Some text in this chapter has been reproduced from our study results paper,22 published under the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited (https://creativecommons.org/licenses/by/4.0/).
C-STICH was a large multicentre, randomised trial designed to assess any difference in the pregnancy outcome comparing monofilament and braided suture material at vaginal CC. Its primary end point showed no difference in pregnancy loss between the materials when performing a vaginal CC. Following conclusion of the C-STICH RCT we can be relatively confident that the use of a monofilament suture is unlikely to have a substantial impact on pregnancy loss compared to the use of a braided suture. The uncertainty around our comparative estimate for the pregnancy loss outcome is, at most, 2% in favour of monofilament in absolute terms. The prevention of pregnancy loss means that a small difference in outcomes would still be important clinically, and while this margin may not completely rule out missing a clinically important difference, we consider this scenario to be unlikely.
This was a well-conducted trial which has sought to establish the optimal suture thread with scientific rigour. One of the strengths of this trial is the appropriate increase in the sample size, implemented following the independent DMEC advising the TMG of a lower-than-anticipated pooled event rate during the trial and, thus, recommending the sample size was increased from 900 to 2050 women to ensure a conclusive trial was delivered. In the original retrospective study that was used to inform the sample size, pregnancy loss rates were between 12% and 9%.15 Within C-STICH, the pregnancy loss rate was 8%. There are several possible reasons why the observed event rate was lower than anticipated. One reason is that women with complicated pregnancy histories who were perceived to be at higher risk of pregnancy loss were not approached about the trial, although from our screening logs and monitoring with sites we identified high levels of approach to women undergoing a CC. Alternatively, this lower rate could represent improvements in outcomes secondary to changes in preterm prevention in the UK with the Saving Babies Lives Care Bundle version 2 advocating care within specialist clinics and the expanded use of cervical length screening. It may also represent an increased use of CC in women who have a low background risk of pregnancy loss. The rate within the trial is consistent with the 2017 Cochrane review of CC where the pregnancy loss rate in the cerclage group was 10.7%, with this review being published during the trial.11 There were no differences between the suture threads in terms of time from conception to pregnancy end and the prevention of prematurity, with 9% of deliveries occurring before 32 weeks and 28% of deliveries before 37 weeks.
We identified a decreased risk of maternal sepsis in the monofilament group (4%) compared with the braided group (7%) and a decreased risk of chorioamnionitis, of 3%, in the monofilament group compared with 6% in the braided group. The decreased risk of infection in the monofilament group is in keeping with the hypothesis that braided sutures are reservoirs for bacteria that predispose to infection.14 This potential reduction in infectious morbidity could have important health benefits for mothers. A systematic review evaluating the effect of chorioamnionitis on maternal morbidity identified increased risks of haemorrhage, operative interventions and HDU admission.23 This potential benefit in reduced infectious morbidity must be considered relative to the increase in the rate of difficulty in removing the suture (usually close to term) and the need for an anaesthetic for removal.
There were no detectable differences in neonatal outcomes between the two suture threads. The neonatal outcomes collected in this trial are rare neonatal outcomes related to prematurity, and the trial was not powered to detect differences between the two groups. Maternal chorioamnionitis is associated with an increased risk of both early and late neonatal sepsis,23 yet this trial did not detect a difference in clinically diagnosed neonatal sepsis between the monofilament group (11%) and the braided group (13%) [RR 0.90 (95% CI 0.72 to 1.11)]. There was also no significant difference in the proportion of neonates with confirmed neonatal sepsis. There were high levels of neonatal antibiotic use within both groups at 26–27%. The longer-term neonatal consequences of chorioamnionitis are unclear in the medical literature, with some studies reporting an increased risk of adverse neonatal complications and others demonstrating no difference, with most studies only finding a link between histologically confirmed chorioamnionitis and worsening infant neurodevelopmental outcomes.22 Infection in combination with prematurity confers an additional risk of cerebral palsy and a worsening of neurodevelopmental outcomes. There were no long-term neurodevelopmental outcomes collected within C-STICH and, therefore, limited conclusions can be drawn from this finding at present. There is an opportunity within C-STICH to seek funding to evaluate longer-term paediatric outcomes. The maternal infections are outcomes that could be subjected to bias, as the outcome collectors were unable to be masked to the suture thread used and may have been biased in diagnosing infection based upon the hypothesis of the trial.
