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

(BQ) Part 1 book Keelings fetal and neonatal pathology presentation of content: The perinatal postmortem from a clinician’s viewpoint, the perinatal necropsy, genetic and epigenetic basis of development and disease, the placenta and umbilical cord, perinatal imaging, epidemiology of fetal and neonatal death,...and other contents.

Keeling’s Fetal and Neonatal Pathology

T Yee Khong Roger D.G Malcomson

Editors

Fifth Edition

Keeling's Fetal and Neonatal Pathology

T Yee Khong • Roger D G Malcomson

Editors

Keeling's Fetal and Neonatal Pathology

Fifth Edition

Leicester United Kingdom

ISBN 978-3-319-19206-2 ISBN 978-3-319-19207-9 (eBook)

DOI 10.1007/978-3-319-19207-9

Library of Congress Control Number: 2015947612

Springer Cham Heidelberg New York Dordrecht London

© Springer International Publishing 2015

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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 confi dence in me.

RDGM

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 text-book of Fetal and Neonatal Pathology would be a useful addition to their list He was a little wary at fi rst, perhaps anticipating much overlap with another title, but, having perused the aims, objectives, and provisional contents of the proposal, became most enthusiastic For sev-eral 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 fi rst edition was a very steep learning curve for me The most important son 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 pathol-ogy 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 facili-tated 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 diffi cult 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 fi fth 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 fi fth 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 fl attered that my name is attached to it I am grateful for the effort put in by many tors over the years and for the continued support, effort, and expertise of the staff at Springer

When Dr Keeling conceived the fi rst 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 fi nd-ings 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 hon-ored 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 fi rst half covering general areas in perinatal pathology The second half is based on organ systems and covers specifi c 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: tech-niques of the autopsy have to be adapted to meet these expectations and also to meet the practi-cal challenges in undertaking detailed fetal examinations at increasingly earlier gestations As

a further example, in the medicolegal setting, the forensic pathologist may not see suffi cient 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 fi nd 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 benefi t of another generation of pathologists

North Adelaide , SA , Australia T Yee Khong Leicester , UK Roger D G Malcomson

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 signifi cant 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 signifi cant contribution made by Dr Elisabeth S Gray, former Consultant Paediatric and Perinatal Pathologist at the Aberdeen Royal Infi rmary, Scotland, UK, as author of earlier versions of this chapter pub-lished 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

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

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

29 Acquired Diseases of the Nervous System 743

Colin Smith and Thomas S Jacques

30 Skeletal Muscle and Peripheral Nerves 767

34 Forensic Aspects of Perinatal Pathology 863

Liina Kiho and Roger D G Malcomson

Index 875

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 Infi rmary , 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 Infi rmary ,

Newcastle upon Tyne , UK

Vicki Flenady , PhD, MMedSc (ClinEpid) Mater Research Institute ,

University of Queensland , South Brisbane , QLD , Australia

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 Infi rmary , 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

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

© 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

from a Clinician’s Viewpoint

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 fi nd-ings can facilitate the process of grieving and aid in planning future pregnancies For pro-fessionals, 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 benefi ts the rate of perinatal postmortem examination is decreasing in many settings We review the evidence for perinatal postmortem (and associated) examina-tion 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 tem examination Finally, we consider what the likely developments in perinatal postmor-tem examination may be and how these will affect clinicians and parents

Keywords

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

Stillbirth and neonatal death represent one of the most

sig-nifi cant challenges to the health of newborn infants, with 2.6

million stillbirths and 2.9 million neonatal deaths

world-wide 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

coun-tries (HICs) [ 1 3 ] Although with different outcomes,

still-birth and neonatal death frequently result from similar

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 post-mortem 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 examina-tion in LMIC settings but highlights the need for good-qual-ity international studies

Due to the relationship between complications in nancy and the neonatal period, obstetricians and neonatolo-gists have a close working relationship Therefore, we consider most elements of the clinician’s perspective on peri-natal postmortem examination jointly, addressing specifi c circumstances when appropriate (e.g., where there are legal

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: Alexander.Heazell@manchester.ac.uk

A Fenton , MD, MRCP

Newcastle Neonatal Service , Royal Victoria Infi rmary ,

Newcastle upon Tyne , UK

1

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

mul-tidisciplinary team involving obstetricians, neonatologists,

perinatal pathologists, midwives, neonatal nurses,

sonogra-phers, 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

post-mortem 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

spe-cifi cally 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

histo-logical 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

indi-vidual elements should also be viewed as parts of a

comprehen-sive 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

rec-ommended for the investigation of stillbirth by three

authori-ties: 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

pla-centa and cytogenetic, biochemical, and hematological

inves-tigations 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

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 postmor-tem 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 coro-ner or their offi cers is warranted However, we would recom-mend 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 identifi cation of a cause for stillbirth has important sequences, 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 chil-dren [ 13 , 14 ]; this increased risk is particularly important where a placental or genetic cause for stillbirth has been iden-tifi ed as these conditions can recur in subsequent pregnancies

con-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 under-standing 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

likely to provide an explanation, full or partial, for the

still-birth (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 signifi cantly more likely to regret

not having had a postmortem examination than to regret

hav-ing one [ 15 , 16 ] However, there is huge variation in the

fre-quency with which parents consent and the examination

undertaken In some maternity units more than 50 % of

par-ents consent to a full or partial examination, as they want to

fi nd out as much as they can about the cause of the loss of

their child Improvements in care, such as restricting

coun-seling for autopsy to senior clinicians, or specially trained

bereavement staff, involvement of perinatal pathologists, and

education in the value of perinatal autopsy, can increase

con-sent 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

still-birth [ 18 ] In reality, the attainment of high-grade evidence to

direct practice in this fi eld 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 fi ndings of case series that

may be identifi ed 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

con-genital anomaly, or who come from certain ethnic

back-grounds, 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

still-birth; indeed, it may be the only opportunity to do so in the

absence of a detailed ultrasound assessment of fetal anatomy

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 stud-ies were more optimistic, suggesting that the diagnosis was changed in 34 % of cases or identifi cation of a specifi c condi-tion 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 clin-ical diagnosis was confi rmed by postmortem examination in 48.9–58 % [ 19 , 20 ] Where series were restricted to specifi c abnormalities, such as nonimmune hydrops, few examina-tions were inconclusive: 3.9 % and 5.4 % [ 22 , 25 ] Unselected series described inconclusive fi ndings in 26–44.3 % [ 26 – 28 ]

Utility of Postmortem Examination After Neonatal Death

Postmortem examination after neonatal death occurs in a ferent context to that of stillbirth, in that clinicians have the benefi t of their clinical observations and the results of any investigations that were undertaken prior to death In this scenario, postmortem examination can also provide impor-tant information regarding the quality of care prior to death

dif-as well dif-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 clin-ical 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 differ-ences, the postmortem examination found additional condi-tions 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 identifi ed 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 confi rmed the specifi c reason for death in 97 % of cases However, in 79 % of cases, new diagnoses were discovered; this information signifi -cantly 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 signifi cant implications for auditing the quality of neonatal care [ 30 ]

