Lung Biology in Health & Disease Volume 151 Fetal Origins of Cardiovascular and Lung Disease

FETAL ORIGINS OF CARDIOVASCULAR AND LUNG DISEASE

LUNG BIOLOGY IN HEALTH AND DISEASE Executive Editor Claude Lenfant Director, National Heart, Lung and Blood Institute National Institutes of Health Bethesda, Maryland

1. Immunologic and Infectious Reactions in the Lung, edited by C. H. Kirkpatrick and H. Y. Reynolds 2. The Biochemical Basis of Pulmonary Function, edited by R. G. Crystal 3. Bioengineering Aspects of the Lung, edited by J. B. West 4. Metabolic Functions of the Lung, edited by Y. S. Bakhle and J. R. Vane 5. Respiratory Defense Mechanisms (in two parts), edited by J. D. Brain, D. F. Proctor, and L. M. Reid 6. Development of the Lung, edited by W. A. Hodson 7. Lung Water and Solute Exchange, edited by N. C. Staub 8. Extrapulmonary Manifestations of Respiratory Disease, edited by E. D. Robin 9. Chronic Obstructive Pulmonary Disease, edited by T. L. Petty 10. Pathogenesis and Therapy of Lung Cancer, edited by C. C. Harris 11. Genetic Determinants of Pulmonary Disease, edited by S. D. Litwin 12. The Lung in the Transition Between Health and Disease, edited by P. T. Macklem and S. Permutt 13. Evolution of Respiratory Processes: A Comparative Approach, edited by S. C. Wood and C. Lenfant 14. Pulmonary Vascular Diseases, edited by K. M. Moser 15. Physiology and Pharmacology of the Airways, edited by J. A. Nadel 16. Diagnostic Techniques in Pulmonary Disease (in two parts), edited by M. A. Sackner 17. Regulation of Breathing (in two parts), edited by T. F. Hornbein 18. Occupational Lung Diseases: Research Approaches and Methods, edited by H. Weill and M. Turner-Warwick 19. Immunopharmacology of the Lung, edited by H. H. Newball 20. Sarcoidosis and Other Granulomatous Diseases of the Lung, edited by B. L. Fanburg 21. Sleep and Breathing, edited by N. A. Saunders and C. E. Sullivan 22. Pneumocystis carinii Pneumonia: Pathogenesis, Diagnosis, and Treatment, edited by L. S. Young 23. Pulmonary Nuclear Medicine: Techniques in Diagnosis of Lung Disease, edited by H. L. Atkins 24. Acute Respiratory Failure, edited by W. M. Zapol and K. J. Falke 25. Gas Mixing and Distribution in the Lung, edited by L. A. Engel and M. Paiva

26. High-Frequency Ventilation in Intensive Care and During Surgery, edited by G. Carlon and W. S. Howland 27. Pulmonary Development: Transition from Intrauterine to Extrauterine Life, edited by G. H. Nelson 28. Chronic Obstructive Pulmonary Disease: Second Edition, edited by T. L. Petty 29. The Thorax (in two parts), edited by C. Roussos and P. T. Macklem 30. The Pleura in Health and Disease, edited by J. Chrétien, J. Bignon, and A. Hirsch 31. Drug Therapy for Asthma: Research and Clinical Practice, edited by J. W. Jenne and S. Murphy 32. Pulmonary Endothelium in Health and Disease, edited by U. S. Ryan 33. The Airways: Neural Control in Health and Disease, edited by M. A. Kaliner and P. J. Barnes 34. Pathophysiology and Treatment of Inhalation Injuries, edited by J. Loke 35. Respiratory Function of the Upper Airway, edited by O. P. Mathew and G. Sant’Ambrogio 36. Chronic Obstructive Pulmonary Disease: A Behavioral Perspective, edited by A. J. McSweeny and I. Grant 37. Biology of Lung Cancer: Diagnosis and Treatment, edited by S. T. Rosen, J. L. Mulshine, F. Cuttitta, and P. G. Abrams 38. Pulmonary Vascular Physiology and Pathophysiology, edited by E. K. Weir and J. T. Reeves 39. Comparative Pulmonary Physiology: Current Concepts, edited by S. C. Wood 40. Respiratory Physiology: An Analytical Approach, edited by H. K. Chang and M. Paiva 41. Lung Cell Biology, edited by D. Massaro 42. Heart–Lung Interactions in Health and Disease, edited by S. M. Scharf and S. S. Cassidy 43. Clinical Epidemiology of Chronic Obstructive Pulmonary Disease, edited by M. J. Hensley and N. A. Saunders 44. Surgical Pathology of Lung Neoplasms, edited by A. M. Marchevsky 45. The Lung in Rheumatic Diseases, edited by G. W. Cannon and G. A. Zimmerman 46. Diagnostic Imaging of the Lung, edited by C. E. Putman 47. Models of Lung Disease: Microscopy and Structural Methods, edited by J. Gil 48. Electron Microscopy of the Lung, edited by D. E. Schraufnagel 49. Asthma: Its Pathology and Treatment, edited by M. A. Kaliner, P. J. Barnes, and C. G. A. Persson 50. Acute Respiratory Failure: Second Edition, edited by W. M. Zapol and F. Lemaire 51. Lung Disease in the Tropics, edited by O. P. Sharma 52. Exercise: Pulmonary Physiology and Pathophysiology, edited by B. J. Whipp and K. Wasserman 53. Developmental Neurobiology of Breathing, edited by G. G. Haddad and J. P. Farber 54. Mediators of Pulmonary Inflammation, edited by M. A. Bray and W. H. Anderson 55. The Airway Epithelium, edited by S. G. Farmer and D. Hay

56. Physiological Adaptations in Vertebrates: Respiration, Circulation, and Metabolism, edited by S. C. Wood, R. E. Weber, A. R. Hargens, and R. W. Millard 57. The Bronchial Circulation, edited by J. Butler 58. Lung Cancer Differentiation: Implications for Diagnosis and Treatment, edited by S. D. Bernal and P. J. Hesketh 59. Pulmonary Complications of Systemic Disease, edited by J. F. Murray 60. Lung Vascular Injury: Molecular and Cellular Response, edited by A. Johnson and T. J. Ferro 61. Cytokines of the Lung, edited by J. Kelley 62. The Mast Cell in Health and Disease, edited by M. A. Kaliner and D. D. Metcalfe 63. Pulmonary Disease in the Elderly Patient, edited by D. A. Mahler 64. Cystic Fibrosis, edited by P. B. Davis 65. Signal Transduction in Lung Cells, edited by J. S. Brody, D. M. Center, and V. A. Tkachuk 66. Tuberculosis: A Comprehensive International Approach, edited by L. B. Reichman and E. S. Hershfield 67. Pharmacology of the Respiratory Tract: Experimental and Clinical Research, edited by K. F. Chung and P. J. Barnes 68. Prevention of Respiratory Diseases, edited by A. Hirsch, M. Goldberg, J.P. Martin, and R. Masse 69. Pneumocystis carinii Pneumonia: Second Edition, edited by P. D. Walzer 70. Fluid and Solute Transport in the Airspaces of the Lungs, edited by R. M. Effros and H. K. Chang 71. Sleep and Breathing: Second Edition, edited by N. A. Saunders and C. E. Sullivan 72. Airway Secretion: Physiological Bases for the Control of Mucous Hypersecretion, edited by T. Takishima and S. Shimura 73. Sarcoidosis and Other Granulomatous Disorders, edited by D. G. James 74. Epidemiology of Lung Cancer, edited by J. M. Samet 75. Pulmonary Embolism, edited by M. Morpurgo 76. Sports and Exercise Medicine, edited by S. C. Wood and R. C. Roach 77. Endotoxin and the Lungs, edited by K. L. Brigham 78. The Mesothelial Cell and Mesothelioma, edited by M.-C. Jaurand and J. Bignon 79. Regulation of Breathing: Second Edition, edited by J. A. Dempsey and A. I. Pack 80. Pulmonary Fibrosis, edited by S. Hin. Phan and R. S. Thrall 81. Long-Term Oxygen Therapy: Scientific Basis and Clinical Application, edited by W. J. O’Donohue, Jr. 82. Ventral Brainstem Mechanisms and Control of Respiration and Blood Pressure, edited by C. O. Trouth, R. M. Millis, H. F. Kiwull-Schöne, and M. E. Schläfke 83. A History of Breathing Physiology, edited by D. F. Proctor 84. Surfactant Therapy for Lung Disease, edited by B. Robertson and H. W. Taeusch 85. The Thorax: Second Edition, Revised and Expanded (in three parts), edited by C. Roussos

86. Severe Asthma: Pathogenesis and Clinical Management, edited by S. J. Szefler and D. Y. M. Leung 87. Mycobacterium avium—Complex Infection: Progress in Research and Treatment, edited by J. A. Korvick and C. A. Benson 88. Alpha 1–Antitrypsin Deficiency: Biology • Pathogenesis • Clinical Manifestations • Therapy, edited by R. G. Crystal 89. Adhesion Molecules and the Lung, edited by P. A. Ward and J. C. Fantone 90. Respiratory Sensation, edited by L. Adams and A. Guz 91. Pulmonary Rehabilitation, edited by A. P. Fishman 92. Acute Respiratory Failure in Chronic Obstructive Pulmonary Disease, edited by J.-P. Derenne, W. A. Whitelaw, and T. Similowski 93. Environmental Impact on the Airways: From Injury to Repair, edited by J. Chrétien and D. Dusser 94. Inhalation Aerosols: Physical and Biological Basis for Therapy, edited by A. J. Hickey 95. Tissue Oxygen Deprivation: From Molecular to Integrated Function, edited by G. G. Haddad and G. Lister 96. The Genetics of Asthma, edited by S. B. Liggett and D. A. Meyers 97. Inhaled Glucocorticoids in Asthma: Mechanisms and Clinical Actions, edited by R. P. Schleimer, W. W. Busse, and P. M. O’Byrne 98. Nitric Oxide and the Lung, edited by W. M. Zapol and K. D. Bloch 99. Primary Pulmonary Hypertension, edited by L. J. Rubin and S. Rich 100. Lung Growth and Development, edited by J. A. McDonald 101. Parasitic Lung Diseases, edited by A. A. F. Mahmoud 102. Lung Macrophages and Dendritic Cells in Health and Disease, edited by M. F. Lipscomb and S. W. Russell 103. Pulmonary and Cardiac Imaging, edited by C. Chiles and C. E. Putman 104. Gene Therapy for Diseases of the Lung, edited by K. L. Brigham 105. Oxygen, Gene Expression, and Cellular Function, edited by L. Biadasz Clerch and D. J. Massaro 106. Beta2-Agonists in Asthma Treatment, edited by R. Pauwels and P. M. O’Byrne 107. Inhalation Delivery of Therapeutic Peptides and Proteins, edited by A. L. Adjei and P. K. Gupta 108. Asthma in the Elderly, edited by R. A. Barbee and J. W. Bloom 109. Treatment of the Hospitalized Cystic Fibrosis Patient, edited by D. M. Orenstein and R. C. Stern 110. Asthma and Immunological Diseases in Pregnancy and Early Infancy, edited by M. Schatz, R. S. Zeiger, and H. N. Claman 111. Dyspnea, edited by D. A. Mahler 112. Proinflammatory and Antiinflammatory Peptides, edited by S. I. Said 113. Self-Management of Asthma, edited by H. Kotses and A. Harver 114. Eicosanoids, Aspirin, and Asthma, edited by A. Szczeklik, R. J. Gryglewski, and J. R. Vane 115. Fatal Asthma, edited by A. L. Sheffer 116. Pulmonary Edema, edited by M. A. Matthay and D. H. Ingbar 117. Inflammatory Mechanisms in Asthma, edited by S. T. Holgate and W. W. Busse 118. Physiological Basis of Ventilatory Support, edited by J. J. Marini and A. S. Slutsky

119. Human Immunodeficiency Virus and the Lung, edited by M. J. Rosen and J. M. Beck 120. Five-Lipoxygenase Products in Asthma, edited by J. M. Drazen, S.-E. Dahlén, and T. H. Lee 121. Complexity in Structure and Function of the Lung, edited by M. P. Hlastala and H. T. Robertson 122. Biology of Lung Cancer, edited by M. A. Kane and P. A. Bunn, Jr. 123. Rhinitis: Mechanisms and Management, edited by R. M. Naclerio, S. R. Durham, and N. Mygind 124. Lung Tumors: Fundamental Biology and Clinical Management, edited by C. Brambilla and E. Brambilla 125. Interleukin-5: From Molecule to Drug Target for Asthma, edited by C. J. Sanderson 126. Pediatric Asthma, edited by S. Murphy and H. W. Kelly 127. Viral Infections of the Respiratory Tract, edited by R. Dolin and P. F. Wright 128. Air Pollutants and the Respiratory Tract, edited by D. L. Swift and W. M. Foster 129. Gastroesophageal Reflux Disease and Airway Disease, edited by M. R. Stein 130. Exercise-Induced Asthma, edited by E. R. McFadden, Jr. 131. LAM and Other Diseases Characterized by Smooth Muscle Proliferation, edited by J. Moss 132. The Lung at Depth, edited by C. E. G. Lundgren and J. N. Miller 133. Regulation of Sleep and Circadian Rhythms, edited by F. W. Turek and P. C. Zee 134. Anticholinergic Agents in the Upper and Lower Airways, edited by S. L. Spector 135. Control of Breathing in Health and Disease, edited by M. D. Altose and Y. Kawakami 136. Immunotherapy in Asthma, edited by J. Bousquet and H. Yssel 137. Chronic Lung Disease in Early Infancy, edited by R. D. Bland and J. J. Coalson 138. Asthma’s Impact on Society: The Social and Economic Burden, edited by K. B. Weiss, A. S. Buist, and S. D. Sullivan 139. New and Exploratory Therapeutic Agents for Asthma, edited by M. Yeadon and Z. Diamant 140. Multimodality Treatment of Lung Cancer, edited by A. T. Skarin 141. Cytokines in Pulmonary Disease: Infection and Inflammation, edited by S. Nelson and T. R. Martin 142. Diagnostic Pulmonary Pathology, edited by P. T. Cagle 143. Particle–Lung Interactions, edited by P. Gehr and J. Heyder 144. Tuberculosis: A Comprehensive International Approach, Second Edition, Revised and Expanded, edited by L. B. Reichman and E. S. Hershfield 145. Combination Therapy for Asthma and Chronic Obstructive Pulmonary Disease, edited by R. J. Martin and M. Kraft 146. Sleep Apnea: Implications in Cardiovascular and Cerebrovascular Disease, edited by T. D. Bradley and J. S. Floras 147. Sleep and Breathing in Children: A Developmental Approach, edited by G. M. Loughlin, J. L. Carroll, and C. L. Marcus

148. Pulmonary and Peripheral Gas Exchange in Health and Disease, edited by J. Roca, R. Rodriguez-Roisen, and P. D. Wagner 149. Lung Surfactants: Basic Science and Clinical Applications, R. H. Notter 150. Nosocomial Pneumonia, edited by W. R. Jarvis 151. Fetal Origins of Cardiovascular and Lung Disease, edited by David J. P. Barker 152. Long-Term Mechanical Ventilation, edited by N. S. Hill

ADDITIONAL VOLUMES IN PREPARATION

Environmental Asthma, edited by R. K. Bush Asthma and Respiratory Infections, edited by D. P. Skoner Airway Remodeling, edited by P. H. Howarth, J. W. Wilson, J. Bousquet, and R. Pauwels Respiratory-Circulatory Interactions in Health and Disease, edited by S. M. Scharf, M. R. Pinsky, and S. Magder The Lung at High Altitudes, edited by T. F. Hornbein and R. B. Schoene The opinions expressed in these volumes do not necessarily represent the views of the National Institutes of Health.

This page intentionally left blank

FETAL ORIGINS OF CARDIOVASCULAR AND LUNG DISEASE Edited by

David J.P. Barker University of Southampton Southampton, United Kingdom

ISBN: 0-8247-0391-X This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright © 2001 by Marcel Dekker, Inc. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10 9 8 7 6 5 4 3 2 1

PRINTED IN THE UNITED STATES OF AMERICA

INTRODUCTION

Is it nature or nurture? At any time in our lives, this question can, and probably should, be asked, especially when we are affected by some pathological state. During the past few years, we have witnessed the emergence of molecular medicine, which has brought, and will continue to bring, remarkable advances in the diagnosis, prevention, and treatment of inherited diseases. Genomics and genetics, the basic roots of molecular medicine, are undoubtedly contributing greatly to uncovering the determinants of what we are, and of what may happen to any of us. About four or five decades ago, the concept of risk factors was introduced, largely as a result of the work done in the Framingham Heart Study. Since that time, much research has been done to examine the role of risk factors in the development of cardiovascular and respiratory diseases. In addition, it has been established that one can successfully prevent, or at least control, a disease by reducing, if not eliminating, the risk factors. The new concept is that the expression of genes may, to some extent, iii

iv

Introduction

be regulated by environmental factors or conditions. This is to say that, in effect, both nature and nurture are the determinants of our fate! The impact of genes begins at the time of conception—but when do the nurture determinants begin to influence and modulate gene expression? That is what this book is about. David Barker has been the leading proponent of the thesis that health is, in part, programmed by prenatal life. Surprisingly, this concept has been accepted only slowly in spite of significant biological observation and powerful societal comparison. However, today, the weight of evidence is so strong that it cannot be resisted. What was termed the “Barker hypothesis” has become a scientific movement that rallies basic and clinical researchers as well as experts in epidemiology, nutrition, and other disciplines. This volume, Fetal Origins of Cardiovascular and Lung Diseases, edited by David Barker, assembles what is known today about the prenatal programming of cardiovascular, pulmonary, and renal disease. The chapter authors are most distinguished for their scientific expertise. Moreover, the fact that they are from many continents attests to the universal interest in the subject of this book. That so many, from so many places, work on this subject is further testimony to the importance of David Barker’s foresight. The Lung Biology in Health and Disease series of monographs was conceived with the goal of informing, educating, and challenging those interested in important scientific, medical, and public health issues. This new volume is a major contribution to this goal. As the Executive Editor of this series of monographs, I am extremely grateful to Dr. Barker and to the contributors for the opportunity to present it. Claude Lenfant, M.D. Bethesda, Maryland

PREFACE

Living things are “plastic” in their early lives: their growth and development are molded by the environment. Biology provides us with many dramatic examples of developmental paths operated by environmental switches. Whether an American alligator develops as a male or female depends on the temperature at which the egg is incubated. Whether a male Gelada baboon adopts a rapid or slow growth trajectory at puberty depends on the number of other males in the area. There are many reasons why it may be advantageous, in evolutionary terms, for the body’s structure and function to remain plastic in early life and this is a general phenomenon of early development. Humans are not an exception. The human embryo does not contain a description of the person to whom it will give rise. Rather, it contains in its genes a generative program for making a person, a program that has been likened to a recipe for which the mother provides the ingredients. The plasticity of human development has been known for a long while. Only recently, however, has evidence appeared suggesting that the origins of important chronic diseases of adult life, including coronary heart disease, v

vi

Preface

stroke, and Type 2 diabetes, may lie in fetal responses to the intrauterine environment. The “fetal origins” hypothesis proposes that these disorders originate through adaptations that the fetus makes when it is undernourished. These adaptations permanently change the body’s structure, function, and metabolism. A feature of the early findings, which came mainly from epidemiological studies, was the strength of the associations between small body size at birth and later disease. Important biological effects must underlie such associations, and it soon became evident that these effects could be replicated experimentally in animals, usually by reducing food intake around the time of conception and during pregnancy. Through the efforts of a group of epidemiologists, clinicians, and basic scientists that includes many of the contributors to this book, the early epidemiological findings have been extensively replicated, and incorporated into a framework of ideas derived from fetal physiology, human metabolism, and endocrinology. The framework is described in this book. The first six chapters focus on the cardiovascular system. The substantial body of evidence showing that small size at birth is linked with later coronary heart disease, stroke, hypertension, and chronic renal failure is reviewed. New findings show that the mother’s body composition in pregnancy and particular paths of childhood growth are also associated with later cardiovascular disease. Chapter 3 reviews how fetal cardiovascular adaptations may have lifelong effects on the physiology and structure of the vascular system and thereby lead to hypertension. Chapter 5 examines the effects of fetal nutrition on cardiovascular development. The development of the cardiovascular system in embryonic and fetal life, and possible links with later diseases, are described in Chapter 6. Chapter 7 describes clinical and epidemiological studies of the links between reduced fetal growth and impaired glucose tolerance and Type 2 diabetes in later life. Insulin resistance may be viewed as the long-term price of successful metabolic adaptations in utero. Studies in animals have indicated that undernutrition for brief periods in early life produces a range of persisting metabolic alterations, and Chapter 8 suggests that these may prove disadvantageous if undernutrition in utero is followed by “overnutrition” in later life. Professor Joseph Hoet, a pioneer in this area of experimental science, died during the preparation of this book and an additional chapter (17) has been added in his honor. Clinicians studying the fetal origins of adult disease have to engage with the complexities of the fetus’ metabolic and endocrine responses to undernutrition and other influences. In Chapter 9 reduced fetal growth, with consequent