Cerclage insertion complications included a low rate of ruptured membranes during insertion, occurring in two cases; this is in keeping with the anticipated rate.8 These data can support the counselling of women, with the risk of rupture of membranes during cerclage insertion at approximately 1 : 1000 where the suture is placed electively or on the basis of a short cervix seen on ultrasound. Removal complications for the monofilament group include an increase in clinician-reported difficulty in removing the suture, an increased requirement for anaesthetic and an increase in cervical tears during removal (2% vs. 1%). There were two cases of retained thread in the monofilament group and one case of retained thread in the braided group; these required removal postnatally and this was an unexpected complication of a CC identified through the SAE process. These insertion and removal complications are already-known risks of CC, particularly where a Shirodkar technique is employed, which by definition buries the knot of the suture, but there are limited data published to accurately inform counselling. Therefore, this trial will improve the counselling of women undergoing a CC procedure due to the generalisability and reliability of the trial, having recruited a large proportion of all CCs being placed within units across the UK.
The surgical technique for CC placement was included as a minimisation criterion within C-STICH to ensure balance between the treatment groups in whom bladder dissection was planned. It was hypothesised that a bladder-dissected cerclage would result in a lower pregnancy loss rate, since the placement of a cerclage is closer to the cervical internal OS. In the planned key subgroup analysis of planned bladder dissections, there was evidence of a potential differential treatment effect. In women where it was planned to dissect their bladder during the CC, the rate of pregnancy loss was lower in the monofilament suture group than in the braided group; however, the effect within this stratum was not statistically significant. The result must be interpreted with caution in view of the small number of women within this analysis and its exploratory nature. This is an important area of future research and any reduction in pregnancy loss in this high-risk group is clinically important. Given the low event rate, a further RCT to evaluate this would not be feasible and, therefore, we would recommend utilising a large observational cohort or registry approach.
There was no evidence of a differential treatment effect for concomitant progesterone treatment in our pre-defined subgroup analysis. Whether or not concomitant progesterone is a predictor of pregnancy loss is a prioritised research recommendation within the NICE preterm birth guideline,10 and this trial did not evaluate this. Therefore, we would recommend further research within this cohort utilising the data collected within the C-STICH trial to inform predictors of pregnancy loss and preterm birth.
Study strengths
This study is the largest RCT evaluating suture materials during a vaginal CC. A total of 2049 women, from 56 trusts and 75 individual sites within the UK, were randomised to have their cerclage performed with either monofilament or braided suture threads. The centres varied in their size (related to the number of births and, thus, the number of sutures performed), geographical location and the characteristics of their populations. Standard care was conducted according to national guidance and, thus, the results are generalisable to the UK population.
This trial was robustly conducted with central randomisation and included important minimisation criteria that has allowed a valid comparison to be made between the groups. The primary outcome and the majority of the secondary outcomes collected during the C-STICH trial were objective (rather than subjective descriptions) which allowed a true comparison between the groups with minimal bias. We had a low attrition rate. Primary outcome data were available for 98% of those randomised, and an exploration of the impact of this minimal data loss were undertaken to support the ITT analysis.
Limitations and critique
In our opinion, the trial was designed and conducted in a methodologically robust manner. Nevertheless, there are some limitations of the study that should be considered. There were no long-term infant and paediatric outcomes collected and we did not collect data on the outcomes for women who did not take part in the C-STICH trial. The trial could have been strengthened by further considering the effect of suture thread colonisation on outcomes other than pregnancy loss and preterm birth.
Patient and public involvement
In the C-STICH trial, patient and public involvement (PPI) was utilised in the study design, development and monitoring. We powered the trial to evaluate the difference between suture threads in terms of evaluating pregnancy loss, which is the outcome that was considered the most important following our PPI work. We have continued to receive support from our PPI representatives and their voice was essential in supporting the increase in the sample size to ensure a powered trial and in reopening the trial and extending recruitment timelines to allow us to reach sample size. The trial was supported by patient advocacy groups such as the Miscarriage Association and Tommy’s. We aim to develop infographics explaining the results of the trial to support dissemination.
Generalisability
The sites participating in C-STICH were geographically spread across the UK and included large preterm birth centres performing significant numbers of cerclages and small sites performing less frequent cerclages. This improved the generalisability of the results for women. Women in the trial also had a broad range of indications for CC, which reflected the population of women who have a CC to reduce pregnancy loss. The exclusion criteria were kept to a minimum and the heterogeneity of the population was reflected in the characteristics of the trial participants.