Postmortem examination also has value in specifi c tal conditions; in cases of hypoxic ischemic encephalopathy (HIE), detailed examination of the brain after neonatal death can be used to defi ne 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

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

signifi cant 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 identifi ed 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

infor-mation in a signifi cant proportion of cases In a retrospective

study of 132 postmortems where an abnormality was

identi-fi ed by ultrasound scan, 72 % conidenti-fi rmed the suspected

diag-nosis, 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

abnormal-ity prior to 24 weeks’ gestation found that there was

com-plete agreement between scan and postmortem in 86 % of

cases, with 5 % of cases fi nding additional information

Critically, in 9.1 % of cases there was disagreement between

the postmortem and some or all of the ultrasound fi ndings

[ 34 ] The concordance between ultrasound and postmortem

fi ndings appears to be affected by the site of the abnormality,

with higher detection of central nervous system and

cardio-vascular anomalies (91.5 % and 90.2 %, respectively)

com-pared 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

informa-tion, and, in a further 13 % of cases, it provided a defi nitive

diagnosis [ 35 ] Postmortem examination can also be useful

to differentiate between conditions that have the same

ultra-sound 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

pla-cental 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 classifi cation of the cause of stillbirth

[ 37 – 45 ] The proportion of studies when the placental

histo-pathology was deemed useful ranged from 31.5 % to 84.0 %,

with an average of 59.8 % [ 18 ] This wide variation was in

part due to the use of 8 different classifi cation systems (see later discussion) Despite the wide variation in the estimates

of the utility of placental examination, all of the authors cluded that placental examination was useful A small retro-spective analysis of 71 cases of stillbirth found that histological examination of the placenta was associated with

con-a signifi ccon-ant reduction in the probcon-ability of con-an “unexplcon-ained” stillbirth (OR 0.17; 95 % CI 0.04–0.70); the additional diag-noses were suggested by fetal growth restriction, placental insuffi ciency, 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 exam-ination 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 Classifi cation System Used

Many (>30) different classifi cation systems have been described for perinatal death, some developed specifi cally 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 classifi cation 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 classifi cation systems was clearly demonstrated by Vergani et al who compared 154 stillbirths from a single institution with a universally imple-mented protocol to determine the cause [ 47 ]; in this study, postmortem examination provided information to aid classifi -cation in 24.7 % of cases, placental histology in 77.3 %, chro-mosomal analysis in 11.7 %, and infection screen in 18.8 % Four different classifi cation systems were then used: Wigglesworth, ReCoDe, de Galan- Roosen, and Tulip The application of different classifi cation 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 classifi cation [ 47] Similarly, Ptacek et al described the use of 17 different classifi cation systems to describe placental “causes” or disorders associated with still-birth [ 18 ] This analysis further demonstrates that suffi cient sensitivity is required to record conditions associated with stillbirth; the more categories the classifi cation system had to record placental conditions, the more placental diagnoses were recorded However, there was little agreement between classifi cation 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

other diagnoses occurred in less than half of the systems

Thus, the fi ndings of studies using different classifi cation

sys-tems cannot be easily compared However, the use of a

mod-ern classifi cation 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

still-births between 1996 and 2006 and calculated healthcare cost

including labor, birth, and any fetal testing The mean

hospi-tal 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 benefi t by cost reduction

Presently, there are no studies that address this with data

acquired directly from patients However, Mistry et al

mod-eled 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

hypoth-esized that in the case of stillbirth, some of the cost of a

post-mortem 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

useful-ness of the perinatal postmortem examination in cases of

still-birth, 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

exami-nation rates of 53 % of stillbirths and 69.3 % of neonatal deaths

[ 54 ]; furthermore, this analysis suggests a decline in tem 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 %

postmor-of cases (Table 1.1 ) Recently reported postmortem tion 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 confi dential inquiries suggesting lower uptake of perinatal postmortem examination may more accurately refl ect the situ-ation for whole populations

Due to the wide geographical variation of the reported quency of postmortem examination, it is unlikely that a single factor is responsible for this reduction, but it may refl ect that postmortem examinations are becoming less common in other fi elds 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 post-mortem examination, which has (at least transiently) had an impact on the proportion of parents consenting for postmor-tem 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 pro-cess 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 post-mortem These include: legal requirements, how to obtain con-sent, 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 fi cal/medical examiner, all parents whose baby has died should have a discussion with an appropriate healthcare

Table 1.1 Rates of postmortem examination after stillbirth and neonatal death

Author Location Years Rate (%) Author Location Years Rate (%) Fretts et al 1992,

Obstet Gynecol

Montreal, Canada 1961–1988 97 Valdes-Dapena et al

1970, J Pediatrics

Philadelphia, USA 1960–1966 96 Magani et al 1990,

Paediatr Pathol

Galway, Ireland 1972–1982 64 Tibrewala et al

1975, Indian Pediatr

Bombay, India 1961–1972 23 Hovatta et al 1993,

Manitoba, Canada 1977–1982 80 Munan L et al 1975,

Arch Dis Child

Pittsburgh, USA 1985 83 Golding 1982, In

Fetal and Neonatal

Turk J Paed

Istanbul, Turkey 1988–1991 94 Craft et al 1986, Am

J Dis Child

Durham, NC, USA 1981–1984 63 Saller et al 1995,

JAMA

Rochester, UK 1990–1991 83 Porter et al 1987, J

Clin Pathol

Oxford, UK 1981–1985 >90 Pattison et al 1992,

NZ Med J

Auckland, New Zealand

1991 64 Van Marter et al

Kinshasa, DRC 1985–1986 3

professional regarding a postmortem examination The

pro-fessionals 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 offi cers

Professionals should not make any assumptions about which

parents might or might not consent

The consent process will inevitably require several

con-versations 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 benefi ts 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 mortem examination must have a full understanding of what the examination entails, what options are available (e.g.,

post-Table 1.1 (continued)

