25), but even as late as the mid-1980s, goiter was a major problem in some European countries such as Germany, Spain, Portugal, Italy, Turkey, and Greece where national programs to iodize salt did not exist (26–29). Even by 1992, iodine deﬁciency was

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Table 2 Prevalence of Goiter and Cretinism Worldwide, Based on WHO Global IDD Database WHO region Africa Americas Southeast Asia Eastern Mediterranean Europe Western Paciﬁc TOTAL

Total population (Millions)

Population affected by goiter

%

1,612 1,788 1,477 1,473 1,869 1,639 5,857

124 139 172 152 130 124 740

20 15 12 32 15 18 13

Adapted from ref. (24).

considered to be under control in Europe only in several northern European countries and Switzerland (30). The global prevalence of goiter and cretinism is currently changing in the face of efforts to iodize salt worldwide.

4.3 Risk factors The most important risk factor for iodine-deﬁciency disorders is residence in an area where soil and water are poor in iodine and where the primarily sources of plant and animal foods are locally derived. Substances known as goitrogens are widely found in some vegetables and can interfere with the metabolism of iodine (31). Cabbage, sweet potato, brussel sprouts, and turnips contain goitrogens. Cassava contains high concentrations of thiocyanates and has been implicated in the pathogenesis of goiter in Zaire (32). Women of reproductive age, pregnant women, and young children are at the highest risk of iodine deﬁciency. Among school children, girls appear to be at a higher risk of goiter than boys.

5. METABOLISM OF IODINE 5.1. Iodine Absorption and Transport Dietary iodide (inorganic, bound form of iodine) is rapidly absorbed in the stomach and intestine. Iodate, the form of iodine used in iodized salt, is reduced in the blood and rapidly absorbed. The normal requirement for iodine is 100–150 µg/d (33). Iodide circulates freely in the blood, not bound to proteins, and it is trapped by the thyroid and kidney. Iodine is excreted by the kidney, and the concentration of urinary iodine correlates well with the intake of iodine. Small amounts of iodine are excreted in saliva, sweat, and tears.

5.2. Iodine Storage The human body contains about 15–20 mg of iodine, of which 70–80% is found in the thyroid gland. The thyroid traps iodine through an active transport mechanism known as the iodine pump, and iodine trapping is regulated by thyroid stimulating hormone (TSH), or thyrotrophin, released from the pituitary gland. More trapping of iodine occurs if an individual has been with long-standing iodine deﬁciency than in a situation of adequate iodine intake. The thyroid must trap about 60 µg of iodine per

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day to maintain an adequate supply of thyroxine (21). The iodine content of the thyroid is generally related to iodine intake. In the situation where the iodine supply has been abundant, the thyroid may contain 10–20 mg of iodine, but in a situation of chronic iodine deﬁciency, the thyroid may contain as little as 200 µg of iodine.

5.3. Synthesis of Thyroid Hormones The thyroid is a highly vascularized organ that contains many follicles. The follicles consist of thyroid cells surrounding colloid, and the main constituent of the colloid is thyroglobulin, a storage form of thyroid hormones. Iodine is an essential constituent of thyroid hormones 3,5,3v,5v-tetraiodothyronine, thyroxine ( T4), and triiodothyronine (T3) (Fig. 3). Thyroglobulin is synthesized from amino acids in thyroid cells and moves into the colloid. Iodide moves into the colloid of the thyroid by passive diffusion. In the colloid, iodide is oxidized by hydrogen peroxide from the thyroid peroxidase system, combines with tyrosine in thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). MIT and DIT continue oxidation and couple to form iodotyrosines. The iodinated thyroglobulin is absorbed back into thyroid cell by pinocytosis and subsequently undergoes proteolysis, and triiodothyronine (T3) and thyroxine (T4) are released into the blood. Iodine metabolism and the synthesis of thyroid hormones is regulated by complex interactions involving the brain, pituitary, thyroid, and iodine intake. Iodine uptake by the thyroid, synthesis of MIT and DIT, and secretion of T3 and T4 are regulated by TSH, which is secreted by the pituitary. Secretion of TSH in turn is regulated by the level of circulating thyroxine (T4) and also by thyrotrophin releasing hormone (TRH) secreted by the hypothalamus. TRH release is inﬂuenced by neurotransmitters such as adrenalin, noradrenalin, serotonin, and dopamine. Further details of this complex regulation can be found elsewhere (34).

5.4. Transport and Turnover of Thyroid Hormones In the blood, T3 and T4 are bound by different proteins produced in the liver, such as transthyretin, albumin, and thyroid-binding globulin (TBG). About three quarters of T4 is normally bound to TBG. T4 is found in much higher concentrations in the blood than T3, and most of the T3 in plasma is derived from peripheral tissues where it is generated by monodeiodination of T4. Other metabolic derivatives of thyroid hormones, such as rT3 and 3,3v-diiodo-L-thyronine, are also found in the blood. Three deiodinases have been identiﬁed that catalyze monodeiodination of the outer ring (35). Further deiodination of the inner ring deactivates T3 and T4. The three deiodinases contain selenocysteine, thus, selenium status may have an important inﬂuence on thyroid hormone metabolism, as discussed elsewhere in this chapter (see Subheading 8).

5.5. Thyroid Hormones and Gene Expression Thyroid hormones are involved in the regulation of development and differentiation of nearly all organs and systems through their influence on gene expression. T3 inﬂuences gene expression through thyroid hormone receptors (TRs), nuclear receptors that belong to a superfamily of DNA-binding proteins, which includes receptors for retinoic acid (RAR, RXR), vitamin D (VDR), and steroids. Different isoforms of TRs, TR_1 ,TR_2, TR`1, and TR`2 have been described (36), and the expression of TR isoform varies by organ type (37). Speciﬁc sequences of DNA that bind TRs are known as thyroid hormone response elements (TREs) (38). TRs bind T3 and form heterodimers

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with retinoid X-receptors (RXR) in the form of RXR-TR (39). The ligand for RXR is 9-cis retinoic acid. In addition, RXR can form heterodimers with vitamin D receptor (VDR) (40). T3-responsive genes can be repressed by RXR-RXR homodimers (41). A complex network of interaction exists between TRs, retinoid receptors, and other nuclear receptors. Thyroid hormone coactivators, corepressors, and cointegrators are involved in regulation of transcription by TR, and transcriptional activities are regulated by the relative presence or absence of T3 (42,43).

6. ROLE OF IODINE IN BIOLOGICAL FUNCTIONS 6.1. Metabolism Thyroid hormones have major effects on the metabolism of proteins, carbohydrates, and lipids and are prime regulators of the basal metabolic rate. Thus, a wide variety of physiological activities, including heart rate, respiration, oxygen consumption, and nutrient metabolism are affected. Much of this regulation occurs through modulation of gene transcription by thyroid hormones. Thyroid hormones may also inﬂuence energy metabolism through direct and indirect regulation of mitochondrial activities (44).

6.2. Growth and Development The synthesis of growth hormone is regulated in part by thyroid hormones (45), and physiological concentrations of circulating thyroid hormones appear to be necessary to maintain normal secretion of growth hormone by the pituitary (46). Thyroid hormones play a role in normal bone cell growth and development (47), and in vitro studies suggest that thyroid hormones inﬂuence osteoblastic differentiation (48).

6.3. Brain Development Thyroid hormones play a critical role in fetal brain development. These hormones are involved in the early growth and differentiation of the brain and nervous system of the fetus (49). Thyroid hormones appear to ensure the coordination of developmental events through regulation of oligodendroglial and neuronal differentiation and cell death (50). T3 has been shown to regulate several speciﬁc brain genes (50). Extensive studies have been conducted on the effects of iodine deﬁciency and hypothyroidism in retarding fetal brain development in the sheep, rat, and marmoset monkey (51). These studies followed the demonstration of the prevention of fetal brain damage owing to iodine deﬁciency by correction of the deﬁciency before pregnancy (52).

6.4. Iodine and Immune Function There is some indirect evidence that iodine deﬁciency may contribute to abnormalities in immune function, but research in this area has largely been limited to animal studies of hypothyroidism and studies of the in vitro effects of thyroid hormones on immune effector cells. Thyroid hormones appear to be essential for normal lymphopoiesis and generation of antibody responses. Removal of the thyroid gland in rats resulted in the reduction of circulating peripheral blood lymphocytes, depression of antibody responses to experimental antigens, and reduced proliferative responses of spleen cells to mitogen, and abnormal immune responses could be restored by injections with thyroxine (53). Antibody responses to sheep erythrocytes were depressed by a thyroid block in an avian model (54). T3-treated mice had higher antibody responses to

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sheep red blood cells (55). Natural killer cell activity was enhanced by T4 administration in mouse studies (56,57). Decreased proliferative responses of thymocytes to mitogen have been noted in chicks with hypothyroidism (58). T3 enhanced proliferation of murine lymphocytes to phytohemagglutinin in vitro (59) and enhanced differentiation of human B lymphocytes in vitro (60). The function of polymorphonuclear leukocytes from adults with hypothyroidism seems to be impaired (61). In western India, the seroprevalence of toxoplasmosis was signiﬁcantly higher among children with grade II goiter than children with no goiter or grade I goiter (62).

7. PATHOPHYSIOLOGY OF IODINE DEFICIENCY 7.1. Dietary Sources and Intake of Iodine The richest dietary sources of iodine are seafood and seaweeds. Meat from animals that have grazed in areas with sufﬁcient iodine in the soil can also constitute a signiﬁcant source of iodine. Crops grown in iodine-sufﬁcient soils supply dietary iodine. Iodine in drinking water is usually only a small part of total iodine intake, providing <10% of daily iodine in the most iodine-rich areas. Some iodine is usually lost from foods during cooking, for example, during frying or boiling, as much as half the iodine content of ﬁsh may be lost.

7.2. Goitrogens Environmental goitrogens are substances found in foods and water that interfere with the metabolism of iodine and in some circumstances will exacerbate iodine deﬁciency. These goitrogens include cyanogenic glycosides, thioglycosides, isothiocyanates, and thiocyanates (63), and goitrogens can compete with iodine at the site of the iodine pump of the thyroid (21). Several goiter endemias have been attributed to environmental goitrogens, for example, in eastern Nigeria, Columbia, and Greece (64). High serum thiocyanate concentrations have been described in neonates in an area with severe endemic goiter in northern Zaire (65). It should be recognized that goitrogens are usually active only if iodine supply is limited and/or goitrogen intake is of long duration. In general, iodized salt or other interventions with iodine can overcome the negative effects of environmental goitrogens.

7.3. Iodine Dietary Requirements Recommended intakes of iodine have been made by the WHO, and recommendations are highest for pregnant and lactating women (Table 3) (66).

8. CLINICAL MANIFESTATIONS OF IODINE DEFICIENCY DISORDERS 8.1. Goiter Goiter, an enlargement of the thyroid gland, usually represents thyroid hyperplasia in response to insufﬁcient iodine intake. With iodine deﬁciency, T4 concentrations in the blood fall, and the feedback of low T4 on the pituitary leads to increased production of TSH. TSH stimulates hyperplasia of the thyroid with increased uptake of iodide, and the size of the thyroid increases, resulting in a goiter. By palpation on physical examination, goiter is deﬁned as enlargement of the thyroid such that the lateral lobes

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Table 3 Recommended Daily Intakes of Iodine Age/state

µg/d

0–12 mo 1–6 yr 7–12 yr 12 yr - adulthood Pregnancy Lactation

150 190 120 150 200 200

Adapted from ref. (66).

are larger than the terminal phalanx of the thumb of the person who is being examined. The severity of goiter is usually proportional to the severity of iodine deﬁciency, and with persistent enlargement of the thyroid, nodules can form. Extremely large goiters may compress the trachea and interfere with respiration. In areas of goiter endemics, the daily iodine intake is usually well below 100 µg/d, and in the most severe goiter endemics, iodine intakes as low as 10 µg/d are known (67). Goiter has been associated with malnutrition (68,69). Nutritional status and blood retinol concentrations were lower among individuals with goiter (70). Impaired intestinal absorption of iodine has been described in children with malnutrition (71). In Senegal, preschool children with acute malnutrition had lower serum T3 concentrations than controls, and levels returned to normal after 2 wk of refeeding (72). Selenium deﬁciency has been implicated in the pathogenesis of goiter, and this may be related to the selenocysteine involved in thyroid hormone metabolism (73). Multiple micronutrient deﬁciencies have been associated with poor iodine status in children (74).

8.2. Cretinism Endemic cretinism is characterized by mental retardation, which may be mild to severe, and sometimes a spectrum of growth and neurological manifestations. Two types of cretinism have been described, neurological cretinism, and myxoedematous, or hypothyroid cretinism (21). In neurological cretinism, stature is usually normal, mental retardation is often severe, and deaf mutism and cerebral diplegia are often present. In hypothyroid cretinism, severe growth retardation is present, mental retardation is less severe, and coarse, dry skin, and husky voice are present, but deaf-mutism and cerebral diplegia are absent (21). Sporadic cretinism is not related to iodine deﬁciency and is used to describe cretinism owing to a congenital defect in thyroid hormones or congenital absence or defect of a thyroid gland, and the incidence of sporadic cretinism is 3 in 10,000 in industrialized countries that are receiving adequate iodine (21). Neurological signs of endemic cretinism appear to be the result of hypothyroxinaemia in the mother and fetus at different periods of pregnancy (75). Iodine treatment to the mother up to the end of the second trimester of pregnancy can protect the fetal brain from iodine deﬁciency (76), and when given prior to conception, correction of iodine deﬁciency is completely effective in preventing endemic cretinism (52). Endemic cretinism is usually found where the prevalence of endemic goiter is higher than 30% and

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Table 4 Controlled Trials of Iodine Supplementation and Perinatal, Infant, and Child Mortality Location

Subjects

n

Zaire

Pregnant 5471 women Papua New women, 522 Guinea infants Indonesia Infants, 617 6 wk China Villages, 37,000 all population

Treatment effect

Reference

One-third reduction in infant mortality

(90)

~50% Reduction in 15-yr mortality

Pharoah 1987 (91) Cobra 1997 (92) DeLong 1997 (93)

50% Reduction in mortality to 6 mo ~50% Reduction in infant mortality

the median urinary iodine concentration is less than 25 µg/g creatinine (77). Selenium deﬁciency may contribute to the pathogenesis of endemic cretinism (78,79).

8.3. Growth and Development Maternal iodine deﬁciency during pregnancy causes retarded development of the fetus, and the more severe consequences include cretinism, as mentioned earlier. Other more insidious effects include impaired psychomotor and cognitive development (80). Children growing in iodine-deﬁcient areas appear to have impaired psychomotor development and lower school performance. Impaired psychomotor development was found in apparently normal schoolchildren from an area of iodine deﬁciency in Iran (81). Lower school performance with signiﬁcant differences in I.Q. have been reported in various studies comparing children from iodine-deﬁcient and iodine-sufﬁcient areas (82). In a case-control study of preschool children in northern Zaire, endemic goiter without cretinism was not associated with any major growth impairment, but no studies of thyroid status were performed in either cases or controls (83). Thyroid function was evaluated in children with short stature in north India, and nearly half the children had abnormal thyroid function (84).

8.4. Reproductive Failure Iodine deﬁciency in women is associated with infertility (85) and impaired fetal development (86). Higher rates of spontaneous abortions and stillbirths have been reported from areas of iodine deﬁciency (21) and correction of hypothyroidism in pregnant women reduces these adverse outcomes (87). Treatment with oral iodized oil during pregnancy were shown to signiﬁcantly lower the rates of abortions, stillbirths, and premature births in a mountainous area in Algeria (88). Trends in salt iodization suggest that improvement of iodine status is associated with reductions in stillbirth and congenital anomalies (89).

8.5. Perinatal, Infant, and Child Mortality High perinatal mortality has been associated with goiter during pregnancy (90). Clinical trials conducted in different parts of the world suggest that iodine supplementation, in the form of iodized oil injections, oral iodized oil, or iodinated water supply, can reduce neonatal, infant, and child mortality (Table 4). Infant mortality was lower

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Fig. 2. Cumulative survival rates of children whose mothers received either iodinated oil or saline (bars indicate 95% CI). Adapted with permission from ref. (91).

among infants born to women who were treated with intramuscular iodized oil around the 28th wk of pregnancy compared with infants born to control women in Zaire (90). In a controlled clinical trial in Papua New Guinea, cumulative long-term survival of children was signiﬁcantly higher among those whose mothers received iodinated oil before conception (Fig. 2) (91). The causes of death of children in this study were not known. In a rice-farming community in West Java, Indonesia, oral iodized oil, 100 mg, given directly to 6-wk-old infants reduced mortality between 6 wk and 6 mo by about 50% compared with placebo (Fig. 3) (92). Comparison of infant mortality rates between villages that received iodine in irrigation water vs control villages that did not in rural China suggested that iodinated water could reduce infant mortality by approximately half (Fig. 4) (93).

9. ASSESSMENT OF IODINE STATUS Several indicators exist for the assessment of iodine status, both on the individual and population level. The WHO has developed criteria for iodine deﬁciency as a public health problem in populations (94) (Table 5).

9.1. Goiter Rate The goiter rate is often used for the assessment of iodine status in a population, and the goiter rate includes both visible and palpable goiter. The WHO has adopted a grading classiﬁcation for goiter (Table 6) (94). Determination of thyroid size by

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Fig. 3. Survival curves of infants receiving oral iodized oil or placebo in West Java, Indonesia. Adapted with permission from ref (92).

ultrasonography is more accurate than palpation, especially in areas where iodine deﬁciency is mildly endemic and goiters in children are small. Health workers who are well-trained in ultrasonography can conduct up to 200 examinations per day (95). The WHO and the ICCIDD has recently recommended reference values for thyroid volume in school-aged children (95) based on variation in thyroid size varies by age, height, and weight (96) and data from a survey from 12 European countries (97).

9.2. Urinary Iodine Concentrations Urinary iodine concentrations are a good indicator of iodine status in groups of subjects, and iodine can be easily measured in large numbers of samples (98). Because urinary iodine concentrations tend to be skewed, the median value is usually used in describing urinary iodine concentrations in a population. A recent large study conducted among schoolchildren in Indonesia suggested that urinary iodine concentrations were the best indicator for ﬁeld studies for the assessment of iodine deﬁciency (99). Urinary iodine concentrations are classiﬁed as: <20 µg/L (severe deﬁciency), 20–49 µg/L (moderate deﬁciency), 50–99 µg/L (mild deﬁciency), and 100–200 µg/L (adequate).

9.3. BLOOD THYROID STIMULATING HORMONE Blood thyroid stimulating hormone (TSH) can be used as a indirect indicator of iodine status and has been used for screening of neonatal hypothyroidism. Heel-stick blood samples can be collected from neonates, spotted on ﬁlter paper, dried, and later eluted and measured using enzyme-linked immunorbent assay (ELISA) (100). A normal range of TSH is 0.17–2.90 µU/mL (0.17–2.90 mU/L).

10. PREVENTION OF IODINE-DEFICIENCY DISORDERS Iodized salt is currently the primary strategy for the prevention of iodine-deﬁciency disorders worldwide, and oral iodized oil is being used in some areas to target speciﬁc

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Fig. 4. Infant mortality rates in rural villages in China which received iodinated irrigation water (A) or were control villages (B). Adapted with permission from ref. (93).

communities at risk of iodine-deﬁciency disorders. Intramuscular iodized oil injections were used in earlier investigations of iodine-deﬁciency disorders. Iodination of the water supply is being explored as a potential strategy in some communities.

10.1. Iodized Salt “Iodized salt” is a term used to describe two different forms of iodine in salt: iodide, such as potassium iodide (KI), and potassium iodate (KIO3) (21). Potassium iodide was ﬁrst used in salt iodization, but iodate is more stable under different climatic conditions and is now the recommended form for salt iodization. Universal salt iodization is deﬁned as fortiﬁcation of all salt for human and animal consumption (101). The goal of salt iodization is to provide about 150 µg of iodine per day in dietary salt, taking

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Table 5 WHO Criteria for Iodine Deﬁciency as a Public Health Problem in Populations Indicator Goiter by palpation (%) Thyroid volume by ultrasound (>97th percentile) (%) Median urinary iodine (µg/L) TSH (>5 mU/L whole blood)

Population assessed

Mild

Moderate

Severe

School children School children

05–19.9 05–19.9

20–30 20–30

*30 *30

School children Neonates

50–99.9 03–19.9

20–49 20–40

<20 *40

Table 6 Classiﬁcation for Goiter Grade 0 Grade 1

Grade 2

No palpable or visible goiter. A mass in the neck that is consistent with an enlarged thyroid that is palpable, but not visible when the neck is in the normal position; it moves upward in the neck as the subject swallows; nodular alteration(s) can occur even when the thyroid is not enlarged. A swelling in the neck that is visible when the neck is in a normal position and is consistent with an enlarged thyroid when the neck is palpated.

into account factors such as heat and humidity. Warm and humid conditions can inﬂuence the retention of iodate in salt. The recommended levels of iodine in salt are 20–40 mg/kilo. The usual salt intakes can vary from country to country, but the usual consumption levels are 5–15 g/d for children and adults (101). Some studies suggest that the level of iodine in salt is often below the minimum required by local governments. A survey of iodine in salt samples across the country in Guatemala showed that more than 60% of samples were below the legally mandated level for iodized salt (102). A national survey in Kenya in 1990 and 1991 showed that most samples of iodized salt did not reach the minimal iodine concentrations as required by government regulation (103). Under the National Iodine Deﬁciency Disorder Control Programme in India, iodized salt containing at least 15 ppm iodine is supposed to be provided to beneﬁciaries, however, a survey of salt samples showed that nearly a ﬁfth of samples did not contain adequate iodine (104).

10.2. ORAL IODIZED OIL Oral iodized oil has been used to prevent iodine-deﬁciency disorders in populations where iodized salt is difﬁcult to procure and in situations where certain groups, i.e., pregnant women, are at high risk (105). In adults, a single dose of 460 mg of iodine is recommended (106), and a single annual dose of 240 mg of iodine seems to be adequate for children (105). Lower doses of 47 mg and 118 mg of iodine in oral iodized oil were also found to be effective in reducing hypothyroidism in children in Zaire (107). Among school children in western Sudan, oral iodized oil was as effective as an iodized oil injection in reducing goiter and preventing the recurrence of goiter (108), and in a clinical trial in eastern Zaire, oral iodized oil was also found to be an effective

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alternative to iodized oil injections (109,110). Oral iodized oil seemed to increase the mental performance of school-age girls in a trial conducted in Bolivia (111). For correction of iodine deﬁciency in children, single oral doses of 240 mg iodine in poppy seed oil appeared to be the optimal dose for 6-mo coverage (112). A trial conducted among schoolchildren in Malawi suggests that intestinal parasitic infections may interfere with the absorption of oral iodized oil (113). Oral iodized oil is considered to be safe for pregnant women and can be given any time during pregnancy (114,115). Childhood immunization programs may provide infrastructure for the delivery of oral iodized oil to infants in areas where iodine-deﬁciency disorders are a public health problem and iodized salt is not readily available (116). There was initial concern that oral iodized oil might theoretically interfere with trivalent oral poliovirus vaccine when given together, because the iodide could potentially inactivate the live poliovirus. In vitro studies suggested that there was no interference (117), and a recent clinical trial in Indonesia demonstrated that oral iodized oil given at 6 wk of age does not interfere with seroconversion to trivalent oral poliovirus vaccine (118). The WHO recommends the following doses of oral iodized oil every 12–18 mo in areas where iodine-deﬁciency disorders are a serious problem: for children <1 yr, 0.5 mL (240 mg), for children >1 yr and for women of childbearing age: 1.0 mL (480 mg) (119).

10.3. Iodized Oil Injections Much knowledge about the use of iodized oil injections came from studies conducted in Papua New Guinea from the late 1960s and 1970s (21). In part because of concern over the AIDS pandemic and use of needles, oral iodized oil has largely replaced iodized oil injections.

10.4. Other Strategies Monthly administration of 30 mg iodine in the form of a 10% potassium iodide oral solution was effective in the prophylaxis of iodine deﬁciency in school children in Zimbabwe (120). Iodization of drinking water has been used as a strategy to reduce iodine-deﬁciency disorders in developing countries such as Malaysia (121) and Mali (122). Iodization of irrigation water improved iodine content of soil, crops, and animals in an area of rural China, and the annual costs of the project ranged from $0.05/person in the ﬁrst year to $0.12/person in the second year (123). In a study in western Sudan, iodine-saturated silicon matrices placed in wells and hand pumps signiﬁcantly increased media urinary iodine concentrations and greatly reduced the prevalence of goiter (124). Other strategies that have been proposed for prevention of iodine-deﬁciency disorders include iodine fortiﬁcation of ﬂour (125), addition of iodine to fertilizers, and incorporation of iodine into school snacks and beverages. Increasing the dietary iodine consumption by chickens and livestock by the use of ﬁsh ﬂour, seaweed, or iodine supplementation may be another strategy to increase the iodine content of meat, poultry, and dairy products.

11. CONCLUSIONS Iodine deﬁciency is the leading cause of preventable mental retardation in the world and is a preventable cause of morbidity and mortality. Great progress has been made recently in providing access to iodized salt. As indicated by a recent

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WHO/UNICEF/ICCIDD report to the World Health Assembly in 1999 (24), of 5 billion people living in countries with iodine-deﬁciency disorder, 68% now have access to iodized salt. Of 130 countries affected by IDD, 104 countries (81%) have an intersectoral coordinating body, and 98 (75%) have legislation in place for iodized salt. Major challenges remain in ensuring the sustainability of salt iodization through monitoring and enforcement. The goals for monitoring include salt iodine at a level of 90% effectively iodized and urine iodine in the normal range (median excretion of 100–300 µg/L). The lower level of 100 µg/L is necessary to ensure normal brain development in the fetus and young infant, and the upper level of 300 µg/L is to minimize the occurrence of iodine-induced hyperthyroidism. Further momentum on the governmental level and in the scientiﬁc and medical community should help ensure the practical elimination of iodine-deﬁciency disorders worldwide.

ACKNOWLEDGMENT The author would like to thank Dr. Basil Hetzel for his helpful review of this chapter.

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Chapter 15 / Multiple Micronutrient Malnutrition

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Multiple Micronutrient Malnutrition What Can Be Done?

Usha Ramakrishnan and Sandra L. Huffman 1. INTRODUCTION The basic cause of malnutrition (protein-energy malnutrition [PEM] and micronutrient malnutrition) is poverty. Although lack of care, health, and environmental conditions are important components in the etiology of malnutrition, lack of access to food is still one of the major underlying causes of malnutrition. There is strong correlation between a country’s gross national product (GNP) and its level of malnutrition. However, the challenge facing nutritionists and other professionals in the ﬁeld of health is to identify strategies to prevent malnutrition that are economically feasible. Although originally protein was considered the main factor in the etiology of malnutrition (see Chapter 16), lack of energy was later understood to be as important as the underlying cause. In the last two decades, much work has been carried out in the ﬁeld of micronutrient deﬁciencies. The role of vitamin A deﬁciency in children had a major impact on the role and implications of micronutrient deﬁciences. The poor strata in developing countries have a lack of purchasing power and spend a large percentage of their income on staple food. Animal product and fruits that are important sources of micronutrients are often more expensive and unaffordable, and therefore, it can be expected that, multiple micronutrient deﬁciencies rather than singular deﬁciencies are common in these settings (1–3). The micronutrient deﬁciencies of concern are vitamin A, vitamin B complex, vitamin C, iron (FE), iodine, and zinc (Zn). Although reduced energy intake remains a problem in many settings, sub-optimal intakes of several micronutrients are more widespread and may be present even when energy needs are met. Micronutrients can affect a variety of health and disease outcomes, for example, child growth and development via direct independent effects (e.g.: Zn, folic acid); and indirect effects through interactions with each other (e.g.: Vit A, Zn and Fe), and promoting appetite, which leads to increased food intake and thereby higher intake of other macro and micronutrients. The conceptual framework that describes the mechanisms by which multiple micronutrient malnutrition can affect health and disease outcomes is shown in Fig. 1. Poor dietary quality and inadequate intakes are the underlying determinants of several From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Fig. 1. Causes and consequences of multiple micronutrient malnutrition.

micronutrient deﬁciencies. For many micronutrients, bio-availability is affected by the mix of foods eaten, the presence of inhibitors, mode of preparation, and drug-diet interactions (4,5). Exceptions would be trace elements such as iodine and selenium; the concentrations of these nutrients in foods depend on the soil and/or water content of the region where they are grown or harvested. Infections such as diarrhea and parasitic infestations, which are common in these settings, can also contribute to multiple micronutrient malnutrition by inﬂuencing nutrient absorption, utilization, and excretion (6,7). However, these infections are also exacerbated by micronutrient deﬁciencies. At the physiological and metabolic level, there is considerable evidence of several micronutrient interactions that may have the potential to affect outcomes such as child growth and development. The interactions are more important when nutrient intakes are inadequate. There is some evidence that suggests that multiple micronutrient deﬁciencies result in decreased appetite and anorexia, and these conditions disappear as soon as a dietary balance is restored (8,9). Micronutrients can also interact at the level of nutrient absorption. For example, vitamin C is a known enhancer of iron absorption, whereas zinc and calcium can interfere with the absorption and availability of iron (10). The interrelationship between iron and zinc may also be bi-directional (11). In terms of nutrient utilization, studies have shown that vitamin A affects both iron and zinc metabolism (12,13). For example, zinc is required for the synthesis of retinol binding protein, which is required to transport vitamin A in the body. This interaction has been extensively studied in animal models and to a certain extent in young children (14–16). Vitamin A deﬁciency also inhibits iron

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utilization and thereby accelerates the development of anemia (17). Some studies have shown that improving vitamin A status improves hematological indices in both children and pregnant women (12,18,19). Copper and zinc metabolism is also inter-related. The focus of this chapter is to examine the signiﬁcance of multiple micronutrient malnutrition by addressing the role of micronutrient interactions and the potential beneﬁts of strategies to increase the intakes of multiple micronutrients simultaneously. Speciﬁcally, the prevalence, functional consequences and programmatic implications of multiple micronutrient malnutrition will be discussed. Details of the direct independent effects of various single micronutrients, which are described elsewhere, are not included.

2. PREVALENCE OF MULTIPLE MICRONUTRIENT MALNUTRITION Diets are often low in several nutrients simultaneously owing to low intake of animal products and fortiﬁed products. Because the importance of multiple micronutrient deﬁciencies have only been recently recognized, there are only a few surveys that have established the prevalence of multiple micronutrient deﬁciencies. The evidence on the prevalence of multiple micronutrient malnutrition will be presented, based on data from dietary surveys and prevalence surveys of single nutrients. The speciﬁc groups at greatest risk include women of reproductive age—especially those who are either pregnant or lactating or both—infants and young children, adolescents, and the elderly. Because of the increased requirements for many micronutrients to meet the demands for growth, adolescents are at increased risk of deﬁciencies of multiple micronutrients. However little data exist on the prevalence of such multiple deﬁciencies.

2.1. Dietary Surveys Recent dietary surveys, especially from the Nutrition Collaborative Research Support Program (CRSP) in Mexico, Kenya, and Egypt show that multiple micronutrient deﬁciencies, rather than single deﬁciencies, are common and, that low dietary intakes and poor bioavailability of micronutrients account for the high prevalence of this complex of multiple deﬁciencies (5,20–22). Studies of dietary intake in Kenya, Mexico, and Egypt showed vitamin and mineral intake to be low for several nutrients: Kenya (zinc, calcium, vitamin A, E, riboﬂavin, and B12), Mexico (zinc, iron, vitamins A, E, C, thiamin, riboﬂavin, and B12), and Egypt (iron, calcium vitamin A, E, and riboﬂavin). Macrocytosis was observed in 18% of the Kenyan toddlers, and suggested to be caused by poor B12 status (35,20). Allen et al. (21) found low serum B12 in 14% of toddlers examined in Mexico. The authors suggest that absorption may have been impaired because of intestinal parasitism (Giardia was present in 40% of the Mexican toddlers, but only in 3% in Kenya).

2.2. Women of Reproductive Age Micronutrient malnutrition is common among women of reproductive age, particularly during pregnancy and lactation when demands are high. More than half the pregnant women in South Asia and sub-Saharan Africa are anemic, most of which is owing to iron deﬁciency (23). Other reported deﬁciencies include iodine, zinc, vitamin A, and vitamin B complex, including thiamine, riboﬂavin, folic acid, B6 and B12. Condi-

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tions such as night blindness as a result of vitamin A deﬁciency and endemic goiter owing to iodine deﬁciency during pregnancy are also common in many parts of the world (24,25). The occurrence of multiple deﬁciencies has been observed among pregnant and postpartum women in Indonesia for zinc, vitamin A, and iron (26). Signiﬁcant rates of B12, B6, riboﬂavin, and folate deﬁciency have also been reported among women in India (27). Low serum vitamin B12 has been observed among pregnant and lactating women in Mexico, and low breast-milk B12 was reported in Kenya (28). Sub optimal vitamin B6 status has been observed in Egypt among more than one-third of breastfeeding women, based on low breast-milk concentrations (29). Riboﬂavin deﬁciency is considered endemic in The Gambia, and is common in other parts of Africa, the former Soviet Union, Indonesia, and China (30). In a Kenyan study, 6–8% of anemia in pregnancy was related to folate deﬁciency among the 48% of pregnant women found to be anemic (31). Based on a review of studies conducted in Latin America, Mora and Mora (32) report that riboﬂavin, thiamin, niacin, vitamins E and C, as well as folate and vitamin B12 in pregnant women, appear to affect important segments of the population, mostly rural, low-income groups.

2.3. Infants and Young Children Few surveys have collected information on deﬁciencies in micronutrients other than vitamin A, iodine, or iron in children. A 1996 national survey in Costa Rica found that folate deﬁciency was a signiﬁcant problem in preschool-aged children, especially in rural areas (32). A 1986 national survey in Ecuador found that 30% of children under age 5 yr were deﬁcient in riboﬂavin (based on low glutathione reductase) (32). Low serum zinc levels have been documented in many areas of Latin America. Zinc supplementation trials among children in Ecuador, Chile, Brazil, Guatemala, Mexico, and Peru suggest that zinc deﬁciency is a problem of public health signiﬁcance in Latin America (33) as well as in India, Bangladesh, Thailand, Vietnam, Indonesia, Papua New Guinea, and The Gambia (34).

3. SIGNIFICANCE/FUNCTIONAL OUTCOMES OF MULTIPLE MICRONUTRIENT MALNUTRITION Very little work has been done to examine the signiﬁcance of multiple micronutrient deﬁciencies. A recent review on the nutritional determinants of child growth concluded that “poor child growth seen in developing countries to due, not to deﬁciency in one or two key nutrients, but to multiple nutrient deﬁciencies and poor dietary quality” (36). Most of the research and programmatic efforts to eliminate micronutrient malnutrition to date have focused on single nutrients especially vitamin A, iodine, and iron. This is a major concern, in light of the limited resources that are available to many programs and countries worldwide, and the need for more cost-effective and sustainable strategies. The rationale and scientiﬁc evidence supporting the role of multiple micronutrient malnutrition in determining important health outcomes such as prematurity, low birth weight (LBW), young child growth and development, and morbidity are described in this section.

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3.1. Maternal Mortality and Pregnancy Outcomes Considerable research has been done to date supporting the role of micronutrients in determining adverse pregnancy outcomes such as prematurity and intra-uterine growth retardation (37). In a recent review, Ramakrishnan, et al. (37) concluded: • The majority of the randomized controlled trials (RCTs) conducted to date have been carried out in populations that were not truly deﬁcient and hence less likely to beneﬁt from the intervention. • Whereas some nutrients have been studied extensively (e.g., calcium, zinc), much less is known about others (e.g., vitamin B complex). • Most studies have used the single nutrient approach, i.e., examining the relationship between one speciﬁc nutrient and pregnancy outcomes, and little is known about the signiﬁcance of selected nutrient interactions and multiple micronutrient malnutrition.

Based on our knowledge of the interrelationships between iron, zinc, and vitamin A metabolism, and their role in growth and development, the combined beneﬁts of these three micronutrients on pregnancy outcomes warrant immediate attention. Other nutrients of interest that may interact with the above nutrients and/or with each other are folic acid, copper, and selenium. The evidence from prospective longitudinal studies and/or intervention studies on the role some of these interactions and, multivitamin/mineral (MVTM) supplements for improved pregnancy and other related reproductive health outcomes is brieﬂy reviewed in the following sections. 3.1.1. TWO-WAY MICRONUTRIENT INTERACTIONS 3.1.1.1. Iron and Zinc. The provision of a daily supplement of zinc gluconate (30 mg Zn) along with routine iron supplementation during pregnancy has been shown to reduce the incidence of fetal distress, fetal demise (still births and neonatal deaths), preterm deliveries, and infection rates, when compared to iron supplementation alone in a RCT of high-risk African-American women (38). Iron-deﬁcient women who began zinc supplementation early in pregnancy also gave birth to longer infants compared to those who had adequate iron status and received zinc supplements later in pregnancy. Head and chest circumferences were also larger among infants born to the zinc-treated anemic women. These ﬁndings demonstrate the potential beneﬁts of providing zinc supplements with routine iron, despite the concerns of reduced bio-availability of iron (11). 3.1.1.2. Iron and Vitamin A. In a randomized double-blind trial of pregnant women (n = 251) in Indonesia, the proportion of anemic women who became nonanemic (Hb< 110 g/L) following 16 wk of supplementation was 97, 68, 35, and 19%, for those who received iron and vitamin A, iron only, vitamin A only, and placebo, respectively (18). However the effect on other outcomes such as birth weight are not known. 3.1.1.3. Iron and Folate. Although folic acid and vitamin B12 are provided with iron supplements as part of routine prenatal care to treat nutritional anemia in some parts of the world, the beneﬁts of this combination in improving pregnancy outcomes especially reducing the prevalence of (LBW) has not been studied. Achadi et al. (39), in a study in Indonesia, reported that the consumption of one or more iron-folate pills per week by pregnant women was associated with an increase in birth weight (172 g) and length (1 cm).

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In summary, few intervention trials that have addressed the role of speciﬁc nutrient interactions during pregnancy have been conducted and also, little is known on the relevance of several other interactions, for example, vitamin A and zinc. 3.1.2. MULTIVITAMIN/MINERAL SUPPLEMENTS In a prospective study of drugs and pregnancy, that was conducted in the 1960s in Sweden, Kullander and Kallen (40) found that the prevalence of LBW was signiﬁcantly lower among women who reported the use of iron and/or MVTM supplements during pregnancy. However, data on other potential confounding factors, such as the use of prenatal care, smoking and other nutritional factors that may have been associated with supplement use, were lacking. More recently, Scholl et al. (41), in a well-designed prospective follow-up study of low-income, urban women in the U.S., reported that the risk of preterm delivery (<33 wk) and LBW was reduced by at least half among women who used prenatal MVTM supplements regularly compared to those who did not, after adjusting for several known confounders. The protective effect of the supplements was greater if started earlier (ﬁrst vs second trimester) and for very LBW (<1500g). The plausibility of these ﬁndings are also strengthened by the fact that the blood levels of several micronutrients were similar for both users and nonusers at entry and, they increased signiﬁcantly by 28 wk of gestation among the users. Wu et al. (1998) (42), using data from the 1988 National Maternal and Infant Health Survey found that regular MVTM supplement use during pregnancy might reduce the risk of fetal death associated with maternal smoking, after adjusting for several confounders. Although supplement use was not associated with a reduced risk for fetal death in nonsmokers, these ﬁndings suggest potential beneﬁts for “high-risk” individuals. In another recent retrospective case-control study, Shaw et al. (43) found that women who consumed multivitamin supplements containing folic acid during the periconceptual period (4 mo) were 62% less likely (OR = 0.38, 95% CI 0.16, 0.88) to deliver a preterm baby when compared to those who did not consume supplements. There were no differences in the prevalence of LBW. The majority of randomized clinical trials using MVTM supplements were conducted in developed countries and, originally demonstrated that the periconceptual use of folic acid-containing supplements reduced the risk of occurrence and recurrence of neural tube defects (44–46). Periconceptual use of MVTM supplements has also been shown to affect other reproductive health outcomes, i.e., more regular menstrual cycles, 5% increase in the rate of conception, and an increased risk of multiple births (47–50). More recently, reductions in the occurrence of other congenital abnormalities such as cleft palate, congenital urinary tract anomalies (51), and cardiovascular malformations have also been associated with MVTM supplements (42,52–55). However, these events are less common and rare when compared to the prevalence of adverse pregnancy outcomes such as maternal mortality, prematurity, and LBW in developing countries. Of the two large experimental trials that compared the efﬁcacy of different combinations of MVTM supplements on neural tube defects, only one permits us to draw probabilistic causal associations between the use of MVTM supplements and birth weight; it was the prospective, double-blind, randomized trial conducted in Hungary on a sample of 4,753 women who received different combinations of micronutrient supplements from pre-conception to 12 weeks gestation (45). One group (Group I) was given all water soluble vitamins, vitamins A, D, and E, and calcium, phosphorus,

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magnesium, iron, copper, manganese, and zinc. Group II was given only copper, manganese, zinc, and vitamin C. Group I had a signiﬁcantly lower proportion of congenital abnormalities, but no differences were found in birth weight between the two groups. This may have been owing to the fact that both groups received zinc, which could have a positive effect on prenatal growth (56–57). Although there was no evidence of micronutrient deﬁciency in this sample, the rates of ectopic pregnancies, miscarriages, and stillbirths as well as preterm births and LBW were signiﬁcantly lower for both the supplemented groups when compared to the population ﬁgures (45). Both groups also had greater mean birth weights than the general population. In the trial that was conducted among women who were at risk of giving birth to infants with neural tube defects in the United Kingdom (46), signiﬁcant reductions were found in the recurrence of neural tube defects (RR = 0.28), for those who received MVTM supplements containing folic acid when compared to those who received the placebo. There were no differences in the rates of miscarriages or stillbirths. Although the study design of this trial would have permitted comparisons in birth weight, these data were not reported. To date, we could identify only one RCT that examined the beneﬁts of MVTM supplements during pregnancy in a developing country where poor dietary intakes and multiple micronutrient malnutrition are common (58). This trial was conducted among 1078 HIV-infected pregnant women in Tanzania, who received any of the following treatments: placebo, Vitamin A only, multivitamins excluding Vitamin A, and multivitamins including Vitamin A. Women were recruited between 12 and 29 wk of gestation and followed until delivery; they were given supplements containing 2–38 times the RDAa of several vitamins and iron either with or without vitamin A; the placebo group received only iron and folic acid. Multivitamin supplementation resulted in improved immune status (measured by increase in CD4, CD8, and CD3, and proportion of CD4 cells) and a signiﬁcant reduction in the risk of fetal death, LBW (44%), severe preterm birth (39%), and small for gestational age (43%); whereas vitamin A supplements alone did not confer any beneﬁts. The groups were similar at baseline, which ruled out possible confounding. This study provides compelling evidence supporting the beneﬁts of this low cost intervention to HIV-positive pregnant women in a developing country setting. A randomized, double-blind, controlled trial is currently underway in Mexico in which the effects of multiple micronutrient supplementation during pregnancy will be compared to a control group of women who receive standard iron supplements during pregnancy (59). The compelling evidence from research to date suggests that provision of multiple micronutrient supplements to pregnant women will have numerous beneﬁts for pregnancy outcome over those now seen with only iron/folic acid. However, further studies to document these beneﬁts are needed.

3.2. Micronutrients in Breast Milk Although considerable research has been done on the relationship between breast milk intake, its energy content and child growth, little work has been done on the aMultivitamins

contained 20 mg B1, 20 mg B2, 25 mg B6, 100 mg niacin, 50 µg B12, 500 mg C, 30 mg E, 800 µg folic acid, with or without vitamin A (30 mg `-carotene plus 5000 IU preformed vitamin A). All groups also received 120 mg iron and 5 mg folic acid.

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micronutrient content of breast milk in developing countries. The mother’s nutritional status during pregnancy and/or lactation should, in theory, affect the growth of the newborn during the early postnatal period by determining the level of nutrient reserves in the newborn and the breast-milk quantity and quality, including micronutrient concentrations. Allen (28), in a recent review on the importance of maternal micronutrient status during lactation, concluded that, in general, milk composition is most affected by the woman’s intake of water-soluble vitamins, less by the consumption of fat soluble vitamins, and relatively unaffected by mineral intake or status. According to Allen (28), micronutrients can be classiﬁed into two priority categories for lactating women as described here. Priority I micronutrients are those where deﬁciencies have been shown to result in lower concentrations in breast milk but are responsive to supplementation. They are vitamins A, B1, B2, B6, and B12, and perhaps iodine and selenium in deﬁcient populations. For example, postpartum, high-dose vitamin A supplementation or consumption of fortiﬁed foods by lactating women living in vitamin A-deﬁcient population has been shown to increase breast-milk retinol concentrations (60,61). Studies in the Gambia have shown that riboﬂavin, vitamin A, and ascorbic acid concentrations in breast milk can also be improved by supplementation of lactating women (62–64). In a doubleblind study of low income lactating women in the U.S., breast-milk levels of vitamin B6, B12, and folate increased in the supplemented group (65). More recently, evidence of improved child growth was found in an intervention trial in which lactating women received vitamin B6 supplementation (66). On the other hand, Priority II micronutrients are those whose levels in breast milk appear to be relatively protected even during maternal deﬁciency and do not seem to respond to maternal supplementation. These include vitamin D, folate, iron, calcium, copper, and zinc. For example, although zinc may be an important limiting nutrient for child growth, some studies indicate that the zinc content of breast milk in developing countries does not appear to be affected by supplementation during lactation (67–69). Similarly, iron supplementation during the last trimester of pregnancy did not alter the concentrations of iron, copper, selenium, and zinc in breast milk in a RCT of pregnant women in Niger (70). No studies to date have assessed the beneﬁts of correcting multiple micronutrient malnutrition on lactation performance. In the current study underway in Mexico, the effects of MVTM supplementation during pregnancy on the micronutrient composition of breast milk are being evaluated.

3.3. Child Growth and Development 3.3.1. CHILD GROWTH Recent estimates indicate that nearly half the young children in South Asia, which represents a large segment of the world’s population, are underweight (below –2 SD of the international reference for weight for age), and 10–50% are underweight in Latin America and sub-Saharan Africa (71). In these settings, severe growth retardation occurs during the prenatal and early postnatal periods, and although there may be potential for catching up during adolescence, currently available data indicate that this does not generally occur (72–74). Therefore, identifying interventions aimed at preventing growth retardation during pregnancy and early childhood should be high priority and may help prevent adverse outcomes later in adolescence and during adulthood (75).

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The role of nutrition in determining child growth has been an area of considerable research since the 1950s. Historically, the strong belief until the 1960s was that improving protein intakes alone would solve the problem of malnutrition in poor countries. The focus, however, moved from protein to energy during the late 1970s and early 1980s (76–78) when it was shown that (1) while protein intakes were satisfactory, it was total energy intakes that fell far short of requirements in these settings; and (2) that severely malnourished children could gain weight well on high energy/low protein diets (79,80). Subsequently, in the late-1980’s, certain micronutrients were identiﬁed as playing a key role in child growth. To date, considerable research has been done in identifying the role of selected single micronutrients in promoting child growth, notably vitamin A, iron, iodine, and zinc; less is known on the role of the B vitamins. The main ﬁndings from published studies to date on the role of single micronutrients and child growth, based on a recent review of the nutritional determinants of child growth (36), are summarized here: • Vitamin A: Despite the protective effect of vitamin A in reducing child mortality and severity of infections (81,82), several randomized placebo-controlled vitamin A intervention trials have failed to show improvements in the growth of preschool-aged children (83). • Iron: Improvements in child growth following iron supplementation may be limited to anemic children who are severely iron-deﬁcient (36). • Iodine: Severe iodine deﬁciency especially during pregnancy results in endemic cretinism, which is typically characterized by severe growth failure (84–86). However, evidence of improved growth after treating mild and moderate forms of iodinedeﬁciency disorder is limited. • Zinc: Zinc supplements have been shown to improve the growth of infants and preschool children deﬁcient in zinc (87,88), and of children recovering from severe malnutrition (89,90). A recent meta-analysis of over 20 intervention trials, concluded that zinc supplementation can be expected to improve both height and weight in young children (91). • Vitamin B complex: Limited data are available. Some studies suggest a possible role for vitamin B12 and folic acid in predicting the linear growth of infants (92,93).

More recently, the recognition that multiple nutrient deﬁciencies frequently co-exist and that the type of food (e.g. animal vs vegetable) affects utilization has initiated discussions of the importance of “dietary quality” for growth (9,21). For example, animal products are rich sources of several key micronutrients, namely, vitamin A, iron, zinc, and vitamin B12, as well as macronutrients such as protein and calcium, all of which can separately and/or jointly affect growth. CRSP provides the best observational data to support the role of multiple micronutrient malnutrition in child growth (92,94). In Mexico, although individual nutrients failed to predict size, certain dietary patterns such as the consumption of more animal products and fruits were associated with bigger size in young children. Other observational studies have also found that dietary diversity deﬁned as the number of food items consumed in a given period of time was positively associated with greater heights in Jamaica, Kenya, and Peru (36). Some studies showing the importance of animal foods in promoting growth (94,95) also support the role of multiple micronutrient malnutrition. However, very few intervention trials have examined the impact of improving intakes of several micronutrients simultaneously either by supplements, fortiﬁed products, or animal foods.

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To date only a few intervention trials using multiple supplements have been conducted with varying degrees of impact on child growth. An early intervention trial conducted in Thailand (96), provided a daily MVTM supplementb that failed to improve growth in preschool-aged children. However, the extent of the deﬁciency, the appropriateness of the dosage and whether the treatment was randomly allocated are unclear. In China, Liu et al. (97) failed to detect any differences in growth in a RCT of children aged 6–13 mo using a micronutrient fortiﬁed ruskc, which may have been owing to the short duration of intervention (i.e., 3 mo) and the limited sample size. However, there were signiﬁcant improvements in hemoglobin levels and some improvements in vitamin A status (97). In contrast, a recent study in Mexico among children 8–14 mo demonstrated signiﬁcant improvements in growth following supplementation with a MVTMd syrup daily for 4–7 mo. An increase of 1.2 cm was seen in length in children under 1 yr of age (98). A study in Vietnam compared the effect of daily and weekly micronutrient supplementse on the growth of young Vietnamese children aged 6–24 mo (99). Although signiﬁcant improvements in hemoglobin, serum retinol, and serum zinc were observed in both groups, improvements in growth were only seen among children who were initially stunted. A study of multiple micronutrient supplementation of children 6–11 yr of age in Tanzania also found beneﬁts on growth (100).f These ﬁndings suggest that factors such as the extent of the deﬁciencies, the age of the child, and the content of the supplement may affect the likelihood of impacts on growth. 3.3.2. MOTOR AND MENTAL DEVELOPMENT Inadequate nutrition can also disrupt cognition and intellectual functioning (101–103). In a recent review of the published literature, Martorell (103) concluded that poor nutrition during early childhood, especially in developing country settings, can have varied effects on intellectual functioning. Our knowledge of the mechanisms by which malnutrition during these years disrupts these functional outcomes, however, is still evolving (104). Brown and Pollitt (101) proposed that malnutrition can hinder cognitive development through several interactive routes. For example, malnutrition could lead to delayed motor development and physical growth, lethargy, and withdrawal, which in turn may result in reduced exploration of the environment and/or reduced caregiver

b Containing

0.9 mg thiamin hydrochloride, 1 mg riboﬂavin, 12 mg niacin, 1.3 mg pyridoxine hydrochloride, 0.2 mg folic acid, .0025 mg vitamin B12 , 0.5 mg vitamin A, 200 mg Ca, 5 mg iron (iron sulphate), 10 mg zinc (zinc chloride), and 0.09 mg iodine (potassium iodide). c Containing 300 mg calcium, 5 mg iron, 3 mg zinc, 224 µg vitamin A, 4 µg vitamin D, 0.15 µg thiamin, 0.2 mg riboﬂavin, 2.5 µg niacin, 25 µg folate, and 0.3 µg vitamin B12 per rusk. d The syrup contained either approx 1 RDA of multiple micronutrients or a placebo 6 d/wk for 2 mo (98). e Containing either daily 333 µg retinol , 8 mg iron (as ferrous sulfate), 5 mg zinc (as zinc sulfate), and 20 mg of vitamin C, or weekly 1700 µg retinol, 20 mg iron, 17 mg zinc, or 20 mg vitamin C or placebo. f The supplement contained 30–120% the RDA (for iron, vitamin A, iodine, zinc, ascorbic acid, riboﬂavin, folic acid, B12 , B6, and vitamin E ) and was provided daily during school for 6 mo.

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expectations and thereby delayed intellectual development and behavioral deﬁcits especially in suboptimal learning environments. The association between generalized PEM and mental development has been examined in several observational and intervention trials that have been carried out in many developing countries (101,103,105). Pollitt and Oh (106) in a metaanalysis of nutrition intervention trials, concluded that there were beneﬁcial effects of supplementation on the motor development of infants 8–19 mo of age and on the motor and mental development of older children. However, these studies do not permit us to isolate the role of micronutrients vs energy or protein because the food supplements provided energy, protein and other nutrients. Most of our knowledge on the role of micronutrients for motor and mental development is limited to iodine and iron. Cretinism, an outcome of severe iodine deﬁciency, is typically characterized by serious and irreversible mental retardation that occurs during fetal life and postnatally (107). Mental deﬁcits have also been documented even among noncretinous populations residing in iodine-deﬁcient areas. A meta-analyses of 18 studies concluded that a reduction of about 1 SD in cognitive development could be attributed to iodine-deﬁciency disorders (108), but only a few of them were randomized controlled trials. Iron-deﬁciency anemia has also been associated with impaired performance on the mental and motor scores of the Bayley or similar scales used for infants and toddlers (109–111). Anemic infants treated with iron as early as 2–3 mo of age and fully rehabilitated to normal hemoglobin levels have shown improvements at 1 yr of age using either the Bayley development test or tests of habituation in Papua New Guinea (112) and Chile (113), respectively. A double-blind randomized trial conducted in Indonesia also found large improvements in cognitive and motor development among anemic preschool age children who received iron supplements daily for 4 mo (114). The ﬁndings, however, are less consistent in the case of nonanemic, iron-deﬁcient children. Iron supplementation of children over 2 yr of age with iron-deﬁciency anemia can also improve some cognitive functions and school achievement (105,115,116). Behavioral data from observational studies, especially the CRSP study from Egypt, suggest a role for several other micronutrients, namely vitamins B6, B12, and calcium in child development (102,117). Poor vitamin B6 status has been associated with reduced attention and child-caregiver interaction in Egyptian infants, which in turn may inﬂuence cognitive development (29,118,119). Neonates who were more responsive to adverse stimuli, more easily consoled, and less likely to show extreme distress were born to mothers with higher levels of vitamin B6 in their breast milk (120). Vitamin B12 status has also been positively associated with the amount of symbolic play in infants (117). Another nutrient of interest is zinc, which has been shown to play a role in brain function and development in animal models. Evidence of reduced activity and responsiveness in animals suggest that zinc may play a role in learning, attention, and memory (121). Several studies have studied its role in young child development. Two randomized trials that examined the effects of zinc supplementation on cognitive development of preschool children in Canada (87) and school-aged children in Guatemala (122) failed to detect any differences. In another study in Guatemala, zincsupplemented infants ages 6–9 mo followed for 7 mo, were more frequently observed sitting up and playing compared to the nonsupplemented infants (123). These infants

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were also somewhat less likely to be observed whining and crying compared to the placebo group. Sazawal (124) reported a positive effect of zinc supplementation on motor activity of children 12–24 mo of age studied in a periurban community in north India. Ashworth et al. (125) reported that daily zinc supplementation (5 mg/d) during the ﬁrst 8 wk of life improved responsiveness in LBW infants in Brazil, but did not detect any signﬁcant differences in mental and psychomotor development at 6 and 12 mo of age when compared to those who received a placebo. Despite the evidence relating several micronutrients with child development, no study to date has examined the signiﬁcance of nutrient interactions or multiple micronutrient malnutrition in child development. In summary, although observational data suggest that strategies addressing multiple micronutrient malnutrition most likely will improve child growth and development, few studies have examined the effect of interventions such as MVTM supplements and/or food-based strategies on child growth and development. Randomized, controlled trials to test the hypothesis that provision of multiple micronutrients will result in better child growth and development are currently underway in Mexico and Guatemala. These projects will provide answers to a major gap in our understanding of the role of multiple micronutrient deﬁciencies in the etiology of suboptimal child growth and development, both of which are common in many developing countries as well as in certain sub-groups in developed countries.

3.4. Morbidity 3.4.1. INFECTIOUS DISEASES Several micronutrients play essential roles in immune function, including vitamins A, B1, B2, B6, B12, C, E, folic acid, zinc, and iron (126). Therefore deﬁciencies are likely to inﬂuence the rate of infections and/or their duration and severity. Zinc plays an important role in immune function and susceptibility to a broad range of pathogenic agents is affected by zinc (127). Numerous studies have illustrated the beneﬁts of zinc supplementation in children for reduced incidence of acute and persistent diarrhea and decreased acute lower-respiratory infections (128,129). A study by Shankar et al. (130) in Papua New Guinea assessed the relationship between zinc and malaria among children 6–60 mo of age. The zinc group received 10 mg of zinc /6 d a week for 10 mo. Clinical attack rates of malaria (Plasmodium falciparum) were reduced by 40%, but there was no effect on Plasmodium vivax. Zinc supplements have also been reported to reduce the intensity of Schistosoma mansoni reinfection among children in Zimbabwe (131). Vitamin A status may also be related to attack rates of malaria. In the NNIPS-2 study, the percentage of women with malaria (P. vivax ) was 23% in the placebo group, 23% in the `-carotene group and only 14% in those who received vitamin A (132). Shankar et al. (133) have also shown that vitamin A supplements reduced malaria (P. falciparum) in children in Papua New Guinea among children ages 6–54 mo. Fever due to malaria was reduced by 30–35% in the vitamin A group compared to the placebo group. Several studies have examined the role of micronutrients and HIV, including effects on immune response, the rate of transition from HIV to AIDs, and maternal-infant transmission. Maternal micronutrient deﬁciencies may also inhibit the infant’s immune function by reducing the infant’s micronutrient status, and thereby increasing the

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infant’s susceptibility to infections. HIV-infected individuals often have low serum concentrations of vitamins A, B 6, B 12, C, E, folate, carotenoids, selenium, and magnesium (134), even in developed countries where intakes of these nutrients are relatively high. In developing countries where intakes are often inadequate, micronutrient status is even further compromised. Another factor affecting illnesses is related to oxidative stress. The immune response releases oxygen radicals that can be damaging to cell membranes (128). Nutrients that act as anti-oxidants (including iron, zinc, vitamin C, vitamin E, and selenium) can reduce the damage done to cells. Deﬁciencies in antioxidants and associated increases in oxidative stress injure T-cells, and therefore compromises cell-mediated immunity. Oxidative stress appears also to be related to cancer and to coronary heart disease, and several anti-oxidant nutrients (especially vitamin E and selenium) have been related to reduced risk of these illnesses (135). It has also been suggested that oxidative stress may increase HIV replication (134). Few randomized trials have examined the role of multiple micronutrients on infection. The NNIPS-2 study reported a 10–30% decrease in infections lasting for more than 7 d during pregnancy and lactation in Nepal among women consuming either vitamin A or `-carotene (136). Maternal mortality was reduced in the NNIPS-2 study by nearly half owing to vitamin A and `-carotene (704 deaths per 100,000 births in the placebo group compared to 426 in the vitamin A group and 361 in the `-carotene group) (137). The elderly represent a population that is known to show a decline in immune response, which has been hypothesized to be owing in part to nutritional deﬁciencies found among the elderly, due to their lower intakes of food and gastric problems inﬂuencing absorption. Therefore, they are in some ways similar to populations in developing countries with low nutrient intakes. Thus, several studies have tried to improve immune status through supplementation with micronutrients. Zinc, selenium, MVTM supplements and vitamin E supplements have all been associated with improved immune status among the elderly (138–141). 3.4.2. CARDIOVASCULAR DISEASE There is an emerging epidemic of cardiovascular disease in developing countries, in part owing to increased life expectancy, so that more people are now susceptible, and because of increased levels of obesity, decreased exercise, adverse dietary changes, and increased smoking (142). Low intakes of several micronutrients (including folic acid, vitamins B6, B12, and E) have been implicated in an increased risk of cardio-vascular disease. Both increased folic acid and B6 intake have been shown in large-scale epidemiological studies to be associated with reduced risk of fatal coronary heart disease (CHD) and nonfatal myocardial infarctions and with decreased risk of arteriosclerosis among women (143,144). A case-control study that was conducted in 19 centers in 9 European countries assessed the relationship between homocysteine levels and cardiovascular risk (145). Subjects in the top 20% of the control distribution had a twofold increase in the risk of vascular disease compared to the lower 80%, a risk similar to that of hypercholesterolemia or smoking. Plasma folate, B6 and B12 concentrations were inversely related to

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homocysteine levels, and users of vitamin preparations containing these nutrients had a .38 relative risk (95% CI, 0.2–0.72) of cardiovascular disease compared to nonusers. A recent meta-analyses of 20 studies found an increased risk of coronary artery disease with the odds ratio 1.6 for men and 1.5 for women per 5 µmol/L increase in total plasma or serum homocysteine (146). Several randomized controlled trials have assessed the impact of folic acid on homocysteine levels. Brouwer et al. (147) showed that daily intakes of 250 µg or intakes of 500 µg of folic acid on every other day were associated with signiﬁcant declines in homocysteine levels after 12 wk that persisted 8 wk after the end of the intervention. Another recent study found that inclusion of vitamin B12 along with folic acid in a supplement was more effective in lowering homocysteine levels that folic acid alone (148). Considerable evidence shows that consumption of fruits and vegetables is associated with a decreased risk of cardiovascular disease, hypertension, and some cancers, presumably for their anti-oxidant effects (149). Vitamin E has been suggested to offer a protective effect against atherosclerosis: oxidized low-density lipoproteins (LDL) are involved in atherogenesis and studies showing the association of vitamin E supplementation has been associated with reduced risk of disease (150). However, the association of other anti-oxidants such as vitamin C and `-carotene is less clear, leading to the interpretation that components of fruits and vegetables other than vitamins (such as phenolic compounds) may be those with stronger anti-oxidant effects (149).

