Title: Cerclage Suture Type for an Insufficient Cervix and its effect on Health outcomes (C-STICH)
Funder: Department of Health and Social Care

Abstract: Approximately 50,000 babies are born prematurely. Approximately 1,500 of them die. Moreover, an early birth puts survivors at risk of serious long-term disabilities. These outcomes pose a significant burden on parents and have significant economic implications on health services. It is estimated that 10% of healthcare recourses in developed countries are spent on treating diseases in children resulting from preterm birth (PTB). Cervical incompetence is one of the important causes of PTB for which cerclage has been one of the established management options. A recent Cochrane review showed a trend to a reduction in neonatal death and neonatal morbidity, neither alone was significant. Traditionally, clinicians have used Mersilene tape (a braided suture) for cervical cerclage because of its perceived strength and ease of removal. However, braided sutures, particularly mesh-like macroporous sutures, have been associated with an increased risk of infection and operative complications in other surgical disciplines. Both low-grade chronic and acute infections are risk factors for PTB. Some surgeons opt to use monofilament sutures for cerclage. Conversely, detractors suggest that monofilament sutures are not as strong and can potentially traumatise the cervix at insertion. However, these claims are not substantiated by any scientific or clinical evidence. Hypothesis: Based on the above, we hypothesise that the use of monofilament sutures are associated with reduced risk of miscarriage and perinatal mortality after cerclage. Preparatory work: We conducted a national survey of O&G consultants, which confirmed variability in practice - with 86% and 14% reported using braided and monofilaments sutures for cerclage procedures respectively. Significantly, 75% of respondents stated that there was no guidance for which suture material to use within their units. We conducted a systematic literature review and identified only 2 non-randomised studies (NRS). The NRS meta-analysis demonstrated that monofilament sutures, compared to Mersilene, were associated with a pregnancy loss rate of 4% compared to 16% respectively (OR 0.24 95% CI 0.06 - 0.96). We ran a small feasibility RCT to test protocol, recruitment strategy, decline rates and data collection (ISRCTN17866773). Aim: The overall aim is to investigate the clinical effectiveness of nylon monofilament suture material in reducing pregnancy loss rate following cervical cerclage compared to the Mersilene suture. Plan: The original sample size for C-STICH was informed by our meta-analysis of the available evidence with some allowance made for the fact that this evidence was non-randomised. Here, the pregnancy loss rate was 7.1% with monofilament sutures compared to 19% with braided sutures, a reduction of 66% (RR: 0.34, 95% CI: 0.18 to 0.63). A total sample of 326 women would be enough to detect a difference of this size with 90% power (p=0.05). However, we inflated this to a total sample target of 900 (gaining full outcome data on 878) which enabled us to detect a more plausible relative reduction of 41% (19% with braided to 11.2% with monofilament) with 90% power (p=0.05). Given there was some uncertainty around the estimates of pregnancy loss, it was agreed that the DMEC would monitor the overall (pooled) event rate throughout the study to ascertain how any deviation from the original assumptions would impact on the sample size calculation. Indeed, in July 2017 the DMEC advised the C-STICH TMG that the current estimate of pooled event rate was lower than anticipated and may impact on the trials ability to detect a difference between groups, should one exist. They advised that to maintain 90% power to detect the same relative reduction of 41% the sample size should be increased to 2050 women. Benefits: If the currently perceived benefit of monofilament sutures is confirmed, this policy will be adopted nationally and can potentially save more than 300 babies from dying per annum in the UK. Moreover, reducing the risk of prematurity will reduce neonatal unit and hospital stay, the morbidity associated with early gestation and the associated long-term morbidity. The marginal difference in cost of the sutures will ensure any reduction of pregnancy loss is cost-effective.

Lay abstract: Every year approximately 3750 women in the UK will have complications where their cervix (the neck of the womb) becomes loose and opens during the early months of pregnancy. This can require a stitch being sewn into the cervix in an attempt to keep it closed. This is often referred to as ‘cervical suture’ or ‘cervical cerclage’. If this procedure is not performed the cervix can open too early and can result in a miscarriage or premature birth. Inserting a stitch into the cervix does not guarantee to keep the cervix closed, but it can sometimes allow the pregnancy to continue for a few more weeks. The stitches used for this procedure are available in different sizes and materials. Some of the stitch threads are made from a single, smooth fibre (e.g. nylon) while others are composed of many fibres which are braided to form a fine ‘rope’ or ‘net-like’ structure. A survey of consultants in the UK has shown most use braided threads when they stitch the cervix merely because it is the traditional material used and because it is thought to offer strength and enhanced support to an otherwise loose cervix. However, the survey also revealed that some surgeons are concerned that braided stitches can increase the risk of infection as the spaces between the woven fibres could facilitate an environment for infection to grow. Infection could then spread upwards into the womb and cause serious complications during pregnancy and for both the mother and her baby, including premature labour. It is therefore essential to investigate whether the thread-type used for stitching the cervix increases or decreases risk of infection. The C-STICH study will therefore compare outcomes from the use of either smooth or braided stitches during this procedure. The results of this study can potentially save the lives of more than 300 babies a year in the UK alone who would otherwise be at risk of severe prematurity or miscarriage. The best way to compare the two methods of treatment is to undertake a clinical trial where the decision regarding the type of stitch to be used is independent, and thus ensures the decision is generated randomly. Computer software, specifically designed for this purpose will be used, at a specialised unit at the University of Birmingham (Birmingham Clinical Trials Unit). Eligible pregnant women can opt to be part of the C-STICH study if they are due a planned stitch in the cervix during their pregnancy. Apart from the type of thread used, participants in the C-STICH study will receive identical medical treatment. Several pregnancy outcomes will be collected though the central outcome for the study, as decided by the groups of women consulted, will be the risk of losing a baby during pregnancy or within a week of birth. Information will also be collected concerning the number of weeks pregnancy lasted prior to birth; whether the baby was admitted to a Neonatal Unit; the length of stay in the unit and any sign of vaginal or womb infection.

Research activity codes: 6.3 MEDICAL DEVICES
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH