Jean W. Keeling (Ed.)

Fetal and Neonatal Pathology

With 587 Figures

Springer-Verlag Berlin Heidelberg GmbH

Jean W. Keeling. MB. BS. FRCPath. Consultant Paediatric Pathologist. John Radcliffe Maternity Hospital. Headington. Oxford OX3 9DU

ISBN 978-1-4471-3525-8 ISBN 978-1-4471-3523-4 (eBook) DOI 10.1007/978-1-4471-3523-4

British Library Cataloguing in Publication Data Fetal and neonatal pathology. 1. Fetus - Diseases I. Keeling. Jean W. 618.3'2 RG626

Library of Congress Cataloging-in-Publication Data Fetal and neonatal pathology. Includes bibliographies and index. 1. Fetus-Diseases. 2. Infants (Newborn)-Diseases. 3. Fetus-Abnormalities. I. Keeling. Jean [DNLM: 1. Fetal Diseases-pathology. 2. Infant. Newborn. Diseases-pathology. WQ 211 F4192] RG 626.F45 1987 618.3'2 87-9476

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Preface

This book is primarily intended for the histopathologist who is called upon to provide a perinatal necropsy service. It will help the junior pathologist to achieve competence in the performance of perinatal necropsies and fetal examination. It does not attempt to provide an exhaustive review of every aspect of fetal pathology but concentrates on common problems. particularly where recognition of morbid anatomical abnormalities indicates the direction of subsequent investigations.

Some years ago. I was advised to consider a move away from paediatric pathology because both birth rate and perinatal mortality were falling and there would be a dramatic reduction in workload and interest. Nothing could have been further from the truth. The downward trend in birth rate has reversed. and. although in Europe. Australia and North America perinatal mortality has continued to fall. the effect has been to direct more attention to those deaths which still occur. Neonatal Paediatrics has emerged as a field for specialisation. The availability of non-invasive techniques for fetal assessment and the rapid expansion of prenatal diagnosis of malformations and inherited disorders have increased the demand for detailed pathologial examination of the deceased fetus and infant. Obstetricians and neonatalogists have become increasingly aware that infor­mation obtained from post-mortem examination can make a useful contribution to clini­cal management. It has an important audit function and provides the most reliable basis for parental counselling about future pregnancies.

The histopathologist is almost the last generalist in hospital practice. The development of specialised areas of interest and expertise within the major medical specialties has made heavy demands on pathology departments. It is difficult to keep abreast of new methodology and changing views about the interpretation of pathological findings in every specialist field. As most births take place away from teaching centres. in hospitals where pathologists with particular interests in perinatal pathology are unlikely to be based. it is the general histopathologist. often with no specific training in this field. who is expected to investigate the majority of fetal and perinatal deaths.

Provision of satisfactory answers for clinicians depends as much on an understanding of their day-to-day problems. so that answers may be provided to fundamental questions which may have gone unasked. as it does on answering questions related to the specific case in hand. The first part of this book (Chapters 1-15) aims to provide essential clinical and physiological information related to currently important problems in fetal and neonatal pathology as well as a guide to their investigation. Chapter 1 discusses the relevance of post-mortem examination to obstetric and neonatal practice and the need to resist preoccupation with a cause of death as the only reason for necropsy. Details of necropsy techique appropriate to the fetal and neonatal periods are described and the

viii Preface

necessity for modifications in technique discussed. Chapter 2 describes the normal pro­gression of implantation of the ovum and placentation in the human, together with methods of placental examination and normal findings as well as its appearance in abnor­mal pregnancies and specific pathological states.

The following four chapters discuss particular aspects of fetal pathology in the first and second trimesters of pregnancy. Chapter 3 addresses the pathology and pathogenesis of spontaneous abortions. Chapter 4 examines some of the problems related to exam­ination of the fetus from terminated pregnancies. This is a new and important area of morbid anatomy, and fetal examination is particularly valuable following ultrasound diagnosis of fetal anomaly. Chapters 5 and 6 examine the pathologist's contribution to the investigation of malformations and inherited metabolic disease.