4. PROGRAMMATIC IMPLICATIONS The National Academy of Sciences (NAS) (151) suggests that a strategy to promote increased consumption of multiple micronutrients simultaneously would be more effective than the promotion of a select few. Combining multiple micronutrients in a single delivery mechanism has been suggested as a cost-effective way to achieve multiple beneﬁts (152,153). Approaches available to do so include improving dietary intake though increased consumption of nutrient-rich foods or through fortiﬁed foods, and the use of micronutrient supplements. Each has particular beneﬁts and constraints.

4.1. Improving Dietary Intake When feasible, improving the diet to include animal products, fruits, vegetables, and legumes will beneﬁt nutrient status for several micronutrients simultaneously. Increasing consumption of animal ﬂesh products results in improvements, especially in iron and zinc status, as well as vitamins B6, B12 , thiamin, and riboﬂavin. Increased consumption of organ meat also improves vitamin A, E, D, and folate. Increased intake of red and orange fruits and vegetables increases intake of provitamin A carotenoids. Although increased intake of `-carotene from vegetables or fruits improves vitamin A status, it does not appear to do as well as preformed vitamin A or puriﬁed `-carotene, for example in the form of red palm oil (154,155). Thus, animal products (milk, eggs, liver) containing vitamin A are also needed. Increased consumption of dark green, leafy vegetables can improve of folic acid, vitamin A, calcium, and vitamin C status. Intake of legumes can enhance thiamin, riboﬂavin, and folic acid status. Increasing consumption of fruits and vegetables will also increase the intake of anti-oxidants other than vitamins that appear to be important in preventing cardiovascular disease and some cancers.

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Programs that have been successful in promoting dietary changes such as these have been conducted in Bangladesh, Niger, and Peru, among others. Helen Keller International, in conjunction with numerous Bangladeshi nongovernmental organizations promoted home gardens. The baseline study showed that women in families that had home gardens with more varieties of fruits and vegetables had higher intakes of vitamin A than those with fewer varieties. An evaluation of another program to increase the production of carotene-rich foods in Bangladesh had a measurable impact on the diets of young children under three years (156). Although the focus was on pro-vitamin A-rich foods, increased consumption of vegetables is also likely to have improved intake for other nutrients. In Niger, mass media—including use of drama, radio skits, and counseling cards— led to increases in the proportion of mothers who fed their young children dark leafy greens. In the week prior to the survey, the proportion of children who had eaten dark-green leafy vegetables increased from 57% to 94%. The proportion of mothers who had eaten liver in the week prior to the survey increased from 43 to 73% (157). A social marketing campaign in Indonesia increased consumption of eggs and dark green, leafy vegetables among mothers and young children, which would beneﬁt not only vitamin A intake, but vitamin D, riboﬂavin, and B12 as well (158). A study in Bangladesh measured the ability of mothers to feed dark green, leafy vegetables to their young children in order to assess whether the children were able to consume sufﬁcient (40 g) quantities to meet vitamin A requirements. Median intakes among 118 children were 41 g for children 6–11 mo of age, 71 g for those aged 12–17 and 129 g for those 18–35 mo (159). These studies show that it is feasible to improve dietary intake with increased dietary diversity. However, there is a big difference between improving dietary intake of micronutrients and providing adequate micronutrient intake through these types of strategies. It would be challenging to provide an adequate diet at low cost especially when the new conversion rate of `-carotene is used. Therefore, these strategies, although very useful for many reasons will not provide the vulnerable groups with adequate intake of micronutrients. It is also essential that proposed changes in diets be assessed for their total nutrient composition, and not just a single nutrient. It is particularly difﬁcult, but not impossible, to promote complementary foods adequate in all nutrients without fortiﬁcation (160). Requirements for both iron and zinc during pregnancy (161) generally cannot be met through dietary sources alone unless foods have been fortiﬁed. However expanding the availability of low-cost, nutrient rich foods though home gardening, animal production, and involvement of the agriculture sector is needed for long-term improvements in dietary intake.

4.2. Fortiﬁcation Fortiﬁcation is the addition of nutrients at levels higher than those found in the original or comparable food. Fortiﬁcation of staple foods with multiple micronutrients has become more common in developing countries, particularly in Latin America. Wheat flour is the most common vehicle for multiple micronutrient fortification and, more recently, maize ﬂour has been fortiﬁed with multiple micronutrients. Iron fortiﬁcation of wheat is mandatory in most countries of Latin America, and it usually involves more than one nutrient (162). Table 1 shows the added nutrients mandated

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Table 1 Compulsory Flour Enrichment Worldwide (Mg/kg or ppm) Country

Thiamin

Belizea 6.0 Boliviaa 3.6 Canadab 4.4–7.7 Central American 6.0 Micronutrient Initiative (CARMI) Agreement Chile b 6.3 Colombia 6.5 Costa Ricaa 6.0 Dominican Republicb 4.5 Ecuador b 4.5 El Salvador a 4.0–6.0 Guatemalaa 4.0–6.0 Hondurasa 4.4 Jamaicaa 6.3 Nicaragua Nigeriab 4.5–5.5 Panamaa 6.0 Perua — Saudi Arabiab *6.38 U.K.b *2.4 U.S.b 6.4 Venezuelaa 1.5

Riboﬂavin

Niacin

Folic Acid

Iron

2.5–3.5 2.2 2.7–4.8 4.0

35–45 31 35–64 55

0.35–0.45 1.4 (0.4–0.5) 1.5

55–65 51 29–43 60

1.3 4.0 4.0 2.7 7.5 2.5–3.5 2.5–3.5 2.6 3.9

13 55 55 36 55 35–40 35–40 35.6 53

— 1.5 1.5 — 0.6 0.35–0.45 0.35–0.45 1.5 —

30 60 60 30 60 55–65 55–65 60 44

2.7–3.3 4.0 — *3.96

35.5–44.4 55 — *52.91 *16 52.9 20

— 1.5 — — —

28.9–36.7 60 30 *36.3 *16.5 44.1 20

4.0 2.0

c

—

aAdapted

with permission from Darnton-Hill et al. (167). with permission from Raunhardt and Bowley (168). cAdapted with permission from U.S. Department of Health and Human Services, Food and Drug Association Regulations, (169). bAdapted

by legislation for fortiﬁed wheat ﬂour in several developing countries. While thiamin, riboﬂavin, and niacin are commonly added along with iron, currently folic acid is also being used in many countries. Fortiﬁcation of staples with vitamin A, zinc, calcium, copper, or other minerals is as yet uncommon. The U.S. has recently passed regulations mandating fortiﬁcation of ﬂour with folic acid at a level of 140 µg folic acid to every 100 g of grain, which is projected to result in a mean additional intake of 100 µg folic acid per day (163). However, in order to reduce neural tube defects substantially, an additional 200–400 µg of folic acid has been suggested to be needed and the Centers for Disease Control and Prevention (CDC) in the U.S. recommends that women of reproductive age consume a supplement containing 400 µg of folic acid daily (164). As countries expand fortiﬁcation efforts, there are many logistical and quality-control measures needed for fortiﬁcants to be added and sustained at appropriate levels. It will also be necessary to assure that the target population consumes sufﬁcient quantities of the fortiﬁed products. However, even in the U.S., where fortiﬁcation of foods has been a long-standing practice, because of the low intakes of certain foods and limited

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number of foods that are fortiﬁed, signiﬁcant proportions of women consume less than adequate intakes of micronutrientsg. Many countries have voluntary fortiﬁcation of processed food products, such as margarine, noodles, and orange drink in the Philippines with vitamin A, and the soy sauce in China with iron (Na EDTA). However, micronutrient deﬁciencies are still highly prevalent in many countries and often most of the fortiﬁed products are mainly consumed by the middle class. Zinc is added to many breakfast cereals in the U.S., and is included in the standard formula for fortiﬁed blended foods used by the World Food Program (see Table 2). Premixes are typically used to add fortiﬁcants to foods. They include a blend of several micronutrients, a ﬁller (cornstarch, wheat starch, or calcium sulfate) and a free-ﬂowing agent (such as tricalcium phosphate). The bioavailability and stability of the nutrient, and its organoleptic properties are especially important concerns for premixes. CODEX Alimentarius (165) speciﬁes that “when a supplementary food for older infants and young children is supplemented with one or more nutrients, the total amount of the vitamins and minerals should be at least 2/3 the reference daily requirements per 100 grams of the food on a dry matter basis.” However the CODEX also states that this table is “simply a guideline to emphasize the nutrients to be considered in the development of a supplementary food”, and that “appropriate modiﬁcations might have to be made for adapting them (the guidelines) to speciﬁc conditions”. Table 2 compares the WHO requirements speciﬁed in the CODEX to the levels found in current World Food Program fortiﬁcation guidelines and the US RDAs. Encouraging the involvement of industry in promotion of fortiﬁed foods targeted to at-risk groups (such as fortiﬁed complementary foods for toddlers, and fortiﬁed tonics to pregnant and breast-feeding women) is an important mechanism to improve multiple micronutrient status in developing countries. Also, educating industry and governments on the beneﬁts of multiple fortiﬁcation of staples with additional nutrients (iron, zinc, folic acid, vitamin A) would help to address deﬁciencies of these nutrients.

4.3 Multiple Micronutrient Supplements Dietary approaches have not been shown to be effective strategies in Asia, speciﬁcally the Indian subcontinent, whereas vitamin A supplementation has been one of the few successful strategies in those countries. Though improving micronutrient intake through dietary approaches is the desirable approach, supplements can play a particularly important role for selected nutrients. For example, supplements can be especially important during pregnancy, for adolescents and women of reproductive age, and for the elderly. For children under the age of two, because of the need to have a liquid supplement, it is logistically difﬁcult to provide sufﬁcient quantities of supplements at low cost, although pilot efforts have tried the use of MVTM sprinkles as additions to complementary foods. For young children, fortiﬁed complementary foods may be a more appropriate means to increase micronutrient intake than supplements, but has not been evaluated adequately. gFor

women 19–51 yr of age in the U.S. in 1977, only 5% met the RDA for iron from naturally occurring sources, but when iron provided through fortiﬁcation was included, 12% met the RDAs (166). The differences were even greater for thiamin, riboﬂavin and niacin (12 vs 35%, 27 vs 43%, and 34 vs 52%, respectively).

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Table 2 Comparison of CODEX, WFP Speciﬁcations for Blended Foods, and U.S. RDAs for Young Children

Nutrients Vitamin A µg RE Vitamin D IU Vitamin E mg/IU B1 (Thiamin) mg B2 (Riboﬂavin) mg Niacin mg B6 mg B12 µg C mg Zn mg Iron mg

Calcium mg Folic Acid µg Pantothenic Acid Iodine 䊐g Copper mg (ESADI)

WHO Ref. Daily requirements Codex 1991 Per day (161)

WFP speciﬁcations UNIMIX per/100 gm food

400

1664 IU = 500 µg RE 10 µg = 100 IU

10 µg (=100 IU) 5 0.5 8 9 0.9 1 20 10 12 Requirement with low (5% ) bioavailability 800 50 50–70

5 0.128 0.448 4.8 1.2 48 5 (as zinc sulfate) 8 (as ferrous fumarate) 100 (as calcium carbonate) 60

RDAS @ 6–11 mo Per day (170,171,171a)

RDAS 1–3 yr Per day (170,171, 171a)

375a

400a

200b(AI)

200b(AI)

4* 0.3b(AI) 0.3b(AI) 4b(AI) 0.1b(AI) 0.5b(AI) 35a 5a

6a 0.5b 0.5 6b 0.5b 0.9b 40a 10a

10a

10a

270b(AI)

500b(AI)

80b(AI) 1.8b(AI) 50a 0.6–0.7a

150b 2b(AI) 70a 0.7–1.0a

AI Adequate intake, no RDAs have been established; ESADI, estimated safe and adequate intake. a1989 RDAs (171a) b1999 RDAs (170,171)

Only a few countries provide multiple micronutrient supplements through the health system. In Cuba, a multiple supplement containing 35 mg of iron is provided to pregnant women. At prenatal care visits, pregnant women in Honduras and Thailand receive a multiple supplement. The only country to distribute multiple vitamins on a population basis is Cuba, in response to the neuropathy epidemic related to thiamin and other micronutrient deﬁciencies. National distribution of supplements to Cubans over one year of age began in 1993 (172). In the U.S. the CDC also recommend that pregnant women should consume of supplements providing 30 mg/d of iron starting at the ﬁrst prenatal visit (173) and that women of reproductive age should take folic-acid supplements. Other than these recommendations, there is no recognized policy in the U.S. concerning multiple

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supplement use. Even so, 97% of pregnant women reported being advised to take supplements during pregnancy in the National Maternal and Infant Health Survey conducted in 1988. This survey also found that 81% of women reported consuming supplements at least 3 d/wk during the 3 mo after they found out they were pregnant (174). The National Health Interview Surveys collect information on adults in the U.S. regarding supplement use in the past year. In the 1987 survey, 51% of all adults reported that they had consumed any type of vitamin or mineral supplement within the last year, 39% had taken a supplement for more than 2 d in the past month, and 23% reported that they had consumed a supplement on a daily basis over the last year (175). Among the age group 25–34 yr, 15% of white men and 23% of white women took a daily supplement. Supplement use in the U.S. increases with age, with 28% of men and 38% of white women ages 65–74 consuming supplements. The 1989–1991 Continuing Survey of Food Intakes by Individuals found that 34% of white men and 43% of white women reported using supplements every day or “every so often” (176). A 1997 national telephone survey found that 43% of women of reproductive age reported consuming a supplement containing folic acid, with 32% consuming it on a daily basis, and 12% taking it less than daily (177). In 1992, the U.K. Department of Health began recommending that all women who plan to become pregnant should consume additional folic acid prior to conception and during the first 12 wk of pregnancy by eating more folate-rich foods and taking a dietary supplement of 400 µg folic acid. In a study of 411 women attending prenatal clinics between July and October 1993, only 14% of the pregnancies were unplanned. However, only 2% of the women had increased their intake of folate-rich foods, only 3% had taken folate-containing supplements prior to conception, and none had done both (178). Only one-third of the women had heard of the recommendation and of those, only 37% received information before conception. Thus, even in countries where animal products provide 60% of the food and where there is widespread availability of fruits, vegetables, and fortiﬁed foods, supplements form an important component of nutrient intake for a large proportion of the population. While in the U.S. and other developed countries, supplements are easily accessible, the availability of appropriate supplements is limited in most developing countries. Multiple micronutrient supplements are just becoming available from UNICEF, but the International Dispensary Association (IDA) and other nonproﬁt agencies procure them for sale to nonproﬁt organizations and developing country governments. However, the micronutrient supplements available for purchase through these agencies are inappropriate because they do not contain sufﬁcient iron, zinc, copper, vitamin A, or folic acid. A recent assessment of supplements available for retail sale in several developing countries and found limited availability, high cost, and inappropriate levels of nutrients in supplements (179). Although multiple supplements are currently recommended for consumption on a daily basis, their use on a weekly basis—especially for women of reproductive age and adolescents—is a strategy that should be tested. Weekly or biweekly doses of iron, iodine, vitamin A, vitamin D, and riboﬂavin (153,180) have been shown to be effective. Theoretically, daily supplementation should not be necessary because requirements are based on average daily intakes, although a recent meta-analysis of daily vs weekly iron supplements concluded that iron should be provided daily during pregancy (181).

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MVTM supplements are widely prescribed by obstetricians and pediatricians in many developed countries. However, the effectiveness of these supplements in promoting better maternal and child health in well-nourished populations has been questioned. Although the presence of multiple, micronutrient deﬁciencies offers justiﬁcation for the use of these supplements in developing areas, the cost of the supplements is an important limitation. Evidence of positive effects on maternal, fetal, and infant health would increase the rationale for multinutrient supplements to be used. Expanding the availability of supplements to consumers through private-sector involvement, especially with social marketing of products to keep costs low, would help meet some of the current constraints to increased supplement use in developing countries.

5. CONCLUSION Some have suggested that dietary approaches are the most sustainable and/or costeffective strategies. However data to support this are limited. Promotion of dietary changes often necessitates continued marketing or educational efforts, which have their own costs. The recent effort to increase egg consumption in Indonesia held great promise for improving status of several micronutrients. However the Asian economic crisis has led to reductions in availability of chickens, and thus this approach became less viable. A recent RCT illustrated the different biologic effects that each of these approaches can have on improving folate status (182). Women who received folic-acid supplements had signiﬁcantly greater intakes of folic acid than those who received fortiﬁed foods, foods high in folate, dietary advice on which foods to consume to improve folate status, or controls. Improvements in red-cell folate were 4–5 times higher in those who received supplements or fortiﬁed foods than the dietary folate or dietary advice groups. However these two groups still showed some improvement over controls in red-cell folate. Another analysis compared three approaches for increasing folic-acid intake in relation to reducing cardiovascular disease. Boushey et al. (183) compared projected savings in lives with three strategies to increase folate intake: increases in fruits and vegetables, fortiﬁcation of ﬂour and cereal products, and use of supplements. If dietary interventions were able to increase the consumption of fruits and vegetables by 2–3 more times/d, resulting in 100 µg of additional folate/d, and if 40% of the population complied with this change, the number of prevented deaths would be 7,500 in men and 6,000 in women. Fortiﬁcation of grain products with 350 ug/100 g folic acid were estimated to reduce 30,000 deaths among men and 19,000 deaths among women. Use of supplements containing 400 ug by 50% of the population would result in 15,500 and 12,500 preventable deaths among men and women, respectively. Such analyses are extremely useful developing program options. Each approach may be needed depending on in the context. The issues associated with program interventions (education, social marketing, procurement, monitoring, distribution, compliance, etc.) and the costs to optimize the success of each strategy need to be considered in the selection of strategies to improve multiple micronutrient intake.

ACKNOWLEDGMENTS Support for this chapter came from LINKAGES: Breastfeeding, Lactational Amenorrheic Method, Complementary Feeding and Maternal Nutrition Program. LINKAGES

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is supported by the United States Agency for International Development (USAID) under Cooperative Agreement HRN-A-0097-00007-00. The contents of this document do not necessarily reﬂect the views or policies of USAID.

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Chapter 16 / Malnutrition

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Malnutrition Dirk G. Schroeder

1. INTRODUCTION Malnutrition is widespread among disadvantaged populations living in developing countries. The consequences of malnutrition are severe and long-lasting. Children who are malnourished have longer and more severe illnesses (1,2) and have a higher risk of dying (3,4), compared to better-nourished children. Malnourished children also have delayed motor development (5) and lower cognitive function and school performance (6). In adulthood, individuals who were malnourished as children have impaired work capacity (7) and worse reproductive performance (8). Finally, malnutrition can have negative effects, not only on those afﬂicted, but on their offspring as well (9). The causes of malnutrition are numerous. These causes are intertwined with each other and are hierarchically related. The most immediate (or proximate) determinants of malnutrition are poor diet and illness (10). Poor diet and illness are themselves caused by a set of underlying factors that include family access to food and maternal care-taking practices. Finally, these underlying factors are inﬂuenced by the basic socioeconomic and political conditions within which poor families are attempting to raise well-nourished children. An accurate understanding of the relationships among these various causes of malnutrition and the relative contribution of each is essential for the design of efficient and effective programs to reduce malnutrition and its consequences. Because the resources directed at improving nutritional status are relatively scarce, it is critical that these resources are directed at interventions that will have the largest “bang for the buck” and will lead to lasting improvements. The primary objectives and content of this chapter are as follows. In the ﬁrst sections, key terms are deﬁned and the global prevalence of malnutrition is described. Next, a conceptual framework and the epidemiological evidence of the primary determinants and consequences of malnutrition are presented. Programmatic implications of these ﬁndings are then examined. The chapter concludes by identifying key gaps in knowledge that would beneﬁt from additional research, focusing on those most likely to increase the effectiveness of interventions and programs aimed at ameliorating malnutrition.

From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Table 1 Origin and Introduction of Some Terms Describing Nutritional Deﬁciency Among Children in Developing Countries Year(s)

Term

1900–1930

Distroﬁa pluricarencial

1935

Kwashiorkor

1955

Protein deﬁciency

1959– 1960s

Protein-calorie malnutrition (PCM) Protein-energy malnutrition (PEM)

1980s–90s

Energy-nutrient malnutrition (ENM)

1990s

Micronutrient malnutrition

Late 1990s

Malnutrition

Notes Term used by early Latin American workers meaning “multiple deﬁciency state.” From the Ga language of West Africa. Translation is “the disease of the deposed child.” Term reﬂected current thinking on primary cause of kwashiorkor. PCM ﬁrst introduced late 1950s. Evolved into protein-energy malnutrition (PEM). Used to cover whole range of malnutrition other than states caused primarily by speciﬁc nutrients (e.g., Vitamin C deﬁciency, pellagra). PEM still widely used. In recognition that other nutrients besides protein (e.g., zinc, vitamin A) signiﬁcantly contribute to malnutrition and growth faltering. Not widely used. Used to refer to key micronutrient deﬁciencies: vitamin A, iodine, and iron. Term used widely by international organizations (e.g., UNICEF) to refer to ENM and growth-faltering.

1.1. Deﬁnitions and Historical Overview “Malnutrition” is a common and widely used term to refer to suboptimal nutritional health. In international health (and in this chapter), malnutrition generally refers to undernutrition (e.g., poor growth) rather than overnutrition (e.g., obesity). A wide range of terms has been used to refer to the clinical and functional manifestations of undernutrition. A familiarity with the historical evolution of these terms is instructive because, as would be expected, the introduction and use of these terms closely reﬂected the evolving scientiﬁc understanding of the causes of, and solutions to, malnutrition. Table 1 summarizes the introduction of key terms over the past century. More detailed accounts of the history of international nutrition may be found elsewhere (11). In the early decades of the 19th century, health workers in Latin America identiﬁed a clinical syndrome that they referred to as Distroﬁa pluricarencial, meaning “multiple deﬁciency state” (Table 1). The clinical signs of this syndrome were likely similar

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to those identiﬁed in West African infants by Cicely Williams in the mid-1930s, who adopted for the syndrome the local name of “kwashiorkor.” The causes of kwashiorkor were unknown at the time, but Williams suggested that “some amino acid or protein deﬁciency cannot be excluded” (12). Between the mid-1930s and late-1950s, the international nutrition community focused almost exclusively on kwashiorkor with the belief that it was “the most serious and widespread nutritional disorder known to medical and nutritional sciences” (13). This perspective, along with the belief that kwashiorkor was owing to protein deﬁciency, led to the suggestion that improving protein intakes alone would solve the problem of malnutrition in poor countries. From a programmatic standpoint, activities during the 1950s and 1960s thus focused on increasing protein intakes through such means as improving the protein quality of grains (14). Collectively these efforts were commonly referred to as the “Green Revolution.” At about the same time, a great deal of effort was invested in the development of protein-rich, vegetable-based food mixtures, such as Incaparina (15), still in use throughout Central America. As early as the 1950s, however, the focus on protein as the exclusive cause of malnutrition and poor growth began to be questioned. Data began emerging that suggested that severely malnourished children could gain weight well on high-energy/lowprotein diets (16,17). Also, surveys from areas other than Africa indicated the existence of forms of malnutrition besides kwashiorkor, including marasmus and nonspeciﬁc stunting, both of which were thought to be primarily owing to deﬁciencies in energy rather than protein. In recognition of these early ﬁndings, Jelliffe (18) introduced the term protein-calorie malnutrition (PCM). This evolved into protein-energy malnutrition (PEM), a term still widely used today. Research during the 1960s further shifted the focus from protein to energy. Dietary studies suggested that protein intakes and the protein/energy ratio from traditional foods were generally near requirements, but that total energy intakes fell far short of requirements (19). By not meeting energy needs, protein, however ample in the diet, would tend to be metabolized for its energy, causing signs of protein deﬁciency to appear. Conversely, it was believed that providing energy, even “empty calories,” would “spare” protein and improve nutritional status. Finally, scientists began to question whether kwashiorkor itself was owing to protein deﬁciency, a controversy that remains to the present. Together, these ﬁndings led some international nutritionists to conclude in the mid1970s that the “protein gap is a myth and that what really exists, even for vulnerable groups, is a food gap and an energy gap” (19). In a stinging critique, McLaren (20) called the ﬁxation on protein by the international scientiﬁc community and the resources spent to close this gap a “ﬁasco.” Such authors argued that if most traditional diets were consumed at levels sufﬁcient to satisfy energy needs, protein needs would also be met. Programmatic efforts during the late 1970s and early 1980s thus emphasized simple recommendations to increase energy intakes such as “add two tablespoons of oil to the child’s diet” (21,22). In the mid-1980s, however, the focus shifted yet again. Scientiﬁc evidence began accumulating that the continued high rates of growth stunting around the globe could not be overcome simply by providing more energy from more of the same foods. Rather, certain micronutrients were identiﬁed as playing a key role in linear growth and infection. Speciﬁcally, vitamin A and iron, and more recently, zinc, have been

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suggested as key growth-limiting nutrients (23). Traditional diets given to young children are generally low in these key micronutrients and of poor dietary quality. It is also now recognized that multiple nutrient deﬁciencies frequently co-exist and that the type of food (e.g., animal vs vegetable) affects utilization; this has initiated discussions of the importance of “dietary quality” (24). A review of the current scientiﬁc evidence for the role of speciﬁc nutrients and dietary quality for growth is presented later in this chapter. In sum, the scientiﬁc understanding of the primary causes of undernutrition and poor growth has come “full circle” during the 20th century. As was recognized by workers in Latin America nearly a century ago, the clinical, somatic, and functional consequences of inadequate nutrition are most commonly owing to multiple nutrient deﬁciencies, usually in combination with high rates of disease. Only in very rare cases is the poor growth seen among children in the developing world due to inadequacies of a single nutrient. The term “malnutrition” is thus used throughout this chapter as it is currently employed by the international health and nutrition community in general: to refer to the syndrome of inadequate intakes of protein, energy, and micronutrients, combined with frequent infections, that result in poor growth and body size. Because poor growth is such an important result and indicator of undernutrition, a brief overview of the issues related to measuring and evaluating growth in an international context is presented next.

2. MEASURING PHYSICAL STATUS AND GROWTH 2.1. Anthropometric Indices of Nutritional Health Anthropometry is the external measuring of the human body. The tools used for anthropometry (i.e., scales, tapes) can be simple and portable and are therefore widely used in developing countries for determining body growth, proportions, size, and composition (25,26). In children, weight and height (or length) are the most commonly measured, although mid-upper-arm circumference (MUAC) is also used. Supine length rather than height is commonly measured in under-2-yr-old children, but there is wide variation among programs in this regard. Young (2–3-yr-old) children measured standing are approx 0.5–1 cm shorter than if measured lying down (27). For simplicity, the term “height” will be used throughout this chapter to refer to both supine length and standing height. Individual measures such as weight and height are uninformative on their own. When combined with age (i.e., weight-for-age, height-for-age) or each other (i.e., weightfor-height) and compared to reference values, however, they create useful indices that describe the physical status of individuals and populations. Deﬁcits in height-for-age, weight-for-height, and weight-for-age usually reﬂect distinct processes or outcomes of growth impairment and have been described using a range of terms, some of which are more accurate than others (28). Low height-for-age in younger children (under 2–3 yr) in poor countries reﬂects an ongoing process of “failing to grow” or “stunting,” whereas in older children, it reﬂects the state of “having failed to grow” or “being stunted” (29). The term “chronic malnutrition,” is frequently used in association with low height-for-age, but this term can be misleading and should be discouraged (28).

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Low weight-for-height measures “thinness” and is best described as “wasting.” One of the advantages of weight-for-height is that it does not require age, which is often unknown or inaccurately reported in developing countries. The terms “acute malnutrition,” “current malnutrition,” and “severe malnutrition” are commonly used, but are less appropriate descriptors than wasting (28). Weight-for-age is a measure of body mass relative to chronological age. Because body mass is determined by both height and weight, it is often difﬁcult to determine whether a child who is low weight-for-age is stunted, wasted, or both. After age 3 yr, low weight-for-age is primarily owing to stunting in most developing countries, although in famine situations or in certain key countries, such as India, low weight-forage among older children may in fact represent wasting. The terms “lightness” and “underweight” are the preferred terms for low weight-for-age (28). MUAC has been promoted as an alternative measure of wasting because of the high portability of the equipment (i.e., a measuring tape) and the belief that MUAC is independent of age (30). The belief that MUAC is age- and sex-independent has led to the promotion of ﬁxed cut-off points (usually 12.5 or 13.0 cm). Recent research, however, suggests that MUAC does, in fact, increase over the ﬁrst 5 yr of life (31). The World Health Organization (WHO) has therefore concluded that MUAC-for-age or MUAC-for-height, rather than a ﬁxed cut-off, should be promoted (32). MUAC-for-age reference data have been published (33). Importantly, the use of MUAC without age in situations where rapid identiﬁcation is essential (i.e., in famine situations where ages are unknown) is acceptable, in that this will tend to over-identify younger children, who are most at risk for morbidity and mortality (33). Under research conditions, in which small changes in growth are being measured over short time periods, alternate and more accurate anthropometric methods than just weight and height may be necessary. For example, kneemometers to measure knee-heel length are increasingly used (34).

2.2. Growth References In privileged populations, differences in growth and attained height within an ethnic group are primarily owing to differences in genetic potential (35), whereas in disadvantaged societies, environmental factors account for much of the variation among individuals. At a population level, the large variation in child growth seen worldwide among social classes and among countries is fundamentally owing to environmental factors, such as poor diets and high burdens of infection, rather than genetic makeup (36). Children of varying ethnic origins born into environments in which diets are adequate and the burden of morbidity is low will attain similar pre-adolescent heights (37). This, along with the desire to be able to compare the nutritional status of populations across all parts of the world, has led to the promotion and widespread use of a single international growth reference (38). The recommended international growth reference as of the writing of this chapter is referred to as the National Center for Health Statistics/World Health Organization (NCHS/WHO) growth reference. The data for this reference come from U.S. children and were collected before 1975 (39,40). These NCHS/WHO curves are the basis for the majority of growth monitoring “road to health” cards used throughout much of the developing world.

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In the nearly 20 years since its adoption, the NCHS/WHO reference has been criticized on a number of points. One set of criticisms has focused on the technical ﬂaws in the curves (41), a discussion of which is outside the scope of this chapter and may be found elsewhere (41,42). Other areas of continued debate are whether breast- and bottlefed children grow similarly in relation to the reference (43) and the appropriateness of a single international reference for use in all ethnic groups (44). East and Southeast Asian populations have been identiﬁed as most likely to be genetically shorter than other ethnic groups (45,46). Recent studies from Thailand (47), Indonesia (48), and the U.S. (49), however, provide evidence that Asian children can grow as tall as other children of similar socioeconomic strata. For example, Droomers et al. (48) reported that the mean height-for-age Z-score of preschool age (2–5 yr) Indonesian children from high socioeconomic strata living in Jakarta, Indonesia was 0.24 ± 0.94 Z, above the NCHS reference median. In sum, differences in the genetic potential of child growth among ethnic groups, even among East and Southeast Asian children, are likely to be very small. Differences in adult height owing to ethnicity are likely less than 2 cm on average compared to deﬁcits of 10 cm or more at age 5 yr owing to the poor diets and infection found in poor countries. The use of a single international reference is thus still recommended (28). However, a WHO expert panel recently concluded that the NCHS/WHO reference is not the best choice for this single reference and that a new reference should be developed (50). As of the writing of this chapter, the process of developing this new international reference was still ongoing.

2.3. Expression of Anthropometry Anthropometric data may be expressed as centiles (percentiles), percent of median, and standard deviation (SD) (or Z) scores relative to the reference (51). A centile score reﬂects a child’s size (e.g. weight) relative to the entire distribution of reference values at a certain age. A value falling below the third centile is commonly used as an indicator of growth retardation. Percent of median is the child’s achieved size relative to the reference median value with cut-offs of less than 80% of median commonly used as indicating growth retardation. Finally, Z-scores indicate the number of SD the child’s value is from the reference mean. Two SD below the mean (<–2 Z) is often used as an indicator of growth retardation. Centiles are more commonly used in industrialized countries, whereas in developing countries, percent of median is more common, in part because so many children in developing countries fall below the third percentile cut-off. Z-scores are recommended for research purposes because they are easier to interpret across various anthropometric variables and ages (28,52). In summary, anthropometry, along with a single international reference, is the best and most common method of assessing nutritional status in developing countries.

3. PATTERNS AND TIMING OF GROWTH RETARDATION 3.1. Prevalence and Patterns of Global Anthropometric Status At the close of the 20th century, approimately half a billion children under age ﬁve were living in developing countries. Of these about 37% are stunted, 11% are wasted, and

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30% are underweight (10). Although mortality rates have declined substantially over the past 20 years, rates of malnutrition have declined more modestly during this time (53). Between 1980 and 1995, under-ﬁve mortality rates in the developing world declined from 133 per 1,000 to 80 per 1,000 while percent underweight went from 38% to 31% (54,55). And, owing to increases in global population, the total number of undernourished children has remained essentially stable, at about 170 million, during this period. There are region differences in the patterns of malnutrition. Weight deficits, particularly in relation to height, tend to be highest in Asia and lowest in Latin America. Regions with high rates of stunting do not necessarily have a lot of wasting, however. Victora (56), in an analysis that used country as the unit of analysis, found that the correlation between wasting and stunting within countries was highest in Asia and the Eastern Mediterranean (Pearson’s correlation coefﬁcient of approx 0.7), nonexistent in Africa, and actually inverse in Latin America (correlation of -0.3). This last ﬁnding is owing to the apparently contradictory existence of very high rates of stunting in Latin America, but almost no wasting. Based on this ecological analysis, Victora suggested that the determinants for stunting are different from those for wasting. Empirical evidence conﬁrming this hypothesis and the importance of national level factors has recently been published by Frongillo et al. (57), although additional research in this area is critically needed. In sum, malnutrition and poor growth among children are enormous problems throughout the developing world. The timing at which this growth faltering occurs in a child’s life and the potential for recovering these deﬁcits, i.e., catch-up growth, are examined next.

3.2. Timing of Growth Faltering and Potential for Catch-Up Growth The process of growth retardation frequently begins even before birth, i.e., in utero, in poor societies (58). Good research on intrauterine growth is rare; however, this can be inferred from the high prevalence of low birth weight (LBW) in developing countries: 17% in developing countries compared to 6% in industrialized countries (59). Even fewer studies have examined the prevalence of intra-uterine stunting (IUS) at birth in developing countries or whether IUS predicts stunting later in life. In rural Malawi, Neufeld et al. (60) found that 48% of full-term infants were below the 10th percentile of the reference length-for-gestational age. In Guatemala, at 15 d of age, full-term infants were on average about -1.0 Z below the NCHS/WHO reference length-for-age Z-score, representing an absolute difference of around 2–3 cm (61) with 13% of the sample more than 2 SD below the reference median (62). The magnitude of these length deﬁcits are similar to those found in Pakistan (63). Shortness at birth is a strong predictor of subsequent growth during childhood. Some research shows that IUS is the best predictor of stunting at 3 yr of age compared to measures of growth retardation based on birth weight, intrauterine growth retardation (IUGR), or LBW (62). Growth in weight between birth and approx 3 mo of age in developing countries is generally similar or even a little better than reference values from developed countries (64). Linear growth during the ﬁrst 3 mo of life generally tracks reference values; in other words, no additional faltering occurs on top of the deﬁcits seen at birth (65), although fattening during this early period has been documented in Guatemala (66).

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Fig. 1. Linear growth among children in Guatemala, U.S. to 36 months of age.

These good growth rates during the ﬁrst 3 mo of life have been attributed to the high rates of breast-feeding initiation during the early postnatal period. By about 3 mo, however, linear growth in many developing country communities begins to falter and by 9–12 mo stunting in these populations is often severe with length-for-age Z-scores of close to -2 not uncommon; (65,67). Fig. 1 presents data from Guatemala of typical growth patterns of poor developing country children. It is important to reiterate that the exact timing at which severe growth faltering is initiated during infancy depends on the speciﬁc conditions to which the infant is exposed and will thus vary both within and across populations. An important task for programmers is to determine the age at which faltering occurs in the local situation. Accurate knowledge of the age at which growth begins to falter will provide important clues to the determinants of the faltering and thus allow the design of effective interventions to prevent it. Some of the difﬁculty in determining the timing of growth faltering of infants in developing countries is owing to the fact that the current NCHS/WHO growth reference is based on formula rather than breast-fed children (44). Research has shown that growth differs between these two feeding modes, even among otherwise healthy children (68) and infants born small-for-gestational-age in industrialized conditions (69). The use of a fully breast-fed reference leads to different conclusions concerning the age at which children in developing countries begin faltering in weight, although the effect is less for length (68). Development of an international growth reference that includes predominantly breast-fed children is underway.

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At about 3 yr of life, growth faltering relative to reference values plateaus and between about 3 yr and adolescence, linear growth velocity of developing country children generally parallels reference centile lines (61), although continued decline through school age (7–14-yr-olds) has been documented in Zanzibar (70). Growth during adolescence in developing countries is poorly documented. Maturation is often delayed and the growth period may be prolonged in poor societies by two or more years, such that a small portion of the early growth deﬁcit in height may be made up (71). In general, however, once individuals are growth-stunted, these deﬁcits are rarely recovered, i.e., through “catch-up” growth (71). The exception is for very young children who are born into poor environments but then are exposed to radically improved dietary and environmental conditions through, for example, adoption. The biological mechanisms promoting catch-up growth, when it occurs, are complex and still relatively poorly understood (72). For example, with adoption, maturity may be “overly-accelerated” and short stature may result. In summary, more than a third of all children under ﬁve in developing countries experience malnutrition to a signiﬁcant enough degree to become permanently growthretarded. This growth retardation, particularly linear growth retardation, generally begins very early in the child’s life and once it has occurred, is rarely reversible. Put another way, this means that most of the absolute height deﬁcits seen in adults in developing countries are already present by about 3 yr of age. But, what is so bad about a person being smaller? the reader may be asking. Some have argued that individuals can be “small but healthy” and that there are, in fact, global advantages to populations being smaller in that smaller people eat less food (73). This view has been criticized by other authors who point out that focusing on growth is important, not so much because it is essential that each individual achieve maximal adult height, but because poor growth is an excellent indicator that the body is compromised as performing suboptimally on a wide range of other functions, e.g., immune function (74,75). In the next sections, the current epidemiologic evidence of the substantial consequences and complex causes of poor malnutrition and growth are reviewed in detailed.

4. EPIDEMIOLOGIC EVIDENCE 4.1 Conceptual Diagram A modiﬁed version of the UNICEF conceptual framework; (10,76) of child health and survival is used to guide the next sections of this chapter (Fig. 2). The strength of this framework is that it recognizes and integrates the biomedical consequences, as well as the underlying socio-economic, determinants, and consequences, of malnutrition. Landmark papers of such integrated models include those by Mosley and Chen (77) and Bongaarts (78). In the next sections of this chapter, the contribution of malnutrition (poor growth) to higher mortality (Arrow 1), more infection (Arrow 2), and other functional impairments (Arrow 3) will be reviewed ﬁrst. Next, the key proximate determinants of malnutrition, namely infection (Arrow 4) and inadequate diet (Arrow 5) will be reviewed. An examination of the bi-directional relationship between dietary intakes and infection (Arrows 7 and 8) and the impact of infectious disease on mortality (Arrow 9) are outside the scope of this chapter. The underlying determinants of dietary intake and

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Fig. 2. Modiﬁed version of the UNICEF conception framework of child health and survival.

disease, namely, insufﬁcient access to food (Arrow 10), inadequate child-care practices (Arrow 11), poor water and sanitation and inadequate health services (Arrow 12) will then be presented, primarily in relation to programmatic efforts to alleviate malnutrition. A discussion of the basic causes of malnutrition (e.g., the agricultural and economic environment) is outside the scope of this chapter, but may be found elsewhere (79).

4.2. Consequences of Malnutrition 4.2.1. MORTALITY Approximately 12 million children under 5 yr of age die each year in developing countries (10). Until very recently, the “causes” of these deaths were overwhelmingly attributed to diseases such as diarrhea, pneumonia, and vaccine-preventable diseases. Figure 3 is reproduced from a 1993 United Nations International Children’s Emergency Fund (UNICEF) document that classiﬁed the causes of child deaths, and is representative of the lack of importance given to malnutrition, where, in this case, it is only brieﬂy mentioned in the footnote. This focus on disease as the “main” cause of death among children essentially ignored the long-recognized synergistic relation between malnutrition and infection on mortality. As Scrimshaw et al. (80) noted more than 30 yr ago, “the simultaneous presence of malnutrition and infection results in an interaction that is more serious for the host than would be expected from the combined effect of the two working independently.” Thus, most children in the developing world die, not from an infectious

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Fig. 3. Main causes of child deaths

disease or frank starvation alone, but from the simultaneous presence of malnutrition and infection that together, greatly increase the child’s risk of death. Despite the broad theoretical acceptance of this dual causality, attempts to improve child survival in developing countries have focused disproportionately on preventing or managing infectious diseases rather than eliminating or addressing malnutrition (81). In 1990, UNICEF spent just 13% of expenditures on direct nutrition activities (82). The reasons for this emphasis on infectious disease included the apparently higher feasibility of addressing disease compared with malnutrition (83), and the belief that if infections could be reduced, improvements in nutritional status (84) and survival (85) would certainly follow. By the 1990s, child mortality rates in the developing world had dropped dramatically, from 216 per 1000 in 1960 to 97 per 1000 in 1996 (10). During the same period, epidemiologic information was accumulating that strongly suggested that the majority of deaths that were still not being prevented were owing to the potentiating effects of malnutrition. In the early 1990s, a series of papers were published that reviewed all previous prospective studies that had examined the relation between anthropometric status and risk for mortality (3,4,86,87). In the review by Pelletier (3), 28 community-based, prospective studies in 12 Asian and sub-Saharan African countries were examined. Mortality rates from the eight most comparable studies that reported nutritional status as weight-for-age are presented in Fig. 4 and were used to estimate overall relative risks by weight-for-age nutritional status category. A key ﬁnding from these analyses was that, in the vast majority of studies, the risk of mortality was increased not only with severe malnutrition, but also with mild and moderate malnutrition, a ﬁnding that contradicted an early, landmark paper on this topic (88). Summary estimates based on these studies found that the risk of death was 8.4, 4.6, and 2.5 times greater for a child whose weight-for-age was <60, 60–69, and 70–79% of the reference median (3), respectively, compared to a child whose weight-

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Fig. 4. Mortality rates by weight-for-age in eight community-based studies.

for-age was above 80% of the reference median. Thus, decrements in nutritional status were found to increase risk of death in an exponential, rather than linear fashion. Calculated another way, the risk of mortality increased at a compounded rate of 5.9% (± 0.8% standard error) for each decrease of 0.1 Z-score units below –1.0 (87). In subsequent papers by Pelletier and co-authors (89,90), these summary relative risk estimates were used in conjunction with prevalence rates of the various levels of malnutrition to calculate population attributable risks (PAR). In this case, PAR is an estimate of the percentage of child deaths attributable to malnutrition’s potentiating impact on infectious disease. As noted by Yip and Scanlan (91) PAR is the “the bottom line” when expressing the cost of malnutrition on mortality. Population attributable risk estimates were calculated for 53 developing countries with nationally representative data on children’s weight-for-age (90). Results indicated that 56% of child deaths (aged 6–59 mo) were attributable to malnutrition’s potentiating effect, and that 83% of these were attributable to mild-to-moderate rather than severe malnutrition. These two ﬁndings, that over half of all child deaths are owing, in part, to malnutrition and that mild-to-moderate malnutrition accounts for the vast majority of these malnutrition-related deaths, have led many international organizations to re-conceptualize their global strategies to child survival. A concrete example of the impact of this work is represented in more recent presentations of the causes of global child mortality in which the role of malnutrition is literally placed “front and center” (Fig. 5).

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Fig. 5. Malnutrition and child mortality. Adapted with permission from ref. (87).

4.2.2. INFECTION AND DISEASE One of the reasons that there is such a strong association between malnutrition and child mortality is that a malnourished child tends to suffer more days of infectious disease. The total number of days of disease a child experiences is a combination of the number of episodes (i.e., incidence) and the duration of each episode. Early studies of these relationships suggested that malnutrition results in longer durations of disease, but not more episodes. An early paper by Black et al. (1), for example, found that malnutrition was associated with longer diarrheal durations, but not incidence, among young Bangladeshi children. Figure 6, adapted from this paper, shows the clear relationship between anthropometric status at the start of an episode and the average duration of diarrheal episodes associated with enterotoxigenic Escherichia coli. Subsequent studies have conﬁrmed this strong relationship between initial nutritional status and duration or severity of an infectious disease episode (92) and some studies ﬁnd an association with an increased number (incidence) of episodes as well (93,94). In a study from Brazil for example, Guerrant et al. (92) found that children with weightfor-age * 3 SD below the median (i.e., ) – 3 Z) had 37% more episodes, 73% longer durations, and 100% more days of diarrhea than their better-nourished counterparts. However, it should be noted that the relationship between nutritional status and diarrhea incidence is highly subject to confounding by socioeconomic and environmental context; not all analyses have adequately controlled for these factors. Mechanisms by which malnutrition increases the incidence and prevalence of infectious disease are numerous and complex. Some of the factors include impaired host defenses, including protective mucous, gastric acidity, and humoral and cellular immunity. In-depth reviews of these factors are available elsewhere (95). It should be noted that malnutrition is not associated with more disease in all cases. For example, Aaby has made a strong case for the fact that malnutrition has little to

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Fig. 6. Relationship between arthropometric status and duration of diarrheal episode. Adapted with permission from ref. (1).

do with measles incidence (96). Also, a recent paper by Genton et al. (97) found that stunting among Papua New Guinean children was actually protective against malaria. These instances, however, are the exceptions. Overall, the evidence that malnutrition increases the burden of illness is consistent and strong (98). 4.2.3. FUNCTIONAL OUTCOMES Malnutrition impairs functional performance. These impairments may be physical, such as reduced physical activity and work capacity, as well as cognitive and behavioral. A challenge in understanding these myriad effects of malnutrition is that many of these functional outcomes, e.g., physical activity and social interaction, are highly related (99). The impact of malnutrition on cognitive and behavioral development is brieﬂy summarized next. The impact of malnutrition on other functional outcomes, such as work capacity and reproductive health, can be found elsewhere (100). A number of reviews of the impact of malnutrition on mental development are available (101,102). The paper by Martorell (102) thoroughly reviewed the published literature and came to nine key generalizations in regards to the impact of undernutrition during pregnancy or early childhood on cognitive and behavioral development. These generalizations are summarized in Table 2. Two points should be highlighted from this list. First, the theories by which malnutrition leads to developmental delays have changed radically over the past 40 years or so. In the mid-1960s, many scientists believed the impact of malnutrition on cognitive deﬁcits was owing exclusively to physical damage to the brain during critical periods (103). It is now recognized that malnutrition hinders cognitive abilities through a variety of interrelated routes as presented in Fig. 7 adapted from Brown and Pollitt

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Table 2 Nine Generalizations About the Impact of Undernutrition During Pregnancy or Early Childhood on Cognitive and Behavioral Development Area Effects are severe and varied

Findings Poor nutrition during intrauterine life and early years leads to profound and varied effects that include: Delayed physical growth and motor development; Impaired cognitive development and lower IQs; More behavioral problems and deﬁcient social skills; and Decreased attention, impaired learning, and lower educational achievement. Mild-to-moderate malnutrition as well as severe malnutrition can have signiﬁcant negative effects

Not only the severely malnourished are affected Mechanisms Both organic-based mechanisms (e.g., damage to the brain) as well as such mechanisms as reduced exploration and interest in stimuli, separately or in combination, likely play a role. Who is The poorest segments of society are most likely to be malnourished and affected? the negative effects of malnutrition on cognitive development are likely to be greatest among these populations. Which It is difﬁcult to identify one or two key nutrient deﬁciencies that are most nutrients? associated with impaired development because nutritional deﬁciencies tend to cluster. The safest course is to make sure children meet all of their requirements for all nutrients from breast and complementary foods. Which ages? There is strong evidence that the earlier the nutritional intervention in the life of the child, the greater the beneﬁt in preventing impaired physical and cognitive development. Effects are Although there is scientiﬁc evidence that improvements in cognition can largely be achieved through intensive educational and dietary therapy, few irreversible children in developing countries have the beneﬁt of such therapy. Thus, in poor countries, once cognition is impaired, it is largely permanent. Effects are Nutritional supplementation trials have found that improved nutrition long lasting during preschool age persists as long as adolescence and adulthood. Stimulation Combining stimulation programs with nutritional programs results in greater cognitive development than either alone. Adapted with permission from ref. (102).

(104). As seen in this ﬁgure, a poorly nourished child may be less physically active, and therefore less likely to interact with his/her environment, which may or may not lead to impaired learning. The second point to be highlighted relates to the timing of the insult. In general, the earlier the malnutrition in the life of the child, the more severe, longer-lasting, and less amendable to reversal are the negative consequences. Also, like the effects on mortality reviewed earlier, even mild and moderate forms of malnutrition can have measurable effects on cognition and behavior. Finally, there are not one or two single nutrients that

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Fig. 7. Malnutrition and delayed intellectual development. Adapted with permission from ref. (104).

can be held most responsible for the relationship between malnutrition and cognitive deﬁcits. This ﬁnding parallels the evidence for the impact of speciﬁc nutrients on physical growth as will be discussed in a later section. 4.2.4. SUMMARY In summary, the consequences of malnutrition are varied, severe, and long-lasting, particularly if the malnutrition occurs early in the child’s life. It is not only children with severe malnutrition who suffer additional negative consequences; rather, there is now ample evidence that mild and moderate forms of malnutrition have signiﬁcant, measurable consequences. And, at a population level, because most children who are malnourished have mild or moderate rather than severe forms of malnutrition, the overwhelming proportion of the impairments owing to malnutrition is due to these milder or moderate forms. Thus, it is clear that malnutrition should be prevented. But how? In the next sections, the literature in the main causes of malnutrition is summarized. An accurate understanding of these causes is essential in order to design effective programs.

4.3. Causes of Malnutrition and Poor Growth The most immediate (or proximate) causes of malnutrition are illness (infection) and poor diet. The evidence that these conditions negatively impact growth, particularly linear growth, is summarized next. The focus on linear growth is in recognition of the fact that relative weight (i.e., weight-for-height) may be lost and more easily recovered, whereas linear growth deﬁcits are generally permanent.

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Fig. 8.

4.3.1. INFECTION It is indisputable that infectious diseases have an important and signiﬁcant impact on the growth of individual children. Diarrheal disease and lower-respiratory infections have been particularly implicated in this regard. One of the ﬁrst studies that documented this in a developing country was directed by Dr. Leonardo Mata in the community of Santa María Cauqué, Guatemala between 1962–1967 (105). During this study, Dr. Mata followed 45 children from birth and daily gathered information on growth, illnesses, and stool samples, among other information. Dr. Mata then plotted weight gains of these children against growth references and superimposed the illnesses and durations of illnesses that they experienced. An example of these plots is presented in Fig. 8, often referred to as a “Matagram.” The biological mechanisms that underlie the impact of infectious disease on growth are well-documented and include decreased dietary intakes owing to catabolism, malabsorption, and anorexia (106), among others. Although the impact of infection on growth of individual children is clear, the impact of infectious disease on growth at the population level is more controversial. The central question is: how much of the average growth deﬁcits seen among developing country children is owing to infectious disease vs, for example, poor diet? Early community-based studies suggested that infections were the primary causes of poor childhood growth at the population level (107,108). For example, Rowland et al. (109) analyzed data on 126 Gambian infants who were followed from birth until 2 yr of age, and calculated that lower respiratory-tract infections (LRTI) reduced weight gain by 14.7 g/d of infection and diarrheal diseases reduced weight gain by 3.7 g/d during the ﬁrst 2 yr

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Table 3 Impact of Diarrhea on Linear Growth

Author, Year Schorling and Guerrant (1990) Black et al. (1984) Briend (1989) Martorell et al. (1975) Walker (1992) Condon-Paoloni (1977) Rowland (1988) Moy (1994) aNS,

Reference

Country

Age (m)

(94) (1) (111) (152) (153) (154) (109) (155)

Brazil Bangladesh Bangladesh Guatemala Jamaica Mexico Gambia Zimbabwe

2–48 6–35 0–84 9–48 0–36 0–24 9–24

% Total length deﬁcits 21 20 20 10 17 NSa NSa NSa

nonsigniﬁcant.

of life. Because children were sick with diarrhea most often, the overall impact of the diseases on weight gain at the community-level was greatest for diarrheal diseases. The authors estimated that diarrheal diseases were responsible for approx one-half and LRTI for one-quarter of the approx 1.2 kg shortfall in weight below the NCHS reference at age 1 yr. Notably, infectious diseases were not found to have any impact on length gain. Also, negative effects of diarrhea were much reduced in breast-fed children, a phenomenon that has subsequently been conﬁrmed by Lutter et al. (110). In the late 1980s, however, the widely-accepted notion that diarrhea and other infectious diseases were the primary causes of poor childhood growth began to be questioned. In a novel analysis of a community-based study of Bangladeshi children (6–35 m), Briend et al. (111) compared weight and length gains in which diarrhea had occurred at the beginning to those that occurred at the end of 3-mo intervals. Based on 1,772 3-mo intervals, the authors found that although weight gain and linear growth were lower in intervals with diarrhea than in intervals without diarrhea, comparison of weight and height gains in intervals during which diarrhea occurred at the beginning or at the end showed that after nonbloody diarrheas children catch up and that deﬁcits in weight gain and linear growth were no longer apparent a few weeks later. The authors thus concluded that the effect of diarrhea on growth is transient and that efforts to control diarrhea are unlikely to improve children’s nutritional status in the long term. This and similar analyses prompted a series of review papers which asked whether the elimination of diarrheal disease would signiﬁcantly reduce malnutrition; (98,112). Black (112), for example, noted that the magnitude of impact of diarrheal diseases on growth was very dependent on a number of other factors, including feeding practices during and after the illness. A summary table of the aforementioned studies, along with others that have been published since these reviews quantiﬁed the impact of diarrheal disease on length gain deﬁcits, is presented in Table 3. As seen, diarrheal disease likely accounts for only approx 10–15% of the overall total length deﬁcits seen in developing countries. In summary, although it is indisputable that infectious disease has detrimental effects on the growth of individual children, infectious disease does not appear to be the primary cause of growth retardation at the population level. Of the approx 10 cm that

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children are linearly growth-retarded by age 5 yr, it appears that this shortfall could only be reduced by 2–3 cm by programmatic efforts focused exclusively on bring infectious disease rates in developing countries down to those seen in industrialized countries. Black (112) and others have thus concluded that although reduction of infectious diseases is desirable for many reasons, the relative feasibility of eliminating or significantly reducing infectious diseases to improve nutritional status should be balanced against the cost, feasibility, and effectiveness of more direct nutrition interventions. So, what accounts for the remaining 7–8 cm shortfall in heights seen among children in developing countries? Some of this deﬁcit is owing to intergenerational effects in which shorter mothers give birth to shorter newborns (9). The balance of the deﬁcit, however, is owing mostly to the young child’s diet and, perhaps more importantly, the combined impact of simultaneous exposure to poor diet and high rates of infection. 4.3.2. DIET Dietary intakes unquestionably affect nutritional status and growth. Dietary intakes of infants and young children in developing countries come from a combination of breast milk and complementary (or transitional) foods. As presented in the historical overview, the scientiﬁc understanding regarding which nutrients are most responsible for the widespread growth faltering seen in developing countries, however, has evolved signiﬁcantly over the past half-century. In this section, the most up-to-date evidence for the impact of individual nutrients is brieﬂy summarized; more detailed reviews are available elsewhere (23,113,114). 4.3.2.1. Breast Feeding. The epidemiologic evidence for the advantages of exclusive breast feeding early in life and the continuation of breast feeding during the ﬁrst 2 yr of life is extensive and convincing. The literature on beneﬁts of breast feeding has been reviewed and summarized elsewhere so it will not be addressed here. Particularly important, however, is the evidence that exclusive breast feeding early in life protects against infections (Arrow 7 in Fig. 2), even in industrialized countries (115–117). And, when a child does get ill, the breast-feeding child suffers less in terms of reduced intakes and growth faltering that the nonbreast-fed child (106). 4.3.2.2. Nutritional Determinants of Growth. The current literature on the nutritional determinants of growth has been reviewed by this author as well as others (23,113,114,118). In these reviews, the evidence for the relation between speciﬁc nutrient deﬁciencies, alone and in combination, and growth was reviewed; some of the key ﬁndings of these papers are summarized in Table 4. One of the key limitations of attempting to draw conclusions about the role of speciﬁc nutrients and growth is that many of the published studies did not adequately take into account the fact that the nutrients of interest were also being provided along with other nutrients. For example, many of the studies that concluded that calcium intakes increase growth were based on an observed association between cow’s milk intake and growth, without adequately considering the other nutrients that are also present in cow’s milk (e.g. zinc, protein) (119). Randomized, supplementation trials with calcium, on the other hand, generally failed to ﬁnd an impact on growth (120). Of the individual nutrients examined in these reviews, the evidence for an impact of zinc on growth appeared to be the most consistently positive. In a meta-analysis of randomized zinc trials, the overall effect of sizes were signiﬁcant, but small (at

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Table 4 Evidence for the Nutritional Determinants of Childhood Growth in Developing Countries Availability of good-quality studies

Likelihood that provision of nutrient/food will improve growth

Energy alone

Low

Low-moderate

Protein alone

High

Low

Nutrient

Notes (key references)

Macronutrients Few studies have isolated the effect of energy.

