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Fetal Growth Edited by F. Sharp, R.B. Fraser and R.D.B. Milner With 71 Figures Springer-Verlag London Berlin Heidelberg New York Paris Tokyo Hong Kong F. Sharp, MD, FRCOG R.B. Fraser, MD, FRCOG, DCH Department of Obstetrics and Gynaecology, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7 AU R.D.G. Milner, MA, ScD (Cantab), MD (Lond), FRCP (Lond) Department of Paediatrics, University of Sheffield, Children's Hospital, Sheffield S 10 2TH ISBN-13: 978-1-4471-1709-4 e-ISBN-13: 978-1-4471-1707-0 DOl: 10.1007/ 978-1-4471-1707-0 British Library Cataloguing in Publication Data Royal'College of Obstetricians and Gynaecologists Study Group (20th: 1988) Fetal growth. I. Man. Foetuses. Development I. Sharp, F. (Frank), 1938- II. Fraser, R.B. (Robert Bruce), 1948- III. Milner, R.D.G., 1937- 612'.647 Library of Congress Cataloging-in-Publication Data Fetal Growth edited by F. Sharp, R.B. Fraser, and R.D.G. Milner p. cm. Includes bibliographies and index. I. Fetus--Growth. 2. Fetus--Growth retardation. 3. Growth disorders. I. Sharp, F. (Frank), 1938- II. Fraser, R.B. (Robert Bruce), 1948- III. Milner, R.D.G. [DNLM: Fetal Development. WQ 210 F4185] RG613. F473 1989 612'.647 dc20. DNLMIDLC for Library of Congress 89-6434 CIP The work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specially those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying, machine or similar means, and storage in data banks. © The Royal College of ObstetriCians and Gynaecologists 1989 Softcover reprint of the hardcover 1st edition 1989 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Typeset and Printed by the Peacock Press Ltd., Ashton-under-Lyne, Lancashire England. 2128/3916-543210 Preface This book is based on the 20th Study Group of the Royal College of Obstetricians and Gynaecologists, which concerned the important topic of fetal growth. Basic scientific, and both obstetric and paediatric aspects of the subject were addressed in contributions from many different disciplines, and we are greatly indebted to all the international experts who took part in this workshop at the RCOG in London in November 1988. The deliberations covered the broad topics of normal fetal growth, fetal over growth and undergrowth. Clinical implications of these entities, especially fetal undergrowth, played a large part in the proceedings as dictated by c.1inical con cerns. Definitions, epidemiology, aetiology and screening were covered, as were technological developments, with special reference to blood flow and volume flow measurements, both fetal and placental. Other aspects of clinical fetal monitoring, including fetal activity measurement, and biophysical evaluation were rationalised and placed in context, and the important newly emerging areas of cordocentesis and therapy in IUGR addressed. Finally, neonatal management of the SGA baby, mortality and long-term morbidity were considered. This volume represents the edited proceedings of an important study group, along with a much-edited transcript of the discussion periods which followed the formal presentations. We are very grateful to all the participants who gave us a valuable three days of their time and also to Sally Barber, Postgraduate Education Secretary, and Diane Morgan, Publications Officer of the RCOG, without whose unstinting input this publication could not have been produced so rapidly. We hope they feel their efforts have been worthwhile. London Frank Sharp March 1989 R.D.G. Milner R.B. Fraser Participants PROFESSOR E.D. ALBERMAN Department of Clinical Epidemiology. The London Hospital Medical College. London E I IBB MR J.M. BRUDENELL 73 Harley S!reet, London WIN I DE PROFESSOR S. CAMPBELL Professor and Head, Department of Obstetrics and Gynaecology. King's College School of Medicine and Dentistry. Denmark Hi II. London SE5 8RX PROFESSOR T. CHARD Professor of Reproductive Physiology. St Bartholomew's Hospital Medical College, West Smithfield, London ECIA 7BE PROFESSOR J.F. CLAPP III Department of Obstetrics and Gynecology. The University of Vermont. College of Medicine. Given Building, Burlington, VT 05405, USA PROFESSOR F. COCKBURN Samson Gemell Professor of Child Health. University Department of Child Health. Royal Hospital for Sick Children, Yorkhill. Glasgow G3 8SJ MR J.O. DRIFE Department of Obstetrics and Gynaecology. Clinical Sciences Building. Leicester Royal Infirmary, P.O. Box 65, Leicester LE2 7LX PROFESSOR S.H. EIK-NES Department of Obstetrics and Gynaecology. Ultrasound Section. University Hospital Clinic, Trondheim N-7006. Norway MR R.B. FRASER Department