Ebook Keelings fetal and neonatal pathology (5th edition) Part 1

T. Yee Khong
Roger D.G. Malcomson
Editors

Keeling’s Fetal and
Neonatal Pathology
Fifth Edition

123


Keeling's Fetal and Neonatal Pathology



T. Yee Khong • Roger D.G. Malcomson
Editors

Keeling's Fetal and Neonatal
Pathology
Fifth Edition


Editors
T.Yee Khong
Department of Pathology
Department of Obstetrics and Gynaecology
University of Adelaide
North Adelaide
South Australia
Australia

Roger D.G. Malcomson
Department of Histopathology
University Hospitals of Leicester NHS Trust
Leicester Royal Infirmary
Leicester
United Kingdom

Department of Histopathology
Women’s & Children’s Hospital
North Adelaide
South Australia
Australia

ISBN 978-3-319-19206-2
ISBN 978-3-319-19207-9
DOI 10.1007/978-3-319-19207-9

(eBook)

Library of Congress Control Number: 2015947612
Springer Cham Heidelberg New York Dordrecht London
© Springer International Publishing 2015
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction
on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation,
computer software, or by similar or dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, 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.

The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed
to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty,
express or implied, with respect to the material contained herein or for any errors or omissions that may have been made.
Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media (www.springer.com)


For my wife Anne, and our sons, Jonathan and Jeremy, for all their love.
TYK
To Karen—for unwavering support (and sustenance), come what may.
To my parents, Vera and Brian—for their confidence in me.
RDGM



Foreword

It is more than 30 years (during a Pathological Society Meeting in Edinburgh) since I
approached Michael Jackson, then Medical Editor at Springer, with the suggestion that a textbook of Fetal and Neonatal Pathology would be a useful addition to their list. He was a little
wary at first, perhaps anticipating much overlap with another title, but, having perused the
aims, objectives, and provisional contents of the proposal, became most enthusiastic. For several years, I had been conscious of the need for such a text, directed towards the general
Histopathologist and trainees. It was not until I felt able to pick up any chapter where I couldn’t
clearly identify an author or where one pulled out (and there were both) that I felt able to
approach a Publisher.
Preparing the first edition was a very steep learning curve for me. The most important lesson from that experience was that should a problem arise, go straight to the Medical Editor!
The help and support I received during the process had underpinned my editorial activities ever
since. Its publication was greeted by a dinner for contributors during the Pathological Society
Meeting in Southampton where the dessert was a Springer-blue, book-shaped cake.
Each new edition has brought changes in chapter, subject, and authorship to accommodate
advances in pathology and changes in clinical practice. The book’s content has, inevitably,

become more detailed over time. This, too, is appropriate as changes in the provision of pathology services has moved increasingly towards specialisation and regionalisation, such that, in
the UK and many other countries, a much higher proportion of fetal and perinatal necropsies
are performed by specialist pathologists to the advantage of both clinicians and parents.
The role of Editor has become easier with computerisation of the process—no more “cut
and paste” (literally) of reference lists, no galley proofs to pore over and much more rapid
communication with contributors. The introduction of inexpensive colour printing has facilitated production of illustrations and improved quality.
The decision to move to joint Editorship for the fourth edition was prompted by growth of
knowledge and increasing specialisation even within perinatal pathology. The choice was not
a difficult one, Yee and I had maintained regular contact since Oxford and our interests were
complementary. I was very happy when he accepted the invitation and his suggestions for both
content and authorship have worked well. It was Yee’s suggestion that it was time for a fifth
edition. It was his decision to retain joint Editorship and I was delighted when Roger
Malcomson accepted the role. With Editors who were former trainees of mine, one in Oxford,
the other in Edinburgh, I was comfortable that “my baby” was in safe hands!
This fifth edition is again appropriately different from what has gone before. I have enjoyed
reading contributions as they have come in—the more for having put the blue pencil to one side.
I am flattered that my name is attached to it. I am grateful for the effort put in by many contributors over the years and for the continued support, effort, and expertise of the staff at Springer.
Edinburgh 2015

Jean W. Keeling

vii



Preface

When Dr. Keeling conceived the first edition of this book more than 30 years ago, she saw a
very real need for a textbook that provided an overview of fetal and perinatal pathology. Her
book concentrated on the common problems, especially where the anatomical pathology findings guided the direction of further investigations. This has not changed. The aim of this newly

updated edition of Dr. Keeling’s book remains to provide general guidance to practicing
pathologists, particularly those who are called upon to regularly provide a perinatal pathology
service.
Both of us count ourselves extremely privileged to have been Dr. Keeling’s last trainees
during her specialist consultant appointments in Oxford and Edinburgh and we feel most honored that she has chosen us to carry on her commission by assuming editorial responsibility for
her book. We welcome several new authors who bring new concepts, ideas and knowledge,
along with their authority on those chapter subjects.
The format of the book remains the same as previous editions with the first half covering
general areas in perinatal pathology. The second half is based on organ systems and covers
specific pathological entities, now including discussion of the relevant molecular pathology.
There are several new chapters. In the 8 years since the publication of the last edition, imaging
techniques have advanced rapidly and are contributing new insights into perinatal disease and
its detection. The genetic and epigenetic basis of disease is much better understood while
improvements in molecular testing have also permitted interrogation of many of the disorders
encountered during the perinatal period. Community expectations have also changed: techniques of the autopsy have to be adapted to meet these expectations and also to meet the practical challenges in undertaking detailed fetal examinations at increasingly earlier gestations. As
a further example, in the medicolegal setting, the forensic pathologist may not see sufficient
fetal and neonatal deaths, while the pediatric/perinatal pathologist may be less well acquainted
with the forensic aspects; communities expect that an expertly conducted necropsy, which may
need to be conducted jointly, will provide answers to very high standards of documentation
and proof. In whatever setting, the pathologist needs to be informed about the most appropriate
and cost-effective investigations before, during, and after a meticulously performed autopsy,
the last directing further testing, including the use of molecular techniques.
We sincerely hope that the reader will find this book as incisive and insightful as Dr. Keeling
always has been. We are also hopeful that this 5th edition of her work will live up to and extend
her professional legacy for the benefit of another generation of pathologists.
North Adelaide, SA, Australia
Leicester, UK