Author Location Years Rate (%) Author Location Years Rate (%) Khong et al 2006,

West Ind Med J

West Indies 2002–2008 60 Rushton 1991, Br J

Obstet Gynaecol

West Midlands, UK 1986 61 Tan et al 2010,

Paediatr Dev Pathol

Malaysia 2004–2009 5 Niobey et al 1990,

Revista de Saude

Publica

Rio de Janeiro, Brazil

1986–1987 43

Centre for Maternal

and Child Health

NZ Med J

Auckland, New Zealand

1991 38 Cartlidge et al 1995,

BMJ

Wales, UK 1993 42 Thornton et al 1998,

Neonatology

Dublin, Ireland 2004–2009 47 Centre for Maternal

and Child Health Enquiries, UK, 2010

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

whether the postmortem examination will be full or limited to

a specifi c area of the body), and the appearance of the baby

afterward Parents should be informed whether they are able

to see the body afterward In our experience this is possible in

most cases and incisions should be made and repaired in such

a way that they can be hidden by a hat and baby clothes

It is essential that wherever possible, the process of a

postmortem examination undertaken within a hospital (as

opposed to one undertaken by a coroner/procurator fi scal)

causes minimal disruption to the family’s wishes regarding

funeral arrangements This is particularly important where

the transfer of the body to another hospital for postmortem

examination is required There should be protocols in place

to ensure that unnecessary delays do not occur and that

healthcare professionals communicate clearly with funeral

directors and families to avoid causing additional distress

Cultural and Religious Considerations

Neither Orthodox Judaism nor Islam specifi cally forbids

postmortem examination In Judaism there is a general

pro-hibition against postmortem examination, deriving from a

prohibition of disgracing a corpse, but if there is a chance that the procedure may directly contribute to saving the life

of another patient (e.g., in the perinatal setting by ing the cause of death as a hereditary condition), an excep-tion can be made Postmortem blood samples and needle biopsies are permitted There is no reference to the issue of postmortem examination in the Koran or Sunna, but as in Judaism there is a signifi cant cultural emphasis on leaving a body in peace In order to avoid diffi culties with the issue of postmortem examination, it may be appropriate to take sam-ples for antemortem metabolic and genetic testing (e.g., skin for fi broblast culture and liver and muscle biopsy) when these conditions are suspected

What Factors Are Important for Parents

in Deciding About a Perinatal Postmortem Examination?

Due to the falling rates of perinatal postmortem examination, several studies have attempted to describe barriers and prob-lems with the consent process Data from the UK showed an encouraging increase in the proportion of parents where

100

Bristol publicity

Redfern report

Perinatal pathology moves to SCRH

Unit guidelines changed 90

Fig 1.1 Perinatal postmortem examination rate in a single tertiary UK

unit showing the negative impact of adverse publicity on postmortem

examination rate after stillbirth Tertiary center in dark line UK

national rate in dotted line showing a continued fall Timing of signifi cant negative publicity shown in blue- fi lled arrows (Modifi ed from

-Stock et al [ 17 ] with permission from Elsevier)

postmortem was discussed from less than 80 % of stillbirths

in 2002 to more than 90 % in 2008 and less than 70 % of

neonatal deaths in 2002 to more than 80 % in 2008 [ 59 ]

However, this increase in the offer of perinatal postmortem

examination was not associated with an increase in the rate

This suggests that the process may itself be a barrier to

con-sent for perinatal postmortem examination Consequently,

several studies have explored factors that affect parents’

decisions about perinatal postmortem examination Breeze

et al., Heazell et al., and Holste et al reported the fi ndings of

questionnaire studies (from the UK and Sweden) exploring

parents’ motivations for having a postmortem examination

after stillbirth [ 16 , 60 , 61 ] The primary factor for parents

was to obtain information regarding why their baby died and

in particular how this might impact future pregnancies The

important secondary benefi ts of postmortem examination for

bereaved parents were to increase medical understanding of

perinatal death and thereby reduce the burden of these deaths

in the future [ 16 , 60 , 61 ] Importantly, staff and consenting

parents for postmortem examination held different beliefs

regarding potential barriers to the consent process to parents

(Table 1.2 ); this may lead to a disconnection between parents

and staff, which impairs the consent process

The need to move the baby’s body to another unit was

felt to be a barrier by twice as many parents as obstetricians,

whereas only a small proportion of parents responding to the

questionnaire ranked cultural or religious considerations as

a barrier compared to the majority of professionals These

fi ndings highlight the importance of shared

understand-ing between parents and professionals and not enterunderstand-ing the

counseling process with preconceived ideas about parents’

views and beliefs Meaney et al reported a detailed

qualita-tive analysis of ten parents’ decision-making about perinatal

postmortem examination in Ireland Parents consenting to postmortem examination were motivated to do so to rule out self-blame and to aid future pregnancies, whereas those who declined the procedure wanted to protect their baby from fur-ther harm [ 62 ] Qualitative analysis from obstetricians, mid-wives, and perinatal pathologists in the UK was used to form the following argument that “both professional views and family decision-making about postmortem after stillbirth are affected by the education and training of staff, local resources, and the quality of information available All of these structural issues are interpreted by individual staff, women and families through personal beliefs and emotions, and professional and social discourses” [ 63 ] Taken together, these fi ndings empha-size the importance of clinicians’ knowledge and experience

of the postmortem procedure so that the likelihood of ing useful information can be conveyed and information given about the process of the examination to address parents’ con-cerns about the treatment of their child’s body

What Can Clinicians Do to Facilitate the Consent Process for Perinatal Postmortem Examination?

Due to the individual nature of the circumstances surrounding each child’s death, clinicians must adapt their approach and behavior to the context of that interaction We cannot recom-mend a “one size fi ts all” approach There are no data to guide clinicians regarding when is the “best” time to approach par-ents to discuss postmortem examination or how many times postmortem examination should be discussed with parents The majority of clinicians responding to a survey in the UK reported discussing postmortem examination after stillbirth

Data adapted from Heazell et al [ 16 ] The most signifi cant differences between staff and parents are highlighted in gray

Table 1.2 Proportion of

respondents that rated factors as

“strong barriers,” “somewhat of a

barrier,” or “a signifi cant barrier”

to obtaining postmortem

examination after a stillbirth

on one or two occasions with parents, and the fi rst mention of

the examination was either at the time of diagnosis of

still-birth (for obstetricians) or at the time of admission (for

mid-wives) [ 16 ] It is important for clinicians to be aware that

parents are often overwhelmed by information at these times,

describing feelings such as “ your head is … you ’ re not …

people ’ s talking to you and you ’ re going ‘ uh - huh ’ but

some-times you ’ re not taking it all in ” Therefore, the provision of

written information is recommended to allow parents to

absorb information at their own pace [ 10 ] Although a

sys-tematic review assessing whether the provision of additional

information for parents improved information delivery and

access to investigations could not fi nd any high-quality

evi-dence to guide practice [ 64 ], clinicians should make every

effort to provide up-to-date information about the

postmor-tem examination for parents To this end Sands (the Stillbirth

and Neonatal Death Charity) in the UK has developed a

vari-ety of materials for parents and professionals that can be

accessed online at www.uk-sands.org/sites/default/fi les/

Deciding%20about%20a%20post%20mortem%20LINKED

pdf (for parents) and at www.hta.gov.uk/_db/_documents/5._

Sands Guide_for_consent_takers_Jan_2013.pdf (for

con-sent takers)

The critical importance of good-quality information about

postmortem examination is highlighted by the following

quote from a parent, “Just before I went into delivery, they

started talking about a postmortem We were discouraged by

the midwives who were telling us that it was a pointless

activity It was prolonging the agony before you could

actu-ally say goodbye to your baby But I know I would have made

a different decision today if I had been talked to in the right

way and explained about how it could help” [ 65 ]

