Study to evaluate the prevalence, importance, and treatment of women with congenital uterine anomalies

Background Congenital uterine anomalies result from the abnormal formation, fusion, or resorption of Müllerian duct during fetal life. They are present in 1–10% of the unselected population, 2–8% of infertile women, and 5–30% of women with a history of miscarriage. The discrepancy in the prevalence rates are likely to be related to the use of different diagnostic tests and the use of non-standardized classification systems to diagnose these anomalies. These anomalies have long been associated with increased rates of subfertility, miscarriage, preterm delivery, and other adverse fetal outcomes. However, such associations might be artefactual. Over the years, surgical treatments have been offered to women diagnosed with congenital uterine anomalies. Abdominal metroplasty is associated with significant morbidities, such as prolonged hospital stay, long post-op recovery, intra-abdominal adhesions, uterine rupture in subsequent pregnancies etc. In the recent years, hysteroscopic metroplasty has taken over abdominal approach as this procedure is deemed safer. However, no randomised controlled trial has been performed to assess its risks and benefits. Aims The overall aim of the thesis is to evaluate the prevalence of congenital uterine anomalies; the reproductive impact of these anomalies; and treatment available for women with uterine malformation (in particularly women with septate or subseptate uteri). Methods Systematic reviews I have performed systematic reviews and meta-analyses of the available literature on four aspects of congenital uterine anomaly research: Prevalence of congenital uterine anomalies; impact of these anomalies on reproductive outcomes; treatment options for congenital uterine anomalies; and finally reproducibility of three-dimensional ultrasound scan in diagnosing these anomalies. Prevalence of Congenital Uterine MAlformations (PUMA) in High Risk Women Three groups of women were recruited prospectively into this study over a period of 16 months according to specific inclusion and exclusion criteria. Control group consisted of women who only had previous term deliveries (birth at 37 or more weeks gestation), Preterm group consisted of women with history of preterm +/- miscarriage and finally Miscarriage group consisted of women with history of miscarriage +/- term deliveries only. All these women underwent three-dimensional transvaginal ultrasound scans according to standard operating procedure. Diagnoses of congenital uterine anomalies were recorded. Ultrasound parameters (uterine length, cervical length, uterine volume; and cervical volume) were measured and recorded where possible. Development of a Randomised Controlled Trial of Hysteroscopic Resection for Uterine Septae Part of the thesis is to aid the design of a multi-centred randomised controlled trial to assess the effect of hysteroscopic surgery for uterine anomalies on various pregnancy outcomes in women with septate uteri. Two surveys were conducted first, to ask the general public and medical experts with a proven interest, to give their opinion on the need and feasibility of a randomised controlled trial of hysteroscopic resection for uterine septae. With the survey results from general public and experts available, protocol for a prospective randomised pilot feasibility study was designed as part of the thesis. The primary objective of the pilot study is, to test the hypothesis that hysteroscopic septal resection in women with septate uteri and a history of miscarriage or preterm birth, improves reproductive outcomes. Applications were put in to secure study funding, ethical and R&D approvals. Results Systematic reviews The systematic reviews demonstrated the prevalence of uterine anomalies diagnosed by optimal tests was 5.5% in the unselected population, 6.5% in infertile women, 12.9% in those with miscarriages, 24.5% in those with miscarriages and infertility, and 36% in those undergoing IVF. Arcuate and septate/subseptate uteri were the most common anomalies. The reviews also showed that women with congenital uterine anomalies appeared to have increased risks of poor reproductive outcomes (including decreased conception rate; increased miscarriage rate, and preterm birth rate) but this is dependent on the types of anomalies. It was shown in the systematic review that surgical division of a uterine septum improves reproductive outcome by reducing miscarriage and increasing term birth. However, the exact effects are dependent on the type of surgery performed and the underlying defect. Surgery for unification defects, such as the bicornuate uterus, does not appear to have any impact on reproductive performances. Our systematic review showed that three-dimensional ultrasound has high inter-observer agreement in diagnosing congenital uterine anomalies. The diagnostic reproducibility was dependent on the classification system used in diagnosing these anomalies. Unfortunately all these systematic reviews only consisted of observational studies, with varying study qualities and they have significant clinical heterogeneity among studies, including use of different diagnostic tests of unknown accuracy; different classification systems and varying background populations. Prevalence of Congenital Uterine MAlformations (PUMA) in High Risk Women In this study, there were a total of 50 women with abnormal shaped uteri and 161 women had normal uteri. There were more abnormal uteri in the miscarriage group than the other groups. 13.2% were abnormal in the control group, 33.7% were abnormal in miscarriage group, and 16.7% were abnormal in the preterm group. The most common type of anomaly seen was arcuate uterus (90%). High risk women with congenital uterine anomalies were found to have shorter uterine lengths. However, other ultrasound parameters such as cervical length and myometrial volume of uterine body showed no significant difference when compared to control group. The surprising finding was the larger cervical volume in women with history of miscarriage as opposed to those of low risk population. Development of a Randomised Controlled Trial of Hysteroscopic Resection for Uterine Septae Survey results from the general public and clinicians demonstrated support and willingness of these people in participating in the trial. We have set up a patient group (Patient led Research into Early Pregnancy and Reproduction: PREPARE) to further help us in study design. A full protocol for a pilot study was designed with input from patients, clinicians, researchers; and statisticians. Application for a Pump Priming grant by the Nottingham University Hospitals Charity and Nottingham University Hospitals Department of Research and Development was approved for this study. Towards the end of my thesis, the pilot trial had obtained ethical and R&D approval and was ready to start. Conclusions The systematic reviews carried out as part of the thesis have confirmed the lack of evidence in various aspects of congenital anomalies, due to variable study designs, background population, the lack of standardised diagnostic tools and classification system. Even though the prevalence of uterine anomalies appeared to be increased in high risk populations, the evidence of their associations with poor reproductive outcomes and the benefit of surgical treatments remain debatable. It was shown by our systematic review that three-dimensional ultrasound scan is a reproducible tool in diagnosing congenital uterine anomalies. Our prospective study with a control group further confirmed that congenital uterine anomalies are more common in women with history of miscarriage. However, this does not appear to be the case in women with history of preterm births. In this study, women were assessed prospectively using three-dimensional ultrasound scan. Women with history of miscarriage have shorter uterine lengths. Surprisingly, women with history of miscarriage had larger cervical volume than the control group. By using all the information from systematic reviews and prospective study I performed, the thesis finishes by setting up a pilot study of randomised controlled trial of hysteroscopic resection for uterine septae