The remainder of this problem-orientated section relates largely to the second half of pregnancy, beginning with epidemiological analyses and related problems. The topics covered in subsequent chapters are those where clinical information is particularly relevant to the appropriate direction of pathological investigations.

The second part of the book (Chapters 16-28) is system orientated and describes and illustrates those pathological abnormalities which are likely to be encountered in the fetus and neonate. Each chapter is prefaced by a concise account of the development of the particular system and, where relevant, a description of the changes which occur at birth or an account of normal function in the neonatal period. Cross-referencing between sections by chapter and page number provides ready access to relevant pathologi­cal detail or related conditions.

Acknowledgements

It is a pleasure to acknowledge the generosity of colleagues in Britain and Europe who have made available photographs and material for illustrations or have read chapters during their preparation. I am particularly grateful to Drs. Ashley King, Simon Knowles and Helen Porter who read my own contributions. Miss Sheila Moore patiently prepared sections for illustrations and Geoffrey Richardson and Julian Markham produced illustra­tions for several chapters.

Mr. Michael Jackson and Mrs. Judy Watt of Springer-Verlag have generously given help, advice and encouragement throughout the preparation of this book.

Particular thanks are owed to Miss Shirley Martin, who has cheerfully typed and kept track of the manuscripts throughout.

Oxford, 1 9 8 7 Jean W. Keeling

Contents

Chapter 1 The Perinatal Necropsy Jean W. Keeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Introduction .......................................................... 1 Importance of Negative Findings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Adequate Clinical Information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Place of Structured Request Forms in Perinatal Pathology . . . . . . . . . . . . . . . . . . . . . 3 Growth and Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Equipment for Perinatal Necropsy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 Post-mortem Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 Examination of the Embryo and Fetus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 Examination of the Placenta ............................................. 27 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

Chapter 2 Placenta and Umbilical Cord Patricia A. Boyd. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Introduction .......................................................... 45 Development of the Placenta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Mature Delivered Placenta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Circulation in the Placenta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Abnormalities of Placentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Placenta in Multiple Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 Placenta in Genetic and Congenital Abnormalities of the Fetus ..... . . . . . . . . . . . . 57 Umbilical Cord and Placental Membranes .................................. 57 Placenta in Maternal Disorders ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Intrauterine Growth Retardation ......................................... 62 Macroscopic Abnormalities Within the Placenta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Placenta Following Intrauterine Fetal Death ....... . . . . . . . . . . . . . . . . . . . . . . . . . 66 Placental Oedema . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66 Placental Infection ..................................................... 67

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Chapter 3 Spontaneous Abortion and the Pathology of Early Pregnancy S. Knowles ............................................................ 77

Introduction .......................................................... 77 Frequency of Spontaneous Abortion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 Causes of Spontaneous Abortion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 Maternal Disease-General ................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Maternal Disease-Gynaecological. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Drugs-Social . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Drugs-Therapeutic. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Immunological Rejection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Environmental Hazards to Early Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Other Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Pathological Classification of Spontaneous Abortion. . . . . . . . . . . . . . . . . . . . . . . . . . 81 Mechanisms of Spontaneous Abortion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Pathological Examination of Abortion Material . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Examination of Placental Tissue .......................................... 84 Changes Following Fetal Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Causes of Fetal Death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Repeated Spontaneous Abortion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 Criminal Abortion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Disorders of Twinning. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 7 Ectopic Gestation .......... '. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 Gestational Trophoblastic Neoplasia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93

Chapter 4 Examination ofthe Fetus Following Prenatal Suspicion of Congenital Abnormality Jean W. Keeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

Introduction .......................................................... 99 Review of Prenatal Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 Complications of Methods of Antenatal Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . .. 101 Information for the Pathologist . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 102 Examination of Fetus and Placenta. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 102 Artefactual Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 104 Specific Fetal Anomalies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 106 Fetal Abnormalities and Elevated Alpha-fetoprotein Levels in Amniotic Fluid or Maternal Serum ....................................................... 114 Chromosome Anomalies ................................................ 116 Amnion Rupture Sequence .............................................. 117

Chapter 5 Congenital Abnormalities and the Pathologist Mary J. Seller and M. Bobrow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 123