Individual Vitamins and Minerals Vitamin A

High

Low-moderate

Vitamin B6

Low

Low-moderate

Vitamin B12

Low

?

Calcium

Moderate

Low

Copper

Low

Moderate

Low Moderate

? Low

Iron

High

?

Zinc

High

Moderate-high

Multiplemicronutrients

Low

Moderate

Animal products

Low

Moderate

Low-moderate

Moderate

Folic acid Iodine

Improved growth with vitamin A apparently limited to the severely vitamin A deﬁcient. Lactating infants of supplemented mothers grew better. Very few studies. Difﬁcult to separate Vitamin B12 from other components of animal products. Most positive studies based on studies with cow’s milk. Supplementation trials generally found no impact. Most studies have been too short to measure impact on linear growth. Very few studies Wide-spread programs to increase fortiﬁcation with iodine provides opportunity to test impact on growth. Effects likely depend on degree of iron depletion, baseline nutritional status, and underlying causes of iron deﬁciency. Meta-analysis found signiﬁcant impact of zinc supplementation on both weight and length (121).

Other

Dietary quality

Programmers are considering widespread supplementation with multiple micronutrients, despite lack of good studies. Correlational results studies consistently positive, but open to confounding (e.g., SES). Randomized trials needed. Deﬁnitions highly variable. Need more consistent deﬁnition.

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about 0.22 SD units and 0.26 SD for height and weight, respectively), but effects were about twice as large in children who were stunted (<–2 HAZ) on entry. The authors of a meta-analysis of randomized trials that examined the impact of studies of zinc on child growth thus concluded that, “there is now sufﬁcient information to indicate that, in those settings with high rates of stunting and/or low plasma zinc concentrations, programs to enhance zinc status should be considered to improved children’s growth” (121) (see Chapter 12). The more mixed results seen in the studies that attempted to isolate the impact of a single nutrient on growth are likely owing, as least in part, to the fact that malnourished children are typically deﬁcient in a number of nutrients simultaneously. If one nutrient is increased through supplementation, the nutrient that is the next most deﬁcient then becomes limiting (122). Thus, there is currently great interest in determining whether provision of multiple micronutrients will improve growth (123,124). To date, there have been just four well-designed studies examining the impact of multiple micronutrient supplements on growth (125–128) and only one of these has found a signiﬁcant impact on growth (127). As suggested by Ramakrishnan and Huffman in this volume (124), the extent of deficiencies and age of the children are likely important factors in whether the supplements have positive and sustainable effects on growth. As of the writing of this chapter, a number of additional trials with multiple micronutrients were ongoing, the results of which will improve our understanding of the potential of such supplements for improving child growth. In spite of the current lack of scientiﬁc evidence of the beneﬁts and risks of supplementation with multiple micronutrients, there is serious discussion among the large, multinational organizations (e.g., UNICEF) about going ahead with large-scale supplementation with multiple micronutrients (123). Many in the scientiﬁc community believe that such large-scale efforts may be premature. An alternative, or perhaps complementary, strategy to improving diets of developing country children is to focus, not on speciﬁc nutrients, but on speciﬁc types of foods, e.g., animal products or even the whole diet, a concept often referred to as “dietary quality.” A high-quality diet is deﬁned as one that has the proper concentrations, balance, and bioavailability of both the macro- and micronutrients needed for growth and health (24). Some of the best reports on the importance of dietary quality come from the nutrition CRSP studies in Mexico which showed that while intakes of individual nutrients failed to predict size, dietary patterns, such as consumption of more animal products and fruit, were associated with larger size whereas high tortilla consumption was associated with small body size. This ﬁnding was in spite of the fact that the high tortilla pattern was associated with higher total intakes of such individual nutrients as iron, thiamine, zinc, energy, calcium, and niacin among preschoolers. This apparent contradiction between high absolute nutrient intakes from tortilla, but worse growth, was attributed to the low bioavailability of nutrients from tortillas owing to the high ﬁber and phytate content (129). Inclusion of animal products may be a key strategy for improving dietary quality. Observational studies in developing studies consistently ﬁnd a strong positive correlation between animal product intakes and height (130). This correlation is often attributed to the extra protein found in animal products (131–133); but nutritional aspects of animal products other than protein may in fact be responsible (134,135).

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Animal products are an excellent source of a number of micronutrients and minerals, including iron, zinc, calcium, vitamin A, and phosphorus; vitamin B12, of course, is only found in animal products. Alternately, it has been suggested that sulfur, primarily found in amino acids such as methionine and cystiene, (136,137) or the higher dietary fat content of animal foods (138) are responsible for the associations. Regardless of the reasons for the effect, it is generally agreed that increased consumption of animal products would likely have a signiﬁcant impact on increased growth among children in developing countries (114). Remarkably few well-designed, randomized studies of the use of animal products, however, have been conducted. This is an important area of research for the future. 4.3.2.3. Impact of State-Of-The Art Dietary Interventions On Growth and Mortality. To what degree can improving dietary intakes among children alone reduce global malnutrition and improve survival? There are strikingly few good studies that can be used to answer this question. Caulﬁeld et al. (139) recently summarized programmatic efforts to improve dietary intakes and growth of 6–12-mo old infants in 5 efﬁcacy trials and 16 programs conducted in 14 different countries. Improvements in dietary intakes (ranging from 65–302 kcal/d) were found in almost all of these trials and programs. Caulﬁeld et al. (139) calculated that such improvements in intake were associated with improvements in growth range 0.10–0.50 SD units. The authors also estimated that improvements of this magnitude would translate into reductions in malnutrition (<–2 SD weight-for-age) at 12 mo of 1–19% and that these reductions in malnutrition could, in turn, reduce deaths owing to malnutrition by 2–13%, depending on the initial prevalence of malnutrition in the target community. 4.3.2.4. Summary. In summary, poor dietary intakes, both by pregnant women and by young children, are responsible for a signiﬁcant portion of the growth stunting that occurs in developing countries. As seen from this review, however, lack of no single nutrient can be highlighted as primarily responsible. This is in contrast to our earlier understanding of the causes of poor growth, which focused, for example, on protein as the main cause of malnutrition. Rather, diets served to young children by poor mothers in developing countries do not allow optimal nutrition and growth for a number of reasons: such diets are often inadequate in a variety of nutrients, especially certain micronutrients; contain high amounts of inhibitors, such as phytates, that reduce the absorption of the nutrients that are consumed; and are low in promoters of absorption, such as vitamin C and fat. 4.3.3. RELATIVE AND COMBINED EFFECTS OF INFECTION AND POOR DIET ON CHILD GROWTH The previous two sections summarized the strong epidemiologic evidence that high burdens of infection and poor diet are each important, independent determinants of the widespread growth retardation seen in developing countries. Most of the studies cited have examined the impact of either infection or diet on growth. A key question for programmers, however, is what approaches will have the greatest impact on improving growth—reducing infection, improving diets, or both? These questions go to the heart of the design of international nutrition policies and distribution of resources. Strikingly few published studies have examined the effects of the simultaneous improvements in diet and health on growth. A notable exception is a study by Becker et al. (140) that used random-effect regression methods to model monthly weight changes

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Fig. 9. Monthly weight changes in children, aged 5–18 mo, in two Bangladeshi villages. Adapted with permission from ref. (140).

in 70 children aged 5–18 mo from two Bangladeshi villages. Estimates indicated that increasing energy intakes to the recommended WHO level would have a signiﬁcantly greater effect on weight gain than would the elimination of diarrhea and fever (Fig. 9). With energy at recommended intake and diarrhea and fever prevalence as found in U.S. children, weight gain was predicted to be near that of the international reference population. The authors concluded, therefore, that interventions aimed at improving dietary intake may be as important as infection-control programs for improving growth of children in poor developing nations. Additional research on the magnitude of the improvements in child growth if diets are improved and infections are reduced are urgently needed.

4.4. The Underlying Determinants: Food, Care, and Heath The UNICEF conceptual framework identiﬁes three primary underlying causes of poor diet and excess disease: insufﬁcient food; inadequate maternal and child care, and poor environment; and inadequate health services. Historically, nutritionists have focused primarily on increasing food availability while the medical community has emphasized the availability of health services. The recognition of the importance of “care” in this equation, however, is new. As recently noted by WHO:

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“The placement of child care as one of the three critical determinants of adequate nutrition, along with access to food and health services, represents an important breakthrough in the understanding of good nutrition as more than just a problem of food security and health.” (114).

Reviews of the scientiﬁc data on the importance of food security, maternal feeding behaviors and the health-care sector are outside the scope of this chapter. The reader is directed to the recent monographs on these topics for additional detail (114,141). 4.4.1. PROGRAMMATIC IMPLICATIONS The relatively slow decline in the rates of malnutrition and consistently massive number of malnourished suggests that past approaches to improve child nutritional status over the past two decades could have been more effective. In part, this may be owing to the emphasis on elimination of infectious disease as a primary means to reduce malnutrition. It is now much more widely recognized that improving dietary intakes of the pregnant women and under-ﬁves is essential if there is to be signiﬁcant and sustained reductions in childhood malnutrition. As indicated, improvements in diets will contribute not only to better nutrition, but also to reductions in illness burden prevalence and mortality. The next question is, how can the aim of improving dietary intakes and quality for women and young children be achieved in a timely, effective, and cost-effective manner?

5. NUTRITION-ORIENTED INTERVENTIONS AND PROGRAMS: NECESSARY ELEMENTS AND OPTIMAL DESIGNS Nutrition programs are perceived by many to be extremely complex and/or ineffective. Reviews of past nutrition programs experiences indicate that this perception is at least partially accurate because such programs have often been too rigid in their design (i.e., not adapted to local needs and conditions) and inadequately targeted (e.g., at older children) among other ﬂaws (142). During the 1980s and 1990s, however, a great deal of effort was invested in addressing these design ﬂaws and developing improved and novel approaches. Furthermore, it was found that programs that are effective at reducing undernutrition have a number of common features (102,139,143). These features can be grouped as: who should receive the most attention, when should the target individuals receive this attention, what should the content of the nutrition interventions be, and how should these interventions be delivered, as summarized in Table 5. Programs that are likely to have the most signiﬁcant impact on reducing global malnutrition are those that are targeted at the populations for which inadequate nutrition has its largest effects, namely pregnant women and children under 3 yr of age. It is in these populations and during these ages that nutritional interventions have the greatest potential for beneﬁt. In children, a clear relationship between earlier supplementation and greater improvements in growth per unit of supplement has been documented (144). Effective programs will promote adequate diets for pregnant women. For the newborn, promotion of exclusive breast feeding for newborns through 6 mo of age and partial breast feeding through 2 yr is recommended. Once the child reaches about 6 mo, programs should emphasize the promotion of complementary foods that are of

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Table 5 Characteristics of Programs That Will Effectively Promote Child Growth Who and when What

How

Other

Women, especially when pregnant Young children, less than 2–3 yr of age Adequate dietary intakes during pregnancy Exclusive breast feeding to around 6 mo Partial breast feeding through the second year of life High-quality, locally available complementary foods of high nutrient densities fed with adequate frequency and encouragement Supplementary feeding when necessary Micronutrients, through foods, supplements and/or fortiﬁcation for both pregnant women and young children Built around gaining weight (during pregnancy) and promoting healthy growth of young children Behavior change through communication and dialogue Participant involvement in process and design of interventions Integrated with health services when appropriate Well-managed and adequately staffed Strong local and political commitment Combine with psychosocial stimulation

high quality, particularly in respect to micronutrient density. Ample amounts of these foods should be served by caretakers frequently enough and with a gentle persistence, such that young children consume adequate quantities of the foods, especially during illness. A key conceptual shift is that, in the end, the ultimate objective of nutrition programs is to change behavior. Whether the intervention involves development of a new food, fortiﬁcation of an existing product, or simply educating mothers to feed the foods they already feed more frequently, success can only be achieved if caretakers change their current practices. Another paradigm shift is that nutritional problems and the solutions to these problems are very context speciﬁc. There is not and will unlikely ever be a single “magic bullet” that signiﬁcantly and sustainable improves child growth across a wide variety of settings. Rather, the components of a nutrition-oriented program must be tailored to the particular problems, cultural conditions, and resource constraints of the local context. It should be noted that this is in stark contrast to the promotion of universal recommendations for child feeding that many international organizations still promote. For example, standardized recommendations such as “add two tablespoons of oil to children’s foods” have been widely promoted in the past though such media as UNICEF’s Facts for Life (145). Such recommendations may be appropriate for certain communities or mothers, but in areas where energy and energy density is not the problem, the addition of oil to foods may even be harmful in that it actually decreases the micronutrient densities of the food mixtures. In sum, state-of-the-art approaches to improving young child feeding recognize that it is essential that behavior-change strategies are based on the local needs and conditions of the population and that they take advantage of the knowledge and resources of which

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caretakers can feasibly avail themselves. In addition, these strategies need to be based on well-grounded behavior-change theory, be ﬂexible enough to take into account changing individual participant situations and needs (e.g., seasonality), and have long-term community and national support.

5.1. Manuals and Guides to Assist with Designing Programs A number of manuals have recently become available or are in press that guide the user in how to develop strategies for improving maternal and young child diets. One of the most comprehensive is Designing by Dialogue, produced by the Academy for Educational Development in Washington, DC (146). This manual provides a step-bystep approach to developing a behavior-change strategy that avoids unidirectional proselytizing (i.e., “education”) and builds on bi-directional conversation with local caretakers and populations. Two other manuals have recently been published. The ﬁrst, produced by Save the Children, U.S. utilizes the concept of “positive deviance” to identify behaviors that are being used by poor mothers to raise well-nourished children (147). This approach thus employs a technique that has been identiﬁed as a common element of successful programs in the past, i.e., building on what mothers already “do right” (139) Another key aspect of the positive deviance approach is that it emphasizes the importance of community involvement in identifying the positive deviant families and the behaviors. It has been hypothesized that much of the success with the positive-deviant approach is owing to this community involvement, which causes families and the community to become more empowered to solve, not only the nutritional problems of their children, but other health and well-being problems as well (148). A separate manual has recently been published by Helen Keller International that focuses on increasing the consumption of micronutrient-rich foods (149). Finally, an integrated strategy for improving child feeding in Latin America was developed by the Pan American Health Organization (PAHO). A unique aspect of the PAHO strategy is the inclusion of computer software that will assist with the analysis of local nutrition problems and identiﬁcation of potential solutions.

6. RESEARCH NEEDS AND PRIORITIES Gaps in our understanding of the causes and consequences of malnutrition have been noted throughout this review. Research into a number of these areas would signiﬁcantly improve the design and therefore effectiveness of program aimed at preventing malnutrition in developing countries. There is ample information on the patterns of growth failure in developing countries. There is still a great deal yet unknown about the causes of growth failure. In particular, there is poor understanding of why malnutrition rates and the patterns of stunting and wasting vary so widely across different regions. For example, it has been hypothesized that the signiﬁcantly greater rates of malnutrition seen in Southeast Asia compared to Africa may be owing, in part, to women’s perceived self-efﬁcacy, and how her role in the family and society affect her control over, and abilities related to, child care (150). Future research should consider both underlying and proximate determinants of malnutrition (Fig. 2) and distinguish between stunting and wasting-type growth failure.

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There are numerous additional examples of needed research with each domain that has been examined in this chapter. This review found that there is renewed recognition that malnutrition is a key determinant of child mortality and that adequate young child feeding is an essential element of preventing malnutrition. It was also noted, however, that the manner in which programmers can best improve young child feeding in an efﬁcient, cost-effective, and sustainable manner is still evolving. Speciﬁc examples of research gaps in the area of complementary feeding are therefore listed in Table 9. Research needs more directly related to breast-feeding promotion are available elsewhere. A similarly detailed listing of research topics related to promotion of improved dietary practices of pregnant women should be drawn up. In addition to the more biological and epidemiological-type of research listed in Table 6, more rigorous evaluations of the efﬁciency, effectiveness and costs of programmatic efforts are also desperately needed. There are literally thousands of organizations, both governmental and nongovernmental, that are working throughout the developing world to improve child health and nutrition. Extremely few of the lessons learned through these attempts, however, are documented and made available to the larger international health community. Designers and ﬁnancial backers of these programs are encouraged to invest the relatively small additional resources that are required to rigorously evaluate and document their efforts. Key issues regarding the design and interpretation of such program-based evaluations were recently described by Habicht et al. (151). Wider application and publication of the lessons learned through such evaluations will allow other programmers to use their own resources more effectively.

7. SUMMARY AND CONCLUSIONS In summary, this review has provided an overview of malnutrition in the developing world. The evolution of the various terms that have been used in relation to under nutrition and the perceived causes of this malady over the past century have been described. An in-depth review of the current scientiﬁc knowledge of the causes and determinants of malnutrition was then presented. Through this review, the substantial effects that malnutrition, even in its mild or moderate forms, has on child mortality and impaired cognitive and behavior outcomes were noted. In terms of the causes of malnutrition, there has been a shift away from a belief that preventing infectious disease would necessarily lead to signiﬁcantly lower rates of malnutrition. Rather, it is now very widely recognized that inadequate young child feeding, both in regards to breast feeding and complementary feeding, is perhaps the key determinant of poor child growth in developing countries. It is also increasingly recognized that many of the previous efforts to address malnutrition were poorly designed. Over the past decade or so, more effective interventions that are targeted at the pregnant mother and the very young child and are ﬂexible and situation-speciﬁc, among other attributes, have recently been developed. Over the next decade, it is critical that these new approaches are adequately supported, rigorously evaluated, and further reﬁned so that the scourge of malnutrition can become a historical footnote. The widespread application of these approaches within the context of integrated efforts to improve the socioeconomic and societal status of poor women and families could signiﬁcantly improve the growth and nutritional status

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Table 6 Research Recommendations Related to Complementary Feeding Area Relationship between breast feeding and complementary feeding

Factors affecting intake of complementary foods and total intakes

Macronutrient content of complementary foods

Micronutrient content of complementary foods

Organoleptic characteristics of complementary foods

Feeding behaviors

Food processing

Planning and evaluating programmatic interventions

Adapted from ref. (114).

Examples of speciﬁc research gaps Which factors (e.g. maternal nutritional status) affect the appropriate timing of the introduction of complementary foods? How do various presentations of complementary foods (e.g., liquid vs solid) and methods of serving these foods (e.g., cup vs spoon) affect breast-milk intakes? What is the relationship between energy density, feeding frequency, total daily energy intake, and energy intake from breast milk and complementary foods? What are the causes of poor appetite among children? What are the effects of aggressively feeding children with poor appetites? More information is needed on essential fatty acid requirements of young children. What is the ability of low-protein staple foods (e.g., cassava) to meet protein requirements and what can be done to improve protein content of these foods? Additional information on the absorption and utilization of micronutrients, especially problem nutrients (iron, zinc, calcium, and Vitamin A) from complementary foods is needed. Approaches to improve overall micronutrient content and bioavailability of local diets are needed. Additional information on the viscosity of traditional complementary foods and the impact of varying viscosity on intakes is needed The inﬂuence of other organoleptic characteristics of complementary foods, i.e., ﬂavor, aroma, color, texture, in developing country settings is almost totally undocumented. Additional research on caregiver techniques (e.g., passive/active) and how these affect child intakes. What is the effect of feeding mode (cup, self-feeding, etc.) on intakes? More information is needed on the effects of different food-processing techniques on nutritional value of foods, acceptability, toxicology, etc. Additional strategies for reducing viscosity of foods should be explored. How can current information on nutritional needs of childrenbe adapted to local circumstances? Additional evaluations that assess the efﬁcacy, effectiveness, efﬁciency, and costs of different approaches are needed.

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of young children through the developing world. The economic and social beneﬁts to the global society of signiﬁcantly reducing malnutrition are immense. The ethical reasons for doing so are unquestionable.

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108. Rowland MGM, Cole TJ, Whitehead RG. A quantitative study into the role of infection in determining nutritional status in Gambian village children. Br J Nutr 1977; 37:441–450. 109. Rowland MG, Rowland SG, Cole TJ. Impact of infection on the growth of children from 0 to 2 years in an urban West African community. Am J Clin Nutr 1988; 47:134–138. 110. Lutter CK, Mora JO, Habicht JP, et al. Nutritional supplementation: effects on child stunting because of diarrhea. Am J Clin Nutr 1989; 50:1–8. 111. Briend A, Hasan KH, Aziz KMA, Hoque BA. Are diarrhoea control programmes likely to reduce childhood malnutrition? Observations from rural Bangladesh. Lancet 1989; 2:319–322. 112. Black RE. Would control of childhood infectious diseases reduce malnutrition? Acta Paed Scan (Suppl) 1991; 374:133–140. 113. Schroeder DG, Ramakrishnan U, Martorell R. Nutritional determinants of child growth. In: Nutrition in Developing Countries. Solomons N, Brown K, Caballero B, eds. 114. Brown KH, Dewey K, Allen L. Complementary Feeding of Young Children in Developing Countries: A Review of Current Scientiﬁc Knowledge. Geneva: WHO, 1998. 115. Scariati PD, Grummer-Strawn LM, Fein SB. A longitudinal analysis of infant morbidity and the extent of breastfeeding in the United States. Pediatrics 1997; 99:E5. 116. Feachem RG, Koblinsky MA. Interventions for the control of diarrhoeal diseases among young children: promotion of breast-feeding. Bull WHO 1984; 62:271–291. 117. de Zoysa I, Rea M, Martines J. Why promote breast-feeding in diarrhoeal disease control programmes? Health Policy Plann 1991; 6:371–379. 118. Waterlow JC, Schürch B. Summary of causes and mechanisms of linear growth retardation (stunting). Eur J Clin Nutr 1994; 48:S210. 119. Takahashi E. Secular trend in milk consumption and growth in Japan. Hum Biol 56:427–437. 120. Lee WTK, Leung SSF, Xu YC, Zeng WP, Lau J, Oppenheimer SJ, Cheng JCY. Double-blind, controlled calcium supplementation and bone mineral accretion in children accustomed to a lowcalcium diet. Am J Clin Nutr 1994; 60:744–750. 121. Brown KH, Peerson JM, Allen LH. Effect of zinc supplementation on children’s growth: a metaanalysis of intervention trials. Biblio Nutr Dieta 1998; 54:76–83. 122. Allen LH. The nutrition CRSP: what is marginal malnutrition, and does it affect human function? Nutr Rev 1993; 51:255–267. 123. Huffman SL, Baker J, Shumann MA, Zehner ER. The Case for Promoting Multiple Vitamin/Mineral Supplements for Women of Reproductive Age in Developing Countries. Washington, DC: USAID/ LINKAGES, 1998. 124. Ramakrishnan U, Huffman SL. Multiple micronutrient malnutrition: What can be done? In: Nutrition and Health in Developing Countries. Semba R, Bloem M, eds. Humana, Totowa, NJ. pp. in press. 125. Gershoff SN, McGandy RB, Nondasuta A, Tantiwongse P. Nutrition studies in Thailand: effects of calories, nutrient supplements, and health interventions on growth of preschool Thai village children. Am J Clin Nutr 1988; 48:1214–1218. 126. Liu D-S, Bates CJ, Yin T-A, Wang X-B, Lu C-Q. Nutritional efﬁcacy of a fortiﬁed weaning risk in a rural area near Beijing. Am J Clin Nutr 1993; 57:506–511. 127. Rivera J, et al. Effect of multiple micronutrient supplementation on the growth of young rural Mexican children FASEB J 1996; 10:A245. 128. Thu BD, Schultink W, Dillon D, Gross R, Leswara ND, Khoi HH. Effect of daily and weekly micronutrient supplementation on micronutrient deﬁciencies and growth in young Vietnamese children. Am J Clin Nutr 1999; 69:80–86. 129. Allen KG, Backsstrand J, Stanek EJ, Pelto GH, Chavez A, Molina E, et al. The interactive effects of dietary quality on the growth and attained size of young Mexican children. Am J Clin Nutr 1992; 56:353–364. 130. Torres A, Orav J, Willett W, Chen L. Association between protein intake and 1-y weight and height gains in Bangladeshi children aged 3–11 y. Am J Clin Nutr 1994; 60:448–454. 131. Chernichovsky D, Coate D. The choice of diet for young children and its relation to children’s growth. J Hum Res 1980; 15:255–263. 132. Smith T, Earland J, Bhatia K, Heywood P, Singleton N. Linear growth of children in Papua New Guinea in relation to dietary, environmental and genetic factors. Ecol Food Nutr 1993; 31:1–25. 133. Sigman M, Neumann CG, Baksh M, Bwibo NO, McDonald MA. Relation between nutrition and development in Kenyan toddlers. J Ped 1989; 115:357–364.

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Chapter 17 / Nutrition Transition

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The Nutrition Transition and Its Relationship to Demographic Change Barry M. Popkin

1. INTRODUCTION Scientists have long recognized the importance of the demographic and epidemiological transitions in higher-income countries and more recently have understood that similar sets of broad-based changes are occurring in lower-income countries. What has not been recognized is that concurrent changes are occurring in nutrition with equally important resource allocation implications for many low-income countries. This chapter provides a heuristic framework that accommodates the dynamic nature of nutrition.1 Human diet and nutritional status have undergone a sequence of major shifts among characteristic states, deﬁned as broad patterns of food use and corresponding nutritionrelated disease. Over the last three centuries, the pace of dietary change appears to have accelerated, to varying degrees in different regions of the world. The concept of the nutrition transition focuses on large shifts in diet, especially its structure and overall composition. These dietary changes are reﬂected in nutritional outcomes, such as changes in average stature and body composition. Further, dietary changes are paral-

1There

are two extant theories of change that address key factors that affect and are affected by nutritional change. One relates to the demographic transition—the shift from a pattern of high fertility and high mortality to one of low fertility and low mortality (typical of modern industrialized nations). Even more directly relevant is the concept of the epidemiologic transition, ﬁrst described by Omran (1). The epidemiologic transition describes the shift from a pattern of high prevalence of infectious diseases and malnutrition, resulting from pestilence, famine, and poor environmental sanitation, to a pattern of high prevalence of chronic and degenerative diseases strongly associated with lifestyle. A fourth pattern of delayed degenerative diseases has been more recently formulated (2). Accompanying this progression is a major shift in age-speciﬁc mortality patterns and life expectancy. The concepts of demographic and epidemiologic transition share a focus on the ways in which populations move from one pattern to the next. The framework developed here mirrors these concepts of demographic and disease change. From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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leled by major changes in health status, as well as by major demographic and socioeconomic changes. This chapter uses data from nationwide surveys to present a brief case study of an emerging issue of international importance: the coexistence of the problems of sideby-side under- and overnutrition. In many low-income countries, this rapid transition in diet is creating a situation where undernutrition and overnutrition exist side by side. Thus, in some nations that are still developing, policies to address nutritional problems related to poverty, and problems related to excess, have begun to appear. Such a situation is rapidly developing in China, Brazil, and a number of other higher income South American countries, inter alia. The rapid shift in the structure of diet in many low-income countries does not mean that the thesis posed by Behrman and others that income changes are not improving diet is invalid (3,4). Rather, it is important to note that these researchers, whose primary concern was poverty elimination, focused on improvements in caloric and protein intake and missed many of the more subtle and equally important changes in nutrition that occur with development. This chapter reviews patterns of dietary change that have occurred in the post-World War II period in east Asia and that are emerging in other low-income regions and the former U.S.S.R. to provide some context for a brief discussion of policy issues that either are already being faced by others or will soon become prominent.

2. BACKGROUND: PATTERNS OF THE NUTRITION TRANSITION A summary of changes in nutrition and the major features of each pattern are presented in five broad patterns in Table 1. These patterns are not restricted to particular periods of human history. For convenience, the patterns are outlined in past tense as historical developments; however, “earlier” patterns are not restricted to the periods in which they ﬁrst arose, but continue to characterize certain geographic and socioeconomic subpopulations.

2.1. Pattern 1: Collection of Food This diet was high in carbohydrates and ﬁber and low in fat, especially saturated fat (5,6). In the wild-animal meat consumed, the proportion of fat that was polyunsaturated was signiﬁcantly higher than in modern domesticated-animal meat (7). These early humans were relatively tall, but had short life expectancies (some speculate that the beneﬁts of a good diet were offset by high levels of infectious disease (7).

2.2. Pattern 2: Famine The diet became much less varied and subject to larger variations and episodic periods of extreme hunger. These dietary changes are hypothesized to be associated with nutritional stress and a reduction in stature (estimated by some at about 4 inches [8,9]). During the later phases of this pattern, social stratiﬁcation began to appear, and dietary variation according to gender and social status increased (10). The pattern of famine (as with each of the patterns) was manifested heterogeneously over time and space. Some civilizations were more successful than others in alleviating famine and chronic hunger, at least for their more privileged citizens (11). This pattern of famine accompanied the development of agriculture (the “first agricultural revolution”); however, the causal relationship between these developments is widely debated.

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2.3. Pattern 3: Receding Famine The consumption of fruits and vegetables and animal protein increased, and starchy staples became less important in the diet. Many earlier civilizations did make great progress in reducing chronic hunger and famines, but it is only in the last third of this millennium that these changes became widespread and led to marked shifts in diet. However, famines continued well into the 18th century in portions of Europe and still continue in some regions of the world. Spatially, famine has become limited mainly to sub-Saharan and southern Africa over the past decade.

2.4. Pattern 4: Degenerative Disease A diet high in total fat, cholesterol, sugar, and other reﬁned carbohydrates and low in polyunsaturated fatty acids and ﬁber, often accompanying increasingly sedentary life, is characteristic of most high-income societies (and increasingly of portions of the population in lower-income societies), resulting in increased prevalence of obesity and contributing to the degenerative diseases of Omran’s ﬁnal epidemiologic stage (1).

2.5. Pattern 5: Behavioral Change Consumption patterns resemble more the pattern of collecting food than that of the pattern of degenerative disease. Increased intake of fruits and vegetables, and carbohydrates, and reduced intake of processed foods, meat, and dairy products are some aspects of this pattern. This “new” dietary pattern appears to be emerging as a result of changes in diet evidently associated with the desire to prevent or delay degenerative diseases and prolong health. Whether these changes, instituted in some countries by consumers and in others by a combination of government policy and consumer behavior, will constitute a large-scale transition in diet structure and body composition remains to be seen (12–15). If they do occur, they may be very important in our goal of enhancing successful aging, that is, the period between the age at which a person suffers permanent inﬁrmity and the age at death (16,17).

3. ECONOMIC CHANGE AND THE NUTRITION TRANSITION A major change in economic structure associated with the nutrition transition is the shift from a pre-industrial agrarian economy to industrialization. This transformation then accelerates; the service sector grows rapidly, industrial production is dominated by capital-intensive processes, and time-allocation patterns change dramatically. Associated socioeconomic changes especially important in the nutrition transition are changes in the role of women (especially with respect to patterns of time allocation), in income patterns, in household food preparation technology, in food production and processing technology, and in family and household composition (18). Some of the effects of income changes are reviewed to put in context much of the recent debate on the question “Does income matter?” Only since the Industrial Revolution have widespread variations in income and large income discrepancies among segments of the population became important, and only with these developments has diet become consistently related to income. The patterns of receding famine and of degenerative disease are characterized by restructuring of the diet as income increases. The rapidity and the nature of this restructuring depends on many factors. With increasing income, the proportion of energy in the diet from various sources changes in the following ways:

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Table 1 The Nutrition Transition Pattern 1: Transition Proﬁle Collecting food

Pattern 2: Famine

Pattern 3: Receding famine

Pattern 4: Degenerative disease

Pattern 5: Behavioral change

1. Nutrition Proﬁle Diet Plants, low-fat wild animals; varied diet

Cereals predominant; diet less varied

Fewer starchy staples; more fruits, vegetables, animal protein; low variety continues Continued MCH nutrition problems; many deﬁciencies disappear; weaning diseases emerge; stature grows

More fat (especially from animal products), sugar and processed foods; less ﬁber Obesity; problems for elderly (bone health, etc.); many disabling conditions

Less fat and processing: increased carbohydrates, fruits, and vegetables

Nutritional status

Robust, lean, few nutritional deﬁciencies

Children, women suffer most from low fat intake; nutritional deﬁciency diseases emerge; stature declines

Hunter-gathers

Agriculture, animal husbandry, homemaking begin; shift to monocultures

Household production

Primitive; onset of ﬁre

Income and assets

Subsistence; primitive stone tools

Labor-intensive, primitive technology begins (clay cooking vessels) Subsistence; few tools

Reduced body-fat levels and obesity; improved bone health

2. Economy Second agricultural Fewer jobs with heavy Service sector revolution (crop rotation, physical activity; service mechanization, industrial fertilizer); Industrial sector and mechanization; robotization dominate; Revolution; women join household technology leisure exercise grows to labor force revolution offset sedentary jobs Primitive water systems; Household technology Food-preparation cost falls clay stoves; cooking mechanizes and signiﬁcantly with technology advance proliferates technological change Rapid growth in income and income disparities; technology proliferation

Income growth slows; home and leisure technologies increase

Popkin

Increasing income disparity; agricultural tools; industrialization rises

Age of Malthus; high natural fertility, low life expectancy, high infant and maternal mortality Epidemics; endemic disease (plague, smallpox, polio, tuberculosis); deﬁciency disease begins; starving common Young; very few elderly

Morbidity

Much infectious disease; no epidemics

Age structure

Young population

Residency patterns

Rural, low density

Rural; a few small, crowded cities

Nonexistent

Food storage begins

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3. Demographic Proﬁle Mortality/fertility Low fertility, high mortality, low life expectancy

Slow mortality decline, Life expectancy hits unique Life expectancy extends later rapid; fertility static, levels (60s–70s); huge to 70s, 80s; disabilitythen declines; small, fertility declines and free period increases cumulative population ﬂuctuations (e.g., postwar growth, later explodes baby boom) Tuberculosis, smallpox, Chronic disease related to Increased health promotion infection, parasitic diet, pollution (heart (preventive and disease, polio, weaning disease, cancer); therapeutic); rapid disease (diarrhea, infectious disease decline in coronary heart retarded growth) declines disease, slower change expand, later decline in age-speciﬁc cancer proﬁle Chieﬂy young; shift to Rapid fertility decline; Increasing proportion of older population elderly proportion elderly >75 begins increases rapidly Chieﬂy rural; move to Urban population disperses; Lower density cities cities increases; rural green space reduced rejuvenate; urbanization international migration of rural areas encircling begins; megacities cities increases develop

4. Food Processing Storage process (drying, salting); canning and processing technologies; increased food reﬁning and milling

Numerous foodtransforming technologies

Technologies create foods and foodconstituent substitutes (e.g., macronutrient substitutes)

Reprinted with permission from ref. (47).

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• • • •

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Unseparated animal fat and animal protein increase Unseparated vegetable fat and vegetable protein decrease Carbohydrate decreases Sugar and separated edible fat increase

The well-known relationship based mainly on cross-country comparisons, but buttressed with a number of within country time series studies, is summarized in Fig. 1 (19). The responsiveness of dietary total energy, total and saturated fat, and other macro- and micronutrients to income change depends on the nature of the demand for particular foods as well as overall eating patterns. For example, in the Philippines, the coconut palm is a major source of cooking oil, and income increases are associated with increased away-from-home consumption of foods that are frequently fried; thus, saturated fat and total fat consumption are highly responsive to income increases, particularly for income increases accruing to women (20). Similarly, in China, pork consumption is highly responsive to increases in income, which thus result in large increases in the proportion of energy from fat (21,22). In contrast, where income increases are spent on more elaborate packaging and processing or higher quality of speciﬁc foods, rather than larger quantities of food or shifts in the types of foods, changes in income will have little effect on dietary structure. Another apparent relationship between income and diet is that as income increases (beyond the point where total food energy needs are met), people spend more per food item (23), partly to obtain higher quality. As many have shown, food demand is much more price- and income-elastic among the poor than among higher income groups (24,25). Changes in diet with increased income also relate to the reduced time needed to consume higher quality and higher priced goods that have undergone more processing before purchase (26). Much controversy surrounds study of the process by which increases in income lead to increased energy intake. Clearly, changes in income per capita at the national level will not necessarily translate into short-term improvements in diet. Variations in the distribution of income, how it is spent, and other factors mean that improved national income will not necessarily translate into improved purchasing power for the poor or, in turn, improved diets for the most needy households. Behrman and his colleagues argue that increased income does not affect quantity of diet (3,4,27); their analyses focus primarily on short-term effects of income on energy and protein intake. Behrman et al. (4) summarize changes associated with income increases that improve the quality of the diet, though not necessarily by increasing its protein or energy content. These include a shift from broken and dirtier grains to whole and cleaned grains, increased processing of the product before it is purchased (a remarkable example is the effect of the introduction of portable rice milling machinery in Indonesia), a shift from consumption of root crops to cereals as the staple, a switch from inferior to superior grains (e.g., corn to rice), and an increase in the variety of foods consumed. For lower-income countries, a crucial dimension of the relationship between socioeconomic status (SES) and nutrition is the distribution of chronic disease risk factors by income group.2 In particular, a recent World Bank study on adult health in Brazil (34) indicates that where income constraints among the poor are not too severe, many risk factors for cardiovascular disease will likely be greater among the poor than among the rich. Monteiro et al. (35) use 1996 data from Brazil to show that there is

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Fig. 1. Structure of the diet and income (country-level sources of energy, 1962). Reproduced with permission from ref. (19).

an independent effect of economic variables on the risk of female obesity only in rural areas (the poorer the woman, the lower the risk of overweight). In the urban context, income does not matter and either formal education or access to information are each independently and inversely related to overweight (35).

4. DEMOGRAPHIC CHANGE AND THE NUTRITION TRANSITION Urbanization is the major demographic force linked with the nutrition transition, but it is not the only important population factor in terms of effects on diet. Recent decades have seen remarkable shifts in fertility and mortality patterns and, with them, a shift toward an older age distribution in all regions of the world. In many lower income countries, rapid fertility declines have led to larger increases in the proportion of persons aged over 65 than in higher-income countries (36). The inﬂuence of such 2Economists have given a great deal of attention to another dimension of economic change, namely, the transition from a subsistence to a cash economy. The most impressive body of knowledge on the dietary effects of commercialization comes from six large case studies conducted by the International Food Policy Research Institute (IFPRI) in the Philippines, Guatemala, The Gambia, Rwanda, Kenya, and Malawi. These studies indicate that commercialization substantially helped to alleviate hunger; however, increased income alone did not solve the problems of malnutrition (17,28–33). In some cases (e.g., The Gambia), income increases were converted directly into food consumption; in others, particularly in environments where food markets were undeveloped, such as Rwanda, diet was still more inﬂuenced by the subsistence economy than by cash income.

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a shift in age distribution on diet is not clear. However, physical and psychological difﬁculties associated with aging are expected to have major effects on dietary patterns. In addition, signiﬁcant cohort effects may change overall dietary patterns.

4.1. Key Dimensions of World Urbanization Several major demographic shifts began after World War II; they continue unabated and have even accelerated in some regions. One is the vast increase in the proportion of persons who reside in urban areas. A second is urban agglomeration. A third is the shift of poverty toward the urban areas, particularly toward squatter and slum areas.

4.2. Proportion Living in Cities Urban growth was relatively modest before the Industrial Revolution. Rapid urban development ﬁrst occurred in the higher-income countries; now, lower-income countries are undergoing even more rapid urbanization. In Table 2, United Nations population research is used to show that the higher-income world is comprised predominantly of urban residents today whereas that is not the case for the less-developed and poorest, least-developed countries. Nevertheless, by 2025, urban residency will be the common form of residence throughout all but the poorest African countries. The rates of population growth are far greater in urban than rural areas because of the continuation of long-term patterns of in-migration. Table 3 shows that these patterns accelerate in the next century.

4.3. Concentrated Population Growth Urban growth, particularly in lower-income countries, has been skewed toward a few larger cities, often called urban conglomerates. As is seen in Table 4, the most explosive growth of these mega-cities is in Asia.

4.4. Shift in the Proportion of Poor Living in Cities Concomitant with increased concentration of the population in urban areas is a dramatic shift in the proportion of poor people living in cities. In absolute and relative terms, the majority of the poor of the lower-income world live in cities. At the same time, a disproportionate share of the higher-income middle- and upper-income population also lives in urban areas. One of the most inﬂuential changes has been in the spatial distribution of population. Rapid growth in urban populations profoundly affects diet (38). Compared with rural diets, urban diets show trends toward increased consumption of grains, which are felt to be more desirable or superior (e.g., rice or wheat, rather than corn or millet), more milled and polished grains (e.g., rice, wheat), food higher in fat, more animal products, more sugar, more food prepared away from the home, more processed foods, and reduced breast feeding and earlier supplementation of infant diets. Some of the key factors responsible for the urban dietary patterns are improved transportation and food-distribution systems, greater penetration of commercial food-sector marketing practices, increased heterogeneity of diet, changes toward occupational patterns less compatible with home food production and consumption, changes in household composition and structure, and differences in disease and health service availability patterns.

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Table 2 Urban Population, 1970, 1994, and 2025 Urban population (Millions) Urban share (Percentage) Region

1970

1994

2025

1970

1994

2025

World Less developed regions Least developed countries More developed regions

1353 1676 1138 1677

2521 1653 1122 1868

5065 4025 1506 1040

36.6 25.1 12.6 67.5

44.8 37.0 21.9 74.7

61.1 57.0 43.5 84.0

Adapted with permission from ref. (37).

Table 3 Average Annual Growth Rate of Urban and Rural Population, Less Developed Regions Percentage Region Less developed region Urban Rural Africa Urban Rural Asia Urban Rural Latin America Urban Rural Oceania Urban Rural

1965–1970

1990–1995

2020–2025

3.58 2.18

3.51 0.96

2.33 –0.28

4.64 1.98

4.38 2.03

3.34 0.72

3.28 2.34

3.68 0.81

2.31 –0.57

3.97 0.81

2.60 –0.20

1.26 –0.61

7.26 1.62

3.13 1.90

3.32 0.22

Table 4 Megacities, 1970–2015 Region World Less developed region Africa Asia Latin America More developed regions

1970

1994

2000

2015

11 15 10 12 13 16

22 16 12 10 14 16

25 19 12 12 15 16

33 27 13 19 15 16

Megacities, cities with eight million or more residents.

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In one recent study, it was shown that the effect of urbanization on diet led to a signiﬁcant increase in the consumption of edible oils and sweeteners, even in the very lowest income countries (19). They used national food balance data for most countries along with urbanization and income patterns. A cross-national regression model was used to examine the effect of rapid urbanization on the structure of diet shown in Fig. 1. At lower-income levels, according to the regression model, urbanization can more than double the amount of sweeteners in the diet and increases considerably the total fat consumed. The model conﬁrms previous observations that people living in urban areas consume diets distinct from those of their rural counterparts. The potential impact of urbanization in ﬂattening the income-sweetener relationship deserves further analysis; however, it is clear that the increased urbanization of lower-income nations is accelerating the shift to increased consumption of sweeteners and fats (19). An important dimension of urban growth is its associated pattern of migration. Migration from rural areas to cities (and to a lesser extent from small to larger cities) and international migration have affected diet profoundly. For example, populations of Samoans who moved to San Francisco, Polynesians and Maori who moved to New Zealand, Japanese who moved to the United States, and Yemenite Jews who moved to Israel all showed large changes in diet, followed by large increases in diet-related chronic diseases (39–40). Similarly, migration within countries is believed to affect the diets of the migrants and the diets of their communities of origin and destination; however, the causes and dimensions of such dietary changes are poorly understood. Lower-income countries, with much larger differences in dietary patterns between urban and rural populations, are experiencing the most rapid changes in population distribution now. Migrants to urban areas tend to adopt the urban dietary pattern, though the timing of such changes is unstudied (Popkin and Bisgrove review this subject (38). There are clearly other crucial determinants of the nutrition transition. These include the shifting role and impact of the food industry, household technology, women’s roles, and knowledge and attitudes related to food.

5. THE NATURE AND PACE OF THE NUTRITION TRANSITION The interaction among these epidemiologic, socioeconomic, and demographic changes determines the nature and pace of nutritional change. This section outlines patterns of recent dietary change in several countries.3 We begin with countries in East Asia that have undergone major economic change in the last 40 years.

3Unfortunately,

most low-income countries and many higher-income ones have no national survey systems for collecting dietary intake data. Rather than relying on imperfect food balance sheets, which may mismeasure trends in dietary change, we present information for countries where household survey data are available. This is because there is a strong possibility that some of the trends we discuss may be hidden by food balance sheets, which omit changes in food processing and preparation at the household and food-market level. Research shows that on an aggregate level, fat trends derived from these data diverge signiﬁcantly from aggregate statistics derived from individual food consumption data (43–45).

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5.1. Japanese and Korean Accelerated Model Energy intake in Japan increased during the post-World War II period slowly toward a peak around 1970–1975, whereas intake of animal products and fat increased continuously from 1946–1987.4 During this period, daily per capita consumption of animal products increased by 257 g, daily per capita total fat consumption increased 341%, and the proportion of energy from fat increased from 8.7% to 24.8% (46,47). Fat intake in Japan is still only about two-thirds the U.S. level, and the Japanese diet includes much more marine ﬁsh; average consumption of omega-3 fatty acids (thought to be protective against coronary heart disease) in Japan is more than twice that in the U.S. (48). However, older Japanese consume much more marine ﬁsh and much less of the foods high in saturated fat than do younger Japanese, and overall consumption of marine ﬁsh is decreasing (49). Thus, as the population ages, the younger cohort whose diet resembles the “Western diet” may begin to experience the associated health problems. South Korea, another Asian country that has achieved remarkably rapid economic growth during the last three or four decades, appears to be experiencing a change in dietary structure similar to that of Japan. Trends in the South Korean diet for the last three decades include a marked decline in consumption of grains and a large increase in consumption of ﬁsh, meat, and milk (47,50). Increased consumption of animal products, particularly in the last decade, is reﬂected in an increasing proportion of energy from animal fat, which rose from about 2% in 1961 to 8% in 1988. By the late 1980s, total fat intake as a proportion of energy in Korea had reached only 15%; Japan reached this level in 1965 and increased to 25% of energy from fat by 1987. The South Korean diet might be expected to continue changing rapidly in a similar manner, resulting in a transition in disease patterns similar to that experienced by Japan.

5.2. Low-Income Countries with Rapid Income Increases: The Case of China5 During the 1980s, real income in China has more than doubled in urban areas and tripled in rural areas. In China, energy availability increased dramatically from 1961–1988; since the 1980–1984 period, the main change has been in dietary structure, including increases in intake of total fat and animal fat. These effects are ampliﬁed in certain subpopulations; for children (aged 2–6) and adults (aged 20–45), increased income is associated with a marked increase in the proportion of energy from fat and from animal fat, and in adult obesity (22).6 Coronary heart disease and its precursors, high serum cholesterol levels and hypertension, have also increased in China, particularly in the subpopulations that have changed their diets most rapidly (51). 4The

equivalent set of changes occurred in the United States, but close to a century ago (44,45). 5Other countries that have experienced equally impressive gains in reduced infant mortality and malnutrition and have not experienced major economic change, namely Sri Lanka, Kerala (a state of India), and Cuba have achieved these gains without undergoing the nutrition transition experienced by China. 6 These data come from the 1989 panel of the China Health and Nutrition Survey, a longitudinal nationwide survey (see ref. 22 for a review of these data).

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Fig. 2. Changes in Food Consumption: Annual Intake of Selected Foods, Soviet Union, 1950–1989. Reproduced with permission from ref. (52).

5.3. Degenerative Dietary and Epidemiologic Transition with Limited or No Economic Improvement Prior to the current economic adjustment period, Eastern European countries and the former Soviet Union consumed a diet with over 25% of energy from animal fat. This high-saturated fat diet is thought to be one of the causes of Russia’s pattern of high obesity and corresponding high cardiovascular mortality rate—the highest in the world. In the past two decades in the U.S.S.R., consumption of cereals and starchy roots (mainly potatoes) declined greatly, and consumption of sugar and red meat increased (Fig. 2). For added detail on the nutrition situation in Russia, see Popkin et al. (52,53). This Russian diet was found among all social classes. In 1991, the poor in Russia (the bottom 12% of the income distribution, or about 18 million people) consumed about 2121 kilocalories per capita daily, with about 28% of energy from meat and dairy sources as shown in Table 5. In the more recent reform period, price subsidies on meat and dairy products were removed and there has been a marked shift in the proportion of energy from fat and a smaller shift in the proportion of energy from protein (54).

5.4. Other Low-Income Countries The changes in diet noted in China and Korea are also seen in many Central and South American countries, particularly in countries where income increases have been greatest, such as Chile, Brazil, Colombia, and Argentina, and in Malaysia. For example, Malaysia has experienced slower and more moderate economic progress than China,

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Table 5 Food Consumption of the Poor in the Russian Federation, 2nd Quarter, 1991a,b At home consumption (kg/cap/yr) 1. Bread products 2. Potatoes 3. Vegetables 4. Melons 5. Fruits, grapes 6. Sugar and confectioneries 7. Meat and meat products 8. Milk amd milk products 9. Eggs 10. Fish amd ﬁsh products 11. Vegetable oil 12. Margarine Total aPoor

Away from home (kg/cap/yr)

Calorie intake (per kcal/d)

98.76 107.40 39.24 0.36

3.67 3.89 1.44

874 179 26

21.12 38.16 296.40 147.96 7.44 2.16 1.68

0.78 1.40 10.82 0.03 0.28 0.09 0.06

237 229 367 48 16 54 33 2112

households have a monthly income below 150 rubles per capita or the poorest 12%. from ref. (53a). (n = 60,000.)

bAdapted

but its income level is much higher and it is at a higher current level of obesity (55,56). Its diet has shifted markedly in the 1980s so that over 25% of the energy is now derived from fat. Brazil and Chile are two of the other countries that have moved far along in the transformations of their diets (57). In all other Latin American and Caribbean countries, all Asian countries, and most African and Middle Eastern countries, the urban populations have begun to consume this diet as well. Thus, diseases of afﬂuence, often those associated with higher-fat and lower-ﬁber diets, have begun to appear in these populations. Moreover, with increased economic development, chronic-disease risk factors are likely to increase disproportionately among the lower-income populations (35). For example, elsewhere we present evidence for urban Brazil that showed a negative correlation between socioeconomic factors and obesity (35).

6. DISCUSSION An important aspect of the nutrition transition concept lies in its ability to help us understand the manner in which modern diets of large segments of the population of many developing countries seem to be converging on a pattern of high saturated fat, sugar, and reﬁned foods and low ﬁber, while other segments of the population experience hunger and undernutrition. Often termed the “Western diet,” this dietary pattern is felt by many to be associated with high levels of chronic and degenerative diseases and with reduced disability-free time (58,59). Our purpose is not just to understand the dietary and health changes taking place, but also to begin to focus attention on deﬁning the program and policy changes that could redirect the nutrition transition in many regions of the world. The diet of the Chinese is rapidly changing to one similar to the typical high-fat, highsugar diet of the West. As income continues to increase, we expect that the percentage

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of energy from fat and the proportion of meat in the diet will increase unless policies are adopted to discourage this pattern. Cardiovascular researchers in China report that among Beijing women and Beijing urban men, over 25% of the adults they study are classiﬁed as obese according to international standards (60). In the China data presented here, less than 10% of the sample fell in this obesity category (body mass index; BMI >25). At the same time, portions of the population show indications of undernutrition. Among adults in the 1989 China Health and Nutrition Survey, over 8% had inadequate body fat (BMI <18.5). Among children aged 1–6, one-third were stunted in stature, and about 8% had weight-for-height Z-scores so low as to indicate current acute malnutrition.7 Food and nutrition planners in China are acutely aware of these patterns of coexisting excess and deﬁcit diet and of the trend toward a diet conducive to degenerative disease, particularly in urban areas (21). A large-scale survey of diet and cancer carried out in China has provided important descriptive statistics on the possibilities of many chronic diseases related to this high-fat diet. Similarly, more sophisticated cardiovascular research in China has demonstrated that hypertension and stroke are now important health problems (60). The data presented here in combination with these cardiovascular research results indicate that cardiovascular disease can be expected to become a problem in the future, given current trends. In China, the concern for employment generation and production of protein have overshadowed an understanding of the contribution of consumption of pork and other animal and saturated fat products to increased fat intake (61). It will take a concerted effort for policymakers to reverse this agenda and to respond to nutritional concerns. Food and nutrition planners have proposed that the Chinese government change current food policies that focus on increased production of pork and other similar animal products for generating employment and income (21). Focusing instead on health concerns, nutrition planners emphasize the need to encourage consumption of soybeans and other healthier, lower-fat products. In Brazil, a country that the World Bank feels is facing a similar pattern of nutritional problems, the emphasis is on the need to consider other preventive and low-cost strategies to deal with the concentration of obesity and hypertension among the poor. The encouragement of exercise is one of the alternatives proposed (34). Many other macroeconomic mechanisms, including price controls, could be used by governments to shift the structure of the diet in countries like China. However, decades of ﬁghting poverty and of working to increase fat and animal consumption as one aspect of this attack builds up a strong body of programs and policies and a bureaucracy trained to encourage such activities. There are many examples where hunger prevention conﬂicts with addressing the shift to the Western diet. The hunger prevention programs in the United States provide examples of programs designed to provide a basic balanced diet to meet the needs of the undernourished as deﬁned decades ago and reﬁned over time, with minimal consideration of such problems as obesity, hypertension, and high cholesterol (62,63). For instance, although we have long been aware of problems with the diets of children and adolescents, including their atherogenic nature (64), the National School Lunch 7The

equivalent value for Sri Lanka in 1986 was 10% and it would be double that for Bangladesh or India.

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and Breakfast Programs set acceptable ranges for a wide range of nutrients, but long ignored and to some extent still ignore the problems of excess sodium, cholesterol, and fat (particularly animal and other saturated fats) and lack of ﬁber in the diet. This failure has come despite more than a decade of discussion of these issues and our understanding that degenerative diseases related to the high-fat, low-ﬁber diet appear to be a greater problem among the poor. One must go to Scandavia and Mauritius to ﬁnd countries that have attempted systematically to deal with the transition’s negative effects. The example of Norway demonstrates the difﬁculty of producing major changes in the structure of the diet (12). Over a decade of very active food and nutrition policy implementation in Norway has included extensive agricultural, health, and nutrition education, and regulatory sector efforts to reduce saturated fat intake. These policies resulted in a decrease in the proportion of total and animal fat in the national diet. In lower-income countries, the most positive case is that for Mauritius. This small island republic in the Indian Ocean found such a high level of cardiovascular disease as part of an adult health survey conducted in 1987 that it launched a broad comprehensive health promotion program. They used the mass media, price policy, other legislative and ﬁscal measures, and widespread education activity in the community, workplace, and schools. The results were remarkable: hypertension was reduced considerably, cigarette smoking in men and women declined, heavy alcohol use declined, mean serum cholesterol decreased, and there was increased activity (65,66). Obesity levels continued to increase and there was little change in the rate of glucose intolerance. The health and education sectors have also addressed these concerns, and changes in their activities could contribute to efforts to change dietary patterns. In China, an increasing proportion of health spending has gone towards hospitals and treatment costs (51), rather than prevention, and public information and school education efforts do not appear to emphasize prevention. This overemphasis on cure, coupled with improvements in treatment that reduce the case-fatality rate for many important degenerative diseases, particularly cardiovascular-related conditions, will only exacerbate the impact of these chronic diseases on Chinese society. Certainly, the health and education sectors must play an important part in any effort to understand and change eating patterns and nutritional status, and primary prevention must be emphasized as an important activity for the health sector. Implementation of such a preventive strategy may have important consequences for health care. Improved nutrition can lengthen the life span and the period of disabilityfree, healthful living (16,17). Policies to improve diets thus appear to be an important way to delay the onset of disabling conditions, reducing the relative costs of health care. It is important to understand the spatial, economic, and other factors that determine the distribution of diet types among a society’s population. The Chinese experience provides an example of a population where problems of dietary excess and resulting degenerative diseases coexist with problems of dietary deﬁcit and malnutrition. Development of food and nutrition and health policies for countries where problems of dietary excess and deﬁcit exist side by side represents a new and pressing agenda. In such countries, the prevailing policies to promote agricultural and health change to address problems of deﬁcit are quite different from those needed to address problems of excess.

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ACKNOWLEDGMENTS Preparation of this article was supported in part by grants from the U.S. National Institutes of Health (R01-HD30880). The author thanks the following staff of the Carolina Population Center, University of North Carolina at Chapel Hill: Tom Swasey for his work on the graphics, Lynn Igoe for editorial assistance, and Frances Dancy for administrative assistance. The author also credits collaborators on the China Health and Nutrition Survey, in particular Drs. Keyou Ge and Fengying Zhai, Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine; and on the Russian research, Alexander Baturin, Russian Institute of Nutrition, Academy of Medical Sciences.

REFERENCES 1. Omran AR. The epidemiologic transition: A theory of the epidemiology of population change. Milbank Mem Fund Q 1971; 49:509–538. 2. Olshansky SJ, Ault AB. The fourth stage of the epidemiologic transition: the age of delayed degenerative diseases. Milbank Q 1986; 64:355–390. 3. Behrman JR, Wolfe BL. More evidence on nutrition demand: income seems overrated and women’s schooling underemphasized. J Dev Econ 1984; 14:105–128. 4. Behrman JR, Deolalikar AB, Wolfe BL. Nutrients: Impacts and determinants. World Bank Econ Rev 1988; 2:299–320. 5. Harris DR. The prehistory of human subsistence: a speculative outline. In: Food, Nutrition and Evolution: Food as an Environmental Factor in the Genesis of Human Variability. Kretchmer N, Walcher DN, eds., New York: Masson, 1981 pp. 15–39. 6. Truswell AS. Diet and nutrition of hunter-gathers. Health and diseases in tribal societies. Ciba Foundation Symposium 149. Amsterdam: Elsevier, 1977. 7. Eaton SB, Shostak M, Konner M. The paleolithic prescription: a program of diet and exercise and a design for living. New York: Harper and Row, 1988. 8. Eaton SB, Konner M. Paleolithic nutrition: A consideration on its nature and current implications. N Engl J Med 1985; 312:283–289. 9. Vargas LA. Old and new transitions and nutrition in Mexico. In: Disease in Populations in Transition: Anthropological and Epidemiological Perspectives. (Swedlund AC, Armelagos GJ, eds., New York: Bergin and Garvey, 1990 pp. 145–160. 10. Gordon KD. Evolutionary perspectives on human diet. In: Nutritional Anthropology. Johnston FE, ed. New York: Liss, 1987 pp. 3–39. 11. Newman LF, Crossgrove W, Kates RW, Matthews R, Millman S. Hunger in History: Food Shortage, Poverty, and Deprivation. Cambridge, MA: Blackwell, 1990. 12. Milio N. Nutrition policy for food-rich countries: a strategic analysis. Baltimore: The Johns Hopkins University Press, 1990. 13. Popkin BM, Haines PS, Reidy KC. Food consumption of the U.S. women: patterns and determinants between 1977 and 1985. Am J Clin Nutr 1989;49:1307–1319. 14. Popkin BM, Haines PS, Patterson R. Dietary changes among older Americans, 1977–1987. Am J Clin Nutr 1992; 55:823–830. 15. Popkin BM, Siega-Riz AM, Haines PS. A comparison of dietary trends between racial and socioeconomic groups in the United States. N Engl J Med 1996; 335:716–720. 16. Crimmins, EM, Saito Y, Ingegneri D. Changes in life expectancy and disability-free life expectancy in the United States. Popul Devel Rev 1989; 15:235–267. 17. Manton KG, Soldo BJ. Dynamics of health changes in the oldest old: new perspective and evidence. Milbank Mem Fund Q Health Soc 1985; 63:206–285. 18. McGuire J, Popkin BM. Beating the zero sum game: Women and nutrition in the Third World. Food Nutr Bull 1989; 11:38–63, 1989; 12:3–11. 19. Drewnowski A, Popkin BM. The nutrition transition: new trends in the global diet. Nutr Rev 1997; 55: 31–43.