Evidence suggests that health professionals underestimate

the value of postmortem examination with approximately

one-third of obstetricians and midwives believing that ≤20 %

of postmortem examinations after stillbirth would yield

use-ful information (Fig 1.2 ) [ 16 ] Given that 22 % of parents had

a postmortem examination based upon professional advice, a

message from clinicians that postmortem examination is

“pointless” will greatly reduce the number of examinations

performed Following neonatal deaths, professionals reported

not offering postmortem examination due to concerns about

further upsetting the parents (20 % of respondents), the

con-sent form itself (15 %), negative media coverage of organ

retention after postmortem examination (9 %), and being

uncomfortable with the postmortem process (4 %) and that

the result might question clinical judgment (2 %) [ 66 ]

Some of these issues can be addressed by good-quality

staff training However, staff training is often lacking In a

UK survey in 2010, 26.1 % of midwives and 12.4 % of

obste-tricians had received no training regarding counseling for

autopsy consent, and a further 32.9 % of midwives and

10.7 % of obstetricians were not satisfi ed with the training

that they had received [ 16 ] Consequently, over one-third of midwives had low confi dence in the information they were able to provide to parents [ 16 ] Understandably when profes-sionals had seen a postmortem examination, their knowledge improved A desire to improve clinicians’ knowledge regard-ing postnatal care for parents has led to the development of specifi c educational initiatives such as the IMPROVE course (IMproving Perinatal mortality Review and Outcomes Via Education) from the Australia and New Zealand Stillbirth Alliance ( www.stillbirthalliance.org.au/education.htm ) and InSight study, which is designed to evaluate the role of staff training in provision of bereavement care The evaluation of these programs is under way, which will assess the impact of improved staff training on practice and rates of investigation after perinatal death To maximize postmortem consent it is essential that clinicians are educated about the benefi ts of the procedure and the nature of the postmortem examination and trained to take consent using the tools in their local setting

Interpreting the Postmortem Report and Giving Information Back to Parents

As stated earlier, the primary purpose of the postmortem information from both parents’ and clinicians’ perspectives

is to provide information about why the baby died Therefore, the postmortem fi ndings should be viewed in the light of information from other sources including the maternal his-tory and examination, maternal investigations (e.g., blood tests), and, in the case of neonatal death, the history and examination fi ndings of the infant Therefore, it is good prac-tice to provide this information to the pathologist in order that they can interpret their fi ndings accordingly

provide useful information Midwives and obstetricians had a signifi cantly lower expectation than pathologists that a postmortem would provide useful information ( P < 0.001, Fisher’s exact test) Approximately one- third of professionals signifi cantly underestimated the value of perinatal postmortem (Modifi ed from Heazell et al [ 16 ])

Practice regarding the provision of information for

par-ents from the postmortem examination varies between

dif-ferent centers However, as parents frequently need this

information to allow them to understand events surrounding

their child’s death, it is essential it is given in a timely

man-ner; guidelines in the UK recommend that postmortem

examination results are available within 10–12 weeks of the

stillbirth or death of the infant and that parents have met with

a senior member of staff within 12 weeks [ 67 ] When the

coroner has requested a postmortem examination, the

infor-mation in the postmortem examination report may be subject

to legal restrictions, but in other cases parents should be

given access to as much information as they wish from the

examination Our experience is that this varies between

indi-vidual cases from a desire to know the conclusions alone to

viewing the full report In the latter case, it is imperative that

the language contained within the report is appropriate for

parents to read

Parents frequently report anxiety about having to return to

the maternity or neonatal unit where their baby died Thus,

consideration should be given to the location of the

consulta-tion; it may take place in the parents’ home, a healthcare

center, or another suitable venue in the hospital In the case

of neonatal deaths, it may be appropriate for parents to meet

with both the maternity and neonatal professionals

simulta-neously Parents should be encouraged to ask questions so

that their concerns can be addressed In some cases, this

requires more than one consultation Although the content of

the consultation will vary, the RCOG guideline for the

man-agement of stillbirth recommends that parents should be

advised about the cause of stillbirth, the chance of

recur-rence, and any specifi c means of preventing further loss [ 10 ]

Women should be offered general prepregnancy advice,

including support for smoking cessation, and advised to

avoid weight gain if they are already overweight (body mass

index over 25) and to consider weight loss An offer should

be made to discuss the potential benefi t of delaying

concep-tion until severe psychological issues have been resolved

Parents can be advised that the absolute chance of adverse

events with a pregnancy interval less than 6 months remains

low and is unlikely to be signifi cantly increased compared

with conceiving later [ 10 ] We recommend writing a letter to

the parents to summarize the fi ndings of investigations and

the plans for their management in the future

New Developments in Postmortem

Investigation from a Clinical Viewpoint

Technological advances in several fi elds, particularly in

medi-cal imaging and genomics, have led to developments in

post-mortem examination that have been referred to as “minimally

invasive autopsy” (MIA) and “molecular autopsy.” MIA uses

either computerized tomography (CT) or magnetic resonance imaging (MRI) techniques to image the fetus combined with endoscopic-assisted internal examination to obtain tissue biopsies At present, MIA is at an experimental stage, per-formed in expert centers, but preliminary studies suggest that

it is feasible [ 68 ] Data regarding the effectiveness of MIA suggest an ongoing improvement in results Early studies were not as effective as postmortem examination; in one study of 58 cases, abnormalities were identifi ed at postmortem examina-tion in 26 cases, only 10 of which were detected by MRI [ 26 ] Another study of limited brain and spinal cord MRI showed signifi cant information was lost in 71 % of cases [ 69 ] However, more recent studies suggest much better concor-dance between MIA and conventional autopsy Cardiovascular magnetic resonance imaging was able to detect 73 % of car-diac abnormalities found at postmortem examination, which increased to 93 % in major structural heart disease [ 70 ] In a series of 400 postmortem examinations (69 % stillbirths), the results of MIA were in agreement with conventional postmor-tem examination in 89 % of cases; agreement was 96 % for stillbirths and 81 % for neonatal deaths [ 71 ] Importantly, a survey of 224 healthcare professionals described that 50 % thought MIA would be as acceptable as conventional postmor-tem examination, but 40 % thought that MIA was more accept-able [ 72 ] Further studies describing the views of bereaved parents are needed to draw fi rm conclusions that MIA would

be acceptable in clinical practice Nevertheless, MIA may vide another means to increase information available for par-ents after stillbirth and neonatal death

Genetic conditions are increasingly thought to be present

in perinatal deaths Newer technologies such as microarrays allow much more detailed interrogation of the genome than traditional G-band karyotyping Reddy et al investigated

523 stillbirths using both approaches, fi nding that microarray gave a result more frequently than karyotyping (87.4 % ver-sus 70.5 %) and better detection of genetic abnormalities (8.3 % versus 5.8 %) The detected abnormalities included deletions (from 509 Kb to 4.9 Mb), duplications (500 Kb–3.1 Mb), and aneuploids [ 73 ] Furthermore, using microarray, Harris et al reported 24 copy number variants in

17 samples of placental DNA [ 74 ] Other groups have also investigated the role of specifi c genes Crotti et al studied the three most prevalent long QT syndrome-susceptibility genes, KCNQ1 , KCNH2 , and SCN5A , in 91 unexplained stillbirths; loss of function mutations were found in three cases (3.3 %) and other variants were found in another fi ve cases [ 75 ] Further research is needed to determine whether these mutations identifi ed might have a causal relationship in some stillbirths or neonatal deaths As genomic technologies develop, particularly high-throughput gene sequencing, the role of genetic abnormalities in perinatal deaths is likely to become better understood, increasing the role of the “molec-ular autopsy.”