Introduction .......................................................... 123 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 123 ClinicaUmportance of Accurate Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 124 Factors Involved in Genesis of Congenital Abnormalities ...................... 127 Aetiology of Congenital Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 129 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 133

Contents xi

Chapter 6 Genetic Metabolic Disease G. A. Machin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 135

Introduction .......................................................... 135 PrenatalDiagno~s ..................................................... 136 Pathogenesis and Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 139 Clinical Presentation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 141 Screening. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 146 Necropsy and Biopsy Investigation .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 147 Reference Laboratories forInvestigation of Metabolic Disorders. . . . . . . . . . . . . . . .. 147

Chapter 7 Epidemiology of Fetal and Neonatal Death Jean Golding .............................................. . . . . . . . . . . . .. 151

Introduction .......................................................... 151 Accuracy of Perinatal Death Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 151 Epidemiological Analyses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 153 Studies of Perinatal Mortality. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 153 Causes of Perinatal Death. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 158 Avoidability ofDeath ................................................... 162 Discussion 163

Chapter 8 Macerated Stillbirth Jean W. Keeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 167

Introduction .......................................................... 167 Changes of Maceration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 167 Problems and Limitations of Examination .................................. 169 Histological Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 169 Examination of the Placenta ............................................. 169 Microbiological Studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 172 Chromosome Culture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 1 72 Radiographic Examination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 173 Pathological Abnormalities in Macerated Stillbirth. . . . . . . . . . . . . . . . . . . . . . . . . .. 173 Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 177

Chapter 9 Prematurity Gillian Batcup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 179

Introduction and Definitions ............................................. 179 Predisposing Factors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 180 Pathology of the Preterm Infant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 184 Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 197

Chapter 10 Intrapartum Asphyxia and Birth Trauma Jean W. Keeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 199

Introduction .......................................................... 199 Fetal Response to Asphyxia ............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 199 Fetal Response to Labour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 200 Incidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201 Placental Factors During Labour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 201

xii Contents

Maternal Factors in Labour 201 Fetal Factors in Labour. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 202 Intrapartum Asphyxial Insult .......................... . . . . . . . . . . . . . . . . .. 203 Traumatic Birth Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 205

Chapter 11 Fetal Hydrops Jean W. Keeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 211

Introduction .......................................................... 211 Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 212 Causes of Fetal Hydrops ................................................. 212 Investigation of Fetal Hydrops. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 225

Chapter 12 Congenital Tumours P. J. Berry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 229

Introduction .......................................................... 229 Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 230 Aetiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 230 Investigation of Congenital Tumours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 232 Teratomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 233 Congenital Neuroblastoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 23 5 Renal Tumours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 237 Liver Tumours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 240 Congenital Mesenchymal Tumours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 241 Congenital Leukaemia .................................................. 243 Tumours of the Central Nervous System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 244 Maternal Malignant Disease in Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 245

Chapter 13 Immunology Helen M. Chapel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 249

Normal Mechanisms .................................................... 249 Pathology ............................................................ 255

Chapter 14 Infection in Pregnancy and the Neonatal Period Helen Holzel ................................................ . . . . . . . . . .. 265

Adverse Effects ofInfection During Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 265 Introduction .......................................................... 265 Viral Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 265 Parasitic Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 271 Bacterial Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2 72 Infection in the Neonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 274 Introduction .......................................................... 274 CongenitalInfection: Toxoplasma, Rubella, CMV and HSV .................... 274 Bacterial Infection in the Neonate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 279

Contents xiii

Acute Neonatal Viral Infection 284 Other Infection ........................................................ 286 Investigation ofInfection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 286

Chapter 1 5 Iatrogenic Disease Jean W. Keeling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295

Introduction .......................................................... 295 Maternal Medication During Pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295 Prenatal Diagnosis ..................................................... 296 Intrapartum Monitoring. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 298 Breech Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 298 Neonatal Intensive Care. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 299 Medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 306 Nutritional Rickets. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 309 Necrotising Enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 310

Chapter 16 The Gastrointestinal Tract and Exocrine Pancreas S. Variend . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 315

Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 31 5 Oral Cavity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 316 Oesophagus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 317 Stomach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 31 7 Small Intestine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 318 Colon and Rectum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 326 Anorectal Malformations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 329 Abdominal Wall Defects and Hernias ...................................... 329 Exocrine Pancreas. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 333