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20. Bisgrove EZ. Work and income as determinants of urban Filipino women’s nutrient intake from commercially prepared at home prepared foods. PhD dissertation, University of North Carolina at Chapel Hill, 1991. 21. Chen C. Dietary guidelines for food and agricultural planning in China. In: Proceedings of the International Symposium on Food, Nutrition and Social Economic Development. Beijing: Chinese Academy of Preventive Medicine, 1991. 22. Popkin BM, Ge K, Zhai F, Guo X, Ma H, Zohoori N. The nutrition transition in China: a crosssectional analysis. Eur J Clin Nutr 1993; 47:333–346. 23. Chaudri R, Timmer CP. The impact of changing afﬂuence on diet and demand patterns for agricultural commodities. World Bank Staff Working Papers 785. Washington DC: World Bank, 1986. 24. Alderman H. New research on poverty and malnutrition: what are the implications for research and policy? In: Including the Poor: Proceedings of a Symposium Organized by the World Bank and the International Food Policy Research Institute. Lipton M, Van der Gaag J, eds. World Bank Regional and Sectoral Studies. Washington, DC: World Bank, 1992. 25. Timmer CP, Falcon WP, Pearson SR. Food Policy Analysis. Baltimore: Johns Hopkins University Press for the World Bank, 1984. 26. Mincer J. Market prices, opportunity costs, and income effects. In: Measurement in Economics: Studies in Mathematical Economics and Econometrics in Memory of Yehuda Grunfeld. Christ CF, Friedman M, Goodman LA, Griliches Z, Harberger AC, Liviatan N, et al., eds. Standord, CA: Stanford University Press, 1963. 27. Behrman JR, Kenan WR. Nutrition and Incomes: Tightly Wedded or Loosely Meshed? Pew/Cornell Lecture Series on Food and Nutrition Policy. Ithaca, NY: Cornell Food and Nutrition Policy Program, Division of Nutritional Sciences, Cornell University, 1988. 28. Bouis HE, Haddad LJ. Effects of agricultural commercialization on land tenure, household resource allocation, and nutrition in the Philippines. Research Report 79. Washington, DC: International Food Policy Research Institute in collaboration with the Research Institute for Mindanao Culture, 1990. 29. Kennedy ET. The effects of sugarcane production on food security, health and nutrition in Kenya: a longitudinal analysis. Research Report 78. Washington, DC: International Food Policy Research Institute, 1989. 30. von Braun J. The importance of non-agricultural income sources for the rural poor in Africa and implications for food and nutrition policy. Ithaca, NY: Pew/Cornell Lecture Series on Food and Nutrition Policy. Cornell University, 1989. 31. von Braun J, Hotchkiss D, Immink M. Nontraditional export crops in Guatemala: effects on production, income, and nutrition. Research Report 73. Washington DC: International Food Policy Research Institute, in collaboration with the Institute of Nutrition of Central America and Panama, 1989a. 32. von Braun J, Puetz D, Webb P. Irrigation technology and commercialization of rice in the Gambia: effects on income and nutrition. Research Report 75. Washington DC: International Food Policy Research Institute, 1989b. 33. von Braun J, de Haen H, Blanken J. Commercialization of agriculture under population pressure: effects on production, consumption, and nutrition in Rwanda. Research Report 85. Washington DC: International Food Policy Research Institute, 1991. 34. Briscoe J. Brazil: The new challenge of adult health. A World Bank country study. Washington DC: The World Bank, 1990. 35. Monteiro CA, D’ABenicio MH, Popkin BM. Economic and cultural-educational predictors of overweight in urban and rural Brazilian women. Rev Brasilian Nutr Clinical 2000; 15:253–260. 36. Jamison DT, Mosley WH, Measham AR, Bobadilla JL, eds. Disease control priorities in developing countries. New York: Oxford University Press for the World Bank, 1993. 37. United Nations. Department for Economic and Social Information. World Urbanization Prospects: The 1994 Revision. ST/ESA/SER.A/150. New York: United Nations, 1995, Table 11, p. 20. (UN is author of original data.) 37a. United Nations. Department for Economic and Social Information. World Urbanization Prospects: The 1994 Revision. ST/ESA/SER.A/150. New York: United Nations; urban ﬁgures from Table 16, p. 27; rural ﬁgures from Table 19, p. 29. (UN is author of original data.) 37b. United Nations. Department for Economic and Social Information. World Urbanization Prospects: The 1994 Revision. ST/ESA/SER.A/150. New York: United Nations, Table 2, p. 6. (UN is author of original data.)

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38. Popkin BM, Bisgrove EZ. Urbanization and nutrition in low-income countries. Food Nutr Bull 1988; 10:3–23. 39. Marmot MG, Syme SL, Kagan A, Hiroo K, Rhoads G. Epidemiologic studies of CHD and stroke in Japanese men living in Japan, Hawaii, and California: prevalence of coronary and hypertensive heart disease and associated risk factors. Am J Epidemiol 1975; 102:514–525. 40. Prior I, Tasman-Jones C. New Zealand Maori and Paciﬁc Polynesians. In: Western Diseases: Their Emergence and Prevention. Trowell HC, Burkitt DP, eds., Cambridge, MA: Harvard University Press, 1981. 41. Toor M, Katchalsky A, Agmon J, Allalouf D. Serum-lipid and atherosclerosis among Yemenite immigrants in Israel. Lancet 1957; 1:1270–1273. 42. Worth RM, Kato H, Rhoads GG, Kagan K, Syme SL. Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii, and California: Mortality. Am J Epidemiol 1975; 102:481–490. 43. Crane NT, Lewis CJ, Yetley EA. Time trends in macronutrient intake and availability using national databases. FASEB J 1990; 4:A374. 44. Slattery ML, Randall DE. Trends in coronary heart disease mortality and food consumption in the United States between 1909 and 1980. Am J Clin Nutr 1988; 47:1060–1067. 45. Stephen AM, Wald N J. Trends in individual consumption of dietary fat in the United States, 1920–1984. Am J Clin Nutr 1990; 52:457–469. 46. Yamaguchi K. Changes in nutritional and health status in Japan after the Second World War. In: Proceedings of International Symposium on Food, Nutrition and Social Economic Development. Beijing: Chinese Academy of Preventive Medicine, 1991, pp. 394–401. 47. Popkin BM. Nutritional patterns and transitions. Popul Dev Rev 1993; 19:138–157. 48. Lands WE, Hamazaki T, Yamazaki K, Okuyama H, Sakai K, Goto Y, Hubbard VS. Changing dietary patterns. Am J Clin Nutr 1990; 51:991–993. 49. Fukuba H. Positive and negative effects of nutritional improvement in Japan. Typescript. Tokyo: Japan Science Council, 1990. 50. Kim S, Sojae M, Popkin BM. The nutrition transition in South Korea. Chapel Hill, NC: Carolina Population Center, University of North Carolina at Chapel Hill, 1998. 51. The World Bank. China: long-term issues and options in the health transition. A World Bank country-study, 0253–2123. Washington DC: World Bank, 1990. 52. Popkin BM, Kohlmeier L, Zohoori N, Baturin A, Martinchik A, Deev A. Nutritional risk factors in the former Soviet Union. In: Premature Death in the New Independent States. Bobadilla JL, Costello C, Mitchell F, eds. Washington DC: National Academy Press, 1997, pp. 314–334. 53. Popkin BM, Baturin A, Kohlmeier L, Zohoori N. Russia: Monitoring nutritional change during the reform period. In: Implementing Dietary Guidelines for Healthy Eating. Wheelock V, ed. London: Blackie Academic and Professional, 1997, pp. 23–46. 53a. Consumer Budget Survey. Moscow, Russia: State Statistical Ofﬁce, Goskomstat. 54. Zohoori N, Kozyreva P, Kosolapov M, Mroz TA, Swafford M, Popkin BM, et al. Monitoring the economic transition in the Russian Federation and its implications for the demographic crisis—the Russian Longitudinal Monitoring Survey. World Devel (In Press). 55. Popkin BM. The nutrition transition and its health implications in lower income countries. Public Health Nutr 1998; 1:5–21. 56. Popkin BM, Doak CM. The obesity epidemic is a worldwide phenomenon. Nutr Rev 1998; 56:106–114. 57. Monteiro CA, Mondini L, de Souza A L, Popkin BM. The nutrition transition in Brazil. Eur J Clin Nutr 1995; 49:105–113. 58. National Research Council. Committee on Diet and Health. Diet and health: implications for reducing chronic disease risk. Washington DC: National Academy Press, 1989. 59. United States. Ofﬁce of the Assistant Secretary for Health. Surgeon general’s report on nutrition and health. Washington DC: U.S. Department of Health and Human Services, Public Health Service, 1988. 60. USA-PRC Collaborative Study of Cardiovascular and Cardiopulmonary Epidemiology. Data Preview. Washington DC: National Heart Lung and Blood Institute, 1989. 61. Guo X, Popkin BM, Mroz TA, Zhai F. Food price policy can signiﬁcantly reduce the negative effects of the nutrition transition in China. Chapel Hill, NC: Carolina Population Center, University of North Carolina at Chapel Hill, 1998.

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62. Popkin BM, Akin JS, Haines PS, MacDonald MM, Spicer D. Nutrition program options for maternal and child health. Institute for Research on Poverty Special Report Series No. SR28. Madison, WI: Institute for Research on Poverty, 1980. 63. Popkin BM, Akin JS, Kaufman M, MacDonald MM. Nutrition program options for maternal and child health: a summary. In: Vol. IV Background Reports. Washington DC: 1981. 64. Gortmaker SL, Dietz WH Jr., Sobol AM, Wehler CA. Increasing pediatric obesity in the United States. Am J Dis Child 1987; 141:535–540. 65. Dowse GK, Gareeboo H, Alberti KG, Zimmet P, Tuomilehto J, Purran A, et al. Changes in population cholesterol concentrations and other cardiovascular risk factor levels after ﬁve years of the non-communicable disease intervention programme in Mauritius. BM J 1995; 311:1255–1259. 66. Uusitalo U, Feskens EJ, Tuomilehto J, Dowse G, Haw U, Fareed D, et al. Fall in total cholesterol concentration over ﬁve years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996; 313:1044–1046.

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Chapter 18 / Obesity in Developing Countries

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The Emerging Problem of Obesity in Developing Countries Colleen M. Doak and Barry M. Popkin

1. INTRODUCTION This century has witnessed a remarkable change in patterns of disease. The control of infectious disease, together with changing life styles, has led to longer life expectancies and the emergence of chronic disease as a primary cause of death. This change from infectious to chronic disease is known as the epidemiologic transition. Although this transition occurred ﬁrst in industrialized nations, developing countries are experiencing the same changes in disease prevalence and mortality patterns, but at a much accelerated rate. In conjunction with the increase in chronic disease are lifestyle patterns, such as diet and physical activity, that have led to increasing rates of obesity in addition to related diseases. This corollary to the epidemiologic transition is known as the nutrition transition (1). The nutrition transition involves the emergence of obesity at levels that are felt to be highly excessive, together with the corresponding changes in diet and physical activity. This phenomenon is no longer conﬁned to the industrialized nations of Europe and North America. The vast changes in diet and physical activity in lower and middle income countries of Asia, Latin America, the Carribean, Africa, and the Middle East have led to an emerging epidemic of obesity as a worldwide phenomenon. Previously, there were insufﬁcient nationally representative samples to measure the prevalence of obesity in many regions of the world. In the past, we were forced to use smaller, focused samples to get some sense of the emergence of this problem. Now we have data for adults available from a number of countries in each region of the world that allow us to document not only the extent of the problem, but also the rapid increase in obesity and the most recent trends. Elsewhere we show that there are equally important problems emerging among children and adolescents in lower-income countries, but we focus our attention here on adults because there is insufﬁcient data on adolescents to include them in this chapter (2). In the next part of this chapter, we outline the methods used for this presentation. Large nationwide surveys provide some sense of body-composition patterns and trends in obesity prevalence. Then we focus brieﬂy on some of the health effects of this epidemic. From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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2. METHODS 2.1. Survey Design and Sample Data come from a large number of sources. Analyses conducted for this chapter that have not been published elsewhere are based on Chinese and Russian surveys. A thorough presentation is made of the China Health and Nutrition Survey (CHNS), an on-going, longitudinal survey covering eight provinces in China. A multistage, random, cluster sampling procedure was used to draw the sample from each province. Additional detail on the research design of this survey is presented elsewhere (3). Other data sets presented in detail are the Russian Longitudinal Monitoring Survey (RLMS), the ﬁrst nationally representative sample of the Russian Federation. Additional detail on the research design of this survey is found elsewhere (4,5). Data collection is identical with that for the China survey except that in China, doctors and nutritionists collected all data, whereas in Russia, trained nonmedical interview specialists collected the data. In addition, we use data from published surveys conducted in all regions of the world. We focus mainly on large representative samples of adults. Our selection criteria for presenting data from other surveys was size, sampling design, and geographic area. If a study were representative of a region or country, it was always used. If it came from a country with few studies and did not ﬁt our criteria of national representativeness, we used it if the sample size were large and it seemed reasonably representative of the population being sampled. Since there are few studies of trends in obesity, those that provide reasonably comparable measurement and sampling criteria were always selected.

2.2. Measures Body mass index (BMI) is the standard population-based measure of overweight and obesity status. For adults, the World Health Organization (WHO) cutoffs are used to delineate obesity: less than 18.5 for thinness (chronic energy deﬁciency), 18.5–24.99 for normal, 25.0–29.99 for overweight Grade I, 30.0–39.99 for overweight Grade II, and 40.0 and above for overweight Grade III (6). For this chapter, Grades II and III are combined. Ideally we would follow these cutoffs universally; unfortunately, many published results use earlier cutoffs (e.g., many use a level for Grade I of a BMI above 25 and others use the National Center for Health Statistics percentile cutoffs that gave males a cutoff of 27.8 and females 27.3) and the data sets are unavailable for revision.

3. RESULTS Elsewhere we present some information on comparable trends in higher-income countries (7). This chapter focuses on lower-income countries.

3.1. The Prevalence in Lower- and Middle-Income Countries 3.1.1. PREVALENCE Before exploring trends in these countries, we provide some sense of current knowledge on the prevalence of obesity. We have both data from nationally representative surveys from a range of middle- and lower-income countries, and very large surveys from selected population groups in other countries. We report both sets of results in Table 1 for adults. We look at three measures of obesity and overweight, Grade I (text continues on page 452)

Obesity Country Latin America Brazil (8) Peru (9) Colombia (10) Mexico (11) Caribbean Cuba (12) 449

Asia China (13) Kyrgystan India (14) India (9) India (15) Thailand (16) Philippines (17)

% Obese

Year

Sample (n)

criteria

Age group (yr)

Males (M)

Females (F)

Total

1989 1975–1976 1975–1976 1988–1989 1995 1995

23,544 3,145 3,145 1,572 2,042 (U)a 2,042 (U)

>30 *25 >30 *27.3 *25 *30

25–64 Adults Adults 18–44 Adults Adults

15.9 — — — 50.0 11.0

13.3 — — 11.1 58.0 23.0

19.6 33.8 19.0 — — —

1982 1982 1982

30,063 20,539 (U) 9,513 (R)b

*25 *25 *25

20–59 20–59 20–59

31.5 36.0 22.6

39.4 41.8 33.9

36.4 39.7 29.4

1992 1992 1992 1993 1993 1989 1988–1990 1988–1990 1994 1993–1994 1985 1985 1993 1993

54,006 18,472 (U) 35,534 (R) 4,053 4,053 1,784 (U) 21,361 21,361 1,832 1,319 (U, slum) 3,495 (U) 3,495 (U) 9,585 9,585

>25 >25 >25 *30 25–<30 *25 *25 >30 >25 >25 *25 *30 >30 25–30

>20 yr >20 yr >20 yr 18–59 18–59 15–76 Adults Adults 12–47 12–47 35–54 35–54 *20 yr *20 yr

11.9 20.8 17.4 14.2 26.4 36.9 — — — — 25.5 12.2 11.7 11.0

17.0 25.1 12.7 10.7 24.3 44.1 — — 16.6 11.6 21.4 13.0 13.4 11.8

14.6 23.1 10.2 — — 40.9 13.5 10.5 — — 24.6 12.4 — —

Chapter 18 / Obesity in Developing Countries

Table 1 Obesity Patterns in Lower- and Middle-Income Countries (Adults: Studies with Large Sample Size)

449

(continued)

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Table 1 (continued) Obesity Patterns in Lower- and Middle-Income Countries (Adults: Studies with Large Sample Size) Obesity

% Obese

Country

Year

Sample (n)

criteria

Age group (yr)

Males (M)

Females (F)

Total

Malaysia (18)

1990 1990

4,747 4,747

>25–30 >30

18–64 18–64

24.0 14.7

18.1 17.9

21.4 16.1

1987–1988 1987–1988 1994 1992–1994 1992–1994 1994

3588 3588 1,344 6,503 (R) 641 (U) 345

Western Samoa (22)

1995

475

Tonga (23)

1986

654 1190 1226

>30 25–<30 >30 *25 (F) *27 (M) *25 (F) >25 >30 >25 >30 >32 (M) >30 (F) >26 (M) >24 (F) >=27 >=25

15–49 15–49 25–69 30–59 30–59 25–58 25–58 25–58 25–58 20–49 20–49 >18 >18

80.2 44.6 59.1 63.8 45.9 83.8 37.1 101. 47.6 26.6 181.

31.9 33.2 78.6 71.4 79.6 96.9 87.8 92.2 66.2 39.1 77.9 47.4 33.9

3,435 3,435 13,177 13,177 290 >20 2,836 433 (R) 433 (R) 41,921 41,921

>30 >25–30 >30 25–30 >30 16 >30 NCHS OB NCHS OVE >30 25–29.99

*18 *18 15–95 15–95 >20 31.4 >25 15–74 15–74 Adults Adults

32.3 35.2 16.0 29.0 26.3 24.1 32.7 16.8 12.9 — —

West Paciﬁc Micronesia (19) Nauru (20) New Caledonia (21) American Samoa (22) 450

37.8 25.9

40.6 32.3 24.0 27.0 29.4

36.4 33.8 19.8 28.0 27.9

59.8 10.1 25.1 — —

49.7 19.0 21.0 15.2 18.7

Doak and Popkin

Fiji, Fijians (24) 1993 Fiji, Fijians (24) 1993 No. Africa/Middle East Kuwait (25) 1993–1994 1993–1994 Saudi Arabia (26) 1996 1996 Bahrain (27) 1991–1992 25–30 Jordan (28) 1994–1996 Egypt (29) 1983–1985 1983–1985 Morocco (30) 1984–1985 1984–1985

79.4 59.0 72.7 83.5 70.8 88.2 52.2

Sub-Sahara Africa Congo (9) Congo (31) 451

Mali (9) South Africa (32) South Africa (33) Mauritius (34)

1990 1990 1986–1987 1986–1987 1991 1992 1991 1991 1979 1979 1990 1992 1992

8,611 8,611

>30 *25

2,295 *25 2,295 >30 3,004 (U) >25 1,344(R) >25 4,868 *25 4,868 >30 7,187 >30 7,187 *25–30 (M) *24–30 (F) 986 (Bc) *30 5,111 >30 5,111 >25

Adults Adults

12.4 20.0

18.3 32.7

15.3 26.3

>18 >18 *18 *18 Adults Adults 15–64 15–64 15–64 25–74 25–74

— — — — — — 14.7 41.9 17.9 15.3 35.7

15.2 13.4 — — — — 18.0 38.8 44.4 15.1 47.7

— — 23.6 14.1 17.2 10.8 16.5 40.3 28.0 10.6 42.2

Chapter 18 / Obesity in Developing Countries

Tunisia (9)

aU,

Urban. Rural. cBl, Black. bR,

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Fig. 1. Obesity patterns in Latin America.

(overweight), Grades II and above (obesity), and Grades I and above (overweight and obesity). Overall, the results show that the highest levels of obesity (Grade II and above) are in the Middle East, Western Paciﬁc, and Latin America. 3.1.1.1. Latin America. The levels of overweight and obesity in Latin America are reasonably high (see Fig. 1). For example, more than 50% of the population is overweight (grade I) in Mexico, and over 30% are overweight in Peru. The prevalence is lower in other South American countries. Several of these South American examples come from urban only samples. In all three countries, where we have gender-speciﬁc data, women have higher levels of overweight and obesity than do men. There are few large-scale surveys in the Caribbean; however, based on other studies and the Cuban data presented here, other Caribbean nations may also have high levels of obesity (35). 3.1.1.2. Asia. Aside from a few exceptions, there is less Grade II and above obesity in Asia, and most countries have levels in the 5–15% range for Grade I (Fig. 2). The documented exceptions are urban Thailand, Malaysia, and the Central Asian countries such as Kyrgyzstan that were members of the Soviet Union prior to 1992. There is no clear gender pattern to obesity levels in Asia. The prevalence of obesity in Malaysia and urban Thailand may be related to a relatively higher level of economic development. 3.1.1.3. Western Paciﬁc. The island nations such as Samoa and Nauru, Fiji, and Melanesia have been the subject of many studies related to their high rates of obesity and related chronic diseases. In some countries, over half the population has Grade II or above obesity (Fig. 3). In most countries, female obesity is much greater than is male obesity. 3.1.1.4. Middle East. The limited data for the oil-exporting countries such as Kuwait and Saudi Arabia indicates over a third of the adult population is overweight or obese (data not shown for overweight prevalence) (Fig. 4). In the North African countries,

Chapter 18 / Obesity in Developing Countries

453

Fig. 2. Obesity patterns in Asia.

Fig. 3. Obesity patterns in Western and South Paciﬁc.

the situation reﬂects an emerging problem with considerable Grade I overweight and less Grade II and above. Again, female obesity is higher in all countries where data were available for both genders. 3.1.1.5. Sub-Saharan Africa. Aside from Mauritius, there are no nationally representative surveys in sub-Saharan Africa. The scattered data from South Africa, Mali, and the Congo indicates high levels of obesity in urban sub-Saharan Africa (Fig. 5). There are few data on rural areas, but what exists shows a minimal problem. South Africa might be the exception: limited studies on Africans, particularly women, indicate the possibility of high levels of obesity in urban and rural areas (36).

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Fig. 4. Obesity patterns in North Africa and the Middle East.

Fig. 5. Obesity patterns in sub-Saharan Africa.

3.2. Obesity Trends in Lower- and Middle-Income Countries We have excellent data on trends in body composition for a small number of lower and middle income countries. Where we have data (Brazil in Latin America; China and India in Asia; Mauritius in Africa; Nauru and Western Samoa in the South Paciﬁc; and Russia), we ﬁnd signiﬁcant increases in obesity occurring. See Table 2 and Fig. 6. In Fig. 6 we have, for the purpose of comparison, converted all the trends into percentage points of increase during a 10-year period. (text continues on page 458)

Obesity Country South America Brazil (37) Brazil (37) Brazil (8) Mexico (11) Mexico (11) 455

Mexico (11) South Paciﬁc Nauru (20) Nauru (20) Rural Western Samoa (3) Urban Western Samoa (3) Fiji (Ethnic Fijian) (24)

% Obese

Chapter 18 / Obesity in Developing Countries

Table 2 Obesity Trends Among Adults in Lower- and Middle-Income Countries

Sample (n)

criteria

Males (M)

Females (F)

Total

1974–1975 1989 1996 1974–1975 1989 1974 1989 1988 1995 1996 1988 1995 1996

94,699 23,544 3,179 94,699 23,544 94,699 23,544 19,022 2,042 (U) 203 (R) 19,022 2,042 (U) 203 (R)

*25 *25 *25 25–29.99 25–29.99 >30 >30 *25–<27 *25–<30 *25–<30 >27 >30 >30

19.6 31.1 — 16.8 24.9 3.1 5.9 — 39.0 20.0 — 11.0 4.0

27.2 50.8 35.8 20.1 37.6 8.2 13.3 10 35.0 26.0 15.0 23.0 19.0

23.5 38.9 — 18.5 29.9 5.7 9.6 — — — — — —

1975–1976 1982 1987 1994 1978 1991 1978 1991 1958–1970 1980 1993 1993

— — — 1,344 745 960 744 769 1,947

>30 >30 >30 >30 >30 >30 >30 >30 >=26 >=25 >=27 >=25

63.2 70.7 67.2 80.2 18.7 34.8 38.2 48.4 34.7 32 26.8 —

72.4 75.8 69.8 78.6 37.9 52.1 60.3 72.1 57.8 64 47.4 64.4

— — — 79.4 29.7 44.1 50.0 61.9 46.7 49 37.8 46.9

455

Year

(continued)

456

Table 2 (continued) Obesity Country Fiji (Ethnic Indian) (24)

American Samoa, age 25–39 (22)

American Samoa, age 40–58 (22)

456

Western Samoa, age 25–39 (22)

Western Samoa, age 40–58 (22)

Asia China (38)

Rural China (13)

Year

Sample (n)

criteria

Males (M)

Females (F)

Total

1958–1970 1980 1993 1993 1990 1994 1990 1994 1990 1994 1990 1994 1991 1995 1991 1995 1991 1995 1991 1995

485 1,288 1,226 1,226

>=26 >=27 >=25 (M) >=27 >=25

22.1 38 — 33.9 98.4 100 78.7 86.1 95.7 97.8 85.8 90 87.3 89 54.9 55.1 93.6 95.8 70 78.2

14.4 26 21.4 25.9 94.4 95.7

>30 >30 >25 >25 >30 >30 >25 >25 >30 >30 >25 >25 >30 >30

3.6 11 9 18 >25 >25 76.6 80.3 97.9 97.5 80.2 81 88 84.9 32.9 33.3 83.9 82.5 45.8 41.7

1982 1989 1982 1989 1992 1982 1989 1992

6,459 4,965 5,510 1,606 8,477 7,814 3,556 20,911

*25 *25 >25 >25 >25 >25 >25 >25

— — — — — — — —

— — — — — — — —

6.0 8.9 9.7 12.0 14.9 6.1 7.5 8.4

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Urban China (13)

% Obese

India (15) Africa Mauritius (34) Mauritius (34) 457

Europe Russia

Russia

Russia

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China

1989 1991 1993 1989 1991 1993 1975–1979 1988–1990 1994

5,056 5,353 4,920 5,056 5,353 4,920 6,428 13,422 1,832

25–30 25–30 25–30 >30 >30 >30 >25 >25 >25

5.9 9.5 8.3 0.3 0.5 0.7 — — —

10.3 11.4 11.3 0.6 0.8 0.7 3.4 4.1 6.6

8.2 9.5 9.9 0.5 0.7 0.7 — — —

1987 1992 1987 1992

5,021 5,111 5,021 5,111

<25–30 <25–30 >30 >30

22.7 30.4 3.4 5.3

27.5 32.6 10.4 15.1

25.2 31.6 7.1 10.6

1991–1992 1992–1993 1988–1993 1911–1993 1912–1994 1910–1995 1910–1996 1991–1992 1992–1993 1988–1993 1911–1993 1912–1994 1910–1995 1910–1996

7,305 9,058 9,238 8,278 6,967 6,528 6,231 7,305 9,058 9,238 8,278 6,967 6,528 6,231

30–45 30–45 30–45 30–45 30–45 30–45 30–45 25–30 25–30 25–30 25–30 25–30 25–30 25–30

8.4 9.7 9.2 10.0 9.5 9.3 10.8 33.5 34.4 34.1 34.4 35.4 31.8 33.4

23.2 25.8 25.7 25.7 26.6 27.2 27.9 33.1 32.5 32.6 32.2 31.6 31.4 30.5

— — — — — — — — — — — — — — 457

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Fig. 6. Obesity trends: the percentage increase in obesity prevalence per 10-yr period.

3.2.1. BRAZIL Elsewhere we present in detail the trends in Brazil (8). The proportion of obesity among adults males almost doubled (3.1 to 5.9%) between 1989 and 1974. For females of reproductive age, data over a 21-yr period show a far greater increase, from 4.4% (in 1975) to 10.1% (in 1996) in obesity (37). However, the rate of increase in female obesity (per decade) is greatest in the most recent time interval—between 1975 and 1989, there was a 2.2% increase compared to a 3.7% increase between 1989 and 1996. 3.2.2. CHINA The shifts in diet, physical activity, and overweight status in China are among the most rapid ever documented. Elsewhere we show that among school-age children, Chinese obesity rates are rapidly reaching levels comparable with the U.S., although this is not so for adults (2). These changes are much greater among urban residents of all income backgrounds and greater still among middle and higher income rural residents (38,39). In China we have found that, although obesity prevalence is lower among the lowest income tertile, the rate of increase among this group is the greatest. The rates of obesity based on national nutrition surveys in China in 1982–1992 indicate a moderate increase; however, this obscures more rapid shifts in diet, activity, and obesity seen in the last few years (13,40). During the more recent period, the CHNS 1989 to 1993 show that there has been a consistent increase in obesity in urban and rural areas among adults. 3.2.3. INDIA Unlike China, there is much less information available for India. Data are available only for women of child-bearing age. These data indicate a small increase over 19 yr but a more rapid increase at a rate of 5.0 percentage points per 10-yr period for women during 1989–1994.

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3.2.4. KUWAIT Both grade I and grade II obesity rose rapidly in Kuwait. In 1980–1981 the prevalence of Grade I and above was over 50% for females and nearly as high for males. This prevalence of overweight rose to approx 70% for both males and females by 1994, a rate of 14.5 percentage points per decade. Grade II obesity increased by a total of 12.8%, representing a per-decade percentage point increase of 9.8%. 3.2.5. MAURITIUS This small island republic has a very high prevalence of noninsulin-dependent diabetes mellitus (NIDDM) (34) Among males and females, a rapid increase in obesity is occurring. In particular, the increase in female Grade II and above obesity is higher than that found in many high-income countries. During a 5-yr period (1987–1992) there were marked increases in Grades I and II obesity. It is important to note that this increase in obesity occurred despite the existence of a national health-promotion campaign that successfully used the mass media, price policy, other legislative and ﬁscal measures, and widespread education activity in the community, workplace, and schools to change many behaviors related to coronary heart disease and hypertension. The results were remarkable: hypertension was reduced considerably, cigarette smoking in men and women declined, heavy alcohol use declined, mean serum cholesterol decreased, and there was increased activity (41,42). Of course, it is quite possible that the reduction in the extent and amount of smoking is linked partially with this weight increase (43). However, it is also possible that the rate of increase in obesity would have been much higher without the national health-promotion campaign. 3.2.6. RUSSIA Russia has one of the highest rates of mortality related to coronary heart disease in the world. Despite marked shifts toward a lower fat diet in the postreform period, during which price subsidies of meat and dairy products were removed, there is evidence of an increase in adult obesity. We have collected data for seven rounds of the nationally representative Russian Longitudinal Monitoring Survey and found a consistent increase in adult and also elderly obesity (5). The remarkable point to note is that the effects of the economic reform-induced dietary changes have not been linked with meaningful changes in obesity patterns. Prevalence of Grade I overweight among females showed a consistent decline between 1992 and 1996, whereas males showed virtually no difference between the ﬁrst and last rounds of the survey. The survey showed an overall increase in grade II obesity for males and females, and an increase in total obesity of over ﬁve percentage points per 10-yr period for Russia. Despite the overall increase in obesity, year-to-year ﬂuctuations underscore the fact that the economy is in ﬂux, and that these changes cannot be used to predict future directions of this trend. 3.2.7. WESTERN PACIFIC A large literature documents the high rates of obesity, in particular Grade III and above overweight status, in populations residing in the Western Paciﬁc Islands. Modernization has been associated with a very high prevalence of obesity in the West and South Paciﬁc islands, particularly among urban residents (44–46). In those islands (e.g., Fiji, Kiribati, Nauru, American and Western Samoa, Vanatu), high rates of severe obesity are seen that mirror the rates found among Native American groups in the U.S.

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(47). The trends reported in these studies of Hodge and colleagues (48) indicate not only that obesity levels are high but that the prevalence of obesity continues to increase considerably in each island. In Nauru and Western Samoa, the levels of Grades I and II obesity are among the highest found and are still increasing steadily.

4. IMPLICATIONS FOR PUBLIC HEALTH Adult-onset diabetes and many other comorbidities of obesity are increasing rapidly in many lower income countries (48,49). The most relevant comorbidities are hypertension, dyslipidemia, and atherosclerosis. The epidemiological prevalence data are spotty but indicate serious and high levels of these conditions, in particular NIDDM. Recently, a most provocative cancer study has laid a strong basis for linking the diet, activity, and body composition trends discussed earlier to the likelihood of increased rates of prevalence for a larger number of cancers (50). A clear literature has shown that in terms of mechanisms and epidemiology, obesity and activity are closely linked to NIDDM. Several reviews lay out the case for these factors. Zimmet and his colleagues (51,52) have been particularly earnest in exploring these issues at the population level in a number of lower income and transitional societies. Some basic characteristics of NIDDM may provide a clear basis for linking key components of the nutrition transition—increases in obesity and reductions in activity—to the rapid increases in NIDDM in lower-income countries.

4.1. Obesity It is clear that obesity, and more particularly, the upper-body regional distribution of body fat, is a key parameter in the etiology of NIDDM. A vast literature has shown signiﬁcant direct obesity relationships with NIDDM, and animal studies support this relationship. The work on abdominal obesity and its effects is more recent, but appears to be promising in explaining more precisely the role that body composition plays. In addition, there is a strong relationship between weight gain and risk of developing diabetes. The odds of getting diabetes are considerable with a weight gain of 5–8 kg for adults and the strength of association is even higher as weight gain goes up (53).

4.2. Physical Activity It is understood that exercise may help to prevent NIDDM in an obese patient. Exercise may offset the hyper-insulinemia that is associated with obesity and reduces the likelihood that a person will display the signs that allow him/her to be categorized as having NIDDM, after controlling for a given level of obesity. Because exercise is associated with lower insulin levels, it may help to offset (or prevent) the hyperinsulinemia that is common among obese persons, and consequentially the development of insulin-resistence. Zimmet (51) reviews these relationships and notes other critical studies on this topic (52).

4.3. Interactions of Obesity and Activity Physical activity and obesity have independent effects on serum insulin, but together they interact such that the impact of physical activity differs according to the level of obesity. For example, studies show that for each level of BMI or waist-hip ratio, there is a different effect of physical activity on serum insulin level.

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4.4. Genetic Component Zimmet and others who have focused on this issue as it relates to lower-income countries have felt that the highest genetic susceptibility for NIDDM was for Paciﬁc Islanders, American Indians, Mexican Americans and other Hispanics, and Asian Indians (51,52). Those with modest genetic susceptibility include Africans, Japanese, and Chinese. McGarvey and colleagues (22) and O’Dea and colleagues (54) also have explored thoroughly the same issues among Australian Aborigines and other South Paciﬁc groups and have provided careful documentation of this linkage of the nutrition transition with NIDDM.

5. RESEARCH AND POLICY IMPLICATIONS It is clear that the nutrition transition as noted elsewhere in this volume is closely linked with rapid increases in obesity. It is also clear that there is great potential for serious adverse public health consequences from the nutrition transition and the resultant large increase in obesity. These trends in obesity are not limited to one region, country, or racial/ethnic grouping. The overall levels that we ﬁnd in selected countries such as Mexico, Egypt, South Africa, and Malaysia and nations of the Western Paciﬁc are indicative of major public health problems. That these changes appear to be occurring across so many countries lends weight to the need to understand the underlying environmental causes, rather than focus attention solely on genetic causes of obesity. It also opens up the possibility that international studies can help to clarify the causes for these patterns. Clearly, excess body fat develops when dietary energy intake exceeds energy expenditure. Diet and physical activity are major direct determinants. These direct determinants of obesity may, in fact, be shared across all populations. The relative contribution of metabolic differences, inactivity, dietary energy, and fat intake in each population is unknown (55), but it is clear that diet and activity have been shown to matter a great deal in a few longitudinal studies in lower-income countries (56). Although there will be large differences in the underlying socioeconomic and behavioral factors related to obesity in each country, the policies and programs that alter these patterns may be best understood by examining settings around the world. At present there are few examples of lower income countries that have developed national programs and policies focused on the rapid increases in obesity and the related changes in the structure of diet and activity. There are discussions underway in several countries, and smaller efforts are being made in many countries, but Mauritius and Singapore are unique in following a systematic national approach. The small island republic of Mauritius in the Indian Ocean found such a high level of cardiovascular disease as part of an adult health survey conducted in 1987, that it launched a broad comprehensive health promotion program, described in chapter 17. This program used the mass media, price policy, other legislative and ﬁscal measures, and widespread education activity in the community, workplace, and schools. The results were remarkable in terms of health effects but overall there was no decrease in obesity (41,42). But it is clear that if diet changed in a positive manner and activity increased, there must have been some decline in the rate of increase of obesity. Singapore has also developed a national program in the schools to address child obesity. The results have not been written up but the unpublished information suggests a very effective intervention was developed.

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The challenge we face in lower-income countries is in determining how to arrest this rapid increase in obesity before the health system is overwhelmed with obesity-related problems.

ACKNOWLEDGMENTS Preparation of this chapter was supported in part by grants from the U.S. National Institutes of Health (R01-HD30880). The authors thank the following staff of the Carolina Population Center, University of North Carolina at Chapel Hill: Tom Swasey for his work on the graphics, Lynn Igoe for editorial assistance, and Frances Dancy for administrative assistance. The authors also credit collaborators on the China Health and Nutrition Survey, in particular Drs. Keyou Ge and Fengying Zhai, Institute of Nutrition and Food Hygiene, Chinese Academy of Preventive Medicine; and on the Russian Longitudinal Monitoring Survey, Alexander Baturin, Russian Institute of Nutrition, Academy of Medical Sciences.

REFERENCES 1. Popkin BM. The nutrition transition and its health implications in lower income countries. Public Health Nutr 1998; 1:5–21. 2. Popkin BM, Richards MK, Monteiro CA. Stunting is associated with overweight in children of four nations that are undergoing the nutrition transition. J Nutr 1996; 126:3009–3016. 3. Popkin BM, Ge K, Zhai F, Guo X, Ma H, Zohoori N. The nutrition transition in China: a cross-sectional analysis. Eur J Clin Nutr 1993; 47:333–346. 4. Mroz T., Popkin BM. Poverty and the economic transition in the Russian Federation. Econ Devel Cult Change 1995; 44:–1–31. 5. Popkin BM, Zohoori N, Baturin A. The nutritional status of the elderly in Russia, 1992 through 1994. Am J Public Health 1996; 86:355–360. 6. World Health Organization Expert Committee. Physical Status: the Use and Interpretation of Anthropometry: Report of a Who Expert Committee. Geneva: WHO Technical Report Series 854. WHO, 1995. 7. Popkin BM, Doak C. The obesity epidemic is a worldwide phenomenon. Nutr Rev 1998; 56: 106–114. 8. Monteiro CA, Mondini L, de Souza ALM, Popkin BM. The nutrition transition in Brazil. Eur J Clin Nutr 1995; 49:105–113. 9. Shetty PS, James WPT. BMI Distribution in Developed and Developing Countries. In Body Mass Index: a Measure of Chronic Energy Deﬁciency in Adults. FAO Food and Nutrition Papers No. 56. Rome: Food and Agriculture Organization of the United Nations, 1994. 10. Dufour DL, Staten LK, Reina JC, Spurr GB. Anthropometry and secular changes in stature of urban Colombian women of differing socioeconomic status. Am J Human Biol 1994; 6:749–760. 11. Sánchez-Castillo C, Lara JJ, James WPT. Diet and nutritional trends in Mexico. In: Proceedings of the 16th International Congress of Nutrition, Montreal. Canadian Federation of Biological Sciences, Ottawa: Canadian Federation of Biological Sciences, 1998. 12. Berdasco A. Body mass index values in the Cuban adult population. Eur J Clin Nutr 1994; 48(suppl 3): S155–S164. 13. Ge K, Zhai F, Yan H. The Dietary and Nutrition Status of Chinese Population. Beijing: People’s Medical Publishing House, 1996. 14. Dhurandhar NV, Kulkarni PR. Prevalence of obesity in Bombay. Intl J Obesity 1992; 16:397–375. 15. Sachdev HPS. Nutritional status of children and women in India: recent trends. NFI Bull, 1997; 18(3). 16. Tanphaichitr V, Kulapongse S, Pakpeankitvatana R, Leelahagul P, Tamwiwat C, Lochaya S. Prevalence of obesity and its associated risks in urban Thais. In: Progress in Obesity Research 1990. Oomura Y, Tarui S, Inoue S, Shimazu T, eds. London: Libbey, 1991, pp. 649–653.

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17. Solon FS. Nutrition Related Chronic Diseases in the Philippines. Nutrition Center of the Philippines Report Series, 2(1). Makati City, Philippines: Nutrition Center of the Philippines, 1997. 18. Ismail MN, Zawaih H, Chee SS, Ng KK. Prevalence of obesity and chronic energy deﬁciency (CED) in adult Malaysians. Malay J Nutr 1995; 1:1–9. 19. Federated States of Micronesia. Department of Human Resources, Ofﬁce of Health Services. Technical Report Prepared for the Government and Department of Human Resources of the Federated States of Micronesia: The 1987/88 National Nutrition Survey of the Federated States of Micronesia. Noumea, New Caledonia: South Paciﬁc Commission, 1989. 20. Hodge AM, Dowse GK, Zimmet PZ. Obesity in Paciﬁc populations. Pac Health Dialog 1996; 3(1): 77–86. 21. Tassie JM, Papoz L, Barny S, Simon D. The CALDIA Study Group, Nutritional status in adults in the pluri-ethnic population of New Caledonia. Intl J Obes Relat Metab Disord 1997; 21:61–66. 22. McGarvey ST, Quested C, Tufa J. Correlates and predictors of cross-sectional and longitudinal adiposity in adults from Samoa and American Samoa. Manuscript. Providence, RI: Department of Medicine, Brown University, 1998. 23. Tonga, Kingdom of. National Food and Nutrition Committee. The 1986 National Nutrition Survey of the Kingdom of Tonga. Technical Report. Noumea, New Caledonia: South Paciﬁc Commission, 1987. 24. Saito S. 1991 National Nutrition Survey, Main Report. Republic of Fiji, Suva, Fiji: National Food and Nutrition Committee, 1995. 25. Al-Isa AN. Prevalence of obesity among adult Kuwaitis: a cross-sectional study. Intl J Obes Relat Metab Disord 1995; 19:431–433. 26. Al-Nuaim AR, Al-Rubeaan K, Al-Mazrou Y, Al-Attas O, Al-Daghari N, Khoja T. High prevalence of overweight and obesity in Saudi Arabia. Intl J Obes Relat Metab Disord 1996; 20:547–552. 27. al-Mannai A, Dickerson JWT, Morgan JB, Khalfan H. Obesity in Bahraini adults. J R Soc Health 1996; 116:30–32, 37–40. 28. Ajlouni K, Jaddou H, Batieha A. Obesity in Jordan. Intl J Obes Relat Metab Disord 1998; 22:624–628. 29. Khorshid A, Galal OM. National Agricultural Research Project. Final Technical Report. Development of Food Consumption Monitoring System for Egypt, Oct. 1, 1992–Aug 31, 1995. 30. Morocco, Kingdom of. Dirreccion de la Statistique. Consommation et dispueses des ménages1984/85. Vol 6, Situation nutritionnelle de la population du Maroc. Rabat, Morocco: Ministere de Affaire Economique et Sociale, 1992. 31. Delpeuch F, Cornu A, Massamba J-P, Traissac P, Maire B. Is body mass index sensitively related to socio-economic status and to economic adjustment? A case study from the Congo. Eur J Clin Nutr 1994; 48(suppl 3):S141–S147. 32. Jooste PL, Steenkamp HJ, Benade AJS, Rossouw JE. Prevalence of overweight and obesity and its relation to coronary heart disease in the CORIS study. S Afr Med J 1988; 74:101–104. 33. Steyn K, Fourie J, Rossouw JE, Langenhoven ML, Joubert G, Chalton DO. Anthropometric proﬁle of the coloured population of the Cape Peninsula. S Afr Med J 1990; 78:68–72. 34. Hodge AM, Dowse GK, Gareeboo H, Tuomilehto J, Alberti KG, Zimmet PZ. Incidence, increasing prevalence, and predictors of change in obesity and fat distribution over 5 years in the rapidly developing population of Mauritius. Intl J Obes Relat Metab Disord 1996; 20:137–146. 35. Forrester T, Wilks R, Bennett F, McFarlane-Anderson N, McGee D, Cooper R, Fraser H. Obesity in the Caribbean. In: The Origins and Consequences of Obesity. Chadwick DJ, Cardew G, eds. Ciba Foundation Symposium 201. Chichester, UK: Wiley, pp. 17–31. 36. Bourne LT, Walker ARP. The nutrition transition in the Republic of South Africa. In: Proceedings of the 16th International Congress of Nutrition. Monrtreal: Canadian Federation of Biological Sciences (In Press). 37. Monteiro CA. The changing nature of nutritional disorders in the developing countries: the case of Brazil. In: Proceedings of the 16th International Congress of Nutrition. Montreal: Canadian Federation of Biological Sciences (In Press). 38. Popkin BM, Paeratakul S, Zhai F, Ge K. Body weight patterns among the Chinese: results from the 1989 and 1991 China health and nutrition surveys. Am J Public Health 1995; 85:690–694. 39. Popkin BM, Paeratakul S, Zhai F, Ge K. Dietary and environmental correlates of obesity in a population study in China. Obes Res 1995; 3(suppl 2):135S–143S. 40. Ge K, Weisell R, Guo S, Cheng L, Ma H, Zhai F, Popkin BM. The body mass index of Chinese adults in the 1980s. Eur. J. Clin. Nutr. 1994; 48(suppl 3):S148–S154.

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41. Dowse GK, Gareeboo H, Alberti KG, Zimmet P, Tuomilehto J, Purran A, et al. Changes in population cholesterol concentrations and other cardiovascular risk factor levels after ﬁve years of the noncommunicable disease intervention programme in Mauritius. BMJ 1995; 311:1255–1259. 42. Uusitalo U, Feskens EJ, Tuomilehto J, Dowse G, Haw U, Fareed D, et al. Fall in total cholesterol concentration over ﬁve years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996; 313:1044–1046. 43. Flegal KM, Troiano RP, Pamuk ER, Kuczmarski RJ, Campbell SM. The inﬂuence of smoking cessation on the prevalence of overweight in the United States. N Engl J Med 1995; 333:1165–1170. 44. Hodge AM, Dowse GK, Toelupe P, Collins VR, Imo T, Zimmet PZ. Dramatic increase in the prevalence of obesity in western Samoa over the 13 year period 1978–1991. Intl J Obes Relat Metab Disord, 1994; 18:419–428. 45. Hodge AM, Dowse GK, Zimmet PZ, Collins VR. Prevalence and secular trends in obesity in Paciﬁc and Indian Ocean Island populations. Obes Res 1995; 3(suppl 2):77S–87S. 46. Taylor R, Badcock J, King H, Pargeter K, Zimmet P, Fred T, et al. Dietary intake, exercise, obesity and noncommunicable disease in rural and urban populations of three Paciﬁc Island countries. J Am Coll Nutr 1992; 11:283–293. 47. Brown PJ, Konner M. An anthropological perspective on obesity. Ann NY Acad Sci 1987; 499: 29–46. 48. Hodge AM, Dowse GK, Toelupe P, Collins VR, Zimmet PZ. The Association of modernization with dyslipidaemia and changes in lipid levels in the polynesian population of western Samoa. Intl J Epidemiol 1997; 26:297–306. 49. Levitt NS, Katzenellenbogen JM, Bradshaw D, Hoffman MN, Bonnici F. The prevalence and identiﬁcation of risk factors for NIDDM in urban Africans in Cape Town, South Africa. Diabetes Care 1993; 16:601–607. 50. World Cancer Research Fund in association with American Institute for Cancer Research. Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington DC: American Institute for Cancer Research, 1997. 51. Zimmet PZ. Kelly West Lecture. Challenges in diabetes epidemiology—from West to the rest. Diabetes Care 1991; 15:232–252. 52. Zimmet PZ, McCarty DJ, de Courten MP. The global epidemiology of non-insulin-dependent diabetes mellitus and the metabolic syndrome. J Diabet Complic 1997; 11:60–68. 53. Ford ES, Williamson DF, Liu S. Weight change and diabetes incidence: ﬁndings from a national cohort of US adults. Am J Epidemiol 1997; 146:214–222. 54. O’Dea K, Patel M, Kubisch D, Hopper J, Traianedes K. Obesity, diabetes, and hyperlipidemia in a central Australian aboriginal community with a long history of acculturation. Diabetes Care 1993; 16: 1004–1010. 55. Bray GA, Popkin BM. Dietary fat intake does affect obesity! Am J Clin Nutr 1998; 68:1157–1173. 56. Paeratakul S, Popkin BM, Ge K, Adair LS, Stevens J. Changes in diet and physical activity affect the body mass index of Chinese adults. Intl J Obesity 1998; 22:424–432.

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Rapid Urbanization and the Challenges of Obtaining Food and Nutrition Security Marie T. Ruel, Lawrence Haddad, and James L. Garrett

1. INTRODUCTION Over the period 2000–2025, the urban population of the developing world is projected to double—from 2.02 billion to 4.03 billion, and the rural population is projected to increase from 2.95 billion to 3.03 billion (1). Caveats to these projections abound,1 nevertheless, the numbers are striking. As Figure 1 indicates, 47% of the population, some 2.9 billion people, now lives in urban areas. About 75% of Latin American lives in cities, and a little more than one-third of Africans and Asians live in cities (2). The urban population in developing countries is growing three times faster (3% annually) than the rural population (less than 1% annually). Over the period 2000–2025, the urban population of Africa is expected to increase from 310 million to 804 million (the rural population is projected to increase from 521 to 692 million); for Asia, the urban population will increase from 1.4 billion to 2.7 billion (the rural population is projected to decline from 2.3 to 2.2 billion); and for Latin America, the corresponding numbers show an increase in the urban population from 401 million to 601 million (and a decline of the rural population from 123 to 109 million). For those who produce and use food policy research, these numbers raise several issues that we will attempt to address in this paper. First, although we can be sure that the number of people living in urban areas in the developing world will increase rapidly in the next 25 years, we do not know how many of them will be poor and undernourished. The absolute number of urban poor and undernourished will increase unless urban poverty incidence and undernutrition prevalence rates are reduced in direct proportion to the growth in urban populations. Second, will the absolute number of urban poor and undernourished increase more quickly than the rural number? In other words, will there be a shift of poverty and undernutrition from rural to urban areas? Third, for those living in urban areas, are the constraints to, and the opportunities for,

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Fig. 1. Trends in percent of the population living in urban areas by region (1795–2025). Adapted with permission from ref. (2).

the generation of income, food security, and improved nutrition status different from what is faced in rural areas? Fourth, what do the answers to the ﬁrst three questions imply for policy research and for policymaking?

2. INCREASING URBAN POVERTY AND UNDERNUTRITION Reliable numbers on the growth of urban poverty and undernutrition and their share in national poverty and undernutrition are generally not available. Speciﬁcally, there is a lack of readily available data to answer the questions: (1) are the absolute numbers of poor people and underweight young children living in urban areas increasing, and (2) do they represent an increasing share of the total poor and underweight young children? We used data from the World Bank for poverty and from the World Health Organization (WHO) for malnutrition to examine these issues.2 The data sets gathered provided information disaggregated into rural and urban areas for a number of countries over at least two points in time. From the available data, we selected the 8 countries that had the most credible rural and urban headcount poverty incidence at two points in time. Similarly, from the WHO data set, we selected 14 countries with the most comparable rural and urban underweight prevalence numbers at two points in time. Precise information on the criteria used for the selection of the data sets and detailed tables with all the numbers used are presented elsewhere (3). Only a summary of the main ﬁndings is presented here.

2.1. Poverty Data The results of the poverty data are summarized in Fig. 2 and Table 1. They show that for 7 of the 8 countries included, the share of poor people in urban areas is increasing over time, and for 5 out of 8 countries, both the absolute number of urban poor and the share of poor people living in urban areas are increasing over time (Bangladesh, China,

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Table 1 Summary of Poverty Results Absolute number of urban poor increasing Share of urban poor increasing

Share of urban poor decreasing

Bangladesh 1983–1992 China 1988–1995 Ghana 1987–1993 India 1977–1994 Nigeria 1985–1993 Indonesia 1990–1993

Absolute number of urban poor decreasing Pakistan 1984–1991 Colombia 1978–1992

Ghana, India, and Nigeria). Note that the 8 countries selected account for approx twothirds of the developing world’s people. The only country for which the share of poor people in urban areas is decreasing is Indonesia over the 1990–1993 period, but this is the country for which the interval between the two points in time was the shortest (only 3 yr). It is also striking to observe that for many of these countries, the share of poor people that live in urban areas in the 1990s has now reached a quarter to a third of all poor households. These data strongly support the argument that urban poverty has been increasing between the 1980s and the 1990s in these large countries.3

2.2. Nutrition Data Similar results were found for the prevalence of underweight children:4 the share of underweight children in urban areas is increasing for 11 out of 14 countries (Fig. 3) and both the absolute number of underweight children in urban areas and the share of underweight children contributing to total undernutrition are increasing for 9 out of 14 countries (Table 2). Again, this latter set of countries constitutes a large percent of the developing world, given that it contains China, Bangladesh, Nigeria, Egypt, and the Philippines. Note that the share of undernourished children living in urban areas reaches 40% and more in 4 countries (and more than 50% in Brazil). Only China, Bangladesh and Nigeria overlap from the poverty and underweight children data sets, and they show the same pattern in urban poverty as they do in urban underweight. Hence, for the majority of the countries examined, we can say: (1) the number of urban poor is increasing, (2) the share of the urban poor in overall poverty is increasing, (3) the number of underweight preschoolers in urban areas is increasing, and (4) the share of urban preschoolers in overall numbers of underweight preschoolers is increasing. Thus, the locus of poverty and undernutrition does seem to be changing from rural to urban areas, at least based on the data we have presented.

3. CHALLENGES TO OBTAINING FOOD, NUTRITION, AND HEALTH SECURITY IN AN URBAN ENVIRONMENT The premise of this section is that the causes of malnutrition and food insecurity in urban and rural areas are different, owing primarily to a number of phenomena that are unique to or are exacerbated by urban living and by the circumstances that brought

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Fig. 2. Trends in the percentage of poor people who reside in urban areas. Adapted with permission from ref. (3).

Fig. 3. Trends in the percentage of underweight children living in urban areas. Adapted with permission from ref. (3).

the individual to the urban area in the ﬁrst place. We brieﬂy discuss the following phenomena (or “urban facts of life”) and the pressure they place on the attainment of household and individual food, nutrition, and health security: 1. 2. 3. 4. 5.

A greater dependence on cash income for food and nonfood purchases; Weaker informal safety nets; Greater labor-force participation of women and its consequences for child care; Lifestyle changes, particularly those related to changes in diet and exercise patterns; Greater availability of public services such as water, electricity, sewage, and health, but questionable access by poor slum dwellers;

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Table 2 Summary of Underweight Children Results Absolute number of urban underweight children increasing Share of urban underweight children increasing

Share of urban underweight children decreasing

Bangladesh, 1985–1996 China 1992–1995 Egypt, 1990–1995 Honduras 1987–1994 Madagascar 1992–1995 Malawi 1992–1995 Nigeria 1990–1993 Philippines 1987–1993 Uganda 1988–1995 Tanzania 1991–1996

Absolute number of urban underweight children decreasing Brazil 1989–1996 Mauritania 1990–1996

Peru 1991–1996 Zambia 1992–1997

6. Greater exposure to environmental contamination (water, food, and air); and 7. Governance by a new, possibly nonexistent, set of property rights.5

The main focus of the discussion is on identifying what is different about urban areas, which should help frame the program and policy responses that are discussed in the ﬁnal section.

3.1. The Importance of Markets and Money in Urban Areas Compared to rural consumers, who can often produce their own food, urban consumers must depend largely on food purchases. This dependence on the market is further increased by the fact that, unlike their rural counterparts, they cannot rely on exploitation of natural resources to provide for housing, energy, and water. Food expenditures almost always comprise a larger percentage of total outlays for urban than rural households in the developing world. A survey of the 100 largest metropolitan areas of the world showed that food costs were greater than 50% of household expenditures in 23 cities (4). In Accra we found that households on average purchase 90% of their food (5). Clearly food prices and the ability to earn cash income are crucial to the achievement of food security in urban areas. The cost of food for urban consumers depends on a number of factors including: (1) the efﬁciency of the food production and marketing system, (2) the availability and access to food subsidies or other food programs, and (3) exchange-rate policies. Urban marketing systems are highly diverse, but are not especially well-integrated. Wholesale markets that connect producers and traders with retailers are often run-down and obsolete, with ineffective and often obstructive management. Urban retailers, particularly in poor areas, are small and scattered. In the absence of well-integrated markets, food prices are higher than what they could be and are particularly susceptible to seasonal ﬂuctuations (6). Macroeconomic policies can also have a signiﬁcant impact on the price of urban food. For many years, “cheap food” policies, including widespread subsidies, overvalued

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exchange rates, and trade restrictions deliberately kept the price of urban food low, but structural adjustment programs have reversed many of these policies. As anticipated, the urban poor have not done well in the short-run (7,8). Demery and Squire report that even in Ghana, a country that has shown substantial commitment to economic reform and where rural poverty has decreased, poverty in the capital city of Accra has increased (7). The ability of the urban poor to obtain enough food for a healthy and active life depends primarily on their ability to earn income, yet most urban dwellers work in sectors such as petty trade or construction where wages are low and job tenure is insecure. In sub-Saharan Africa, for instance, employment in sectors that pay regular wages, such as manufacturing and industry, accounts for less than 10% of total employment (9). Some households improve their access to food by growing food on their own plots inside or outside the city. Urban agriculture is practiced by as much as 40% of the population in African cities, and up to 50% in Latin America (10,11). But even where widely practiced, it is rarely the primary source of food. For example, approx 55% of poor urban households in peri-urban Dar es Salaam farm, but they only rely on production from their plots for 2 or 3 mo each year (12). Still, urban agriculture can be an important coping strategy for some households and may have an important impact on nutrition, especially among poorer households (13).

