Health Technology Assessment (Aug 2024)
Cerclage suture type to prevent pregnancy loss in women requiring a vaginal cervical cerclage: the C-STICH RCT
Abstract
Background Second trimester miscarriage and preterm birth is a significant global problem. Surgical cervical cerclage is performed to prevent pregnancy loss and preterm birth. It utilises either a monofilament or braided suture. It is hypothesised that a braided material becomes colonised with pathogenic bacteria that causes vaginal dysbiosis, infection and cerclage failure. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material as opposed to a braided suture material on pregnancy loss in women requiring a vaginal cervical cerclage. Design Superiority open randomised controlled trial. Setting Seventy-five maternity sites across the UK. Participants Women experiencing a singleton pregnancy requiring a cervical cerclage. Interventions Monofilament suture or braided suture. Main outcome measures The primary outcome was pregnancy loss (miscarriage and perinatal mortality, including any stillbirth or neonatal death in the first week of life). Secondary outcomes included the core outcome set for preterm birth. Methods Women were randomised on a 1 : 1 basis to monofilament or braided cerclage utilising a bespoke randomisation service with minimisation dependent on the site, indication for cerclage, intention to use progesterone and planned surgical technique. The inclusion criteria were three or more previous mid-trimester losses or preterm births, insertion of a cerclage in a previous pregnancy, a history of a mid-trimester loss or preterm birth with a shortened cervical length in the current pregnancy or in women who clinicians deemed at risk of preterm birth. The exclusion criteria were an emergency or rescue cerclage, age of < 18 years, being unable to give informed consent or the cerclage having to be placed abdominally. The original sample size was calculated based on a relative risk reduction of 41% from a pregnancy loss rate of 19% in the braided group to 11% in the monofilament group with 90% power and alpha at p = 0.05. The independent data monitoring committee noted a lower-than-anticipated pooled event rate within the trial and recommended an increase in sample size to 2050. The outcome data were collected using clinical record forms from the maternal and neonatal medical records and reported to Birmingham Clinical Trials Unit. Results A total of 2049 women were randomised, after withdrawals and loss to follow-up, data on 1005 women in the monofilament group and 993 women in the braided group were included. The baseline demographics between the groups were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups (80/1003 vs. 75/993; adjusted risk ratio: 1.05, 95% confidence interval: 0.79 to 1.40; adjusted risk difference: 0.002, 95% confidence interval: −0.02 to 0.03). Limitations The trial did not collect long-term paediatric outcomes. There were no safety concerns. Conclusions There was no evidence of a difference in pregnancy loss between a monofilament suture and a braided suture. Future work Long-term follow-up of neonates born within the C-STICH (cerclage suture type for an insufficient cervix and its effects on health outcomes) trial. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award information. Plain language summary Cervical cerclage is an operation performed in pregnancy to prevent miscarriage and preterm birth. A cervical cerclage is sometimes recommended in women who have had babies born prematurely before or who have had previous cervical surgery. A cerclage operation involves a stitch being inserted around the neck of the womb (cervix) to keep it closed during pregnancy and to prevent it opening prematurely. When performing the operation, the doctor can use different types of threads made of different materials. The threads used to perform the operation are called sutures. One suture type is a single strand or monofilament thread, and the other is a multifilament braided thread with lots of thin strands woven together. Some evidence has suggested that using a monofilament suture thread prevented pregnancy loss by preventing infection. Therefore, we performed a randomised controlled trial of the use of monofilament suture thread versus braided suture thread, aiming to reduce pregnancy loss in women who were having a cerclage as part of their routine care. The women consented to take part in the study and were randomly allocated to their cerclage performed with either a monofilament or braided suture thread; there was no other change to their planned pregnancy care. What happened in their pregnancy was recorded from their medical records and analysed. A total of 2049 women agreed to take part in the study and consented to the analysis of their pregnancy and neonatal outcomes. Cerclage suture type for an insufficient cervix and its effects on health outcomes showed