Chapter 17 Liver and Gall Bladder D. 1. Rushton. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 339

Embryology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 339 Physiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 339 Classification of Fetal and Neonatal Liver Disease ............................ 341 Cholestasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 342 Neonatal Giant Cell Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 343 Conjugated Hyperbilirubinaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 343 Extrahepatic Biliary Atresia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 344 Paucity of the Intrahepatic Bile Ducts. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 345 Infectious Causes of Conjugated Hyperbilirubinaemia . . . . . . . . . . . . . . . . . . . . . . . .. 346 Non-viral Infections .................................................... 348 Metabolic Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 350 Cirrhosis. Fibrosis and Cystic Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 352 Trauma and Iatrogenic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 353 Circulatory Disorders ................................................... 355 Liver Disease in Babies of Diabetic Mothers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 356 Malformations of the Liver . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 357 Tumours ............................................................. 357 Gall Bladder and Extrahepatic Bile Ducts (Excluding EHBA) . . . . . . . . . . . . . . . . . . .. 359

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Chapter 18 The Respiratory System Gillian S. Gau .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 363

Introduction .......................................................... 363 Normal Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 364 Developmental Anomalies of the Upper Respiratory Tract ..................... 365 Developmental Anomalies of the Lower Respiratory Tract. . . . . . . . . . . . . . . . . . . .. 367 Effects of Birth Asphyxia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 371 Pulmonary Pathology Associated with Immaturity. . . . . . . . . . . . . . . . . . . . . . . . . .. 372

Chapter 19 The Cardiovascular System J. N. Cox and J. Briner. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 381

Introduction .......................................................... 381 Development ofthe Heart. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 381 Changes in the Circulation at Birth. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 384 Examination of the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 385 Congenital Heart Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 386 Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 394 Endocardial Fibroelastosis ............................................... 395 Myocardial Necrosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 395 Tumours ............................................................. 397 Conduction System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 399 Pericardium. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 399 Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 400 Aorta and Peripheral Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 401 Lymphatics ........................................................... 402

Chapter 20 The Urogenital System R. Anthony Risdon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 407

Kidneys and Urinary Tract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 407 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 407 Malformations of the Kidney ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 409 Tumours of the Kidney in the Neonate ..................................... 417 Hereditary Abnormalities of Renal Tubular Transport ........................ 418 Renal Hypoperfusion ................................................... 418 Congenital Nephrotic Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 418 Renal Infection .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 421 Renal Glomerular Lesions in Cyanotic Congenital Heart Disease . . . . . . . . . . . . . . .. 421 Congenital Abnormalities ofthe Renal Pelvis and Ureter ...................... 422 Congenital Abnormalities ofthe Bladder. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 422 Congenital Abnormalities of the Urethra ................................... 423 Reproductive Organs ................................................... 424 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 424 Congenital Anomalies of the Male Genital Tract ............................. 427 Congenital Anomalies of the Female Genital Tract ........................... 427

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Chapter 21 The Endocrine System Elizabeth S. Gray ....................................................... 429

Introduction .......................................................... 429 Pituitary/Hypothalamic Axis ............................................. 429 Adrenal Glands ........................................................ 432 Thyroid Gland. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 440 Parathyroid Glands. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 442 Endocrine Pancreas .................................................... 444

Chapter 22 The Reticuloendothelial System and Blood C.1. Berry ............................................................ 453

Components ofthe Immune Response. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 453 Morphological Development ............................................. 453 Cellular Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 454 Functional Aspects of Cellular Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 455 Abnormalities of the Immunoreactive Cells and Tissues. . . . . . . . . . . . . . . . . . . . . .. 456 Thymus .............................................................. 457 Spleen ................................................................ 458 Lymph Nodes .......................................................... 459 Rhesus Isoimmunisation ................................................ 459 Anaemia in Infancy .................................................... 460

Chapter 23 Hydrocephalus and Malformations ofthe Central Nervous System K. M. Laurence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 463

