Pre-pregnancy Obesity, Pre-existing Diabetes, and the Risks of Serious Adverse Fetal Outcomes

293 Pages·2016·6 MB·English

Pre-pregnancy Obesity, Pre-existing Diabetes, and
the Risks of Serious Adverse Fetal Outcomes

Peter William George Tennant
Submitted for the degree of Doctor of Philosophy

Institute of Health & Society, Newcastle University

June 2016

DECLARATION
I declare that this Doctoral Statement is my own work. I have correctly acknowledged the
work of others, in accordance with University and Institute guidance on good academic
conduct. No part of the material offered has been previously submitted for a degree or other
qualification in this or any other university. For joint works, my independent contributions
have been outlined in the appropriate co-authorship forms.
SIGNATURE

DATE
27 June 2016

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ABSTRACT
The epidemics of obesity and diabetes are two of the leading threats to health in the 21st
century. Maternal obesity complicates a large and increasing minority of pregnancies, and
pre-existing diabetes is one of the most common maternal chronic health complications of
pregnancy. This Doctoral Statement presents a portfolio of six published articles that draw on
the North of England’s long-standing population-based registries of maternal and perinatal
health to investigate the effects of pre-pregnancy obesity and diabetes on a range of serious
adverse pregnancy outcomes.
The first two articles examined a cohort of pregnant women who delivered in five of the
region’s hospitals during 2003-2005 to explore the associations between maternal body
mass index and the risks of, 1) congenital anomaly and 2) fetal and infant death. The next
three examined a cohort of pregnant women with pre-existing diabetes who delivered during
1996-2008 to explore the effects of the condition on, 1) congenital anomaly, 2) birth weight,
and 3) fetal and infant death. The final article examined women with pre-existing diabetes
who had delivered two successive pregnancies to explore the influences of recurrent adverse
pregnancy outcome. Maternal pre-pregnancy obesity and diabetes were both associated with
increased risks of congenital anomaly, stillbirth, and infant death, with stronger effects for
diabetes than obesity. In diabetes, peri-conception glycaemic control was strongly associated
with birthweight and the risks of congenital anomaly, stillbirth, and infant death, and previous
adverse outcome was associated with a doubled risk in the second pregnancy.
For each article I provide a contemporary analysis of its contribution to the literature and
critique of the methodology. The wider relevance of the research is also considered by
discussing the evidence for causality, potential mechanisms, and implications for public
health. Finally, I reflect on my individual contributions and my development towards an
independent epidemiologist.

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ACKNOWLEDGEMENTS
Producing my PhD has been far more than just a challenge of academic exertion. I would
therefore like to thank all those who have helped me in one way or another during these past
years, whether intellectually, emotionally, or otherwise. There are too many to name, or even
recall, individually but the following especially come to mind.
Thanks first to my supervisors Judith Rankin and Ruth Bell for providing me with the
opportunity to carry out this work and for their advice, knowledge, patience, and
encouragement. I was not always the easiest student to supervise, and it may often have
seemed like a thankless task, but I really do appreciate all their time, energy and wisdom.
Thanks next to all my co-authors for their invaluable contributions and insight, especially
Rudy Bilous for his expert clinical perspective and Svetlana Glinianaia, who I thoroughly
enjoyed working with, not just for her interesting and thoughtful questions, but because of her
kind nature and truly delicious ‘grated cake’. Thanks also to the all the funders who
supported this research (the Newlife Foundation, NHS North of Tyne, Diabetes UK, and the
South Tees Hospitals NHS Foundation Trust).
Thanks to the staff at the former Regional Maternity Survey Office – particularly Mary Bythell,
Nicola Miller, and Danielle Crowder – for their unending work running and maintaining the
various registers, for answering my inquiries so politely and efficiently, and for providing such
a fantastic collection of nibbles at the annual Christmas ‘pot luck lunch’. Further thanks to all
the clinical staff throughout the region that collected and supplied data to the registers, and to
the funding organisations that supported them (the region’s former Primary Care Trusts, the
Northern England Strategic Clinical Networks, the Healthcare Quality Improvement
Partnership, and Public Health England).
Thanks to all those people with who I shared an open plan office with – particularly Kate
Best, Lindsay Bramwell, Svetlana Glinianaia, Louise Hayes, Nicola Heslehurst, Susan
Hodgson, Tanja Pless-Mulloli, Judith Rankin, Judy Richards, and Emma Slack – for their
patience with my unpredictable mood, and for providing such amusing conversation and
scrumptious snacks.
Thanks to my mentor Mark Gilthorpe for his invaluable advice and perspective, for his
continued support, and for giving me the confidence to continue in academic research.
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Thanks to my employers at the School of Healthcare in the University of Leeds (Linda
McGowan, Janet Hirst, and Andrea Nelson) for giving me the time and space to finish my
PhD without pressure or criticism of the ever-extending timeframe.
Thanks to my annual assessors (Jean Adams and Richard Thompson) and thesis examiners
(Fiona Matthews and Sarah Wild) for their helpful thoughts, feedback, and advice.
Thanks to my Dad and Tuba Mazhari for reading some of my early drafts and giving me the
confidence and belief to push on. Thanks also to my Dad for paying for my survival when I
was too ill to work, without quibble or judgement.
Special thanks to my dear friends Erin Graybill, Suzanne McDonald, Nicki O’Brian, Lucia
Rehackova, Shannon Robalino, and Ângela Rodrigues for providing advice, support,
encouragement, distraction, fun, and laughter whenever I most seemed to need it. I will
always look back fondly on my time in Newcastle, largely due to their true and loyal
friendship.
Special thanks to the NHS for helping me to keep (mostly) functioning without charging for
my misfortune. Thanks especially to Johnathan Pearce, for his remarkable patience (listening
to me talk about my anxieties for the best part of three years) and his tremendous wisdom
and insight, which have genuinely changed my life.
Finally, and most importantly of all, I would like to express my deepest thanks to my dearest
Anna. Not just for her unending patience, support, and forgiveness; nor for her infinite
kindness, comfort, and love; but for her very existence. Even through my very darkest
moments, she kept me going. Without her, I would not have finished this PhD.