Conclusion

Perinatal postmortem examination remains an essential

tool for obstetricians and neonatologists to understand the

causes of perinatal death This has implications for

mater-nity and neonatal services from the bottom up For

indi-vidual parents, it helps them to understand why their baby

died and the implications for future pregnancies and

births For healthcare providers, this information enables

understanding of underlying causes, which can facilitate

the development of campaigns, guidelines, or policies to

reduce the number of perinatal deaths Obstetricians,

neo-natologists, midwives, and other professionals have a

commitment to supporting parents through the process to

decide whether to have a postmortem examination This

requires education regarding the value of postmortem

examination, understanding of parents’ needs and

expec-tations of the examination, developments in the fi eld, and

a willingness to work as part of a multidisciplinary team

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© 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_2

T Yee Khong

Abstract

There are many reasons for performing a perinatal necropsy, foremost of which is ing an accurate cause of death Pathologists and administrators who fail to understand the importance and enormity of the problem of stillbirths and neonatal losses and the important role of the necropsy fail the many parents who suffer these losses By doing so, it can also exclude some causes of death and identify disorders with implications for counseling for the family as well as for future pregnancies The standard of perinatal necropsies is far superior when performed by pediatric pathologists to when histopathologists other than pediatric pathologists perform them, and this may necessitate the regionalization of perina-tal services

This chapter summarizes the equipment requirements and formalities for performing a necropsy The necessary preliminary examinations and investigations prior to any dissec-tion, such as mensuration to document growth, imaging, and photography, are discussed A proposed method of dissection of the body is provided, and the reasons for sampling for histology, biochemistry, microbiology, and molecular studies are provided

Keywords

Autopsy • Necropsy • Method • Intrauterine growth • Dysmorphology • Cause of death

Why Is the Perinatal Necropsy Necessary?

It is essential that parents be afforded the opportunity of a

high-quality perinatal autopsy service when they lose their

babies during the perinatal period There are many reasons

why a perinatal necropsy is necessary (Table 2.1 [ 1 ]), some

of which have been explored in Chap 1 Foremost, it can

identify an accurate cause of death By doing so, it can also

exclude some causes of death and identify disorders with

implications for counseling for the family as well as for

future pregnancies

A parental expectation of pregnancy, particularly in high- income countries, is a normally formed healthy infant Parents would not normally contemplate a stillbirth, a dys-morphic baby, or one dying shortly after birth, and the par-ents would be concerned about the risks of a recurrence in either outcome Knowing the cause of death can also offer some succor to parents to assuage them of any guilt

From the point of view of providing optimal management

in subsequent pregnancies, the obstetrician needs to know whether clinical estimates of gestation and fetal growth were correct, if the results of prenatal investigations accurately predicted fetal growth and maturity and the presence or absence of malformation He will also want to know whether uterine response to gestation was appropriate and whether there was evidence of infection in either fetus or gestation sac In some circumstances he will be particularly concerned about the possibility of asphyxial or mechanical insult dur-ing labor The neonatologist wants confi rmation of diagnoses

T Yee Khong , MBChB, MSc, MD, FRCPath, FRCPA

Department of Pathology, Department of Obstetrics and

Gynaecology , University of Adelaide ,

North Adelaide , SA , Australia

Department of Histopathology , Women’s & Children’s Hospital ,

North Adelaide , SA , Australia

e-mail: yee.khong@adelaide.edu.au

2

made during life and whether any treatable conditions went

unrecognized He will be concerned about complications of

treatment and will welcome information about gestation-

related characteristics (see Chap 1 )

The audit functions of the necropsy are recognized, both in

the general hospital [ 2 ] and in specialized institutions [ 3 4 ]

If perinatal necropsy is to be an effective audit tool, then it is

important that a high necropsy rate is achieved Although the

rate in fetuses and neonates is higher than in adults and had

dropped in the 1990s and early 2000s [ 5 , 6 ], perinatal

nec-ropsy rates appear to have stabilized or improved since [ 7 ]

Necropsies of neonatal deaths remain less frequent than for

stillbirths [ 5 , 8 ] Staff education and commitment, based on

an understanding of the advantages of postmortem

examina-tion, can improve necropsy rates in individual units [ 9 , 10 ]

National perinatal mortality data are an important index

of a nation’s health The diffi culties of collecting data and

classifying causes of perinatal death are discussed later (see

Chap 6 ), but it is important that causes of death are verifi ed

by postmortem examination Postmortem investigations may

reveal a cause of death that is unexplained clinically and thus

deaths that have not been investigated by necropsy are in fact

unexplored Vis-à-vis the need for a high necropsy rate, the

rate of unexplained antepartum deaths is inversely

propor-tional to the necropsy rate It is in both local and napropor-tional

interest to improve the accuracy of perinatal mortality data to

inform public health policy

An aspect of necropsy examination that is often forgotten

is its importance to the continuing education of doctors and

other hospital staff, irrespective of seniority (see Chap 1 ) To

this end, it is important that perinatal necropsies are not just

delegated to junior staff and then forgotten Performance of

necropsies should be part of the training of all junior

histopathologists, with careful supervision and

demonstra-tion of appropriate techniques by an experienced perinatal

pathologist

When clinicians take time to attend postmortem tion on their patients, it does a great deal to encourage the pathologist concerned, to educate him about current clinical practice and the clinical relevance of information that he can readily obtain In this way, both clinician and pathologist gain satisfaction, and the value of necropsy examination is enhanced Attendance of senior clinical staff in the mortuary demonstrates to junior doctors the importance of postmor-tem examination in a way that no amount of exhortation from pathologists can ever do

An Apology That Is Not Necessary

Worldwide, per year, there are 2.6 million stillbirths and 3.8 million neonatal deaths (of which 3 million are early neona-tal deaths) [ 11 ] Histopathologists/anatomical pathologists who provide a predominantly biopsy-oriented service, focused mainly on identifi cation of cancers, often fail to appreciate the extent and burden of perinatal losses By com-parison, worldwide, there are 1.59 million lung cancer, 745,000 liver cancer, 723,000 stomach cancer, 694,000 colorectal cancer, 521,000 breast cancer, and 400,000 esoph-ageal cancer deaths per year, numbers that are dwarfed by the perinatal losses annually [ 12 ] Medical workforce short-ages in pathology, coupled with increasing anatomical pathology workloads, have resulted in neglect for the perina-tal necropsy or its lower priority