Preface

vii

small size at birth, is viewed as an appropriate adaptation to impaired nutrient supply in utero. This adaptation is partly mediated through hormones, which act as nutritional signals throughout fetal development (Chapter 10). Steroid hormones are powerful mediators of fetal programming and are known to be programmable by physiological stimuli during the course of development (Chapter 11). Chapter 12 shows that insights into the long-term effects of hormonal changes in utero may come from the clinic as well as the laboratory. Our understanding of fetal nutrition is currently too slight for us to change dietary advice to women before and during pregnancy. Fetal nutrition depends on the concentrations of nutrients in the maternal circulation, on utero-placental blood flow and transfer across the placenta. Nutrient concentrations in maternal blood are the product of the mother’s diet, body composition, and metabolism. Understanding these processes will be essential if we are to prevent chronic disease by improving fetal nutrition. Chapters 13 and 14 review the evidence in humans and animals. Chapter 15 extends the range of diseases linked to developmental plasticity to include asthma and gives an account of lung embryology and the ontogeny of host defense mechanisms. Chapter 16 examines the implications of the fetal origins hypothesis for the “nutritional transition,” during which societies move from chronic malnutrition to adequate nutrition. This transition exacts a heavy toll of rising epidemics of coronary heart disease and Type 2 diabetes. One of the two goals of the new agenda for medical research set out in this book is to lessen these epidemics by improving the body composition and nutrition of girls and young women and by protecting the growth of young children. There is already sufficient evidence to begin implementing new public health policies without further delay, but a deeper understanding of the biological processes is needed to refine these policies. The other goal of fetal origins research is earlier detection and better treatment of disease. To realize both goals, clinicians, public health physicians, epidemiologists, and basic scientists must join forces. My thanks go to the contributors to this book who have done just that in order to write it. Thanks also to my colleagues, Shirley Simmonds and Pamela Freeman, who helped with the editing, to Sandra Beberman and Paige Force of Marcel Dekker, Inc., who produced the book, and final thanks to Claude Lenfant, who conceived the book and was patient during its long gestation. David J. P. Barker

This page intentionally left blank

CONTRIBUTORS

David J. P. Barker, M.D., Ph.D., F.R.S. Professor and Director, Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton, United Kingdom Holly E. Bendall, M.Sc Statistician, Medical Research Council Environmental Epidemiology Unit, University of Southampton and Southampton General Hospital, Southampton, United Kingdom John R. G. Challis, Ph.D., D.Sc., F.R.S.C. Professor and Chair, Department of Physiology, University of Toronto, Toronto, Ontario, Canada David B. Cox, Ph.D. Department of Physiology, University of Toronto, Toronto, Ontario, Canada ix

x

Contributors

Francis de Zegher, M.D., Ph.D. Professor, Department of Pediatrics, University of Leuven, Leuven, Belgium Lisa Edwards, B.Sc. Department of Physiology, University of Adelaide, Adelaide, Australia Brent M. Egan, M.D. Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina Alison J. Forhead, B.Sc., Ph.D. Department of Physiology, University of Cambridge, Cambridge, United Kingdom Abigail L. Fowden, B.A., M.A., Ph.D. Department of Physiology, University of Cambridge, Cambridge, United Kingdom Inge Francois Department of Pediatrics, University of Leuven, Leuven, Belgium Kathryn L. Gatford, B.Agr.Sc., Ph.D. Department of Physiology, University of Adelaide, Adelaide, Australia Peter D. Gluckman, M.B.Ch.B., D.Sc., F.R.A.C.P., F.R.S.N.Z. Professor of Perinatal and Pediatric Biology, Research Centre for Development Medicine and Biology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand Keith M. Godfrey, B.M., Ph.D., F.R.C.P. Clinical Scientist, Medical Research Council Environmental Epidemiology Unit, University of Southampton and Southampton General Hospital, Southampton, United Kingdom Stephen E. Greenwald, Ph.D. Reader in Cardiovascular Biomechanics, Histopathology and Morbid Anatomy Department, Royal London Hospital, London, United Kingdom C. Nicholas Hales, M.A., M.D., Ph.D., F.R.C.Path., F.R.C.P., F.Med.Sc., F.R.S. Professor and Head of Department, Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom

Contributors

xi

Mark A. Hanson, B.A., D.Phil. Professor, Department of Obstetrics and Gynecology, Royal Free and University College Medical School, University College London, London, United Kingdom Jane E. Harding, M.B.Ch.B., D.Phil. Professor, Research Centre for Developmental Medicine and Biology, Faculty of Medicine and Health Science, University of Auckland, Auckland, New Zealand Joseph J. Hoet* Professor, Laboratory of Cell Biology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium Lourdes Ibáñez, M.D., Ph.D. Attending Physician, Pediatric Endocrinology, Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain B. J. Jennings Professor, Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom Catherine A. Jones, Ph.D. Allergy and Inflammation Sciences Division, School of Medicine, University of Southampton and Southampton General Hospital, Southampton, United Kingdom Karen Kind Department of Physiology, University of Adelaide, Adelaide, Australia Ilona Koupilová, M.D., Ph.D., M.Sc., Dr.Med.Sc. Clinical Lecturer in Epidemiology, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom Daniel T. Lackland, Dr.P.H. Associate Professor, Department of Biometry and Epidemiology, Medical University of South Carolina, Charleston, South Carolina David A. Leon, Ph.D. Reader in Epidemiology, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom __________________ * Deceased.

xii

Contributors

S. J. Lye Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada Christopher N. Martyn, M.A., D.Phil., F.R.C.P. Senior Clinical Scientist, Medical Research Council Environmental Epidemiology Unit, University of Southampton and Southampton General Hospital, Southampton, United Kingdom Stephen G. Matthews, Ph.D. Assistant Professor, Department of Physiology, University of Toronto, Toronto, Ontario, Canada Roger B. McDonald, Ph.D. Professor, Department of Nutrition, University of California, Davis, California Caroline McMillen Department of Physiology, University of Adelaide, Adelaide, Australia Janna L. Morrison, M.Sc. Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada Clive Osmond, Ph.D. Reader in Medical Statistics and Senior Scientist, Medical Research Council Environmental Epidemiology Unit, University of Southampton and Southampton General Hospital, Southampton, United Kingdom Julie Owens Department of Physiology, University of Adelaide, Adelaide, Australia Susan Ozanne, Ph.D. Department of Clinical Biochemistry, University of Cambridge, Cambridge, United Kingdom David I. W. Phillips, Ph.D., F.R.C.P. Professor, Medical Research Council Environmental Epidemiology Unit, University of Southampton and Southampton General Hospital, Southampton, United Kingdom Barry M. Popkin, Ph.D. Professor, Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Contributors

xiii

C. Remacle Department of Biology, Laboratory of Cell Biology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium B. Reusens, Ph.D. Department of Biology, Laboratory of Cell Biology, Université Catholique de Louvain, Louvain-la-Neuve, Belgium Jeffrey S. Robinson, B.Sc., M.B., B.Ch., B.A.O., F.R.C.O.G., F.R.A.N.Z. C.O.G. Professor, Department of Obstetrics and Gynaecology, University of Adelaide, Adelaide, Australia Deborah M. Sloboda, M.Sc. Ph.D. Student, Department of Physiology, University of Toronto, Toronto, Ontario, Canada Eric Jackson Thomas, M.D., M.R.C.O.G., F.Med.Sci. Professor, Obstetrics and Gynecology Department, Princess Anne Hospital, Southampton, United Kingdom Kent L. Thornburg, Ph.D. Director, Heart Research Center, and Professor, Department of Physiology and Pharmacology, Oregon Health Sciences University, Portland, Oregon John O. Warner, M.D., F.R.C.P., F.R.C.P.C.H., F.Med.Sci. Professor of Child Health, and Director, Allergy and Inflammation Sciences Division, School of Medicine, University of Southampton and Southampton General Hospital, Southampton, United Kingdom E. Marelyn Wintour, Ph.D., D.Sc. Howard Florey Institute of Experimental Physiology and Medicine, University of Melbourne, Parkville, Victoria, Australia

This page intentionally left blank

CONTENTS

Introduction Claude Lenfant Preface Contributors 1. Introduction David J. P. Barker I. The Undernourished Baby II. Other Diseases That Originate In Utero III. Mothers and Babies Today References

iii v ix 1 2 14 17 18

xv

xvi 2. Birth Weight, Blood Pressure, and Hypertension: Epidemiological Studies David A. Leon and Ilona Koupilová I. Birth Weight and Blood Pressure in Children and Adults II. Systolic Blood Pressure III. Diastolic Blood Pressure IV. Effect of Concurrent Body Size V. Is the Birth Weight–Blood Pressure Association Modified by Age? VI. Birth Weight and Hypertension VII. Studies of Births with Abnormal Obstetric or Neonatal Characteristics VIII. Socioeconomic and Behavioral Pathways IX. Maternal Influences X. Conclusion References 3. Mechanisms for In Utero Programming of Blood Pressure Christopher N. Martyn and Stephen E. Greenwald I. Structure of the Aorta and Large Conduit Arteries II. Summary III. Capillary Density and Microvascular Dilation IV. Renal Size and Function References 4. Low Birth Weight and the Emerging Burden of Renal Disease in the United States Daniel T. Lackland, Holly E. Bendall, Clive Osmond, and Brent M. Egan I. ESRD in South Carolina References 5. Intrauterine Nutrition: Its Importance During Critical Periods for Cardiovascular and Endocrine Development Joseph J. Hoet and Mark A. Hanson I. Summary II. Introduction

Contents

23 24 33 35 36 37 38 39 40 41 43 44 49 50 54 55 56 57 61 66 68 73 73 74

Contents III. IV. V. VI. VII. VIII. IX. X.

xvii Cardiovascular Development Endocrine Pancreas Insulin-Sensitive Tissues Kidney Brain Comparison of Dietary Restriction with Maternal Diabetes Worldwide Perspective Acknowledgments References

6. Physiological Development of the Cardiovascular System In Utero Kent L. Thornburg I. Introduction II. Heart Development in Embryonic Life III. Maturation of the Cardiomyocyte IV. Arrangement of the Fetal Circulation V. Metabolic Features and Cardiovascular Adaptations in the Fetus VI. Fetal Arterial Pressure VII. Regulation of Fetal Cardiac Output VIII. Differences Between the Right and Left Ventricles IX. Alterations in Myocardial Growth with Mechanical Stress X. Redistribution of Cardiac Output with Hypoxemia XI. Regulation of Fetal Coronary Flow XII. Fetal Cardiovascular Development and Adult Disease References 7. Non–Insulin-Dependent Diabetes and Obesity David I. W. Phillips I. Birth Weight and NIDDM II. Fetal Growth and Insulin Resistance III. Fetal Growth and Insulin Secretion IV. Mechanisms Linking Reduced Fetal Growth with Insulin Resistance V. Fetal Growth and Obesity in Adult Life

75 81 84 85 85 85 86 89 89 97 97 98 104 108 110 112 113 118 121 124 125 131 133 141 142 145 148 148 152

xviii VI. VII. VIII.

Contents Early Nutrition and Adult Body Weight Mechanisms Linking Early Environmental Influences with Adult Body Weight Conclusions References

8. Metabolic Alterations After Early Growth Retardation Susan Ozanne, B. J. Jennings, and C. Nicholas Hales I. Introduction II. Early Growth Retardation Consequent on Maternal Protein Deprivation III. Conclusions IV. Future Directions References

153 154 155 155 161 161 162 175 176 177

9. Growth, Metabolic, and Endocrine Adaptations to Fetal Undernutrition 181 Jane E. Harding and Peter D. Gluckman I. Introduction 181 II. Fetal Nutrition and Fetal Growth 182 III. Fetal Metabolic Adaptations to Undernutrition 184 IV. Endocrine Adaptations to Fetal Undernutrition 186 V. Cardiovascular Adaptations to Fetal Undernutrition 187 VI. Factors Influencing Fetal Adaptation to Undernutrition 188 VII. Fetoplacental Adaptations to Refeeding 190 VIII. Cardiovascular Adaptations to Refeeding 191 IX. Endocrine Adaptations to Refeeding 191 X. Conclusion 192 References 193 10. The Role of Hormones in Intrauterine Development Abigail L. Fowden and Alison J. Forhead I. Introduction II. Nutritionally Induced Hormonal Changes III. Endocrine Regulation of Fetal Growth and Development

199 199 200 204

Contents IV. V. VI.

xix Long-Term Consequences of the Nutritionally Induced Hormonal Changes In Utero Conclusions Acknowledgments References

11. The Hypothalamic-Pituitary-Adrenal and HypothalamicPituitary-Gonadal Axes in Early Life: Problems and Perspectives Stephen G. Matthews, David I. W. Phillips, John R. G. Challis, David B. Cox, Eric Jackson Thomas, Caroline McMillen, S. J. Lye, Roger B. McDonald, E. Marelyn Wintour, Janna L. Morrison, Deborah M. Sloboda I. Introduction II. Programming of the HPA Axis III. The HPG Axis IV. Conclusions References 12. Reduced Fetal Growth and Pediatric Endocrinopathies Francis de Zegher, Inge Francois, and Lourdes Ibáñez I. Somatotropic Axis II. Pronounced Adrenarche and Precocious Pubarche III. The Entities of Male Pseudohermaphroditism and Subfertility, Ovarian Hyperandrogenism, and Anovulation IV. Dyslipidemia and Insulin Resistance V. Conclusion References 13. Maternal Nutrition and Fetal Development: Implications for Fetal Programming Keith M. Godfrey I. Introduction II. Size at Birth III. Fetal Nutrient Demand IV. Maternoplacental Nutrient Supply

213 220 220 221

229

229 231 236 237 237 241 242 244 244 246 246 247 249 249 250 251 252

xx

Contents V. VI.

Fetal Adaptations and Developmental Changes An Integrated Framework and Future Research References

14. Maternal and Placental Influences that Program the Fetus: Experimental Findings Jeffrey S. Robinson, Caroline McMillen, Lisa Edwards, Karen Kind, Kathryn L. Gatford, and Julie Owens I. II. III. IV. V. VI.

Introduction Rat Guinea Pig Sheep Conclusion Acknowledgments References

15. Fetal Origins of Lung Disease John O. Warner and Catherine A. Jones I. II. III. IV. V. VI. VII. VIII. IX. X. XI. XII. XIII. XIV. XV.

Introduction Lung Embryology Molecular Basis of Lung Growth Ontogeny of Host Defense Congenital Lung Malformations Fetal Growth and Later Lung Function Infant Wheeze and Fetal Growth The Fetus and Allergic Sensitization Pregnancy as an Allergic Phenomenon Fetal and Maternal Influences on Atopy Maternal Atopy Timing and Concentration of Allergen Exposure and IgG Antibodies Maternal Nutrition and Atopy Conclusions Acknowledgments References

261 264 265

273

273 276 280 282 289 290 290 297 297 298 299 300 302 304 306 307 308 309 310 311 313 315 316 316

Contents 16. The Nutrition Transition and its Implications for the Fetal Origins Hypothesis Barry M. Popkin I. Introduction II. The United States: Immigrants and Other At-Risk Populations III. The Developing World IV. Conclusion References

xxi

323 323 325 327 336 336

17. Effects of Maternal Nutrition and Metabolism on the Developing Endocrine Pancreas: Experimental Findings B. Reusens and C. Remacle I. Introduction II. Programming the Endocrine Pancreas III. Short-Term Consequences IV. Long-Term Consequences V. Mechanism Involved in Altered Beta-Cell Mass VI. Changes in Other Organs VII. Prevention of Programmed Changes VIII. Conclusion References

339 340 341 342 347 349 350 353 353

Author Index Subject Index

359 387

339

This page intentionally left blank

FETAL ORIGINS OF CARDIOVASCULAR AND LUNG DISEASE

This page intentionally left blank

1 Introduction

DAVID J. P. BARKER University of Southampton Southampton, United Kingdom

The search for biological influences in the adult environment that determine the risk of cardiovascular disease has met with limited success. Obesity and cigarette smoking have been implicated and evidence on dietary fat has accumulated to the point where a public health policy of reduced intake is prudent, if not proven. Much, however, remains unexplained. For example, the steep rise in coronary heart disease in many western countries during the past century has been associated with rising prosperity. So why, in many countries, do the poorest people in the least affluent places now have the highest rates? Surprisingly, a clue to the possible importance of early development came from geographical studies. The geographical distribution of neonatal mortality (deaths before 1 month of age) in England and Wales at the beginning of the last century was found to closely resemble the distribution of death rates from cardiovascular disease today (Fig. 1) (1). At that time, most neonatal 1

2

Barker

Figure 1 Similarity between the distribution of neonatal mortality and cardiovascular disease mortality in England and Wales.

deaths were attributed to low birth weight. One interpretation of this geographical association was that harmful influences that act in fetal life, and slow fetal growth, permanently set or “program” the body’s structure and function in ways that are linked to cardiovascular disease. Because fetal growth is mainly determined by the supply of nutrients, undernutrition was an obvious possible harmful influence. As is described later in this book (Chs. 5, 8, 14), numerous studies in animals have shown that undernutrition during gestation permanently programs the body’s physiology and metabolism (2,3). 1. The Undernourished Baby In fetal life, the tissues and organs of the body go through what are called “critical” periods of development that may coincide with periods of rapid cell division. “Programming” describes the process whereby a stimulus or insult at a critical period of development has lasting effects. Rickets has for a long while served as a demonstration that undernutrition at a critical stage of early life leads to persisting changes in the body’s structure. Only recently

Introduction

3

have we realized that some of the persisting effects of early undernutrition become translated into pathology, and thereby determine chronic disease, including cardiovascular disease, in later life. That this has gone unremarked for so long is perhaps surprising, given the numerous animal experiments showing that undernutrition in utero leads to persisting changes in a range of metabolic, endocrine, and immune functions known to be important in human disease (3,4), and given that the heart and blood vessels are “plastic” during intrauterine development (Chs. 3, 4), ie, molded by physical and other influences to which they are subjected. Later chapters in this book (Chs. 9, 10, 11) describe how the human fetus adapts to undernutrition by metabolic changes, redistribution of blood flow, and changes in the production of fetal and placental hormones that control growth (5). Its immediate response to undernutrition is catabolism; it consumes its own substrates to provide energy (6). More prolonged undernutrition leads to a slowing in growth. This enhances the fetus’ ability to survive by reducing the use of substrates and lowering the metabolic rate. Slowing of growth in late gestation leads to disproportion in organ size because organs and tissues that are growing rapidly at the time are affected the most. For example, undernutrition in late gestation may lead to reduced growth of the kidney, which develops rapidly at that time (Ch. 4). Reduced replication of kidney cells in late gestation will permanently reduce cell numbers, because after birth there seems to be no capacity for renal cell division to catch up. Animal studies show that a variety of different patterns of fetal growth result in similar birth size. A fetus that grows slowly throughout gestation may have the same size at birth as a fetus whose growth was arrested for a period and then caught up. Different patterns of fetal growth will have different effects on the relative size of different organs at birth, although overall body size may be the same. Animal studies show that blood pressure and metabolism can be permanently changed by levels of undernutrition that do not influence growth. Preliminary observations point to similar effects in humans. Such findings emphasize the severe limitation of birth weight as a summary of fetal nutritional experience. While slowing its rate of growth, the fetus may protect tissues that are important for immediate survival, especially the brain. One way in which the brain can be protected is by redistribution of blood flow to favor it (7). This adaptation is known to occur in many mammals, but in humans it has exaggerated costs for other tissues, notably the liver and other abdominal viscera, because of the large size of the human brain. Metabolic fetal adaptations may result in the fetus sacrificing muscle growth and being born thin.

