Title: C-STICH 2: Rescue Cervical Cerclage To Prevent Miscarriage and Preterm Birth a Randomised Controlled Trial
Funder: Department of Health and Social Care

Abstract: Design A randomised controlled, multicentre trial (RCT) with internal pilot and a nested qualitative study and cost-effectiveness analysis. Setting Maternity units within the UK, utilising established CSTICH network of over 60 sites. Target Population Pregnant women presenting with premature cervical dilatation and exposed, unruptured fetal membranes will be invited to take part in a RCT of rescue cervical cerclage (RCC) vs no cervical cerclage. Inclusion Criteria: Premature cervical dilatation with exposed, unruptured fetal membranes, singleton pregnancies, gestational age 16+0 to 27+6 weeks, viable pregnancy confirmed by fetal heart activity and willing and able to give informed consent Exclusion Criteria: significant vaginal bleeding as judged by clinician, evidence of maternal / fetal infection as judged by clinician (e.g. fever, systemically unwell, offensive discharge), significant uterine contractions as judged by clinician, multiple pregnancy Health technology being assessed: RCC +/- other usual adjuncts (e.g.progesterone/antibiotics/tocolytics) will be compared with no RCC +/- other usual adjuncts . The other adjuncts will be at the discretion of the clinical team caring for the women. This trial will be pragmatic and will employ randomisation minimisation by site, intention to use other adjunctive treatment. Minimisation criteria will be confirmed utilising data from the proposed audit of standard care, prior to grant commencement. We feel this pragmatic trial design has facilitated a large network of sites in CSTICH and is much more acceptable to both clinicians and women. Treatment allocation: Participants will be randomised on-line via a secure internet facility in a 1:1 ratio. A 'minimisation' procedure using a computer-based algorithm will be used to avoid chance imbalances in important prognostic variables. Outcomes: Primary obstetric outcome: Composite of miscarriage, stillbirth and neonatal death within 7 days of birth. Secondary outcomes: Core outcome set for preterm birth, all 13 outcomes. Two year outcomes: Assessment of developmental attainment using the PARCA-R. Parent questionnaires to collect data on specific diagnoses at 2 years e.g. cerebral palsy. Sample size: 260 women. We anticipate a sample size of 260 women (130 each arm) with exposed fetal membranes, assuming a 60% event rate in the expectant group and a 40% event rate in the rescue cerclage group with 90% power and alpha set at p=0.05. Project timetables including recruitment rate: Pilot phase 24 months, to include 6 month setup with 12 (wave 1) lead sites opening. Continued site opening at 4 per month through the pilot to approximately 60 sites. This will facilitate an accurate calculation of recruitment rate potential across all sites. Main trial- if pilot criteria met then continue with further 24 months recruitment followed by 6 months follow-up for the primary outcome and 2.5 years total follow-up for the 2 year developmental outcomes. Analysis and reporting 6 months. Total study length 7 years. Expertise in team: The team comprises the CSTICH trial team, experts in miscarriage and preterm birth, methodologist and statisticians (Birmingham Clinical Trials Unit), midwifery, bereavement, neonatologist, qualitative and health economics. We have linked with The Netherlands and Australia and have included co-applicants who agree to seek local funding and run the same trial protocol internationally to facilitate IPD meta-analysis.

Lay abstract: A cervical cerclage is the placement of a stitch to keep the neck of the womb closed. A stitch can be placed in a planned way because of a perceived risk of pre term birth based on a woman’s pregnancy history or because the neck of the womb is shorter than normal on an ultrasound scan but still closed. Sometimes the neck of the womb can start to open early and the bag of water around the baby can come through the neck of womb. If this happens between 16 and 28 weeks of pregnancy an emergency /rescue stitch can be performed to try and delay delivery. Prolonging the pregnancy so that the baby can be born when they are bigger and stronger may give them a better chance of surviving and suffering from fewer complications of prematurity. Doctors do not know if a rescue cerclage works. There is some evidence it may prolong pregnancy but it is possible that it may also speed up delivery by causing infection or cause damage to the neck of the womb of the mother. It is therefore very important to perform a study to decide if rescue cerclages delay delivery and if it does whether this benefits the baby (and mother). The best way to work out if rescue cerclage works, and is safe, is to ask women to be randomly allocated to the treatment. This is what we need to do to ensure we know what is best for future women and babies to prevent harm. This study will ask women who have an open neck of the womb with the bag of waters around the baby coming through, to have either a rescue stitch or no rescue stitch the treatment arm will be decided by a process that randomly allocate to one group or the other. All women in the study irrespective of the allocated group will be able to have other treatments that may help prolong pregnancy such as antibiotics, progesterone and medicines that stop the womb contracting (although none of these have been proven to delay labour or improve health of babies). The study team will collect what happens to the mum and baby from their medical notes. All babies will also be reviewed at 2 years of age to assess how they are developing by a postal questionnaire completed by the parents.

Research activity codes: 6.4 SURGERY
Health categories: REPRODUCTIVE HEALTH AND CHILDBIRTH