Cause and effect of Asherman syndrome Dr Rebecca Deans School of Women and Children Faculty of Medicine August 2016 Acknowledgments Firstly, I would like to express my sincere gratitude to my main supervisor, Associate Professor Jason Abbott. I am appreciative of his continuous support of my Ph.D study and the related research, as well as being grateful for his patience, motivation, and immense knowledge. His guidance helped me throughout the research and writing of this thesis. His eternal energy and motivation is truly inspirational, and although his maddening attention to detail drove me close to insanity, I could not have imagined having a better advisor and mentor for my Ph.D. Besides my main supervisor, I would like to also thank my co-supervisors: Professor William Ledger and Professor Thierry Vancaillie. I am grateful for their insightful comments and encouragement, as well as their hard questions, which drove me to widen my research from various perspectives. It was truly amazing that in spite of their extremely busy lives, they selflessly gave me time and care that was sometimes all that kept me going. My sincere thanks also goes to Dr. Daniel Moses and the team at Spectrum Radiology, whose contribution were invaluable for the perfusion MRI study. Without Dr Moses’ precious support, it would not have been possible to conduct this research. Thanks also goes to Dr Toos Sachinwala, whose great mind for the vascular pathology behind Asherman Syndrome started me along my journey towards the causes and not just the effects of Asherman Syndrome. ii I thank Jinzhu Liu, who gave me endless guidance in the statistical analysis and was always happy to meet and discuss various tests and re-tests of the data at short notice. Not only did she provide statistical advice, but she was also a great sounding board and emotional support throughout the analysis of my data. Last but not least, I would like to thank my family: my husband James and my four children, Thomas, Oliver, Madeleine, and Jeremy – several of whom have been born along the way. They have endured endless weekends without their wife / mother and seen me on the brink of defeat. However, they supported me unquestioningly, and gave me the time and space to devote myself to this very lonely and at times thankless task. Their endless support throughout writing this thesis and my life in general is overwhelming, and I really could not have done this without them. iii Table of contents Chapter title Page Acknowledgements iv List of tables vii List of figures xii Glossary of abbreviations xv Abstract 1 Introduction 3 Chapter 1: Literature review 6 Chapter 2: Gynaecological and obstetric outcomes following surgery for Asherman syndrome 84 Chapter 3: Adhesions barriers and their role in Asherman syndrome 156 Chapter 4: Perfusion MRI in Asherman syndrome 226 Chapter 5: Discussion 281 Conclusions 292 References 295 Appendices 317 iv List of tables List of tables Table Description 1.1 Prevalence of intrauterine adhesions in different populations 1.2 Aetiology of IUA, and proportion of IUA attributable to cause 1.3 Intrauterine adhesions: Hysteroscopic diagnosis, classification, treatment and reproductive outcome (Valle and Sciarra) 1.4 Classification of intrauterine adhesions (Wamsteker, European Society for Hysteroscopy [ESH]) 1.5 Modified classification system of European Society for Gynaecological Endoscopy (ESGE) 1.6 The American Fertility Society classifications of adnexal adhesions, distal tubal occlusion, tubal occlusion secondary to tubal ligation, tubal pregnancies, Müllerian anomalies, and intrauterine adhesions 1.7 Hysteroscopic adhesiolysis of intrauterine adhesions in Asherman syndrome (Donnez and Nisolle) 1.8 A clinicohysteroscopic scoring system of intrauterine adhesions (Nasr) 2.1 Demographic overview of cohort 2.2 Gravidity of cohort v List of tables 2.3 Parity of cohort 2.4 Cause of intrauterine adhesions 2.5 Correlations between grade and cause of Asherman syndrome 2.6 Menstrual function of the women after diagnosis of AS, but prior to adhesiolysis surgery 2.7 Menstrual function of the women post Asherman syndrome treatment 2.8 Pelvic pain 2.9 Fertility 2.10 Pregnancies across grades of Asherman syndrome 2.11 Pregnancies following surgery for Asherman syndrome – maternal outcomes 2.12 Pregnancies following surgery for Asherman syndrome – neonatal outcomes 2.13 Fertility outcomes following hysteroscopic treatment of intrauterine adhesions 3.1 Mean age by group 3.2 Mean age of first and second pregnancy prior to Asherman syndrome 3.3 Gravidity by group 3.4 Parity by group 3.5 Grade of Asherman syndrome by group vi List of tables 3.6 Gynaecological surgical procedures prior to diagnosis of intrauterine adhesions compared between groups 3.7 Non-gynaecological