that there was no difference in pregnancy loss between the two suture threads. There was decreased maternal sepsis and decreased chorioamnionitis (which is an infection inside the womb during labour) in the women who received a monofilament suture, which needs further investigation. Although more women who had a cerclage using the monofilament thread needed a small operation and an anaesthetic, often between 36 and 37 weeks, to remove the monofilament suture prior to a vaginal birth, there were no differences in the outcomes for their babies. Scientific summary Background Preterm birth and second trimester miscarriage is a significant cause of worldwide neonatal morbidity and mortality. The aetiology is complex and multifactorial with a number of causes, including cervical insufficiency. One treatment to prevent preterm birth and second trimester miscarriage caused by cervical insufficiency is the placement of a vaginal cervical cerclage (CC). A CC is the placement of a purse string suture thread around the cervix aiming to prevent pregnancy loss and preterm birth. A CC can be performed with either a monofilament suture thread or a braided suture thread. The choice of thread used during surgical operations is dependent on the properties of the thread, with braided threads being multifilament in nature with lots of single strands woven together, which predisposes it to potentially becoming colonised with pathogenic bacteria. A prior feasibility study suggested a difference in pregnancy loss outcomes between monofilament and braided suture threads and the acceptability of either thread for clinicians and women. Therefore, a randomised controlled trial was designed to explore this discrepancy, aiming to reduce pregnancy loss for women at high risk of preterm birth. Objectives The primary objective of the study was to examine the effectiveness of using a monofilament suture material compared to a braided suture material on minimising the risk of pregnancy loss in women requiring a vaginal CC. The secondary objectives of the study included exploring the impact of suture material on maternal and neonatal outcomes. Design A pragmatic open, parallel, multicentre, randomised superiority trial of monofilament versus braided suture type during CC to prevent pregnancy loss. Setting The study was conducted in hospital settings across the UK (75 sites) between 2015 and 2022. Participants Women were eligible for the trial if they required a vaginal CC as part of their routine care within their current pregnancy and they fulfilled the following eligibility criteria: Inclusion Singleton pregnancy. Indication for CC for either: a history of three or more previous mid-term losses or premature births (≤ 28 weeks), OR insertion of cervical sutures in previous pregnancies, OR a history of mid-trimester loss or premature birth with a shortened (≤ 25 mm) cervix, OR women whom clinicians deemed to be at risk of preterm birth either because of their history or because of the results of an ultrasound scan. Exclusion Had taken part in C-STICH previously. Aged < 18 years old at the time of presentation. Requiring a rescue cerclage. Unwilling or unable to give informed consent. Those in whom a cerclage was to be placed by any route other than vaginally (e.g. via an abdominal route). Immediate need for insertion of a suture. Membranes that had ruptured or were surfacing. Interventions Women were randomised at a 1 : 1 ratio via a secure internet facility to have their CC performed using either a monofilament or braided suture thread. Minimisation was employed to balance for the following: indication for cerclage, planned bladder dissection, intention to commence patient on progesterone and recruiting site. Outcome measures The primary outcome measure was pregnancy loss (miscarriage and perinatal mortality). Key secondary outcome: Time from conception to pregnancy end (any reason). Maternal outcomes: Miscarriage and previable neonatal death (defined as delivery < 24 weeks). Stillbirth (defined as intrauterine death ≥ 24 weeks). Gestation at delivery (in live births ≥ 24 weeks). Gestational age of < 28/< 32/< 37 weeks at delivery (in live births ≥ 24 weeks). Time from conception to onset of spontaneous vaginal delivery (in live births ≥ 24 weeks). Sepsis (at any time in pregnancy and until 7 days postnatal). Preterm prelabour rupture of membranes (PPROM). Mode of initiation of labour (spontaneous or induced). Mode of delivery (vaginal, operative vaginal or caesarean). Cerclage placement complications (cervical laceration/bleeding from cervix/ruptured membranes/bladder injury). Cerclage removal complications (cervical tears/need for anaesthetic/difficult to remove). Other maternal complications: vaginal bleeding/steroid use/chorioamnionitis/maternal pyrexia of 38°C (intrapartum/postnatal)/admission to high dependency unit (HDU) or intensive therapy unit (ITU) (pre/post delivery). Neonatal