When cost becomes a gatekeeper for a thorough gation, there may well be losers in clinical care It is petty to argue that too many tissue blocks are taken for histology in a perinatal necropsy, labeling that accusation particularly at macerated stillbirths, as it does not do any justice to both adult and perinatal pathology, especially when the many blocks taken in an adult cancer resection are considered Similarly, there is no place for limiting ancillary testing in a perinatal necropsy: as will be seen in the other chapters in the rest of this book, molecular and biochemical metabolic test-ing is as much a mainstay of perinatal pathology as is the necropsy itself, but these can be guided by a careful necropsy that can potentially narrow down the list of differential diag-noses for those testing

For a pathologist accustomed to the plethora of tions of degenerative disease evident at adult necropsy, the lack of fi ndings during perinatal postmortem examination is often a disappointment Pathologists who are not familiar with perinatal pathology are misguided in believing that a report with no specifi c diagnosis or that contains only nega-tive fi ndings after a carefully executed necropsy is of no value This cannot be further from the truth: careful record-ing of negative necropsy fi ndings does a great deal to rule out the possibility of birth injury or of missed, treatable abnormalities To this end, negatives should be clearly and

Table 2.1 The main purposes of a perinatal necropsy [ 1 ]

Identifying an accurate cause of death

Excluding some causes of death

Identifying disorders with implications for counseling and

monitoring for future pregnancies

Obtaining tissues for genetic tests

Assisting in the grieving process by enhancing the parents’

understanding of the events surrounding the death

Informing clinical audit of perinatal deaths including deaths due to

iatrogenic conditions and confi rmation of antenatally diagnosed

or suspected fetal pathology

Fostering research; e.g., recognition of new disease entities and

expansion of the body of knowledge on known diseases

Teaching pathologists and medical students

Providing evidence for medicolegal reasons; e.g., in a coronial

investigation or cases of litigation

unambiguously stated in the necropsy report, a copy of which

is usually fi led in the mother’s notes In subsequent

pregnan-cies it may be consulted by relatively junior members of both

medical and nursing staff to answer specifi c parental queries

or as a basis for management decisions There must be no

room for doubt about negative fi ndings For this reason too,

the signifi cance of the presence or absence of necropsy fi

nd-ings should be clearly stated, especially those opinions

formed after recourse to the literature or discussion with

col-leagues with particular experience in the fi eld

Imaging using computerized tomography (CT) and/or

magnetic resonance (MR) has been suggested as alternatives

to the conventional necropsy especially when parents may

not wish, for social or cultural reasons, for a necropsy or to

limit the extent of the necropsy Apart from detailed

evalua-tion of the central nervous system in situ, which still requires

complementing information derived from subsequent

patho-logical and histopatho-logical examination, magnetic imaging has

not proven, thus far, to be superior to the necropsy [ 13 ]

While lack of familiarity of perinatal pathology and

correla-tion with necropsy fi ndings by the radiologists may well be

overcome in time, imaging does not allow for tissue samples

to be obtained for metabolic studies, genetics, or

microbiol-ogy, which may be critical as a perinatal necropsy is more

than just a morphologic examination Targeted tissue

sam-pling may yet overcome this defi ciency [ 14 ]

Where Should the Perinatal Necropsy

Be Performed?

Studies have shown consistently that the standard of

perina-tal necropsies is far superior when performed by pediatric

pathologists to when histopathologists other than pediatric

pathologists perform them [ 2 , 15 – 18 ] General

histopatholo-gists also fail to recognize clinically signifi cant placental

lesions, more often due to underdiagnosis than to

misdiagno-sis [ 19 ] The reasons for this difference include disinterest

and lack of familiarity of lesions and the range of normality

A recommendation that a perinatal pathologist should be

performing at least 50 necropsies annually is designed to

maintain expertise A further recommendation is that there

should be at least two pathologists per region to allow for

cover and for intradepartmental consultations [ 20 ] This may

necessitate the regionalization of perinatal services and

transportation of the bodies, but this is feasible both in

devel-oping countries where expertise may be located remotely

from where the perinatal loss occurred [ 21 ] and in high-

income countries where numbers of perinatal losses that are

consented for autopsy are fewer [ 22 ] Service level

arrange-ments will vary between different jurisdictions and may be

infl uenced by geographic, population density, and fi nancial

considerations An argument against regionalization is the

adverse reaction from parents to transporting the body of their perinatal loss [ 22 ] but whether a necropsy should be performed in the delivery room following delivery, poten-tially provoking a rushed consent and less time for grieving, and by non-pathologist qualifi ed medical practitioners merits further evaluation [ 23 ]

Equipment for Perinatal Necropsy

The facility requirements of a perinatal pathology service must be a dedicated mortuary or a dedicated section of a larger mortuary There should be access to photographic and appropriate radiology services for all cases Access to a clin-ical genetics service is preferred but, in its absence, there should be access to a clinical genetics database Other inves-tigations, such as microbiology and virology, biochemistry and metabolic studies, and hematology and genetics, are often diagnostically important, and there should be close liaison with these pathology services

Measuring

Accurate weighing scales for measurement of both body and organ weights are essential Mature babies can usually be weighed on scales suitable for adult organ weighing For organ weights and the weighing of fetuses less than 20 weeks’ gestation, scales accurate to 0.1 g are needed An electronic balance with digital display is very convenient

A metric ruler and calipers or measuring board with one

fi xed end are required for measurement of body and foot lengths and skull diameters [ 24 ] Circumferential measure-ments are best made with string and read off against a ruler;

a tape measure is less accurate Techniques of mensuration have been described [ 25 , 26 ]

Dissection Instruments

Instruments of appropriately small size make fetal dissection much easier to carry out without damage to structures before examination is complete Scissors with tapering blades and rounded ends (Mayo) reduce the frequency of inadvertent perforation, which often occurs when pointed scissors are used Iridectomy scissors are a useful size for dissection of second trimester abortuses Non-toothed forceps are less damaging to fetal tissues than those with teeth A range of models is available and a selection of round-ended, tapering- blade forceps of different lengths, such as 10–17 cm (4–7 in.),

is useful

Size 3 and 4 scalpel handles and a range of blades to fi t will suit most purposes during fetal examination Neck dis-section in the neonate is a great deal easier with a narrow scalpel blade of small size

A selection of probes, down to small lachrymal duct size, makes demonstration of abnormal anatomy easier A pair of