of Obstetrics and Gynaecology. Clinical Sciences Centre. Northern General Hospital, Sheffield S5 7AU MR M.D.G. GILLMER Consultant Obstetrician and Gynaecologist. Maternity Department. John Radcliffe Hospital, Headington, Oxford OX3 9DU DR M.H. HALL Consultant Obstetrician and Gynaecologist. Aberdeen Maternity Hospital. Cornhill Road. Aberdeen AB9 2ZA DR V.K.M. HAN Department of Paediatrics. Lawson Research Institute. University of Western Ontario. London, Ontario N6A 4V2, Canada PROFESSOR W.W. HAY JR Professor of Pediatrics, Division of Perinatal Medicine. University of Colorado School of Medicine, 4200 East Ninth Avenue, Denver. CO 80262. USA PROFESSOR D.J. HILL Professor of Diabetes Research. Lawson Research Institute, St Joseph's Health Centre, 268 Grosvenor Street, London. Ontario N6A 4V2. Canada PROFESSOR P.W. HOWIE Department of Obstetrics and Gynaecology, University of Dundee Medical School, Ninewells Hospital, Dundee DDI 9SY PROFESSOR M.I. LEVENE Department of Paediatrics and Child Health, Leeds University School of Medicine, Clarendon Wing, The General Infirmary of Leeds, Leeds LS I 3EX PlOFESSOR T. LIND Consultant Obstetrician and Gynaecologist, MRC Human Reproduction Group, t>rincess Mary Maternity Hospital, Great North Road, Newcastle upon Tyne NE23BD DkK.MARSAL Department of Obstetrics and Gynaecology, University of Lund, S-214 0 I Malmo, Sweden PROFESSOR R.D.G. MILNER Department of Paediatrics, University of Sheffield, Children's Hospital, Sheffield SI02TH Mk K. H. NICOLAIDES Harris Birthright Centre for Fetal Medicine, Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, Denmark Hill, London SE5 8RX DR N. PATEL Department of Obstetrics and Gynaecology, Ninewells Hospital, Dundee DD I 9SY PROFESSOR P.-H. PERSSON Erikslustvagen 22, Box 20037, 20074 Malmo, Sweden MR G.D. PINKER President, Royal College of Obstetricians and Gynaecologists, 27 Sussex Place, Regent's Park, London NW I 4RG PROFESSOR D. RUSH Head, Epidemiology Program, Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111, USA PROFESSOR F. SHARP Department of Obstetrics and Gynaecology, Clinical Sciences Centre, Northern General Hospital, Herries Road, Sheffield S5 7 AU DR M.H.L. SNOW MRC Mammalian Development Unit, Wolfson House, University College London, 4 Stephenson Way, London NWI 2HE Mk P.J. STEER Senior Lecturer, Department of Obstetrics and Gynaecology, St Mary's Hospital Medical School, Praed Street, London W2 I PG DR A. STEWART Senior Lecturer in Pennatal Medicine, Departments of Obstetrics and Paediatrics, University College and Middlesex School of Medicine, The Rayne Institute, University College London, University Street, London WClE 6JJ DR M.J. WHITTLE Consultant Obstetrician/Perinatologist, The Queen Mother's Hospital, Yorkhill, Glasgow G3 8SH PROFESSOR J.S. WIGGLESWORTH Professor of Perinatal Pathology, Departments of Histopathology and Paediatrics, Royal Postgraduate Medical School, Du Cane Road, London Wl2 OHS Additional Contributors MR D.L. ECONOMIDES Harris Birthright Research Centre for Fetal Medicine, Department of Obstetrics and Gynaecology, King's College Hospital, London SE5 8RX MRS F.A. FORD Research Dietician, Department of Obstetrics and Gynaecology, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7A U DR R.J.S. HOWELL Departments of Reproductive Physiology, and Obstetrics and Gynaecology, St Bartholomew's Hospital Medical College and the London Hospital Medical College, London ECIA 7BE MR G. THORPE-BEESTON Harris Birthright Research Centre for Fetal Medicine, Department of Obstetrics and Gynaecology, King's College Hospital, London SE5 8RX DR P.G. WHITTAKER Department of Obstetrics and Gynaecology, University of Newcastle, Princess Mary Maternity Hospital, Great North Road, Newcastle upon Tyne NE2 3BD Contents SECTION 1 - NORMAL FETAL GROWTH Effect of genome on size at birth 3 Dr M.H.L. Snow Fetal growth curves 13 Professor P.-H. Persson Discussion 27 Placental control of fetal metabolism 33 Professor W.W. Hay lr. The placenta as an endocrine regulator 53 Professor T. Lind and Dr P.G. Whittaker Discussion 69 SECTION 2 - NORMAL FETAL GROWTH (Continued) Genetic mechanisms of regulation of fetal growth 77 Dr V.K.M. Han Control of cellular multiplication and differentiation 83 Professor D.l. Hill and Dr V.K.M. Han Discussion 99 Maternal diet and fetal substrate provision 101 Mr R.B. Fraser and Mrs F.A. Ford Environmental influences on fetal growth: effects and consequences 115 Dr M.H.L. Snow Discussion 127 SECTION 3 - FETAL OVERGROWTH Fetal growth: an overview 133 Professor F. Cockburn Mechanisms of overgrowth 139 Professor R.D.G. Milner