4

Barker

It is becoming increasingly clear that nutrition has profound effects on fetal hormones and on the hormonal and metabolic interactions between the fetus, placenta, and mother, on whose coordination fetal growth depends (6). Fetal insulin and insulin-like growth factors (IGFs) are thought to have a central role in the regulation of growth and to respond rapidly to changes in fetal nutrition. If a mother decreases her food intake, fetal insulin, IGF, and glucose concentrations fall, possibly through the effect of decreased maternal IGF. This leads to reduced transfer of amino acids and glucose from mother to fetus, and ultimately to reduced rates of fetal growth (8). In late gestation and after birth, the fetus’ growth hormone and IGF axis take over, from insulin, a central role in driving linear growth. Undernutrition leads to a fall in the concentrations of hormones that control fetal growth and a rise in cortisol, the main effects of which are on cell differentiation (5). One current line of research aims to determine whether the fetus’ hormonal adaptations to undernutrition tend, like many other fetal adaptations, to persist after birth and exert lifelong effects on homeostasis and hence on the occurrence of disease. A. Body Size at Birth and Cardiovascular Disease

The early epidemiological studies on the intrauterine origins of coronary heart disease and stroke were based on the simple strategy of examining men and women in middle and late life whose body measurements at birth were recorded. Sixteen thousand men and women born in Hertfordshire during 1911 to 1930 were traced from birth to the present day. Death rates from coronary heart disease fell twofold among those at the lower and upper ends of the birth weight distribution (Table 1) (9, 10). A study in Sheffield showed that Table 1 Death Rates From Coronary Heart Disease Among 15,726 Men and Women Birth weight (lbs [kg]) ≤5.5 [2.50] 5.5–6.5 [2.95] 6.5–7.5 [3.41] 7.5–8.5 [3.86] 8.5–9.5 [4.31] >9.5 [4.31] All

Standardized mortality ratio

Number of deaths

100 81 80 74 55 65 74

57 137 298 289 103 57 941

Introduction

5

people who were small at birth because they failed to grow, rather than because they were born early, were at increased risk of the disease (11). The association between low birth weight and coronary heart disease has been confirmed in studies in Uppsala, Sweden (12); Helsinki, Finland (13,14); Caerphilly, Wales (15); and among 80,000 women in the United States who took part in the American Nurses Study (16). An association between low birth weight and prevalent coronary heart disease has recently been shown in a study in south India (17). B. Body Proportions at Birth and Cardiovascular Disease The Hertfordshire records and the Nurses and Caerphilly studies did not include measurements of body size at birth other than weight. The weight of a newborn baby without a measure of its length is as crude a summary of its physique as is the weight of a child or adult without a measure of height. The addition of birth length allows a thin baby to be distinguished from a stunted baby with the same birth weight. With the addition of head circumference, the baby whose body is small in relation to its head, which may be a result of brain-sparing redistribution of blood flow, can also be distinguished. Thinness, stunting, and a low birth weight in relation to head size are the result of differing fetal adaptations to undernutrition and other influences, and have different consequences, both immediately and in the longterm. In Sheffield, death rates for coronary heart disease were higher in men who were stunted at birth (18). The mortality ratio for coronary heart disease in men who were 18.5 inches (47 cm) or less in length was 138 compared with 98 in the remainder (18). Similarly, coronary heart disease in south India was associated with stunting (17). Thinness at birth, as measured by a low ponderal index (birth weight/length3), is also associated with coronary heart disease. Table 2 shows findings among men born in Helsinki, Finland during 1924 to 1933. Death rates for coronary heart disease were related to low birth weight (13). Although this was not statistically significant, the strength of the association was similar to that in Hertfordshire and elsewhere. There was, however, a much stronger association with thinness at birth, especially in men born at term (Table 2). Men who were thin at birth, measured by a low ponderal index (birth weight/length3), had death rates that were twice those of men who had a high ponderal index. Interestingly, among women in the same cohort the association between low birth weight and coronary heart disease was similar to that in men, but there was a much stronger association with short body length at birth rather than thinness (14). An inference from this is

6

Barker

Table 2 SMRs for Coronary Heart Disease in 3302 Finnish Men Born During 1924–1933 Birth weight (kg [lbs])

≤2.5 [5.5]

2.5–3.0 [6.6] 3.0–3.5 [7.7] 3.5–4.0 [8.8] >4.0 [8.8] All p value for trend

Ponderal index at birth* (kg/m3) ≤25 25–27 27–29 >29 All p value for trend

SMR (number of deaths) 84 (11) 83 (44) 99 (124) 76 (80) 66 (27) 85 (286) 0.09 SMR (number of deaths)* 116 (59) 105 (88) 72 (64) 56 (33) 86 (244) < 0.0001

* Term babies only. Abbreviation: SMR, standardized mortality ratio.

that girls and boys have different paths of fetal growth at the same levels of maternal nutrition. Girls grow more slowly than boys. Slower-growing fetuses are, in general, less vulnerable to undernutrition, and one may speculate that the lower rates of coronary heart disease in women may originate in their slower rates of intrauterine growth. Trends in stroke, which in Sheffield have only been reported among men, are different from those in coronary heart disease. Although stroke has a similar association with birth weight, it is not related to stunting or thinness. Rather, high rates are associated with a low ratio of birth weight to head circumference. This finding has recently been confirmed in Finland (66). C. Infant Growth and Cardiovascular Disease Information routinely recorded in Hertfordshire included the infant’s weight at 1 year. In men, failure of weight gain during the first year of life predicted

Introduction

7

coronary heart disease and stroke independently of birth weight (18). Figure 2 shows that among men who weighed 17 lbs (7.7 kg) or less at 1 year of age, hazard ratios for coronary heart disease were three times greater than among men who weighed 27 lbs (12.2 kg) or more. The highest rates of the disease among men were in those who had both low birth weight and low weight at 1 year of age. In contrast, the highest rates among women were in those who had low birth weight but whose weight caught up before 1 year. The reasons for this are unknown, although it may reflect sex differences in the endocrine control of infant growth. Growth during infancy can be regarded

Figure 2 Hazard ratios for coronary heart disease in 10,141 men according to weight at 1 year.

8

Barker

as a postnatal continuation of the fetal phase of growth which is controlled by insulin and insulin-like growth factor I, and continues until growth hormone takes over at around the age of 1 year (19). Confounding Variables These findings suggest that influences linked to fetal and infant growth have an important effect on the risk of coronary heart disease and stroke. It has been argued, however, that people whose growth was impaired in utero and during infancy may continue to be exposed to an adverse environment in childhood and adult life, and it is this later environment that produces the effects attributed to programming (20–23). There is strong evidence against this. In three of the studies that have replicated the association between birth weight and coronary heart disease, data on lifestyle factors, including smoking, employment, alcohol consumption, and exercise, were collected (12, 15, 16). The associations between birth weight and coronary heart disease remained after allowing for them. D. Hypertension and Non–Insulin Dependent Diabetes In studies exploring the mechanisms underlying these associations, the trends in coronary heart disease with birth weight have been found to be paralleled by similar trends in two of its major risk factors: hypertension and non–insulin dependent diabetes mellitus (24,25). The extensive literature on these associations is described in detail in later chapters (Chs. 2, 7). Table 3 illustrates the Table 3 Prevalence of NIDDM and Impaired Glucose Tolerance in Men Aged 59–70 Years

Birth weight (lbs [kg]) ≤5.5 [2.50] 5.5–6.5 [2.95] 6.5–7.5 [3.41] 7.5–8.5 [3.86] 8.5–9.5 [4.31] >9.5 [4.31] All

Number of men

Percent with impaired glucose tolerance or NIDDM (plasma glucose ≥ 7.8 mmol/L)

20 47 104 117 54 28 370

40 34 31 22 13 14 25

Odds ratio adjusted for body mass index (95% confidence interval)

Abbreviation: NIDDM, non–insulin dependent diabetes mellitus.

6.6 (1.5–28) 4.8 (1.3–17) 4.6 (1.4–16) 2.6 (0.8–8.9) 1.4 (0.3–5.6) 1.0

Introduction

9

size of these trends. The prevalence of non–insulin dependent diabetes mellitus and impaired glucose tolerance in Hertfordshire men falls threefold across the range of birth weight (25). The associations between small size at birth and hypertension and non–insulin dependent diabetes are again independent of social class, cigarette smoking, and alcohol consumption. Influences in adult life, however, add to the effects of the intrauterine environment. For example, the prevalence of impaired glucose tolerance is highest in people who had low birth weight but became obese as adults. E. Cholesterol and Fibrinogen The published literature on the association between size at birth and the two other main biological risk factors for cardiovascular disease, raised plasma lipid and fibrinogen concentrations, is limited and smaller than that on the associations between size at birth and blood pressure or glucose-insulin metabolism. In studies in Hertfordshire, low birth weight was associated with low-serum high-density lipoprotein (HDL) cholesterol and raised triglyceride concentrations (26). Low birth weight was not related to low-density lipoprotein (LDL) cholesterol concentrations but was strongly related to the insulin resistance syndrome in which impaired glucose tolerance, hypertension, and raised serum triglyceride concentrations, together with other dyslipidemias, occur in the same patient (27). In a study in Sheffield where the birth measurements included abdominal circumference, it was this measurement that most strongly predicted plasma concentrations of total and LDL cholesterol and apolipoprotein B (28). A small abdominal circumference predicted raised lipid concentrations in both men and women (Table 4). Because abdominal circumferTable 4 Mean Serum Cholesterol Concentrations in Men and Women Aged 50–53 Years Abdominal circumference at birth (in [cm])

Number of people

Total cholesterol (mmol/L)

Low density lipoprotein cholesterol (mmol/L)

≤11.5 [29.2] 11.5–12.0 [30.5] 12.0–12.5 [31.8] 12.5–13.0 [33.0] >13.0 [33.0] All

53 43 31 45 45 217

6.7 6.9 6.8 6.2 6.1 6.5

4.5 4.6 4.4 4.0 4.0 4.3

10

Barker

ence at birth reflects, among other things, liver size, and cholesterol metabolism is regulated by the liver, an inference is that impaired liver growth in utero resets cholesterol concentration towards a more atherogenic profile. A small abdominal circumference also predicted raised plasma fibrinogen concentrations, a measure of blood coagulability that is also controlled by the liver (29). Recent studies suggest that differences in gestation will not distinguish low–birth weight children who are at special risk of disturbed lipid homeostasis (30). Among a group of 485 prepubertal Jamaican children, serum cholesterol concentrations were not related to birth weight but were inversely related to length at birth (31), further evidence that retarded trunk and visceral growth, including liver growth, may be associated with alterations in lipid metabolism (32). In a group of 517 20-year olds in France, the mean plasma lipid concentrations of those who were born small for gestational age were similar to those of a control group with normal birth weights (33). The small-for-gestational-age group were, however, insulin resistant. Perhaps disturbances of lipid homeostasis that are associated with insulin resistance do not manifest until adult life. F. Maternal Dietary Balance and Body Composition Indications that the balance of macronutrients in the mother’s diet can have important short- and long-term effects on offspring have come from a series of experimental studies on pregnant rats. It was found that maternal diets with a low ratio of protein to carbohydrate and fat alter fetal and placental growth, and result in lifelong elevation of blood pressure in the offspring (34). A follow-up study of 40-year-old men and women in Aberdeen, United Kingdom suggested that alterations in the maternal macronutrient balance during pregnancy could have similar adverse effects on the offspring (35); the relations with maternal diet were, however, complex. Among women with low intakes of animal protein, a higher carbohydrate intake was associated with a higher adult blood pressure in the offspring; among those with high animal protein intakes, a lower carbohydrate intake was associated with higher blood pressure. These increases in blood pressure were associated with decreased placental size (35). The effects of maternal dietary balance are described further in Chapter 13. As is described in Chapter 13, the availability of nutrients to the fetus is determined by the mother’s body size and composition at conception as well as by her diet in pregnancy. Size at birth, however, depends mainly on the mother’s body size; even extreme undernutrition during pregnancy has only modest effects on birth size. The size and composition of the mother’s

Introduction

11

body reflects her growth and nutrition from her own fetal life, through childhood, adolescence, and into adult life. All these stages of her life have to be embraced within maternal nutrition. As Mellanby wrote in 1933, “[I]t is certain that the significance of correct nutrition in childbearing does not begin in pregnancy itself or even in the adult female before pregnancy. It looms large as soon as a female child is born and indeed in its intrauterine life.” Evidence that maternal body composition has important effects on the offspring has come from studies showing that extremes of maternal body composition in pregnancy are associated with adverse long-term outcomes in the offspring. Follow-up of a group of Jamaican children showed that those whose mothers had thin skinfold thicknesses in pregnancy and a low pregnancy weight gain had higher blood pressure at the age of 11 years (36). A subsequent study of 11-year-old children in Birmingham, United Kingdom found similar associations (37). In Gambia, low pregnancy weight gain was associated with higher blood pressure in childhood (38). Studies in India have found that a low maternal weight in pregnancy is associated with an increased risk of coronary heart disease in the offspring in adult life (17). Among men and women who were in utero during the wartime famine in Holland, those whose mothers had low weight in pregnancy had the most impaired glucose tolerance and evidence of insulin resistance (39). In China, men and women whose mother had a low body mass index in pregnancy were insulin resistant (67). At the other extreme of maternal body fatness, evidence for long-term effects of maternal obesity has come from follow-up of a group of men in Finland born earlier this century (13). Markedly raised coronary heart disease rates were found in men whose mothers had a high body mass index in pregnancy (Table 5). This effect was independent of the association between thinTable 5 SMRs for Coronary Heart Disease in Finnish Men Body mass index of mother in late pregnancy (kg/m2) Ponderal index of baby (kg/m3) 29 All

–26

56 [6] 88 [12] 46 [5] 38 [2] 62 [25] *

134 87 76 61 89

[20] [21] [17] [7] [65]

–28 158 123 55 45 89

–30 [17] [26] [13] [7] [63]

131 104 98 68 97

[7] [11] [12] [6] [36]

>30 171 131 116 72 111

All

[7] 124 [57] [11] 104 [81] [16] 76 [63] [9] 58 [31] [43] 89 [232]

First number indicates standardized mortality ratio; number in brackets indicates number of deaths.

*

12

Barker

ness at birth and increased rates of adult coronary heart disease (Table 5), and it was confined to the offspring of short women (3,13). A study in India has also shown that the offspring of mothers who have a high body mass index in pregnancy are at increased risk of non–insulin dependent diabetes (40). G. Childhood Growth Studies in Helsinki have shown that the path of growth through childhood modifies the risk of disease associated with size at birth (41). The highest death rates from coronary heart disease occurred in men who were thin at birth but had accelerated weight gain in childhood (Table 6). We do not yet know whether this association is attributable to the pathological effects of a high fat mass persisting into adult life, deleterious effects of catch-up growth, or the intrauterine resetting of endocrine axes that control growth. It does suggest that although the primary prevention of coronary heart disease and non–insulin dependent diabetes may depend on changing the body composition and diets of young women, more immediate benefit may come from preventing imbalances between pre- and postnatal growth among today’s children. H. Chronic Obstructive Lung Disease In Hertfordshire, standardized mortality ratios for chronic bronchitis among men with birth weights of 5.5 lbs (2.5 kg) or less were twice those among men with birth weights of more than 9.5 lbs (>4.3 kg). There were even stronger trends with weight at 1 year of age. When the lung function of a sample of the men was measured, the mean forced expiratory volume (FEV1), which largely reflects airway size, rose between those with low and those with Table 6 Hazard Ratios for Death From Coronary Heart Disease, Adjusted for Length of Gestation Body mass index (kg/m2) at age 11 years Ponderal index at birth (kg/m3)

≤15.5 HR [ND]

≤25 25–27 27–29 >29

2.7 1.5 2.2 1.0

[21] [14] [17] [4]

15.5–16.5 HR [ND] 3.3 3.2 1.6 1.7

[26] [40] [18] [11]

Abbreviations: HR, hazard ratio; ND, number of deaths.

16.5–17.5 HR [ND] 3.7 [19] 4.0 [35] 1.8 [19] 1.5 [12]

17.5 HR [ND] 5.3 2.7 3.2 1.9

[14] [14] [21] [12]

Introduction

13

high birth weight. This association was independent of the subjects’ height, age, and smoking habits. FEV1 was not related to weight at 1 year, independent of birth weight, which suggests that it is linked to growth in utero rather than growth during infancy. In contrast to FEV1, the forced vital capacity (FVC) was not related to birth weight but was reduced in men with lower weights at 1 year of age. An interpretation of this is that aspects of lung physiology that determine FVC are programmed in infancy rather than intrauterine life. For many years there has been interest in the hypothesis that lower respiratory tract infection during infancy and early childhood predisposes to chronic airflow obstructions in later life (42–46). The large geographical differences in death rates from chronic bronchitis in England and Wales are closely similar to the differences in infant deaths from respiratory infection earlier in this century (47). Follow-up studies of individuals provide direct evidence that respiratory infection in early life has long-term effects. When the national sample of 3899 British children born in 1946 were studied as young adults, those who had had one or more lower respiratory infections before 2 years of age had a higher prevalence of chronic cough (48). A link between lower respiratory tract infection in early childhood and death from chronic bronchitis has been shown in follow-up studies in Hertfordshire and Derbyshire (49,50). Among 639 men in Hertfordshire, 59 were recorded as having had an attack of bronchitis or pneumonia during infancy. Table 7 shows Table 7 Mean FEV1 (Liters) Adjusted for Height and Age Among Men Aged 59–67 Years

Bronchitis or pneumonia in infancy Birth weight (lbs [kg])

Absent*

≤5.5 [2.5] 5.5–6.5 [2.9] 6.5–7.5 [3.4] 7.5–8.5 [3.9] 8.5–9.5 [4.3] >9.5 [4.3] All

2.39 (22) 2.40 (70) 2.47 (163) 2.53 (179) 2.54 (103) 2.57 (43) 2.50 (580)

Present* 1.81 2.23 2.38 2.33 2.36 2.36 2.30

Abbreviation: FEV1, forced expiratory volume in 1 sec. * Number in parentheses indicates number of people.