20-cm (8-in.) straight, sprung bone forceps will cut ribs,

ver-tebral pedicles, and femoral shafts and open middle ears A

domestic cake slicer is invaluable for handling brain slices

A mounted magnifying lens with an integral light source

is especially useful during the examination of second

trimes-ter fetuses A dissecting microscope for detailed examination

of very small hearts is recommended

Preliminary Formalities

Consent

Legal formalities regarding the necropsy need to be

commu-nicated between the parents or legal guardians and the

pathologists through the responsible medical attendant

These include the extent of the authorization for performing

the necropsy It is important that any ambiguity about any

request for examining the body that requires an invasive

pro-cedure on the body be clarifi ed, as it would be distressing to

the parents if their wishes were inadvertently misinterpreted

As important are their wishes for care and disposal of the

body and any body parts (see Chap 1 )

Adequate Clinical Information

The importance of the availability of clinical information

before the start of any necropsy examination cannot be

over-stated This is especially important in necropsy examination

of neonates, when information about the mother is always

required and may in some circumstances be of equal or

greater importance than that concerning the baby

Maternal notes are frequently unavailable before a

nec-ropsy examination Sometimes necnec-ropsy examination is

undertaken in a hospital far removed from the place of

deliv-ery In these circumstances, clinicians are reluctant to allow

removal of notes from the maternity unit

Availability of clinical notes does not negate the benefi t to

both sides of discussion between clinician and pathologist

before necropsy commences Direct communication between

colleagues is, without doubt, the best way to ensure that

important clinical questions are answered and unrealistic

expectations modifi ed before unproductive or even

antago-nistic attitudes are allowed to interfere This is also an

oppor-tune time to clarify any ambiguities arising from the request

or consent for necropsy It is important to both clinical and

pathological practices that questions are clearly formulated

and that techniques are modifi ed to realize the best chance of

an unambiguous answer Clinicians are often disappointed

when they do not get answers to questions relevant to patient

management following postmortem examination This

dis-appointment pales into insignifi cance beside the irritation of

the pathologist who is faced at the end of necropsy with a question that could have been answered if it had been asked

at the appropriate time – before starting the necropsy The essential information that should be provided is tabled (Table 2.2 ), and such information can form the basis

of a structured necropsy request form

Place of Structured Request Forms in Perinatal Pathology

Many necropsy forms are mandated by jurisdictions that do not permit any variations Bewilderingly, when adult hospi-

Table 2.2 Information in a perinatal necropsy request form

Past obstetric history

Date, parity, labor, puerperium, sex, outcome, any change in paternity

Body mass index Alcohol, recreational drug use, if known Known infections

Maternal complications Hypertension – type, treatment Diabetes – type, treatment Antepartum hemorrhage Amniotic fl uid volume – polyhydramnios/oligohydramnios/ anhydramnios; ultrasound amniotic fl uid index

Fetal complications Intrauterine growth restriction – and time of onset/detection Delivery

Labor – induced/spontaneous/augmented Rupture of membranes – time

Liquor – amount, color, odor First stage, duration; second stage, duration Presentation – vertex, breech (and type), others Fetal outcome

Evidence of fetal distress – cardiotocograph, fetal blood sampling Neonatal outcome

APGAR scores Neonatal problems Investigations Procedures Therapy – antimicrobials, respiratory interventions

Other relevant information

Participation in any clinical trial pertinent to pregnancy or neonatal course

Specifi c questions for necropsy

Differential diagnosis, antemortem clinical diagnosis

tal necropsy rates and absolute numbers are orders of

magni-tude lower than those of the perinatal necropsy, these forms

are often insensitive to the differences between bereaved

par-ents who have lost babies in the perinatal period and other

kinds of next of kin They also lack the clinical details that

are unique to the perinatal period and the fact that there are

two patients – i.e., the mother and the baby – with every

peri-natal loss

Notwithstanding the jurisdictional constraints and

bureaucratic myopia, where separate adult and perinatal

necropsy forms are permitted and input is sought from

peri-natal pathologists and parent advocates, an emotionally

sensitive and clinically useful perinatal necropsy request

form can be constructed A carefully completed structured

perinatal request form provides the pathologist with

consis-tent, minimal clinical information that is always available

before the necropsy begins Information (Table 2.2 ) on

such forms is not a substitute for access to clinical notes

Their use should not deter clinicians from submitting

addi-tional information that they consider relevant Including

information about parental wishes for disposal of the body

and body parts in the request form is also valuable in

guid-ing the mortuary staff

Besides being a convenient means of transfer of essential

information, structured request forms achieve other ends

The process of their completion affords an opportunity to

clinical staff in obstetric and neonatal units for critical review

of individual patient management It may be the fi rst

oppor-tunity to look at the case as a whole and observe the way in

which problems interrelate at a time when they are no longer

distracted by a stressful clinical situation A structured

request form also serves to guide the pathologist through the

complexities of management of a baby who has received

prolonged intensive care, when clinical notes are likely to be

voluminous

Prior Discussions

Having now been armed with the knowledge of the extent or

limitations of the consent for the necropsy and with the

clini-cal information, the pathologist should be as fully informed

as possible before commencing the postmortem

examina-tion Any suggestion of dysmorphism should prompt the

pathologist to consult with his clinical geneticist, especially

if one is fortunate to have such colleagues who are dedicated

to reproductive and developmental clinical genetics, as they

may prompt additional or rare associations to be sought at

the necropsy or to direct appropriate ancillary testing The

latter may even dictate prioritization of the necropsy or

col-lection of tissues or fl uids for timeliness As indicated earlier,

access to a clinical genetics database is most helpful in these

a wide range of pathological and developmental ties and to use them for all perinatal necropsies than to use a variety of minor modifi cations of technique when a particu-lar abnormality is suspected This promotes familiarity with the techniques adopted and means that abnormalities that were not diagnosed during life are less likely to be missed Perinatal necropsy protocols have been detailed [ 24 , 29 –

abnormali-32] Guidelines summarizing essential investigations are published by the Royal College of Pathologists and the American College of Pathologists [ 33 , 34 ]

Measurement

As is evident in this section and in the following sections on weighing organs, normality or otherwise is assessed against the means for gestational age The frequency of growth restriction among babies who die in the perinatal period can infl uence the pathologist’s concept of normality to the extent that signifi cant growth restriction may be ignored The body weight, to the nearest gram if less than 5 kg, must be recorded and compared with standardized population-based weight charts corrected for gestational age and sex Charts custom-ized for parity or birth order are also available, and these are preferred as it has been shown consistently that later-born babies are heavier than fi rst-born babies There are argu-ments for and against the use of charts that are customized for maternal characteristics [ 35 , 36 ] Maternal and paternal birthweights contribute only a small fraction to the fetal growth, which is similar across diverse geographical settings when mothers’ nutritional and health needs are met and envi-ronmental constraints on growth are low Accordingly, a multiethnic growth chart that is applicable globally has been compiled from eight carefully selected urban areas [ 37 ] Notwithstanding some limitations, such as accounting for time to cord clamping following delivery of the baby [ 38 ], the chart is relevant in European, North American, and Australasian countries, which are characterized by high rates

of immigration and intermarriage [ 39 ] (Fig 2.1 , Table 2.3 [ 37 ]) The chart does not cover births below 33 weeks’ gesta-tion as there were few early preterm deliveries that were not

at higher risk of intrauterine growth restriction and other major pregnancy and neonatal complications, for which it may be diffi cult to construct [ 37 ]