Development of the Central Nervous System ................................ 463 Hydrocephalus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 465 Introduction .......................................................... 465 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 466 Types of Hydrocephalus ................................................. 466 Malformations Leading to Hydrocephalus .................................. 468 Inflammation Causing Hydrocephalus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 472 Tumours Leading to Hydrocephalus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 473 Neural Tube Defects .................................................... 473 Introduction .......................................................... 473 Anencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 474 Cranial Meningocele and Encephalocele .................................... 476 Myelocele (Myelomeningocele) ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 477 Meningocele .......................................................... 479 Spina Bifida Occult a .................................................... 479 Other Malformations of the Spinal Cord .................................... 480 Other Disorders with NTD as a Constant or Common Component . . . . . . . . . . . . . .. 480 Arhinencephaly ....................................................... 482 Hydranencephaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 484 Agenesis of the Corpus Callosum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 485 Cerebellar Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 486 Microcephaly. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 486 Megalencephaly ....................................................... 487 Micropolygyria .............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 487 Porencephaly .......................................................... 488 Pachygyria. Lissencephaly and Agyria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 488

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Chapter 24 Acquired Disorders ofthe Central Nervous System R. N. Laurini . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 491

Introduction .......................................................... 491 Mechanical Birth Trauma ............................................... 491 Haemorrhage ......................................................... 492 Hypoxic and Ischaemic Cerebral Injury .................................... 499 Intrauterine Brain Damage .............................................. 502 Vascular Abnormalities ....... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 503 Kernicterus ........................................................... 503 Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 504 Infection. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 504

Chapter 25 Skeletal Muscle and Peripheral Nerves Margaret M. Esiri . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 509

Development of Skeletal Muscle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 509 Development of Muscle Innervation .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 510 Generalised Abnormalities of Muscle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 510 Arthrogryposis or Arthrogryposis Multiplex Congenita. . . . . . . . . . . . . . . . . . . . . . .. 51 0 Investigation of Neuromuscular Disease in Infants ............... . . . . . . . . . . .. 511 Classification of Neonatal Neuromuscular Disease. . . . . . . . . . . . . . . . . . . . . . . . . . .. 511

Chapter 26 The Skeletal System H. J. van der Harten ..................................................... 529

Introduction .......................................................... 529 Normal Development of the Skeleton ...................................... 529 Osteochondrodysplasias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 530 Other Generalised Skeletal Abnormalities Associated with Perinatal Death ....... 539 Other Skeletal Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 541 Fractures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 542 Osteomyelitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 542

Chapter 27 - The Skin Beryl Crossley. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 545

Development of the Skin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 545 Disorders of Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 546 Dermal Developmental Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 549 Developmental Abnormalities of Pigment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 550 Common Neonatal Skin Conditions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 550 Birthmarks. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 5 52 Congenital Infections with Skin Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 556 Congenital Genetically Determined Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 558 Congenital Blistering Disorders-Epidermolysis Bullosa . . . . . . . . . . . . . . . . . . . . . .. 561 Skin Infiltrations and Tumour-like Lesions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 564

Contents xvii

Chapter 28 Special Senses Beryl Crossley. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 567

The Eye .............................................................. 567 Development. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 567 Developmental Abnormalities of the Eye. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 569 Developmental Abnormalities Associated with Specific Chromosomal Defects . . . .. 571 Infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 572 Cataract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 574 Retinal Disorders of Infancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 575 The Ear ............................................................... 577 Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 577 Developmental Abnormalities of the Ear. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 578 Ears of the Stillborn. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 578 Congenital Rubella Infection and Hearing Loss ............ . . . . . . . . . . . . . . . . .. 579

Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 581

Contributors

Gillian Batcup. MB. BSc. MRCPath. Consultant Paediatric/Perinatal Pathologist. Pathology Department. D. Floor. Clarendon Wing. General Infirmary. Belmont Grove. Leeds LS2 9NS

C. L. Berry. MD. PhD. FRCPath. Professor of Morbid Anatomy. The London Hospital Medical College. The London Hospital, London El IBB

P. Jeremy Berry. BA. MBBChir. MRCP. MRCPath. Consultant Paediatric Pathologist. Bristol Royal Hospital for Sick Children. St. Michael's Hill. Bristol BS2 8BJ and Bristol Maternity Hospital, Southwell Street. Bristol BS2 8EG