(4) (10) (25) (12) (5) (3) (59)

14

Barker

that at each birth weight their mean FEV1 values were lower than those of men not recorded as having had bronchitis or pneumonia. A total of 63 men were recorded as having had an attack of bronchitis or pneumonia between 1 and 5 years of age, but their mean FEV1 and FVC values were similar to those of all the other men. This suggests that infancy may be a critical period in which infection may change lung function. Further evidence of the longterm effects of respiratory infection in early life came from a study of 70year-old men in Derbyshire, England, which also made use of health visitors’ records (50). The FEV1 of men who had had pneumonia before the age of 2 years was 0.65 L less than that of other men, a reduction in FEV1 of approximately twice that associated with lifelong smoking. The simplest explanation of these observations is that infection of the lower respiratory tract during infancy has persisting deleterious effects which, added to the effects of poor airway growth in utero, predispose to the development of chronic bronchitis in later life. This issue is further discussed in Chapter 15. II. Other Diseases That Originate In Utero Although this book focuses on the fetal origins of cardiovascular and lung disease, there are a number of other common diseases for which there is evidence of in utero programming. They will be briefly reviewed in this section. They do not represent the extent and range of the effects of programming; fresh evidence linking in utero life with other diseases regularly appears. Because programming of hormonal release or tissue sensitivity to hormones is a central theme of this book, a chapter on reproductive endocrinopathies has been included (Ch. 12). A. Osteoporosis Bone mass at two common sites of osteoporotic fracture, the femoral neck and lumbar spine, has been shown to be positively associated with weight at 1 year in young women and in elderly men and women (51,68). This suggests that skeletal development tracks from early life and that growth retardation in prenatal and postnatal life may set in motion a series of pathological processes that lead eventually to osteoporotic fracture. Bone mass is a function of bone size and mineral density. Growth is the most important determinant of size, whereas density within the bony envelope is modified by a host of local factors, including hormonal status and physical activity. Studies of the 24hour growth hormone profiles of elderly men in Hertfordshire showed that

Introduction

15

peak growth hormone concentrations were related to bone density in the femoral neck (52), which suggests that this aspect of growth hormone secretion is one of the influences that modify bone density through life. Median growth hormone concentrations in old age were related to weight at the age of 1 year. This particular aspect of the growth hormone secretory profile may therefore be programmed in utero or during infancy, initiating changes that lead ultimately to hip fracture. B. Schizophrenia The advent of new imaging techniques has revolutionized ideas about the cause of schizophrenia. “Decades of scientifically unfounded psychological and social theories that blamed family and society have given way to increasingly compelling scientific evidence that schizophrenia is a brain disorder” (53). Subtle reductions in cortical volume revealed by neuroimaging, together with necropsy observations of altered architecture in the cortex, have led to the conclusion that the disorder originates through defective migration of cells into the cortex during the second trimester of gestation. Epidemiological evidence that schizophrenia originates in utero comes from the increased frequency of obstetric complications in the birth histories of patients (54,55), and delay in their motor and speech milestones during childhood (56). There is preliminary evidence that both infection and undernutrition in utero may initiate the defects in early brain development that are subtly manifest in childhood but become dramatically evident in early adult life. In a study of people who were at risk of in utero exposure to the 1957 influenza epidemic, those at risk during the second trimester had higher rates of hospital admission for schizophrenia than those at risk during other trimesters or those not at risk (57). The results of other similar studies have, however, been inconsistent (53,58). People exposed to the Dutch famine during the first 2 months of gestation had a twofold increase in risk of being hospitalized for schizophrenia (59). C. Depression For many years, depression in adult life has been thought to originate through parental indifference, abuse, and other adverse influences in childhood. A study in Hertfordshire found that men and women who committed suicide, which is commonly the result of depression, had low weight gain in infancy (60). Although this could be attributable to adverse psychosocial influences in infancy, there is nothing in the Hertfordshire records that supports this, and

16

Barker

it raises the possibility that adult depression is initiated by in utero programming of hormonal axes that influence growth in infancy and mood in later life. Patients with depression have been found to have abnormal secretion of growth hormone and abnormalities in the hypothalamic-adrenal and hypothalamic-thyroid axes (61). There is evidence that each of these axes are programmed in utero. D. Cancers of the Breast and Ovary Cancers of the breast have been linked to high birth weight. Among women in the Nurses’ Study in the United States, odds ratios for breast cancer doubled across the range of birth weight (69). This trend was little influenced by adjusting for other variables, such as body mass and family history of breast cancer. Other data support a link between high birth weight and breast cancer (62), and it has been suggested that high concentrations of estrogen in pregnancy may play a role (63). In the Hertfordshire study, rates of ovarian cancer increased, not with increasing birth weight, but with increasing weight at 1 year (64). The suggested explanation is that hormonal or nutritional influences acting in utero imprint an altered pattern of gonadotrophin release. Experiments in rats show that the hypothalamus is imprinted by androgens during a sensitive perinatal phase. Low concentrations of androgen lead to cyclical release of gonadotrophins (the female pattern); high concentrations result in continuous secretion of gonadotrophin (the male pattern). In humans, an altered pattern of gonadotrophin that increased estrogen release would also promote infant weight gain. It is suggested that in later life it might induce malignant change in the ovary. E. Polycystic Ovary Syndrome Direct evidence that events in utero may imprint an altered pattern of gonadotrophin release, and thereby program disorders of the female reproductive tract, comes from a study of polycystic ovaries, a common disorder associated with menstrual irregularities, subfertility, hirsutism, acne, and a spectrum of endocrine abnormalities including high plasma luteinizing hormone (LH) concentrations, a high ratio of LH to follicle stimulating hormone (FSH), and excessive androgen production. In one of the two common forms of the disorder, women are obese and androgenized, whereas in the other they are thin and have normal testosterone concentrations. The former group of women tends to have high birth weight and are born to heavy mothers (65). The latter

Introduction

17

group, however, tends to be born after term. A possible explanation of why this latter group develops polycystic ovaries is that they have an altered hypothalamic-pituitary “set point” for LH release as a result of their prolonged gestation. The human fetus produces large amounts of androgens, which are converted to estrogen by the placenta and pass to the maternal circulation. Placental failure associated with postmaturity could expose the fetal hypothalamus to increased concentrations of androgens or estrogens and reset its responses to them. III. Mothers and Babies Today The findings described in this book suggest that coronary heart disease, stroke, non–insulin dependent diabetes, and hypertension originate through undernutrition and other adverse influences in utero. Protecting the nutrition and health of young women and their babies must therefore be a priority. Today, even in the Western World, many babies are born thin, stunted, or short and fat. Encouraged by the fashion industry, many young women are unduly thin. Encouraged by sections of the food industry, other young women are unduly fat. Many have diets that are imbalanced according to established criteria. If we are to protect babies, we must also protect girls in childhood and adolescence. Body composition is established by childhood growth. Obesity and eating habits are entrained during childhood and adolescence. The path of fetal growth modifies responses to adverse influences encountered in later life. One such influence is obesity. In the Third World, and in less-affluent areas of the Western World, the transition from chronic malnutrition to good nutrition needs to be managed in such a way that people who were undernourished in utero do not become obese as adults (Ch. 16). As yet, we do not know the true impact of maternal nutrition on fetal development. The relatively disappointing effects of nutritional interventions in pregnancy on birth weight in humans have led to the view that fetal development is little affected by changes in maternal nutrition. It is, however, clear that birth weight alone is an inadequate summary measure of fetal experience. We need a more sophisticated view of optimal fetal development that takes account of the long-term sequelae of fetal adaptations to undernutrition. For effective interventions to prevent or arrest disease, we need to progress beyond the epidemiological associations to greater understanding of the

18

Barker

cellular and molecular processes that underlie them. We need to know what factors limit the delivery of nutrients and oxygen to the human fetus, how the fetus adapts to a limited supply, how these adaptations program the structure and physiology of the body, and by what molecular mechanisms nutrients and hormones alter gene expression. This book sets out an agenda for future research. We need to respond so that we can prevent disease in the next generation and offer better treatment to the present one. References 1. 2. 3. 4.

5. 6. 7. 8.

9. 10. 11.

12.

13.

Barker DJP, Osmond C. Infant mortality, childhood nutrition and ischaemic heart disease in England and Wales. Lancet 1986; 1:1077–1081. McCance RA, Widdowson EM. The determinants of growth and form. Proc R Soc Lond B 1974; 185:1–17. Barker DJP. Mothers, babies and health in later life. 2nd ed. Edinburgh: Churchill Livingstone; 1998. Lucas A. Programming by early nutrition in man. The Childhood Environment and Adult Disease. 1st ed. Bock GR, Whelen J, eds. Chichester: Wiley, 1991; 38–55. Fowden AL. Endocrine regulation of fetal growth. Reprod Fertil Dev 1995; 7: 351–363. Harding JE, Johnston BM. Nutrition and fetal growth. Reprod Fertil Dev 1995; 7:539–547. Rudolph AM. The fetal circulation and its response to stress. J Dev Physiol 1984; 6:11–19. Oliver MH. Harding JE, Breier BH, Evans PC, Gluckman PD. Glucose but not a mixed amino acid infusion regulates plasma insulin-like growth factor-1 concentrations in fetal sheep. Pediatr Res 1993; 34(1):62–65. Barker DJP, Osmond C, Winter PD, Margetts B, Simmonds SJ. Weight in infancy and death from ischaemic heart disease. Lancet 1989; 2:577–580. Osmond C, Barker DJP, Winter PD, Fall CHD, Simmonds SJ. Early growth and death from cardiovascular disease in women. BMJ 1993; 307:1519–1524. Barker DJP, Osmond C, Simmonds SJ, Wield GA. The relation of small head circumference and thinness at birth to death from cardiovascular disease in adult life. BMJ 1993; 306:422–426. Leon DA, Lithell H, Vagero D, et al. Biological and social influences on mortality in a cohort of 15,000 Swedes followed from birth to old age. J Epidemiol Community Health 1997; 51(abstr):594. Forsen T, Eriksson JG, Tuomilehto J, Teramo K, Osmond C, Barker DJP. Mother’s weight in pregnancy and coronary heart disease in a cohort of Finnish men: follow up study. BMJ 1997; 315:837–840.

Introduction

19

14. Forsen T, Eriksson JG, Tuomilehto J, Osmond C, Barker DJP. Growth in utero and during childhood among women who develop coronary heart disease: longitudinal study. BMJ 1999; 319:1403–1407. 15. Frankel S, Elwood P, Sweetnam P, Yarnell J, Davey Smith G. Birthweight, bodymass index in middle age, and incident coronary heart disease. Lancet 1996; 348:1478–1480. 16. Rich-Edwards JW, Stampfer MJ, Manson JE, Rosner B, Hankinson SE, Colditz GA, Willett WC, Hennekens CH. Birth weight and risk of cardiovascular disease in a cohort of women followed up since 1976. BMJ 1997; 315:396–400. 17. Stein CE, Fall CHD, Kumaran K, Osmond C, Cox V, Barker DJP. Fetal growth and coronary heart disease in South India. Lancet 1996; 348:1269–1273. 18. Martyn CN, Barker DJP, Osmond C. Mothers’ pelvic size, fetal growth, and death from stroke and coronary heart disease in men in the UK. Lancet 1996; 348:1264–1268. 19. Karlberg J. A biologically-oriented mathematical model (ICP) for human growth. Acta Paediatr Suppl 1989; 350:70–94. 20. Kramer MS, Joseph KS. Commentary: enigma of fetal/infant origins hypothesis. Lancet 1996; 348:1254–1255. 21. Paneth N, Susser M. Early origin of coronary heart disease (the “Barker hypothesis”). BMJ 1995; 310:411–412. 22. Elford J, Whincup P, Shaper AG. Early life experience and adult cardiovascular disease: longitudinal and case-control studies. Int J Epidemiol 1991; 20:833– 844. 23. Ben-Shlomo Y, Davey Smith G. Deprivation in infancy or in adult life: which is more important for mortality risk? Lancet 1991; 337:530–534. 24. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens 1996; 14(8):935–941. 25. Hales CN, Barker DJP, Clark PMS, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303:1019–1022. 26. Fall CHD, Osmond C, Barker DJP, Clark PMS, Hales CN, Stirling Y, Meade TW. Fetal and infant growth and cardiovascular risk factors in women. BMJ 1995; 310:428–432. 27. Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS. Type 2 (non–insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36:62–67. 28. Barker DJP, Martyn CN, Osmond C, Hales CN, Fall CHD. Growth in utero and serum cholesterol concentrations in adult life. BMJ 1993; 307:1524–1527. 29. Barker DJP, Meade TW, Fall CHD, Lee A, Osmond C, Phipps K, Stirling Y. Relation of fetal and infant growth to plasma fibrinogen and factor VII concentrations in adult life. BMJ 1992; 304:148–152.

20

Barker

30. Decsi T, Erhardt E, Markus A, Burus I, Molnar D. Plasma lipids, phospholipid fatty acids and indices of glycaemia in 10-year-old children born as small-forgestational-age or preterm infants. Acta Paediatr 1999; 88:500–504. 31. Forrester TE, Wilks RJ, Bennett FL, Simeon D, Osmond C, Allen M, Chung AP, Scott P. Fetal growth and cardiovascular risk factors in Jamaican school children. BMJ 1996; 312:156–160. 32. Forrester TE, Wilks RJ, Bennett FI, Simeon D, Osmond C, Allen M, Chung AP, Scott P. Fetal growth and cardiovascular risk factors in Jamaican schoolchildren. BMJ 1996; 312:156–160. 33. Leger J, Levy-Marchal C, Bloch J, Pinet A, Chevenne D, Porquet D, Collin D, Czernichow P. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. BMJ 1997; 315:341–347. 34. Langley-Evans SC, Jackson AA. Increased systolic blood pressure in adult rats induced by fetal exposure to maternal low protein diets. Clin Sci 1994; 86:217– 222. 35. Campbell DM, Hall MH, Barker DJP, Cross J, Shiell AW, Godfrey KM. Diet in pregnancy and the offspring’s blood pressure 40 years later. Br J Obstet Gynaecol 1996; 103:273–280. 36. Godfrey KM, Forrester T, Barker DJP, Jackson AA, Landman JP, Hall JStE, Cox V, Osmond C. Maternal nutritional status in pregnancy and blood pressure in childhood. Br J Obstet Gynaecol 1994; 101:398–403. 37. Clark PM, Atton C, Law CM, Shiell A, Godfrey K, Barker DJP. Weight gain in pregnancy, triceps skinfold thickness and blood pressure in the offspring. Obstet Gynaecol 1998; 91:103–107. 38. Margetts BM, Rowland MGM, Foord FA, Cruddas AM, Cole TJ, Barker DJP. The relation of maternal weight to the blood pressures of Gambian children. Int J Epidemiol 1991; 20(4):938–943. 39. Ravelli ACJ, van der Meulen JHP, Michels RPJ, Osmond C, Barker DJP, Hales CN, Bleker OP. Glucose tolerance in adults after prenatal exposure to famine. Lancet 1998; 351:173–177. 40. Fall CHD, Stein CE, Kumaran K, Cox V, Osmond C, Barker DJP, Hales CN. Size at birth, maternal weight, and type 2 diabetes in South India. Diabet Med 1998; 15:220–227. 41. Eriksson JG, Forsen T, Tuomilehto J, Winter PD, Osmond C, Barker DJP. Catchup growth in childhood and death from coronary heart disease: longitudinal study. BMJ 1999; 318:427–431. 42. Holland WW, Halil T, Bennett AE, Elliott A. Factors influencing the onset of chronic respiratory disease. BMJ 1969; ii:205–208. 43. Reid DD. The beginnings of bronchitis. Proceedings of the Royal Society of Medicine 1969; 62:311–316. 44. Samet JM, Tager IB, Speizer FE. The relationship between respiratory illness

Introduction

45. 46. 47. 48.

49.

50.

51.

52.

53. 54.

55. 56.

57.

58. 59. 60.

21

in childhood and chronic air-flow obstruction in adulthood. Am Rev Respir Dis 1983; 127:508–523. Phelan PD. Does adult chronic obstructive lung disease really begin in childhood? Br J Dis Chest 1984; 78:1–9. Strachan DP. Do chesty children become chesty adults? Arch Dis Child 1990; 65:161–162. Barker DJP, Osmond C. Childhood respiratory infection and adult chronic bronchitis in England and Wales. BMJ 1987; 292:1271–1275. Mann SL, Wadsworth MEJ, Colley JRT. Accumulation of factors influencing respiratory illness in members of a national birth cohort and their offspring. J Epidemiol Community Health 1992; 46:286–292. Barker DJP, Godfrey KM, Fall C, Osmond C, Winter PD, Shaheen SO. Relation of birth weight and childhood respiratory infection to adult lung function and death from chronic obstructive airways disease. BMJ 1991; 303:671–675. Shaheen SO, Barker DJP, Shiell AW, Crocker FJ, Wield GA, Holgate ST. The relationship between pneumonia in early childhood and impaired lung function in late adult life. Am J Respir Crit Care Med 1994; 149:616–619. Cooper C, Cawley M, Bhalla A, Egger P, Ring F, Morton L, Barker DJP. Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res 1995; 10:940–947. Fall C, Hindmarsh P, Dennison E, Kellingray S, Barker D, Cooper C. Programming of growth hormone secretion and bone mineral density in elderly men: a hypothesis. J Clin Endocrinol Metab 1998; 83:135–139. Weinberger DR. From neuropathology to neurodevelopment. Lancet 1995; 346:552–557. Hultman CM, Ohman A, Cnattingius S, Wieselgren IM, Lindstrom LH. Prenatal and neonatal risk factors for schizophrenia. Br J Psychiatry 1997; 170:128– 133. Gunther-Genta F, Bovet P, Hohlfeld P. Obstetric complications and schizophrenia: a case-control study. Br J Psychiatry 1994; 164:165–170. Jones P, Rodgers B, Murray R, Marmot M. Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 1994; 344:1398– 1402. Mednick SA, Machon RA, Huttunen MO, Bonnett D. Adult schizophrenia following prenatal exposure to an influenza epidemic. Arch Gen Psychiatry 1988; 45:189–192. Venables PH. Schizotypy and maternal exposure to influenza and to cold temperature: the Mauritius study. J Abnorm Psychol 1996; 105:53–60. Susser E, Neugebauer R, Hoek HW, Brown AS, Lin S, Labovitz D, Gorman JM. Schizophrenia after prenatal famine. Arch Gen Psychiatry 1996; 53:25–31. Barker DJP, Osmond C, Rodin I, Fall CHD, Winter PD. Low weight gain in infancy and suicide in adult life. BMJ 1995; 311:1203.

22

Barker

61. Neuroendocrinology. Checkley S, Paykel ES, eds. Handbook of Affective Disorders. Edinburgh: Churchill Livingstone; 1992. 62. Ekbom A, Trichopoulos D, Adami HO, Hsieh CC, Lan SJ. Evidence of prenatal influences on breast cancer risk. Lancet 1992; 340:1015–1018. 63. Sanderson M, Williams MA, Malone KE, Stanford JL, Emanuel I, White E, Daling JR. Perinatal factors and risk of breast cancer. Epidemiology 1996; 7:34– 37. 64. Barker DJP, Winter PD, Osmond C, Phillips DIW, Sultan HY. Weight gain in infancy and cancer of the ovary. Lancet 1995; 345:1087–1088. 65. Cresswell JL, Barker DJP, Osmond C, Egger P, Phillips DIW, Fraser RB. Fetal growth, length of gestation and polycystic ovaries in adult life. Lancet 1997; 350:1131–1135. 66. Eriksson JG, Forsen T, Tuomileto J, Osmond C, Barker DJP. Early growth, adult income and risk of stroke. Stroke 2000 (in press). 67. Mi J, Law CM, Zhang K-L, Osmond C, Stein CE, Barker DJP. Effects of infant birthweight and maternal body mass index in pregnancy on components of the insulin resistance syndrome in China. Ann Intern Med 2000; 132:253–260. 68. Cooper C. Growth in infancy and bone mass in later life. Am Rheum Dis 1997; 56:17–21. 69. Michels KB, Trichopoulos D, Robins JM, Rosner BA, Manson JE, Hunter DJ, Colditz GA, Hankinson SE, Seizer FE, Willett WC. Birthweight as a risk factor for breast cancer. Lancet 1996; 348:1542–1546.

2 Birth Weight, Blood Pressure, and Hypertension Epidemiological Studies

DAVID A. LEON and ILONA KOUPILOVÁ London School of Hygiene and Tropical Medicine London, United Kingdom

This chapter reviews the human epidemiological evidence for an association between fetal factors and postnatal blood pressure in childhood and adult life. The past few years have seen a substantial expansion of the literature in this field. This chapter therefore draws on an evidence base up to January 1999 that goes beyond earlier reviews (1,2), which only covered the literature up to early 1996. Nearly all of the available human data addressing the link between fetal factors and later blood pressure and hypertension come from observational studies. This inevitably means that results need to be interpreted with caution. There is certainly no definitive study, and each set of findings must be regarded as contributing to the overall patchwork of evidence, which includes animal experimental models and mechanistic studies in humans. However, this chapter focuses on the epidemiological evidence and does not discuss issues of underlying biological mechanisms. 23

24

Leon and Koupilová

This chapter mainly deals with a systematic review and tabular summaries of epidemiological studies that have published quantitative estimates of the strength and direction of the association between birth weight and later blood pressure treated as a continuous variable. Unlike the review by Law and Shiell (2), we review and summarize the results for diastolic as well as systolic blood pressure. We also cover issues raised by adjustment for current body size; whether the strength of the birth-weight blood pressure association changes with age; studies of size at birth in relation to hypertension; how far associations between birth weight and later blood pressure involve socioeconomic and behavioral pathways in addition to the purely biological pathway of fetal programming; and whether any specific maternal factors (including maternal nutrition) have been implicated as driving the associations of fetal factors with later blood pressure. I.

Birth Weight and Blood Pressure in Children and Adults

None of the observational studies reported to date were set up as prospective investigations from birth specifically to investigate the association of birth weight with blood pressure in later life. In many cases, information about fetal characteristics has been collected retrospectively for study subjects whose blood pressure was initially measured for reasons unrelated to the issue of fetal programming. A. Criteria for Inclusion in Summary Tables

Tables 1 and 2 summarize the results of papers that have reported quantitative measures of the association between birth weight and blood pressure from age 1 year onwards for systolic and diastolic pressure, respectively. These papers were identified through searches of Medline and PubMed (ww.ncbi.nlm.nih.gov/PubMed), and from reference lists of papers known to the authors. To be included in the tables, a paper had to meet the following criteria: • The study reported had to be either cross-sectional or a prospective cohort. • Quantitative estimates of the association between birth weight and blood pressure had to be given. These could take the form of regression coefficients, correlation coefficients, or mean blood pressure levels across a range of birth weight categories.

Birth Weight, Blood Pressure, and Hypertension

25

• The study population was not selected with respect to either blood pressure or birth weight. • Estimates of effect were based on office blood pressure. • The language of the paper was English. Papers that included only qualitative statements about the association between birth weight and systolic blood pressure were excluded. Studies of binary outcomes such as hypertension, and follow-up studies of clinically abnormal births (eg, preterm or low birth weight) were also excluded from the summary tables, but are discussed in later sections. Papers that met the criteria and in addition included regression coefficients for the effect of birth weight on systolic blood pressure based on the same subjects at successive ages are summarized in Table 3. The studies included in this table should be distinguished from those summarized in Tables 1 and 2, which include estimates of the association between birth weight and blood pressure at different ages for different sets of subjects, along with papers reporting different analyses of the same data. B. Structure of Summary Tables

Tables 1 to 3 all have the same basic structure. Papers appear in ascending order of age at which blood pressure was measured. The first few columns identify each paper and indicate the age at which blood pressure was measured (mean and/or range), the year of birth of subjects, and sex. The column headed “Bwt” specifies which of three possible sources birth weight information was obtained from: (1) obstetric or other contemporaneous medical records (Obs); (2) other routine records such as birth registrations or medical birth registries (Rout); and (3) reported by study subjects or their parents (Recall). All estimates of the strength and direction of the association between birth weight and blood pressure in the tables were adjusted for age where appropriate. Estimates were included for males and females separately only when no combined estimate for both sexes together was available. The column in which an estimate was placed depended on the nature of statistical adjustment for other variables. If the estimate of effect was not adjusted for any factor (other than age and/or sex) it was placed in the column “Crude.” Estimates adjusted for body size only, measured at the time that blood pressure was taken, were placed in the next column in the table. Papers varied according to whether these adjustments were for weight, height, ponderal index, body mass index, or some combination thereof. The direction of the association between birth weight and blood pressure (adjusted for concurrent body size

26

Table 1 Systolic Blood Pressure in Children and Adults: Cohort and Cross-Sectional Studies with Casual BP as Outcome Effect* Paper: Setting (year of publication) and (reference number)

Age in years when examined

Japan Niigata cross-sectional study (1996) (49)

mean 38 (p = 021)

UK Salisbury cross-sectional study 1 (1991) (12)

4

1984– 1985

UK Farnborough Longitudinal study (1993) (8) India Pune cross-sectional study (1995) (13) UK Nine towns study (1989) (20)

4

1975– 1977 1987– 1989 1980– 1983

5–7

5–7 mean 65

NK

1982– 1985 1980s

7

1972– 1973

8

1975– 1976 1984 –1985 1984 –1986 1973 –1981

9 8–10 7–11

Source of birth weight

Sex

N

Rout

M+F

195

Obs

M+F

364

Obs

M+F

991

–28 (–41, –14)

Obs

M+F

200

–06 (–44, +31)

Recall

M+F

3524

–18 (–23, –13)

–17 (–23, –12)

Recall

M+F

3061

–21 (–27, –14)†

–19 (–27, –11)

Rout+ Recall Obs

M+F

576

–04 (–18, +11)

M+F

692

Pearson’s r = –006 (p < 005)

Obs

M+F

775

Obs

M+F

239

–05 (–26, +16)

Obs

M+F

52

–34 (–95, +27)†

Obs +Rout

M+F

1438

–004 (–07, +06)‡

Crude

Adjusted for concurrent body size (other adjustments) Adjusted for additional or other factors

Pearson’s r = +009

–62 (–110, –13)

Inverse

BMI, birth length, gestational age, pregnancy SBP, weight gain, oedema + proteinuria Weight, placental weight and gestational age

Weight, maternal age, birth rank, maternal history of hypertension BMI, height, age, sex gestational age

–17 (–33, –02)

–13 (–31, +05)

Weight, placental weight

Leon and Koupilová

UK 10 towns 1990 cross-sectional study (1997) (14) Zimbabwe Harare cross-sectional study (1998) (17) New Zealand Dunedin Child Development Study (1981) (50) Australia Adelaide birth follow-up study (1996) (51) UK Salisbury cross-sectional study 2 (1995) (13) France Nancy Family Study (1996) (52) US Bogalusa Heart Study (1997) (53)

4

Year of birth

Israel Jerusalem follow-up study (1997) (57)

17

1970

Recall

M F M+F

3010

Weak inverse Inverse +04 (–03, +12)†

Obs

M+F

838

–28 (–38, –18)†

Obs

M+F

332

Pearson’s r = –003 (p = 063)

Obs

M+F

77

–18 (–12, +49)†

Obs

M+F

1610

–26(–35, –16)†

1978– 1983 NK

Obs

M+F

105

–42 (–81, –03)†

M F

413 425

1974– 1976

Obs

1983– 1986 1980– 1983 NK 1979– 1981 NK

Obs

Recall

M F

Sweden Conscript study (1997) (16) Croatia Birth cohort study (1993) (58)

+04 (–15, +23) +16 (–02, +35)

6692 Pearson’s r = –001 (p ≥ 001) 4199 Pearson’s r = +001 (p ≥ 001) 130,842 –08 (–09, –07)

–15 (–22, –08)†

–13 (–30, +05) +05 (–13, 23)

–05 (–21, –12) +06 (–12, +25)

–09 (–15, –03) –07 (–15, +01)

18

1973–75

Rout

M

18–23 mean 20

NK

Recall

M

214

Inverse

–03 (p = 005)

F

251

Weak inverse

–05 (p = 002)

Obs

M+F

53

–35(–71, +01)†

Obs+ Recall

M+F

452

17–24 16–26 mean 21

1970– 1977 1959– 1970

–10 (–11, –09)

–22 (p = 006)

–08 (–09, –06)

–17 (p = 015)

BMI, weight height, mother’s height, season, s-e factors, smoking, drinking, exercise Weight, maternal prepregnancy weight, weight gain, BMI and ethnicity BMI, gestational age, maternal age, parity Father’s height, man ual activity, nutrition, s-e factors. BMI, skinfold thickness BMI, skinfold thickness, s-e factors

Weight, sex, parental SBP

27

France Nancy Family Study (1996) (52) Scotland Edinburgh cross-sectional study (1998) (59)

9921

Birth Weight, Blood Pressure, and Hypertension

UK 1970 birth cohort (1989) 10 (4) UK 10 towns 1994 cross-sec 8–11 tional study (1997) (15) mean 105 UK Guilford & Carlisle 9–11 cross-sectional study (1995) (23) Spain Valencia cross-sec6–16 tional study (1996) (54) mean 106 Jamaica Follow-up of mater10–12 nal nutrition study (1994) (47) Jamaica Kingston cross-sec6–16 tional study (1996) (55) France Nancy Family Study 11–16 (1996) (52) Scotland Longitudinal study 15 (1991) (56)

28

Table 1 Continued Effect* Paper: Setting (year of publication) and (reference number)

Age in years when examined

Year of birth

Source of birth weight

Sex

N

Recall

M+F

541

Obs

M F

1396 1553

M F M

1625 1634 1421

F

1409

US San Antonio Heart Study (1994) (60) UK 1946 birth cohort—1 (1985) (3)

32 36

1949– 1963 1946

UK 1946 birth cohort—2 (1989) (4) UK 1946 birth cohort—3 (1993) (5)

36

1946

Obs

36

1946

Obs

Crude

Adjusted for concurrent body size (other adjustments) Adjusted for additional or other factors

Inverse (in both ethnic groups)

Inverse Weak inverse –11 (–20, –03) per SDS bwt –11 (–20, –03) per SDS bwt

1947– 1964 1948– 1954 NK

Recall

F

92,940

Obs

M+F

253

Obs

M+F

620

1935– 1943

Obs

M+F

449

Inverse

UK Preston birth follow-up study—A2 (1992) (7)

1935– 1943

Obs

M+F

327

Inverse (p = 004)

46–54

–45 (p = 003)

–23 (p < 001) –20 (p < 005)

BMI, family history CVD, education, s-e status

–02 (–03, –01)

BMI, parental history of hypertension BMI, sex, alcohol consumption BMI, sex, parental NIDDM status BMI, placental weight, alcohol consumption, sex

–14 (–22, –05) per SDS bwt –12 (–21, –04) per SDS bwt

–48 (p = 001) –20 (p = 008) Inverse

Leon and Koupilová

US Nurses Health Study II 27–44 (1996) (30) mean 37 Scotland Aberdeen diet in mean 41 pregnancy study (1996) (45) Denmark Fredericia NIDDM 41–54 offspring study (1996) (61) mean 47 UK. Preston birth follow-up 46–54 study—A1 (1990) (6)

Inverse (p = 001) Sex and ethnicity

46–50

1935– 1943

Obs

Obs

M F M F M+F

123 116 117 103 139

1935– 1943 1920– 1924 1939–1940

–29 (–92, +37)

Obs

M

1333

–22 (–42, –03)

Obs

M–F

337

–59 (–119, –18)

1921–1946

Recall

F

71,100

–09 (–11, –08)

1911– 1946 1920– 1930

Recall

M

22,846

Obs

M

468

Inverse (p = 0001)

1920– 1930

Obs

1923– 1930

Obs

M F M F F

426 203 418 184 297

–30(–69, +09) –27 (–88, +34) –49 (–88, –10) –55 (–122, +12) –46 (–97, +04)

51–54 UK Preston birth follow-up study—B (1993) (9) Sweden Uppsala crosssectional study (1996) (18) UK Sheffield birth follow-up study (1995) (62) US Nurses Health Study I (1996) (30) US Health Professionals Cohort Study (1996) (31) UK Hertfordshire birth follow-up study—1 (1991) (10) 59–70 UK Hertfordshire birth follow-up study—2 (1993) (8) UK Hertfordshire birth follow-up study—3 (1995) (11)

47–56 49–51 50–53 44–69 mean 56 44–79 mean 60 59–70 mean 64 59–63 64–71 60–71 mean 64

–28 (–93, +37) –27 (–105, +51) –34 (–91, +23) –34 (–136, +68)

–31 (–50, –12)

Inverse

–07 (–10, –04)

BMI, sex, alcohol, gestational age BMI, parental history of hypertension BMI, parental history of hypertension

Birth Weight, Blood Pressure, and Hypertension

UK Preston birth follow-up study—A3 (1992) (8)

Unless otherwise stated, mmHg change per kg increase in birth weight adjusted for age where appropriate † Adjusted for sex ‡ Adjusted for sex and race Note: Shaded rows indicate study populations for which estimates are presented from more than one paper The papers reporting the results of studies from Preston of middle age men and women involve two independent populations (denoted as A and B). There are three papers based on the A population6-8 and one paper based on the B population9 A small number of cross-sectional or follow-up studies that meet the criteria specified in the main text are nevertheless excluded from these summary tables The paper by Seidman, et al6 which reported a study of 17-year-old Israeli conscripts, was excluded because of inconsistencies between text and tables in terms of the direction of association between birth weight and blood pressure: the paper by Launer, et al2 was excluded because it did not include a simple linear regression coefficient for the effect of birth weight on blood pressure at age 4 Abbreviations: BP, Blood pressure: N, Number of subjects: NK, Not known; BMI, Body mass index: SBP. Systolic blood pressure: Rout, Routine records; Obs, Obstetric medical records: s-e. Socio-economic; CVD, Cardiovascular disease; SDS bwt. Standard deviation score of birth weight *

29

30

Table 2 Diastolic Blood Pressure in Children and Adults: Cohort and Cross-Sectional Studies with Casual BP as Outcome Effect* Age in years when examined

Year of birth

Source of birth weight

Sex

N

Japan Niigata cross-sectional study (1996) (49) Zimbabwe Harare crosssectional study (1998) (17) Australia Adelaide birth follow-up study (1996) (51) UK 10 towns 1994 crosssectional study (1997) (15) UK Guilford & Carlisle cross-sectional study (1995) (23) Spain Valencia cross-sectional study (1996) (54) US Bogalusa Heart Study (1997) (53) Scotland Longitudinal study (1991) (56)

mean 38

NK

Rout

M+F

195

mean 65

1980s

Rout+ Recall

M+F

576

Israel Jerusalem perinatal follow-up study (1997) (57)

8

1975– 1976

Obs

M+F

775

8–11 mean 105

1983– 1986

Recall

M+F

3010

9–11

1980– 1983

Obs

M+F

838

Obs

M+F

332

1973– 1981 NK

Obs+ Rout Recall

M+F

1426

M F

413 425

1974– 1976

Obs

M

6692

F

4199

6–16 mean 106 7–11 15

17

NK

Crude

Adjusted for concurrent body size (other adjustments) Adjusted for additional or other factors

Pearson’s r = +011 (p = 013) –11 (–26, +04)

–10 (–24, +04)

Weight, placental weight

+12 (–04, +28) +07(–09, +24)

+06 (–10, +23) +07 (–13, +26)

Pearson’s r = +0003 (p ≥ 001) Pearson’s r = +0009 (p ≥ 001)

–03 (–07, +01) –03 (–08, +03)

BMI, weight, height, mother’s height, season. s-e factors, smoking, drinking, exercise Weight, maternal pre-pregnancy weight, weight gain, BMI and ethnicity

+02 (–02, +07)†

–03 (–08, +01)†

–14 (–21, –07)†

Pearson’s r = +007 (p = 020) –004 (–11, +03)‡

Leon and Koupilová

Paper: Setting (year of publication) and (reference number)

32 36

1949– 1963 1946

Recall

M+F

Obs

M F

US Nurses Health Study II (1996) (30) Scotland Aberdeen diet in pregnancy study (1996) (45) Denmark Fredericia NIDDM offspring study (1996) (61) UK Preston birth followup study—I (1990) (6) Sweden Uppsala cross-sectional study (1996) (18) UK Sheffield birth followup study (1995) (62) US Nurses Health Study I (1996) (30) US Health Professionals Cohort Study (1996) (31)

27–44 mean 37 41

41–54 mean 47 46–54 49–51 50–53 44–69 mean 56 44–79 mean 60

1947– 1964 1948– 1954 NK

1935– 1943 1920– 1924 1939– 1940 1921– 1946 1911– 1946

541 Inverse (in both ethnic groups) 1421 –05 (–12, +02) per SDS bwt 1409 –03 (–10, +04) per SDS bwt 92,940

Inverse (p = 0005) Sex and ethnicity –08 (–15, –01) per SDS bwt –04 (–10, +03) per SDS bwt

Recall

F

Obs

M+F

253

M+F

620

–10 (p = 005)

BMI, sex, parental NIDDM status

Obs

M+F

449

Inverse

Placental weight

Obs

M

1333

Obs

M+F

337

–42 (–64, –20)

Recall

F

71,100

–05 (–06, –03)

Recall

M

22,846 No clear association

–03 (–05, –01)

BMI, sex, alcohol, gestational age BMI, parental history of hypertension BMI, parental history of hypertension

Obs

–02 (–03, –01)

–36 (p = 002)

–10 (–22, +01)

–39 (p = 0006)

BMI, parental history of hypertension BMI, sex, alcohol consumption

–17 (–29, –06)

Birth Weight, Blood Pressure, and Hypertension

US San Antonio Heart Study (1994) (60) UK 1946 birth cohort—3 (1993) (5)

* Unless otherwise stated, mmHg change per kg increase in birth weight, adjusted for age where appropriate † Adjusted for sex ‡ Adjusted for sex and race Abbreviations: Bwt, Birth weight; N. Number of subjects; NK. Not known: BMI, Body mass index; Rout, Routine records: Obs, Obstetric medical records; s-e. Socio-economic: SDS. Standard deviation score

31

32

Table 3 Systolic Blood Pressure in Children and Adults: Longitudinal Studies with Repeat Measures of Casual Blood Pressure as Outcome Effect* Paper: Setting (year of publication) and (reference number)

Age in years when examined

Year of birth

UK Farnborough Longitudinal study (1993) (8) Restricted to births 38–42 weeks gestation

1 1985 2 3 4 5 6 7 8 9 UK Guilford & Carlisle longitudinal 5–7 1980– analysis (1995) (23) 9–11 1974 Finland, Longitudinal cardiovascular 6–18 1962– risk factor study (1996) (64) mean 11 1974 Three follow-up examinations at 6–21 3-year intervals 9–24 mean 16

5–9 10–14 15–19 20–24 25–29 30–37

1954– 1973

Obs

Obs Recall

Recall +Obs

Crude

Adjusted for concurrent body size (other adjustments) Adjusted for additional or other factors

Sex

N

M+F M+F M+F M+F M+F M+F M+F M+F M+F M+F M+F M F M F M F

1344 1313 1215 1147 994 1070 1066 1093 961 523 1132 1249 1323 1421 1079 1196

Pearson’s r = –004 Pearson’s r = +0.01 Pearson’s r = –004 Pearson’s r = +002 Pearson’s r = –005 Pearson’s r = –004

M+F M+F M+F M+F M+F M+F

94 208 316 298 213 112

–08 (–41, +2.6)† –05 (–29, +19)† +01 (–18, +21)† –0.7 (–27, +12)† –02(–24, +19)† –02 (–31, –25)†

–04 (–10, +18) –03 (–1.7, +11) –14 (–28, 00) –25 (–37, –13) –11 (–25, +0.3) –19 (–31, –07) –11 (–23, +01) –16 (–26, –06) –07 (–19, +0.5) –23 (–36, –10)† –40 (–57, –22)† –18 (–28, –09) –09 (–19, +00) –19 (–29, –10) –06 (–16, 04) –25 (–35, –1.5) –21 (–31, –10)

–1.7 (p = 001) (N = 967) –23 (p < 0.01) (N = 1047) –0.6 (–32, 20) –25 (–47, –04) –3.1 (–49, –12) –27 (–46, –09) –2.0 (–39, –0.01) –19 (–46, +07)

Weight, full-term birth, duration breast feeding, birth rank, maternal age, and pregnancy BP Weight, height, sex, use of alcohol, smoking, oral contraceptives

* Unless oth ise stated, mmHg change per kg increase in birth weight adjusted for age where appropriate † Adjusted for sex Note Forsen et al reported results of a longitudinal study of Finnish children from age 6 months to 7 years that was excluded from this table because of the absence of estimates of effect in the form of regression coefficients However, this study showed no evidence for the association changing in childhood, at all ages there being a suggestion of a very weak positive association between birth weight and systolic blood pressure Abbreviations: Obs, Obstetric medical records

Leon and Koupilová

Netherlands Zoetermeer longitudinal study of chronic disease risk (1997) (19) Annual follow-up of 483 peoplem with mean duration of follow-up 14 years (range 3–18)

Source of birth weight

Birth Weight, Blood Pressure, and Hypertension

33

alone) is given in the column headed “Type”: negative (or inverse) associations are indicated by a minus sign (–) and positive (or direct) associations are indicated by a plus sign (+). Estimates adjusted for any other factors alone or in addition to body size are given in the final column, together with a list of the variables adjusted for. Particular emphasis is placed on the estimates adjusted for concurrent body size, because these provide the most valid basis for comparison of effects between papers and hence across age groups. The estimates in the final column, which are adjusted for a heterogeneous set of variables, are for obvious reasons the least comparable. The protocols used to measure blood pressure varied between studies, although information about this is not provided in the summary tables. In most studies, blood pressure was measured (after a defined period of rest) more than once, and the mean taken of at least two of the readings. The measurement devices used differed, but most were either automated machines or research instruments such as the random zero sphygmomanometer. There was no consistency in the protocol with respect to cuff size, particularly in the studies of children. In terms of diastolic blood pressure, there were also differences in the Korotkoff phase sounds used. This lack of consistency in the measurement of blood pressure will have introduced varying degrees of misclassification of the main outcome, which may account for some small part of the variation in the strength of the association between birth weight and blood pressure. II. Systolic Blood Pressure The data in Table 1 are derived from 36 papers published from 1981 to 1998. Of these, four were published in the 1980s, 16 were published in 1990 to 1995, and 16 were published in 1996 to 1998. Some papers reported results from more than one study population, defined in terms of geography, birth cohort, sex, or age groups. Conversely, the results from the same study population were reported in several different papers. In summary, the 56 sets (rows) of estimates presented in Table 1 are based on 47 independent study populations. Analyses of the association between birth weight and blood pressure at age 36 from the UK 1946 birth cohort were reported in three papers (3–5); analyses of the UK Preston birth follow-up study at age 46 to 54 years were reported in three papers (6–8), a fourth paper from Preston (9) was based on a subgroup not included in these earlier papers; and analyses from the UK Hertfordshire birth follow-up study at age 59 to 71 years were presented in