T. Yee Khong
Roger D.G. Malcomson

ix



Acknowledgements

Chapter 2: Dr. Khong wishes to acknowledge Dr. Jean Keeling’s contribution from the previous
edition.
Chapter 5: Owen Arthurs is supported by a National Institute for Health Research (NIHR)
Clinician Scientist Fellowship award, and Neil Sebire by a NIHR Senior Investigator awards.
This article presents independent work funded by the NIHR and supported by the Great
Ormond Street Hospital Biomedical Research Centre. The views expressed are those of the
author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.
Chapter 6: Dr. Flenady wishes to acknowledge Hannah Reinebrant and Susannah Leisher
for systematic reviews of classification systems and causes of death, Beth McClure for advice
on aspects relating to low and middle income countries, and Rohan Lourie for providing the
included stillbirth scenario, and would also like to acknowledge Amber Popattia for support in
compiling this chapter.
Chapter 15: Dr. Charles wishes to acknowledge the contributions of Dr. Iona Jeffrey in the
3rd edition and of Dr. Jean Keeling in the 4th Edition.
Chapter 20: Dr. Khong wishes to acknowledge Dr. Steve Gould’s significant contribution as
the author of this chapter from the 2nd through the 4th editions of this book.
Chapter 21: Dr. Khong wishes to acknowledge the contributions of Drs. Jean Keeling and
Dick Variend to versions of this chapter published in previous editions of this book.
Chapter 25: Drs. Malcomson and Nagy wish to acknowledge the significant contribution
made by Dr. Elisabeth S. Gray, former Consultant Paediatric and Perinatal Pathologist at the
Aberdeen Royal Infirmary, Scotland, UK, as author of earlier versions of this chapter published in previous editions of this book.
Chapter 32: The contribution of Peter R. Millard, the original author of this chapter, is
gratefully acknowledged.

Chapter 34: Drs. Kiho and Malcomson wish to thank Prof. Tony Risdon, Drs. Frances
Hollingbury and Michael Biggs, as well as the relevant HM Coroners and Police Forces for
their co-operation in the reproduction of images in this chapter.
Chapters 8, 10, 17: The contributions of Drs. Patricia Boyd and Jean Keeling (Chapter 8),
Dr. Angela Thomas (Chapter 10), Dr. Andrew Lyon (Chapter 16) and Dr. Jean Keeling (Chapter 17)
in the previous edition are acknowledged.

xi



Contents

1

The Perinatal Postmortem from a Clinician’s Viewpoint . . . . . . . . . . . . . . . . . . . . . 1
Alexander Heazell and Alan Fenton

2

The Perinatal Necropsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
T. Yee Khong

3

Genetic and Epigenetic Basis of Development and Disease . . . . . . . . . . . . . . . . . . 47
Peter A. Kaub and Christopher P. Barnett

4

The Placenta and Umbilical Cord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
T. Yee Khong

5

Perinatal Imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Owen J. Arthurs and Neil James Sebire

6

Epidemiology of Fetal and Neonatal Death . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Vicki Flenady

7

Pathology of Early Pregnancy Loss. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
T. Yee Khong

8

Congenital Abnormalities: Prenatal Diagnosis and Screening . . . . . . . . . . . . . . . 183
Christopher Patrick Barnett

9

The Impact of Infection During Pregnancy on the Mother and Baby . . . . . . . . . 219
C.R. Robert George, Monica M. Lahra, and Heather E. Jeffery

10

Perinatal Hematology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
John Kim Choi and Jeremie Heath Estepp

11

Genetic Metabolic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275
Kaustuv Bhattacharya, Francesca Moore, and John Christodoulou

12

Fetal Hydrops . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Anita Nagy and Roger D.G. Malcomson

13

Pathology of Twinning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Robert W. Bendon

14

Macerated Stillbirth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339
Andrew R. Bamber and Roger D.G. Malcomson

15

Intrapartum Problems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
Adrian K. Charles

16

Prematurity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387
Alison L. Kent

17

Iatrogenic Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 413
Peter G.J. Nikkels
xiii


xiv

Contents

18

Congenital Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
Adrian K. Charles

19

The Cardiovascular System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481
Michael T. Ashworth

20

The Respiratory System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531
T. Yee Khong

21

The Alimentary Tract and Exocrine Pancreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . 561
Liina Kiho

22

Liver and Gallbladder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 595
Rachel Mary Brown

23

The Urinary System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619
Jelena Martinovic

24

The Reproductive System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 653
William Mifsud and Liina Kiho

25

The Endocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
Roger D.G. Malcomson and Anita Nagy

26

The Reticuloendothelial System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 703
T. Yee Khong

27

Brain Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 709
Férechté Encha-Razavi

28

Degenerative and Metabolic Brain Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
Casper Jansen

29

Acquired Diseases of the Nervous System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
Colin Smith and Thomas S. Jacques

30

Skeletal Muscle and Peripheral Nerves. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
Nicholas D. Manton

31

The Skeletal System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 789
Peter G.J. Nikkels

32

The Skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 813
Fraser G. Charlton

33

The Special Senses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 839
T. Yee Khong

34

Forensic Aspects of Perinatal Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
Liina Kiho and Roger D.G. Malcomson