3.2. Stronger Formal Safety Nets and Weaker Informal Safety Nets? An important question for this review is whether urban populations tend to have better access to formal safety nets than rural populations. Two factors that suggest that they do would be (1) the ease of reaching urban populations in contrast with the difﬁcult logistics of reaching the rural poor, and (2) the proximity and visibility of the urban poor to those in power. Our review of World Bank Poverty Assessments from sub-Saharan Africa, however, indicates only a very weak bias towards urban areas in terms of formal safety net coverage (14). There were 88 programs in urban areas and 76 in rural areas. Removing the programs where we were not sure as to location resulted in 36 programs in urban areas and 31 in rural areas.6 It would be useful to conduct this exercise for other regions to verify whether these ﬁndings hold elsewhere. The next question is whether urban areas have weaker informal safety nets. Again, there has been very little work on this issue. Informal safety nets take on a number of forms such as food sharing, child fostering, loans, membership in groups, the receipt and provision of remittances, the sharing of housing, and the lending of land and livestock, to name only a few. These links tend to be most extensive and strong within immediate and extended family, because they rely heavily on social trust and reciprocity. Informal safety nets are mechanisms that evolve so as to minimize exposure to adverse shocks, and to maximize the ability to cope, ex-post, with shock. They are underpinned by social capital. Social capital refers to “features of social organization such as networks, norms, and social trust that facilitate coordination and cooperation for mutual beneﬁt” (15). Are stocks of social capital lower in urban areas? This is an open question. Factors associated with urban life that might be expected to diminish social capital include: (1) a looser deﬁnition of community and hence less identiﬁcation with it; (2) a greater incidence of violence, which rapidly diminishes the trust necessary for nonfamily collective action; (3) the nonproximity of family members from different generations,

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which reduces the ability to undertake activities that do not rely on immediate reciprocity. On the other hand, information ﬂows are better, so opportunities for collective action for mutual beneﬁt will be greater. Also, non-government organizations (NGOs) and community-based organizations are often active in urban areas, and can serve as important catalysts for improved social cooperation. It may also be the case that access to formal safety nets diminishes the demand for social capital formation and hence the use of informal safety nets. Haddad and Zeller (16) summarize several studies that indicate that formal safety nets have partially crowded out private informal safety nets.

3.3. The Increased Labor-Force Participation of Women and its Consequences for Child Care It is thought that urban living generally implies greater female labor-force participation and a more distinct separation of dwelling location and work location for both men and women. Other stylized facts suggest that the higher proportion of female-headed households and the smaller household sizes in urban areas reduce the household’s supply of alternate caregivers and result in harsher tradeoffs for women between time spent in income generation (their productive role) and time spent in their reproductive, maternal, and caring roles. Employment conditions are often not ﬂexible enough to reduce the sharpness of these tradeoffs. We analyzed data from the Demographic Health Surveys (DHS) from 11 countries (2 in Asia, 4 in Africa, and 5 in Latin America) to verify some of these facts. We selected data sets that had an urban sample greater than 500 mother/child pairs, and for which data were available on maternal employment and use of alternative child-care. We compared women’s patterns of employment and use of child-care alternatives between rural and urban areas and also looked at differences in the percentage of women-headed households (Table 3). The hypothesis that urban areas host greater percentages of women-headed households was conﬁrmed for Latin American and for two of four African countries, but not for Asia. In Bangladesh and Pakistan, women-headed households represent only about 8 and 6% of households, respectively, and there are no urban/rural differences. Our second hypothesis that more women worked in urban areas, and particularly away from home, was also conﬁrmed only for Latin America (with the exception of Peru). In Asia and Africa, the percentage of women working was consistently greater in rural areas, and even the percentage of rural women working away from home was higher that that of urban women in most of the African and Asian countries studied. In terms of child-care arrangements, a smaller percentage of urban mothers took their child to work with them, probably because they tend to work in the streets, in markets, or in factories rather than in agriculture like rural women do. In Latin America, a greater percentage of urban mothers used relatives as alternative child carers compared to rural dwellers, but no consistent pattern was found in Asia and Africa. Hired help and institutional care were consistently higher in urban areas in all three regions, although institutional care use was almost nonexistent in Asia and very uncommon in three of the four African countries studied. It is likely that such low reported use of institutional care is related to lack of availability of these services in the countries studied. In sum, the DHS data indicate that more than half of the women in both urban and rural areas of Africa and Latin America are involved in income generating activities.

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Table 3 Comparison of Women’s Work and Child-Care Arrangements in Urban and Rural Areas Child care arrangements % Women household heads Country/yr

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Asia Bangladesh (1993) Pakistan (1991) Africa Ghana (1993) Tanzania (1991–1992) Senegal (1992–1993) Zambia (1992) Latin America Brazil (1996) Dominican Republic (1991) Peru (1992) Colombia (1995) Guatemala (1995)

% Mothers who work outside of home (wage or self-employed)

% Mothers who take care of child at all time

% Using relatives for child care

% Using hired help

% Using day-care centers

Urban Rural Urban Rural Urban Rural Urban Rural Urban Rural Urban Rural Urban Rural 18.6 16.2

18.0 16.3

27.7 12.9

38.2 18.4

13.9 14.1

16.0 17.1

47.7 65.0

71.6 62.6

40.2 31.9

25.4 34.5

13.7 10.7

0.3 0.4

10.0 10.0

0.5 0.0

35.1 25.0 25.4 14.8

36.0 14.4 9.2 15.8

66.3 59.7 41.9 46.4

79.2 69.0 46.0 50.5

43.4 38.0 28.5 33.1

50.7 42.2 36.4 32.2

47.6 34.3 47.0 46.4

54.5 42.4 52.4 63.1

32.6 52.0 41.3 47.0

38.0 54.1 45.2 35.4

11.1 19.7 18.6 14.9

0.3 1.1 0.6 0.8

13.8 10.3 11.3 10.6

4.7 0.1 0.3 0.1

20.5 29.6

11.0 17.6

62.0 53.6

56.1 46.4

48.4 30.0

42.2 14.8

20.2 43.8

22.0 60.8

43.9 40.8

33.9 35.1

12.4 17.2

3.9 1.5

19.8 10.5

2.2 0

15.5 26.3 22.2

10.4 15.6 17.1

50.6 62.2 47.1

57.3 50.0 27.6

33.2 46.4 27.3

14.0 27.6 11.3

45.0 22.6 37.2

75.6 37.8 51.0

44.2 41.7 26.3

21.6 33.1 18.9

17.2 18.4 16.3

0.9 1.7 1.9

11.4 15.2 11.2

0.1 1.0 01. Ruel et al.

Adapted from ref. (14).

% Mothers who work

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The greater proportion of women working outside the home in urban areas is conﬁrmed only for Latin American countries. In Africa, more rural women work outside the home than urban women in three of the four countries studied. The main difference between rural and urban areas is in the use of hired help and institutional care, both of which are consistently higher in urban areas. Urban mothers are also less likely than rural mothers to take their child along when they go to work. The greatest threat of maternal employment to child caring is its potential negative impact on breast feeding practices. It is generally believed that urban mothers are less likely to initiate breast feeding and more likely to wean earlier if they do breast feed. Our previous analysis of DHS data from 35 countries, however, does not indicate such clear patterns (17). We found that, although the percentage of children ever breast fed tends to be lower in urban areas, the pattern is not fully consistent and differences are generally of small magnitude. Urban mothers were found to initiate breast feeding at a surprisingly high rate (greater than 90%). The median duration of breast feeding, on the other hand, was consistently shorter in urban areas, sometimes 4–6 mo shorter. Exclusive and full breast-feeding duration was much shorter than the recommended 4–6 mo everywhere, but there were no urban/rural differences.

3.4. Lifestyle Changes 3.4.1. DIETARY PATTERNS The nutrition transition, which is characterized by changes from diets rich in complex carbohydrates and ﬁber (mainly from food staples) to more varied diets with higher proportions of fat, reﬁned sugars, and meat products as populations move from rural to urban areas, is well-documented both globally and in a number of individual countries. A classic study using data from 85 countries showed a positive linear relationship between gross national product (GNP) per capita and energy intake from reﬁned sugars and from vegetable and animal fats (18). Whereas the poorer nations derived approx 5% of their energy from animal fat in 1962, richer countries reached 38%. A recent similar analysis using data from 133 countries in 1990 gives an interesting twist to these ﬁndings. Drewnowski and Popkin (19) show that the income-fat relationship has changed over time, and that total fat consumption is less strongly associated with GNP than before. Overall, richer countries have decreased their total fat intake, whereas poorer countries are now consuming diets much higher in fat than three decades ago. An independent effect of urbanization on changes in diet structure was also apparent in these data, as well as a signiﬁcant interaction between GNP and urbanization, which indicated a greater effect of urbanization on reﬁned sugars and total fat consumption among lower income countries compared to richer nations. These results suggest that the accelerated rates of urbanization currently found in many developing countries are likely to generate rapid and most likely negative shifts in dietary patterns over the next few years. There are various reasons why urban diets tend to be different (and usually more diverse) than rural diets; namely, higher income, changing values and norms, and cultural diversity. Studies have also shown that the greater consumption of processed and prepared foods in urban areas is largely driven by the opportunity cost of women’s time (20–22). Bouis and Huang (23) in an analysis of data from China and Taiwan attribute about 20% of the increases in consumption of meat, ﬁsh, and dairy products to the nonincome or structural factors associated with moving from a rural to an urban residence. Traditional staples are also often more expensive in urban areas than in rural areas,

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whereas the opposite is true for processed foods (24), which means that it is relatively less expensive to shift away from traditional staples to processed foods in urban areas. 3.4.2. ACTIVITY PATTERNS Parallel to these changes in diet, shifts in activity patterns as populations migrate from rural to urban areas also occur. Urbanization is accompanied by trends towards less physically demanding occupations on a worldwide basis, particularly in lower-income countries (25). This results from both an increase in the less physically demanding types of employment such as manufacturing and services, and a decrease in the more labor-intensive agricultural employment, as well as new technologies that have tended to reduce the physical effort involved. The increased use of public and private transportation, of technology, and of paid help for domestic activities, and the shift to more passive leisure activities such as television and computer games, also contribute to reductions in activity levels and affect adults and children alike (26). 3.4.3. HEALTH IMPLICATIONS The health implications of the changes in dietary and activity patterns associated with urbanization are of much concern. Greater dietary diversity may have a positive impact on micronutrient status and malnutrition, but the higher fat and reﬁned sugar content of diets, combined with the more sedentary lifestyle, increase the risks of obesity, cardiovascular diseases, certain forms of cancers, and other chronic diseases. Increased rates of smoking, stress, substance abuse and the overall environmental contamination found in large cities further exacerbate these risks. Obesity, and childhood obesity in particular, has increased so rapidly worldwide in the last few decades that it has been declared a public health problem in many countries and even an epidemic in some (25–29). The co-existence of obesity and stunting in young children (30) as well as the co-existence of obese parents and malnourished children, is also surprisingly common in many large urban areas of the developing world (5). Malnutrition during critical periods of gestation and early infancy, followed by the changes in dietary patterns related to urbanization, is also thought to increase the risks of chronic diseases at adulthood (31,32). The rapid increase in obesity worldwide and in urban areas in particular is rapidly becoming a serious public health concern even for low- and middle-income countries. Considering the unequivocal link between obesity and a large number of chronic diseases risks, the obesity epidemic has to be taken seriously.

3.5. Increased Availability of Services, But Questionable Access by Poor Households Health services, potable water, sanitation facilities, and garbage disposal are usually more available in urban rather than rural areas (33), but the rapid population growth experienced by a large number of cities in the developing world has caused a breakdown in the provision of urban services. Governments are unable to respond to these population pressures, and statistics show that although up to 80% of the rich in developing countries’ urban areas have access to water, less than 20% of the poorer households do (34). In many cases, poor urban dwellers have to buy water at an extravagant cost (35). Poor urban dwellers are also much less likely to have access to

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adequate sanitation and garbage-collection facilities, even in cities where wealthier households all have private bathrooms and regular garbage pick-up. The availability and use of health services are also greater in urban areas. Our review of DHS data from 35 countries conﬁrmed that overall, urban dwellers are more likely to use health services both for curative purposes—when children have acute respiratory infections, fever, or diarrhea—and for preventive services such as immunization (17). Simple urban/rural comparisons have limitations, however, because they mask the enormous differentials found within an area. Pockets of under-covered population are known to exist in poor shanty towns, and these populations are also those that experience the greatest risks of infectious diseases (26). Lower education levels and greater time constraints, combined with limited knowledge and awareness of the existence and potential beneﬁts of these services, make the urban poor less likely to use the facilities even if they are available. Additionally, the lack of supplies, the unfriendly attitude of some health workers, the unsanitary conditions and the overcrowding of the facilities, as well as their inconvenient open hours may discourage poor families from using them.

3.6. Environmental Contamination The lack of access to basic water, sanitation, drainage, and solid-waste disposal services make it almost impossible for poor urban dwellers to prevent contamination of water and food, maintain adequate levels of hygiene, or control insect-vectors of disease (such as malaria). In addition, they are exposed to excessive air pollution (both outdoor and indoor). This results in high rates of infectious diseases among both adults and young children in these areas. 3.6.1. AIR POLLUTION Worldwide, more than 1.1 billion people live in cities with levels of air contamination in excess of the standards established by the World Health Organization (WHO) (33). This affects both the poor and the rich alike. Poor urban dwellers, however, are likely to be more exposed to two additional sources of air pollution: indoor air pollution from poorly functioning cooking stoves and contaminants from industrial sites (33). The latter is owing to the fact that urban squatters are often established close to pollution industries, in sectors of the city that wealthier groups tend to avoid, and poor urban dwellers are also more likely to work in these industries and to be exposed directly to toxic chemicals. Air pollution (both indoor and outdoor) is associated with increased acute respiratory infections, asthma, and mortality from pneumonia in children, as well as chronic lung diseases and cancers in adults (37). In Mexico City, air pollution is estimated to cause 12,500 extra deaths and 11.2 million lost work days per year owing to respiratory illnesses (38). Exposure to lead is also thought to be responsible for the reduced intellectual performance of 140,000 children, and up to 29% of all children living in Mexico City have unhealthy blood lead levels (38). 3.6.2. WATER AND FOOD CONTAMINATION Water-borne diarrheal diseases are known to be highly prevalent in urban areas, mainly as a result of contaminated water and food, crowding, limited access to water, and

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poor food and household hygiene (39). Prevalence of diarrhea among young children in urban areas is often as high as in rural areas. Our review of DHS data from 35 countries (total of 42 data sets) shows higher prevalences of diarrhea in urban compared to rural areas in up to one-third of the data sets reviewed (17). Further analyses of 11 data sets also revealed that differences between low and high socioeconomic status (SES) quintiles within urban areas were consistently larger than differences between low and high SES groups in rural areas (14).7 The prevalence of diarrhea among the urban low SES group was often greater than among the rural low SES group (in 7 of the 11 countries studied). Thus, overall diarrhea prevalence rates in urban areas rival those found in rural areas, and poor urban dwellers are often worst off than the rural poor in that regard. Contamination of water and food, and particularly of street foods are probably largely responsible for a signiﬁcant proportion of gastrointestinal infections in urban areas.

3.7. Legal Rights How do legal rights in the areas of employment, land, residence, and water use vary between rural and urban areas? Whereas employment rights are likely to be well-deﬁned in the urban formal sector, the extent of their enforcement is unclear. In addition, the formality and strength of land and water user rights in rural areas will vary by region, by time, and by the gender of potential owners or users (40). Newcomers to urban areas, if not linked to well-established urban families, may ﬁnd themselves literally on the periphery of the city and relying on a shaky or nonexistent set of rights in the aforementioned domains. These underdeveloped rights will likely have costly effects. We provide three examples where legal and regulatory changes may be needed to promote food and nutrition security in urban areas: urban agriculture, street foods, and land and housing tenure. 3.7.1. URBAN AGRICULTURE In many cities, agriculture is illegal. Frequently, urban farmers do not own the land but use public space or use vacant lots of private owners, with or without their permission. With low-tenure security and questionable legality, the farmer is not motivated either to be efﬁcient or to care for the land. These constraints are often exacerbated by the fact that in many cities it is mostly women who are involved in urban agriculture. Legal and cultural biases against women owning or even leasing land make their attempts at urban farming even more difﬁcult. The uncertain legal status of urban agriculture is such that ofﬁcial projects or programs aimed at improving urban agriculture have been rare. In combination with a weak legal framework, the lack of awareness and of government recognition means that planners often do not think about how to provide water and drainage infrastructure to handle urban farming and that governments make little provision for research and extension of urban farming techniques (11). Success with urban agriculture does exist, however. For decades, city authorities in Lusaka, Zambia, enforced laws against crop production in the city as a health hazard. Faced with economic decline in the 1970s, however, the Lusaka City Council stopped enforcing the anti-urban agriculture laws. Government stores even made subsidized seeds for fruits and vegetables available. In 1977, 43% of Chawama, one of the largest slums in Lusaka, had home gardens. And a decade later 40% of households still had

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home plots (11). With more knowledge of successful experiences with urban agriculture, city administrators and planners can work to remove existing political, administrative, and legal hurdles for urban agriculture. 3.7.2. INFORMAL MARKETING ACTIVITIES SUCH AS STREET FOODS Street food vendors are ubiquitous in the developing world. Selling street foods represents an important informal sector activity. Despite wanting to stimulate microenterprises, the response of many governments is to either sweep mobile sellers off the street into malls or back alleys; prohibit selling altogether; or subject it to strict regulation. Vendors stay mobile because they cannot afford the start-up capital to establish themselves in a permanent market, where they are subject to inspection and they have to pay fees and taxes. Alternatively, the supply of rights or permits to permanent spaces may be severely restricted (22). Strict regulation of mobile vendors may be detrimental. FAO and WHO warn that if vendors are banned only for the sake of trafﬁc requirements or modernization plans, mobile street food vendors would simply go “underground.” It would become much more difﬁcult to reach vendors through ofﬁcial channels to introduce safety measures or provide key environmental infrastructures and services to reduce health hazards (22). 3.7.3. INSECURITY OF TENURE AND DEVELOPMENT ACTIVITY The NGO and research communities are becoming more aware of the need to understand the determinants of the placement of various development interventions and projects. An improved understanding can: (1) improve estimates of project impact (41), (2) identify mismatches between community need and project location, and (3) provide some insight into the political and institutional factors that drive the development process. Recent work by International food policy (IFPRI) and CARE indicates that one of the key determinants of NGO intervention and civic engagement may be the security of tenure of individuals in the community (42).

4. IMPLICATIONS FOR POLICY AND RESEARCH Policy makers need to address the aforementioned issues to promote the welfare of their urban citizens and the stability of government. They need to ﬁnd policy and program instruments that can: 1. Reduce the cost of food to urban consumers and create income generating opportunities for them; 2. Provide low-cost efﬁcient safety nets for those who cannot help themselves and stimulate the generation of social capital; 3. Ease the tradeoffs for mothers by providing acceptable and affordable child-care substitutes, and ensuring the safety of prepared and processed foods sold in the streets; 4. Increase resources to primary health care and nutrition in an attempt to reduce tertiary health expenditures; 5. Improve water and sanitation services, which are so important to households and to food vendors; 6. Reduce the general level of contamination; and 7. Redeﬁne, respect, and enforce property rights that balance the needs of consumers and producers.

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Good information and analysis will shorten the process of trial and error in the design of effective policies and interventions. However, the relatively slow awakening of the policy research community to urban poverty, food insecurity, and malnutrition has left many questions unanswered. First and most basic, we need to answer the question: what is the state of urban poverty, food security, and undernutrition? What are the absolute numbers of the poor and malnourished in urban and rural areas for countries that do not have currently available data? What are the trends over time for other countries? Will the share of poverty and undernutrition that is urban continue to increase for those countries where this pattern is already seen? To answer these questions, we need to collect more data on urban areas and we need to do a better job in addressing some of the difﬁculties faced in getting accurate numbers on urban poverty and undernutrition. Second, we need to explore the reasons for these levels and trends. Why, for example does the share of poverty in urban areas appear to be decreasing in some countries? What are the main determinants of current levels and trends in urban poverty and undernutrition? What are the main constraints to urban income and nutrition generation and how do they differ by country, city size,8 the competence of local governance, the length of residence, the strength of property rights, the maturity of the community, the number of income sources, education levels, health status, and land access? This chapter discusses some of the challenges to income generation, food security, and nutrition that are probably exacerbated in an urban area. Many questions are raised for which there are no ready answers, but as the problems of urban poverty and undernutrition increase, so too will the clamor for answers. Third, where are the models of successful interventions in the policy and program arena? De Haan (43) notes that compared to rural areas, there are fewer examples of successful public policies in urban environments. Whether there truly are fewer examples or whether they have simply not been recorded, best practices in local and national government need to be documented and analyzed. Examples of successful programs and policies that we can learn from are hard to ﬁnd and there have been few systematic attempts to draw out commonalities.9 Last but not least, a whole range of questions and problems remain unanswered and unsolved in relation to our current methods of inquiry in urban areas. First, urban populations are much more spatially mobile than rural populations. This discourages local authorities from drawing up listings of households, and it makes it difﬁcult to rely on existing listings for survey sampling. The larger number of homeless people in urban areas also makes them susceptible to under-representation in any survey. This mobility makes it difﬁcult to track households and individuals over time, which is important if we want to understand the dynamics of poverty and undernutrition. The act of enumerating a questionnaire is much more complex in an environment where there is a dislocation of work and home. Mobility also makes it more difﬁcult to control for community-level effects on household behavior, and indeed to even deﬁne what we mean by a community. Mobility also affects the ease of deﬁning a household unit. The presence of a large proportion of nonfamily household members such as tenants and seasonal residents may be more important for urban households and adds to the complexity of household deﬁnition. Second, time is more scarce in an urban setting, which makes long interviews difﬁcult to administer. Security is also often an issue for ﬁeld workers and night-time inter-

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viewing, which would be the only option, because ﬁnding people at home is often not possible. Finally, in the area of income generation, the relative anonymity of the urban center is likely to make illegal income generation more widespread, and this type of income generation activity is notoriously difﬁcult to capture in a questionnaire. Other censured information includes violence and substance abuse.10

5. CONCLUSIONS The economic reforms of the past 15 years have probably reduced urban bias, and may have even removed it in some countries. The legacy of urban bias remains however, and there is a greater need than ever to stimulate agricultural intensiﬁcation, particularly in the poorer countries of sub-Saharan Africa and South Asia (44). Nevertheless, as we have shown, the best available data indicates that urban poverty and undernutrition are increasing and are doing so at a faster rate than rural poverty and undernutrition. We view this closing of the rural-urban gap as a sufﬁcient basis to call for more research on urban poverty, food, and nutrition issues, and in this chapter we have indicated the areas in which we think more work is needed. It is important to remember, however, that there is still a poverty and undernutrition gap, and in the least urbanized countries, it is wide. Hence it would be very premature to argue for even a small reallocation of government and NGO development resources from rural to urban areas. Can those who inﬂuence development policy and programs avoid the temptation to spend more money on urban problems and instead revisit how the existing envelope of urban resources is allocated? Given political realities, this temptation will be difﬁcult to resist and that is why the documentation of success stories of urban governance will be so important. But is it even reasonable to ask policymakers to respond to increased data and analysis on urban problems without drawing development resources away from rural areas? This is a question that is impossible to answer at this stage. It is our strong opinion that much more can be done with existing resources, but this, like all the other questions posed in this chapter, is a researchable issue and one that should challenge policy researchers and policymakers over the next generation.

ACKNOWLEDGMENTS Many of the ideas in this paper have been developed in the context of a wider IFPRI multicountry research program on Urban Challenges to Food and Nutrition Security. In particular, we would like to thank Daniel Maxwell, Saul Morris, Carol Levin, Patrice Engle, Arne Oshaug, and Bonnie McClafferty for their insights on the issues we present; and Alison Slack of IFPRI and Purnima Menon of Cornell University for their invaluable research assistance.

ENDNOTES 1Two

examples of these are to be found in United Nations Center for Human Settlements (UNCHS) (1). First, the overall numbers are sensitive to different deﬁnitions of what is urban in large countries such as China, India, and Brazil. Second, “urban” does not equal “city,” small market towns and administrative centers are important urban centers. 2The poverty data were assembled in large part from World Bank poverty assessments and the underweight data were assembled from WHO’s Global Database on Child Growth and Malnutrition (2b).

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3A similar analysis was carried out with data from 12 countries from Latin America for which we did not have sufﬁcient information as to whether cost of living adjustments were made over time to include in this table. The ﬁndings, however, are consistent: both the share of urban poverty and the absolute number of urban poor increased between the 1980s and the 1990s in 11 of the 12 countries for which data were available. The exception was Chile. 4The prevalence of underweight, as opposed to stunted children, was examined because data on height-for-age were usually not available in the data sets used. We recognize, however, the limitations of underweight data, which do not allow to differentiate between stunting (low height-for-age) and wasting (low weight-for-height). 5This list was derived based on an extensive survey of the literature (17) and a stakeholder assessment conducted as part of the process of deciding whether IFPRI should launch a program of research on urban poverty, food insecurity, and undernutrition. 6Obviously, not all programs are the same size and have the same coverage. Unfortunately, expenditure ﬁgures were unavailable for most of the programs and in any case it was not possible to verify the accuracy of these reported ﬁgures. 7We created a socioeconomic index score using data on quality of housing and household assets. The score was created separately for rural and urban areas of each country using principal components analysis. The factor scores obtained were ranked to divide the sample in socioeconomic status (SES) quintiles. 8As suggested by Brockerhoff and Brennan (1997) (42b). 9For a selected set of examples of successful interventions, see ref. 14. 10More on the methodological problems associated with research in urban areas can be found in MP14 Team (1997).

REFERENCES 1. UNHCS. An Urbanizing World: Global Report on Human Settlements, 1996. Oxford, UK: Oxford University Press, 1996. 2. United Nations. World Urbanization prospects: The 1996 Review. Department for economic and social affairs. Population division. ST/ESA/SER.A1170. New York: UN, 1998. 3. Haddad L, Ruel MT, Garrett JL. Are urban poverty and undernutrition growing? World Development 2000; 27:1891–1904. 4. Population Crisis Committee (PCC). Cities: Life in the World’s 100 Largest Metropolitan Areas. Washington DC: PCC, 1990. 5. Maxwell D, Levin C, Armar-Klemesu M, Ruel MT, Morris SS, Ahiadeke C. Urban Livelihoods, and Food and Nutrition Security in Greater Accra Ghana. International Food Policy Research Institute Research Report No. 112 Washington DC: International Food Policy Research Institute, 2000. 6. Food and Agriculture Organization of the United Nations (FAO). Food Supply and Distribution to Cities. Rome: FAO, 1997. 7. Demery L, Squire L. Macroeconomic adjustment and poverty in Africa: An emerging picture. World Bank Research Observer. February 1996; 11:39–60. 8. Sahn DE, Dorosh P, Younger S. Structural Adjustment Reconsidered: economic policy and poverty in Africa. New York, Cambridge: University Press, 1997. 9. Rondinelli D, Kasarda JD. Job creation needs in third world cities. In: Third World Cities. Kasarda JD, Parnell AM, eds. London: Sage Publications, 1993, pp. 92–119. 10. Mougeot L. Overview–urban food self-reliance: Signiﬁcance and prospects. IDRC Reports 1993; 21(3): 2–5. 11. United Nations Development Programme (UNDP). Urban Agriculture: Food, Jobs and Sustainable Cities. New York, NY: UNDP, 1996. 12. CARE/Tanzania. Dar es Salaam Urban Livelihood Security Assessment. Summary Report. Dar es Salaam, Tanzania: CARE/Tanzania, 1998. 13. Maxwell D, Levin C, Csete J. Does Urban Agriculture Help Prevent Malnutrition? Evidence From Kampala. Food Consumption and Nutrition Division Discussion Paper #45. Washington DC: International Food Policy Research Institute, 1998.

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14. Ruel MT, Haddad L, Garrett JL. Some urban facts of life: implications for research and policy. World Development. 2000; 27:1917–1938. 15. Putnam R. Bowling alone: America’s declining social capital. J Democ 1995; 6:65–78. 16. Haddad L, Zeller M. How can safety nets do more with less? General issues with some evidence from southern Africa. Dev South Afr 1997; 14:125–153. 17. Ruel MT, Garrett JL, Morris SS, Maxwell D, Oshaug A, Engle P, et al. Urban challenges to nutrition security: a review of food security, health and care in the cities. Food Consumption and Nutrition Division Discussion Paper #51. Washington DC: International Food Policy Research Institute, 1998. 18. Périssé J, Sizaret F, François P. The effect of income and the structure of the diet. FAO Nutr Newslet 1969; 7:1–9. 19. Drewnowski A, Popkin BM. Dietary fats and the nutrition transition: new trends in the global diet. Nutr Rev 1997; 55:31–43. 20. Senauer B, Sahn D, Alderman H. The effect of the value of time on food consumption patterns in developing countries: evidence from Sri Lanka. Am J Econ 1986; 68:920–927. 21. Atkinson SJ. Food for the Cities: Urban Nutrition Policy in Developing Countries. Urban Health Program, Health Policy Unit. London: Department of Public Health and Policy, School of Hygiene and Tropical Medicine, 1992. 22. Tinker I. Street Foods: Urban Food and Employment in Developing Countries. New York, NY: Oxford University Press, 1997. 23. Bouis H., Huang J. Structural Changes in the Demand for Food in Asia. Food, Agriculture, and the Environment Discussion Paper #11. 2020 Vision. Washington DC: International Food Policy Research Institute, 1996. 24. Musgrove P. Basic food consumption in north-east Brazil: effects of income, price, and family size in metropolitan and rural areas. Food Nutr Bull 1988; 10:29–37. 25. Popkin BM, Doak CM. The obesity epidemic is a worldwide phenomenon. Nutr Rev 1998; 56: 106–114. 26. Caballero B, Rubinstein S. Environmental factors affecting nutritional status in urban areas of developing countries. Arch Latinoam Nutr 1997; 47:3–8. 27. Martorell, R, Khan LK, Hughes ML, and Grummer-Strawn LM. Obesity in Latin America women and children. J Nutr 1998; 128:1464–1473. 28. World Health Organization (WHO). Diet, Nutrition and the Prevention of Chronic Diseases. Geneva: WHO, 1990. 29. WHO. Obesity. Preventing and Managing the Global Epidemic. Geneva: WHO, 1998. 30. Popkin BM, Richards MK, Montiero CA. Stunting is associated with overweight in children in four nations that are undergoing the nutrition transition. J Nutr 1996; 126:3009–3016. 31. Barker DJ. Fetal and infant origins of adult disease. BMJ 1990; 301:1111. 32. Barker DJ. Mothers, babies, and disease in later life. London: BMJ Publishing Group, 1994. 33. World Resources Institute (WRI). The United Nations Environmental Programme, The United Nations Development Programme, and The World Bank. World resources 1996–1997. A guide to the global environment. The urban environment. New York: Oxford University Press, 1996. 34. WHO and United Nations International Children’s Emergency Fund (UNICEF). Water Supply and Sanitation Sector Monitoring Report 1993. New York and Geneva: WHO and UNICEF Joint Water Supply and Sanitation Monitoring Programme, 1993. 35. Briscoe J. When the cup is half full: improving water and sanitation services in the developing world. Environment 1993; 35:7–37. 36. Atkinson SJ, Cheyne J. Immunization in urban areas: issues and strategies. Bull WHO 1994; 72: 183–194. 37. Smith KR, Liu Y. Indoor air pollution in developing countries. In: Epidemiology of Lung Cancer (Samet J M, ed.) New York, NY: Marcel Dekker, Inc., 1994, pp. 154–163. 38. Bartone C, Bernstein J, Leitmann J, Eigen J. Toward Environmental Strategies for Cities: Policy Considerations for Urban Environmental Management in Developing Countries. Urban Management Programme Policy Paper No 18. Washington DC: World Bank, 1994. 39. Bradley D, Stephens C, Harpham T, Cairncross S. A review of environmental health impacts in developing country cities. Washington DC: World Bank, 1992. 40. Meinzen-Dick R, Brown LR, Feldstein HS, Quisumbing AR. Gender, property rights, and natural resources. Food Consumption and Nutrition Division Discussion Paper #29. Washington DC: International Food Policy Research Institute, 1997.

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41. Pitt M, Rosenzweig M, Gibbons D. The determinants and consequences of the placement of government programs in Indonesia. In: Public Spending and the Poor: Theory and Evidence. De Walle D, Nead K, eds. Baltimore and London: Johns Hopkins University Press for the World Bank, 1995. 42. CARE/Bangladesh. Report—Urban Livelihood Security Assessment in Bangladesh. February 1998. Dhaka, Bangladesh: CARE/Bangladesh, (mimeo), 1998. 42b. Brockerhoff M, Brennan E. The Poverty of Cities in the Developing World. Working Paper 96. New York, NY: Policy Research Division, The Population Council, 1997. 42c. MP14 Team. Urban Challenges to Food and Nutrition Security. Research Methodology. Washington DC: International Food Policy Research Institute, (mimeo), 1997. 43. de Haan A. Urban poverty and its alleviation. IDS Bulletin 1997; 28:1–8. 44. Pinstrup-Andersen P, Pandya-Lorch R, Rosegrant M. The World Food Situation: Recent Developments, Emerging Issues and Long Term Prospects. Food Policy Report. Washington DC: International Food Policy Research Institute, 1997.

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Assessing and Communicating Impact of Nutrition and Health Programs Saskia de Pee and Martin W. Bloem

1. INTRODUCTION A wide array of programs and projects are conducted for improving nutrition, such as food aid for refugees, support for home gardening, social marketing of vitamin Arich foods, school feeding programs, and campaigns for reducing fat intake and increasing consumption of fruit and vegetables. Annually, a large amount of money is spent worldwide for improving the nutritional situation in developing countries. ‘For example, in 1998, the World Bank spent billions of US dollars on Food and Health programs, and UNICEF spent millions of US dollars on Nutrition programs. To justify these expenditures, programs have to be designed based on a good analysis of the existing nutritional situation. Programs should be critically evaluated, for their implementation as well as for their impact on nutritional status and health. Also, in order to modify them appropriately, evaluation ﬁndings should be properly communicated to the relevant audience. This process is also known as the “triple A” cycle of Assessing a problem, Analyzing its causes, and taking Action based on this analysis (1). Most textbooks to which one can resort for designing a situation-analysis or a program evaluation have been written from a research perspective. They are especially useful when researching information about speciﬁc aspects of nutritional assessment, such as epidemiological design concepts (2), assessment of nutritional status (3–5), or estimation of nutrient intake (7,8). However, when looking for guidance on how to decide what information to collect for a situation-analysis—for example before planning a crisis-relief program targeting poor households, or on how to assess the impact of such a program on health and nutritional status—relatively little information is available. The recently deﬁned ﬁeld of Public Nutrition, which encompasses the range of factors known to inﬂuence nutrition in populations, including diet and health; social, cultural, and behavioral factors; and the economic and political context (8), would focus on such topics and should therefore be of assistance to professionals that have to take a lead in solving nutrition problems.

From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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There are different reasons for the limited amount of information on program-related nutritional assessment. First, because every situation and program is different, it is difﬁcult to give general guidelines about what information to collect and how. Second, only a small portion of a program’s budget is allocated to its evaluation, which is therefore often limited to assessing its implementation. And third, much of the work conducted in the ﬁeld is reported to a limited audience of those directly involved. Therefore, the discussion about dilemmas faced when conducting nutritional assessment for designing, evaluating, and/or adjusting nutrition programs, and the development of knowledge and expertise on this topic is relatively slow. This chapter aims to contribute to such a discussion by suggesting some approaches for designing and conducting datacollection and data-analysis, and communicating and using ﬁndings; and by identifying areas of program-related nutritional assessment that need to be developed. This chapter will ﬁrst focus on the use of a conceptual framework for deciding what information to collect, on designing the survey or evaluation, on preparing the ﬁeldwork, on checking and cleaning the data for analysis, and on communicating the ﬁndings. Then, some examples of situations that may speciﬁcally be encountered when conducting nutritional assessment in developing countries will be discussed. At the end of the chapter, needs for further development of the area of program-related nutritional assessment in developing countries are discussed.

2. CONDUCTING A SITUATION-ANALYSIS OR EVALUATING A PROGRAM’S IMPACT ON NUTRITION AND HEALTH 2.1. Composing and Using a Conceptual Framework In order to evaluate the nutritional situation, a conceptual framework of factors that affect nutritional status has to be composed. Such a framework can be made for a wide array of situations, whether for assessing the situation before designing a program, the impact of a speciﬁc nutrition project, successes in combating vitamin A deﬁciency, the nutritional consequences of a nationwide economic crisis, or the nutritional beneﬁts of a family planning project. Figure 1 gives an example of how UNICEF’s conceptual framework of immediate, underlying, and basic causes of malnutrition (9) has been modiﬁed for vitamin A deﬁciency. In fact, UNICEF’s framework can be adapted to ﬁt many situation-analyses and programs with an impact on nutritional status. Once a conceptual framework has been composed, factors that need monitoring can be identiﬁed and the survey or evaluation can be designed. The designing phase involves several steps (Fig. 2). First, the objective has to be formulated. Second, based on the purpose and scope deﬁned by the objective, a choice has to be made about which of the factors of the conceptual framework information should be collected, by which indicators, and how detailed. Third, a design has to be chosen. And fourth, decisions have to be made about the sample size and sampling scheme. With respect to choosing the factors about which data will be collected, let us consider an example. When a social marketing campaign promotes consumption of dark-green leafy vegetables and eggs, the data-collection should, according to the conceptual framework shown in Fig. 1, at least focus on nutritional status, food intake of individual family members, health, food production (reﬂecting access to food), and mother’s knowledge on nutrition (care). In addition to those factors, which are closely related to nutritional status and/or likely to be affected by the project, other related or

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Fig. 1. UNICEF s conceptual framework of malnutrition applied to vitamin A deficiency. Adapted from ref. (10).

confounding factors, such as socioeconomic status (SES) (basic factor) or distribution of vitamin A capsules (supplementing intake), should also be included. Apart from these impact-related factors, the project s implementation should be monitored. In this case, this could include whether the target population has seen or heard the campaign s messages, as well as the activities of the project, such as number of posters displayed, participation in training sessions, radio spots broadcasted, and so on. For a situationanalysis, the conceptual framework will be similar, but there may be less programrelated factors. After choosing the factors that should be monitored, specific objectives can be formulated and the survey or evaluation be designed.

2.2. Designing the Survey or Evaluation 2.2.1. CHOOSING THE DESIGN The choice of the design depends on the objective. For a situation-analysis, crosssectional data can be collected. For evaluating a program, data should preferably be collected twice, at baseline and at endline, and there may also be a mid-term evaluation. Ideally, the design would also include a control group that is not covered by the program. However, choosing a good control group that is as comparable to the population targeted by the program as possible may be difficult, because the activities of the program—for example, the introduction of seeds and seedlings for home gardening—may spread to nearby communities or households that were not directly targeted by the program. On the other hand, communities that are unlikely to be affected by the program may be relatively far and therefore less comparable to the targeted population. The disadvantage of not having a control group is that it may be difficult to discriminate whether changes are owing to the program or to changes

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Fig. 2. Steps involved in designing a survey or evaluation.

that occurred simultaneously, such as general economic improvement. One way to support the argument that changes of nutritional status are owing to the intervention, in the absence of a control group, is by assessing the changes of various factors of the conceptual framework. When factors that were directly affected by the program changed, changes of nutritional status observed are also likely to be owing to the

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program. Another way that can be used when communities are not all enrolled at the same time (for example, one-third of them per year), is to collect data every year. When changes are related to the program, they should be largest in the communities that were enrolled at the start and smallest in those enrolled last. When changes are to be monitored at a relatively large scale and during a larger period of time, a surveillance system can be set up. For an example of an analysis of the impact of a social marketing campaign in Central-Java on nutritional status using nutrition surveillance data, see ref. 11. A paper on how to design a program evaluation and whether the aim should be to derive a statement on adequacy, plausibility or probability, has been written by Habicht el al. (12). For further information on evaluating implementation and the impact of food-based programs, see refs. 13 and 14. 2.2.2. CHOOSING INDICATORS Before calculating the sample size and choosing the sampling scheme, indicators have to be chosen for the different factors of the conceptual framework about which information will be collected. The best strategy for choosing indicators is to list different topics for each factor, and for each topic, indicators that could be assessed with pros and cons, including speciﬁcity and sensitivity, feasibility of collecting them, and costs. Based on this assessment, a selection can be made. If necessary, a topic can ﬁrst be explored in order to become more familiar with it and to identify relevant indicators or questions. Such an exploration can be done using qualitative methods.1 Some examples of indicators are the following: For vitamin A status, nightblindness and xerophthalmia, which are clinical signs of vitamin A deﬁciency, and serum retinol concentration, a biochemical indicator of vitamin A status. Health indicators often used are diarrhea, body temperature and signs of acute respiratory infections. And for home gardening, an indicator of food production, the following information is often collected, ownership of a garden, source of seeds and seedlings, produce in the previous three months, income from the garden, main use of the income earned, and main person responsible. 2.2.3. SAMPLE-SIZE CALCULATION One of the key questions when designing a survey or evaluation is how many people or households should be surveyed. This should be decided based upon the answers to two questions: (1) what are the most important indicators? and (2) with what precision should their prevalence or their distribution be estimated, or what difference between before and after conducting a program is of interest? The sample size will be larger when the required precision of the estimate is higher, and when the expected prevalence or relative difference is smaller.

1Examples

of qualitative methods are focus-group discussions and participant observation techniques. Often, both qualitative and quantitative methods are needed to get a good impression of a problem and of ways to deal with it. Before a questionnaire can be composed, qualitative research should be done in order to choose and formulate the relevant questions, and after the results have been obtained, qualitative research can reveal why certain relationships exist. How much qualitative research is required depends on familiarity with both the topic and the target population. For a description of qualitative research methods, see Pelto et al. (15), and Smith and Morrow (16).

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The most important indicators are those that reﬂect nutritional status and possibly health (such as mortality or speciﬁc morbidity). However, the sample size required to assess their prevalence or detect a change may be too large in relation to the size of the program or the available budget. In that case, another indicator must be identiﬁed as the most important. The best alternative indicator is one that, when it changes, it is generally accepted that a positive impact on nutritional status is very likely; for example, an increased consumption of animal foods or a doubling of vitamin A intake from vegetables and fruits. But too often, the criticism is rightly made that nutrition programs are not evaluated for their impact on nutritional status or health. Thus, even when sample size may not be sufﬁcient to detect a change, assessing nutritional status or health should be considered. This is because when a relationship is demonstrated between nutritional status and food consumption, this could support the argument that an observed change of food consumption is likely to result in a desired change of nutritional status. The precise calculation of required sample size depends on the sampling frame. When pure random sampling is used, the sample size is smaller than when cluster sampling is used, because of its associated design effect. For further details about sample-size calculations, see Levy and Lemeshow (17), Lwanga and Lemeshow (18), or Kirkwood (19). Sample size is deﬁned as the number of subjects or households required for analysis. Because not all subjects will join, some will drop out, and for some the data set will be incomplete, a larger number of subjects has to be enrolled. For a survey, 5–10% more subjects may be enough, whereas 15–25% more may be necessary for a longitudinal assessment. 2.2.4. SELECTING SUBJECTS The selection of subjects or households should be such that a representative sample is obtained that will allow for a generalization of results to the original, targeted population. Random selection from the entire eligible population would ensure representativeness. However, in contrast to developed countries, because a list of all households or subjects rarely exists, and because it is often not feasible to visit all eligible areas, another sampling scheme is usually needed. Multistage cluster sampling, which is often used, requires that the population is organized in certain units of a known, approximate population size. For example, for the Nutrition Surveillance System in Central Java (11), it was decided to select 7200 households, 1200 in each of the six ecological zones, by multistage cluster sampling. From the smallest sampling unit, the cluster (equivalent to a village), 40 households were to be selected.2 Thus, a total of 30 clusters per zone were needed, which were selected by probability proportional to size (PPS) sampling, as follows. A table was made that listed all the villages in the ﬁrst column, their eligible population size (for example when a survey is to be conducted among a rural population, the urban population is not included) in the second column, and their cumulative population size in the third column. The zone’s population size was then divided by the number 2Because

of heterogeneity within a cluster, a sample size of 30–40 households per cluster is generally recommended (18).

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of villages needed. This for example resulted in 200,000 (6 million/30). Then, the cumulative column was marked for each 200,000th person, starting from a randomly chosen number between 1 and 200,000, for example 53,000. The villages in which these 53,000th, 253,000th, 453,000th, and so on, person was found were selected. From each village, a list of eligible households (those with children under 5 yr old), was obtained, from which households were selected by the same procedure of interval sampling used for selecting the villages. When a population is not organized in some sort of unit of an estimated population size, such as might be encountered in urban slums, for example, drawing a representative sample becomes more difﬁcult. In general, sampling from urban areas is much more complicated than sampling from rural areas, because of the large heterogeneity, the mobility of the population, the changing deﬁnition of what belongs to the urban area, the presence of homeless people who would not be included in a householdsurvey, and so on (see Chapter 19). To our knowledge, general guidelines for sampling in urban areas do not exist, therefore, we will discuss some possible approaches. Analogous to the sampling in Central Java described earlier, different areas can be identiﬁed in a city; from each area, samples can be drawn by interval sampling, using a population listing. However, although this can be done for most residential areas, it is often not possible in slums, because of the lack of a list of households, especially when the settlement is illegal. In that case, a possible approach is to sample from all areas, and select a number of households that is proportional to the area’s size, in terms of estimated population or area covered. A selection can be made using interval sampling starting from various central points and going in one direction. The interval can be based on the number of housholds needed and the number counted between a central point and the border of the area. Or, when the number of eligible households can be estimated, interval sampling can be used that covers the whole area in a systematic way. An approaches that should not be used to select households (because they do not guarantee a representative selection), is one in which all households near one or more central points are asked to participate, or that a key person selects the household. Guidelines are needed for what to do when nobody is at home when a household is visited, or when a household refuses cooperation. When nobody is at home, the enumerator has to come back at a later time, in order to avoid selection bias when such households are not included. Especially in urban areas, where households tend to be smaller and where many people work outside the home, a considerable part of the data collection may have to be done in the evening, which will raise transport and safety issues. A household that refuses collaboration should be replaced by another household. Such a replacement can be the nearest eligible household or a few additional households can be selected from the village list. Good books about sampling populations have been written by Lwanga and Lemeshow (18) and by Levy and Lemeshow (19). 2.2.5. COMPOSING THE QUESTIONNAIRE AND OPERATIONALIZING THE CHOSEN INDICATORS The preparation of data collection instruments includes development of a questionnaire, preparation of guidelines for anthropometric measurements, selection of tools such as weighing scales, and so on. In 1991, a group of six PhD fellows from Cornell University published a series of seven working papers on collecting rural household data in developing

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countries in which they described their collective research experience (20). These papers are a useful guide for designing instruments and methods for data collection.3 Another good reference book when planning to conduct a trial or survey is ‘Field trials of health interventions in developing countries: a toolbox’, which shares the experience of a large number of investigators so that readers can avoid some of the mistakes previously made by others (16). For developing a questionnaire, several things are important. First of all, questions should be phrased clearly and in a language that the respondents understand. Second, answers are best recorded as numbers, for example, family size, or be ticked in pre-coded categories for the most frequent answers. The latter should always include a category “other,” where the enumerators specify the answer. In case a large proportion falls in this category, additional categories can be made before data-entry. Open questions without precoded answers should be avoided, because the subsequent coding is laborintensive and prone to subjectivity. Third, one should think about data entry as well as data analysis when developing the questionnaire, i.e., use clearly marked boxes for recording the answer, use additive codes when multiple answers are possible, and combine codes for a yes/no question that is followed by a speciﬁcation of the yes-answer. Additive codes for household assets would for example be 1 = radio, 2 = television, 4 = bicycle, 8 = motor, and 16 = car. The answer 5 means that the household has a radio and a bicycle, because no other combination would give code 5. An example of combined codes is “have you been ill in the past week?”, and if yes, have you seen a doctor, a nurse, a traditional healer, other or nobody? Coding answers for this question as “no,” “yes, seen doctor,” “yes, seen nurse,” “yes, seen nobody,” and so on, makes data analysis easier. When the questionnaire is ﬁnished, it has to be pretested in a group of respondents that are representative for the study population. Based on pretesting, different aspects of the questionnaire may be changed, such as its length, the sequence of questions, the way questions are phrased, the coding of answers, and so on. After its revision, the questionnaire should be tested again. Together with the questionnaire, a code-book has to be made for the enumerators with detailed explanations about all questions and answers. The code book could, for example, state whether family size should also include those family members that are only home once a month, or whether growing vegetables at the roadside is regarded as home gardening. Where applicable, guidelines should also be formulated for making anthropometric measurements (see Subheading 2.1.), and collecting blood and storing serum (see Subheading 2.2.).

2.3. Preparing the Field Work Once the survey or evaluation has been designed and data-collection instruments developed, the ﬁeldwork has to be planned.

3If you would like to obtain a copy of the papers, contact the Publications Ofﬁce, Department of Agricultural, Resource, and Managerial Economics, Warren Hall, Cornell University, Ithaca, NY 14853-7801, USA.

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2.3.1. SCHEDULING ALL PREPARATIONS The ﬁrst phase of the preparations, including formulation of objectives, contacting collaborators, making a budget estimate, and allocating and/or applying for funds, may take a variable length of time. The steps related to the ﬁeldwork are more strictly scheduled. Often, the ﬁeldwork can only be conducted during a few months of the year owing to seasonality, holidays, Islamic fasting period, and so on. The choice of this period guides the planning of the rest of the preparations described here. 2.3.2. OBTAINING PERMISSION AND ENSURING COLLABORATION Permission and collaboration are needed from the local to the national level. Permission should be obtained from the relevant government bodies, in accordance with national or regional policies. The best way to obtain collaboration varies and requires sensitivity to the local situation. It may, for example, be common rule to access an area through the government’s administrative structure, but without collaboration with the local religious structure, nothing will happen. When working in urban slums, getting collaboration is relatively complicated because often there is a lack of formal organization and people may be suspicious about activities that enquire about their living conditions, employment, and so on. The best way to approach the population may be through organizations operating in the slums. 2.3.3. FORMING AND PREPARING THE DATA-COLLECTION TEAM Because valid conclusions can only be drawn when data are of good quality, enumerators should perform well. They should have the appropriate background for collecting the data (i.e., nutrition, health, or agriculture), be motivated, know what to expect in the ﬁeld, speak the same language as the respondents, be able to establish a good contact with the community, and be well-prepared and well-trained. Therefore, they should be carefully selected, trained, and supervised, and their work has to be checked regularly (see Subheading 2.4.). To minimize between-observer variation, for example, of anthropometric measurements, variation should be assessed during the training, and enumerators with deviant results should practice more. The number of enumerators required depends on the number of respondents, the time needed per interview, the working days and hours of the enumerators, and the period during which the ﬁeldwork should be done. A special team of enumerators should collect quality-control data (see Subheading 2.4.). 2.3.4. BUDGETING THE FIELDWORK Components that should be included in the budget for the ﬁeldwork are costs of preparations, information meetings, salary, transport and accommodation of enumerators and supervisors, equipment for collecting data and taking blood, multiplication of questionnaires, salary of data entry clerks, laboratory analyses, reporting, and so on. A special issue to be considered is whether and how to reward subjects for their participation. When a survey is conducted among poor households, their participation means that they lose precious time that would otherwise have been spent on generating income or caring activities. When respondents have to come to a special location for measurements and/or blood collection, they may even have to spend money on transport. Therefore, surveys among the poor should seriously consider giving a reward for their participation, such as food, money, a kitchen tool, towel, or soap.

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2.3.5. ORDERING EQUIPMENT AND TOOLS Once it has been decided what data will be collected and by how many people, a list of necessary equipment and tools can be made. Items that have to be obtained abroad, for example weighing scales, and equipment for taking and storing blood should be ordered well in advance of the ﬁeldwork. Equipment for enumerators, such as bags, pencils, rubbers, umbrellas, and boots can usually be obtained locally. 2.3.6. SCHEDULING THE FIELDWORK When planning the day-to-day activities, it is important to include time for contacting the next village, for moving the enumerators, and so on. Also, it should be decided how many enumerators will work in one village, who will introduce them there, whether and when the blood collection team will conduct its activities, and so forth. Limiting the number of enumerators per village makes the data collection clear and controllable for the villagers. For example, in Central Java, where 36 enumerators collected data for Helen Keller International (HKI), each village was visited by a team of four enumerators.

2.4. Ensuring a High Quality of Data Requirements for collecting good quality data include a questionnaire that is easy to understand and easy to code, well-prepared and dedicated enumerators, well-organized supervision, and good quality-control of the data collection. Supervision has to be organized at different levels. Ideally, there should be one supervisor for every three enumerators, but in practice this may vary between 3–5. The supervisor can, besides collecting data, arrange logistics in the ﬁeld, receive and crosscheck all questionnaires, and answer questions from villagers and enumerators. Then, for every few supervisors, there has to be a coordinator who organizes the ﬁeldwork, including day-to-day scheduling; makes ﬁrst contact with the communities involved; manages tools, equipment, and money; collects and forwards the ﬁlled in questionnaires; and supervises the quality-control team. The ﬁrst check of the data is a cross-check by the enumerators before they give the questionnaires to their supervisor. The supervisors then check for completeness and validity of answers and give them to the coordinators. When questionnaires are collected by the coordinators on a weekly basis, it will still be possible to return to an interviewed household for clariﬁcation, when necessary. For cross-checking the data collection, a special quality-control team may revisit 5–10% of the households that had already been interviewed and administer the same questionnaire. Obviously, enumerators should not know which households will be revisited, and the second visit should be made within a few days of the ﬁrst visit. Data can be compared immediately as well as after data-entry. In the latter case, performance of each enumerator can be compared to that of the quality-control team and be ranked from best to poorest. This is useful when enumerators will collect data again, for example in the case of a nutrition surveillance system (11,21). Although having a special quality-control team may seem a relatively large investment, it is worth it. Enumerators may make mistakes, wrong judgements, or even fake answers. Examples of wrong data recording that would have remained unnoticed when only checking the questionnaire include problems such as the following: data such as

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age, sex, and breast feeding were recorded on the index child, but, because it did not cooperate with its length measurement, length of the nearest older brother or sister was measured; the height of the woman was not measured, but guessed. In addition to data collection by quality control teams, the coordinator should, together with the ﬁeld director, make some unannounced visits during data collection, in order to observe how the teams are conducting their work. This can for example reveal that height measurements are not conducted properly, or that ﬁeldworkers administer the 24-hour recall questionnaire, but only record the answers after they have returned from the ﬁeld.

2.5. Data Entry, Data Cleaning, and Data Analysis In order to prepare the data for analysis, they have to be entered into a computerized database. Some programs, such as SPSS-Data Entry and FoxPro, have been speciﬁcally designed for data-entry. With these programs, a screen can be designed that, for example, has the same layout as the questionnaire; for each variable, range-checks can be performed, which will prohibit entry of invalid values; and questions can be skipped automatically. For example when a respondent does not use family-planning methods, all questions about such methods are automatically skipped and ﬁlled with the code for “not applicable.” While SPSS and FoxPro are commercially available programs, CDC and WHO have produced a very user-friendly program for data-entry and data-analysis, Epi-Info, which can be downloaded from the Internet at no-cost (http://www.cdc.gov/epiinfo/EI2000). Epi Info is widely used in developing countries.’ Variable names, which are usually limited to eight positions, should be easy to understand and be the same across data-sets. The latter is particularly required when many data-sets are available within an organization, for example from different surveys in different countries. The control of data entry goes through different stages. After each questionnaire, data that were entered should be compared to the questionnaire’s data by the data-entry typists themselves. The data entry supervisor should then do a similar check for a proportion of the questionnaires. Based on that, it can be decided, per data-entry person, whether all of the entered data should be checked. A more rigorous and very objective way to ensure that data are entered correctly is a repeat-entry system, which queries all second entries that are different from the ﬁrst entry. For converting food consumption data into nutrient intake, food composition tables are needed. In principal, local or national tables are preferred, but when certain foods or nutrients are not included, additional or other tables may be selected. See the chapter by West and van Staveren in Margetts and Nelson (22) for a further discussion of this issue. The latest information on nomenclature of food components is available at INFOODS’ homepage: (http://www.crop.cri.nz/foodinfo/infoods/infoods.html). After entering and checking the data, they have to be cleaned. Descriptive statistics should be run for each variable, including minimum and maximum values, histograms, and boxplots. Data that have an unusually low or high value may have been entered wrong, which can be checked at the questionnaire, or been recorded wrong. In the latter case, there are a few options: going back to the household where this value was recorded to check it, keeping the value because it may be a real observation, or delete the value. Whether the value could be real has to be judged by the investigators, but

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data should not be excluded too easily. For guidelines for cleaning anthropometry data, see Subheading 2.1. The next check is for impossible combinations, such as supposedly exclusively breast-fed children for whom 24-h recall data are available, or households without a home garden but with income from a home garden. The ﬁnal step before starting data analysis is making sure that the code book with information on each variable is complete. Once data analysis has started, good administration should be kept of any changes made to the data set. Many books have been written about statistics that could be referred to when analyzing the data (for examples, refs. 19 and 23).

2.6. Using and Communicating Findings To complete the triple A cycle of Assessment, Analysis, and Action, analyses should answer the right questions and results should be communicated in an appropriate way to the relevant audience. First, in order to make sure that an assessment can contribute to the improvement of programs, it should be designed in close collaboration with those that conduct the program. Then, analyses should be performed timely and accurately. For the formulation and communication of ﬁndings, different audiences may be distinguished: at the local level, this includes the population surveyed and the local government and organizations working with them; at a national level, this includes government bodies, such as the Ministry of Health and the National Planning Board, UN organizations, and nongovernmental organizations; and at an international level, this includes donor agencies, international organizations (such as WHO, UNICEF, and World Bank), governments of other countries, and the scientiﬁc community. Emphasis and presentation of ﬁndings should tailor the speciﬁc interests of these different audiences. For example, data from the Nutrition Surveillance System of Helen Keller International/Government of Indonesia about the impact of Indonesia’s political and economic crisis on health and nutrition are communicated to the government in the form of slide shows that identify the emerging problems, the subpopulations most seriously affected, and the most effective interventions. Among a wider (national and international) audience, Crisis Bulletins are distributed that discuss special themes such as maternal wasting, increasing prevalence of micronutrient deﬁciencies, successful maintenance of high-coverage of vitamin A capsules, and so on. And for an even wider, not speciﬁcally addressed, audience, scientiﬁc articles and book chapters are written (24).

3. ISSUES SPECIFIC TO NUTRITIONAL ASSESSMENT IN DEVELOPING COUNTRIES: SOME EXAMPLES The conditions under which high-quality data have to be collected can differ widely because the most appropriate way of collecting data depends on the local situation. Guidelines for collecting data in a Western country may have to be adapted for use in a developing country, because some situations, such as collecting and transporting blood in an area without electricity, are only encountered in some areas in developing countries. We will discuss how some conditions speciﬁc for developing countries affect conducting anthropometry measurements, collecting and processing blood, laboratory analysis of fat-soluble vitamins, and assessing vitamin A intake.

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Fig. 3. Normal distribution curve.

3.1. Anthropometry 3.1.1. WHY DO WE COLLECT ANTHROPOMETRY DATA WHICH INDICATORS DO WE USE? Anthropometry is the measurement of human morphology. It is often used for monitoring growth, at individual or at population level, and for assessing rates of malnutrition and overnutrition. Basic anthropometry measurements include weight, height and mid-upper-arm circumference (MUAC). For children, these measures can be used for indices that assess acute malnutrition, resulting in a thin body or “wasting” (low weight-for-height); chronic malnutrition, which results in reduced vertical growth, i.e., a short stature for age or “stunting” (low height-for-age); or a combination, which results in a low body weight for age (low weight-for-age). MUAC assesses the combined thickness of muscle tissue and fat. For children, a MUAC <125 mm indicates wasting. Stunting reﬂects a prolonged poor nutritional value of the diet in relation to the body’s needs, including a lack of micronutrients. Factors that increase the body’s needs include a larger body size, more or heavier physical activity, and infection. A lack of micronutrients, such as iron and vitamin A, affects growth, especially height, the immune system, mental and psychomotor development, and physical endurance. Thus, high levels of stunting among children suggest that there will also be long-term deﬁcits in mental and physical development, which lowers the population’s potential development. For adults, the two most frequently used anthropometry indices are MUAC and body-mass-index (BMI), which is calculated as (weight/length2 [kg/m2]). For a woman, a MUAC <230 mm indicates that she is underweight. BMI tells whether someone is thin (<18.5), normal (18.5–24.99), overweight (25–29.99), or obese (>30 kg/m2) (5).