34

Leon and Koupilová

two studies for men (8,10) and in two studies for women (8,11). The UK Salisbury cross-sectional study population of children was examined on two separate occasions, 5 years apart, with the results being published separately (12,13). Finally, there were two UK “10 towns” cross-sectional studies conducted in 1990 (14) and 1994 (15). These two study populations were recruited in separate sampling exercises, and as such are regarded as providing independent estimates. Almost half of the 56 sets of estimates (rows) in Table 1 relate to children or young adults: 22 are for those aged less than 17 years, 15 are for those aged between 17 and 39 years, and the remaining 19 are for those aged between 40 and 71 years. The sex distribution of estimates is balanced, with 27 being for both sexes combined and 15 for males and 14 for females. The majority used birth weight data derived from obstetric, neonatal, or other routine records, with only 12 using birth weight data based wholly or in part on the recall or reporting of subjects or their relatives. There are 25 estimates of the crude (unadjusted) association between birth weight and systolic blood pressure, 20 of which indicate a negative or inverse association. Of the negative associations, seven are stated to be statistically significant (p < 0.05). The UK 1946 birth cohort study (4,5) and the UK Preston birth follow-up study (6,7) provide crude estimates based on the same population in more than one paper, all of which show an inverse association between birth weight and systolic blood pressure. If replicate estimates are removed, out of 22 independent crude estimates 17 indicate a negative or inverse association. There are 31 estimates of the association between birth weight and systolic blood pressure that are adjusted for concurrent body size only, of which 29 show negative or inverse relationships that in 14 instances are stated to be statistically significant (p < 0.05). The UK Hertfordshire cohort (8,10,11) provides data for more than one paper. If replicate estimates are removed, out of the total of 29 independent estimates 27 show a negative association between birth weight and systolic blood pressure. Two of the independent estimates in Table 1 present change in blood pressure per birth weight standard deviation score (5). For the remaining 27 independent estimates, there is a mean change in systolic blood pressure per 1 kg increase in birth weight (adjusted for concurrent body size) of –1.70 mmHg (–2.10, –1.30). This mean was calculated weighting each independent estimate directly according to the number of subjects—with the exception of the Swedish conscript’s estimate (16). This was given a nominal weight of 10,000, because otherwise the very substantial sample size (130,842) of this

Birth Weight, Blood Pressure, and Hypertension

35

Figure 1 Change in systolic blood pressure (mmHg) per 1 kg increase in birth weight adjusted for concurrent body size by age.

study would have made it far more influential than could be justified given the other sources of error that are likely to account for between-study variation, such as repeatability of birth weight and blood pressure measurements. The distribution of independent estimates of the association between birth weight and systolic blood pressure adjusted for concurrent body size by age is shown graphically in Figure 1. This shows very clearly that the vast majority of estimates show a negative association. There is no suggestion of any systematic difference in the size of effects according to whether they were for males, females, or both sexes in combination. III. Diastolic Blood Pressure The information available on the association between birth weight and blood pressure is far less extensive for diastolic compared with systolic blood pressure. Of the 36 papers summarized in Table 1 that provide quantitative information about the association of birth weight with systolic blood pressure,

36

Leon and Koupilová

only 18 provide the equivalent for diastolic blood pressure, as summarized in Table 2. Of the other 18 papers that provide quantitative estimates for the association of birth weight with systolic but not diastolic blood pressure, over half included some qualitative remarks on the diastolic association in the text. These remarks are difficult to summarize, because they frequently fail to indicate anything about the direction or magnitude of the association of birth weight with diastolic blood pressure, a typical example being, “[T]here was no clear association between birth weight and diastolic blood pressure” (17). It is reasonable to suspect, in fact, that small or nonsignificant associations of birth weight with diastolic blood pressure were least likely to be reported in quantitative form. To this extent, Table 2 needs to be interpreted with caution, as reporting bias may favor larger effects that are in the same direction as with those for systolic blood pressure. Bearing these caveats in mind, Table 2 does suggest that the association between birth weight and diastolic blood pressure is consistently negative or inverse after adjustment has been made for concurrent body size. Among the 22 independent sets (rows) of estimates, there are seven quantitative estimates adjusted for body size, all of which are inverse, with three being statistically significant (p < 0.05). The strength of these adjusted associations is generally smaller than for systolic blood pressure, ranging from –0.3 to –1.7 mmHg per kg increase in birth weight. Of the 13 crude (unadjusted) estimates, seven indicate a positive association of birth weight with diastolic blood pressure, while five indicate a negative association. IV. Effect of Concurrent Body Size The negative association of birth weight with systolic blood pressure is not dependent on adjustment for concurrent body size. As already noted, three quarters of the crude (unadjusted) estimates shown in Table 1 are negative. This is not the case with diastolic blood pressure, where fewer than half of the crude associations are negative. However, the effect of adjustment for concurrent body size is the same for systolic and diastolic blood pressure. Crude (unadjusted) estimates could be compared with the estimates adjusted for concurrent body size in eight instances for systolic and four instances for diastolic blood pressure. In each case, adjustment for concurrent body size had the effect of strengthening the size of the crude negative association or (equivalently) reducing the size of the crude positive association. This effect

Birth Weight, Blood Pressure, and Hypertension

37

of adjustment for concurrent body size is not surprising because birth weight is positively correlated with body size, which in turn is positively correlated with diastolic and systolic blood pressure. There is evidence that the strength of the association of birth weight with later blood pressure increases directly with body mass index (18,19) and weight (20). This suggests that obesity potentiates the effect of impaired fetal growth on later blood pressure, as has been also reported with respect to fetal effects on insulin resistance (21) and coronary heart disease (22). V. Is the Birth Weight–Blood Pressure Association Modified by Age? It has been hypothesized that the strength of the negative association between birth weight and blood pressure increases or is amplified with age (8). Figure 1 supports this contention with respect to the association with systolic blood pressure adjusted for concurrent body size. The weighted regression line (using the same weights as for the weighted mean already described above) suggests that for every decade of age there is an increase in the slope of the birthweight–systolic blood pressure association of –0.35 mmHg (95% CI, –0.59, –0.11) per kg increase in birth weight. On this basis, at age 10 years the mean change is –1.45 mmHg per kg increase in birth weight, going up to –3.20 mmHg at 60 years of age. Interpreting this apparent progressive strengthening of the birth weight– blood pressure association with age needs to be done with caution, not least because we are lacking estimates of effect between the ages of 25 and 45 years as is evident from Figure 1. It should also be noted that estimates of the effect for those in late middle age are based on cohorts of men and women born prewar, many in the 1920s and 1930s. In contrast, most of the estimates for children and young adults are based on populations born in the 1970s or more recently. With the data we have been considering it is thus not possible to determine how far the effects seen in Figure 1 are attributable to birth cohort effects as distinct from those attributable to age per se. To do this, it is necessary to have data on individuals where the strength of the association between birth weight and blood pressure is estimated at different ages. Four longitudinal studies have provided data on the association of birth weight with systolic blood pressure at different ages. Their findings are summarized in Table 3. Only in the Guilford and Carlisle study (23) was it concluded that strength of the association increased with age (between ages 5–

38

Leon and Koupilová

7 and 9–11 years). In fact, this is the only study in which the estimates at different ages are based on exactly the same subjects. Within the other three studies, the estimates at different ages are based on different subgroups of subjects, making interpretation of changes in estimates with age problematic. The regression line derived from the cross-sectional studies discussed above suggests that there is a change in the strength of association of only – 0.35 mmHg per decade. If such an amplification effect is real, then it is perhaps not surprising that the four studies summarized in Table 3 do not show much evidence to support the phenomenon, given that all of them are based on longitudinal follow-ups of only 10 years or less. The most established modification by age of the association of birth weight with blood pressure occurs in neonates. There is a considerable body of evidence that in the first few weeks of life the association is positive, ie, in the opposite direction to that found in children and adults. Hulman et al. (24) reported a significant positive correlation of birth weight with systolic blood pressure measured in the first day of life. Elevated neonatal blood pressure measured on day 3 to 4 of life has also been correlated with higher birth weight (25), whereas systolic and diastolic blood pressure in the first week of life increased with increasing birth weight (26) with a correlation coefficient of 0.20 (p < 0.001). Similar results were reported for systolic blood pressure by Launer et al. (27). Levine et al. (28) studied blood pressure patterns in twins during the first year of life. Both systolic and diastolic blood pressure at 4 days increased with birth weight. However, as infancy progressed, this positive association became attenuated, as the twins who were lightest at birth had a steeper rise in blood pressure than the heavier twins. A summary of other studies of the birth weight–blood pressure association in neonates, nearly all of which also show a positive association, is provided by Whincup et al. (14). The significance of this reversal of the association of birth weight with blood pressure from being positive in neonates to being negative in children and adults has not been adequately explored. It is likely to be informative with respect to potential biological mechanisms that underlie fetal programming. VI. Birth Weight and Hypertension A small number of studies have looked at the association between size at birth and the binary outcome of the presence or absence of hypertension. The first study to focus on the negative association between birth weight and later blood

Birth Weight, Blood Pressure, and Hypertension

39

pressure, by Gennser et al. (29), found a higher prevalence of low birth weight for gestational age among Swedish male conscripts who had a diastolic blood pressure greater than 99 mmHg compared with normotensive controls (odds ratio = 3.6, 95% CI, 1.1, 12.6). In the US Nurses’ Health Study (30), self-reported history of hypertension was greatest among women who were lightest at birth. In the older of the two nurses’ cohorts (44–69 years), there was a smooth negative association of hypertension with birth weight after adjustment for concurrent body mass index and parental history of hypertension, with an odds ratio of 1.6 between those weighing less than 5 lbs and those weighing greater than 10 lbs at birth. Similar, but slightly smaller associations were seen in the parallel study of male US health professionals (31). Negative associations between birth weight and prevalence of diagnosed hypertension were also seen in a longitudinal study of Swedish men at ages 60 and 70 years (32). VII. Studies of Births with Abnormal Obstetric or Neonatal Characteristics A range of studies have examined blood pressure in cohorts of children who were born preterm, low birth weight, or small for gestational age. Matthes et al. (33) found adolescents born at term weighing less than 2500 g to have a systolic blood pressure that was 1 mmHg (95% CI –1, +3) higher than term births weighing 3000 to 3800 g, having adjusted for concurrent body size. Leger et al. (34) found systolic and diastolic blood pressure adjusted for concurrent body size at age 20 to be greater in small-for-gestational age females born at term compared with those who were of appropriate weight for gestational age. The opposite effect was seen for males. Williams et al. (35) compared systolic and diastolic blood pressure at age 7 and 18 years in relatively small groups of children who had experienced intrauterine growth retardation, large-for-gestational age children, and normal children, adjusting for sex and current weight. No consistent differences in systolic or diastolic blood pressure were found. Morley et al. (36) found a positive association of birth weight for gestational age with both systolic and diastolic blood pressure in a group of 8-yearold children who were born at less than 34 weeks gestation weighing less than 1850 g. This association remained positive after adjustment for concurrent body size. Hack et al. (37) studied blood pressure in very low (< 1500 g) birth weight and normal birth weight children at age 8. Both systolic and diastolic

40

Leon and Koupilová

blood pressures were significantly lower in the very low birth weight children. However, as the very low birth weight children were reported to have significantly lower mean current weight and height, and no adjustments for current weight were made, the results relating to the birth weight–blood pressure association are difficult to interpret. In contrast, Pharoah et al. (38) found higher systolic blood pressure in 15-year-old children of less than 1500 g birth weight than in a quasirandom comparison sample matched on age, sex, and school. A few studies have explored the birth weight–blood pressure association in offspring of women who were hypertensive in pregnancy. For instance, Ounsted et al. (39) examined children born to mothers who had undergone a trial for treatment of hypertension in pregnancy when they were 7 years old, and reported a negative correlation between birth weight and blood pressure. A small study of children born to hypertensive mothers in Sweden also showed a weak, nonsignificant negative correlation between birth weight and systolic and diastolic blood pressure at age 12 years (40). The findings of these studies of offspring of mothers with abnormal pregnancies and in individuals who were very small, small for gestational age, or born preterm are not consistent. Some find blood pressure to be higher in the abnormal group, and others find the reverse. Small sample size and other problems of design may explain some of this lack of consistency. It is also possible that being born at the extremes of the gestational age or birth weight distributions may have effects on later blood pressure that differ from those that would be predicted from studies of individuals spanning the normal range of birth outcomes. The biological mechanisms associated with preterm birth or low or very low birth weight are unlikely to be identical to those determining variation in size at birth within the normal range, and may thus have different programming effects on blood pressure. VIII. Socioeconomic and Behavioral Pathways One of the most commonly voiced concerns about the concept of fetal programming of later disease is that the associations reported from observational epidemiological studies could be attributable to confounding by socioeconomic and behavioral factors. In other words, socioeconomic disadvantage at birth is related to reduced birth weight, and also to socioeconomic disadvantage and hence increased disease risk in later life. This could conceivably be

Birth Weight, Blood Pressure, and Hypertension

41

through behavioral factors including diet, alcohol consumption, and smoking. Surprisingly few studies have attempted to deal with this possibility systematically. Koupilová et al. (41) examined whether the association between birth weight and systolic blood pressure in 50-year-old Swedish men could be explained by socioeconomic circumstances at birth and in adult life, and by behavioral factors such as alcohol consumption. They showed that adjustment for these factors reduced the strength of association only slightly, concluding that these factors could not explain the negative association between birth weight and systolic blood pressure. However, these analyses do suggest that a small part of the association could be so explained, a conclusion reinforced in more recent analyses (42) of the same data set and by others (38). A number of other studies have adjusted for socioeconomic and other factors, ranging from behavioral factors such as smoking and alcohol consumption to maternal characteristics such as blood pressure and height. These adjusted estimates are summarized in the tables. However, the combination and range of factors adjusted for vary substantially between studies. In most cases, estimates unadjusted for these factors are not given, making interpretation of their potential mediating or confounding role very difficult. What is apparent is that nearly all of the adjusted estimates indicate a negative association of birth weight with blood pressure, although where comparisons are possible with estimates adjusted for concurrent body size alone the effect of additional adjustment is to reduce the strength of association slightly.

IX. Maternal Influences One of the central unresolved questions with respect to fetal programming of blood pressure and adult disease is the contribution of maternal factors. Of particular interest is the potential role of maternal nutritional status. Stanner et al. (43) studied a group of men and women who were in utero during the Leningrad siege. The famine conditions resulted in substantial falls in mean birth weight. The mean blood pressure of this group in adult life was compared with that of people born at the same time who were not subject to famine conditions in utero. Neither systolic nor diastolic blood pressure were related to being in utero during the famine, although there was an association with indicators of abnormal endothelial function. In another study (44), one aspect

42

Leon and Koupilová

of endothelial function, flow mediated dilatation, has been associated with low birth weight. Only one reported study has been able to directly assess the impact of maternal nutrition during pregnancy on an offspring’s blood pressure. Campbell et al. (45) took advantage of a survey of diet in late pregnancy conducted in Aberdeen, Scotland between 1948 and 1954. A total of 253 men and women were traced and examined 40 years later. The associations between pregnancy diet and offspring’s blood pressure were complex. In summary, blood pressure was raised among those people whose mothers’ diets had low protein but high carbohydrate intakes and among those whose mothers had a high protein but low carbohydrate intake. Maternal anthropometry has been related to offsprings’ blood pressure in several studies. Systolic blood pressure in children aged 8 to 9 years in the Gambia was negatively associated with maternal weight gain during pregnancy. At younger ages, maternal weight in the last trimester was positively associated with offsprings’ systolic blood pressure. Birth weight was unrelated to systolic blood pressure at any age. In a study of 11-year-old children in the United Kingdom, weight gain in pregnancy between 18 and 28 weeks gestation was also negatively associated with systolic blood pressure, but there was no association with diastolic blood pressure (46). Statistically significant negative associations between maternal weight gain and offsprings’ blood pressure were only found when a subgroup analysis was performed stratified by maternal skinfold thickness. There was a small nonsignificant negative association between birth weight and systolic blood pressure. A study in Jamaica of 10- to 12-year-old children showed negative associations between children’s blood pressure and maternal weight gain in pregnancy between 15 and 35 weeks gestation, maternal triceps skinfold thickness at 15 weeks, and maternal hemoglobin (47). These effects were independent of each other and were adjusted for concurrent weight of the children. Interestingly, this study found a nonsignificant positive association between birth weight and systolic blood pressure adjusted for sex and concurrent weight. Whincup et al. have looked at a range of maternal characteristics to see how far they are related to offsprings’ blood pressure. In a study of 5- to 7year-olds (14), maternal size was positively related to children’s blood pressure, but this association was eliminated on adjustment for the child’s own body build. Maternal social class, educational attainment, and smoking were not related to their children’s blood pressure. Birth weight was negatively associated with systolic blood pressure (see Table 1). Another study of 9- to 11-year-olds (48), found that the only maternal factors that showed a clear

Birth Weight, Blood Pressure, and Hypertension

43

and consistent association with blood pressure were minimum maternal hemoglobin levels and change in mean corpuscular volume in pregnancy. In summary, the relatively few studies that have examined the role of maternal factors have failed to produce a consistent picture. Few of the studies have found clear effects in their main analyses, most of the associations reported being from subgroups. More strikingly, there have been almost no attempts to systematically examine how far birth weight mediates any effects of maternal characteristics on blood pressure in offspring. The hypothesis that aspects of maternal nutritional status or diet before or during pregnancy program offsprings’ blood pressure may be an attractive one, but good human evidence in support of it is lacking. This is a priority area for further work. X. Conclusion Our systematic review has shown that there is substantial and consistent evidence for a negative association between birth weight and systolic blood pressure from childhood through the eighth decade of life. This association is evident in crude, unadjusted data. It is strongest and most consistent when adjusted for concurrent body size. The mean effect of 27 independent estimates shows a change of –1.70 mmHg per 1 kg increase in birth weight. The strength of the negative association increases with age when assessed using estimates from cross-sectional studies. For every decade of age, the negative association of birth weight with systolic blood pressure increases by –0.35 mmHg per 1 kg increase in birth weight. However, true longitudinal data in support of this amplification effect are lacking. A negative association between birth weight and diastolic blood pressure is also apparent from our systematic review, particularly when concurrent body size is taken into account, although this assessment is based on far less evidence than for systolic blood pressure. It is plausible that the picture for diastolic blood pressure may be distorted because of reporting bias. Papers covered in this review focus mainly on systolic blood pressure. Investigators may have tended not to include quantitative estimates of the association of birth weight with diastolic blood pressure unless they were clear and consistent with those for systolic blood pressure. The negative association between birth weight and blood pressure found in our systematic review reflects an effect that is apparent across the entire normal birth-weight range. It is not driven by effects on blood pressure of those at the extremes of the birth weight or gestational age distribution. Indeed,

44

Leon and Koupilová

studies of the effects on later blood pressure in preterm or those who were very light at birth do not show any consistent pattern of association. Only a small number of studies have addressed the issue of whether socioeconomic or behavioral factors can account for any of the negative association between birth weight and blood pressure. Those that have suggest that, although they may account for some of the effect, they cannot account for most of the negative association. The role of maternal factors in driving the negative association has also been underexplored. Although there are some intriguing reports of maternal nutritional status or diet in pregnancy affecting offsprings’ blood pressure, they are not conclusive. To date, the human evidence regarding the potential role of maternal nutritional status in the programming of later blood pressure must be considered as weak. Epidemiology will continue to play an important role in the research agenda on fetal programming of blood pressure. Important areas for future work include investigation of maternal characteristics on offsprings’ blood pressure, whether there is evidence of programming effects before 37 weeks, and how far measures of fetal growth other than birth weight per se may be more informative about the process of fetal programming. References 1.

2.

3.

4.

5.

6.

Lehingue Y. Fetal environment and coronary ischemia risk: review of the literature with particular reference to syndrome X. Rev Epidemiol Sante Publique 1996; 44:262–277. Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertens 1996; 14:935–941. Wadsworth MEJ, Cripps HA, Midwinter RE, Colley JRT. Blood pressure in a national birth cohort at the age of 36 related to social and familial factors, smoking, and body mass. Br Med J 1985; 291:1534–1538. Barker DJP, Osmond C, Golding J, Kuh D, Wadsworth MEJ. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. Br Med J 1989; 298:564–567. Holland FJ, Stark O, Ades AE, Peckham CS. Birth weight and body mass index in childhood, adolescence, and adulthood as predictors of blood pressure at age 36. J Epidemiol Community Health 1993; 47:432–435. Barker DJP, Bull AR, Osmond C, Simmonds SJ. Fetal and placental size and risk of hypertension in adult life. Br Med J 1990; 301:259–262.

Birth Weight, Blood Pressure, and Hypertension 7.

8. 9.

10. 11. 12. 13. 14. 15.

16.

17.

18.

19.

20. 21.

22.

45

Barker DJP, Godfrey KM, Osmond C, Bull A. The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension in adult life. Paed Perinat Epidemiol 1992; 6:35–44. Law CM, de Swiet M, Osmond C, et al. Initiation of hypertension in utero and its amplification throughout life. Br Med J 1993; 306:24–27. Godfrey KM, Barker DJP, Peace J, Cloke J, Osmond C. Relation of fingerprints and shape of the palm to fetal growth and adult blood pressure. Br Med J 1993; 307:405–409. Hales CN, Barker DJP, Clark PMS, et al. Fetal and infant growth and impaired glucose tolerance at age 64. Br Med J 1991; 303:1019–1022. Fall CHD, Osmond C, Barker DJP, et al. Fetal and infant growth and cardiovascular risk factors in women. Br Med J 1995; 310:428–432. Law CM, Barker DJP, Bull AR, Osmond C. Maternal and fetal influences on blood pressure. Arch Dis Child 1991; 66:1291–1295. Fall CH, Pandit AN, Law CM, et al. Size at birth and plasma insulin-like growth factor-I concentrations. Arch Dis Child 1995; 73:287–293. Whincup PH, Cook DG, Papacosta O. Do maternal and intrauterine factors influence blood pressure in childhood? Arch Dis Child 1992; 67:1423–1429. Taylor SJ, Whincup PH, Cook DG, Papacosta O, Walker M. Size at birth and blood pressure: cross sectional study in 8–11 year old children. Br Med J 1997; 314:475–480. Nilsson PM, Ostergren P-O, Nyberg P, Soderstrom M, Allebeck P. Low birth weight is associated with elevated systolic blood pressure in adolescence: a prospective study of a birth cohort of 147,378 boys. J Hypertens 1997; 15:1627– 1631. Woelk G, Emanuel I, Weiss NS, Psaty BM. Birthweight and blood pressure among children in Harare, Zimbabwe. Arch Dis Child Fetal Neonatal Ed 1998; 79:F119–F122. Leon DA, Koupilová I, Lithell HO, et al. Failure to realise growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men. Br Med J 1996; 312:401–406. Uiterwaal CS, Anthony S, Launer LJ, et al. Birth weight, growth, and blood pressure: an annual follow-up study of children aged 5 through 21 years. Hypertension 1997; 30:267–271. Whincup PH, Cook DG, Shaper AG. Early influences on blood pressure: a study of children aged 5–7 years. Br Med J 1989; 299:587–591. Lithell HO, McKeigue PM, Berglund L, Mohsen R, Lithell U-B, Leon DA. Relationship of birthweight and ponderal index to non–insulin-dependent diabetes and insulin response to glucose challenge in men aged 50–60 years. Br Med J 1996; 312:406–410. Frankel S, Elwood P, Sweetnam P, Yarnell J, Davey Smith G. Birth weight, body mass index in middle age, and incident coronary heart disease. Lancet 1996; 348:1478–1480.

46

Leon and Koupilová

23. Whincup P, Cook D, Papacosta O, Walker M. Birth weight and blood pressure: cross sectional and longitudinal relations in childhood. Br Med J 1995; 311:773– 776. 24. Hulman S, Edwards R, Chen YT, Polansky M, Falkner B. Blood pressure patterns in the first three days of life. J Perinatology 1991; 11:231–234. 25. O’Sullivan MJ, Kearney PJ, Crowley MJ. The influence of some perinatal variables on neonatal blood pressure. Acta Paediatr 1996; 85:849–853. 26. Zinner SH, Lee YH, Rosner B, Oh W, Kass EH. Factors affecting blood pressure in newborn infants. Hypertension 1980; 2(suppl I):99–101. 27. Launer LJ, Hofman A, Grobbee DE. Relation between birth weight and blood pressure: longitudinal study of infants and children. Br Med J 1993; 307:1451– 1454. 28. Levine RS, Hennekens CH, Jesse MJ. Blood pressure in prospective population based cohort of newborn and infant twins. Br Med J 1994; 308:298–302. 29. Gennser G, Rymark P, Isberg PE. Low birth weight and risk of high blood pressure in adulthood. Br Med J 1988; 296:1498–1500. 30. Curhan GC, Chertow GM, Willett WC, et al. Birth weight and adult hypertension and obesity in women. Circulation 1996; 94:1310–1315. 31. Curhan GC, Willett WC, Rimm EB, Spiegelman D, Ascherio AL, Stampfer MJ. Birth weight and adult hypertension, diabetes mellitus, and obesity in US men. Circulation 1996; 94:3246–3250. 32. Koupilová I, Leon DA, Lithell HO, Berglund L. Size at birth and hypertension in longitudinally followed 50–70 year old men. Blood Pressure 1997; 6:223– 228. 33. Matthes JWA, Lewis PA, Davies DP, Bethel JA. Relation between birth weight at term and systolic blood pressure in adolescence. Br Med J 1994; 308:1074– 1077. 34. Leger J, Levy Marchal C, Bloch J, et al. Reduced final height and indications for insulin resistance in 20 year olds born small for gestational age: regional cohort study. Br Med J 1997; 315:341–347. 35. Williams S, St George IM, Silva PA. Intrauterine growth retardation and blood pressure at age seven and eighteen. J Clin Epidemiol 1992; 45:1257–1263. 36. Morley R, Lister G, Leeson-Payne C, Lucas A. Size at birth and later blood pressure. Arch Dis Child 1994; 70:536–537. 37. Hack M, Weissman B, Breslau N, Klein N, Borawski Clark E, Fanaroff AA. Health of very low birth weight children during their first eight years. J Pediatr 1993; 122:887–892. 38. Pharoah POD, Stevenson CJ, West CR. Association of blood pressure in adolescence with birthweight. Arch Dis Child Fetal Neonatal Ed 1998; 79:F114– F118. 39. Ounsted MK, Cockburn JM, Moar VA, Redman CW. Factors associated with the blood pressures of children born to women who were hypertensive during pregnancy. Arch Dis Child 1985; 60:631–635. 40. Himmelmann A, Svensson A, Hansson L. Relation of maternal blood pressure

Birth Weight, Blood Pressure, and Hypertension

41.

42.

43.

44. 45.

46.

47.

48.

49.

50.

51. 52.

53.

54.

47

during pregnancy to birth weight and blood pressure in children. The Hypertension in Pregnancy Offspring Study. J Intern Med 1994; 235:347–352. Koupilová I, Leon DA, Vågerö D. Can confounding by socio-economic and behavioural factors explain the association between size at birth and blood pressure at age 50 in Sweden? J Epidemiol Comm Health 1997; 51:14–18. Leon DA. Fetal growth and later disease: evidence from Swedish cohorts. In: O’Brien PMS, Wheeler T, Barker DJP, eds. Fetal Programming. Influences on Development and Disease in Later Life. Proceedings of 36th RCOG Study Group. London: Royal College of Obstetricians and Gynaecologists, 1999: 12–29. Stanner SA, Bulmer K, Andrès C, et al. Does malnutrition in utero determine diabetes and coronary heart disease in adulthood? Results from the Leningrad siege study, a cross sectional study. Br Med J 1997; 315:1342–1349. Leeson CPM, Whincup PH, Cook DG, et al. Flow-mediated dilation in 9- to 11year-old children. Circulation 1997; 96:2233–2238. Campbell DM, Hall MH, Barker DJ, Cross J, Shiell AW, Godfrey KM. Diet in pregnancy and the offspring’s blood pressure 40 years later. Br J Obstet Gynaecol 1996; 103:273–280. Clark PM, Atton C, Law CM, Shiell A, Godfrey K, Barker DJ. Weight gain in pregnancy, triceps skinfold thickness, and blood pressure in offspring. Obstet Gynecol 1998; 91:103–107. Godfrey KM, Forrester T, Barker DJP, Jackson AA, Landman JP, Hall JStE, et al. Maternal nutritional status in pregnancy and blood pressure in childhood. Br J Obstet Gynecol 1994; 101:398–403. Whincup P, Cook D, Papacosta O, Walker M, Perry I. Maternal factors and development of cardiovascular risk: evidence from a study of blood pressure in children. J Hum Hypertens 1994; 8:337–343. Hashimoto N, Kawasaki T, Kikuchi T, Takahashi H, Uchiyama M. The relationship between the intrauterine environment and blood pressure in 3-year-old Japanese children. Acta Paediatr 1996; 85:132–138. Simpson A, Mortimer JG, Silva PA, Spears G, Williams S. Correlates of blood pressure in a cohort of Dunedin seven-year-old children. In: Onesti G, ed. Hypertension in the Young and Old. New York: Grune & Stratton, 1981: 153–163. Moore VM, Miller AG, Boulton TJ, et al. Placental weight, birth measurements, and blood pressure at age 8 years. Arch Dis Child 1996; 74:538–541. Zureik M, Bonithon Kopp C, Lecomte E, Siest G, Ducimetiere P. Weights at birth and in early infancy, systolic pressure, and left ventricular structure in subjects aged 8 to 24 years. Hypertension 1996; 27:339–345. Donker GA, Labarthe DR, Harrist RB, Selwyn BJ, Wattigney W, Berenson GS. Low birth weight and blood pressure at age 7–11 years in a biracial sample. Am J Epidemiol 1997; 145:387–397. Lurbe E, Redon J, Alvarez V, et al. Relationship between birth weight and awake blood pressure in children and adolescents in absence of intrauterine growth retardation. Am J Hypertens 1996; 9:787–794.

48

Leon and Koupilová

55. Forrester TE, Wilks RJ, Bennett FI, Simeon D, Osmond C, Allen M, et al. Fetal growth and cardiovascular risk factors in Jamaican schoolchildren. Br Med J 1996; 312:156–160. 56. Macintyre S, Watt G, West P, Ecob R. Correlates of blood pressure in 15 year olds in the west of Scotland. J Epidemiol Community Health 1991; 45:143– 147. 57. Laor A, Stevenson DK, Shemer J, Gale R, Seidman DS. Size at birth, maternal nutritional status in pregnancy, and blood pressure at age 17: population based analysis. Br Med J 1997; 315:449–453. 58. Kolacek S, Kapetanovic T, Luzar V. Early determinants of cardiovascular risk factors in adults. B. Blood pressure. Acta Paediatr 1993; 82:377–382. 59. Walker BR, McConnachie A, Noon JP, Webb DJ, Watt GCM. Contribution of parental blood pressures to association between low birth weight and adult high blood pressure: cross sectional study. Br Med J 1998; 316:834–837. 60. Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stern MP. Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 1994; 37:624–631. 61. Vestbo E, Damsgaard EM, Froland A, Mogensen CE. Birth weight and cardiovascular risk factors in an epidemiological study. Diabetologia 1996; 39:1598– 1602. 62. Martyn CN, Barker DJP, Jespersen S, Greenwald S, Osmond C, Berry C. Growth in utero, adult blood pressure, and arterial compliance. Br Heart J 1995; 73:116– 121. 63. Seidman DS, Laor A, Gale R, Stevenson DK, Mashiach S, Danon YL. Birth weight, current body weight, and blood pressure in late adolesence. Br Med J 1991; 302:1235–1237. 64. Taittonen L, Nuutinen M, Turtinen J, Uhari M. Prenatal and postnatal factors in predicting later blood pressure among children: cardiovascular risk in young Finns. Pediatr Res 1996; 40:627–632. 65. Forsén T. Nissinen A, Tuomilehto J, Notkola IL, Eriksson J, Vinni S. Growth in childhood and blood pressure in Finnish children. J Hum Hypertens 1998; 12:397–402.

3 Mechanisms for In Utero Programming of Blood Pressure CHRISTOPHER N. MARTYN

STEPHEN E. GREENWALD

University of Southampton and Southampton General Hospital Southampton, United Kingdom

Royal London Hospital London, United Kingdom

The epidemiological evidence that individuals whose birth weight was low tend to have raised blood pressure in later life is, as Leon and Koupilová have shown in Chapter 2, substantial and consistent. Their review is an update of an earlier systematic review published in 1996 (1). Although more data are now available, the conclusions are little changed. In prepubertal children and adults there is a consistent negative relation between birth weight and current systolic blood pressure. There is a suggestion that the strength of the negative association increases with age, but true longitudinal data will be needed to confirm this. Rather less evidence is available about diastolic blood pressure, but what there is indicates that the size of the effect is smaller. Retarded fetal growth may therefore have a greater influence on pulse pressure (ie, systolic pressure minus diastolic pressure) than on mean blood pressure. Two questions immediately arise from these findings. The first concerns underlying biological mechanisms. What is the nature of the adaptations made by the fetus in response to influences that retard its growth that have such a permanent effect? The second question is about the relevance of the relation 49

50

Martyn and Greenwald

between blood pressure and birth weight to understanding why impairment of growth in fetal life is associated with increased risk of atherosclerosis (2), coronary heart disease, and stroke (3). This second question needs to be kept in mind when trying to answer the first because, although the results of studies linking blood pressure to birth weight are remarkably consistent, the absolute size of the effect is small. A change of 1 kg of birth weight corresponds to a change of only 2 or 3 mmHg in systolic blood pressure. By itself, the effect of birth weight on blood pressure can account for only a part of the observed increase in risk of vascular disease associated with low birth weight. Might it be that this small increase in blood pressure signals not just a process in the causal chain linking fetal growth to cardiovascular outcomes in adult life but widespread effects of intrauterine growth retardation on the physiology and structure of the vascular system? No doubt the answers to these questions will prove complex. The control of blood pressure is mediated and influenced by multiple structural, neural, endocrine, and renal mechanisms. Perturbations in one control mechanism inevitably lead to compensatory changes in others and dissecting out which is primary is likely to be difficult. In this chapter, we discuss three hypotheses about possible mechanisms, although we are sure further research will produce other candidates. I. Structure of the Aorta and Large Conduit Arteries Engineers go to a lot of trouble to ensure that the structures they design have the necessary properties of elasticity and resilience. Without these properties, the structure would be poor both in resisting an external force and in recovering its shape when the force is removed. In circumstances where a structure must endure repetitive loading, the materials that it is made of must possess the additional quality of being resistant to fatigue. Biological structures must meet the same requirements. Vertebrates have evolved a unique solution to the demand for a material with a high degree of elasticity and resilience; the rubber-like macromolecule, elastin. Elastin is a high–molecular weight, insoluble protein polymer formed extracellularly by the covalent cross-linking of tropoelastin monomers. The process by which elastin is laid down is complicated (4). Newly synthesized tropoelastin binds to a recycling 67 kDa galactolectin chaperone that prevents premature intracellular aggregation of the monomer. After excretion into the extracellular space, the galactolectin-tropoelastin complex remains on the cell

In Utero Programming of Blood Pressure

51

surface until it comes into contact with a nascent elastin fiber. Here, the chaperone interacts with galactosugars of the microfibrillar component, releasing tropoelastin monomer to be aligned, rapidly modified by lysyl oxidase and incorporated into the elastic network by irreversible polymerization. In the vertebrate lineage, the first appearance of elastin coincides with the evolution of a closed circulatory system (5). This is surely more than accidental. An elastic reservoir is a fundamental requirement of any closed circulatory system powered by a pump whose output is pulsatile. In the adult human, the left ventricle ejects about 70 mL of blood with each contraction even at rest. This ejection takes place into a vessel filled with incompressible fluid at high pressure. Flow of blood out of the ventricle is only possible because the volume of the aorta is able to expand. Most of the energy of left ventricular contraction is stored briefly in the stretch of the aortic wall. In diastole, elastic recoil of the wall maintains the forward flow of blood against a closed aortic valve. The elastic properties of the aorta are important in reducing the tension that must be generated by the left ventricular wall and in limiting the rise in arterial pressure during systole. Further, blood flow in coronary circulation, which occurs almost exclusively in diastole, depends on the elastic recoil of the aortic wall. At a given cardiac output, loss of aortic elasticity results in a widening of pulse pressure and a rise in the circumferential stress in the walls of the aorta and the vessels that branch from it. At the same time, the work that must be done by the left ventricle is increased while the force driving coronary blood flow is lessened. Although these functions of the aorta have been understood by physiologists for many years, their clinical relevance has only recently been appreciated. With the development of noninvasive techniques for measurement of aortic compliance, decreased compliance has been shown to be associated with both systemic hypertension and left ventricular hypertrophy (6,7). Decreased aortic compliance has been recognized as a marker of cardiovascular disease (8), and pulse pressure is a powerful independent predictor of cardiovascular events, especially in patients with impaired left ventricular dysfunction after myocardial infarction (9). A. Molecular Basis of Aortic Compliance As has been mentioned already, the elastic properties of the aorta depend very largely on the presence of elastin in the vessel wall. In the thoracic aorta, elastin accounts for 40% of the dry weight of the tissue, and even in the abdom-

52

Martyn and Greenwald

inal aorta and carotid arteries elastin is a major component. Aortic elastin is arranged in multiple concentric lamellae interspersed with smooth muscle and collagen. The number of these elastic lamellae is greatest in the proximal part of the aorta. They begin to develop early in fetal life, and rates of elastin synthesis in blood vessels increase to a maximum in the perinatal period (10–12). Thereafter, rates of elastin synthesis fall rapidly. Mature cross-linked elastin is remarkable for its longevity. Its metabolic stability has been estimated in animals from changes in specific activity of incorporated radiolabels and in humans by measurement of racemization of L-aspartate and assessment of the prevalence of nuclear weapons–related radiocarbon (13–15). This work has shown both that turnover of elastin is extremely slow—its half-life is about 40 years—and that there is no appreciable synthesis of mature elastin in adult life. In the rat, a brief period of growth inhibition on day 15 of fetal life, when cellular growth in the developing aortic wall is rapid, induced persistent changes in the chemical composition of the aorta, including a reduction in the total content of elastin (16). It seems, therefore, that there is a critical period during development of the aorta and large arteries, and also perhaps other elastin-containing tissues, when elastin is laid down and that failure to synthesize adequate amounts of elastin at this time cannot be rectified later. B. Effects of Aging By middle age, the human aorta has undergone more than 1 billion cycles of expansion and contraction. The effect of cyclic mechanical stress on any material is gradually to reorganize its crystalline structure and cause it to fracture at a load that it was previously able to bear. In the aorta, the fatiguing effects of cyclic stress lead to fracture of elastin fibers and the transfer of stress to collagen fibers (17). This process is visible microscopically as a fragmentation and loss of regularity in the elastic layers of the tunica media. Collagen is about 100 times stiffer than elastin, and the gradual loss of elastin is inevitably accompanied by a reduction in vascular compliance. Loss of compliance leads to a rise in pulse pressure and an increase in the circumferential stress in the arterial wall. Vascular smooth muscle cells respond to mechanical stretch by synthesizing collagen (18,19), which results in thickening of the arterial wall and a further decrease in compliance. A feedback loop is established that tends to maintain higher levels of blood pressure (Fig. 1). The increasing stiffness of the aorta and large conduit arteries is at least part of the reason for the tendency of blood pressure to rise with age. But, by

In Utero Programming of Blood Pressure

53

Figure 1 Inter-relations of arterial compliance, pulse pressure, and synthetic activity of vascular smooth muscle.

itself, it fails to account for the variability of the rise in blood pressure between individuals. Many longitudinal studies have shown that levels of blood pressure in individuals track over long periods of time (20,21). That is to say, within a cohort, people tend to maintain the same position in the rank order of blood pressures from one examination to the next. Tracking of systolic blood pressure is detectable from about 6 months of age (22), which indicates that mechanisms affecting both the distribution of blood pressure within populations and individual risk of adult hypertension are operating from very early in life. A deficiency in vascular elastogenesis during development of the aorta and large arteries may be one of these mechanisms. C. Regulation of Vascular Elastogenesis During Development Animal experiments have shown that the synthesis of elastin in the tunica media of developing arteries is influenced by local hemodynamic conditions. For example, at birth, when pulmonary and systemic pressures are similar, the ratios of elastin to collagen in the pulmonary artery and the aorta of the rabbit are the same. Two months after birth, by which time pulmonary pressure has decreased from 40 to 15 mmHg and systemic pressure increased to 80 mmHg, the ratio of elastin to collagen in the aorta is nearly twice that of the pulmonary artery (23). Human fetal arterial structure also adapts to abnormal levels of pressure and flow. These structural adapations persist, at least in some circumstances, in postnatal life. In fetuses with a single umbilical artery, the entire blood flow

54

Martyn and Greenwald

to the placenta passes through the common iliac artery on one side only. In autopsies of eight children, aged 2 days to 4 years, born with a single umbilical artery, the iliac vessel on the side of the umbilical artery was found to have a lamellar structure rich in elastin, whereas the contralateral artery, which had not been included in the placental circulation, was small in diameter and thin walled (24). A larger study of living children born with a single umbilical artery showed a striking asymmetry in the compliance of the iliac arteries at ages 5 to 9 years (25). As yet, there is no direct evidence that elastin synthesis is impaired in the developing aorta of human fetuses whose growth is retarded. It is known, however, that in such fetuses, Doppler blood flow velocity waveforms are altered in several vascular beds, including the descending aorta. These alterations represent a redistribution of fetal cardiac output that maintains the supply of oxygen and nutrients to the developing brain at the expense of other organs (26,27). At their most extreme, the cardiovascular adaptations made by the growth-retarded fetus result in a reversal of the normal direction of blood flow in the umbilical arteries and in the aorta at the end of diastole (28). It would not be surprising if these hemodynamic changes, which are occurring at a time of rapid vascular development, influenced rates of synthesis of elastin. Indirect evidence comes from the finding in a study of 50-year-old men and women that aortic pulse wave velocity, a measure of the elasticity of the aorta, was related to size at birth (29). People with higher pulse wave velocities, and therefore stiffer aortas, tended to have been smaller babies. The relation persisted after adjustment for current blood pressure, which is consistent with the idea that reduced aortic compliance was a primary event rather than simply a consequence of raised blood pressure. II. Summary One possible explanation of the association of low birth weight with raised blood pressure in adult life is that in fetuses whose growth is retarded, there is impairment in the synthesis of elastin during a critical period of blood vessel development. This impairment may be a consequence of hemodynamic changes in fetal circulation that accompany intrauterine growth retardation although, because expression of the elastin gene is regulated by, among other things, IGF-1 and glucocorticoids, other pathways may be involved. As a result of the relative deficiency in elastin, the compliance of the aorta and large

In Utero Programming of Blood Pressure

55

arteries is reduced. This in turn leads to higher pulse pressures. Over time, the gradual loss of elastin that accompanies aging and its replacement with collagen will tend to amplify the increase in blood pressure and may also predispose to left ventricular hypertrophy and cardiovascular disease. This hypothesis is currently being tested both experimentally in animals and in observational studies in humans. III. Capillary Density and Microvascular Dilation The anatomical correlate of increased vascular resistance in essential hypertension is mainly in microvessels with luminal diameters of less than 100 ìm. In several tissues, capillary density has been found to correlate inversely with blood pressure and peripheral resistance in both hypertensive and normotensive subjects (30). Dermal vessels in men with a familial predisposition to raised blood pressure show impaired microvascular dilation to a heat stimulus and capillary rarefaction (31). A decrease in capillary density may contribute to an increase in vascular resistance, and it has been suggested that defective angiogenesis may be a causal component in the inheritance of raised blood pressure. One does not have to make a large leap to consider the additional possibility that angiogenesis may be impaired in people who experienced intrauterine growth retardation. Empirical evidence on the matter, however, is largely lacking. No associations were found between birth measurements and forearm blood flow, muscle capillary density, or capillary basement membrane thickness in a group of 27 women who were investigated as part of a larger study of the relations between fetal growth, blood pressure, and diabetes in adult life (32). On the other hand, strong relations between microvascular function and both blood pressure and insulin sensitivity have been recently reported in a small study of normotensive glucose-tolerant subjects (33). Eighteen men and women, selected to show a wide range of insulin sensitivity as assessed by the hyperinsulinemic euglycemic clamp technique, had blood pressure measured by 24-hour ambulatory monitoring. Videomicroscopy was used to measure skin capillary density and capillary recruitment after arterial occlusion. Skin blood flow responses after iontophoresis of acetylcholine and sodium nitroprusside were evaluated by laser Doppler fluximetry. A substantial part of the variation in both blood pressure (r2 = 0.38) and insulin sensitivity (r2 = 0.71) could be explained by variation in microvascular function.

56

Martyn and Greenwald

In view of the strong associations between thinness at birth and insulin resistance in adult life, it would be of great interest to carry out a similar investigation in a population who had been measured in detail at birth. IV. Renal Size and Function The kidney, of course, plays a crucial part in the long-term regulation of intravascular fluid volume and pressure (34). It undergoes a period of rapid development in late fetal life, and the complement of nephrons is determined before birth. Nephron number in the human kidney varies from under 300,000 to more than 1,100,000, and there is good evidence both in animal experiments (35) and in observational studies in humans that nephron number is permanently reduced by fetal growth retardation. The idea that nephron endowment at birth influenced risk of developing essential hypertension in later life was first proposed by Brenner more than a decade ago (36,37). He argued that maintenance of raised levels of blood pressure must involve a renal factor favoring sodium retention, thereby preventing a pressure-induced natriuresis from restoring blood pressure toward normal levels. He postulated that this renal factor was a restricted capacity for sodium excretion imposed by a congenital deficit of nephrons. A reduction in renal mass, and therefore in glomerular filtration surface area, tends to produce a rise in blood pressure in the systemic arterial circulation and in the glomerular capillaries. This rise can be viewed as compensatory because it increases the glomerular filtration rate and promotes fluid excretion. However, sustained exposure of nephrons to higher glomerular perfusion pressures gradually causes the development of focal and segmental glomerular sclerosis. This in turn leads to further glomerular loss, a reduction in ability to excrete sodium, and a self-perpetuating cycle of rising blood pressure and progressive glomerular injury. There is already some evidence to link renal function in adult life with fetal growth. In a study of 50-year-old men and women, plasma renin concentrations were related to size at birth (38). In another group of similar age, microalbuminuria was more common in those whose weight or ponderal index at birth had been low (39). Unpublished observations from a recent study of 70-year-old men and women show that plasma creatinine concentrations were higher and creatinine clearance lower in those who had been light at birth. More extensive study of the possible effects of fetal adaptations and renal function would be worthwhile. Meanwhile findings from South Carolina pro-

In Utero Programming of Blood Pressure

57

vide early evidence linking impaired fetal growth with the later development of renal failure.

References

1.

2. 3. 4. 5.

6. 7.

8. 9.

10. 11. 12.

13. 14.

Law CM, Shiell AW. Is blood pressure inversely related to birth weight? The strength of evidence from a systematic review of the literature. J Hypertension 1996; 14:935–941. Martyn CN, Gale CR, Jespersen S, Sheriff SB. Impaired fetal growth and atherosclerosis of carotid and peripheral arteries. Lancet 1998; 352:173–178. Martyn CN, Barker DJP, Osmond C. Mothers pelvic size, fetal growth and death from stroke in men. Lancet 1996; 48:1264–1268. Debelle L, Tamburro AM. Elastin: molecular description and function. Int J Biochem Cell Biol 1999; 31:261–272. Sage H. The evolution of elastin: correlation of functional properties with protein structure and phylogenetic distribution. Comp Biochem Physiol 1983; 74B:373–380. Relf IRN, Lo CS, Myers KA, Wahlqvist ML. Risk factors for changes in aortoiliac arterial compliance in healthy men. Atherosclerosis 1986; 6:105–108. Girerd X, Laurent S, Pannier B, Asmar R, Safar M. Arterial distensibility and left ventricular hypertrophy in patients with sustained essential hypertension. Am Heart J 1991; 122:1210–1214. Lehmann ED. Pulse wave velocity as a marker of vascular disease. Lancet 1996; 348:744. Mitchell GF, Moye LA, Braunwald E, et al. Sphygmomanometrically determined pulse pressure is a powerful independent predictor of recurrent events after myocardial infarction in patients with impaired left ventricular function. Circulation 1997; 96:4254–4260. Davis EC. Elastic lamina growth in the developing mouse aorta. J Histochem Cytochem 1995; 43:1115–1123. Berry CL, Looker T, Germain J. Nucleic acid and scleroprotein content of the developing human aorta. J Pathol 1972; 108:265–274. Bendeck MP, Langille BL. Rapid accumulation of elastin and collagen in the aortas of sheep in the immediate perinatal period. Circulation Res 1991; 69:1165– 1169. Lefevre M, Rucker RB. Aorta elastin turnover in normal and hypercholesterolemic japanese quail. Biochimica et Biophysica Acta 1980; 80:519–529. Powell JT, Vine N, Crossman M. On the accumulation of D-aspartate in elastin and other proteins of the ageing aorta. Atherosclerosis 1992; 97:201–208.

58

Martyn and Greenwald

15. Schapiro SD, Endicott SK, Province MA, Pierce JA, Campbell EJ. Marked longevity of human lung parenchymal elastic fibres deduced from prevalence of D-aspartate and nuclear weapons–related radiocarbon. J Clin Invest 1991; 87:1828–1834. 16. Berry CL, Looker T. An alteration in the chemical structure of the aortic wall induced by a finite period of growth inhibition. J Anat 1973; 114:83–94. 17. Nichols WW, O’Rourke M. Aging, high blood pressure and disease in humans. In: McDonald’s Blood Flow in Arteries. London: Edward Arnold, 1990:398– 420. 18. Folkow B. Structure and function of the arteries in hypertension. Am Heart J 1987; 114:938–947. 19. Leung DYM, Glagov S, Mathews MB. A new in vitro system for studying cell response to mechanical stimulation. Different effects of cyclic stretching and agitation on smooth muscle cell biosynthesis. Experimental Cell Research 1977; 109:285–298. 20. Voors W, Webber LS, Berenson GS. Time course studies of blood pressure in children: the Bogalusa heart study. Am J Epidemiol 1979; 109:320–334. 21. Clarke WR, Schrott H, Leaverton PE, Connor WE, Laver RM. Tracking of blood lipids and blood pressure in school age children: the muscatine study. Circulation 1978; 58:626–634. 22. Labarthe DR, Eissa M, Varas C. Childhood precursors of high blood pressure and elevated cholesterol. Annual Review of Public Health 1991; 12:519–541. 23. Leung DYM, Glagov S, Mathews MB. Elastin and collagen accumulation in rabbit ascending aorta and pulmonary trunk during postnatal growth. Circ Res 1977; 41:316–323. 24. Meyer WW, Lind J. Iliac arteries in children with a single umbilical artery: structure, calcifications, and early atherosclerotic lesions. Arch Dis Child 1974; 49:671–679. 25. Berry CL, Gosling RG, Laogun AA, Bryan E. Anomalous iliac compliance in children with a single umbilical artery. Br Heart J 1978; 40:709–717. 26. Al-Ghazali W, Chita SK, Chapman MG, Allan LD. Evidence of redistribution of cardiac output in asymmetrical growth retardation. Br J Obs Gynae 1989; 96:697–704. 27. Rizzo G, Arduini D. Fetal cardiac function in intrauterine growth retardation. Am J Obstet Gynecol 1991; 165:876–882. 28. Fouron JC, Teyssier G, Shalaby L, Lessard M, van Doesburg NH. Fetal central blood flow alterations in human fetuses with umbilical artery reverse diastolic flow. Am J Perinatol 1993; 10:197–207. 29. Martyn CN, Barker DJP, Jespersen S, Greenwald S, Osmond C, Berry C. Growth in utero, adult blood pressure, and arterial compliance. Br Heart J 1995; 73:116– 121. 30. Prasad A, Dunhill GS, Mortimer PS, MacGregor GA. Capillary rarefaction in the forearm skin in essential hypertension. J Hypertens 1995; 13:265–268.

In Utero Programming of Blood Pressure

59

31. Noon JP, Walker BR, Webb DJ, Shore AC, Holton DW, Edwards HV. Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure. J Clin Invest 1997; 99:1873–1879. 32. Thompson CH, Sanderson AL, Sandeman D, et al. Fetal growth and insulin resistance in adult life: role of skeletal muscle morphology. Clin Sci 1997; 92:291–296. 33. Serne EH, Stehouwer CD, ter Maaten JC, et al. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects. Circulation 1999; 99:896–902. 34. Guyton AC. Blood pressure control—special role of the kidneys and body fluids. Science 1991; 252:1813–1816. 35. Merlet-Bénichou C, Gilbert T, Muffat-Joly M, Lelièvre-Pégorier M, Leroy B. Intrauterine growth retardation leads to a permanent nephron deficit in the rat. Pediatric Nephrology 1999; 8:175–180. 36. Brenner BM, Chertow GM. Congenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis 1994; 23:171– 175. 37. Mackenzie HS, Brenner BM. Fewer nephrons at birth: a missing link in the etiology of essential hypertension? Am J Kidney Dis 1995; 91:98. 38. Martyn CN, Lever AF, Morton JJ. Plasma concentrations of inactive renin in adult life are related to indicators of foetal growth. J Hypertens 1996; 14:881– 886. 39. Yudkin JS, Phillips DIW, Stanner S. Proteinuria and progressive renal disease: birthweight and microalbuminuria. Nephrology, Dialysis and Transplantation 1997; 12:10–13.

4 Low Birth Weight and the Emerging Burden of Renal Disease in the United States

DANIEL T. LACKLAND and BRENT M. EGAN

HOLLY E. BENDALL and CLIVE OSMOND

Medical University of South Carolina Charleston, South Carolina

University of Southampton and Southampton General Hospital Southampton, United Kingdom

The geographic variation in cardiovascular disease risks in the United States has been an enigma for many years. The southeastern region of the United States has been on record for over 6 decades as an area of unusually high death rates from stroke and has been described as the “stroke belt” (1,2). The rates of stroke and cardiovascular disease are particularly high in South Carolina, where stroke incidence and mortality rates are significantly greater than in other areas of the country (Fig. 1) (2,3). Likewise, within a specific geographic area, significant racial differences in risk are observed, with blacks having a twofold stroke risk compared with whites (Fig. 2). However, the geographic variation in disease is not explained by the demographics of the population as the race-sex specific stroke rates remain the highest in South Carolina (3). In addition to the higher overall disease rates in this population, the rates are greater in younger age groups, suggesting an earlier onset of disease in South Carolina compared with other populations (3–8). In fact, the age-specific rates in South Carolina are similar to the rates in the Framingham (4), Rochester (Minnesota) (5), Norway (6), Copenhagen (7), and Minnesota 61

62

Lackland et al.

Figure 1 Age-adjusted stroke mortality rates per 100,000 population and 95% CI for males and females in the United States and South Carolina, 1989– 1991.

Figure 2 Age-adjusted stroke mortality rates per 100,000 population by racesex groups. South Carolina, 1989–1991.

Lows Birth Weight and Renal Disease

63

(8) cohorts 10 years of age older than the South Carolina population (3). Adding to the excess risks puzzle for this population is the recent finding that South Carolina residents who were born in the state have significantly higher rates of stroke than residents who were born out of the Southeast (9). The higher “nativity” stroke risks for South Carolinians are consistent for each of the demographic groups (9). Hypertension is a long-recognized risk factor for stroke, and this relationship is particularly evident in young black males where nearly 50% of the strokes for this group are classified as intracerebral hemorrhage (3,10). Hypertension affects nearly one third of the adult population in South Carolina. As seen in Figure 3, a significant percentage of men and women are hypertensive at early ages, with higher rates among blacks (11). Similar to hypertension, diabetes also affects a significant number of residents in the region, again with higher rates in the black population (12). Although stroke has been the most evident and recognized icon for the southeastern United States, end-stage renal disease (ESRD) is rapidly emerging as another major public health concern for the region. The rates of ESRD, as defined by individuals with renal failure requiring dialysis, are higher for South Carolina compared with the United States, age-race-sex standardized incidence of ESRD in the state being 345 per 1,000,000 compared with an overall rate of 268 per 1,000,000 in the United States (13). Adding to the burden is the incidence of ESRD in South Carolina, which is increasing in dramatic fashion and actually doubled from 1987 to 1996 (13). Similarly high rates and trends are seen in the neighboring states in the southeastern United States (13,14). Typically, ESRD is considered a late complication of chronic diseases, including diabetes and hypertension (15,16). However, in South Carolina 40% of the prevalent cases of ESRD are under 55 years of age (14). Similar to stroke, the disease burden is greater among blacks who have fivefold higher rates of ESRD than the white population even after adjusting for differences in socioeconomic status (15–18). Whereas blacks account for approximately 30% of the South Carolina population, over two thirds (69%) of the ESRD cases are black (Fig. 4) (14). As identified in other populations and areas in the United States, hypertension and diabetes account for 71% of the ESRD cases in South Carolina, with the remainder being attributed to glomerulonephritis, polycystic disease, and other renal disorders (Fig. 5) (14). As previously indicated, hypertension and diabetes are significantly more prevalent among blacks in South Carolina (11,12).

64

Lackland et al.

Figure 3 Prevalance of hypertension among white and black (a) men and (b) women in South Carolina, 1987. Hypertension was defined as blood pressure 140/90 mmHg or greater and/or if the patient was medically treated for high blood pressure.

The reasons for the excess ESRD risks in this population remain unknown. However, events occurring early in life may play a role. One possible assessment could use low birth weight as an index for impaired development in utero. As described in other chapters, individuals with low birth weight have been found to have increased rates of hypertension and non–insulin dependent diabetes (NIDDM) (19–24), although the mechanisms underlying these asso-

Lows Birth Weight and Renal Disease

65

Figure 4 End-stage renal disease cases in South Carolina by race, 1997.

Figure 5 Specific diagnoses for end-stage renal disease cases, South Carolina, 1997.

66

Lackland et al.

Table 1 Low Birth Weight Rates* by Race for South Carolina and United States, 1987

South Carolina United States *

White

Black

Total

6.8% 6.5%

13.5% 13.0%

9.2% 7.5%

Defined as the percent of births less than 2500 g.

ciations remain unclear. As described in the previous chapter, Brenner and colleagues have proposed that chronic renal failure is associated with a reduced number of nephrons in the kidneys of people who had low birth weight (25–28). In humans, 60% of the normal complement of nephrons are laid down during the last trimester and development of kidneys ceases at around week 35 (29). The rate of low birth weight is higher in South Carolina than is the average for the United States, with rates for blacks twice those for whites (Table 1) (30). The increased disease risks, population characteristics, and prevalence of hypertension, diabetes, and low birth weight suggested that events in utero might be linked to ESRD in the high-risk geographic area of the southeastern region of the United States. I.

ESRD in South Carolina

ESRD and birth weight were studied in 1230 young, black and white dialysis patients born in South Carolina after 1950 and still living in the state (31,42). The cases of ESRD were identified from the Southeast Kidney Council dialysis registry and matched to birth certificates in the South Carolina birth registry. The birth registry was also used to select two age, sex, and race-matched controls, of known birth weight, for each case. Birth weights were abstracted from the birth certificates and categorized into five groups: less than 2500 g, 2500 to 2999 g, 3000 to 3499 g, 3500 to 3999 g, and at least 4000 g. The median age of the 1230 cases was 34 years; 70% (858) were black, 73% (892) were male. For 20% (233), the nephrologist’s diagnosis of primary cause of renal failure was diabetes, 29% (359) had hypertension, 46% (571) were recorded as “other,” and for 67 (5%) the primary cause was recorded

Lows Birth Weight and Renal Disease

67

as “unknown.” The mean birth weight, for cases and controls combined, was 3210 g for blacks and 3361 g for whites, and higher in men (3295 g) than in women (3149 g). Table 2 shows odds ratios for renal failure from all causes according to birth weight. The odds ratio for ESRD is highest in the lowest birth weight group (23.5 5.8 5.9 6.6 6.1

(36) (36) (41) (113)

All 6.2 6.5 7.2 6.6

(120) (127) (123) (370)

Numbers of men in parentheses.

As gestational diabetes is associated with high birth weight, a link between high birth weight and the subsequent development of glucose intolerance or diabetes would be expected. Therefore it is of interest that in the Pima Indians, who have a very high incidence of diabetes and among whom gestational diabetes is relatively common, the relationship of birth weight to diabetes was U shaped with highest diabetes prevalence in those with the lowest and highest birth weights (5). This was not observed in the Northern European studies, probably because there were relatively few diabetic pregnancies and their survival 60 or more years ago would have been poor. It is possible that the very few examples of IGT or NIDDM detected in adults in Hertfordshire who had high birth weight were the outcome of pregnancies complicated by hyperglycemia. In this case, the elimination of such pregnancies would greatly strengthen the underlying protective effect of normal fetal growth. II. Fetal Growth and Insulin Resistance NIDDM is the culmination of metabolic abnormalities that have taken several years to develop. Insulin resistance is an early metabolic defect that both precedes and predicts IGT and NIDDM. There is increasing evidence that insulin resistance plays an important role in the link between low birth weight and diabetes. Low birth weight is associated with a higher prevalence of the metabolic syndrome (the coexistence of raised blood pressure, glucose intolerance, and dyslipidemia), which in turn is known to be associated with insulin resistance. In the Hertfordshire study, 56 of the 407 men had the syndrome, defined as a 2 hr plasma glucose concentration of 7.8 mmol/L or more, a systolic blood pressure of 160 mmHg or more, or currently receiving antihypertensive

146

Phillips

Table 4 Prevalence of the Insulin-Resistance Syndrome* in Men Aged 64 Years, According to Birth Weight Birth weight (lb)† ≥5.5 –6.5 –7.5 –8.5 –9.5 >9.5 Total *

Total number of men

Percentage with syndrome X

Odds ratio adjusted for body mass index (95% CI)

20 54 114 123 64 32 407

30 19 17 12 6 6 14

18 (2.6–118) 8.4 (1.5–49) 8.5 (1.5–46) 4.9 (0.9–27) 2.2 (0.3–14) 1.0 p value for trend