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  • Autopsy Investigation in Stillbirth

    1

    AUTOPSY

    INVESTIGATION IN

    STILLBIRTH

    Dr Julie Anne Man

    MBChB

    A thesis submitted for the Degree of

    Doctor of Medicine (Research)

    MD (Res)

    University College London

    (UCL)

  • Autopsy Investigation in Stillbirth

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    I, Julie Anne Man, confirm that the work presented in this thesis is my own. Where

    information has been derived from other sources, I confirm that this has been

    indicated in the thesis.

    Signed:

    May 2016

  • Autopsy Investigation in Stillbirth

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    Abstract

    The UK has the highest rate of stillbirth in the developed world and there are more

    than three million stillbirths worldwide each year. With over 30 different

    classification systems, the rate of unexplained stillbirth varies from 15-60% despite

    postmortem investigation being undertaken in a number of cases. The primary

    aims of this project were to use a unique autopsy database to examine a large well

    characterised series of stillbirth autopsies to assess specific causes of death,

    relationships between fetal maceration, intrauterine and postmortem interval on

    cause of death and fetal intrauterine growth restriction as well as producing

    evidence based guidelines for autopsy practise and investigating the potential role

    of novel techniques in future stillbirth autopsy.

    The analysis of more than 1000 intrauterine and intrapartum fetal deaths revealed

    that two thirds had an unexplained cause of death. Internal examination of the

    fetuses provided a definitive cause of death in 1% of cases; 19% of the overall

    causes of death could have been diagnosed from review of the clinical

    circumstances and a further 18% by placental macroscopic and microscopic

    examination. Significant associations were found between increasing maceration

    and Small for Gestational Age (SGA) fetuses and that using birthweight or

    bodyweight alone erroneously overestimate the role of SGA as an underlying factor

    in stillbirth causation. Other investigations such as modified organ weight ratios

    may contribute to determining cause of death. Proteomic experiments proved that

    in principle significantly different amounts and types proteins could be successfully

    extracted from formalin fixed paraffin embedded stillbirth fetal tissue in different

    case groups, suggesting a possible future investigation into the causation of

    stillbirth.

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    Acknowledgments

    I would firstly like to extend my thanks to my Supervising Professor, Neil Sebire.

    Professor Sebire has been a great inspiration for this research project and provided

    excellent guidance and support for the project from the start. It has been a pleasure to

    work alongside such a committed and motivated Medical Doctor who has not only

    taught me a great deal about Perinatal Pathology and medical research, but also

    helped to improve my confidence and self-belief in my capabilities as a Doctor; for

    this I will be forever thankful.

    Secondly, I must thank my husband, Yu-Hin. Without him I would not be here today

    and it is only through his great support and understanding that I was able to commute

    to London from Southampton to complete my research. He was there to look after

    our house and help care for our dog (Jubly) on my long days in London. Yu-Hin is

    my rock; providing much love and encouragement as well as the most wonderful

    home cooked food to keep me going.

    My colleagues in London, Doctors Andrew Bamber and Jeremy Pryce also deserve

    my thanks. Andrew provided much guidance on the inner workings of the Microsoft

    Access Database used in this project and helped to ‘show me the ropes’ when I

    started at Great Ormond Street Hospital. Jeremy provided much guidance and

    support during my two years of research; also helping me to understand the database,

    as well as the complex world of Proteomics - I would not have been able to even

    imagine completing a chapter about proteomics without Jeremy’s help.

    Finally I must extend my thanks to the Stillbirth and Neonatal Death Charity,

    SANDs who provided the research grant for this project.

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    Table of Contents

    List of Tables .......................................................................................................................10

    List of Figures ......................................................................................................................16

    1. Introduction ....................................................................................................................21

    1.0 Background ...................................................................................................................22

    1.1 Classification systems for perinatal deaths and stillbirth .............................................29

    1.2 The importance of the placenta....................................................................................35

    1.3 Current postmortem investigation is stillbirth .............................................................38

    1.4 The project ....................................................................................................................42

    2. Methods ..............................................................................................................................43

    2.0 The database .................................................................................................................44

    2.1 Modifications to the database ......................................................................................44

    2.2 Data Entry .....................................................................................................................45

    2.3 Histology and Laboratory Work ....................................................................................48

    3. Population Demographics ...................................................................................................49

    3.0 Background ...................................................................................................................51

    3.1 Methods ........................................................................................................................52

    3.2 Results ...........................................................................................................................52

    3.2.1 Total population .....................................................................................................52

    3.2.2 Seasonal distribution of cases ................................................................................54

    3.2.3 Fetal Gender ...........................................................................................................56

    3.2.4 Maternal Age .........................................................................................................57

    3.2.5 Maternal Ethnicity..................................................................................................64

    3.2.6 Maternal Body Mass Index (BMI) ..........................................................................68

    3.2.7 Maternal Smoking ..................................................................................................72

    3.2.8 Maternal Drugs and Alcohol ..................................................................................72

    3.2.9 Previous Maternal obstetric history ......................................................................73

    3.2.10 Relevant gynaecological history...........................................................................74

    3.2.11 IVF Pregnancies ....................................................................................................76

    3.2.12 Diabetes Mellitus (IDDM, GDM) ..........................................................................76

    3.2.13 Maternal Hypertension ........................................................................................80

    3.2.14 Maternal Infection ...............................................................................................82

    file:///C:/Users/Julie%20Man/Documents/Stillbirth/Thesis/Julie%20amended/no%20coloured%20lines%20final%20thesis%20%203.docx%23_Toc437620219 file:///C:/Users/Julie%20Man/Documents/Stillbirth/Thesis/Julie%20amended/no%20coloured%20lines%20final%20thesis%20%203.docx%23_Toc437620225 file:///C:/Users/Julie%20Man/Documents/Stillbirth/Thesis/Julie%20amended/no%20coloured%20lines%20final%20thesis%20%203.docx%23_Toc437620230

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    3.2.15 Multiple pregnancies ...........................................................................................84

    3.3 Discussion ......................................................................................................................85

    4. Cause of death ....................................................................................................................88

    4.0 Background .........