surgical procedures prior to diagnosis of intrauterine adhesions compared between groups 3.8 Responses of women in each group of their perceived cause of Asherman syndrome 3.9 Medical conditions compared between the groups 3.10 Regular medication use compared between the groups 3.11 Number of repeat hysteroscopic resection procedures within six months of index surgery 3.12 Repeat hysteroscopic resection procedures greater than six months following index surgery for recurrent intrauterine adhesions 3.13 Number of pregnancies prior to the diagnosis of Asherman syndrome 3.14 Outcomes of the first pregnancy prior to the diagnosis of Asherman syndrome 3.15 Maternal complications compared between groups 3.16 Outcomes of second pregnancy prior to the diagnosis of Asherman syndrome 3.17 The number of pregnancies defined by group prior to AS vii List of tables 3.18 Maternal complications in live births prior to the diagnosis of Asherman syndrome (AS) 3.19 Maternal complications in live births prior to the diagnosis of Asherman syndrome (AS) according to grade of AS 3.20 Maternal complications in live births prior to the diagnosis of Asherman syndrome (AS) grouped according to grade of AS 3.21 Mean age of first and second pregnancy following Asherman syndrome 3.22 Outcomes of the first pregnancy following adhesiolysis 3.23 Fetal complications following first pregnancy 3.24 Fetal complications in the second pregnancy following index surgery 3.25 Maternal complications in the second pregnancy following index surgery 3.26 Fetal complications in the third pregnancy following index surgery 3.27 Live birth weights in the first and second pregnancy following index surgery 3.28 Combined complications for pregnancies prior to AS 3.29 Maternal complication according to grade of Asherman syndrome 3.30 Sensitivity analysis 4.1 Demographic Data viii List of tables 4.2 Summary of perfusion studies for the group of women with Asherman syndrome 4.3 Perfusion indices according to grade of Asherman syndrome 4.4 Perfusion indices according to number of procedures 4.5 Menstrual status before surgery and perfusion indices 4.6 Analysis of perfusion indices for lower grade Asherman syndrome compared to women with complete cavity obliteration 4.7 Analysis of perfusion indices for women with Asherman syndrome compared to control group 4.8 Overall total perfusion (TP) vs. region of interest (ROI) in the same study ix List of figures List of figures Figure Description 2.1 Tuohy needle with a bevelled edge attached to radio opaque dye 2.2 Hysteroscopy introduced with Tuohy needle in parallel 2.3 Radiographic image of the uterus where the radio opaque dye has entered the vasculature 2.4 Radiographic image showing radio opaque dye injected into the endometrial cavity, showing an anatomically restored endometrial cavity 2.5 Patient disposition following database identification 2.6 Grade of Asherman syndrome 2.7 Number of hysteroscopic synaechiolysis procedures required per patient to treat their IUA for the 154 women in the cohort 2.8 Flow chart illustrating the outcomes of the 157 pregnancies following hysteroscopic synaechiolysis 2.9 Time to pregnancy 3.1 Kaplan-Meier survival curve including only cases where pregnancies occurred, censored for non-live birth events x List of figures 3.2 Kaplan-Meier curve including only cases where pregnancies occurred and including all pregnancy types with no censoring 3.3 Kaplan-Meier curve censored for live births 3.4 Kaplan-Meier curve illustrating all pregnancies in the control and SeprafilmTM group 4.1 MRI pelvis sagittal and coronal planes used to place the four circumferential regions of interest at the upper cavity 4.2 MRI pelvis sagittal and coronal planes used to place the four circumferential regions of interest at the mid cavity 4.3 MRI pelvis sagittal and coronal planes used to place the four circumferential regions of interest at the lower cavity / isthmus 4.4 Region of interest placed at the psoas in the mid uterine cavity 4.5 Perfusion image of the uterus – mean below the region of interest 4.6 Perfusion image of the uterus – mean between the region of interest 4.7 Perfusion image of the uterus – mean above the region of interest 4.8 Pregnancy outcomes in the women pregnant 4.9 ROC pre-operative total perfusion (TP), comparing Grade 4 to Grades I-III xi List of figures 4.10 ROC pre-operative time to peak perfusion (TTP) comparing Grade IV to Grades I-III 4.11 ROC pre-operative gradient of perfusion (GP) comparing Grade IV to Grades I-III 4.12 ROC pre-operative rate of perfusion (RP) comparing Grade 4 to Grades I-III 4.13 ROC pre-operative total perfusion (TP) comparing inoperable IUA with all other AS women 4.14 ROC pre-operative time to peak perfusion (TTP) comparing inoperable IUA with other