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 875


Contributors

Owen J. Arthurs, PhD, FRCR Department of Radiology, UCL Institute of Child Health,
Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Michael T. Ashworth, MD, FRCPath Department of Histopathology, Great Ormond
Street Hospital for Children, London, UK
Andrew R. Bamber, MB, BChir, MA (Cantab), PgDip UCL Institute of Child Health,
London, UK
Department of Cellular Pathology, University Hospital of Wales, Cardiff, UK
Christopher Patrick Barnett, MBBS, FRACP, FCCMG Paediatric and Reproductive
Genetics Unit, Women’s and Children’s Hospital, North Adelaide, South Australia,
Australia
Robert W. Bendon, MD Department of Pathology, Kosair Children’s Hospital,
Louisville, KY, USA
Kaustuv Bhattacharya, MBBS, MRCP, MRCPCH, MD (research) Genetic Metabolic
Disorders Service, Children’s Hospital at Westmead and University of Sydney,
Westmead, NSW, Australia
Rachel Mary Brown, MBChB Department of Cellular Pathology, Queen Elizabeth

Hospitals Birmingham, Birmingham, UK
Adrian K. Charles, MD (Cantab) Department of Pathology, Sidra Medical and Research
Center & Weill Cornell Medical College in Qatar, Doha, Qatar
Fraser G. Charlton, BMedSci, MBBS, PhD, FRCPath Department of Cellular
Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
John Kim Choi, MD, PhD Department of Pathology, St. Jude Children’s
Research Hospital, Memphis, TN, USA
John Christodoulou, MBBS, PhD, FRACP, FFSc, FRCPA Western Sydney Genetics
Program, Children’s Hospital at Westmead, Westmead, NSW, Australia
Férechté Encha-Razavi, MD Department of Genetics, Necker-Enfants Malades,
Paris, France
Jeremie Heath Estepp, MD Department of Hematology, St. Jude Children’s
Research Hospital, Memphis, TN, USA
Alan Fenton, MD, MRCP Newcastle Neonatal Service, Royal Victoria Infirmary,
Newcastle upon Tyne, UK
Vicki Flenady, PhD, MMedSc (ClinEpid) Mater Research Institute,
University of Queensland, South Brisbane, QLD, Australia

xv


xvi

C.R. Robert George, BA, BSc (Hons), MBBS, PhD Southeastern Area
Laboratory Services, NSW Health Pathology, The Prince of Wales Hospital,
Randwick, NSW, Australia
Alexander Heazell, MBChB (Hons), PhD, MRCOG Maternal and Fetal Health
Research Centre, Institute of Human Development, University of Manchester,
Manchester, UK
St. Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust,

Manchester, UK
Thomas S. Jacques, MA, PhD, MB, BChir, MRCP, FRCPath Developmental Biology
and Cancer Programme and Department of Histopathology, UCL Institute of Child
Health and Great Ormond Street Hospital, London, UK
Casper Jansen, MD, PhD Laboratory for Pathology Eastern Netherlands, Hengelo,
The Netherlands
Heather Jeffery, MBBS, PhD, MPH, FRACP, MRCP(UK),AO International Maternal
and Child Health, Sydney School Public Health, University of Sydney, Royal Prince Alfred
Hospital, Camperdown, NSW, Australia
Peter A. Kaub, BSc (Biotechnology) (Hons), MBBS Genetics and Molecular Pathology,
SA Pathology, Women’s and Children’s Hospital, Royal Adelaide Hospital and University
of Adelaide, Adelaide, SA, Australia
Alison L. Kent, BMBS, FRACP, MD Department of Neonatology, Centenary Hospital
for Women and Children, Canberra Hospital, Woden, ACT, Australia
T. Yee Khong, MBChB, MSc, MD, FRCPath, FRCPA Department of Pathology
and Department of Obstetrics and Gynaecology, University of Adelaide,
North Adelaide, SA, Australia
Department of Histopathology, Women’s & Children’s Hospital, North Adelaide,
SA, Australia
Liina Kiho, MD Department of Histopathology, Great Ormond Street Hospital,
London, UK
Monica M. Lahra, BA, MBBS, PhD, FRCPA Southeastern Area Laboratory Services,
NSW Health Pathology, The Prince of Wales Hospital, Randwick, NSW, Australia
Roger D.G. Malcomson, LRSM, BSc, PhD, MBChB, FRCPath Department
of Histopathology, University Hospitals of Leicester NHS Trust, Leicester
Royal Infirmary, Leicester, UK
Nicholas D. Manton, MBBS, BMedSci, FRCPA Department of Anatomical Pathology,
SA Pathology at the Women’s and Children’s Hospital, Adelaide, SA, Australia
Jelena Martinovic-Bouriel, MD Department of Embryo-Fetal Pathology,
Paris-Sud University Group of Schools of Medicine, AP-HP, Antoine Béclère

Hospital, Paris, France
William Mifsud, MD, PhD Department of Histopathology, Camelia Botnar Laboratories,
Great Ormond Street Hospital for Children, London, UK
Francesca Moore, BSc NSW Biochemical Genetics Service, The Children’s Hospital,
Westmead, Westmead, NSW, Australia

Contributors


Contributors

xvii

Anita Nagy, MS, FRCPath Department of Histopathology, Cambridge University
Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge,
Cambridgeshire, UK
Peter G.J. Nikkels, MD, PhD Department of Pathology, University Hospital Utrecht,
Utrecht, The Netherlands
Neil James Sebire, MBBS, BClinSCi, MD, FRCOG, FRCPath Department
of Histopathology, UCL Institute of Child Health, Great Ormond Street Hospital,
London, UK
Colin Smith, BSc, MBChB, MD, FRCPath Department of Academic
Neuropathology, Centre for Clinical Brain Sciences, University of Edinburgh,
Edinburgh, Midlothian, UK