Martin Bobrow. DSc. MB. BCh. FRCP. MRCPath. Prince Philip Professor of Paediatric Research. Paediatric Research Unit. The Prince Philip Research Laboratories. Guy's Tower. London Bridge. London SEI 9RT

Patricia A. Boyd. MBBS. MD. Department of Medical Genetics. Churchill Hospital, Headington. Oxford OX3 7LJ

Jakob Briner. MD. Professor. Head of Paediatric Pathology Section. Institut fUr Pathologie der Universitat Zurich. Schmelzbergstrasse 12. CH 8091 Zurich. Switzerland

Helen M. Chapel. MD. MA. MB. BChir. MRCPath. Regional Consultant Immunopathologist. John Radcliffe Hospital, Headington. Oxford OX39DU

Jerry N. Cox. BSc. MD. FRCPath. Paediatric Pathologist. Institute of Pathology. CMU. 1 rue Michel-Servet. 1211 Geneva 4. Switzerland

Beryl Crossley. MA. BMBCh. MRCPath. Consultant and Senior Lecturer in Histopathology. Bristol Royal Infirmary. Marlborough Street. Bristol BS2 8HW

xx Contributors

Margaret M. Esiri, BA, DM, MRCPath, Hon. Consultant Pathologist and Senior MRC Fellow, Department of Neuropathology, Radcliffe Infirmary, Oxford OX2 6HE

Gillian S. Gau, MD, Consultant Histopathologist and Han. Senior Lecturer, Queen Charlotte's Maternity Hospital, Goldhawk Road, London W6 OXG

Jean Golding, MA, PhD, Wellcome Trust Senior Lecturer, Department of Child Health, University of Bristol, Royal Hospital for Sick Children, st. Michael's Hill, Bristol BS2 8BJ

Elizabeth S. Gray, MB, ChB, MRCPath, Senior Lecturer in Pathology, University Medical School, Foresterhill, Aberdeen AB9 2ZD

Helen Holzel, MSc, MB, MRCPath, Consultant Microbiologist, The Hospital for Sick Children, Great Ormond Street, London WCIN 3JH

Jean W. Keeling, MBBS, FRCPath, Consultant Paediatric Pathologist, John Radcliffe Maternity Hospital, Headington, Oxford OX39DU

Simon Knowles, BSc, MBBS, MRCPath, Staff Histopathologist, Department of Pathology, Queen Victoria Hospital, 160 Fullarton Road, Rose Park, Adelaide, South Australia 5067, Australia

K. M. Laurence, MA(Cantab), MBChB(Liverpool), DSc(Wales), FRCP(Edinburgh), FRCPath, Professor of Paediatric Research, University of Wales College of Medicine, Han, Consultant Paediatric Pathologist and Clinical Geneticist, University Hospital of Waies, Cardiff CF 4 4XN

R. N. Laurini, MD, Head of the Division of Paediatric Pathology, Institute of Pathology, CHUV, CH-l 0 11 Lausanne, Switzerland

G. A. Machin, BA, PhD, BM, FRCP(C), Pediatric Pathologist, Department of Laboratory Medicine, Victoria General Hospital, 35 Helmcken Road, Victoria, BC V8Z 6R5, Canada

R. Anthony Risdon, MD, FRCPath, Professor in Histopathology, The Hospital for Sick Children, Great Ormond Street, London WCIN 3JH

D. Ian Rushton, MB, ChB, FRCPath, Senior Lecturer in Pathology, University of Birmingham, Hon. Consultant Pathologist, Birmingham Maternity Hospital, Queen Elizabeth Medical Centre, Edgbaston, Birmingham B15 2TG

Mary J. Seller, BSc, PhD, Reader in Developmental Genetics, Paediatric Research Unit, The Prince Philip Research

Contributors

Laboratories, Guy's Tower, London Bridge, London SE1 9RT Hans J. van der Harten, MD, Paediatric Pathologist, Pathologisch Instituut, Academisch Zickenhuis, Vrije Universiteit, de Boelelaan 1118, Amsterdam, The Netherlands

S. Variend, MD, MRCP, MRCPath, DCH, Consultant Pathologist, Children's Hospital, Western Bank, Sheffield S10 2TH

xxi