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Reproductive Outcomes in Women with Low Ovarian Reserve

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Reproductive Outcomes in Women with Low Ovarian Reserve REPRODUCTIVE OUTCOMES IN WOMEN WITH LOW OVARIAN RESERVE By DR BALA MURUHAN KARUNAKARAN A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY Institute of Metabolism and Systems Research College of Medical and Dental Sciences University of Birmingham February 2019 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. Abstract The number of women with low ovarian reserve seeking fertility treatment is increasing, due to advancing maternal age at conception. Women with low ovarian reserve have a low IVF success rate. This thesis aims to increase our understanding of women with low ovarian reserve, their reproductive outcomes and their reproductive physiology. The evidence is synthesised using two systematic reviews, a prospective cohort study, a retrospective analysis of data and two qualitative studies. The main findings are: 1. Low ovarian reserve, quantified by AFC, AMH and FSH, is associated with low live birth rates and incidences of pregnancy loss after assisted reproduction. 2. There is inter-cycle variation in AFC, AMH and FSH in women. In this cohort, FSH and AFC appear to have a higher magnitude of variation in comparison to AMH. 3. There is inter-cycle variation in AFC, AMH and FSH in women with low ovarian reserve. 4. Clinicians find treating women with low ovarian reserve challenging. Women with low ovarian reserve are unaware of their low IVF success rates and there is cultural and religious stigma about the acceptance of egg donation. Both clinicians and women with low ovarian reserve express willingness to take part and support research studies. Dedication This thesis is dedicated to my parents, Dr Velupillai Karunakaran and Dr Vasantha Maligah Karunaharan. Without their countless sacrifices and unconditional love, I would not have been able to achieve a fraction of what I have today. My father, Dr Velupillai Karunakaran, a retired obstetrician and gynaecologist, was very proud of me securing my PhD studentship. I sorely miss him and wish he is still with us to see me reach the finishing line. Acknowledgements “If I have seen a little further, it is by standing on the shoulders of giants." Sir Isaac Newton, 1676 My PhD has been a journey with multiple challenges on the way. Without the support of many, it would not have been possible to complete this. I would like to thank my mentor and primary supervisor Professor Arri Coomarasamy, for taking me on in his team and offering guidance and support. I would like to thank my second supervisor, Dr Ioannis Gallos, for his methodology guidance and lending his statistical expertise. I thank my second reviewers Dr Rima Smith and Dr Abey Eapen, as well as my second coder Dr James Cheshire. I would also like to thank Dr Abey Eapen for teaching me AFC and helping me with my scanning. I thank Miss Emily Colley for chaperoning most of my scans, outside normal working hours. I thank Mr Aurelio Tobias for his statistical guidance. I thank Mr Adam Devall and Miss Helen Williams for helping me navigate all the required administration to get my project approved. I thank Mr Yusuf Muhammed for his help with teaching me to create some of the illustrations in this thesis. I thank Dr Justin Chu for providing his study consent form and patient information sheets for me to use as templates. I thank Derick Yates and Jon Andrews for their help with formulating search strategies for the systematic reviews. I thank Dr Rebecca Man for her continuous moral support, encouragement and comments on this thesis. I thank Dr Melody Redman, Dr Tina Verghese, Dr Catherine Dunlop, Dr Amie Wilson, Dr Donald Masi and Dr Laurentiu Craciunas for their constructive comments on various chapters of this thesis. I would like to thank all the clinical research fellows and lecturers, collectively known as the United Colours of Benetton, at the BWCH for their comradery, support and being a great sounding board for ideas. I would like to thank all the women and clinicians who willingly gave their time altruistically for this project. Table of contents Contents Chapter one: introduction to thesis ................................................................................. 1 In vitro fertilisation ................................................................................................................... 1 The cost of IVF ................................................................................................ 2 The IVF process ............................................................................................... 4 Pituitary down regulation ................................................................................. 5 Controlled ovarian hyperstimulation ............................................................... 5 Ovulation trigger .............................................................................................. 7 The problem of poor response .......................................................................................... 8 Ovarian reserve ........................................................................................................................ 9 Follicle stimulating hormone ......................................................................... 10 Anti-mullerian hormone ................................................................................ 11 Antral follicle count ....................................................................................... 12 Factors affecting ovarian reserve and reproductive outcomes ....................... 13 Ovarian reserve markers and ovarian response ..................................................... 14 Biological mechanisms ....................................................................................................... 15 Inter-cycle variation of ovarian reserve markers .................................................. 16 Aims and objectives of this thesis ................................................................................. 19 Chapter two: inter-cycle variation of antral follicle count, anti-mullerian hormone and follicle stimulating hormone- a systematic review ......................................... 24 Preamble to chapter two ................................................................................................... 25 Abstract ..................................................................................................................................... 26 Introduction ............................................................................................................................ 28 Materials and methods ....................................................................................................... 29 Inclusion and exclusion criteria ..................................................................... 29 Literature search strategy ............................................................................... 29 Study eligibility and selection ........................................................................ 30 Data extraction and analysis .......................................................................... 30 Results ....................................................................................................................................... 31 Characteristics of included studies ................................................................ 31 Quality of the included studies ...................................................................... 33 Inter-cycle variation results ........................................................................... 36 Discussion ................................................................................................................................ 42 Conclusion ............................................................................................................................... 45 Chapter three: ovarian reserve tests (FSH, AMH and AFC) and pregnancy loss: a systematic review and meta-analysis .................................................................... 46 Preamble to chapter three ................................................................................................ 47 Abstract ..................................................................................................................................... 48 Introduction ............................................................................................................................ 50 Methods .................................................................................................................................... 51 Data sources ................................................................................................... 51 Results ....................................................................................................................................... 54 AFC ...............................................................................................................
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