The Perinatal Postmortem
from a Clinician’s Viewpoint

1

Alexander Heazell and Alan Fenton

Abstract

The perinatal postmortem examination is one investigation offered to parents after they
experience the death of their child. From both the parents’ and clinicians’ perspective, the
postmortem examination aims to determine what was or was not the cause of death and to
identify any relevant associated factors. For parents, appropriate explanation of these findings can facilitate the process of grieving and aid in planning future pregnancies. For professionals, in addition to information for the parents, these data can provide population-level
information about why babies die, which are key components of audit and ensuring safety
of care. Despite these benefits the rate of perinatal postmortem examination is decreasing in
many settings. We review the evidence for perinatal postmortem (and associated) examination in cases of stillbirth and neonatal deaths. We consider the consent process and feedback
of information to parents and how this affects whether parents give consent for a postmortem examination. Finally, we consider what the likely developments in perinatal postmortem examination may be and how these will affect clinicians and parents.
Keywords

Stillbirth • Perinatal death • Neonatal death • Classification systems • Consent process •
Autopsy • Necropsy • Placenta • Genetic examination

Stillbirth and neonatal death represent one of the most significant challenges to the health of newborn infants, with 2.6
million stillbirths and 2.9 million neonatal deaths worldwide each year [1, 2]. The bulk of stillbirths and neonatal
deaths occur in low- and middle-income countries (LMICs),
with only ~2 % of stillbirths occurring in high-income countries (HICs) [1, 3]. Although with different outcomes, stillbirth and neonatal death frequently result from similar

A. Heazell, MBChB(Hons), PhD, MRCOG (*)
Maternal and Fetal Health Research Centre, Institute of Human
Development, University of Manchester, Manchester, UK
St. Mary’s Hospital, Central Manchester University
Hospitals NHS Foundation Trust, Manchester, UK
e-mail:
A. Fenton, MD, MRCP

Newcastle Neonatal Service, Royal Victoria Infirmary,
Newcastle upon Tyne, UK

causes, which themselves also often relate to maternal death
[4]. Therefore, all three outcomes might be prevented by
appropriate intervention. However, effective interventions
to prevent maternal, neonatal, and fetal death are dependent
on an understanding of the causes of death; this may be
gained from multiple sources, but one key element is postmortem examination to identify the cause(s) of death and
associated factors. Due to resources, much of the evidence
regarding perinatal postmortem comes from HICs; this is
not to diminish the value of perinatal postmortem examination in LMIC settings but highlights the need for good-quality international studies.
Due to the relationship between complications in pregnancy and the neonatal period, obstetricians and neonatologists have a close working relationship. Therefore, we
consider most elements of the clinician’s perspective on perinatal postmortem examination jointly, addressing specific
circumstances when appropriate (e.g., where there are legal

© Springer International Publishing 2015
T.Y. Khong, R.D.G. Malcomson (eds.), Keeling’s Fetal and Neonatal Pathology, DOI 10.1007/978-3-319-19207-9_1

1


2

or practical differences between stillbirths and neonatal
deaths). Furthermore, in HICs we consider that perinatal
postmortem examination consent and subsequent review of
results are most effective when they take place within a multidisciplinary team involving obstetricians, neonatologists,
perinatal pathologists, midwives, neonatal nurses, sonographers, clinical geneticists, and others. In this context, the
impact of perinatal postmortem examination extends beyond

its primary role of provision of information for parents but
facilitates perinatal audit and quality assurance leading to
wider understanding of why babies die, which can then
prompt appropriate intervention to reduce the number of
stillbirths and neonatal deaths. Although it cannot be directly
traced back to the information obtained from perinatal postmortem examination, the introduction of robust perinatal
audit is associated with a reduction in perinatal mortality in
a variety of settings [5–9].

Perinatal Postmortem Examination as Part
of the Investigation of Perinatal Death
The term perinatal postmortem examination can be used specifically to mean the examination of the body of the deceased
infant or can be used to incorporate other investigations such as
biochemical, cytogenetic, and microbiological tests and histological examination of the placenta as well as the examination
of the deceased infant. Investigation to determine the cause of
perinatal death may also include biochemical, hematological,
immunological, and microbiological tests of maternal blood
[10]. On the one hand it is important that the process and value
of these individual components are understood, but these individual elements should also be viewed as parts of a comprehensive investigation to determine the cause of stillbirth. There is a
developing consensus that postmortem examination, placental
histology, and cytogenetic examination represent the three
investigations that are most likely to provide information
regarding the cause of stillbirth. Consequently, these are recommended for the investigation of stillbirth by three authorities: the Royal College of Obstetricians and Gynaecologists,
UK (RCOG) [10], the American Congress of Obstetricians and
Gynecologists, USA (ACOG) [11], and the Perinatal Society
of Australia and New Zealand (PSANZ) [12].
For clarity, when reference is made in this chapter to the
perinatal postmortem examination, we mean the examination
of the body of the deceased infant to determine the cause of
and factors associated with the death. This examination may

take different forms, ranging from an external examination to
opening of the body cavities with assessment and sampling of
all organs. We consider histological examination of the placenta and cytogenetic, biochemical, and hematological investigations separately as (in most settings) they have different
requirements for consent and in some cases may be performed
as part of standard clinical care before death.

A. Heazell and A. Fenton

Arrangements for perinatal postmortem will differ
between (and even within) different countries and may differ
between stillbirths and neonatal deaths due to the differences
in legal status of the infant before and after birth. Using
England and Wales as an example, perinatal postmortem
examination requires the consent of the mother, or the father
if the mother is unable to consent (e.g., unconscious). In the
case of neonatal death, a postmortem examination can be
requested by the coroner (medical examiner) against the
wishes of the parents, but this is not the case for stillbirth
when the coroner presently has no jurisdiction. A postmortem examination may be requested by the coroner if the
cause of death is: unknown, very soon after admission to
hospital, following a medical or surgical procedure, or the
result of an accident, suicide, or suspicious circumstances.
Currently, the individual coroner’s approaches as to
whether a coronial postmortem examination is required vary
widely, and the coronial process itself is subject to national
review. The default position for clinicians at present is that if
there is any doubt around a death, a discussion with the coroner or their officers is warranted. However, we would recommend that even when postmortem examination has been
mandated, parental views and wishes should be explored and
documented when appropriate.

Why Should Clinicians Advise Parents
to Have a Perinatal Postmortem?
The identification of a cause for stillbirth has important consequences, particularly for subsequent pregnancies, as women
who have had one stillbirth have a two to tenfold increase in
perinatal mortality compared to those who have had live children [13, 14]; this increased risk is particularly important
where a placental or genetic cause for stillbirth has been identified as these conditions can recur in subsequent pregnancies.
In the context of neonatal death, recurrent placental problems
may occur (e.g., fetal growth restriction, placental abruption),
but infants may die from structural or metabolic disorders that
have a genetic basis and thus a chance of recurrence. This
information may affect parents’ reproductive choices (e.g.,
use of donor sperm from an unaffected male) or to choose
prenatal diagnosis in subsequent pregnancies. Therefore,
after perinatal death families have the right to be given the
information and support to make an informed choice about
investigations, the results of which may affect their understanding of why their baby died. Thus, the information
obtained has both a short-term impact on their process of
grieving and longer-term implications for their reproductive
health. However, there are wide variations between and
within nations in the standard of counseling and availability
of specialist postmortem and placental examination.
Postmortem examination of the baby and histopathologic
examination of the placenta are the two investigations most


1

The Perinatal Postmortem from a Clinician’s Viewpoint

likely to provide an explanation, full or partial, for the stillbirth (see data reviewed later). Therefore, the postmortem

examination should be considered as a mandatory part of the
care offered to bereaved families. It is an opportunity to
address questions concerning the loss of the individual fetus
or baby and to help answer the question of whether the loss
may have been preventable or indeed whether a recurrence is
possible in future pregnancies.
Critically, parents are significantly more likely to regret
not having had a postmortem examination than to regret having one [15, 16]. However, there is huge variation in the frequency with which parents consent and the examination
undertaken. In some maternity units more than 50 % of parents consent to a full or partial examination, as they want to
find out as much as they can about the cause of the loss of
their child. Improvements in care, such as restricting counseling for autopsy to senior clinicians, or specially trained
bereavement staff, involvement of perinatal pathologists, and
education in the value of perinatal autopsy, can increase consent rates to 67.6 % [17].

What Is the Probability of Finding Useful
Information at Perinatal Postmortem?
We have not been able to identify any systematic reviews,
meta-analyses, or randomized controlled trials to assess the
value of perinatal postmortem examination after stillbirth or
neonatal death. We have been able to identify one systematic
review of the utility of placental examination following stillbirth [18]. In reality, the attainment of high-grade evidence to
direct practice in this field is limited by the sensitive nature
of the topic and associated ethical and legal issues. For
example, it is unrealistic to expect a prospective randomized
trial of postmortem versus no postmortem examination.
Therefore, studies tend to report findings of case series that
may be identified prospectively or retrospectively. It is
important to recognize that these studies have a potential
selection bias as parents who know that their baby has a congenital anomaly, or who come from certain ethnic backgrounds, may be more willing to have a postmortem
examination. Published data provide support for the value of

postmortem examination in the context of stillbirth, neonatal
death, and termination of pregnancy for fetal abnormality.

Utility of Postmortem Examination
After Stillbirth
The postmortem examination in stillbirth represents a key
opportunity to obtain detailed information regarding fetal
structural abnormalities and complications leading to stillbirth; indeed, it may be the only opportunity to do so in the
absence of a detailed ultrasound assessment of fetal anatomy.

3

Three case series ranging between 139 and 336 stillbirths
found that autopsy provided new information that changed
the diagnosis in 9–11 % of cases [19–21]. Two smaller studies were more optimistic, suggesting that the diagnosis was
changed in 34 % of cases or identification of a specific condition in 35 out of 37 cases [22, 23]. As well as providing novel
diagnostic information, postmortem examination provided
additional information in 22–76 % of cases [20, 24]; the clinical diagnosis was confirmed by postmortem examination in
48.9–58 % [19, 20]. Where series were restricted to specific
abnormalities, such as nonimmune hydrops, few examinations were inconclusive: 3.9 % and 5.4 % [22, 25]. Unselected
series described inconclusive findings in 26–44.3 %
[26–28].

Utility of Postmortem Examination
After Neonatal Death
Postmortem examination after neonatal death occurs in a different context to that of stillbirth, in that clinicians have the
benefit of their clinical observations and the results of any
investigations that were undertaken prior to death. In this
scenario, postmortem examination can also provide important information regarding the quality of care prior to death
as well as establishing the cause of death. A study of 162

postmortem examinations in a tertiary unit found complete
agreement between the cause of death as determined by clinical diagnoses and that from postmortem examination in
91 % of cases [29]. In the remaining cases, 4.9 % found
causes that, if they had been found prior to death, could have
led to a cure or a longer life. In addition to these major differences, the postmortem examination found additional conditions in 52 % of cases. Importantly, 18 % of cases found
information of audit value including misinterpretation of
investigations (e.g., antenatal ultrasound) and inadequate or
inappropriate treatment, and in 4 % of cases iatrogenic
adverse events were identified including two fractures and
three intravascular thrombi from cannula placement [29].
One analysis of 29 extremely preterm infants (born 28 weeks’
gestation) in postmortem examination confirmed the specific
reason for death in 97 % of cases. However, in 79 % of cases,
new diagnoses were discovered; this information significantly changed the clinical diagnosis in 28 % of cases. In this
population a higher proportion of cases had iatrogenic
lesions (41 %), and in four the iatrogenic lesion was the main
cause of death. This has significant implications for auditing
the quality of neonatal care [30].
Postmortem examination also has value in specific neonatal conditions; in cases of hypoxic ischemic encephalopathy
(HIE), detailed examination of the brain after neonatal death
can be used to define the nature and timing of the insult.
Infants who died from birth asphyxia were more likely to
show neurological damage and all of these infants had some


4

evidence of prenatal brain damage occurring before the onset
of labor [31]. Even in this circumstance, where the causes of
death are felt to be known, 62.5 % of examinations provided

significant new information [32].