Discussion 149 Obstetric problems of fetal macrosomia 159 Mr J.M. Brudenell Discussion 167 SECTION 4 - FETAL UNDERGROWTH Epidemiology 175 Professor E. D. Alberman Aetiology of fetal undergrowth 185 Professor J.S. Wigglesworth Discussion 197 Effects of changes in maternal energy and protein intake during pregnancy, 203 with special reference to fetal growth Professor D. Rush Discussion 231 Utero-placental blood flow and fetal growth 235 Professor J.F. Clapp III Discussion 245 SECTION 5 - CLINICAL IMPLICATIONS OF FETAL UNDERGROWTH The detection of intrauterine growth retardation 251 Professor S. Campbell Detection of fetal growth retardation by biochemical tests 263 Professor T. Chard and Dr RJ.S. Howell Discussion 273 Technical basis for Doppler blood flow measurement 277 Professor S.H. Eik-Nes Volume flow calculation in the human fetus using pulsed Doppler ultrasound: 287 basic problems Professor S.H. Eik-Nes Fetal and placental blood flow 297 DrK. Marsal Discussion 309 Clinical dating and assessment 319 DrM.H. Hall Discussion 325 SECTION 6 - CLINICAL 1M PLICAT IONS OF FETAL UNDERGROWTH (Continued) Treatment of fetal growth retardation 333 Mr K.H. Nicolaides, Mr D.L. Economides and Mr G. Thorpe-Beeston Fetal activity and biophysical evaluation in IUGR 363 Dr MJ. Whittle Discussion 375 Intrapartum monitoring in IUGR 381 Mr PJ. Steer Discussion 389 Neonatal management of the SGA infant 393 Professor M.I. Levene Fetal growth: mortality and morbidity 403 Dr A. Stewart Discussion 413 CONCLUSIONS 421 SECTION 1 NORMALFETALGRO~H Effect of genome on size at birth Dr M. H. L. Snow INTRODUCTION Size at birth is the outcome of length of gestation and rate of embryo/fetal growth. Among mammals there is a wide range in gestation length although for any partic ular species pregnancy is of characteristic duration. Fetal growth rate also varies and it seems that mammals can be divided into a small number of groups on the basis of their intrauterine growth rate.(I·2) The maintenance of these characteristics is under genetic control although there is an impact of environmental factors such as maternal health, nutrition; hormonal status and the presence of drugs etc. In this consideration of the effect of genome on size at birth these variable environmental influences will not be discussed, although it is clear that their impact on the mater nal/fetal unit varies at least in part because of variations in maternal genotype. The potential effect of the environment on embryonic development is discussed else where in this volume (Section 2). The successful growth and development of the embryo/fetus requires the interac tion between two genomes, those of the embryo and the mother. Two aspects of the genomes will be discussed, sex differences (XX versus XY), and presumptive gene differences resulting from genetic selection for adult body size. A third aspect, aneuploidy and polyploidy will not be considered because such variations in the chromosomal composition of the organism are invariably associated with abnormal development in which growth and size may be compromised as a sec ondary effect. It should be borne in mind that birth weight is a difficult parameter to analyse since gestation length is variable in most species, including man, and it is not always made clear whether adequate allowance is given for this variability. In experimental animals such as the mouse there is the added complication that the observer seldom records birth weight data before it is compromised by food intake by the pups. A better measure is the fetal weight on the day before birth but as this often means sacrificing the mother in order to obtain such fetuses this data is sel dom available in studies which include observation of post-natal development, or which require breeding studies to be done. MATERNAL VERSUS EMBRYONIC GENOTYPE Although XY females are identified in the human population,(3) and in the mouse,(4) where they may be fertile there are no data describing the effect, if any, that this novel maternal genotype may have on fetal development. Our knowledge of maternal-fetal interaction therefore derives only from conventional XX females. The maternal genotype may act on the embryo in two ways. There may be an effect on the development of the oocyte which is subsequently manifested in development of the zygote by virtue of a cytoplasmic interaction with the paternal genome of the fertilising sperm. Two such cytoplasmic effects have been identi fied, hairpin-tail (Thp) and ovum mutant (Om), both in the mouse, and both are
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