The minimum external measurements that must be

recorded are the head circumference (Table 2.4 ), crown–

rump, crown–heel (Table 2.5 ), and foot lengths [ 37 ] Head

circumference is approximately equal to crown–rump length

during the second and third trimesters of pregnancy It

pro-vides a useful indication of the appropriateness of head size

and may also draw attention to growth restriction Foot

length (Table 2.6 ) is a useful gestation-related measurement

to supplement menstrual dating or dating by early ultrasound

measurements [ 40 ] Foot length has the advantage that it is

less open to manipulation of this type, but its range is small

and this measurement should be carefully performed Both

crown–rump and crown–heel lengths are prone to

inaccu-racy, particularly following intrauterine death, when joint ligaments are lax and permit excessive stretching

Information about other measurements at different gestations, such as head and abdominal circumference, biparietal diameter, and femoral length, has become available as a result of prenatal ultrasound fetal measure-ment [ 41 ]

Measurements of facial features are particularly helpful where external examination may not be obvious and can be compared against available anthropometric standards [ 42 ] Examples of this include inner and outer canthal distances and interpupillary distances to confi rm hypertelorism or hypotelorism

Fig 2.1 The 3rd, 10th, 50th, 90th, and 97th smoothed centile curve for birthweight according to gestational age ( a ) Birthweight ( b ) Birth length

( c ) Head circumference (Reprinted with permission from Villar et al [ 37 ])

Gestational age (weeks)

Gestational age (weeks)

Gestational age (weeks)

a

b

Growth and Development

The fetal and neonatal periods are ones of continuing

develop-ment at both organ and tissue levels, fi rst by a process of cell

division and then by growth of individual cells There is rapid

somatic growth, which is roughly linear for most of the second

and third trimesters, slowing down from about 38 weeks’

ges-tation until delivery Growth and development advance

con-currently, and while they are interrelated, they may be affected

together or independently by environmental factors

Many of the babies who die in the fetal and neonatal period

are of low birthweight The term “premature” used to be

applied indiscriminately to this group of babies, and

discrep-ant historical evidence about the length of gestation was ignored Prematurity is defi ned as duration of pregnancy of less than 37 weeks from last menstrual date, “term” as a preg-nancy duration of 37–41 weeks and “postterm” as a preg-nancy of 42 weeks or longer Babies who weigh 2,500 g at birth are designated “low birthweight.” Thus, babies of low birthweight may be preterm and appropriately grown, pre-term and growth restricted, or mature and growth restricted

A more contemporary approach is to ascertain whether the fetus has reached its growth potential or not A fetus that

is of appropriate weight for gestational age (AGA) for the population average may be just that, or it may in fact be growth restricted if it has not achieved its growth potential

(intrauterine growth restriction, IUGR) Similarly, a fetus

that is small for the gestational age (SGA) may be

appropri-ately grown (AGA), where the fetus is small due to its

genetic makeup, or it may be growth restricted (IUGR) if it

should have been born larger but has not because of other

factors

It follows then that key to assessing whether growth is

normal or otherwise is knowledge of the gestational age

Menstrual dating usually permits the best estimate of the

length of gestation Ultrasound measurement of the fetus in

early pregnancy is commonly performed in developed

countries and gives a reliable gestational age The foot

length appears to be least affected by growth restriction and

is used to assess gestational age (together with the

radiol-ogy, brain morpholradiol-ogy, and histological clues) when the

gestational age is unclear, and this is reiterated by a recent

study [ 43 ]

Birthweight is affected by constitutional (e.g., genetic factors, chromosome abnormality) and environmental (e.g., infection, maternal malnutrition or diabetes, drugs such as alcohol or illicit drugs, placental milieu such as multiple pregnancy or poor uteroplacental perfusion in preeclampsia) factors Fetal growth restriction may be of early onset, when it is characteristically “symmetric”; all fetal organs are affected more or less equally and they are smaller but proportionally unchanged Serial measure-ments of head circumference or of biparietal diameter, as

a surrogate for brain growth, show that it grows below, but parallel to, the centile lines This type of growth failure may be the result of intrauterine infection (TORCH organ-isms, see Chap 9 ), genetic constitution, chromosome abnormality (Fig 2.2 ), or malformation syndromes such

as renal agenesis (Table 2.7 ) Late- onset growth tion results in “asymmetric” growth disturbance with rela-

Table 2.5 Smoothed centiles for birth lengths of boys and girls according to gestational age

Reprinted with permission from Villar et al [ 37 ]

Table 2.4 Smoothed centiles for head circumferences of boys and girls according to gestational age

tive sparing of brain growth and therefore of head

circumference and biparietal diameter (Fig 2.3 )

Disturbance of organ weight ratios is observed, for

exam-ple, an increase in brain to liver weight ratio; the normal

is 2.8:1, while a ratio ≥4 is regarded as indicating

asym-metric growth restriction [ 44 ] Serial head size

measure-ments are initially within the normal range but

progressively fall below normal values in late pregnancy

The causes of this type of growth restriction are usually

environmental It may be the result of reduced

uteropla-cental perfusion in conditions such as preexisting or

preg-nancy-associated hypertension, maternal diabetes

mellitus, or nonavailability of nutrients as seen in chronic

maternal undernutrition

Some babies are inappropriately large for gestation age

(heavy for dates) These babies tend to be born to taller,

heavier women who are older and of higher parity

Excessive maternal weight gain may be observed during

pregnancy Maternal diabetes mellitus (Fig 2.4 ) and

gesta-tional diabetes are associated with large babies

Macrosomia is a feature of several syndromes, including

Wiedemann–Beckwith and Soto’s syndromes [ 45 ] Large

babies are at risk of birth injury and intrapartum hypoxia

(see Chap 15 )

Postmortem Imaging

A whole-body radiograph is an important adjunct to tal necropsy and mandatory in the investigation of general-ized skeletal disorders and skeletal deformity [ 46 ] (see also Chap 5 )

perina-Access to the radiography department for postmortem radiographs is often diffi cult An appropriate apparatus sited within the pathology department usually means that radio-graphs are performed regularly A self-contained unit, such as the Faxitron (Hewlett–Packard), using digital (memory card) plates, is ideal for pathologists’ use and gives the best results for fetal radiography and examination of individual bones [ 47 ]

An anteroposterior radiograph of the whole body will detect disproportion between trunk and limbs and between the differ-

Table 2.6 Foot length by gestational age

39 weeks’ gestation (median weight 3,220 g)