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TABLE OF CONTENTS
DECLARATION ........................................................................................................... I
ABSTRACT ................................................................................................................ III
ACKNOWLEDGEMENTS .......................................................................................... V
TABLE OF CONTENTS ........................................................................................... VII
SUBMITTED PUBLISHED WORKS ........................................................................ XII
SUPPORTING PUBLISHED WORKS .................................................................... XIV
LIST OF TABLES .................................................................................................... XV
LIST OF FIGURES ................................................................................................ XVIII
LIST OF ABBREVIATIONS ..................................................................................... XX
CHAPTER 1: INTRODUCTION .................................................................................. 1
1·1 OVERVIEW .................................................................................................................. 1
1·2 EXPOSURES ............................................................................................................... 2
1·2·1 The burden of non-communicable disease ...................................................... 2
1·2·2 Obesity ................................................................................................................ 3
1·2·2·1 Definition ....................................................................................................... 3
1·2·2·2 Prevalence .................................................................................................... 3
1·2·2·3 Risk factors ................................................................................................... 4
1·2·2·4 Pathophysiology ............................................................................................ 6
1·2·2·5 Obesity in pregnancy .................................................................................... 8
1·2·3 Diabetes ............................................................................................................ 10
1·2·3·1 Definition ..................................................................................................... 10
1·2·3·2 Diagnosis .................................................................................................... 11
1·2·3·3 Prevalence .................................................................................................. 12
1·2·3·4 Risk factors ................................................................................................. 14
1·2·3·5 Pathophysiology .......................................................................................... 17
1·2·3·6 Diabetes in pregnancy ................................................................................ 19
1·3 OUTCOMES ............................................................................................................... 21
1·3·1 Serious adverse fetal outcomes...................................................................... 21
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1·3·2 Congenital anomalies ...................................................................................... 22
1·3·2·1 Definition ..................................................................................................... 22
1·3·2·2 Prevalence .................................................................................................. 23
1·3·2·3 General risk factors ..................................................................................... 24
1·3·2·4 Obesity and the risk of congenital anomalies............................................... 25
1·3·2·5 Diabetes and the risk of congenital anomalies............................................. 26
1·3·3 Stillbirths .......................................................................................................... 28
1·3·3·1 Definition ..................................................................................................... 28
1·3·3·2 Prevalence .................................................................................................. 28
1·3·3·3 General risk factors ..................................................................................... 29
1·3·3·4 Obesity and the risk of stillbirth .................................................................... 30
1·3·3·5 Diabetes and the risk of stillbirth .................................................................. 30
1·3·4 Infant deaths ..................................................................................................... 31
1·3·4·1 Definition ..................................................................................................... 31
1·3·4·2 Prevalence .................................................................................................. 31
1·3·4·3 General risk factors ..................................................................................... 31
1·3·4·4 Obesity and the risk of infant death ............................................................. 33
1·3·4·5 Diabetes and the risk of infant death ........................................................... 33
1·4 SUMMARY ................................................................................................................. 35
CHAPTER 2: SUBMITTED PUBLISHED WORKS .................................................. 36
2·1 OVERVIEW ................................................................................................................ 36
2·2 RANKIN et al 2010 (MATERNAL BMI & CONGENITAL ANOMALIES) .................... 38
2·2·1 Overview ........................................................................................................... 38
2·2·2 What was known .............................................................................................. 38
2·2·3 What this study added ..................................................................................... 39
2·2·4 Contribution of the candidate to this work ..................................................... 39
2·2·5 Manuscript ........................................................................................................ 40
2·2·6 Corrigendum ..................................................................................................... 50
2·2·7 Commentary ..................................................................................................... 51
2·3 TENNANT et al 2011 (MATERNAL BMI & FETAL & INFANT DEATH) ..................... 53
2·3·1 Overview ........................................................................................................... 53
2·3·2 What was known .............................................................................................. 53
2·3·3 What this study added ..................................................................................... 53
2·3·4 Contribution of the candidate to this work ..................................................... 54
2·3·5 Manuscript ........................................................................................................ 55
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