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Fig. 4. Distribution of the height-for-age Z-scores of the reference population and of Indonesian children from South Sulawesi and South Kalimantan, aged 18–59 mo (mean Z-score, –1.90, sd, 1.21, n = 2002, unpublished data of HKI Indonesia).

3.1.2. COMPARISONS WITH A REFERENCE POPULATION At an individual level, it is difﬁcult to judge whether a child is malnourished or whether he/she is just one of the smaller subjects of a population. The distribution of anthropometry data from all individuals in a population usually describes a normal curve (Fig. 3). Thus the short individuals are at the left of the distribution, whereas the tall individuals are at its right. A comparison of the distribution of a well-nourished population to that of a population in a developing country will show whether the population of the developing country has reached its optimum growth. Figure 4 shows the distribution of height-for-age Z-scores of Indonesian children aged 18–59 mo, which is shifted to the left relative to that of the well-nourished population. This means that the Indonesian children had not grown as much as possible, indicating that their diet had not been adequate. Data of a well-nourished population that are often used as a reference are the National Center for Health Statistics (NCHS)/WHO reference data (25). How an individual relates to the reference population can be expressed using a Z-score, percentile-score, or percent of median-score. Z-scores are preferred for population-based applications, because their mean and standard deviation (SD) can be calculated. The Z-score expresses how many SD below or above the median of the reference population an individual’s value is. By deﬁnition (see Figure 3) , 2.28% of the reference population has a Z-score below –2 SD. At an individual level, it is best to look at progress through time. Therefore, growth charts are used for recording a child’s weight and/or length at different ages. The most important information from such charts is not whether weight or length is the same as that of the reference population, but whether it increases and follows a pattern similar to that of the reference population. For a further discussion of the use and interpretation

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of anthropometry, see the report of a WHO-expert committee (5), and for a discussion about anthropometry and mortality, see Yip (26). 3.1.3. TAKING ANTHROPOMETRY MEASUREMENTS Here we discuss some critical aspects of the measurement of weight, length/height, and/or MUAC. For a detailed description of how these measurements should be taken, see Cameron (27) or Lohmann et al. (28). Weight should be measured to the nearest 0.1 kg. This is best done with a digital scale, but mechanical scales may also be used. Infants should be weighed without any clothes and nappies/diapers. Older children and adults should wear minimal clothing. Infants and young children are best weighed using a special scale, such as a salter scales with a “sitting bag,” or the UNICEF scale, which automatically calculates the baby’s weight from the weight of the mother alone and the weight of the mother while she holds her baby. When only a standing scale is available, this calculation could be done manually, but mistakes can occur more easily. Weighing scales have to be calibrated before each measurement session. Objects can be used for calibration when their weight has been assessed with either a calibrated scale or with two scales that gave the same result. The weight of calibration objects should be similar to that of the subjects. Good calibration objects are well-closed containers ﬁlled with water. When using two or more scales, they can also be approved for use when they give the same result for the same subject. However, when their result is different, it may be difﬁcult to identify which one is correct. Length or height measurements have to be performed very carefully. Length is measured with subjects in a horizontal position, whereas height is measured with subjects in a vertical position. Subjects should be barefoot and without a hat. Whether length or height should be measured depends on the reference population. When using the NCHS data, of all children younger than 24 mo length should be measured, irrespective of their ability to stand. For length measurement, the child’s legs should be straightened. This requires patience. For height measurements, a vertical wall that is at an angle of 90° with a ﬂat ﬂoor is needed. When using a microtoise, it should be positioned at exactly 2 m from the ﬂoor. The measuring tool should be rested on the subject’s head while it makes an angle of 90° with the wall, and the enumerator should read it while standing at the same height as the subject. A MUAC measurement should be made exactly in the middle of the left arm. Any sleeves should be taken away, and the tape should cover the shortest possible circumference of the arm; it should not be applied tightly. Another crucial part of anthropometric measurements on children is the assessment of age, because it is essential for the indices height-for-age and weight-for-age. But assessing age can be difﬁcult when birth dates are not recorded. An event and/or religious calendar may help respondents to remember their child’s birth date. 3.1.4. OBTAINING RELIABLE DATA In order to obtain reliable anthropometry data, enumerators should be well-trained. This includes a clear demonstration of how to take the measurements, extensive practicing, and comparing results among each other. Enumerators whose results are furthest apart need more practice (for an example, see ref. 29). MUAC and skinfold measurements are usually done in duplicate. When they differ less than 10%, their

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average is recorded, otherwise, another measurement is taken and the most deviant one is discarded. Once data collection has started, cross-checks should be performed by the quality-control team. After all data have been collected, Z-scores can be assigned, manually or by a computer program such as Epi-Info. The Z-scores of weight-for-height, height-for-age, and weight-for-age can be checked per individual by comparing them. A WHO expert committee recommended the following for identifying and excluding improbable values. Flexible criteria exclude all the data that are more than 4 Z-scores away from the observed mean Z-score, with a maximum height-for-age Z-score of +3.0 SD. Fixed criteria, which are suitable when the observed mean Z-score is >–1.5, exclude all the data that are outside the range <–5;3> for height-for-age, <–4;5> for weight-for-height, and <–5;5> for weight-for-age (5). The quality of the anthropometric data can be checked by looking at the sd of the Z-scores, after applying the exclusion criteria mentioned earlier. Good-quality data have an SD of the Z-score of <1.10;1.30> for height-for-age, of <0.85;1.10> for weight-for-height, and of <1.00;1.20> for weightfor-age (5). The WHO committee cautions readers that “studies with an sd outside these ranges require closer examination for possible problems related to age assessment and anthropometric measurements” (5).

3.2. Collecting and Processing Blood Anthropometric data reﬂect overall nutritional status. However, in order to know whether the body contains an adequate amount of particular nutrients, other information is needed. A clinical examination can be used to detect a severe shortage or a severe overload of particular micronutrients. For example, severe vitamin A deﬁciency causes xerophthalmia, severe iron deﬁciency causes severe anemia, which, for example, shows as whiteness at the inside of they eye, and severe iodine deﬁciency causes goiter. Functional tests can detect less severe levels of deﬁciency, such as reduced dark-adaptation owing to vitamin A deﬁciency. However, for less severe deﬁciencies and for micronutrient deﬁciencies that cause systemic, rather than speciﬁc, effects, such as zinc deﬁciency, biochemical tests should assess the level of the micronutrient in the body. Different body tissues can be sampled for biochemical tests, including blood, urine, breast milk, feces, nails, hair, and mucous cells. Because obtaining, storing, and analyzing such body tissues is costly, it should be carefully considered and conducted. Here, we will discuss some particular aspects of collecting and processing blood in developing countries. See Gibson for a description of possible tests for different components (4) and Tietz (30) or Burtis et al. (31) for a description of laboratory methods. 3.2.1. COLLECTING BLOOD: COMMUNITY COOPERATION Collecting blood requires good understanding and cooperation from the community. Experience has taught that even in remote areas where people may not be very familiar with blood collection, cooperation can be good when communication with the community and its leaders is good, the purpose is carefully explained, and possible fears are discussed. Because of the fear that blood would be sold, staff of a project in Indonesia did not speak of blood taking but of blood testing, and explained that the volume of blood obtained was much too small for selling. Beneﬁts that can be mentioned to the respondents include that they will obtain information about their

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health, for example on whether they are anemic, and that they will receive treatment when necessary, such as iron pills. When collecting the blood, the presence of a medical doctor can give trust and he/she can provide some basic medical services and/or vitamin-mineral preparations. 3.2.2. COLLECTING BLOOD: CAPILLARY OR VENOUS BLOOD Depending on how much blood is needed, capillary blood or venous blood can be collected. Capillary blood is usually obtained from the tip of a ﬁnger. The maximum that can be collected is approximately 250 µL (ﬁve capillary tubes of 50 µL each), which is enough for 100 µL serum. When more blood is needed, it should be obtained by venapuncture. This is usually done from the forearm. For respondents, providing one tube of blood is easier than two or more, even if the total amount of blood is less. In principal, capillary blood can be obtained by anybody who can work carefully. The ﬁnger should be warmed, its tip cleaned with alcohol, and a sterile lancet should be used for puncturing. The ﬁrst drop of blood has to be wiped away, because it may be diluted by the alcohol, and the rest can be collected. During collection, the ﬁnger should not be squeezed too much, because tissue ﬂuid may then dilute the blood. Because capillary blood contains slightly less red blood cells and because of the possibility of further dilution by squeezing, venous blood is sometimes preferred, even though the amount of blood needed could be obtained by ﬁnger prick. However, it has recently been reported that when hemoglobin concentration was assessed using a Hemocue (Hemocue, Angelholm, Sweden), a portable tool which gives results immediately, there was nod ifference between that assessed on blood obtained from the ﬁnger and on blood obtained by venapuncture (32). This is probably due to the very small amount of blood needed for the hemoglobin measurement. After collection, cotton soaked in alcohol can be applied to close the wound, and the wound should be covered with plaster to prevent infection. The collection of venous blood requires more skill and is usually done by paramedical staff under supervision of a medical doctor. 3.2.3. PROCEDURES FOR COLLECTING AND PROCESSING BLOOD Blood can be collected at any place that is clean, free of wind, and where visibility is good. Because a centrifuge is needed to obtain serum from the blood, electricity should be available at the place of blood collection or within a few hours’ drive. However, for Cambodia’s National Micronutrient Survey, which was conducted between Feb.–Sept. 2000 by Helen Keller International Cambodia and the Royal Cambodian Government, blood collection teams were equipped with hand-driven centrifuges that had successfully been converted to become battery-operated and with car batteries. In this way, the need for electricity near the place of blood collection was circumvented. Tools and equipment needed for taking blood include a pencil, a book for administration, labels for tubes and vials, tourniquet, plastic gloves, alcohol, cotton, lancets or syringes, (capillary) tubes, container with ice to store the tubes, and band aid. When taking blood, it is important to remember a few things. First, work clean—in order to avoid contamination with blood-borne diseases such as hepatitis B and HIV—by using gloves, and carefully disposing of, not re-using, material contaminated with blood. Second, very carefully record names and numbers of subjects on tubes and vials to enable correct linking of blood data to questionnaire data. Third, keep the blood cool (3–7°C),

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and never freeze it, because that may cause hemolysis (rupture of red blood cells), which will interfere with analyses of serum components. And fourth, protect blood and serum from light, because that may damage components such as retinol and carotenoids. Hemogobin concentration can be assessed in the ﬁeld, or in a nearby or distant laboratory. For assessment in the field, a portable tool, such as a Hemocue can be used. The Hemocue is accurate and easy to use, but relatively expensive. For assessment in a nearby laboratory, 20 µL blood can be dissolved in 20 mL Drabkin’s solution in the ﬁeld. In the laboratory, the absorption of the solution is then assessed with a spectrophotometer. For transporting blood to a more distant laboratory, 20 µL can be stored on ﬁlter paper from which it is redissolved into Drabkin’s solution. Collection on ﬁlter paper is sometimes used for a large survey where blood is collected at many different places, because it allows for analysis of all samples in the same laboratory. However, the method is less accurate, and has been found to underestimate hemoglobin concentration and therefore grossly overestimate anemia prevalence (29). Recently, an overview of methods for assessing hemoglobin concentration has been published (33). For separating serum,3 one needs a centrifuge that turns at 2000–3000 rpm, a pipet, vials, a container in which to store the vials in a freezer, labels, cellotape, and a pencil. After collection and during transport, blood has to be kept cool. When tubes with blood are kept in a container with ice, they should not touch the ice, because blood should never be frozen. Centrifuging should be done on the day of blood collection, at approx 750 × g for 10 min at room temperature. Centrifuging at the place of blood collection avoids the risk associated with transport such as breaking of tubes or hemolysis. After centrifuging, the serum should be pipetted from the clotted blood and stored in small vials that are kept in the freezer until analysis. A new pipet, or pipet tip, should be used for each subject, in order to avoid contamination, and the clotted blood should not be touched. Technicians should protect the serum from light, for example by using a yellow light. Serum should be frozen, but can be kept cool (3–7°C) for a maximum of 48 h after collection. How much serum to store in a vial, and how many vials to use per sample, depends on the analyses that will be done. When 100 µL of serum is needed for an analysis, 120–150 µL should be stored, because not all serum can be collected from a vial. For each analysis, serum should be stored in a separate vial, because defrosting and freezing again will harm its components. It is suggested to keep a spare vial, in case a vial is lost or an analysis has to be repeated. 3.2.4. ORGANIZING A COLD CHAIN FOR TRANSPORTING BLOOD AND SERUM As mentioned earlier, blood should be kept at a temperature of 3–7°C, and serum should be frozen within 48 h. Meeting those temperature requirements is a challenge when collecting blood in the ﬁeld. Cool conditions can be created by using a container with ice or a portable refrigerator that operates on a car’s cigarette lighter. Different forms of ice can be used, including ice blocks (frozen water), ice packs that can be frozen again (often used for cool boxes), and “dry ice” that slowly evaporates (solid 3Serum

is the supernatant that is obtained after blood has been left to clot. This removes the clotting proteins and the red and white blood cells. Plasma is obtained after centrifuging blood to which an anticoagulant, such as heparin, was added. This removes red and white blood cells.

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carbon-dioxide). Ice blocks can be obtained in many places, and ice packs can be re-used when there is a freezer. In an area without electricity, the use of a portable refrigerator or of dry ice, which lasts longer, should be considered. Dry ice might be obtained from ice-cream factories or from beer breweries. An amount of 20 kg should last for 2–3 d when kept in a well-insulated, well-sealed container. If available, liquid nitrogen is also very good for freezing and storing serum samples. When none of the aforementioned possibilities is possible, other solutions are needed. For example, when the team of the Nutrition Research and Development Centre in Bogor, Indonesia, collected blood in Irian Jaya, they kept serum cool in the stem of a banana tree. Once serum has been stored, the freezer’s temperature should be monitored regularly and periods without electricity should not be longer than a few hours. In case of frequent power-cuts, storing ice-packs in the freezer will help to preserve the cold temperature. When transporting frozen serum using dry ice, it is essential that the amount used is adequate (12 kg will last for approx 36 h), and that the container is sealed very well. How long serum can be stored until analysis depends on the freezer’s temperature and on the components that will be analyzed.

3.3. In-Country Assessment of Biochemical Indicators of Nutritional Status, Example of Vitamin A Status Where possible, countries perform their own biochemical analyses. Analyses that do not require very sophisticated and/or expensive equipment, such as the analysis of hemoglobin concentration, have already been performed in many countries for many years. Analyses that are technically more difﬁcult, such as analysis of serum retinol by high-pressure liquid chromatography (HPLC), are conducted by a limited number of laboratories in developing countries. The increasing interest in micronutrient deﬁciencies and the decreasing prevalence of their clinical signs increases the demand for biochemical assessments. This puts a large pressure on laboratory facilities in developing countries, both in terms of number of analyses required and on technology needed. In order for a laboratory, a country, or a region to meet the increased demand for analyses, different steps may be necessary, varying from support for tackling technical problems and quality-control, to upgrading or introducing new equipment and training staff. Because it is impossible to give general guidelines for how to improve laboratory capacity and facilities, we will describe an experience with upgrading of HPLC facilities in a laboratory in Asia. 3.3.1. EXPERIENCE WITH UPGRADING HPLC FACILITIES IN ASIA Because the demand for analyses of serum concentrations of retinol and carotenoids had markedly increased, it was decided to upgrade the HPLC facilities of the laboratory of a nutrition research institute in Asia (biochemical methods for assessing vitamin A status have been described by Arroyave et al. [34]). It was envisaged that with an upgraded system, the laboratory could also serve as a regional training center for other Asian countries. Together with a consultant, the needs and possibilities for upgrading were discussed and equipment was chosen based on the following considerations: the analysis that would be performed, the equipment that was already used at the institute, the possibility of in-country servicing of the equipment, and the consultant’s familiarity with the equipment. A donor was found that ﬁnanced the equipment, the training, and

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the consumables for the ﬁrst few hundred analyses. The supplier’s agent installed the equipment and gave some basic explanations on how to operate the machine, while the consultant’s group provided thorough training. The staff was trained in their own laboratory with the new system, so that any problems that were related to the speciﬁc machine and the laboratory’s own constraints could be tackled as they occurred, and the entire HPLC team could be involved in the training. Because the equipment was only recently released by the manufacturer, a number of problems were encountered. These problems could not have been solved without the consultant’s support, because the local agent, who was supported from the manufacturer’s regional ofﬁce, neither discovered nor acknowledged them. Finally, the more serious problems were solved after the consultant’s own supplier of the same equipment decided to help. This example shows how important it is to investigate thoroughly which suppliers are available in a country and what the experiences with their services are. Also, although general training of laboratory staff can be organized outside a country, the introduction of new equipment or techniques requires speciﬁc training in the own laboratory with the own equipment. 3.3.2. OBTAINING SUPPLIES AND PERFORMING QUALITY-CONTROL The more sophisticated the equipment used, the more maintenance and speciﬁc tools, consumables, and chemical solutions it requires. Therefore, when considering the purchase of sophisticated equipment, the beneﬁts in terms of compounds that can be analyzed and the quality of the results that can be obtained should be weighed against the burden of delays caused by waiting for technical support, spare parts, and consumables. Because parts and consumables are often difﬁcult to obtain in a developing country, it is crucial to identify suppliers and order from them well in advance of the analyses. In case it is decided to re-use materials, because of limited availability and/or high costs, they should be cleaned very thoroughly, and the results obtained with re-used materials should be compared to those obtained with new materials, in order to evaluate the acceptability of re-using them. A laboratory can perform quality control both internally as well as externally. Internal quality control can be done by analyzing a proportion of samples in duplicate and by including a few samples of a pool of control serum in every run. Control serum can for example be a mixture of serum of laboratory staff. External quality control can consist of analysis of some samples by another laboratory and/or of participation in a ring-test between laboratories.

3.4. Assessing Food Consumption: the Example of Vitamin A Intake Food consumption data can be used to assess adequacy of the diet, to identify groups at risk of a low intake of speciﬁc (micro)nutrients, and to determine the most important food sources of particular nutrients. Very good and detailed books have been written about dietary assessment methods (6,7). However, conditions in developing countries may require further adjustments. We will discuss the adjustments we found necessary for assessing vitamin A intake. 3.4.1. HOW TO USE DATA ON VITAMIN A INTAKE When clinical and/or biochemical assessments have identiﬁed a vitamin A deﬁciency problem in a population, one of the next steps is the assessment of vitamin A intake.

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This will provide information on the vitamin A intake of different groups of the population, it will identify the main food sources of vitamin A, and it can serve as a baseline for any program aimed at increasing consumption of vitamin A-rich foods. In general, vitamin A intake data should only be interpreted at group level, because the variation between days and seasons is too large for reliable assessment at the individual level. 3.4.2. APPLYING THE GENERAL RULES FOR THE ASSESSMENT OF VITAMIN A INTAKE Theoretically, vitamin A intake is best assessed with a food-frequency method, because it varies largely between days and between seasons (32). For a food-frequency method, all vitamin A-rich foods are listed and respondents are asked how often they consume each of them per week or month. However, it has been reported that in areas where a large variety of vitamin A richfoods, especially vegetables, is available, food-frequency methods tend to overestimate vitamin A intake (35,36). On the contrary, better data were obtained with a 24-h recall method (35,36). Based upon this ﬁnding, the 24-VASQ method (24-h Vitamin A SemiQuantitative) was developed for estimating vitamin A intake (37). The method is semiquantitative and consists of a 24-h recall questionnaire with subsequent assignment of a food code and a vitamin A content code to each ingredient consumed (see Subheading 3.4.3.). Reproducibility of the method appears to be good and a dose-responsive relationship was found between vitamin A intake and serum retinol concentration (37). Thus, the 24-VASQ method seems to provide data that can be used to group individuals based on their vitamin A intake. There may be different explanations for ﬁnding a better correlation between vitamin A status and vitamin A intake when data were collected with a semi-quantitative method based on a 24-h recall than when data were collected with a food-frequency method. Firstly, most reports about unsatisfactory performance of the food-frequency method are from Indonesia, where the variety of vitamin A-rich dark-green leafy vegetables is very large and where most are prepared in combination with other vegetables. When respondents are asked about the frequency of consumption of a long list of vegetables, overestimation is likely and it is difﬁcult to estimate portion size when vegetables are eaten in many different ways. Secondly, although different dishes may be eaten every day, the diet in most developing countries is relatively monotonous. The daily diet may for example consist of rice, a protein source such as salted ﬁsh, and a vegetable dish, but the variation of the vitamin A content of the vegetable dish may be relatively limited. Therefore, a 24-h recall questionnaire is more likely to capture the general food consumption pattern in a developing country than in many developed countries where dishes of different ethnic cuisines may be consumed regularly. 3.4.3. DESCRIPTION OF THE 24-VASQ METHOD FOR ESTIMATING VITAMIN A INTAKE The 24-VASQ method has been developed for estimating vitamin A intake of populations in a relatively quick and simple way. It can be used in large surveys and surveillance systems. The data can be used to compare vitamin A intake among speciﬁc population groups, monitor changes in intake through time, compare intake among populations, and identify the contribution of four food groups—vegetables, fruits, animal foods, and fortiﬁed foods—to vitamin A intake. Data should not be interpreted at an individual level.

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The 24-VASQ method can be described as follows. A 24-h recall questionnaire is taken from the respondent, which includes all foods and drinks consumed during the previous day. Each vitamin A containing ingredient is then assigned a food code, which is based on the type of food and its vitamin A content/100 g, and a vitamin A content code, which is based on the amount of vitamin A in the amount of the ingredient of a food item consumed. Food codes distinguish for animal foods, vegetables and fruits, categories with a high (>250 RE/100 g), medium (50–250 RE/100 g) or low (<50 RE/100 g) vitamin A content, whereas fortiﬁed foods are combined into one category. Pumpkin and red and yellow sweet potato are classiﬁed as fruits and carrots as vegetables. Vitamin A content codes currently used are: <20, 20–100, 100–250, 250–500, 500–1000, and >1000 RE, but these may soon be changed, based on a recent evaluation of the categories. Because the contribution to vitamin A intake can be calculated per food group, total vitamin A intake can also be recalculated based on the latest insights about bioavailability of carotenoids from different foods (38).

4. RESEARCH AND DEVELOPMENT NEEDS This chapter has discussed ways for successfully completing the triple A cycle of Assessment, Analysis, and Action for nutrition and health programs. It has focused on impact assessment, because although good textbooks are available for speciﬁc aspects of nutritional assessment, there is a lack of knowledge and suggestions for designing a program-related analysis or evaluation. Also, assessment and analysis will only result in appropriate action when there is good communication with the relevant audience before as well as after the assessment. Therefore, the identiﬁcation of different audiences and different ways of reporting various ﬁndings were discussed. But, although there is a need for more program-oriented guidelines, many individuals and organizations have already been designing and evaluating nutrition programs for a long time. Sharing their knowledge, experience, and questions—for example, in meetings, special editions of scientiﬁc journals, and a textbook with contributions from different groups working in this area—would contribute largely to the development of this ﬁeld. The Food Insecurity and Vulnerability Information Mapping Systems (FIVIMS) group, coordinated by FAO, is a good example of a forum for sharing ideas and experiences of collecting and analyzing information about nutrition and health in developing countries. E-mail forums could also play an important role in this respect. In addition to the need for sharing experiences, this chapter also identiﬁed some topics that need to be developed, including composition and use of conceptual frameworks for the cause of malnutrition that apply to speciﬁc situations and/or programs; development of designs that can be used to monitor or evaluate small-scale as well as large-scale programs and developments such as economic crises and disasters; design of data-collection in urban areas; and development of biochemical methods that can be more easily used in the ﬁeld, because they do not require a cold chain. The recognition of public nutrition (8) is likely to enhance the development of this area of assessing and communicating impact of nutrition and health programs.

REFERENCES 1. United Nations International Children’s Emergency Fund (UNICEF). The Progress of Nations. New York, NY: UNICEF, 1997.

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2. Margetts BM, Nelson M, eds. Design Concepts in Nutritional Epidemiology, 2nd ed. New York, NY: Oxford University Press, 1997. 3. Fidanza, F. Nutritional Status Assessment: A Manual for Population Studies. London, UK: Chapman and Hall, 1991. 4. Gibson RS. Principles of Nutritional Assessment. New York, NY: Oxford University Press, 1990. 5. WHO. Physical Status: The Use and Interpretation of Anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series 854. Geneva: WHO, 1995. 6. Cameron ME, van Staveren WA, eds. Manual on Methodology for Food Consumption Studies. New York, NY: Oxford University Press, 1988. 7. Den Hartog AP, van Staveren WA, Brouwer ID. Manual for Social Surveys on Food Habits and Consumption in Developing Countries. Weikersheim, Germany: Margraf Verlag, 1995. 8. Rogers B, Schlossman N. “Public nutrition:” The need for cross-disciplinary breadth in the education of applied nutrition professionals. Food Nutr Bull 1997; 18:120–133. 9. Johnsson U. Towards an improved strategy for nutrition surveillance. Food Nutr Bull 1995; 16: 102–111. 10. Bloem MW, de Pee S, Darnton-Hill I. New issues in developing effective approaches for the prevention and control of vitamin A deﬁciency. Food Nutr Bull 1998; 19:137–148. 11. De Pee S, Bloem MW, Satoto, Yip R, Sukaton A, Tjiong R, et al. Impact of social marketing campaign promoting dark-green leafy vegetables and eggs in Central Java, Indonesia. Intl J Vitam Nutr Res 1998; 68:389–398. 12. Habicht JP, Victora CG, Vaughan JP. Evaluation designs for adequacy, plausibility and probability of Public health programme performance and impact. Int J Epidem 1999; 28:10–18. 13. De Pee S, Bloem MW, Kiess L. Evaluating food-based programs for their impact on reducing vitamin A deﬁciency and its consequences. Food Nutr Bull 2000; 21:232–238. 14. Talukder A, Kiess L, Huq N, de Pee S, Darnton-Hll I, Bloem MW. Increasing the production and consumption of vitamin A-rich fruits and vegetables: Lessons learned in taking the Bangladesh homestead gardening programme to a national scale. Food Nutr Bull 2000; 21:165–172. 15. Pelto GH, Pelto PJ, Messer E, eds. Research Methods in Nutritional Anthropology. Food and Nutrition Bulletin Supplement 11. Tokyo, Japan: United Nations University, 1989. 16. Smith PG, Morrow RH, eds. Field trials of health interventions in developing countries: a toolbox, 2nd ed. London, UK: Macmillan Education Ltd, 1996. 17. Levy S, Lemeshow S, eds. Sampling of Populations, Methods and Applications. New York, NY: Wiley, 1991. 18. Lwanga SK, Lemeshow S. Sample size determination in health studies: a practical manual. Geneva: WHO, 1991. 19. Kirkwood BR. Essentials of Medical Statistics. Oxford, UK: Blackwell Scientiﬁc 1988. 20. Levin C, Rozell S. (series coordinators). Rural household Data Collection in Developing Countries. Working papers in Agricultural Economics (91-13–91-19). Department of Agricultural Ecnomics and Cornell Food and Nutrition Policy Program. Washington, DC: CFNPP Publications Department, 1991. 21. Bloem MW, Hye A, Wijnroks M., Ralte A., West KP, Sommer A. The role of universal distribution of vitamin A capsules in combatting vitamin A deﬁciency in Bangladesh. Am J Epidemiol 1995; 142: 843–855. 22. West CE, van Staveren WA. Food consumption, nutrient intake, and the use of food composition tables. In: Design Concepts in Nutritional Epidemiology, 2nd ed. Margetts BM, Nelson M, eds. New York, NY: Oxford University Press, 1997, pp. 107–122. 23. Rothman KJ. Modern Epidemiology. Boston: Little, Brown, 1986. 24. Bloem MW, Darton-Hill I. Micronutrient deﬁciencies: First link in a chain of nutritional and health events in economic crisis. In: Primary and secondary preventive nutrition. Bendich A, Deckelbaum RJ, eds. Clifton, NJ: Humana, 2000. 25. National Center for Health Statistics (NCHS). NCHS Growth curves for children. Birth–18 years. US Department of Health Education and Welfare Publication No. (PHS) 78-1650. Hyattsville, MD: NCHS, 1977. 26. Yip R. (1994) The relationship between child anthropometry and mortality in developing countries. J Nutr 1994; 124:10S. 27. Cameron N. The Measurement of Human Growth. London, UK: Croom Helm, 1984. 28. Lohmann TG, Roche AF, Martorell R, eds. Anthropometric Standardization Reference Manual. Champaign, IL: Human Kinetics Book, 1988.

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29. Ulijaszek SJ. Anthropometric measurements. In: Design Concepts in Nutritional Epidemiology, 2nd ed. Margetts BM, Nelson M, eds. New York, NY: Oxford University Press. 1997. pp. 289–311. 30. Tietz NW, ed. Clinical Guide to Laboratory Tests, 3rd ed. Philadelphia, PA: W.B. Saunders, 1995. 31. Burtis CA, Ashwood ER, ed. Textbook of Clinical Chemistry, 2nd ed. Philadelphia, PA: W.B. Saunders, 1994. 32. Sari M, de Pee S, Martini E, Herman S, Sugiatmi, Bloem MW, Yip R. Differences in the estimated prevalence of anemia when assessed with the direct cyanmethemoglobin method, the indirect cyanmethemoglobin method or the HemoCue method. 1999, (Submitted). 33. Robinett. Anemia detection in Health Services: Guidelines for Program Managers. Seattle, WA: PATH (Program for Appropriate Technology for Health), 1996. 34. Arroyave G, Mejia LA, Chichester CO, et al. Biochemical Methodology for the Assessment of Vitamin A Status. International Vitamin A Consultative Group report. Washington DC: The Nutrition Foundation, 1982. 35. Beaton GH, Milner J, McGuire V, Feather TE, Little JA. Source of variance in 24-hour dietary recall data: implications for nutrition study design and interpretation. Carbohydrate sources, vitamins and minerals. Am J Clin Nutr 1983; 37:986–995. 36. Humphrey J, Friedman D, Natatisatra G, Muhilal. A 24 hour history is more closely associated with vitamin A status and provides a better estimate of dietary vitamin A intake of deﬁcient preschool Indonesian children compared to a food frequency method. Am J Diet Assoc, 2000. 37. De Pee S, West CE, van Staveren WA, Muhilal. Vitamin A intake of breastfeeding women in Indonesia: critical evaluation of a semi-quantitative food frequency questionnaire. In: Food-Based Approaches for Controlling Vitamin A Deﬁciency: Studies in Breastfeeding Women in Indonesia. PhD Thesis, de Pee, S. Wageningen, Netherlands: Wageningen Agricultural University, 1996. 38. De Pee S, Halati S, Bloem MW, Soekarjo D, Sari M, Martini E, Kiess L. 24-VASQ method for estimating vitamin A intake: reproducibility and relationship with vitamin A status. Report of the XIX International Vitamin A Consultative Group Meeting, p. 96. Washington, DC: IVACG, 1999. 39. De Pee S, West CE, Permaesih D, Martuti S, Muhilal, Hautvast JG. Orange fruit is more effective than are dark-green leafy vegetables in increasing serum concentrations of retinol and `-carotene in schoolchildren in Indonesia. Am J Clin Nutr 1998; 68,1058–1067.

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The Economics of Nutritional Interventions Susan Horton

1. INTRODUCTION Nutrition is a basic need, and as such one of the desired outcomes of economic development. There are compelling reasons for investing in nutrition other than its economic beneﬁts. Nevertheless, quantifying these economic beneﬁts can be useful in order to advocate increased resources for nutrition programs. Economic analysis can also help to make informed decisions about the type of nutrition interventions to fund. This chapter examines in turn the costs of malnutrition (Subheading 2), the costs of nutrition interventions (Subheading 3), and the cost-effectiveness of nutrition interventions (Subheading 4). The ﬁnal section presents implications for future research, and policy conclusions. The discussion draws heavily on previous studies by the author including Horton (1,2) and Ross and Horton (3), and for data draws on the United Nations’ Administrative Council on Coordination/Subcommittee on Nutrition (ACC/SCN) (4).

2. THE COSTS OF MALNUTRITION The focus here is on four aspects of malnutrition, namely protein-energy malnutrition (PEM) and deﬁciencies of three important micronutrients, iodine, iron, and vitamin A. Deﬁciencies of other micronutrients such as calcium and zinc are not addressed, despite their importance in developing countries, because less work has been done in this area. Malnutrition imposes several costs. These include the human costs of premature death (which also imply economic costs), the economic costs owing to lost productivity and output, and the costs of treating ill health, which is associated with malnutrition (both costs to the health service and costs to households). These costs are examined in turn, and some estimates of the magnitude of the ﬁrst two sets of costs are provided. Malnutrition is an important underlying cause of premature death in developing countries. There is a dose-dependent relationship between the severity of malnutrition and the relative risk of mortality. The relative risk of premature mortality, as compared

From: Nutrition and Health in Developing Countries Edited by: R. D. Semba and M. W. Bloem © Humana Press Inc., Totowa, NJ

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Table 1 Regional Estimates of Prevalences of Underweight Children <5, and Estimated Excess Mortality Attributable to Malnutrition (Million Deaths/Year) Region Sub-Saharan Africa Near East North Africa South Asia East Asia Latin America/Caribbean Total

% Moderate malnutrition

% Severe malnutrition

Excess mortality (m)

20 12 32 20 19 19

10 15 19 10 11 11

14.0 10.3 15.4 10.4 10.1 10.2

Adapted from UNICEF (32) for malnutrition rates, author’s calculation for excess mortality. Calculations use a method provided by Jay Ross to convert malnutrition (z-scores) to %-of- median ﬁgures, and use ﬁgures for child population and child death rates by region from UNICEF (32). It is assumed that relative risks are the same for children below 6 mo, as for those 6–59 mo, because separate nutrition and mortality rates below 6 mo by region are not readily available. South Asia includes Southeast Asia.

to normally nourished children, has been estimated at 2.5 for children who are 70–79% of the median in weight for age, 4.6 for children who are 60–69% of the median, and 8.4 for children who are less than 60% of the median, between ages 6–59 mo (5). Malnutrition can account for a large proportion of child deaths in regions of the world where malnutrition is widespread. If all children below 70% of the median weight for age moved above the 70% level (this is equivalent to removing moderate and severe malnutrition on the Waterlow scale), it would prevent an estimated 2 million child deaths per year (Table 1): 1 million in South and Southeast Asia, and 0.8 million in sub-Saharan Africa (the rest in other developing country regions). This represents 20% of the 10 million child deaths annually. Preventable deaths are concentrated in South Asia, Southeast Asia, and sub-Saharan Africa, where malnutrition is highest. Worryingly, the rates are rising in sub-Saharan Africa, although falling slowly elsewhere. Iodine deﬁciency likewise is associated with higher rates of perinatal mortality. However, the magnitude of the relative risks involved is not well-known. The introduction of iodized salt has had a very rapid effect on reducing the population at risk for iodine deﬁciency; nevertheless, it remains an important problem in the Eastern Mediterranean, sub-Saharan Africa, and (owing to the large populations in these countries) South and Southeast Asia (Table 2) (4). Severe iron-deﬁciency anemia is associated with higher rates of maternal mortality, according to some analysts. Ross and Thomas (6) attribute 20% of maternal deaths in Africa and 23% in Asia to anemia, either directly (owing to heart failure, shock, or infection taking advantage of women’s impaired resistance to disease), or indirectly (owing to hemorrage or other causes). Gillespie (7) cites Zucker et al. (8) ﬁnding of a relative risk of death in childbirth for severely anemic women of 8.2 times that of normal women, and cites Carson et al. (9) ﬁnding for industrialized countries where even mild anemia is associated with a higher relative risk of death during surgery. If maternal deaths are as high as Ross and Thomas (6) estimate, in South and Southeast Asia, where 80% of pregnant women are anemic, anemia would account for as many as 57,000 maternal deaths annually. In Africa, where anemia rates are 47% for pregnant

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Table 2 Population At Risk for Iodine-Deﬁciency Disorder (Industrialized and Developing Countries) and Prevalence of Anemia (Developing Countries), WHO Regions (%) Prevalence of Anemia % At-risk IDD %

Children

Women 15–59 yr

Men

WHO Region

1994

1997

0–4 yr

5–14 yr

Pregnant

All

15–59 yr

Africa Americas Eastern Mediterranean Europe Southeast Asia Western Paciﬁc Total

32.8 23.1 42.6 16.7 35.9 27.2 28.9

23.4 16.6 30.3 10.7 14.4 9.8 13.7

33.1 22.9 38.3

52.0 36.9 30.8

46.9 39.0 63.9

37.9 31.0 51.1

28.0 11.0 32.7

52.7 14.7 34.9

63.9 56.9 53.9

79.6 38.5 56.9

60.0 33.8 43.9

42.4 36.0 34.9

Adapted from ACC/SCN (33). Notes: At risk for IDD is deﬁned as ‘living in areas with iodine deﬁciency and a total goiter rate above ﬁve per cent’ (ACC/SCN) (33), and ﬁgures are for industrialized and nonindustrialized countries. Prevalence of anemia is based on national data, and ﬁgures are for nonindustrialized countries only. Southeast Asia includes South Asia.

women, but birth rates are higher than Asia, it would account for an estimated 25,000 maternal deaths annually. There are additional unquantiﬁed effects on infant mortality: maternal anemia is associated with low birth weight (LBW), which in turn is associated with elevated risk of infant mortality. Finally, the importance of vitamin A in combating infection has been appreciated recently. One estimate is that the relative risk of mortality for children with subclinical vitamin A deﬁciency is 1.75 that for nondeﬁcient children (10). If subclinical vitamin A deﬁciency is of the order of 10 times that of clinical deﬁciency, then the proportion of child deaths related to vitamin A deﬁciency can be estimated (Table 3). In both sub-Saharan Africa and South Asia, the excess deaths attributable to subclinical vitamin A deﬁciency are 0.24 million annually in each region, with a total of 0.53 million such deaths annually worldwide (just over 5% of all child deaths). It is not straightforward to estimate total numbers of deaths owing to malnutrition of different types. We cannot simply add up the numbers of deaths attributed to different types of malnutrition, because this does not take account of possible synergies between different nutrient deﬁciencies, or the extent of overlap and multiple deﬁciencies in one individual. Nevertheless, it is clear that malnutrition is an important cause of premature death. The previous estimates are conservative: they exclude deaths of infants and children attributable to iron deﬁciency and iodine deﬁciency; and they exclude effects on mortality of adult chronic disease that is related to fetal malnutrition (11). Premature death involves economic as well as human costs. We do not attempt to quantify these. Putting a dollar value on human life is very difﬁcult. The economic cost of death of the mother may not seem large in market terms in some countries where women’s labor market participation is very low, but the disruption to the family and the social costs may be very large. The economic cost of child deaths are also difﬁcult to calculate.

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Table 3 Prevalence Estimates of Clinical VAD for Children Aged 0–60 mo, 1985–95 (%), and Estimated Excess Child Mortality (Million Deaths/Yr) Region

1985

1995

Excess mortality

South Asia East Asia/Paciﬁc Latin America and the Caribbean East/South Africa Sub-Saharan Africa West/Central Africa Middle East/North Africa Total developing

1.79 0.43 0.35

0.95 0.25 0.24

0.24 0.03 0.01

1.80

1.06

1.40 0.63 1.06

0.87 0.27 0.63

0.24 0.01 0.53

Adapted from The Micronutrient Initiative (34): also quoted in ACC/SCN (33) for prevalences, and author’s calculations for mortality, using relative risks as described in text and data on child deaths and child population by region in UNICEF (32). Note that it is assumed that relative risks are the same for children below 6 mo as for those 6–59 mo, because data on child mortality rates and vitamin A deﬁciency are not available separately for this age group by region.

Malnutrition also entails economic costs owing to lower productivity. Some of these costs are felt immediately—currently, anemic adults have been shown to be less productive in manual labor, and there are almost immediate productivity gains from iron supplementation (12). There are similar studies of productivity effects of calorie supplementation in manual labor (13). Other effects take longer to manifest themselves. Some studies of wages of adults in manual labor suggest that stunted adults (holding other factors constant) earn less, implying lower productivity. Stunting in adulthood is in turn related to malnutrition suffered in early childhood. There are also effects of nutrition on cognition, which take time to manifest themselves. PEM and iron deﬁciency in early childhood can be linked to lower cognitive scores in adults (by inference from studies: there are as yet no panel data for individuals from developing countries for a long-enough duration to show this). Maternal iodine deﬁciency is associated with mental retardation in children. We know from many studies from developing countries that wages are related to cognitive ability, both directly, and indirectly via the effects of higher cognitive scores on schooling attainment. The effects of malnutrition on cognitive ability and hence adult productivity are more subtle than the effects on physical size and strength, but may if anything be larger and more pervasive. After all, use of physical labor tends to decline in the course of development, while cognitive skills become increasingly important. Table 4 presents estimates of the size of these productivity effects. Studies suggest that iron deﬁciency anemia is associated with a 17% loss of productivity in heavy manual labor, and 5% in light blue-collar work, based on supplementation studies (see Table 3 in Ross and Horton, 1998, for references). A 1% deficit in adult height was found to be associated with a 1.38% reduction in agricultural wages in the Philippines (14) and with a 0.3% decrease in rural wages in Pakistan (15). This would imply that adults who were moderately malnourished as children would be 2–6% less produc-

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Table 4 Summary of Productivity Losses Associated with Malnutrition Deﬁciency Protein-energy Iron Iodine Vitamin A

Losses in manual labor 12–6% (Moderate stunting) 12–9% (Severe stunting) 17% (Heavy labor) 15% (Blue collar) — —

Cognitive losses based on childhood malnutrition 10% 14% 10% —

tive, and those who were severely malnourished 2–9% less productive than their nonmalnourished counterparts. There are no estimated effects on physical productivity for iodine and vitamin A. The losses owing to cognitive impairments in childhood are more indirect. Estimates suggest that PEM in childhood is associated with a 15-point decrease in IQ, which in turn is associated with a 10% drop in earnings and hence productivity in adulthood, according to one early study (16). Intervention studies aimed at stunted children between 9 and 24 mo (17) ﬁnd that supplementation combined with psychosocial stimulation can permit these children to catch up with nonstunted controls in development levels. Childhood anemia is associated with a decrease in score on cognitive tests of about one-half of one standard deviation (SD), which in turn is associated with a 4% decrease in hourly earnings, based on carefully controlled studies of adult wages (3). Cognitive impairments associated with maternal iodine deﬁciency are very large. The average productivity loss per child born to a mother with goiter is estimated as 10% (18) (based on a 3.4% chance that the child is a cretin with zero economic productivity, a 10.2% chance that the child has a severe cognitive impairment, associated with a 25% loss of productivity, and an 86.4% chance of mild cognitive impairment with a 5% loss of productivity). ACC/SCN add: “Even in populations known to be at risk of IDD [iodine deﬁciency disorder] where there is no evident cretinism, there is a downward shift in the frequency distribution of IQ in schoolchildren” (4), and provide several references for Spain, Italy, and Indonesia, implying that there are effects of milder maternal iodine deﬁciency without apparent signs of goiter. Translating productivity effects from small-scale interventions and sample surveys into economy-wide effects is a little difﬁcult. One problem is that the effects that are easiest to measure are those in market work. It is more difﬁcult to estimate the costs involved in nonmarket work, causing a bias that works against women, although these nonmarket costs are real. Another problem is that there is overlap between nutrient deﬁciencies. Children who were deﬁcient in iron and hence suffered cognitive impairments may grow up to be adults who are also anemic and hence less productive in physical labor, and the effects may be additive or partially offsetting. Children who are iron-deﬁcient may also be underweight, as well as born of mothers who were iodinedeﬁcient, all of which have effects on cognitive development. A ﬁnal problem is the issue as to how important productivity losses are in economies that are labor-surplus,

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Table 5 Sources of Productivity Loss Owing to Iron-Deﬁciency Anemia, Selected Countries Country Bangladesh India* Pakistan* Mali South Africa Oman

Cognitive loss ($/cap)

Physical loss ($/cap)

Total loss ($/cap)

Total loss (% GNP)

12.57 13.38 13.23 11.12 11.67 49.34

3.23 1.35 1.48 1.82 3.74 8.41

14.19 14.05 13.67 52.30 26.92 51.72

1.90 1.27 0.85 0.92 0.89 1.01

Adapted with permission from ref. 3. Cognitive and physical losses do not sum to total loss, because of the assumption of substitution. We assume a 4% productivity loss owing to cognitive effects, a 5% productivity loss in light manual labor, and a 17% loss in heavy manual labor. The 4% productivity loss owing to cognitive effects is not additive to the 5% loss in light manual labor, but rather completely substitutable. For countries denoted by *, data on anemia in men were not available and anemia in adult males is assumed to be zero (although rates are likely to be higher); hence, ﬁgures are an underestimate.

although this objection applies perhaps more to physical labor and less to work affected by cognitive impairments. There is also the issue of discounting. When examining nutrition interventions, some beneﬁts occur immediately or almost immediately (iron supplementation of adults, iodine supplementation for women of child-bearing age), whereas others occur only with a lag (interventions that reduce PEM in childhood, iron supplementation of young children). The economic productivity losses associated with malnutrition may be substantial. Table 5 presents ﬁgures for the productivity losses owing to anemia for an illustrative group of countries, both cognitive losses and losses in manual labor. (Because there are no historical data on levels of anemia, we assume that levels of anemia have not increased over time in order to estimate cognitive losses.) Cognitive losses become relatively more important as countries become richer, and dominate losses in manual labor in middle-income countries. The losses associated with iron deﬁciency are of the order of 1% of gross domestic product (GDP), and higher in the poorest countries in South Asia where anemia rates are highest and heavy manual labor is more common. In South Asia alone, a loss of 1% of GDP represents US $5 billion annually. Estimates for economic losses owing to PEM and iodine deﬁciency do not exist for all countries. However, one can make estimates of the possible order of magnitude. In South Asia, where 50% of children are underweight (Table 1), a 10% productivity loss associated with lower cognitive achievement could amount to a loss of 2% of GDP (if the share of wages in GDP were around 40%): corresponding losses in Southeast Asia and sub-Saharan Africa would be 1.2–1.3% based on a prevalence of underweight of 31–32%. There could be additional losses of physical productivity owing to stunting, but we do not have data to estimate this. The cognitive losses owing to iodine deﬁciency can be estimated as follows: in the early 1990s (before salt iodization was intensiﬁed), 12% of the global population was affected by goiter. If we assume that rate had been similar for the last generation, and if

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the cognitive loss per birth to a mother with goiter is 10%, then the loss of GDP (again assuming wages are 40% of GDP) would be 0.48% of global GDP. This loss would vary depending on the level of goiter in the population: it could be as high as 2.4% of GDP in Bangladesh (where 55.6% of women 15–44 suffer from goiter), 2.5% in Sri Lanka prior to salt iodization (where 62% of women suffered from goiter), and not much lower in other parts of Asia, where goiter rates in the population are as high as 40% (Pakistan) 25% (India), and 20% (China: all data on prevalence of goiter from Mason, et al. 1999) (19). The economic losses in the future will diminish as salt iodization reduces the prevalence of goiter in pregnant women. The last component of costs identiﬁed was costs imposed on the health sector related to malnutrition. This includes costs of nutritional rehabilitation of severely malnourished children (where this is done), costs of the treating the additional morbidity attributable to malnutrition (owing to increased incidence of illness, longer duration, or greater severity), and costs associated with difﬁculties in childbirth and prematurity/LBW owing to maternal malnutrition. Unfortunately, it is not possible with present data to estimate either the costs to the health system, or the costs to households themselves in lost time, travel, and purchase of drugs. This section has discussed some of the serious costs that malnutrition imposes: these include the human costs of additional deaths, economic costs of lower productivity, and costs imposed on the health system. As we will discuss in the next section, nutrition interventions can be relatively inexpensive and (as the fourth section describes) cost-effective.

3. THE COSTS OF NUTRITION INTERVENTIONS Information about costs of nutrition interventions in isolation is not that useful. What matters ultimately is cost-effectiveness (or the cost of programs that are effective). Nevertheless, cost per participant and per capita are important to know from the perspective of replicability at national level. Given that malnutrition is so pervasive in low-income countries, only interventions that are of modest cost can be replicated nationally; interventions that are more costly can only be implemented if highly targeted, which in itself is a factor of further increasing costs. It is also useful to have in mind some benchmark costs for health interventions. The World Bank (20) has the most comprehensive estimates for a desirable package. They recommend that if existing spending on health care (approx $21 per capita across lowand middle-income countries) were reallocated, that it would be desirable to allocate about $5 to public health interventions, $10 to essential clinical services, and another $6 for “discretionary” clinical services (currently the allocation is $1 for public health, $4–6 for essential clinical, and $13–15 for discretionary clinical services). The components of the public health package recommended for the low-income countries include $14.6 per capita for expanded programme or immunization “(EPI) Plus” (the cost per fully-immunized child, including also some micronutrient interventions such as mass-dose vitamin A), $3.6 for a school health program (deworming, micronutrients, health education), $2.4 per participant for other programs (including family planning; health and nutrition information; plus vector control, surveillance, and monitoring), and additional amounts for tobacco and alcohol control and AIDS prevention. When

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these amounts are averaged over the population (not all of whom are participating at one time), this yields the public health expenditure per capita ﬁgure of $4 per capita in lowincome countries. The same package costs around $6.80 per capita in middle-income countries, which gives the average of $5 per capita in developing countries. The World Bank ﬁgures include the estimated costs of micronutrient interventions (although likely not the full costs of social marketing and the initial costs of introducing new fortiﬁcation, and setting up systems to monitor fortiﬁcation). However there is little allowance in these ﬁgures for community-based nutrition interventions. Only the most modest of programs would ﬁt (along with family planning, vector control, and monitoring) at under $2.40 per participant. In this section we therefore explore additional program components that could be added to the World Bank package, which could have important effects on nutrition. Table 6 summarizes approximate unit costs of several nutrition interventions (1). The table shows that micronutrient fortiﬁcation costs are very modest: $0.05–$0.15 per person per micronutrient, for costs of the fortiﬁcant itself. These costs can ultimately be passed on to the consumer, at least in middle-income countries (as is the practice in developed countries). These minimal costs do not include the costs of social marketing of fortiﬁcants, of technical assistance in identifying appropriate vehicles, of the equipment needed to add the fortiﬁcant to the vehicle, or of the monitoring and surveillance costs necessary to ensure compliance. These one-time costs can be fairly substantial in large countries. In Pakistan, for example, introducing salt iodization was estimated as costing $4.5 million: including $0.5 m in technical assistance, $0.5 m in monitoring, $1.5 m in social marketing, and $2 m initial subsidy of fortiﬁcant (21). This works out to only $0.03 per capita. The same study estimated that, over 10 years, to set up new programs and to support existing micronutrient fortiﬁcation would cost $45 m, which is dominated by the costs of initiating iron fortiﬁcation ($37 m). Although $45 m is a large cost, it works out in Pakistan to about $0.30 to $0.35 per person (less than 0.01% of annual per capita GDP, over the 10 years of the program). Micronutrient supplementation is more costly, although this is often necessary if a suitable vehicle cannot be found for fortiﬁcation for a particular population, or if the needs (especially for pregnant women) exceed what can safely be provided by fortiﬁcation. The costs are still modest ($0.20–1.70 per person per yr, depending on the nutrient involved and the target population). The next most expensive group of programs are those that are primarily educational in focus. Mass media programs exist costing between $0.20 and $2.50 (1). Unfortunately there are very few studies of impact of mass media interventions (one exception for vitamin A is de Pee et al.; see ref. 22) and hence their cost-effectiveness cannot be assessed. Other educational programs also have a practical component, such as providing seeds (home garden demonstration projects), support for breast feeding (breast-feeding promotion programs), revolving credit (water-jar projects), and growth monitoring. These programs cost between $5–10 per participant (1), except for breastfeeding promotion. The only economic study of the latter programs (to the author’s knowledge) found costs of $2–3 per birth for hospitals that had already eliminated formula, and $0.30–0.40 per birth for hospitals that had not (23). Community-based nutrition programs also have a strong educational component as well as activities such as growth monitoring, targeted feeding, providing micronutrient supplements, and so on. Save the Children (U.S.) has a demonstration project (the

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Table 6 Approximate Unit Costs of Interventions with Effects on Malnutrition Intervention Micronutrient fortiﬁcation Iodine Iron Vitamin A Micronutrient supplementation Iodine Iron (per pregnancy) Vitamin A Mass-media education programs Breastfeeding promotion Education programs (home gardening, growth monitoring, etc.) Community-based nutrition programs Less intensive More intensive Feeding programs (per 1,000 cals/day) Food subsidy programs (per 1,000 cals/day)

Cost/beneﬁciary/yr (US $) 30.05 30.09 30.05–0.15 30.50 31.70 30.20 30.20–2.00 32.00–3.00 35.00–10.00 32.00–5.00 35.00–10.00 and up 70.00–100.00 36.00–170.00

Adapted with permission from ref. 19: more intensive community-based programs; ref. 23: breastfeeding promotion; see ref. in Subheading 3: less intensive community-based programs; ref. 1: other programs.

Poverty Allevation and Nutrition Program) in Vietnam that costs $4 per child and is able to remove 90% of children participating from moderate and severe malnutrition. (No formal evaluation exists of this program: cost data from Save the Children [U.S.] Vietnam brochure, and from Save the Children [U.S.] Vietnam ofﬁce.) UNICEF has a pilot project in selected communes in Vietnam that has achieved improvements in child nutrition (children below 3), for $2.60 per child (again, there is no formal evaluation: Marjatta Tolvanen, UNICEF Vietnam, personal communication). The Barangay Integrated Development Approach to Nutrition Improvement (BIDANI) program in the Philippines also has impact on child malnutrition, for a cost of around $2 per child. The Intensive Child Distribution Service (ICDS) program in India is not regarded as very effective as it stands, and costs about $2 per participant for the nonfood component. The Tamil Nadu Intensive Nutrition Program (which has been evaluated, and is quite cost-effective (24), costs $12 per participant, of which a quarter is the supplementary food cost. Finally, a nutrition education program in the Dominican Republic that also improved nutrition cost $23 per participant. It is unfortunate that cost-effectiveness data for community nutrition projects only exist for the more expensive programs. It would be extremely useful to examine costeffectiveness of the less intensive programs—either to reallocate resources to these (if they are cost-effective), or to phase them out/make them more intensive if they are not cost-effective. Either way, there are resources that can be saved. Unit cost data suggest that feeding and food-subsidy programs without a strong educational component represent resources that would be better reallocated on nutritional

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grounds. The leakages away from the most vulnerable populations are usually considerable. Feeding programs are very costly—$70–100 per 1000 calories per person per day, for a year. Food subsidies have a wider range of costs but similar median costs. These unit costs suggest that nutrition interventions are well within the affordable range for “add-ons” to primary health care. Even the most expensive community programs can be afforded if well-targeted to particular regions, and focused on children below 2- or 3-yr old.

4. COST-EFFECTIVENESS OF NUTRITIONAL INTERVENTIONS Cost-effectiveness data are relatively scarce for nutrition interventions, largely because there are few program-impact data. The most consistent recent source is a comprehensive evaluation of 52 health interventions (including 9 nutrition interventions), by Jamison et al. (25). This evaluation is based on program data (where available) as well as extrapolations/estimates (where program data are not available). Estimates from programs are preferable to those from small-scale clinical trials: efﬁcacy in small-scale trials does not always translate into effectiveness in larger-scale programs. The results represent cost-effectiveness in “best-practice” interventions, rather than the average experience. There are likely some unintended biases in the ranking. Interventions with well-deﬁned, easily measurable outcomes (such as micronutrient supplementation) will tend to rank better than those with longer-term, more diffuse outcomes (home-gardening projects, community-based education programs, and so on). The cost-effectiveness of nutrition interventions is very high as compared to many health interventions (results from Jamison et al. are summarized in Table 7) (25). Of the nine nutrition interventions listed, six fall in the most cost-effective category (along with health interventions such as EPI), and the other three are in the next most costeffective category (along with health interventions such as oral rehydration therapy (ORT) and antenatal care) (note that there are 5 categories in total, and 28 of the 52 interventions fall into the ﬁrst two categories). One important nutrition intervention omitted is iron fortiﬁcation; this is probably because there are so few program data (and so few programs in existence) for developing countries. The cost-effectiveness results indicate that micronutrient interventions and breastfeeding promotion should be a very high priority; it would be fair to say, however, that coverage with existing micronutrient interventions lags well behind that of EPI, although substantial efforts have been made for iodine and vitamin A in Asia at least in the 1990s. Efforts are underway via the “Baby Friendly Hospital initiative” to make some improvements in breast feeding. The greatest gap is in programs regarding iron, and breast-feeding promotion for women not delivering in hospitals. The cost-effectiveness results also suggest that feeding programs targeted to vulnerable-age children (less than age 2), and to pregnant women, are also a high priority, on a par with antenatal care. In fact it may make sense to utilize complementaries between community nutrition programs (involving nutrition education and targeted feeding) and the provision of antenatal care, because the target groups are similar. Other studies of cost-effectiveness of individual programs include Taylor et al. (26), Ho (24) (both studies of food supplementation/nutrition education), and Horton et al. (23). Not all programs have in practice cost-effectiveness as low as suggested by

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Table 7 Cost-Effectiveness of Nutrition Interventions Interventions costing <$25 per DALY saved Breast-feeding promotion Salt iodization Fortiﬁcation of sugar with vitamin A Semi-annual mass dose with vitamin A Iodine injections for pregnant women Daily oral iron for pregnant women 16 other health interventions (10 public health, 6 clinical: EPI, smoking prevention, condom promotion, etc.) Interventions costing $25–75 per DALY saved Improved weaning practices Food supplements for children Food supplements for pregnant women 3 other health interventions (2 public health including ORT; 1 clinical—improved antenatal care) Interventions costing more than $75 per DALY saved 24 Interventions (6 public health, 18 clinical) Adapted with permission from ref. 25, Table 1A-6.

Jamison et al. (25). Mills (27) ﬁnds cost per DALY1 saved for vitamin A supplementation exceeds $50 in 1990s ﬁgures, United States Agency for International Development (USAID) (28) provide data which suggest that cost for a nutrition intervention program in the Dominican Republic exceeds $500 per DALY saved (author’s estimates, based on cost per child removed from severe/moderate malnutrition), and Kennedy and Alderman (29) present information that suggests that cost for a food supplementation program in the Philippines would also exceed $500 per DALY saved (author’s estimates, based on cost per child removed from severe/moderate malnutrition). There are also many examples of nutrition interventions with little or no measurable impact, whose cost-effectiveness is very low. The literature suggests some rules of thumb for cost-effective programs: • Interventions are most cost-effective where prevalence of malnutrition is highest: the increased targeting, which becomes necessary as prevalence declines, makes interventions more costly.

1The

DALY (disability-adjusted life-year) is a measure of health improvement that aims to be more comprehensive than deaths-averted. It measures the number of life-years saved by an intervention, adjusting for the quality of these life years with reference to the degree of disability suffered. A number of subjective judgements are required to construct the measure: typically, healthy life years are accorded different weights at different ages (with the highest weight being given to health improvement in adults of working age; future life-year gains are also discounted at 3%. One death-averted for an infant is equivalent to about 32 DALYs saved. The assumptions required make it necessary to evaluate the DALY measure carefully. See World Bank (20) for further technical details.

