Prior, Matthew
(2018)
Feasibility studies for a trial of septal resection to prevent subfertility and miscarriage.
PhD thesis, University of Nottingham.
Abstract
Introduction
Congenital uterine anomalies result from the abnormal embryological development of the paramesonephric (Müllerian) ducts. Debate surrounding their classification is ongoing. During this PhD project both the American Society for Reproductive Medicine and The European Society of Human Reproduction and Embryology (ESHRE) with the European Society for Gynaecological Endoscopy (ESGE) have published different classification systems.
To adequately assess uterine morphology requires concurrent imaging of the external and internal contours of the uterus. Three-dimensional ultrasound can achieve this view and is more acceptable to women than more invasive tests. In view of the inconsistent classification systems and use of various diagnostic tests data regarding prevalence and effect on reproductive outcome must be interpreted cautiously. Nonetheless, it appears that uterine septa are more prevalent in women with poor reproductive outcomes and associated with infertility, miscarriage and preterm birth. The rationale for septal resection is to restore normal uterine anatomy with the intention of improving reproductive outcome. However all previous studies assessing the effect of septal resection are biased due to their observational design using women as their own controls. There have been no randomised controlled trials.
Aims
The aim was to investigate the hypothesis that a trial of septal resection for women with subfertility or miscarriage is feasible to conduct.
Studies
A non-invasive method for assessing uterine septa is a vital prerequisite for a trial, to allow women to be assessed properly and consented before an invasive operative hysteroscopy is done. Furthermore, a test is required to assess the efficacy of septal resection post-procedure as some women are left with a residual septum. So it was important to establish the diagnostic reliability of three-dimensional ultrasound to identify uterine septa. ESHRE recommended using three-dimensional ultrasound, but few data existed demonstrating its reliability. I conducted two reliability studies. The first found that the intra-rater reliability of experts in uterine anomalies was only moderate. This study was limited as it could not differentiate between the manipulation of uterine volumes, uterine measurements or application of classification systems. A second study assessed the intra- and inter-rater reliability of uterine measurements and then used algorithms to classify the volumes. This showed uterine measurements are highly reproducible with cavity indentation showing the highest intra- and inter-rater reliability (both ICC 0.98). Applying classification algorithms to these measurements showed almost perfect intra and inter-rater agreement.
When designing a trial to definitively establish the efficacy of an intervention it is crucial to ensure it is adequately powered to detect a difference which is important to patients. So next I set out to calculate the minimum clinically important difference for women to consider septal resection. Using survey and interviews I calculated that the median minimum clinically important difference for women with a history of poor reproductive outcome was a change in future risk of miscarriage from 30% to 10%. The sample size required to detect this difference was 118, (59 in each arm) where _=0.05 and (1-_)=0.9.
Between August 2014 and August 2017, 6035 women with subfertility and miscarriage were screened in three settings to identify those eligible to participate. Three-dimensional ultrasound was used as initial screening in a tertiary fertility clinic (n=2846) and recurrent miscarriage clinic (n=189). Around 3000 women underwent two-dimensional ultrasound in the early pregnancy unit, of which five had suspected uterine anomalies and were referred for three-dimensional ultrasound. A uterine septum was present in 15, of whom 13 were eligible to participate in the pilot septal resection trial. So identifying one eligible participant required approximately 464 women to be screened. Divided by patient population, to identify one eligible participant the number of women to be screened using three-dimensional ultrasound was 407 women with infertility, or 27 women with recurrent miscarriage. Approximately one septum was identified per 1500 women who had a two-dimensional scan in the early pregnancy unit.
Subsequently I undertook three studies of the willingness of patients and clinicians to participate in the pilot trial. First I undertook a survey of clinicians. Sixty-seven clinicians responded and approximately half would randomise to a septal resection trial, but only 12 clinicians (18%) showed interest in becoming involved in such a trial. The next study investigated the willingness of eligible patients to participate. In Nottingham, 2 of 13 women were randomised to the study. A survey and interview with women who declined participation found that many had strong views on their treatment, either in favour of, or against resection and did not wish to leave it to chance. The third study assessed the willingness of other units to be involved in the trial. Twelve clinicians from eleven units expressed interest in becoming a trial site, but only one unit went on to randomise 4 further patients. Reasons for non-participation included lack of funding, exclusion from the NIHR Clinical Research Network Portfolio, inadequate access to three-dimensional ultrasound and local service configuration. During the study period six women were randomised.
The final two chapters set out to establish if a septal resection trial is a research priority using two different methods. Firstly an economic evaluation and value-of-information analysis. Value of information is the amount a decision maker should be willing to pay for information prior to making a decision. As resources are finite, these methods can be used to direct future research efforts towards the most efficient studies. Septal resection, was compared with progesterone as a large study, the PROMISE trial, was recently funded. Using existing evidence, namely meta-analyses of biased studies, it predicted that there was no value in conducting further research into progesterone or septal resection as with existing evidence, they were both cost-effective interventions.
Nonetheless, when more uncertainty was introduced based on expert opinion the value of information for both interventions increased. Using the most favourable assumptions for our present level of uncertainty, assuming the usual NHS value of £30,000 for a quality adjusted life year (QALY) the expected value over ten years to the NHS of the information from a progesterone trial was £1.6B compared with £80m for a septal resection trial. The main reason for this was that progesterone has a larger potential treatment population, all women with recurrent miscarriage, rather than just those with a uterine septum. Other trials are therefore a higher priority.
Finally, I established the top research priorities for miscarriage. Miscarriage research uncertainties were identified and prioritised collaboratively by women and healthcare professionals. A priority setting partnership was conducted on the topic of miscarriage using methodology advocated by the James Lind Alliance, a subsidiary of NIHR. A total of 2402 unique questions were identified and refined to 58 summary questions. The top 10 research uncertainties were collaboratively agreed by women who have experienced miscarriage, those affected by miscarriage and healthcare professionals at a final workshop. The top question was “What are the effective interventions to prevent miscarriage, threatened miscarriage and recurrent miscarriage?”. This would include septal resection to prevent miscarriage, but would also be any other potential intervention.
Discussion
The high reliability of three-dimensional ultrasound to diagnose uterine septa was demonstrated. This was dependent on taking uterine measurements, as subjective application of any classification system is less reliable.
The low prevalence of septa and the lack of willingness from patients and clinicians to participate would make a trial prohibitively time consuming or expensive. Furthermore, a uterine septum is not the condition for which resection is performed. Instead resection is to prevent infertility, miscarriage or preterm birth, meaning that ideally three separate trials should be performed.
I demonstrated that funding a trial is unlikely to be the best use of resources as the cost of conducting a trial is high compared with the value of information it could provide to decision makers. However, patients and clinicians still consider
further research in this area a priority. Herein lies the dilemma of whether to pursue a trial, which will provide the highest quality evidence but is likely infeasible, or to consider alternative methodology, albeit with limitations, to help guide women and their clinicians who are considering septal resection.
Collaboration with other international groups is the only way to advance this trial further. For example, the Dutch TRUST trial. TRUST has also had difficult recruiting, but has randomised 43 women over nine years. A collaborative approach between the two studies may lead to the completion of a trial. Nonetheless, TRUST is not adequately powered to detect the minimum clinically important difference and has less stringent criteria for diagnosis of a uterine septum.
Conclusion
Presently, a randomised controlled trial of hysteroscopic septal resection for women with a history of subfertility or miscarriage and a uterine septum is not feasible. The reasons for this are that sufficient women and clinicians are not willing to participate to achieve the required sample size. Furthermore the resource required to recruit enough participants would make the trial prohibitively expensive.
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