outcomes: Early neonatal death (defined as a death within 7 days after delivery) (in live births ≥ 24 weeks). Late neonatal death (defined as a death beyond 7 days and before 28 days after delivery) (in live births ≥ 24 weeks). Birth-weight centile adjusted for gestational age and sex (in live births ≥ 24 weeks). Small for gestational age and sex (< 10th centile, in live births ≥ 24 weeks). Resuscitation at birth (in live births ≥ 24 weeks). Additional care required [special care baby unit (SCBU)/neonatal intensive care unit (NICU)/HDU/transitional care] and length of stay in additional care (in live births ≥ 24 weeks). Antibiotics within 72 hours (in live births ≥ 24 weeks). Sepsis (clinically diagnosed/proven) (in live births ≥ 24 weeks). Early neurodevelopmental morbidity (severe abnormality on cranial ultrasound scan) (in live births ≥ 24 weeks). Respiratory support and days on respiratory support (in live births ≥ 24 weeks). Supplementary oxygen requirements at 36 weeks post menstrual age (in live births ≥ 24 weeks). Necrotising enterocolitis (Bell’s stage 2 or 3) (in live births ≥ 24 weeks). Retinopathy of prematurity requiring laser treatment (in live births ≥ 24 weeks). Disabilities (live births ≥ 24 weeks). Congenital anomalies (in live births ≥ 24 weeks). The core outcome set for preterm birth was fully collected within the trial. Sample size The original sample size was based on a meta-analysis of non-randomised studies, where the pooled pregnancy loss rate in the monofilament group was 7% compared to 19% in the braided group. To allow for the observational nature of these data, we powered the study to detect a more plausible relative reduction of 41% (19% with braided sutures to 11.2% with monofilament sutures) with 90% power (alpha = 0.05). We planned to recruit 900 women. As a result of some uncertainty around the sample size parameters, the data monitoring committee reviewed the pooled event rate throughout the study. The sample size was subsequently increased to 2050 women to allow for a lower-than-anticipated event rate in order to maintain sufficient power to detect the same relative risk reduction. The primary analysis was by intention to treat. Results The trial opened for recruitment in August 2015 and completed recruitment in January 2021. A total of 2049 women were randomised into the trial and data for analysis was available for 1003 women in the monofilament group and 993 women in the braided group. The baseline demographic characteristics of women in the monofilament and braided group were similar. There was no evidence of a difference in pregnancy loss rates between the monofilament and braided groups [80/1003 vs. 75/993; adjusted risk ratio (RR) 1.05, 95% confidence interval (CI) 0.79 to 1.40; adjusted risk difference 0.002, 95% CI −0.02 to 0.03]. There was no difference in conception to pregnancy end (median time to pregnancy end: 37.9 weeks vs. 38.0 weeks; adjusted hazard ratio 1.04, 95% CI 0.95 to 1.14). Regarding maternal outcomes there was a decrease in maternal sepsis in the monofilament group (4%) compared to the braided group (7%) (RR 0.58, 95% CI 0.40 to 0.82) and a decreased risk of chorioamnionitis in the monofilament group (3%) compared to the braided group (6%) (RR 0.45, 95% CI 0.29 to 0.71). There was no difference in any neonatal outcomes. CC removal complications showed an increase in the monofilament group (56% vs. 42%, RR 1.25, 95% CI 1.15 to 1.36), with increased difficulty of removal and an increased need for anaesthetic for removal being the most common complications. Conclusions There was no evidence of a difference between a monofilament suture thread and a braided suture for pregnancy outcomes. We can be relatively confident that using a monofilament suture is unlikely to have a substantial impact on pregnancy loss compared to a braided suture. The uncertainty around our comparative estimate for this outcome is at most 2% in favour of the monofilament in absolute terms. While this margin may not completely rule out missing a clinically important difference, we consider this scenario to be unlikely. Therefore, clinicians should consider the relative merits and disadvantages of the physical suture properties when selecting the material to perform a vaginal CC. The trial was robustly conducted with minimal limitations. An important strength of the study is the recognition early in the trial that the event rate was lower than anticipated and, therefore, the sample size was increased allowing the effectiveness of a monofilament versus braided suture thread to be fully evaluated. Trial registration This trial is registered as ISRCTN15373349. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 13/04/107) and is published in full in Health Technology Assessment; Vol. 28, No. 40. See the NIHR Funding and Awards website for further award project information.
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