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• Cost-effectiveness of interventions likely varies by region, and is lower in regions which are less densely populated; this makes nutrition problems in sub-Saharan Africa (where malnutrition is rising) more intractable. (The programmatic evidence for this is limited: Horton [1], has data comparing costs of feeding programs, which are higher in Africa; however, the sample for Africa is small. However, the dispersion of processing facilities makes fortiﬁcation more difﬁcult in Africa, as does the lower proportion of marketed staples.) • Mason (19) makes a strong case for the existence of threshold effects in community nutrition programs. He argues that interventions that are not very intensive (which he deﬁnes as costing less than $5 per child) have little effect. This is an area where cost-effectiveness studies of the limited number of apparently successful, lower-cost programs such as BIDANI (Philippines) and some non-governmental organization (NGO) programs such as the Poverty Alleviation and Nutrition Program (PANP) program of Save the Children U.S. (Vietnam) (both mentioned in the previous section) would be helpful. • The “vehicle” for feeding programs and food subsidies is very important. It is preferable to use “self-targeting” staples (less-preferred staples such as wheat ﬂour in Bangladesh, “atta” wheat ﬂour in Pakistan) than preferred staples or items such as milk. Oil is a reasonable candidate: although it is also desired by rich households, it is useful as an addition to weaning foods to increase calorie-density. It can also be fortiﬁed with vitamin A (currently some food-aid oil is fortiﬁed). • Targeting is very important, both for feeding programs and food subsidies: on targeting of food subsidies see Pinstrup-Andersen (30). Geographic targeting, income targeting (especially for food stamps) and targeting using growth monitoring, are all approaches that have had some success. • Nutrition interventions have to be phased with other interventions, both in health and other sectors. There are no cost-effectiveness data (to the author’s knowledge) comparing the impact of nutrition interventions to that of interventions in clean water and sanitation or in appropriate child care, but these other investments may be limiting factors in improving nutrition in some regions and some countries.

5. CONCLUSIONS This chapter has shown that the costs of malnutrition are very high, both in terms of child (and maternal) deaths, and in terms of lost economic productivity. Moderate and severe malnutrition (as deﬁned by weight-for-age as a % of the median) accounts for 2 million excess child deaths annually (20% of child deaths in developing countries) (31), of which 1 million are in South and Southeast Asia, and 0.8 million are in Africa. Iron-deﬁciency anemia may account for 57,000 maternal deaths annually in South and Southeast Asia, and 25,000 such deaths in sub-Saharan Africa, according to some estimates of risks. Subclinical vitamin A deﬁciency accounts for 0.53 million child deaths annually, over 5% of such deaths. The productivity losses can add up to 1–2% of GDP even for an individual nutrient deﬁciency (and in South Asia, 1% of GDP is $5 billion annually). Well-designed nutrition interventions can be affordable. Micronutrient fortiﬁcation and supplementation are an urgent priority, in terms of their very low unit cost and very high cost-effectiveness; in fact, integrating micronutrient supplementation into EPI Plus makes sense. Micronutrient fortiﬁcation is the long-run solution of choice for the

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majority of the population, and may require outside technical and ﬁnancial assistance with the initial set-up costs. Iron fortiﬁcation is a particular priority because there has been least progress on this. For some countries, there exist ready fortiﬁcation vehicles, and the obstacles are the set-up costs for equipment and monitoring capability (countries where wheat and maize flour are the main staple, and where there is centralized processing, have advantages in fortiﬁcation). For other countries there are more formidable barriers, owing to lack of an obvious vehicle (this is often the case where rice is the staple food). Supplementation programs have an important role, even if they are less cost-effective than fortification. Supplementation may be vital for harder-to-reach populations (in more remote areas, where centrally processed food is not available), for poorer households who do not purchase processed foods, and for population groups with particularly high needs (particularly pregnant women). Mass-media education interventions appear to be low in cost, but there are no cost-effectiveness data. Mass-media programs may be important if there are ways to improve diet without requiring households to buy more expensive food. They may be also useful to complement other interventions, for example, increasing awareness of and demand for fortiﬁed foods. Other primarily educational interventions also lack costeffectiveness data, with the exception of breast-feeding promotion, which has been shown to be highly cost-effective. Community-based nutrition programs are effective if well-designed, and are an attractive investment for countries that have in place EPI and basic public health/primary health-care interventions in the lowest cost per DALY group (25); they are as costeffective as antenatal care, and in fact the maternal component of the community nutrition programs is very complementary to antenatal care programs. One urgent priority is to do some careful cost-effectiveness analysis of selected less-intensive and lower-cost community nutrition programs, to see whether these resources are being well-used. From a nutritional standpoint, feeding programs (without substantial education) and food subsidies represent resources that could be better applied more directly to nutrition interventions. There are regional differences in priorities for nutrition interventions. In South and Southeast Asia, density of population and depth and extent of malnutrition make community-based projects cost-effective. Likewise, patterns of food purchase make fortiﬁcation feasible. As antenatal care coverage is extended, prenatal supplementation with a range of micronutrients should become more widespread. In Latin America, levels of malnutrition are lower and community-based activities (at least from the one example in the Dominican Republic) have higher unit costs (this would be expected, given the higher salary levels than in South Asia). Because formula feeding is fairly widespread (Mexico is a particularly negative example), and diarrheal morbidity rates are high, breast-feeding promotion would be a cost-effective intervention, both in hospitals and in the community. In sub-Saharan Africa, interventions are more problematic. Low population densities are likely to raise the costs of community-based interventions (although the Iringa project was very successful). Moreover, decentralized food processing (and the great variety of staples) makes fortiﬁcation more difﬁcult. Possibly one of the most urgent

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priorities is work on refugee nutrition. The outbreak of micronutrient deﬁciency diseases such as pellagra and scurvy in refugee camps, and the worsening of rates of PEM in some camps, are nothing short of scandalous. In the region the WHO terms the “Eastern Mediterranean” (and that UNICEF includes in the Near East), despite higher levels of income and lower PEM, rates of iodine deﬁciency and anemia remain surprisingly high (higher than in the poorer countries in sub-Saharan Africa). Micronutrient fortification would seem to be a particular priority here, particularly because there are many wheat consuming households for whom iron fortiﬁcation would be possible. As countries become richer, problems of overnutrition emerge (adult chronic disease, heart health). These issues, which are already facing urban elites even in relatively poor countries, are also an issue in Eastern Europe and the former Soviet Union. The present chapter has not addressed the economics of health promotion in the area of overnutrition, but this is another topic worthy of further research.

REFERENCES 1. Horton S. Unit costs, cost-effectiveness and ﬁnancing of nutrition interventions. World Bank PHN Working Papers WPS 952. London: World Bank, 1992. 2. Horton S. Opportunities for investments in nutrition in low-income Asia. Asian Development Review, 1998 (In press). 3. Ross J, Horton S. Economic consequences of iron deﬁciency. Technical paper. Ottawa: The Micronutrient Initiative, 1998. 4. UN Administrative Council on Coordination, Subcommittee on Nutrition (ACC/SCN). Third Report on the World Nutrition Situation. Geneva: WHO ACC/SCN, 1997. 5. Pelletier DL, Frongillo EA Jr, Schroeder DG, Habicht JP. A methodology for estimating the contribution of malnutrition to child mortality in developing countries. J Nutr 1994; 124:2106S–2122S. 6. Ross J, Thomas EL. Iron deﬁciency anemia and maternal mortality. Washington, DC: Academy for Educational Development PROFILES Working Notes Series No. 3, 1996. 7. Gillespie S. Major issues in the control of iron deﬁciency. Ottawa: The Micronutrient Initiative, 1998. 8. Zucker JR, Lackritz EM, Ruebush RK, Hightower AW, Adungosi JE, Were JBO, Campbell CC. Anaemia, blood transfusion practices, HIV and mortality among women of reproductive age in western Kenya. Trans R Soc Trop Med Hyg 1994; 88:173–176. 9. Carson JL, Duff A, Poses RM, Berlin JA, Spence RK, Trout R, Noveck H, Strom BL. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996; 348:1055–1060. 10. Humphrey JH, West KP, Sommer A. Vitamin A deﬁciency and attributable mortality among underﬁve-year-olds. Bull WHO 1992; 70:225–232. 11. Scrimshaw, N. The relation between fetal malnutrition and chronic disease later in life. BMJ 1997; 315: 825–826. 12. Basta SS, Soekirman, Karyadi D, Scrimshaw NS. Iron deﬁciency anemia and the productivity of adult males in Indonesia. Am J Clin Nutr 1979; 32:916–925. 13. Imminck MDC, Viteri FE. Body composition of Guatemalan sugarcane cutters, working productivity, and different settings and conditions. Human Biol 1987; 59:827–836. 14. Haddad LJ, Bouis HE. The impact of nutritional status on agricultural productivity: wage evidence from the Philippines. Oxford Bull Econ Stat 1991; 53:45–68. 15. Alderman H, Behrman JR, Ross DR, Sabot R. The returns to endogenous human capital in Pakistan’s rural wage labor market. Oxford Bull Econ Stat 1996; 58:29–55. 16. Selowsky M, Taylor L. The economics of malnourished children: an example of disinvestment in human capital. Econ Dev Cultural Change 1973; 22(1):17–30. 17. Grantham-McGregor S, Walker SP, Chang SM, Powell CA. Effects of early childhood supplementation with and without stimulation on later development in stunted Jamaican children. Am J Clin Nutr 1997; 66:247–253. 18. Ross J. PROFILES Guidelines: calculating the effects of malnutrition on economic productivity and survival. Washington, DC: The Academy for Educational Development, 1997 (mimeo).

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19. Johnson U, Parker D, and Hurl J. RETA1 Overview. Asian Dell Review, 1999; (In press). 20. World Bank. Enriching Lives. Development in Practice Publication. Washington DC: World Bank, 1994. 21. Applied Economic Research Centre (AERC). Final report on RETA-5671 Pakistan Country Strategy. Karachi: AERC, 1998 (mimeo). 22. de Pee S, Bloem M, Satoto, Yip R, Sukaton A, Tjiong R, et al. Impact of social marketing campaign promoting dark-green leafy vegetables and eggs in Central Java, Indonesia. Int J Vitam Nutr Res 1998; 68:389–398. 23. Horton S, Sanghvi T, Philipps M, Fiedler J, Perez-Escamilla R, Lutter C, et al. Breastfeeding promotion and priority setting in health. Health Policy Plan 1996; 11(2):156–168. 24. Ho TJ. Economic issues in assessing nutrition projects: costs, affordability and cost-effectiveness. PHN Technical Note 85-14. Washington, DC: World Bank, 1985. 25. Jamison DR, Mosley WH, Measham AR, Bobadilla J-L, eds. Disease Control Priorities in Developing Countries. New York, NY: Oxford University Press, 1994. 26. Taylor CE, Faruqee R, Sarma RSS, Parker R, Reinke W. Child and Maternal Health Services in Rural India: the Narangwal Experiments, vol 2: Integrated Family Planning and Health Care. Baltimore: Johns Hopkins University, 1984. 27. Mills M. Bangladesh food and nutrition sector review mission: cost-effectiveness of food and nutrition intervention programs. (Draft.) Washington, DC: World Bank, 1983 (mimeo). 28. USAID. Growth monitoring and nutrition education: impact evaluation of an effective applied nutrition program in the Dominican Republic: CRS/CARITAS, 1983–86. Washington, DC: USAID Ofﬁce of Nutrition, 1988. 29. Kennedy E, Alderman H. Comparative analyses of nutritional effectiveness of food subsidies and other food-related interventions. Washington, DC: IFPRI Joint WHO-UNICEF Nutrition Support Program, 1987. 30. Pinstrup-Andersen, P, ed. Food Subsidies in Developing Countries: Costs, Beneﬁts and Policy Options. Baltimore: Johns Hopkins for International Food Policy Research Institute, 1988. 31. Pelletier DL, Frongillo EA Jr., Habicht JP. Epidemiological evidence for a potentiating effect of malnutrition on child mortality. Am J Public Health 1993; 83:1130–1133. 32. UNICEF. State of the World’s Children, 1998. New York, NY: Oxford University Press, 1998. 33. ACC/SCN. Preliminary results for the third report on the world nutrition situation. (Draft.) Geneva: WHO ACC/SCN, 1996 (mimeo). 34. Micronutrient Initiative, The. UNICEF and Tulane University. Progress in controlling vitamin A deﬁciency. Ottawa: The Micronutrient Initiative, 1998.

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Chapter 22 / Research and Policy Directions

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Research and Policy Directions David Pelletier

1. INTRODUCTION A striking feature of this volume is that its uniﬁed title, Nutrition and Health in Developing Countries, belies an almost overwhelming breadth and depth of scientiﬁc perspective and detail concerning these topics. Although the various chapters do not ﬁt neatly into a single typology, ﬁve of the most obvious analytical foci or frames for organizing the material are as follows: 1. 2. 3. 4. 5.

Disease focus (diarrhea, respiratory, measles, tuberculosis, HIV, obesity). Nutrient focus (vitamin A, zinc, iron, iodine, multiple micronutrients, undernutrition). Special population groups (maternal, intra-uterine, perinatal, child, elderly). Special contexts (urbanization, socioeconomic transitions). Planning and policy development (evaluation, surveillance, economics of interventions).

These ﬁve frames represent the most common ways in which health and nutrition problems are viewed, deﬁned, and analyzed within our professions and institutions. This diversity is necessary and useful for generating knowledge (i.e., research) related to individual diseases, nutrients, population groups, and development contexts. However, it may lead to fragmentation of effort in the development and implementation of health and nutrition policy and misallocation of scarce resources. This possibility arises because the optimal focus for organizing research (by disease, nutrient or population group) may not be the optimal focus for setting priorities and organizing interventions. This is revealed by reﬂecting on a typology of potential actions to improve health and nutrition, one version of which is as follows: 1. Public health system. a. Service delivery (including food and nutrient supplements and various curative and preventive health services). b. Environmental health (including water, sanitation, malaria eradication). 2. Food and nutrient-based approaches. a. Fortiﬁcation (single or multiple nutrients).

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3. 4. 5. 6. 7.

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b. Nutrient supplementation (commercially and via actions outside the public health system). c. Commercial or home-produced complementary foods. d. Home gardening. e. Home processing, preservation, and storage. Health and nutrition education, promotion, and social marketing (directed toward speciﬁc diseases, nutrients, foods, dietary patterns, risk factors or behaviors). Integrated community-based approaches. Food and income transfer policies, programs, and projects. Harmonizing nutrition goals within food and agricultural policy, programs, and projects. Harmonizing nutrition goals within rural and urban development policies, programs, and projects.

The previous categories of actions are familiar to the international nutrition community and widely used throughout the world. However, as diverse as they are, they only begin to reveal the actual complexity of the choices facing health and nutrition planners and policy analysts. In part this is because the scientiﬁc and practitioner knowledge base is still fragmentary regarding many issues, including: when to use each strategy or combination of strategies, how to predict the likely effects in different contexts, the requirements for effective implementation, and how to most effectively promote, manage, and evaluate them at the policy level. These uncertainties are further compounded by diversity (and at times rivalry) among problem foci, disciplinary traditions, professional orientations, and institutions in the international nutrition and health ﬁeld, all of which means we do not yet have an agreed-upon framework for thinking about nutrition policy and guiding policy decisions. The particular analytical frames we employ for guiding policy decisions in international health and nutrition are heavily inﬂuenced by the research traditions within our diverse disciplines and subdisciplines, which evolved primarily as tools for discovery rather than tools for aiding policy development. These research traditions do generate some of the knowledge required for designing individual interventions. However, there are some distinctive analytical and information requirements in the development of public policy that are not adequately addressed by these traditions, nor in the current training and practice of health and nutrition professionals. As a result, we tend to employ a variety of partial approaches to policy analysis and recommendation, a characteristic shared with many other ﬁelds (1,2). The use of partial approaches to policy analysis, and the lack of a larger framework for thinking about scientiﬁc research, public policy, and the relationship between the two, may have several undesirable consequences. Speciﬁcally, it may compromise our ability to incorporate or translate our ﬁndings into policy formulation, fail to provide guidance as to the most fruitful areas for future policy-relevant research, and compromise the appropriateness and effectiveness of policies and programs. In addition, it may contribute to disagreement and controversy within our ﬁeld because of the failure to distinguish scientiﬁc debates from public-policy debates, which involve distinctive logics and procedures for evidence, argumentation, and decision-making (3–5). This chapter outlines a broader conception of policy analysis based on an evolving body of theory and experience in the policy sciences and explores the implications for health and nutrition. The next section describes the nature of public-policy analysis, with

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a particular focus on how it differs from most research in international health and nutrition, followed by a discussion of the implications for research, training, and policy.

2. PUBLIC-POLICY ANALYSIS The diverse disciplines, scholars, and studies concerned with public policy tend to fall into one of three categories: (1) those that develop, use or promote particular technical methods for policy-relevant research and policy analysis; (2) those that study the social and political processes that affect and are affected by policy formation, choice, implementation, and outcomes in various settings; and (3) those that study the relationship between (1) and (2), i.e., the tension that exists between technical analysis and the larger process by which changes take place or ought to take place in policy and society. This chapter adopts the perspective that “sound public-policy analysis” explicitly should take account of all three bodies of knowledge. Table 1 identiﬁes seven forms of rationality that underlie public-policy analysis and disagreements, although these seldom are recognized and distinguished as such (1). This table provides the basis for the claim that policy development in international health and nutrition (as in most policy domains) is based on partial approaches. Without suggesting that all policy decisions should be based on a consideration of all forms of rationality (a clearly impractical scenario), this table does provide a point of departure for identifying the gaps in our approaches so that future research, training, and practice might address some of the gaps considered most relevant to our set of concerns. This table provides the overall framework for this section.

2.1. Technical Rationality Technical methods of policy-relevant research and policy analysis include a wide range of activities designed to study the prevalence of various problems, their causes and consequences, and the potential solutions. They also include methods for quantifying the costs and impacts of various solutions, as seen in cost-effectiveness analysis, and for studying certain aspects of the implementation process. Thus, in the case of international health and nutrition, the major task under this form of rationality is to study the objective reality of diseases, nutrient or nutritional deﬁciencies, their consequences, and the effectiveness and costs of various solutions, to support recommendations concerning what should be done to address these problems. Most of the chapters in this volume fall into this category. 2.1.1. CAUSAL ANALYSIS Causal analysis refers to a wide range of activities, including human and animal experimental research and clinical or epidemiologic research in ﬁeld settings. One way to organize our thinking about this wide range of scientiﬁc activity in relation to policy decisions is to borrow a framework from the ﬁeld of risk assessment in developed countries. In this framework, four types of information are sought, to help prioritize health and safety problems in these countries. Note that the terminology has been slightly altered here to conform to concepts in international health and nutrition, and the example of child mortality is used to illustrate the method (6,7): 1. Causal identiﬁcation: this step involves identifying the causes of a problem based on experimental, clinical, and/or epidemiologic research. Taking the example of child

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Table 1 Forms of Rationality Underlying Public Policy Rationality Technical

Key focus Causal analysis Intervention analysis

Economic

Allocative efﬁciency

Social/Normative

Equity Ethics Democracy

Political

Social allocation, freedom, power

Administrative/ Organizational

Legal

Performance Risk avoidance Survival Expansion Control Reputation Conformity

Multiple/ Integrative

Effective Appropriate

1The

Key concepts/elements1 Cause-effect relationships and mechanisms, dose-response, exposure, objectivity, uncertainty, methodoloty Efﬁcacy, effectiveness, coverage, targeting, quality, technical efﬁciency, unintended consequences Opportunity costs, incentives, self-interest, social welfare, consumer sovereignty, marginality, public and private goods, net social costs/beneﬁts, externalities, information failures, market failures, govt failures Fairness, distributive justice, rights, duties, obligations, autonomy, beneﬁcience, non-maleﬁcience, participation, consent legitimacy, accountability, sovereignty Sovereignty, participation, resources, groups, identities, alliances, interests, values, compromise & reciprocity, ideologies, rules, norms, institutions Routines, rules, authority, jurisdiction, discretion, professionalism, expertise, planning, management, political pressures, timing, opportunism, coping, negotiation, context, interests, beliefs, culture Laws, rules, precedents, rights, enforcement, contestation, due process Wisdom, judgment, justice, dignity, fairness and competence in analysis, deliberation and participation, legitimate representation of public values and interests

concepts shown here are illustrative rather than exhaustive.

mortality in a particular setting, these might include diarrhea, respiratory infection, malaria, and undernutrition; 2. Dose-response analysis: this step involves estimating the relationship between the burden of a given cause (measured in terms of prevalence, incidence, duration, severity, distance to health services, or other measures appropriate to the problem) and the risk of the adverse outcome. In the child malnutrition-mortality example, the dose-response was quantiﬁed as the relative risk, i.e., 2.5 for mild forms, 4.6 for moderate forms, and 8.4 for severe forms; 3. Exposure analysis: this involves estimating the distribution of exposure to a given cause within a particular population. For instance in 1992, 4.6% of Ethiopian children had severe undernutrition, 14.9% had moderate undernutrition, and 32% had mild undernutrition; and

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4. Integrative measures: this involves combining the information from the previous three steps in a policy-appropriate way, which can vary depending on the case and the nature of the information generated in the other steps. In the child-mortality case, the population attributable risk was used, indicating that in Ethiopia, 56% of all child deaths were associated with the synergistic effects of malnutrition and disease, of which 76% were associated with mild-to-moderate malnutrition and 24% to severe malnutrition. These ﬁgures are close to the global estimates of 56% and 83%, respectively, that have become useful summary statistics for policy development at international level.

This example is instructive for two reasons. First, it reveals that much of the research and analysis in international health and development is at the level of steps 1 and 2 (identifying or conﬁrming causes and the strength of the relationships), but there is no systematic tradition, set of methods, or expectation in our ﬁeld for combining it with exposure data and assembling it into policy-relevant, integrative measures such as Step 4. This is illustrated by the fact that the information needed for doing so in the child mortality example was in existence for roughly 10 years prior to the publications by the Cornell team, and the policy implications from step 2 studies had been extensively debated (8–10), but this critical integration of the relevant information had not occurred. If such analytical frameworks could be institutionalized in our thinking and practice it may not only improve the policy relevance of existing information, but also may help distinguish the higher priority from the lower priority areas for research and basic data collection at the international level and in speciﬁc countries or contexts. Before offering this as a strong recommendation, however, it is important to consider the limitations of this approach. Even though this approach does integrate information from steps 1–3 in a policy-relevant way, it still represents a “partial approach” to policy analysis. This is illustrated by the U.S. experience where this four-step procedures has been used for more than two decades and shown itself to be inadequate by itself for supporting the key policy decisions. Four reasons stand out (11,12): 1. The method is best equipped to deal with single exposures rather than multiple exposures, especially when the exposures are correlated among themselves in complex ways. This is well-illustrated by the diarrhea, respiratory, malaria, undernutrition example given earlier, as well as by the recent work by Victora (13). 2. The method can lead to a ranking of various problems or exposures, but under many circumstances constrained public resources should be targeted based on potential marginal improvements in health using “best available practices” rather than on the absolute level of risk. The U.S. experience has revealed that the rankings based on the prevalence (or population attributable risks) of problems and exposures can deviate signiﬁcantly from the rankings based on potential improvements, leading to substantial misallocation of resources (11). As indicated in many of the chapters in this volume, individual researchers and practitioners in international health and nutrition often claim priority status for particular diseases or nutritional deﬁciencies based on prevalences and/or seriousness of consequences as opposed to the prospects for improvement. 3. The methods requires a common metric (e.g., lives lost or DALY’s lost), which may not be available and/or may not reﬂect the other values that the public and society place on each outcome (e.g., in the U.S. some hazards are intrinsically more dreaded by the public, even if their numerical risk is low). 4. Responsibility for health and safety in the U.S. (as with health and nutrition in developing countries) is dispersed across a wide array of public and private institutions

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and, thus, acting upon the priority rankings (as a basis for policy priorities) would require an unusual level of coordination and cooperation in policy development and implementation. In other words, the ability to use the results of comparative risk assessments is adversely affected by inter-agency, and interest group politics and legislative behavior. This latter consideration raises a host of administrative and political complications, that underscores the need to broaden the scope of policy analysis beyond that permitted under a technical rationality model alone (see Table 1).

2.1.2. ANALYSIS OF INTERVENTIONS The previous discussion underscores the importance of Intervention Analysis (Table 1). As distinct from causal analysis, activity in this category generates information on the efﬁcacy and effectiveness of alternative approaches for addressing health and nutrition problems. Such information is essential for not only deciding which actions to use for a given health/nutrition problem, but also for guiding resource allocations across various problems based on the potential for improvement rather than the prevalence of the problem. Many of the chapters in this volume contain partial information in this category, and attempts to integrate this information are reﬂected in the chapter by Horton (Chapter 22) and in other works (14). One of the weaknesses of our collective effort with regard to intervention analysis is that the efﬁcacy trials and the program evaluations to establish effectiveness typically are undertaken without considering the types of information needed at the integration and policy-making phase. Thus, critically-needed information may not be available, or may not be comparable across settings, related to coverage, targeting, quality of services, or program inputs, costs, and a host of contextual factors that affect efﬁcacy and effectiveness. Another way in which intervention analysis could be improved is through a more systematic consideration of unanticipated consequences at the planning stage and during evaluation. Drawing again from the experience in developed countries, the need for considering this is increasingly revealed in the risk-assessment literature, which has begun to conceptualize the analysis of risk-risk trade-offs as an important class of analytical activity. Table 2 provides examples from developed countries in which actions taken to reduce one risk or one problem (the “target risk”) have created or have the potential to create problems in other domains (the “countervailing risk”). As shown in the table, some of the countervailing risks may be of the same type and affect the same individuals/populations, or they may be of a different type and affect different individuals/populations. The four possibilities suggested by this table have important implications for how they are handled in public policy (e.g., as issues requiring information and education to support individual choice, or as externalities that might warrant other forms of government intervention). A variety of examples may exist in international health and nutrition, including the HIV/breast-feeding decision, single vs multiple micronutrient supplements, supplement vs diet-based approaches, weekly vs daily iron supplementation, and a host of others. However, the main point to be drawn from this table is that the narrow analytical frames and research designs commonly used in our ﬁeld tend to focus on individual diseases, nutrients, and population groups, and a limited number of outcomes (i.e., with little systematic interest in potential countervailing risks).

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Table 2 Typology of Risk-Risk Tradeoffs Compared to the Target Risk, the Countervailing Risk Is: Compared to the Target Risk, the Countervailing Risk Affects: Same population

Same Type

Pesticides-cancer Butter-margarine-CHD Weight cycling and CHD Different population `-carotene supplements and lung cancer

Different Type Breastfeeding/HIV Fish/cancer/CHD Height/breast cancer Iron/zinc interactions Folate fortiﬁcation Iron deﬁciency/ overload Water ﬂuoridation “Functional foods” Gestational weight gain

Adapted with permission from ref. 15a.

2.2. Economic Rationality The economics-based version of policy analysis (hereafter called “economic rationality”) is another major form in use. Economic rationality incorporates the causeeffect information from technical analysis described previously, but extends upon it in signiﬁcant ways that lead to policy recommendations often quite different from those of health and nutrition researchers. Speciﬁcally, in this perspective the interest lies not only in knowing the prevalence of various problems and the effectiveness and cost-effectiveness of various interventions, but also in considering concepts such as opportunity costs (i.e., beneﬁts foregone) that are associated with deploying one intervention as opposed to another, or in addressing one problem as opposed to a different problem. Although the technique of cost-beneﬁt analysis often used for this purpose is commonly criticized because it requires a great deal of quantitative information and/or questionable assumptions, the underlying logic of considering opportunity costs and related concepts is compelling, widely applied in daily decisions in private and public life, and should be part of sound public-policy analysis. Remarkably, it often is not evident in the recommendations in international health and nutrition. Some of the strengths (and weaknesses) of this logic can be illustrated with the data shown in Table 3, which compares the estimated cost of averting a lost disabilityadjusted life-year (DALY) by deploying selected health and nutrition interventions. The table shows that the cost-effectiveness of nutrition interventions shown here ranges from $5–82 per DALY. The lowest costs are associated with micronutrient interventions and the higher costs are associated with integrated community-based programs directed at promoting child growth. The most obvious conclusion from these ﬁgures is that some interventions are more expensive than others, but many in the international health and

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Table 3 Cost-effectiveness Estimates for Selected Health and Nutrition Problems in Developing Countries Cause

Intervention

Vitamin A

Fortiﬁcation supplements, children Fortiﬁcation supplements, pregnancy Fortiﬁcation supplements, pregnancy Food supplements, pregnancy Food supplements, children Iringa Screening and referral Behavior change Breastfeeding promotion Improved weaning Behavior change Screening/referral/education

Iron deﬁciency Iodine deﬁciency PEM ARI Diarrhea Cardiovascular disease aplus

Cost per DALY averted ($) 1115 1119 1115 1113 1118 1120 1125 1170 1182 1120–50 1150 1130 1130 1170 1150a

DALYs Saved per $1000 200 111 200 177 125 150 140 114 112 120–50 120 133 133 116 117

$2000–5000/DALY for treatment of referred cases. From ref. (14).

nutrition community feel the advantages of the more expensive options like integrated community-based programs are worth the extra cost and would be inclined to advocate for making these investments. By contrast, the economic rationality takes the analysis a step further by converting these into estimates of the number of DALYs potentially saved through each intervention. (The following discussion assumes, for the moment, that these data represent marginal effects.) The second column reveals in more striking terms the “price” we would pay (in human terms) for favoring the more expensive interventions, assuming a ﬁxed set of resources for improving health. Speciﬁcally, we would forego about 160 DALYs (200 – 40 = 160) for each $1000 invested in a supplementary feeding program for women (compared to a vitamin A or iron-fortiﬁcation program), and we would forego an additional 28 DALYs (40 – 12 = 28) to invest that $1000 in an Iringa-style program instead of a supplementary feeding program (40 – 12 = 28). Moreover, if an advocate of Iringa-style programs did manage to raise $1000 in “new funds” for improving health (rather than accepting the resource constraint imposed earlier), the economic rationality would dictate that even that money would be better spent on fortiﬁcation programs than on the more expensive options (if the only interest is in DALYs). This example reveals that even the most rudimentary concepts in the economic rationality can lay bare the consequences of alternative actions and lead to decisions or policy preferences quite different from those suggested by cause-effect analyses described previously. To be very explicit about this difference, consider a nutrition researcher or practitioner operating under technical rationality (that focuses on effectiveness). This nutrition researcher might demonstrate a signiﬁcant impact of a

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program on child health, nutrition, and/or mortality and might be inclined to conclude that more programs of this type should be implemented, and that new funds should be allocated for this purpose if necessary. This is especially the case when there are organizational, professional, and/or personal incentives for drawing this conclusion. By contrast, a policy analyst operating under economic rationality (and assuming no perverse incentives) would be inclined to compare the cost-effectiveness of such a program to other options for improving the same outcomes and/or to actions that could improve even more highly valued outcomes associated with different problems. An especially important lesson from this example is that the nutrition researcher and economic policy analyst may differ in their conclusions, not because the economist is concerned with limiting the budgetary outlay and the nutrition researcher is concerned with minimizing human suffering; to the contrary, both may share the same goal of maximizing human beneﬁts, but their competing logics lead them to different conclusions. Although the previous example reveals the basic logic underlying opportunity costs, this is only one of the important concepts in the economic framework (15). A more thorough analysis would take into account such factors as: 1. The difference between average cost-effectiveness of an intervention and the marginal cost-effectiveness (with the latter being the more meaningful value in most analyses and holding the potential to reverse the choice between competing intervention options). 2. Costs and beneﬁts beyond those captured in outcome indicators like DALYs; in the present case, for instance, many features of the Iringa-style program would generate social and economic beneﬁts beyond those reﬂected in DALYs. These include increased productivity associated with piped water systems, cooperative child-care arrangements, and access to better health care; spillover effects from the capacity-building activities into other development activities; improved village leadership, and so on. These considerations also hold the potential for reversing the choice among competing options and, even when they cannot be quantiﬁed, they serve the useful purpose of focusing attention and debate on the most valued goals and objectives of the program (and, thus, the inputs/activities required to reach the priority goals).1 3. The possibility that positive or negative externalities might occur (unpriced effects on third parties, such as soil erosion or water contamination associated with agricultural or livestock practices). 4. The distribution of costs and beneﬁts across different social groups (exacerbating problems of equity and power imbalances). 5. Features of the local context that may affect the actual costs and/or effects of various intervention types. 6. The most appropriate institutional arrangements for addressing the problem (e.g., the right mix of market, community, and government inputs). 7. Longer-run expectations regarding costs, effectiveness, equity, and externalities.

1The term “technical efﬁciency” is used in the economic framework to refer to the most efﬁcient way to achieve a given objective, like maximizing DALYs, for which cost-effectiveness analysis is an appropriate tool. The term “social efﬁciency” refers to analyses involving a wider range of social costs and beneﬁts, for which cost-beneﬁt analysis is used and requires that dollar values or some other common metric be attached to all costs and all beneﬁts.

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Owing to limitations in the availability of quantitative data on these issues in particular settings, many of them cannot be incorporated directly into an applied economic model in a particular setting, but they can and should be considered as important components of a sound analysis. For this reason, and because many of these issues involve perspectives, assumptions and logic distinct from the core economic rationality, they are discussed as distinct forms of rationality in Subheadings 2.4. and 2.5.

2.3. Social/Normative Rationality At their core, the technical and economic forms of rationality strive to shed light on the likely or potential consequences of alternative actions. These consequences can vary from the health, well-being, and survival and women and children, to the levels and distribution of wealth and income, to the impacts on the social or natural environment. In this key respect, their core logic and methods are identical to technical and economic analyses of nonhuman systems, such as predicting the consequences of alternative manufacturing technologies on overall productivity, average product quality, variability in productivity and quality, and so on. In other words, there is nothing inherent to these forms of rationality to indicate how much value should be placed on the various consequences. For instance, causal and intervention analysis related to child mortality takes as a given the proposition that child survival is a highly valued outcome, but it does not explicitly weigh the value of that outcome against others (e.g., the life of the mother or a younger sibling). Similarly, economic analysis can predict the consequences of a targeted food subsidy on food consumption of the poor, the national budget, and the economy, but cannot by itself indicate the value to be attached to each of these outcomes. Despite the paramount importance or value placed on the efﬁciency criterion in many economic analyses, arguments, and policy prescriptions, the theory underlying economic rationality acknowledges that the value attached to various outcomes is and should be a socially-deﬁned construct (15–17).2 Social/normative rationality is fundamentally concerned with the implications of public policy for human dignity and the social norms and procedures that respect, protect, and fulﬁll it. Thus, in contrast to the cause-effect focus of technical and economic rationality, the central foci of social/normative rationality are equity, ethics, and democracy (Table 1). In this context, equity involves notions of fairness and distributive justice as important criteria in evaluating policy options; ethics involves a consideration of the rights, duties, and obligations that bind the state, nonstate institutions, and citizens in a just society; and democracy is concerned with the legitimacy and performance of social and political institutions (including norms and procedures) vis-a-vis the pursuit and fulﬁllment of ethical goals and outcomes. It is relevant to note that social/normative considerations receive much greater attention within the legal realm (notably within judicial and constitutional processes) and these aspects are addressed separately in a later section. The present discussion addresses the social/normative considerations within sectoral policy, as it pertains to health and nutrition, while recognizing that these are dependent on the legal frameworks in important ways.

2Note

that cost-beneﬁt analyses and other economic methods may employ various techniques for assigning weights, values or discounts to various outcomes, but all of these are (or should be) socially-deﬁned.

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Consideration of the social/normative dimensions of mainstream public policy (including health and nutrition) has proven difﬁcult in recent decades for several reasons. First, the health and nutrition ﬁeld has come to be dominated by a generation of practitioners whose training and professional socialization has emphasized the technical and economic forms of rationality. In this “techniﬁed” version of public policy or development work, the social/normative questions and considerations have been either overshadowed by demanding requirements for the technical analysis, viewed as “unscientiﬁc” or “subjective,” or taken-for-granted by the practitioners (e.g., when each assumes there is intrinsically high social or moral value associated with the problems they are researching or analyzing without a thoughtful consideration of the legitimacy of competing priorities). Second, there has been an institutional endorsement of this techniﬁed approach, on the part of academia, government institutions, donor agencies, other development institutions, and society at-large. This has permitted and reinforced the notion that technically derived solutions can provide an adequate basis for public policy and development work (18,19). Third, although allocative efﬁciency is an important and useful consideration in public policy (as noted earlier), the extent to which it has been uncritically applied across the policy spectrum, often foreclosing serious consideration of social/normative issues, has become problematic (20–22). Finally, it should be acknowledged that even if there were full agreement on the need for serious analysis of social/normative issues as part of sound policy analysis, the analysis of these issues and the tradeoffs among them inherently is more ambiguous, contestable, and problematic than technical analysis. For this reason, ethical analysis often is considered either a platform for advocacy or a “quagmire/morass” from which there is no clear escape and for which there certainly is no professional reward in the technical ﬁelds. Although the levels of certainty and agreement attributed to technical analysis often is more apparent than real (4,19,23–25), technical analysis has the advantage of being supported by some criteria for evidence, inference, and conﬁrmability that generally are well-established, understood, and accepted by its practitioners. By contrast, universal standards for making social/normative judgments do not have the same level of consensus among scholars in the relevant ﬁelds and do not appear possible because these judgments are so heavily dependent on the social and situational context. For this reason, social/normative rationality includes democracy as one of its key concerns, reﬂecting a desire for the analysis and deliberation of equity and ethics to be grounded in legitimate and authentic democratic values and processes. This highlights the fact that the scientiﬁc (or technical) components and the social/normative components of public policy analysis should proceed according to different sets of assumptions, logics, and procedures for deliberation and judgment (4,26,27), even though “public policy analysis” often is equated and conducted with technical and economic rationality alone. Although the previous discussion may explain why social/normative analysis has been marginalized from technically oriented policy analysis in the past, there is a renewed interest in restoring a more systematic and appropriate balance between these two inputs into public policy as recent literature, innovative forms of practice, and societal trends reveal. The academic literature is evolving from a mere social/normative critique of technocratic approaches, to the development and testing of alternative approaches at community, national, and international levels (4,28,29); the expanding interest in community-based development, civic engagement, and democratic renewal is an expression of the same phenomenon (30–32). In addition, research continues

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on the development of econometric approaches explicitly weighted to account for equity and social-justice considerations in ways that are founded upon, rather than undermined by, inter-subjective utility (33,34). The development and testing of such approaches speciﬁc to health and nutrition represents an important topic for future research, although it has yet to be conceptualized as such and rewarded within the international health and nutrition community. Such research could serve the dual purpose of rescuing social/normative considerations from its current “quagmire” or advocacy status, while fusing normative and technical considerations in appropriate ways, both of which would enhance the public character and legitimacy of health and nutrition policy. The preceding sections, which describe technical, economic, and social/normative rationality, all deal with the what question in public policy: what should be done in order to have an effective and appropriate policy? These three forms of rationality are based on a consideration of cause-effect relationships, the desire to allocate resources to produce the greatest net beneﬁt, and the desire to preserve human dignity in the distribution of social beneﬁts and costs. The next three sections each deal with the two how questions: how are decisions made, implemented, and enforced, and how should the health/nutrition community proceed in the pursuit of effective and appropriate policies? Although there is temptation to consider the what questions separately from the how questions, these sections will reveal the co-dependent nature of these questions.

2.4. Political Rationality Politics is the processes through which values are allocated in society, also known as the processes that determine who gets what, when, and how. According to one scholar (35), all the relevant values can be grouped into eight categories (power, wealth, wellbeing, skill, enlightenment, respect, rectitude, and affection) although their relative importance may vary across time, culture, and situation, and numerous alternative classiﬁcations have been proposed. In the ideal of representative democracy, elected ofﬁcials would faithfully weigh the conﬂicting values and interests of their constituents in a deliberative process, without regard to their own electoral or personal interests, resulting in well-considered public policies. The electoral process would ensure the integrity and accountability of this representation, the executive branch would discharge the will of the legislative body in a value-neutral fashion, and the judicial branch would resolve disputes and uphold constitutional rights and principles. Although this utopic description does not ﬁt any known political systems, it is included here to help distinguish the way politics is from the way it ought to be. It is only by specifying a normative model of politics that one can judge the appropriateness of current politics and public policy, as well as the appropriateness of one’s own actions and recommendations. Note the emphasis here on appropriateness, which is a broader, more inclusive criterion than the effectiveness that is central to technical rationality. Figure 1 is an abstract version of the political process that permits an analysis of actual and desirable processes in many settings.3 In this model, the evolution of public 3Fig.

1 is a conceptual model analogous to the UNICEF conceptual framework for the causes of malnutrition (UNICEF 1990). Speciﬁcally, it does not specify the relative importance of various factors or processes in a universal sense or in a given setting, but rather, identiﬁes the range of possibilities that should be considered in each setting.

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Fig. 1. Conceptual framework for the evolution of issues within policy communities.

policy (viewed as the cumulative result of many individual policies or a single policy) is a function of the patterns of participation (who, in what alliances, when, how), their relative power (including wealth, social standing, and alliances); and the nature and quality of analysis and discourse about the policy issues (including partial policy analyses and distorted communications about the problem and potential solutions). These factors, in turn, affect and are affected by the way in which the policy issue is structured and understood, and thus acted upon. Problem structuring and salience, in turn, are a reﬂection of the fragmented knowledge (including professional and institutional specialization) and the diversity in values, interests, and beliefs of the key participants. As shown, all of these interactions are affected by a series of conditioning factors and the prevailing decision-making processes. With respect to decision-making processes, it is important to note that politics and political rationality applies to the decisions, behavior and interactions of legislatures, agencies, and a variety of nongovernmental groups, typically operating within a coalition or policy subsystem context. This model can be used both to analyze the way politics is being conducted (e.g., through selective and inequitable participation, or through distorted communications concerning the nature of the health/nutrition problem and potential solutions). It also can be used to identify appropriate corrective measures (e.g., by taking steps to correct distorted communications about the problem and potential solutions, by strengthening strategic alliances and participatory processes, and by ensuring that one’s own policy recommendations are consistent with the relevant public values rather than personal, professional, or organizational values and interests). Although “bad politics” often is attributed to politicians and bureaucrats, it is noteworthy that professionals and their institutions also are part of the larger political context (19,36,37). For instance, many of the issues in international health and nutrition have been debated and decided based on a limited sub-set of professional and organizational knowledge, values, and interests (ostensibly on behalf of the affected

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parties), with little direct input or empirical conﬁrmation that these are in line with the values, needs and interests of the affected publics (e.g., micronutrient supplementation vs home gardening, cash crops vs food crops, agricultural intensiﬁcation, selective health care vs integrated community programs, ethical targeting of food aid). There is ample evidence that professional views often depart in important ways from those of “the community” (4,28,38) and may lead to misallocation of scarce resources (e.g., comparative risk assessment), raising the question of whether they truly represent the public interest in a broad sense or the special interests and narrowly deﬁned problems of concern to professionals and their institutions. In this respect, professionals are engaging in politics whenever they make policy recommendations based on a partial analysis, though they typically perceive themselves otherwise. Such practices raise normative concerns (e.g., regarding legitimacy and accountability) and increase the likelihood of ineffective or misguided policies. The latter is because relevant information may not be brought to light concerning the context of the problem or the consequences of the proposed solution, and because it lessens the likelihood of cooperation, compliance, or sustained support (4). Apart from assisting in the assessment of political processes, the literature on which Fig. 1 is based provides a perspective on political rationality that may improve the effectiveness of policy formation efforts related to health and nutrition. This wideranging literature includes descriptions of the forms and strategies of policy coalitions and communities, the political processes that govern and are affected by problem structuring, issue salience and policy/program sustainability, individual and organizational decision-making styles, and the strategies and tactics of policy entrepreneurs (2,39–44). A central message from this literature is that decisions concerning the most appropriate and effective content of a policy must take account of the political processes associated with its initiation, acceptance, promotion, implementation, and sustainability. This often involves uncomfortable compromises for professionals. For example, under technical rationality (with a concern for maximizing beneﬁts to the needy and maintaining cost-effectiveness), professionals norms and standards would dictate that food assistance should be strictly targeted to the poor. However, from the perspective of political rationality, in some settings attempts to strictly exclude the middle class from receiving some beneﬁts might jeopardize political support for the entire program (41). Such examples highlight the fact some of the prescriptions emerging from political rationality may be at odds with the professional standards and the technical rationality of practitioners in the health and nutrition community. Such dilemmas represent another case in which ethical analysis (social/normative rationality) is needed to help resolve the complex and conﬂicting demands of public policy. Such conﬂicting demands are a fundamental feature of public policy even under the best of circumstances, but are made even more complex when ideal political conditions do not prevail.

2.5. Administrative/Organizational Rationality As noted, individual organizations typically are part of larger networks or policy subsystems and as such some of their decisions and behavior are affected or constrained by that external political environment. However, organizations also have some distinctive internal dynamics that affect the formation, implementation, and outcomes of policy, such that these must be understood on their own terms. Contrary to the “machine

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view” of the policy process (in which policies are decided at one level and the only role of organizations is to implement them effectively and efﬁciently), there is now broad recognition in the policy sciences that a reasoned choice of “the most effective and appropriate policy” in a given situation cannot be made in the abstract. Rather, it is highly contingent on the characteristics, capabilities, and tendencies of the implementing organization(s), including its formal and informal structure, the internal and external pressures, and incentives on executives, analysts, managers, and staff; the nature of the tasks to be performed; and a variety of “intangibles” such as senses of cohesion or mission, personal and professional beliefs, informal culture, and recent or distant political relationships within or between various subunits (45). Whether the goal is simply to understand organizational behavior or to develop effective management strategies, it is useful to think of organizations simultaneously from a top-down, bottom-up, inside-inside, and inside-outside perspective (46,47). That is, to recognize that many important features of organizations such as goals, tasks, incentives, politics, beliefs, and culture exist and are shaped from each of these directions, thereby significantly complicating the task of management and control. Moreover, organizations may differ from one another along many of these dimensions (e.g., the nature of external politics and the professional beliefs of staff). The effectiveness of many of the well-recognized management tools (incentives, supervision, training, structural re-organization) depends vitally upon understanding the organizational characteristics. The weakness of many “fads” in the field of organizational change and management (e.g., total quality management and resultsbased management) is the attempt to apply a single set of management principles to a highly diverse set of organizational forms. Some of the most important distinctions for present purposes are (46): 2.5.1. TYPE OF POLITICS A major inﬂuence on executives, analysts, managers, and staff relates to the nature of the interest-based politics that surround the organization. Four basic types are: 1. Client politics, in which a policy or program relates directly to the interests of one dominant interest group, such that the beneﬁts are concentrated but the costs are widely dispersed (e.g., an agricultural credit program may be dominated by farmers or a rural water project may be dominated by pressure from a speciﬁc locality); 2. Entrepreneurial politics, in which the costs of a policy or program are highly concentrated and the beneﬁts are widely dispersed (e.g., regulation of pharmaceutical prices or the cost of health care); 3. Interest-group politics, in which the policy or program creates both high costs and high beneﬁts to many groups, thereby creating diverse and opposing pressures on the agency (e.g., the distribution of food-aid commodities in rural areas that compete with locally produced commodities); and 4. Majoritarian politics, in which the policy or program creates only low cost and low beneﬁts, such that there is little incentive for groups to organize (e.g., many health and nutrition interventions such as nutrition education, growth monitoring, oral rehydration, and so on).

It is important to note that the form of politics surrounding a program or policy can affect ﬁeld staff as well as higher level staff, as illustrated by the “coalition of indifference” to the needs of the rural poor in many agricultural extension programs (48).

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2.5.2. TYPE OF ORGANIZATION Whereas the type of politics is a powerful external inﬂuence on organizational behavior, the ability of exert managerial control is inﬂuenced by a variety of internal characteristics, including the nature of the organization’s production processes and the degree to which they can be observed reliably by managers and other overseers. Wilson (46) identiﬁes four types: 1. Production organizations, in which both activities (work) and results (outcomes) can be observed reliably (e.g., clinic-based immunization programs); 2. Procedural organizations, in which only activities can be observed reliably (e.g., clinic-based nutrition education programs); 3. Craft organizations in which only results can be observed reliably (e.g., communitybased education regarding use of oral rehydration or early referral for acute respiratory infection); and 4. Coping organizations, in which neither activities nor results can be observed reliably (e.g., many community health-worker programs).

The health and nutrition examples provided earlier illustrate that “organization type” is a function of what is supposed to be accomplished and the quality of supervision, training, and reporting. Thus, a growth-monitoring program (GMP) lends itself to observing activities (weighing sessions, implementation of education, and other interventions) and observing outcomes (reductions in malnutrition), but only if supervision, training, and reporting all are functioning adequately. This means a clinicbased GMP program might behave as a production organization if the organizational infrastructure is strong, but a community-based GMP program might behave as a procedural or coping organization if the infrastructure is weak. Thus, the utility of the aforementioned classiﬁcation is in facilitating an appropriate match between program type, program infrastructure, and reward systems and anticipating some of the positive and negative effects. Many programmatic failures in health and nutrition can be traced to a mismatch among these characteristics. Although these four types of organizations and the four types of politics described earlier may each provide useful insights into organizational tendencies and capacities, a moment’s reﬂection reveals that even greater insights can come from considering these two factors together. For instance, the distribution of food aid in remote areas may represent a combination of a coping organization (where neither the staff activities nor the results can be observed reliably) working in the face of client politics (in which one particular group stands to reap the beneﬁts). Such situations should be considered a priori to be particularly vulnerable to misuse. Other combinations of organization type and politics type may lead to useful, though less obvious, predictions. 2.5.3. TASK/GOAL AMBIGUITY When the goals of a program or organization are overly broad, ambiguous, or too many in number, analysts, managers, and staff will tend to respond to the “situational imperatives” to deﬁne their own tasks and routines in ways that may depart signiﬁcantly from ofﬁcials goals. In other words, in situations like this, the effective policy is made “on the ground” rather than at the central level. Contrasting examples in health and nutrition include the immunization and universal vitamin A supplementation (in which a high level of clarity of purpose and technology exists) vs an integrated health and

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nutrition program designed to deliver a variety of services based on local needs and situations (in which a high level of ambiguity and discretion is involved). The latter approach has very high requirements for staff training, supervision, administrative responsiveness, and monitoring of targeting and coverage. However, even with these strong top-down managerial features or strong levels of community participation, high ambiguity/high discretion programs are inherently vulnerable to interest-based pressures from within and outside the organization. It is relevant to note that individual analysts and staff working in ambiguous situations do not necessarily resolve their dilemmas on their own; in many cases peer expectations play an important role in shaping the response, which can create outcomes closer to or even further from the ofﬁcial or desirable goals of the program (46). 2.5.4. BELIEFS Personal and professional beliefs or predispositions are another factor that inﬂuences the task deﬁnition and performance of analysts, managers, and staff. This is especially so in ambiguous situations and when supervisory and reward systems cannot be welltied to observed performance. These predispositions are based on prior experiences (in the organization and elsewhere), degree of adherence to professional standards, political ideology, and personality characteristics. This factor is of particular relevance for health and nutrition professionals because task deﬁnition in this arena can be strongly inﬂuenced by professional training and personal ideology. Some examples are the concern for equity, the desire to help, “above all do no harm,” acting to alleviate human suffering with inadequate attention to opportunity costs or unintended consequences, belief in food-based approaches, and a generalized mistrust of industry, to name a few. These professional and personal beliefs, together with limited experience with and understanding of alternative forms of rationality, tend to compromise the effectiveness of health and nutrition professionals (analysts, managers, and staff) at several stages in the policy process, from policy recommendation through implementation and evaluation. 2.5.5. CULTURE The combination of factors discussed earlier (type of politics, production processes, ambiguity of goals/tasks and situational imperatives, and personal/professional beliefs and rewards), creates a distinctive view of the world and response to it on the part of managers, analysts, and staff within an organization. In many cases, a single organization may possess several subcultures with conﬂicts and rivalries among them, greatly complicating the task of effective management and implementation. This is evident in the health sector in general (e.g., each major disease category may have its own subculture), but it is even more of a concern for nutrition because of its distinctiveness from dominant professions in health and medicine, agriculture, economics, and others. Although nutrition practitioners are well-aware of this phenomenon based on experience, a systematic consideration of the previous factors (among others) would enhance our ability to identify the key features pf organizational cultures and subcultures in a given setting and take them into account both in the policy design and implementation phases. Unlike some of the forms of rationality discussed earlier (e.g., economic), this discussion reveals that there is not a single way of thinking that can be termed

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“organizational rationality.” Rather, each organization and/or subunits within it possess some distinctive characteristics with a large bearing on its response to policy initiatives and subsequent policy outcomes. Because these organizational characteristics can be so variable, can have such strong effects, and can be far more resistant to change than previously assumed, it is the responsibility of policy analysts, planners, advisors, and others to take explicit account of these characteristics as an integral part of the analytical process. In other words, the choice of a “best policy option” cannot be speciﬁed without a clear understanding of organizational characteristics, capacities, and tendencies. The failure to recognizes this has been one of the major causes of policy failure in previous decades.

2.6. Legal Rationality National and international laws are recognized as important policy instruments for international health and nutrition in such areas as ethics (e.g., rights to food, health care), food fortiﬁcation, maternity leave, and enabling legislation for a variety of speciﬁc policies and programs (e.g., food labeling, public health programs, food safety, and so on). The salient characteristics of legal rationality are its emphasis on compliance or consistency with established rules and precedents and, in some political systems, the openness of the legislative process to societal input. These characteristics sometimes generate conﬂict with the goals of effectiveness, efﬁciency, equity, or feasibility that are central to other forms of rationality, thereby justifying the separate label of legal rationality. As discussed previously for other policy instruments, there is an important distinction to be made between the existence of a law and the ability to implement or enforce it. The clearest example of this is the right to food as articulated in the Universal Declaration of Human Rights at the international level, which is not legally enforceable at the country level (49). Given the weak enforcement capacity for many types of laws in developing countries, legal instruments may be viewed as “sometimes useful but not sufﬁcient conditions” for improving health and nutrition. Nonetheless, the existence of laws such as those noted earlier provide a critically important foundation for ongoing national and international advocacy on issues of great importance to health and nutrition. In addition, a growing body of international laws and treaties related to international trade, property rights, environmental protection, and other domains will affect developing countries in profound ways, with a variety of direct and indirect effects on health and nutrition.

2.7. Multiple/Integrative Rationality The preceding sections describe six distinctive forms of rationality that are evident in various phases of the policy cycle, from problem identiﬁcation and agenda-setting through implementation and evaluation. The mix of rationalities and their relative importance varies across different phases of the policy cycle, in different sectors and problem domains, and across different policy issues. The high levels of disagreement, confusion, and dissatisfaction associated with the process and the outcomes of public policy is traceable to: (1) The existence of these distinct forms of rationality in use; (2) The fact that they typically lead to quite different conclusions about what actions should be taken in a given situation; and (3) The fact that most participants or observers of the policy process are not aware that these distinctive logics, criteria, and norms are

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“in play” in a given situation. The resulting mix of science, economics, ethics, politics, administration and law has been termed a “Tower of Babel,” in large part because most participants are not fully aware that their differences reﬂect separate language, logics, and norms (50a). Such collective confusion or chaos is ironic, considering that each of these professions places great value on reason and enlightenment as an important basis for public policy. The perspective reﬂected in the recent policy sciences literature is that sound public policy should be both effective and appropriate (Table 1). “Effective” refers to the notion that a given public policy should be capable of achieving its stated goal (in light of current or foreseeable political, administrative, and legal conditions). “Appropriate” is the notion that doing so is consistent with the other criteria contained in the various forms of rationality (e.g., efﬁcient, ethical, democratic). This dual criterion acknowledges that competing goals and tradeoffs do exist, that competing outcomes are valued differently in society, and that there are enormous complexities and uncertainties associated with social, political, and technological change (i.e., policy change). Accordingly, in an ideal situation, the development of such policies is based on wisdom, as opposed to partial knowledge or incomplete analysis, and it places a high value on social justice and human dignity. Since these characteristics are dependent on social context, this literature emphasizes the need to integrate technical analysis (to project the likely consequences of alternative actions) and with social deliberation (to reﬂect on and resolve value conﬂicts). In contrast to current professional and political practice, the integration of technical knowledge and social values should be conducted through authentic representation of social values as well as fair and competent deliberative processes. The development and evaluation of models based on citizen juries, panels and advisory groups, planning cells, negotiated rulemaking, and policy roundtables is becoming an active area of research for this purpose (4,28). In contrast to the experimental models noted earlier, it is important to note that there is a variety of ways in which incremental improvements in practice can be achieved by employing multiple forms of rationality. These are discussed in the ﬁnal section.

3. IMPLICATIONS FOR TRULY “PUBLIC” HEALTH AND NUTRITION4 This chapter began by noting great diversity in the analytical frames used in the international health and nutrition community: disease focus, nutrient focus, special populations, and so on. It also noted diversity in intervention possibilities, ranging from fortiﬁcation to rural development, and highlighted the uncertainties in our ﬁeld regarding the conditions under which each of these might be most effective. The traditional set of “research and policy recommendations” in a chapter such as the present one would be for more research and program evaluation on the effectiveness, cost-effectiveness, and determinants of cost-effectiveness of these interventions in 4The term “public health” or “public nutrition” is often used to refer to activities that seek to improve conditions at population rather than individual level and/or activities undertaken by the public (government) sector. This chapter argues that truly public health or public nutrition also should embrace a broad view of the public interest and the combination of government, market, and civil society processes required to fulﬁll it (i.e., a concern for effective and appropriate actions).

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various settings. Indeed such research and evaluation work is one of the priorities for our ﬁeld, already is well-recognized as such, and some speciﬁc avenues for investigation are identiﬁed in the individual chapters. Such work falls squarely within the realm of technical rationality that has guided most health and nutrition professionals in the past and will continue to do so for the foreseeable future. Rather than simply reiterating those recommendations and remaining within technical rationality, this chapter has described a much larger and complex view of public policy. According to this view: (1) knowledge emerging from our current research programs is a necessary but not sufﬁcient basis for sound public policy; and (2) even more importantly we, along with other policy analysts operating within only one form of rationality, may actually contribute to poor public policy by making and implementing recommendations based on partial policy analysis. It may be comforting or discomforting to learn that this latter statement describes most policy analysts across all sectors (3,50–52). Such a claim is based on the major re-thinking (since the 1980s) of the most appropriate roles of markets, governments, and civil society in the process of social change (15,19,20). An emphasis on governments characterized most of the century, followed by an embrace of markets beginning in the 1980s and a resurgent interest in community and civil society in the 1990s. The current view of governments, therefore, is that their primary role should be to facilitate the functioning of markets and civil society (rather than trying to solve problems themselves) and maintain appropriate balance and tension between them. Although most health and nutrition practitioners have experienced this re-thinking at community level (e.g., interest in community participation), analogous changes are underway in diverse academic ﬁelds and practice settings concerned with public policy at higher levels. The larger view of public policy described here maintains that effective and appropriate public policy should be capable of achieving its stated goal (in light of current or foreseeable political, administrative, and legal conditions) and should be consistent with or justiﬁed in relation to other criteria (efﬁciency, equity, ethics, democracy). These requirements for truly “public” health and nutrition probably exceed the breadth and expertise of all practitioners and graduate training programs in health and nutrition. This reﬂects the recent history of our professions and training institutions but does not invalidate these as criteria for sound public policy and for guiding incremental improvements in work. As described later, the re-framing of our goals in terms of effectiveness and appropriateness has immediate and longer-term implications for practice, research, and training.