Utility of Postmortem Examination After
Termination of Pregnancy for Fetal
Abnormality
Most terminations for fetal abnormality are carried out for
abnormalities that have been identified by ultrasound or
cytogenetics. Despite the presence of a diagnosis that is
deemed by parents to be so severe that they elect to end the
pregnancy, postmortem examination provides useful information in a significant proportion of cases. In a retrospective
study of 132 postmortems where an abnormality was identified by ultrasound scan, 72 % confirmed the suspected diagnosis, and in 27 % the postmortem examination added
information that altered the risk of recurrence [33]. A study
of 151 cases of termination of pregnancy for fetal abnormality prior to 24 weeks’ gestation found that there was complete agreement between scan and postmortem in 86 % of
cases, with 5 % of cases finding additional information.
Critically, in 9.1 % of cases there was disagreement between
the postmortem and some or all of the ultrasound findings
[34]. The concordance between ultrasound and postmortem
findings appears to be affected by the site of the abnormality,
with higher detection of central nervous system and cardiovascular anomalies (91.5 % and 90.2 %, respectively) compared to abdominal and musculoskeletal anomalies (61.5 %
and 66.7 %, respectively) [34]. One smaller study (47 cases)
found agreement in 47 % of cases. In about 28 % of cases, a
postmortem examination provided major additional information, and, in a further 13 % of cases, it provided a definitive
diagnosis [35]. Postmortem examination can also be useful
to differentiate between conditions that have the same ultrasound appearance but different origins and thus risks of
recurrence, for example, infantile polycystic kidney disease
(recurrence rate 25 %) and cystic renal dysplasia (recurrence
rate 3 %) [36].

Utility of Placental Examination After Stillbirth
A systematic review that aimed to address the utility of placental examination in determining the cause of stillbirth

found 41 publications that met the inclusion criteria [18]. Of
these, nine studies examined the contribution of placental
examination to the classification of the cause of stillbirth
[37–45]. The proportion of studies when the placental histopathology was deemed useful ranged from 31.5 % to 84.0 %,
with an average of 59.8 % [18]. This wide variation was in

A. Heazell and A. Fenton

part due to the use of 8 different classification systems (see
later discussion). Despite the wide variation in the estimates
of the utility of placental examination, all of the authors concluded that placental examination was useful. A small retrospective analysis of 71 cases of stillbirth found that
histological examination of the placenta was associated with
a significant reduction in the probability of an “unexplained”
stillbirth (OR 0.17; 95 % CI 0.04–0.70); the additional diagnoses were suggested by fetal growth restriction, placental
insufficiency, constricting loop or knot of umbilical cord,
placental abruption, and chorioamnionitis [39]. Due to the
frequency of placental lesions and the relatively low cost of
placental histological examination compared to postmortem
examination and cytogenetic analysis, histopathologic examination is more cost-effective per piece of new information
obtained than both of the latter two investigations [46].

Utility of Postmortem Examination Is
Dependent on Classification System Used
Many (>30) different classification systems have been
described for perinatal death, some developed specifically for
stillbirth or neonatal death and others for perinatal death as a
whole. The authors are not aware of any system that has been
tested in a robust manner in different cohorts from high- and
low-income settings. Several classification systems in use are
more than 30 years old (e.g., Wigglesworth and Aberdeen)

and lack the variety of diagnoses that modern investigations
can identify. Critically, this means that data are lost as there is
no means to record it. The impact of classification systems
was clearly demonstrated by Vergani et al. who compared 154
stillbirths from a single institution with a universally implemented protocol to determine the cause [47]; in this study,
postmortem examination provided information to aid classification in 24.7 % of cases, placental histology in 77.3 %, chromosomal analysis in 11.7 %, and infection screen in 18.8 %.
Four different classification systems were then used:
Wigglesworth, ReCoDe, de Galan-Roosen, and Tulip. The
application of different classification systems demonstrated
unexplained rates from 14.3 % with ReCoDe, 16.2 % with
Tulip, 18.2 % with de Galan-Roosen, and 45.5 % with the
Wigglesworth classification [47]. Similarly, Ptacek et al.
described the use of 17 different classification systems to
describe placental “causes” or disorders associated with stillbirth [18]. This analysis further demonstrates that sufficient
sensitivity is required to record conditions associated with
stillbirth; the more categories the classification system had to
record placental conditions, the more placental diagnoses
were recorded. However, there was little agreement between
classification systems about “placental causes” of stillbirth.
Placental abruption was the most widely accepted, included
in 77 % of systems as a placental cause of stillbirth, but most


1

The Perinatal Postmortem from a Clinician’s Viewpoint

other diagnoses occurred in less than half of the systems.
Thus, the findings of studies using different classification systems cannot be easily compared. However, the use of a modern classification system is recommended to reduce the
proportion of unexplained stillbirths [48].

Economic Evaluation of Postmortem
Examination
The postmortem examination and investigation of stillbirth
has an economic cost for healthcare providers. To date this
has been determined in three studies. Michalski et al. reported
a cost-consequence analysis of comprehensive stillbirth
assessment in 1,477 cases obtained from the Wisconsin
Stillbirth Service Program (WiSSP). They estimated that
investigations cost approximately USD$1,450 (in 2002
prices) [49]. Gold et al. reviewed patient records of 533 stillbirths between 1996 and 2006 and calculated healthcare cost
including labor, birth, and any fetal testing. The mean hospital cost for a stillbirth was USD$7,495 in 2010 costs (range:
$659–$77,080) [50]. Mistry et al. determined the cost of
stillbirth investigation in the UK according to the RCOG
guideline to be £721 up to £1,283 (in 2010 prices). To assess
the cost-effectiveness of postmortem examination one must
appreciate that it could bring benefit by cost reduction.
Presently, there are no studies that address this with data
acquired directly from patients. However, Mistry et al. modeled care in subsequent pregnancies and found that care for
women with a previous stillbirth with an unknown cause
(£3,751) was more costly than for women with a history of
stillbirth from a nonrecurrent cause (£3,235) or a known
recurrent cause (£3,720) [51]. Therefore, it could be hypothesized that in the case of stillbirth, some of the cost of a postmortem examination might be offset by an altered pattern of
care in a subsequent pregnancy.

Frequency of Perinatal Postmortem
Examination
Despite ongoing evidence demonstrating the clinical usefulness of the perinatal postmortem examination in cases of stillbirth, neonatal death, and termination of pregnancy, the rates of
perinatal postmortem examination have fallen in many parts of
the world. In the UK in 1988, a joint working party of the Royal

College of Obstetricians and Gynaecologists and Royal College
of Pathologists considered a perinatal postmortem examination
rate of less than 75 % as unacceptable [52], although a later
working party felt that such a target was inappropriate [53].
Khong reviewed the rates of perinatal postmortem examination
from the 1960s to 1990s and found overall postmortem examination rates of 53 % of stillbirths and 69.3 % of neonatal deaths

5

[54]; furthermore, this analysis suggests a decline in postmortem examination across this period of study (Table 1.1).
However, more recent estimates suggest a further decline in
both stillbirths and neonatal deaths to levels of about 40–45 %
of cases (Table 1.1). Recently reported postmortem examination rates after stillbirth include: 5.3 % (Nigeria, 2010) [55],
42.4 % (UK, 2008) [56], and 59.6 % (West Indies, 2002–2008)
[57]. For neonatal death, reported rates are 22.6 % (UK, 2008)
[56], 33.9 % (Kansas, USA, 2001–2010) [58], 47.9 % (West
Indies, 2002–2008) [57], and 48–50 % (Ireland, 2004–2009)
[29]. It should be noted that the higher rates are often reported
from interested single units, whereas the lower rates found in
confidential inquiries suggesting lower uptake of perinatal
postmortem examination may more accurately reflect the situation for whole populations.
Due to the wide geographical variation of the reported frequency of postmortem examination, it is unlikely that a single
factor is responsible for this reduction, but it may reflect that
postmortem examinations are becoming less common in
other fields of medicine or that there may also be resource or
service implications such as the availability of a perinatal
pathologist. In some HICs, there has been negative publicity
regarding the retention of infants’ organs after perinatal postmortem examination, which has (at least transiently) had an
impact on the proportion of parents consenting for postmortem examination after stillbirth or neonatal death (Fig. 1.1,
bold arrows). However, the effect of this negative publicity

seems to be transient, and efforts made within units to improve
the consent process can optimize the proportion of parents
consenting for perinatal postmortem examination [17].

Consenting Parents for Postmortem
Examinations
As previously discussed, postmortem examination should be
seen as an integral part of perinatal care where fetal death or
neonatal death has occurred. As a consequence, the consent process should be approached in the same way as any other part of
care—namely, undertaken by appropriately trained personnel
who are knowledgeable about all the issues concerning a postmortem. These include: legal requirements, how to obtain consent, what happens at a postmortem examination, options
available to families (e.g., limiting the postmortem examination
to a single cavity), and local arrangements for the procedure and
returning the body to the parents for burial or cremation.

Practical Considerations
Unless a death is being referred to the coroner/procurator fiscal/medical examiner, all parents whose baby has died
should have a discussion with an appropriate healthcare


A. Heazell and A. Fenton

6
Table 1.1 Rates of postmortem examination after stillbirth and neonatal death
Stillbirth
Author
Fretts et al. 1992,
Obstet Gynecol
Magani et al. 1990,
Paediatr Pathol

Hovatta et al. 1993,
Br J Obs Gynaecol

Location
Montreal, Canada

Years
1961–1988

Rate (%)
97

Galway, Ireland

1972–1982

64

Helsinki, Finland

1974–1979

100

Mutch et al. 1981,
BMJ

Avon, UK

1976–1979

90

Morrison et al.
1985, Am J Obstet
Gynecol
Mueller et al. 1983,
NEJM
Rayburn et al. 1985,
Obstet Gynecol

Manitoba, Canada

1977–1982

80

Seattle, USA

1979–1981

100

Ann Arbor, USA

1979–1983

>90

Golding 1982, In

Fetal and Neonatal
Pathology
Meier et al. 1986,
Obstet Gynecol
Porter et al. 1987,
J Clin Pathol

UK

1980

61

Denver, USA

1981–1983

81

Oxford, UK

1981–1985

~85

Lammer et al. 1989,
JAMA
Rajashekar et al.
1996, Indian J
Paediatr

MacPherson et al.
1991, Textbook of
fetal and perinatal
pathology
Bétrémieux et al.
1993, Pédiatrie
Rushton 1991, Br J
Obstet Gynaecol
Tasdelen et al. 1995,
Turk J Paed
Saller et al. 1995,
JAMA
Pattison et al. 1992,
NZ Med J