3.1. Implications for Practice The multiple forms of rationality described here have several immediate effects on and/or implications for practitioners. Some illustrative examples are provided here, from the perspective of practitioners involved with policy/program analysis or policy research in national and international agencies and applied research institutes and academic settings. 1. Each form of rationality provides a distinct “lens” for re-examining a speciﬁc policy situation and revealing features overlooked by other forms. For instance, the concept of opportunity cost or marginalism in economic rationality could reverse the policy preferences formed under technical rationality alone; consideration of political

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rationality in the policy (re-)design phase could dramatically improve the prospects for continued funding of a program; and consideration of organizational rationality at the (re-)design phase could dramatically improve program effectiveness and efﬁciency. Thus, familiarity with multiple forms of rationality could be an asset for those who make policy decisions, those who advise policy makers, and those who manage programs. 2. Each form of rationality represents a distinctive language, logic, and set of norms and assumptions used by other professionals. In many practice settings the technical (and/or ethical) rationality of health and nutrition professionals is the “minority viewpoint.” After a certain point, persistence in pressing that viewpoint can lead to conﬂict and the marginalization of individuals and their agendas. Success in promoting the health and nutrition agenda within or outside one’s organization often may depend on the ability to re-frame the issue(s) in terms better understood and accepted by those with greater access to power and resources (e.g., economics or politics) and the ability to form strategic alliances with them. This requires familiarity with the dominant rationalities, which is far less demanding to acquire than the level of expertise required for detailed analytical work within that rationality. 3. In many settings practioners are in a position to evaluate or respond to proposals, situation assessments or evaluations produced by practitioners in the same or different institution. In most cases, the work of others will employ limited forms of rationality and/or selective elements within a given form. For instance, it may emphasize technical or economic rationality but reﬂect little or no organizational or political rationality; or it may include certain elements of technical rationality but omit others (e.g., by emphasizing a high regression coefﬁcient but overlooking the low prevalence or population attributable risk). Familiarity with multiple forms of rationality will permit practioners to “make sense” out of the partial analyses conducted by others (i.e., systematically decipher and analyze the implicit logic, identify gaps, and so on) and provide constructive feedback or critique as appropriate. 4. On many occasions, practioners confront ethical dilemmas in policy/program design and implementation. Beyond being familiar with social/normative rationality, a proper analysis of many ethical situations requires “inputs” from other forms of rationality. For instance, weighing the principle of “do no harm” against the principle of “provide humanitarian assistance when needed” in a refugee situation requires some type of predication concerning the degree of harm and the numbers harmed from a proposed intervention (in various ways) as well as a projection of the numbers in need and the degree to which they may beneﬁt. It may also require anticipating the behavior of program staff, local elites, and various population groups under different implementation scenarios. These examples illustrate that even when there is a concern for a single policy outcome (providing humanitarian assistance), the ethical/normative analysis might require familiarity with and/or inputs from multiple forms of rationality.

The previous examples illustrate that familiarity with multiple forms of rationality can facilitate a variety of incremental improvements in practice. Often these improvements do not require a thorough consideration of all six forms, nor do they always require high levels of expertise in each. They do require familiarity with applying the various forms of rationality to speciﬁc cases. In addition, they require that practitioners operating in this mode acquire certain skills, dispositions and/or working styles, including: the ability to recognize that one’s own view of “the problem” and what “ought to be done” is shaped by one’s own professional development, values, and

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beliefs, combined with the ability to entertain alternative views of the problem and potential solutions; the ability to decide which forms of analysis are needed in a given situation; the ability to acquire and maintain working relationships with those who can assist with various forms of analysis; and recognition of the limits of one’s own ability in conducting various forms of analysis. These latter skills are particularly important in institutional settings where disciplinary or topical expertise is sharply delineated and defended. Apart from these skills, practitioners operating in this mode often will face severe difﬁculties acquiring or accessing the relevant information required by different forms of rationality. This may be because information is highly fragmented across different institutions (e.g., academic departments or government units), it is not in the form required (e.g., statistical information), there is little incentive or support to produce it in the form required, or it does not exist at all. It may be comforting to note that this situation is the rule rather than the exception in most high level policy making situations (e.g., expert committees), but does not invalidate the need to consider the issue from multiple perspectives. It does highlight the need for more explicit linkages between research and the informational needs for policy making. Some suggestions are provided in the next section.

3.2. Implications for Research The recognition that six forms of rationality are relevant to the development and implementation of health and nutrition policy has broad implications for future applied research. In many cases the relevant perspectives, theories, and methods already exist in other disciplines (e.g., economics, policy sciences, organizational behavior, ethics, anthropology, sociology) and the challenge is to apply them to the types of situations most commonly encountered in international health and nutrition. Without attempting to be exhaustive, some examples follow. 3.2.1. TECHNICAL RATIONALITY For reasons provided earlier, the information most urgently needed in policy making relates to comparative risk assessment (knowledge of causes, dose-response relations, exposures, and integrative measures), comparative effectiveness and costs, and unintended consequences (to support analysis of risk-risk tradeoffs). This requires continued research in specialized areas (e.g., speciﬁc diseases, nutrients, special subpopulations, and with various intervention types) but using methods explicitly designed to permit comparative analyses at a later date. Given the importance of context (social, ecological, institutional) much of this work would need to be conducted in multiple and contrasting settings. 3.2.3. ECONOMIC RATIONALITY The use of economic rationality in health and nutrition policy analysis would be facilitated by three types of research. The ﬁrst involves the application of existing economic methods to health and nutrition concerns, for instance, to estimate marginal propensities of various subpopulations to “consume” foods, nutrients, and health/education services. These estimates are fundamental to many types of policy analyses. A second type involves the application of existing methods to the evaluation of the impacts of policies and programs in diverse sectors (health, agriculture, food, economic and trade policy,

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de-centralization). This type of research is highly relevant to all countries because of the combined inﬂuence of changes in international trade, domestic policies, and forms of governance. The third and arguably most important type is to use health and nutrition concerns as empirical cases for developing methods for the explicit integration of equity and other social/normative considerations into economics-based policy analysis. Ideally this would take place as part of the ﬁrst two types of research noted earlier and would build on the clear and growing concern for the externalities (environmental, labor, human rights, and other social concerns) associated with trade liberalization. 3.2.3. SOCIAL /NORMATIVE In addition to the integration of social/normative considerations with economic analysis noted earlier, the ability to incorporate normative concerns into policy discussions and analysis could be greatly enhanced by the development and application of methods for: (1) documenting and making visible the “normative sentiments” of various stakeholders in speciﬁc policy situations (including, among others, analysts, managers, policy makers, the affected populations, and the public at-large); (2) incorporating these into policy discussions and analyses; and (3) evaluating the effects of these methods on the views and decision propensities of various stakeholders, as well as on policy decisions themselves. 3.2.4. POLITICAL As noted in the sole volume on the subject (41), there has been little systematic study of the role of political strategies and processes on policy decisions and outcomes with respect to food and nutrition in developing countries. The subject has received somewhat more attention in developed countries in recent years (53–57), and has been extensively studied in other policy domains such as agriculture, environment, economics, and planning. Given the nascent stage of this research in developing countries, two types of applied research might be most useful: First, a systematic and comparative analysis of purposely chosen cases for retrospective analysis. Second, the initiation of prospective studies of the policy process in “real-time,” using methods and approaches from the action research tradition that involve regular interviews, analysis and reﬂection by and with various practioners and policy participants. The latter approach is most likely to provide practical and useful insights, especially if conducted in tandem with purposeful and innovative methods for improving the policy process. 3.2.5. ORGANIZATIONAL Similar to the situation with political rationality, organizational issues have received surprisingly little systematic study in health and nutrition considering the pervasiveness of these concerns in everyday practice. A combination of retrospective and prospective studies appears warranted, as noted for the political rationality earlier. The present case has the added advantage that many features of health and nutrition programs may be under the more direct control of program staff (e.g., training, supervision, communications, incentives) and thus more amenable to experimental study. 3.2.6. LEGAL Two types of studies might be particularly useful in the legal realm. The ﬁrst is retrospective study of how and why some countries have adopted particular laws related

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to health and nutrition (e.g., maternity leave, food fortiﬁcation). These studies may provide guidance for practioners in other countries concerning strategy as well as choice of issues. The second type is retrospective or prospective study of the consequences of laws once adopted. Laws, as with other policy instruments, may vary in their effectiveness with respect to stated goals, but also may create a variety of unintended consequences. For instance, laws mandating maternity leave may have little effect if they are not enforced and may have the unintended effect of inducing discriminatory hiring against women (depending on the existence and enforcement of laws against that practice). There is a tendency, particularly pronounced in the legal realm, to declare victory with the passage of seemingly positive laws without actually conducting follow-up studies. 3.2.7. MULTIPLE /INTEGRATIVE The existence of several form of rationality, and the goal of applying multiple forms to improve the effectiveness and appropriateness of policy, raises several issues for research. First would be documentation of the forms of rationality actually applied by current health and nutrition practitioners in various settings and the quality with which they are applied. This would serve to conﬁrm or disconﬁrm the notion that “partial policy analyses” are the norm and that the blind spots are a signiﬁcant concern. Second would be the development and evaluation of methods and procedures for applying multiple forms in speciﬁc policy situations. Some of these may involve methods for use by individual analysts, whereas others might involve the interaction of diverse stakeholders as part of analysis and/or deliberation. Some examples have been noted earlier in relation to speciﬁc forms of rationality, but a much larger set of methods could be developed and evaluated. Third, in addition to “process evaluation” of these methods, it would be desirable to study the effects of these methods on effectiveness and appropriateness in order to assess whether the results are worth the added effort. Even without being exhaustive, the previous examples highlight the diverse nature of the research required to support “effective and appropriate” policy as deﬁned here, and its distinctiveness from the current research topics in international health and nutrition. Two of the preconditions for this to occur are that funding agencies would value and fund these types of research, and health and nutrition researchers will collaborate with specialists in other forms of rationality in conducting the research. Some positive signs that this can occur are provided by the fact that the World Bank and UNICEF recently initiated an assessment of the progress these agencies have made in promoting nutrition policy in selected countries, and have employed theories and methods from outside the health and nutrition ﬁelds in doing so (personal communication). This assessment builds upon a growing recognition that success in achieving health and nutrition goals will require a broadening of perspectives and an emphasis on practical research (58–60).

3.3. Implications for Training The recognition of multiple forms of rationality as being relevant to health and nutrition policy may, at ﬁrst glance, appear to require sweeping and unrealistic changes in the training of researchers and practitioners. In reality, the use of the following strategies may be effective and feasible in improving research and practice. Additional suggestions for training have been published elsewhere (61,62).

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3.3.1. POLICY SUBSPECIALTIES IN HEALTH AND NUTRITION The recognition of multiple forms of rationality does not require sweeping revisions in the training of all health and nutrition professionals. Rather, it could be accomplished by ensuring that opportunities for specialized training in health and nutrition policy exist at appropriate institutions, that the curriculum cover a breadth of theoretical and methodological perspectives, and that the training includes opportunities to integrate multiple forms of rationality in speciﬁc case studies. At present a health and nutrition “policy specialization” is available at relatively few sites and often is not designed with the notion of multiple rationalities and integration in mind. 3.3.2. DISTINGUISH FAMILIARITY, COMPETENCE, AND EXPERTISE A pyramid based on these three levels of mastery (with expertise at the top) is a valuable asset in curriculum planning. In the present context it can guide decisions concerning those areas in which health/nutrition policy specialists should obtain a high level of expertise (e.g., technical aspects of health or nutrition) and those in which they may need competence (e.g., economics and organizational behavior) or familiarity (e.g., other forms of rationality and subject matter). This pyramid also can be used to ensure that health and nutrition specialists not in the policy track do receive some familiarity-level exposure to other forms of rationality and an appreciation of their role in future research and practice. 3.3.3. LIFELONG LEARNING The goal of integrating multiple form of rationality should anticipate the need and opportunity for lifelong learning to occur, such that knowledge and skills in integration will be improved during one’s career and need not be a “ﬁnished product” at graduation. 3.3.4. PLAN TO COLLABORATE If the expectation is that researchers and practitioners will seek out and collaborate with specialists in other disciplines, then principles in Subheadings 3.3.2. and 3.3.3. are more easily justiﬁed. By the same token, development of a broad-based specialty in health and nutrition policy is more feasible if undertaken as a collaborative effort with faculty from diverse disciplines at the training institutions. 3.3.5. CASE STUDY MATERIALS, RESEARCH SITES, AND INTERNSHIPS Successful training of integrative policy specialists requires repeated experiences in applying different forms of rationality to case studies as part of classroom instruction, as part of thesis research, and as part of postgraduate internships. At present the case study materials do not exist and, given the effort required to develop them, should be shared among institutions. Research sites should be chosen based on the availability of appropriate project or institutional opportunities, but an organized network of internships and training institutions would facilitate practical training.

4. CONCLUSION This chapter has described a broader view of health and nutrition policy than that prevalent in our ﬁeld at present. The justiﬁcation for doing so is based on three considerations: ﬁrst, the development and implementation of sound public policy

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requires a concern for multiple and often competing goals, and consideration of far more than the technical rationality emphasized in our training. Extensive bodies of theory and experience exist in other ﬁelds to assist in broadening our perspectives and approaches. Second, the use of relatively narrow research foci (based on individual diseases, nutrients, and population groups) does not foster sound public-policy analysis related to health and nutrition and fails to generate the data most needed for sound policy analysis. Third, the use of relatively narrow research foci and technical rationality, although consistent with disciplinary specialization and “discovery research,” often detracts from the goals of health and nutrition policy by diffusing and fragmenting political resources within the health and nutrition community and interfering with the ability to form alliances with other policy communities. Some of the actions described in this chapter may help achieve the goals of public health and public nutrition.

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Index

551

Index prevalence, 346–347 malnutrition, diarrheal disease, 99 maternal mortality ratio, 34 tuberculosis, 209–210, 214 vitamin A deficiency, 271–272, 273, 277–278 African-Americans, tuberculosis, incidence, 216 zinc supplementation, 48 Age, acute lower-respiratory infections, 138 maternal mortality, 38 vitamin A deficiency, 279–280 Agriculture, urban, 476–477 Air pollutants, indoor, acute lower-respiratory infections, 136 Air pollution, 475 American Association for the Study and Prevention of Infant Mortality, 10 Analysis of variance, historical development of, 5 Anemia, assessment, 334–335 clinical examination, 335 conditions contributing to, 336 defined, 327 maternal mortality, 35 mortality, 333 pathogenesis, 331–333 pregnancy, 44–45, 337 prevalence, 328 risk, vitamin A deficiency, 45–47 Anopheles, 182 Anthropometric screening, nutritional intervention, 64 Anthropometric status, global, prevalence, 398–399 Anthropometry, 396–398, 495–498

A Aaby, Peter, 164 Abortions, spontaneous, defined, 59 Accidents, pregnancy, 32 Acquired immunodeficiency syndrome (AIDS), 243–244. See also Human immunodeficiency virus infection Active tuberculosis, HIV infection, 225 treatment, 224–255 Acute lower-respiratory infections, 131–153 case-fatality ratios, 141 case management, 145–146 causes, 132 clinical presentation, 141–142 duration, 140 future directions, 150–152 growth, 145 historical background, 131–132 incidence, 139–140 nutrition, 145, 149–150 nutritional intervention, 146–147 pathogens, children, 142–143 pathophysiology, 143–144 prevention, 147–152 public health importance, 131 risk factors, 132–139, 151 seasonality, 140 Addis Ababa, maternal mortality, 38 Administrative/organization rationality, 535–540 Aeromonas, 98 Africa, acute lower-respiratory infections, incidence, 139 HIV infection, children, 244 iodine deficiency, 551

552 Antibiotics, measles, 168 Antimalarial chemoprophylaxis, 85 Antioxidant supplementation, pre-eclampsia, 44 Argentina, breast feeding, acute lower-respiratory infections, 134 Asia, acute lower-respiratory infections, incidence, 139 cholera, 94 HIV infection, 239 HPCL, 501–502 iodine deficiency, prevalence, 346–347 maternal mortality ratio, 34 obesity, 452 tuberculosis, 209, 214 incidence, 216 vitamin A deficiency, 271–272, 277–278 vitamin A supplementation, 381 Asian immigrants, tuberculosis, vegetarian diet, 221 Atopy, acute lower-respiratory infections, 138 Atwater, Wilbur, 9 Auramine-rhodamine, 222 Average man, mathematical expression of, 5 B Bacilli Calmette-Guerin (BCG), tuberculosis, 213 vaccination, 226–227 Balanced protein/energy supplementation, 86–87 Bangladesh, diarrheal disease, children, 110–111 hand contamination, 95–96 undernutrition, 101 home births, 50 maternal mortality, 38–39 TBA training, 49 vitamin A deficiency, 286 Bayle, Gaspard-Laurent, 211 Bednets, insecticide-treated, malaria, 179 Behavioral change, 429

Index Behavioral development, malnutrition, 407 Beliefs, program analysis, 539 Bentham, Jeremy, 6 Beriberi, 11–13 Beta-carotene, maternal mortality, 39–40 Bifidobacterium bifidum, diarrheal disease, 106 Biomass fuels, acute lower-respiratory infections, 137 Birth, preterm, 58–63 Birth attendants traditional, training, 48–49 Birth intervals, maternal mortality, 39 Bitot’s spots (X1B), 274 conjunctival xerosis with, 287–288 treatment, 291 Blastomycosis, acute lower-respiratory infections children, 143 Blended foods, RDAs, children, 382 Blood, collection, 498–500 transport, 500–501 TSH, 354 Body mass index (BMI), 448 Boussingault, Jean Baptiste, 328, 344 Boyle, Robert, 328 Brazil, acute lower-respiratory infections, breast feeding, 134 LBW, 132–133 malnutrition, 134 diet, 440 EPEC, diarrheal disease, 104 fetal death, prepregnancy obesity, 63 obesity, 458 Breast feeding, acute lower-respiratory infections, 134, 149 cost-effectiveness, 516 diarrheal disease, 95, 111–112 infant mortality, 10

Index malnutrition, 411 vitamin A deficiency, 283 Breast milk, micronutrients, 371–372 Bretonneau, Pierre Fidele, 8 British Public Health Act of 1848, 6 Budd, William, 7, 8 C Calcium deficiency, pre-eclampsia risk, 43–44 Campylobacter, 98 Capillary blood, collection, 499 Cardiovascular disease, micronutrients, 377–378 Care, malnutrition, 415–416 Caritat, Marie, 2 Catalase, iron, 331 Catch-up growth, 399–401 Causal analysis, 525–528 Centrifugation, blood, 500 Cephalo-pelvic disproportion, short stature, 42 Chadwick, Edwin, 6 Chapin, Charles V., 8 Chatin, Gaspard Adolphe, 344 Chi-square test, 5 Children, acute lower-respiratory infections, pathogens, 142–143 anthropometric indices, 396–397 behavior, iron deficiency, 333 blended foods, RDAs, 382 care, urban mothers, 471–473 diarrhea, zinc supplementation, 317–319 folate deficiency, 368 growth, dietary interventions, 414 indicators, 74–76 malaria, 192–193 malnutrition, 414–415 nutritional determinants, 411–413 growth references, 397–398

553 health and survival, UNICEF conceptual framework, 401–402 HIV infection, 244 antiretroviral therapy, 255 classification, 245–246 progression, 245 treatment, 253–254 malaria, zinc supplementation, 319 mortality, 402–405 growth retardation, 82–83 iodine, 352–353 malnutrition, 402–405, 508 vitamin A deficiency, 271–273, 509 pneumonia, 136 respiratory disease, zinc supplementation, 319 stunted, 80–82 reduction, 65 Chile, malnutrition, acute lower-respiratory infections, 134 China, breast feeding, acute lower-respiratory infections, 134 diet, 440 home births, 50 iodinated irrigation water, infant mortality rates, 355 malaria, 178 maternal mortality, 38 obesity, 458 rapid income increase, 437 China Health and Nutrition Survey (CHNS), 448 Chlamydia pneumoniae, acute lower-respiratory infections, children, 142 Chlamydia trachomatis, acute lower-respiratory infections, children, 142 Chloroquine, malaria, 178, 184 Cholera, 7, 94 Cinchona tree bark, malaria, 184 Circumsporozoite protein (CSP), 179–180 Cities, poor, population increase, 434–436 Client politics, 537

554 Cod-liver oil, tuberculosis, 212–213 Cognitive development, malnutrition, 407 Cognitive impairment, costs, 511–512 iron deficiency, 512–513 Coindet, Jean-Francois, 344 Collaboration, 547 Colombia, acute lower-respiratory infections, seasonality, 140 Community nutrition projects, cost, 514–515 Conjunctival xerosis, with Bitot’s spots, 287–288 Contagion, vs miasma, 7–8 Contaminated water, 8, 475–476 Contraceptives, maternal mortality, 38 Copper, diarrheal disease, 102 Corneal ulceration, 288–289 Corneal xerophthalmia, treatment, 291 Corneal xerosis, 288–289 Indonesia, 280 Coronary heart disease (CHD), micronutrients, 377–378 Correlation, 5 Correlation coefficients, 5 Cost-effectiveness, nutritional interventions, 516–518 Costs, malnutrition, 507–513 mass media, 514 micronutrient supplementation, 514 salt iodization, 514 Courtoise, Bernard, 344 Cretinism, 351–352 historical background, 343 prevalence, 347 Cryptosporidium parvum, 98, 99, 100, 109 Cuba, multiple micronutrient supplements, 382 Cullen, William, 211 Culture, program analysis, 539–540 Cytochromes, iron, 331 D Day-care centers, acute lower-respiratory infections, 136–137 DDT,

Index malaria, 178 De Chateauneuf, Francois Benoiston, 5 Death. See also Morbidity fetal, defined, 59 maternal nutrition, 63–64 maternal, 33 neonatal, maternal nutrition, 64 obstetric, 33 pregnancy-related, 33 Degenerative disease, 429 Descartes, Rene, 2 Diabetes, genetic component, 461 obesity, 460 Diarrheal disease, 93–117 breastfeeding, 95 children, growth, 99–100 pathogens, 98 zinc supplementation, 317–319 diagnosis, 102 duration, 96 EGF, 107 epidemics, in Paris, 11 feeding, timing, 103 fiber, 105–106 future directions, 115–116 geographical distribution, 94 glutamine, 108 historical background, 93–94 incidence, 96 infant mortality, 10 intestinal function, 100–101 lectins, 109 malnutrition, 409–410 morbidity, 99 micronutrient supplementation, 109–110 mixed diets, 104–105 mortality, 98–99 nucleotides, 108–109 nutrient absorption, 100–101 nutrition management, 102–103 nutritional interventions, 113 ORT, 102 pathophysiology, 98 persistent dietary management, 111 incidence, 97

Index prebiotics, 107 prevention, 111–115 probiotics, 106–107 public health importance, 93 risk factors, 94–95 seasonality, 96 short-chain fatty acids, 107–108 transmission, 94 undernutrition, 101 vitamin A, 101 zinc, 101–102 Diderot, Denis, 1–2 Diet, beriberi, 13 Brazil, 440 China, 440 France, 17–18 income, 18, 429–433 long term trends, 17–18 malnutrition, 411–414 mortality, 5 Norway, 441 Russia, 438–439 Scandinavia, 441 vegetarian, tuberculosis, 221 vitamin A deficiency, 283–284, 292–293 Western, 437 Diiodotyrosine (DIT), 348 Diphtheria, 8 Diphtheria-pertussis-tetanus vaccine, 148 Direct obstetric death, ICD-10 definition, 33 Directly observed therapy, tuberculosis, 224–225 Disability-adjusted life-year (DALY), 517 Diseases, dietary recommendations for, 10 Distrofia pluricarnical, 394–395 Drug-resistant malaria, nutrition, studies, 190–191 Drug-resistant tuberculosis, 216–217 E Early neonatal death, maternal nutrition, 64 East Indies, cholera, 94 Economic change, nutrition transition, 429–433 Economic rationality, 529–532, 544

555 Education Provision of Meals Act of 1906, 18 Educational level, height-for-age, 73 Egypt, hospital delivery, 50 maternal mortality, avoidable factors, 50 tuberculosis, 210 Eijkman, Christiaan, 13 El Salvador, child growth, malaria, 193 Elderly, tuberculosis, incidence, 216 Elizabethan Poor Laws, 6 Energy, maternal mortality, 39–42 pregnancy, 62 England, food production, growth in, 17 industrialization of, 6 infant mortality, 41 maternal mortality ratio, 35–36 statistics, historical development of, 4 vitamin A deficiency, 273 Enlightenment, 1–3, 5–6 Entamoeba histolytica, 98 Enteropathogenic E. coli (EPEC) diarrheal disease, 104 Entomological inoculation rate (EIR), 182 Entrepreneurial politics, 537 Environmental factors, acute lower-respiratory infections, 136–137 Environmental goitrogens, 350 Environmental tobacco smoke, acute lower-respiratory infections, 137 Epidermal growth factor (EGF), diarrheal disease, 107 Escherichia coli, 98, 109 enteropathogenic, 104 Ethambutol, tuberculosis, 224 Ethiopia, children, rickets, 136 Europe, diarrheal disease epidemics, 94 maternal mortality ratio, 34 Expanded programme on immunization (EPI), 171

556 F Family planning, maternal mortality, 38–39 Famine, 6, 428 malaria, 191 receding, 429 Farr, William, 4 Fetus, death, defined, 59 maternal nutrition, 63–64 growth, impaired, 79, 84–89 measurement, 72–74 Fiber, diarrheal disease, 105–106 Fisher, Ronald A., 5 Flour fortification, multiple micronutrient malnutrition, 379–380 vitamin A deficiency, 293 Folate, deficiency, children, 368 women, 368 malarial morbidity, 195–196 supplementation, 87 periconceptual, 65 Food, blended, RDAs, 382 caloric value of, 9 collection, 428 consumption, changes, 438 contamination, 475–476 defined, 9 malnutrition, 415–416 nitrogenous vs non-nitrogenous, 9 prices, urban areas, 469–470 production, growth in, 17 Food and Agricultural Organization (FAO), 22 Food Insecurity and Vulnerability Information Mapping Systems (FIVIMS), 504 Food vendors, street, 477 Fortification, multiple micronutrient malnutrition, 379–380 vitamin A deficiency, 293–294

Index France, diet trends, 17–18 food production growth in, 17 Frank, Johann Peter, 3 Fuels, biomass, acute lower-respiratory infections, 137 Funk, Casimir, 14 G Galton, Francis, 5 Gambia, acute lower-respiratory infections, breast feeding, 134 incidence, 139 malnutrition, 134 child growth, malaria, 193 fetal death, maternal nutrition, 63 maternal mortality, 42 TBA training, 49 undernourished pregnancy, 65 Garki Project, 193 Gay-Lussac, Joseph, 344 Gender, acute lower-respiratory infections, 138 vitamin A deficiency, 281 Genovesi, Antonio, 6 Germ theory of disease, 8 German Union for the Protection of Infants, 10 Germany, measles, 164 Ghana, Plasmodium falciparum, 180 vitamin A, diarrheal disease, 114 Giardia lamblia, 109 Giardia muris, 109 Global anthropometric status prevalence, 398–399 Godwin, William, 2 Goiters, 350–351 historical background, 343 prevalence, 347 rate, 353–354 Goitrogens, environmental, 350 Goldberger, Joseph, 15 Grant, John, 4 Greece

Index malaria, 178 Growth, curves, 74 data, interpretation, 76–78 deficits, assessing, 78 faltering, timing, 399–401 impaired, health consequences, 82–84 measurement, 72–78 social consequences, 82–84 promotion, 84–89 references, 397–398 retardation, child mortality, 82–83 patterns, 398–401 prevalence, 78–82 status, school performance, 83 Guatemala, acute lower-respiratory infections, malnutrition, 134 seasonality, 140 children, growth rate, 399–400 diarrheal disease, nutritional interventions, 113 Guatemalan Longitudinal Study, 83 Guatemalan women, short stature, prevalence, 85 H Haemophilus influenzae, acute lower-respiratory infections children, 142 Halley, Edmund, 4 Handwashing diarrheal disease, 112 Health malnutrition, 415–416 Heavy metal absorption iron deficiency, 334 Height-for-age educational level, 73 low, 75 Hematopoietic abnormalities HIV infection, 250 Hemocue, 336, 500

557 Hemoglobin, field testing, 336 frequency distributions, 335–336 iron, 330 Hemorrhage, zinc deficiency, 47–48 Henle, Jacob, 8 Herbal drugs, malaria, 184 Hereditary hemochromatosis, 339 Hib vaccine, 148 High-pressure liquid chromatography (HPLC), Asia, 501–502 Highly active anti-retroviral therapy (HAART), 239 Hispanics, tuberculosis, incidence, 216 HIV vaccines, 256 Home births, 50 Hopkins, Frederick Gowland, 14 Hospital delivery, 50 House flies, diarrheal disease, 96 Household diet, vitamin A deficiency, 283–284 Human immunodeficiency virus (HIV) infection, 237–257 active tuberculosis, 225 acute lower-respiratory infections, 138 asymptomatic, 243 children, 244 classification, 245–246 progression, 245 treatment, 253–255 clinical features, 241–242 defined, 237 diagnosis, 252 drugs, 252–253 geographical distribution, 239–240 global distribution, 238 highest-risk groups, 239 historical background, 239 host micronutrient status, 247–248 incidence, 215, 240–241 nutrition, 248–252 micronutrient supplementation trials, 251–252 natural history studies, 251 pathogenesis, 247 prevalence, 241 prevention, 254–256

558 primary, 242–243 progression, 240 public health, 237 risk factors, 240 symptomatic, 243 WHO classification, 242 zinc supplementation, 320 Human waste, diarrheal disease, 112–113 Hydrogen peroxidase, iron, 331 Hypogeusia, 317 I Immunity, acute lower-respiratory infections, 136 vitamin A, 15–16 Immunization, acute lower-respiratory infections, 148–149 Impaired fetal growth, estimates, 79 prenatal interventions, 84–89 Impaired growth, health consequences, 82–84 measurement, 72–78 social consequences, 82–84 Incaparina, 395 Income, diet, 18, 429–433 India, LBW, acute lower-respiratory infections, 133 malaria, 178 National Iodine Deficiency Disorder Control Programme, 356 nutritional interventions, diarrheal disease, 113 obesity, 458 vitamin A supplementation, 381 Indigent, 6 Indirect obstetric death, ICD-10 definition, 33 Indonesia, anemia, 47 corneal xerosis, 280 vitamin A deficiency, 272, 274 Indoor air pollutants, acute lower-respiratory infections, 136 Industrialization, of England, 6 Infants, mortality,

Index England, 41 historical development of, 4 iodinated irrigation water, 355 and social reform, 10 Wales, 41 zinc supplementation, 47 Infectious diseases, compulsory notification of, 8 micronutrients, 376–377 Infectious morbidity, vitamin A deficiency, 285–286 Infertility, iodine, 352 Influenza epidemics, historical accounts, 131–132 Influenza virus, acute lower-respiratory infections, 137 Inositol hexaphosphate, zinc absorption, 313 Insecticide-treated bednets, malaria, 179 Institute Pasteur, 21 Intellectual achievement, growth status, 83 Intellectual development, malnutrition, 408 Interest-group politics, 537 International Classification of Diseases (ICD-10), maternal mortality, 32, 33 International Office of Public Health, 22 International reference growth curves, 74 International reference population, 74 Internships, 547 Intervention analysis, 528 Intestinal helminth infection, 338 Intestinal parasites, nutritional status, 16–17 Intrapartum stillbirths, obstructed labor, 63 Intrauterine growth restriction (IUGR) classification, 74 definition, 74 determinants, rural developing countries, 59 maternal nutrition, 62–63 prevalence rates, 60–61 vs LBW and PTB, 58 Intrauterine growth restriction (IUGR)-low birth weight (LBW), incidence, 78–79 Iodine,

Index absorption, 347 assessment, 353–354 brain development, 349 child growth, 373 child mortality, 352–353 dietary requirements, 350–351 dietary sources, 350 growth, 349 growth and development, 352 immune function, 349–350 metabolism, 349 natural cycle, 346 reproductive failure, 352 storage, 347–348 supplementation, controlled trials, 352 transport, 347 urinary concentrations, 354 Iodine deficiency, 343–358 clinical manifestations, 350–353 costs, 508–509, 512 geographical distribution, 345–346 historical background, 343–345 pathophysiology, 350 prevalence, 346–347 prevention, 354–356 public health, 343 risk factors, 347 WHO criteria, 356 Iodized oil, oral, 356–357 Iodized salt, 354–355 cost, 514 Iran, zinc deficiency, 308 Iron, abnormal loss, 332–333 absorption, 329 child growth, 373 fortification, 339–340 immune function, 331 malarial morbidity, 193–194 nutrition status, assessment, 334–336 overload, 339–340 requirements, 332 storage, 330 supplementation, 337, 339 transport, 329–330 turnover and loss, 330 Iron deficiency, 327–340 clinical manifestations, 333–334

559 cognitive impairment, 512–513 control, 336–340 defined, 327 historical background, 328 nutrition education, 339 pathogenesis, 331–333 pregnancy, 44–45, 367 prevalence, 328 risk factors, 328–329 tests, 334–335 Iron-deficiency anemia, costs, 512 mental development, 375 Iron-folate interactions, 369–370 Iron-Vitamin A interactions, 369 Iron-zinc interactions, 369 Isoniazid, tuberculosis, 224, 226 J Japan, measles, 164 vitamin A deficiency, 274 Japanese accelerated model, 437 Java, anemia, 45 Jurisprudence, 6 K Kenya, anemia, maternal mortality, 35 diarrheal disease, undernutrition, 101 vitamin A therapy, measles, 169 Kimball, O.P., 344 King’s Evil, 211 Klebsiella pneumoniae, acute lower-respiratory infections, children, 143 Koch, Robert, 8, 212 Korean accelerated model, 437 Kuwait, obesity, 459 Kwashiorkor, 15, 395 L Lactobacillus acidophilus, diarrheal disease, 106 Lactobacillus bulgaricus, diarrheal disease, 106

560 Lactobacillus casei GG, diarrheal disease, 106 Lactobacillus reuterii, diarrheal disease, 106 Lactose, diarrheal disease, 103–104 Laennec, Rene, 211 Late maternal death, ICD-10 definition, 33 Latent tuberculosis, treatment, 226 Latin America, iodine deficiency prevalence, 346–347 maternal mortality ratio, 34 obesity, 452 Latrines, diarrheal disease, 112–113 Le Rond, Jean, 1–2 Learning, lifelong, 547 Lectins, diarrheal disease, 109 Legal rationality, 540, 545–546 Legionella pneumonia, acute lower-respiratory infections children, 143 Lifelong learning, 547 Ligue Francaise contre Mortalite Infantile, 10 Lister Institute, 21 London, diarrheal disease epidemics, 94 Low birth weight (LBW), acute lower-respiratory infections, 132–133 defined, 57 incidence, 73–74 prevention, acute lower-respiratory infections, 149 vs IUGR and PTB, 58 Low height-for-age, 75 Low income countries, 438–439 Low weight-for-age, 75 Low weight-for-height, 74–75 Lower respiratory tract infection, acute. See Acute lower-respiratory infections malnutrition, 409 Lunin, Nicholai, 13 M Magendie, Francois, 9 Magnesium, HIV infection, 250

Index supplementation, 87 Majoritarian politics, 537 Malaria, 7, 177–198 animal studies, 191–192 children, zinc supplementation, 319 clinical disease, 183 diagnosis, 184 drug-resistant, nutrition, 190–191 drug treatment, 184–185 endemnicity, classification, 182–183 eradication, 178–180 geographic distribution, 180–181 historical overview, 178 host-parasite interactions, 185 indicators, cross-sectional studies, 190 morbidity, 185–186, 193–197 nutrition, 186–197 parasite, life cycle, 181–182 severe, epidemiology, 183–184 hospital admissions, 187, 190 vaccine, 179–180 vitamin A, 376 zinc, Papua New Guinea, 376 Malaysia, home births, 50 Malnutrition, 393 acute lower-respiratory infections, 134–135 children, HIV infection, 254 mortality, 402–405, 508 costs, 507–513 diet, 411–414 etiology, 393, 408–415 functional performance, 406–408 infection, 405–406, 409–411 malaria, 187, 190–192 measles, 166 mortality, 402–404 multiple micronutrient. See Multiple micronutrient malnutrition obstructed labor risk, 42–43 prevention, acute lower-respiratory infections, 149 productivity, 510–511 research needs, 418–420

Index terminology, 394–395 tuberculosis, 218–219 Malthus, Thomas Robert, 2 Man, average, mathematical expression of, 5 Manicus, August Henrik, 7 Marasmus, 210, 395 Marine, David, 344 Markets, urban areas, 469–470 Mass media, costs, 514 Maternal death, ICD-10 definition, 33 Maternal energy supplementation, selective, 64–65 universal, 65 Maternal health, vitamin A deficiency, 273–274 zinc supplementation, 319–320 Maternal mortality, age, 38 birth intervals, 39 defined, 32 education, 36–37 Egypt, avoidable factors, 50 energy, 39–42 family planning, 38–39 life-time risk, 36 measuring, 32–33 medical causes, 34–35 micronutrient deficient, 39–42 multiple micronutrient malnutrition, 369 poverty, 36 rate, defined, 33 ratio, defined, 33 reduction, 35–36 socioeconomic development, 36–37 by United Nations regions, 34 Maternal nutrition, early neonatal death, 64 fetal death, 63–64 IUGR, 62–63 preterm birth, 63 Maternal obesity, prevention, 65 Maternal smoking, acute lower-respiratory infections, 136–137

561 reduction, 85 Mauritius, obesity, 459 McCarrison, Robert, 344 McCollum, Elmer, 14 McKeown, Thomas, 19, 213 McNamara, Robert, 23 Measles, 7, 163–173 case fatality rate, 20 case management, 169 clinical features, 166–167 defined, 163 epidemiology, 164–165 historical background, 163–164 immunization, diarrheal disease, 113 nutrition, 166 pathophysiology, 165 prevention, 171–172 public health, 163 research needs, 172–173 treatment, 168–171 vaccine, 148, 171 Mefloquine, malaria, 185 Megacities, growth, 435 Mellanby, Edward, 16 Mendel, Lafayette, 14 Menghini, Vincenzo, 328 Metropolis Water Act of 1852, 8 Mexico, nutritional interventions diarrheal disease, 113 Miasma, vs contagion, 7–8 Microbiology, advances in, 8 Micronutrients, acute lower-respiratory infections, 135–136 bioavailability, 366 breast milk, 371–372 child growth, 372–374 deficiencies, HIV infection, 249–250 maternal mortality, 39–42 interactions, 366 supplementation, costs, 514 two-way interactions, 369–370 Mid-upper arm circumference (MUAC), 75, 497 Middle East,

562 obesity, 452–453 Midwives, 50 Milk, breast, micronutrients, 371–372 nonhuman, diarrheal disease, 103–104 Mineral supplements, 370–371 utilization, 383 Miscarriages, defined, 59 Money, urban areas, 469–470 Monkeys, malaria, 191–192 Monoiodotyrosine (MIT), 348 Monster Soup, 8, 9 Morley, David, 164 Mortality. See also Death anemia, 333 child. See Children decline, 19–20 diet, 5 dietary interventions, 414 infant. See Infants maternal. See Maternal mortality Mother-to-child transmission, HIV infection, 240–241, 244, 255–256 Mulder, Gerrit Jan, 9 Multiple deficiency state, 394–395 Multiple/integrative rationality, 540–541, 546 Multiple micronutrient malnutrition, 365–384 causes, 366 dietary intake improvement, 378–379 dietary survey, 367 fortification, 379–380 maternal mortality, 369 morbidity, 376–378 motor and mental development, 374–376 pregnancy outcomes, 369 reproductive age women, 367–362 Multiple micronutrient supplements, 381–384 Multivitamin supplements, 370–371 Murat, Joachim, 6 Mycobacterial culture, 222–223 Mycobacterium bovis, 209 vitamin A deficiency, 219 Mycobacterium tuberculosis, 209 transmission, 217–218 vitamin A deficiency, 219 Myoglobin, iron, 331

Index N NADH dehydrogenase, iron, 331 Nairobi, maternal mortality, 31 National Center for Health Statistics/World Health Organization (NCHS/WHO), growth references, 397–398 international reference population, 76 National Institutes of Health, 21–22 National Iodine Deficiency Disorder Control Programme, India, 356 Neonatal death, early, maternal nutrition, 64 Nepal, anemia, 45 children, vitamin A deficiency, 283–284 night blindness, 46 vitamin trials, 39–40 Netherlands, hospital delivery, 50 maternal mortality ratio, 35–36 Newman, George, 10, 19 Newsholme, Arthur, 10 Niacin, 15 Nigeria, child growth, malaria, 193 maternal mortality ratio, 35 measles, 164 Night blindness (XN), clinicopathological features, 286–287 historical background, 274 Nepal, 46 treatment, 291 Nonhuman milk, diarrheal disease, 103–104 Nonspecific stunting, 395 Northern America, maternal mortality ratio, 34 Norway, diet, 441 Nucleotides, diarrheal disease, 108–109, 114–115 Nutrition Collaborative Research Support Program (CRSP), 367 Nutrition interventions, costs, 513–516 Nutrition program assessment

Index conceptual framework, 484–485 data, 492–494 developing countries examples, 494–504 results, 494 survey design, 485–492 Nutrition programs, 416–418 Nutrition projects community, cost, 514–515 Nutrition transition, 427–442 demographics, 433–436 economic change, 429–433 nature, 436–439 patterns, 428–429 Nutritional health, anthropometric indices, 396–397 Nutritional immunology, 15–17 Nutritional interventions, anthropometric screening, 64 cost-effectiveness, 516–518 Nutritional science, in nineteenth century, 9–10 Nutritional status, biochemical indicators, 501–502 O Obesity, 447 lower- and middle-income countries, 448–460 maternal, prevention, 65 prepregnancy, fetal death, 63 research implications, 461–462 Obstetric death, direct, ICD-10 definition, 33 Obstructed labor, intrapartum stillbirths, 63 risk, malnutrition, 42–43 Oceania, maternal mortality ratio, 34 Oral iodized oil, 356–357 Oral rehydration salts (ORS), 94 Oral rehydration therapy (ORT) diarrheal disease, 102 Organization, types, 538 Organization rationality, 545 Orr, John Boyd, 22

563 Osborne, Thomas, 14 Oxidative stress, 377 P Pan American Health Organization (PAHO), 22 Pan American Sanitary Bureau, 22 Panum, Peter, 7, 164 Papua New Guinea, malaria, zinc, 194–195, 376 Parakeratosis, 208 ParaSight-F test, 184 Parasitemia, 192 Paris, diarrheal epidemics, 11, 94 Paris Medical School, 211 Pasteur, Louis, 8 Pearson, Karl, 5 Pekelharing, Cornelius, 14 Pellagra, 14–15 Percent of median, 77 Percentiles, 77 Periconceptual folate supplementation, 65 Perinatal mortality, 59–60 rate, defined, 59 Periodicity, vitamin A deficiency, 281–282 Persistent diarrhea, dietary management, 111 incidence, 97 Peru, acute lower-respiratory infections incidence, 139 anemia, 45 Cryptosporidium parvum, 100 diarrheal disease, feeding timing, 103 mixed diets, 104–105 malaria, 178 nutritional interventions, diarrheal disease, 113 zinc supplementation, 48 Petty, William, 4 Philippines, acute lower-respiratory infections, breast feeding, 134 LBW, 133 malnutrition, 134–135 tuberculosis, vitamin A, 219

564 Phthisis, 210–211 Physical activity, obesity, 460 Physical growth, interventions, combined interventions, 88 WHO review, 87–88 Phytate, zinc absorption, 313 Plasmodium, life cycle, 181–182 Plasmodium falciparum, 180–181 life cycle, 181–182 malnutrition, 188–189 Plasmodium malariae, life cycle, 181–182 Plasmodium ovale, life cycle, 181–182 Plasmodium vivax, 180–181 life cycle, 181–182 Plastic food, 9 Pneumococcal vaccine, 148 Pneumocystis pneumonia (PCP), 239 children, 253 Political rationality, 534–535 Politics, 537 Population, resources, 6 urban, 435–436 Population-based assessment, 77 Population growth, 434 Potassium iodide, 355 Poverty, 6 growth, 88 maternal mortality, 36 urban, 466–467 Pre-eclampsia, antioxidant supplementation, 44 risk, calcium deficiency, 43–44 vitamine deficiency, 46–47 Prebiotics, diarrheal disease, 107 Pregnancy, accidents, 32 anemia, 44–45, 337 energy expenditures, 62 iron deficiency, 44–45, 367 outcomes, multiple micronutrient malnutrition, 369 suicide, 32 zinc deficiency, 315

Index Pregnancy-related death, ICD-10 definition, 33 Prenatal care, 48 Prepregnancy obesity, fetal death, Brazil, 63 Preterm birth (PTB), determinants, rural developing countries, 59 early neonatal death, 59–60 maternal nutrition, 63 prevalence rates, 60–61 vs LBW and IUGR, 58 Preventive medicine, early foundations of, 5–6 Primaquine, malaria, 185 Primigravida, sulphadoxine-pyrimenthamine, 45 Probability, historical development of, 4–5 Probiotics, diarrheal disease, 106–107 Productivity, malnutrition, 510–512 Professional delivery care, access to, 49–51 Proguanil, malaria, 184–185 Protein, origin of, 9 tuberculosis, 218–219 Protein-calorie malnutrition (PCM), 15 tuberculosis, 219 Protein deficiency, 15 Protein energy malnutrition (PEM), 395 malaria, 187, 192 mental development, 375 poverty, 365 tuberculosis, 219 zinc deficiency, 314–315 Protein gap, 15, 395 Psychological development, interventions, combined interventions, 88 WHO review, 87–88 Public health, graduate education, 20–21 progress in, 1–2 Public policy analysis, 525–541 administrative/organization rationality, 535–540

Index causal analysis, 525–528 economic rationality, 529–532 intervention analysis, 528 political rationality, 534–535 social/normative rationality, 532–533 Public water supply, monitoring of, 8 Pyrazinamide, tuberculosis, 224–225 Pyrimethamine, malaria, 184–185 Q QBC column, 184 Qing-hao-su, malaria, 184 Quetelet, Adolphe, 4–5 Quinine, malaria, 184 R Rationality, practice implications, 542–544 research implications, 544 training implications, 546–547 Reactive oxygen intermediates (ROI), HIV infection, 248 Receding famine, 429 Reference growth curves, international, 74 Regression, 5 Research sites, 547 Resources, population, 6 Respiratory disease, children, zinc supplementation, 319 Respiratory food, 9 Respiratory syncytial virus (RSV), acute lower-respiratory infections, 137 children, 142 Retinol, infections, 46 Retinol equivalents (RE), 269–270 Riboflavin, deficiency, women, 368 malarial morbidity, 196 Rickets, 14 Rifampin, tuberculosis, 224, 226 Risk approach, 64–65

565 Rockefeller Institute, 21 Romania, diarrheal disease, feeding timing, 103 Rome, malaria, 178, 186 Rotavirus, 98 Rural population growth, 435 Russia, diet, 438–439 obesity, 459 Rwanda, vitamin A, tuberculosis, 219 S Saccharomyces boulardii, diarrheal disease, 107 Safe Motherhood Initiative, 31 Safety nets, formal vs. informal, 470–471 Sahelian famine, malaria, 191 Salmonella, 98 Salt, iodized, 354–355 cost, 514 Sanitary idea, 6–7 Save the Children, Vietnam, cost, 514–515 Scandinavia, diet, 441 maternal mortality, 42 School performance, growth status, 83 Sedgwick, William, 8 See, Germain, 10 Selective maternal energy supplementation, 64–65 Selenium, acute lower-respiratory infections deficiency, 135–136 supplementation, 147, 150 diarrheal disease, 102 malarial morbidity, 196 Services, availability vs. accessibility, urbanization, 474–475 Sexual transmission, HIV infection, 240, 254–255

566 Shanghai, anemia, 45 Shattuck, Lemuel, 6 Shigella, 98, 99 Shigellosis, vitamin A supplementation, 110 Short-chain fatty acids, diarrheal disease, 107–108 Short stature, cephalo-pelvic disproportion, 42 Simon, John, 20 Small-for-gestational-age infants, vs IUGR, 73 Smoking, acute lower-respiratory infections, 136 Snow, John, 7 Social medicine, 3 Social/normative rationality, 532–533, 545 Social reform, and infant mortality, 10 Socioeconomic factors, acute lower-respiratory infections, 136–137 Socioeconomic status (SES), vitamin A deficiency, 281 Spain, nucleotides, diarrheal disease, 115 SPf66, 180 Spontaneous abortions, defined, 59 iodine, 352 Sri Lanka, home births, 50 LBW, acute lower-respiratory infections, 133 maternal mortality, 31 Standard deviation (SD), 5, 77 Staphylococcus aureus, acute lower-respiratory infections, children, 142 State of the World’s Children, LBW rates, 60–61 Statistics, historical development of, 4–5 integrated with experimental design, 5 Stepp, Wilhelm, 14 Stillbirths, defined, 59 iodine, 352 Street food vendors, 477 Streptococcus agalactiae, acute lower-respiratory infections,

Index children, 143 Streptococcus pneumoniae, acute lower-respiratory infections, children, 142 penicillin-resistant strains, 141 Streptococcus pyogenes, acute lower-respiratory infections, children, 142–143 Streptococcus thermophilus, diarrheal disease, 106 Streptomycin, tuberculosis, 213 Stunting, nonspecific, 395 prevalence, 78, 80–82 Sub-Saharan Africa, HIV infection, 239 obesity, 453 Succinate dehydrogenase, Iron, 331 Sugar fortification, vitamin A deficiency, 293 Suicide, pregnancy, 32 Sulfaadoxine-pyrimenthamine, primigravida, 45 Sulfadoxine-pyrimethamine, malaria, 184–185 Sydenham, Thomas, 164 T T-test, 5 Tabes, 210 Takaki, Kanehiro, 11–13 Tanzania, anemia, maternal mortality, 35 vitamin A deficiency, 273 vitamin A therapy measles, 169 Task/goal ambiguity, 538–539 Technical rationality, 544 Thailand, acute lower-respiratory infections, seasonality, 140 Thalassemia major, 339 Thames River, 9 contamination of, 8 Thiamin, malarial morbidity, 196 Thyroid hormones, gene expression, 348–349

Index synthesis, 348 transport, 348 turnover, 348 Thyroid stimulating hormone (TSH), blood, 354 Tobacco smoke, environmental, acute lower-respiratory infections, 137 Traditional birth attendants (TBAs), training, 48–49 Tuberculosis, 209–228 active, treatment, 224–255 case-fatality rates, 214 clinical features, 217 cod-liver oil, 212–213 decline, industrialized countries, 213–214 defined, 209 diagnosis, 222–223 drug-resistant, 216–217 environmental measures, 227 geographic distribution, 214 historical background, 210–212 HIV infection, 225 incidence, 215–216 children, 215–216 elderly, 216 nutrition, 218–222 pathophysiology, 217–218 PCR, 223 public health, 209–210 risk factors, 215 Twentyfour -VASQ method vitamin A intake, 503–504 Typhoid fever, 8 U Underweight, prevalence, 78 United Kingdom (UK), vitamin A therapy, measles, 169 United Nations International Children’s Emergency Fund (UNICEF), 22 conceptual framework, child health and survival, 401–402 LBW rates, 60–61 United States, diarrheal disease epidemics, 94 dietary changes, 19 food production,

567 growth in, 17 maternal mortality ratio, 35–36 Universal maternal energy supplementation, 65 Urban agriculture, 476–477 Urban population growth, 435–436 Urban poverty, 466–467 Urbanization, 465–466 activity patterns, 474 dietary patterns, 473–474 environmental contamination, 475–476 health implications, 474 legal rights, 476–477 lifestyle changes, 473–474 nutrition data, 467 research implications, 477–479 Urinaryiodine concentrations, 354 Utilitarian ethics, 6 V Vaccines, diarrheal disease, 115 diphtheria-pertussis-tetanus, 148 Hib, 148 HIV, 256 malaria, 179–180 measles, 148, 171 pneumococcal, 148 Vegetarian diet, tuberculosis, Asian immigrants, 221 Venous blood collection, 499 Vietnam, nutritional interventions diarrheal disease, 113 Save the Children cost, 514–515 Villemin, Jean-Antoine, 212 Villerme, Louis Rene, 5 Virchow, Rudolf, 211 Vital statistics, historical development of, 4–5 Vitamin A, 267–269 characterization, 13–14 child growth, 373 diarrheal disease, 101, 110, 114 dietary sources, 268–269 immunity, 15–16 malaria, 376 malarial morbidity, 195 maternal mortality, 39–40

568 measles, 168–172 nomenclature, 268 structure, 268 tetragenicity, 47 tuberculosis, 219–222 Vitamin A deficiency, 267–296. See also Xeroophthalmia, acute lower-respiratory infections, 135 anemia risk, 45–47 children, mortality, 271–273 children mortality, 509 clinicopathological features, 286–290 global distribution, 270 historical background, 274–276 HIV infection, 249–250 infection, 289 location, 177–178 maternal health, 273–274 poor growth, 289–290 prevalence, 269–270 prevention, 292–296 proximal causes, 282–286 risk factors, 279–281 seasonality, 281–282 treatment, 290–292 Vitamin A intake, assessment, 501–504 Vitamin A supplementation, 294–296 acute lower-respiratory infections, 147, 150 HIV infection, 251 measles, 168–171 Vitamin B complex, child growth, 373 mental development, 375 tuberculosis, 220 Vitamin C, deficiency, HIV infection, 250 tuberculosis, 220–221 Vitamin D, tuberculosis, 220 Vitamin deficiency pre-eclampsia, 46–47 Vitamin E, deficiency, HIV infection, 250 malarial morbidity, 196 Vitamin supplements, utilization, 383 Vitamin theory, 14 Vitamins,

Index emergence of, 10–14 Von Bunge, Gustav, 328 Von Liebig, Justus, 9 Von Voit, Carl, 9 W Waksman, Selman, 213 Wales, infant mortality, 41 maternal mortality ratio, 35–36 Waste, human, diarrheal disease, 112–113 Wasting, prevalence, 78 Wasting syndrome HIV infection, 250–251 Water, contaminated, 8, 475–476 diarrheal disease, 112 Water supply, public monitoring of, 8 Weaning, diarrheal disease, 112 Weight-for-age, low, 75 Weight-for-height, low, 74–75 West Africa, diarrheal disease, intestinal function, 101 measles, 164 Western diet, 437 Western Pacific, obesity, 452, 459–460 tuberculosis, 214 Wheat flour fortification, multiple micronutrient malnutrition, 379–380 vitamin A deficiency, 293 Wheezing, acute lower-respiratory infections, 138 WHO Collaborative Study of Maternal Anthropometry and Pregnancy Outcome, 60–62 WHO Global Database on Child Growth and Malnutrition, 79 WHO Global Database on Low Birth Weight, 78–82 Williams, Cicely, 15 Women. See also Gender

Index folate deficiency, 368 Guatemalan, short stature, 85 increased labor-force participation, 471–473 riboflavin deficiency, 368 Work performance, iron deficiency, 333–334 World Bank, 22–23 benchmark costs, nutritional intervention, 513–514 World urbanization, 434 X Xerophthalmia. See also Vitamin A deficiency clinicopathological features, 286 preschool children, risk, 279 prevalence, 270 vitamin A supplementation, 294–295 Y Yellow fever, 7 Yersinia enterocolitica, 989 Yogurt, diarrheal disease, 106 Z Z-scores, 77 Zanzibar, anemia, 45 Zidovudine, 255–256 Ziehl-Neelsen procedure, 222 Zinc, absorption, 309–310, 313 bioavailability, 313

569 biomembranes, 311 child growth, 373 diarrheal disease, 101–102, 109–110 dietary assessment, 316–317 dietary requirements, 313 dietary sources, 312–313 erythrocytes, 317 excretion, 310–311 fingers, 311 HIV infection, 248 immune function, 311 malaria, Papua New Guinea, 376 malarial morbidity, 194–195 mental development, 375–376 metalloenzymes, 311 serum concentrations, 315–316 storage, 310 transport, 310 Zinc deficiency, 307–321 acute lower-respiratory infections, 135 clinical manifestations, 313–315 epidemiology, 308–309 hemorrhage, 47–48 historical background, 308 HIV infection, 250 pathophysiology, 312–313 prevention, 320 public health, 307 risk factors, 309 tuberculosis, 221 Zinc supplementation, 87, 317–320 acute lower-respiratory infections, 146, 149–150 diarrheal disease, 113–114

Nutrition and Health in Developing Countries Edited by

Richard D. Semba, MD, MPH Department of Ophthalmology, Division of Ocular Immunology, Johns Hopkins School of Medicine, Baltimore, MD

Martin W. Bloem, MD, PhD Helen Keller International—Regional Headquarters, Jakarta, Indonesia Foreword by

Nevin S. Scrimshaw, PhD, MD, MPH “The chapters of this book…represent a tour-de-force that contribute importantly to efforts to improve the nutrition and health of developing nations.” —From the Foreword by Nevin S. Scrimshaw

The major burden of health problems worldwide exists in developing countries, where there is much suffering from malnutrition, from increased levels of infection, and from an inequitable share of the world’s health care resources. In Nutrition and Health in Developing Countries, a team of leading public health and infectious disease experts, epidemiologists, and clinical nutritionists break new ground by reviewing the major health problems of these countries and detailing the role that poor nutrition plays in their etiology. In their treatment of the epidemiology, prevention, and control of these health problems, the contributors examine a variety of such pressing medical problems as maternal mortality, low birth weight, infant mortality, and child growth and development, as well as the most common associated diseases (measles, malaria, tuberculosis, HIV/AIDS, diarrhea, and respiratory disease). Specific nutritional problems are also addressed in cutting-edge articles on vitamin A and zinc deficiencies; iron deficiency and anemia; and multiple micronutrient malnutrition. Additional articles review the latest thinking on how best to design effective policies to solve the nutrition and health problems of developing countries. Innovative and interdisciplinary, Nutrition and Health in Developing Countries synthesizes the latest knowledge concerning the major infectious disease and nutritional problems in these countries and demonstrates the fundamental importance of addressing the problems of malnutrition and “hidden hunger” (vitamin and mineral deficiencies) needed to resolve these all too widespread health problems. ■ Reviews the major infectious diseases and nutritional problems of developing countries

■ Discusses the newly emerging health problems of heart disease, diabetes, and obesity

■ Shows how malnutrition underlies infectious diseases in developing countries

■ Suggests policies to improve the nutrition and health problems in developing countries CONTENTS

Nutrition and Development: A Historical Perspective. Maternal Mortality in Developing Countries. Low Birth Weight and Perinatal Mortality. Child Growth and Development. Diarrheal Diseases. Acute Lower-Respiratory Infections. Measles. Malaria. Tuberculosis. Human Immunodeficiency Virus Infection. Vitamin A Deficiency. Zinc Deficiency. Iron Deficiency and Anemia. Iodine Deficiency Disorders. Multiple Micronutrient Malnutri-

tion: What Can Be Done? Malnutrition. The Nutrition Transition and Its Relationship to Demographic Change. The Emerging Problem of Obesity in Developing Countries. Rapid Urbanization and the Challenges of Obtaining Food and Nutrition Security. Assessing and Communicating Impact of Nutrition and Health Programs. The Economics of Nutritional Intervention. Research and Policy Directions. Index.

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A volume of Nutrition and Health Nutrition and Health in Developing Countries ISBN: 0-89603-806-8 http://humanapress.com

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