Massachusetts, USA

1982

61

Pondicherry, India

1983–1990

5

Pittsburgh, USA

1985

83

Rennes, France

1985–1987

52

West Midlands UK

1986

79

Istanbul, Turkey

1988–1991

94

Rochester, UK

1990–1991

83

Auckland, New
Zealand

1991

64

Cartlidge et al.
1995, BMJ

Wales, UK

1993

58

Thornton et al.
1998, Br J Obstet
Gynaecol

Northern Ireland,
UK

1993

47

Khong et al. 2006,
J Paediatr Child
Health

Adelaide, Australia

2001–2002

71

Neonatal death
Author
Valdes-Dapena et al.
1970, J Pediatrics
Tibrewala et al.
1975, Indian Pediatr
Nézelof et al. 1980,
Arch Fran de
Pédiatrie
Autio-Harmainen
et al. 1983, Acta
Paediatr Scand
Munan L et al. 1975,
Arch Dis Child

Location
Philadelphia, USA

Years
1960–1966

Rate (%)
96

Bombay, India

1961–1972

23

Paris, France

1966–1971

60

Helsinki, Finland

1969–1978

100

Quebec, Canada

1970–1971

58

Banerjee et al. 1975,
Indian Pediatr
Singh et al. 1990,
Annals of Trop
Paediatrics
Scott et al. 1978,
BMJ

Chandigarh, India

1971–1974

62

New Delhi, India

1972–1988

44

Northern Ireland,
UK

1974–1975

<10

Mutch et al. 1981,
BMJ
Maniscalco et al.
1982, Am J Dis
Child
Mueller et al. 1983,
NEJM
Husain et al. 1991,
In Autopsy and
medical research
Golding 1982, In

Fetal and Neonatal
Pathology

Avon, UK

1976–1979

69

Rochester, USA

1978–1980

79

Seattle, USA

1979–1981

100

Maywood, IL, USA

1979–1988

44

UK

1980

54

Wood et al. 1984,
BMJ
Meier et al. 1986,
Obstet Gynecol
Craft et al. 1986, Am
J Dis Child
Porter et al. 1987, J
Clin Pathol
Van Marter et al.
1987, Am J Dis
Child
Rajashekar et al.
1996, Indian J
Paediatr
MacPherson et al.
1991, Textbook of
fetal and perinatal
pathology
Sengeyi et al. 1990,
Journal de Gyn,
Obs, Biol de Réprod

Wessex, UK

1981–1982

77

Denver, USA

1981–1983

81

Durham, NC, USA

1981–1984

63

Oxford, UK

1981–1985

>90

Boston, USA

1982–1984

72

Pondicherry, India

1983–1990

33

Pittsburgh, USA

1985

62

Kinshasa, DRC

1985–1986

3


1

The Perinatal Postmortem from a Clinician’s Viewpoint

7

Table 1.1 (continued)
Stillbirth
Author
Khong et al. 2006,
J Paediatr Child
Health
Bishop et al. 2013,
West Ind Med J
Tan et al. 2010,
Paediatr Dev Pathol

Centre for Maternal
and Child Health
Enquiries, UK, 2010
Kumar et al. 2014, J
Mat Fet Neonatal
Med

Location
Adelaide, Australia

Years
2002–2004

Rate (%)
63

West Indies

2002–2008

60

Malaysia

2004–2009

5

UK

2008

42

New Delhi, India

2009–2013

77

Neonatal death
Author
Bétrémieux et al.
1993, Pédiatrie

Location
Rennes, France

Years
1985–1987

Rate (%)
72

Rushton 1991, Br J
Obstet Gynaecol
Niobey et al. 1990,
Revista de Saude
Publica
Tasdelen et al. 1995,

Turk J Paed

West Midlands, UK

1986

61

Rio de Janeiro,
Brazil

1986–1987

43

Istanbul, Turkey

1988–1991

90

Landers et al. 1994,
J Perinatol

Houston, USA

1990–1991

59

Saller et al. 1995,
JAMA
Pattison et al. 1992,
NZ Med J
Cartlidge et al. 1995,
BMJ
Thornton et al. 1998,
Br J Obstet
Gynaecol
Salamati et al. 2008,
Indian J Pediatr
Khong et al. 2006, J
Paediatr Child
Health
Swinton et al. 2013,
Am J Perinatol
Khong et al. 2006, J
Paediatr Child
Health
Costa et al. 2011, J
Mat Fet Neonatal
Med
Tan et al. 2010,
Paediatr Dev Pathol
Hickey et al. 2012,
Neonatology
Centre for Maternal
and Child Health
Enquiries, UK, 2010

Rochester, UK

1990–1991

64

Auckland, New
Zealand
Wales, UK

1991

38

1993

42

Northern Ireland,
UK

1993

48

Tehran, Iran

1998–2003

21

Adelaide, Australia

2001–2002

31

Kansas, USA

2001–2010

34

Adelaide, Australia

2002–2004

50

Porto, Portugal

2004–2008

48

Malaysia

2004–2009

7

Dublin, Ireland

2004–2009

47

UK

2008

23

Developed from Khong [54] and Gordijn et al. [24]

professional regarding a postmortem examination. The professionals involved in these discussions may vary between
hospitals and whether the baby was stillborn or admitted to
the neonatal unit but often include obstetricians, midwives,
neonatologists, neonatal nurses, or bereavement officers.
Professionals should not make any assumptions about which
parents might or might not consent.
The consent process will inevitably require several conversations with the baby’s parents. Discussions should be
undertaken in a quiet, uninterrupted setting free from distractions.

The reasons for the examination and the potential benefits
should be explained without the use of medical jargon. It is
important to appreciate that even a “negative” postmortem
examination (i.e., where no additional information is
obtained) may be viewed as a positive outcome by many
families, as, for example, it excludes underlying congenital

malformation.
The healthcare professional obtaining consent for postmortem examination must have a full understanding of what
the examination entails, what options are available (e.g.,