Cerclage Plus Progesterone vs Progesterone Alone in Twin Short Cervix

Overview

This study aims to compare the effectiveness of cervical cerclage combined with progesterone versus progesterone alone in preventing preterm birth among women with twin pregnancies and a short cervix (cervical length ≤ 30 mm). Participants will be randomly allocated to either the intervention group (cerclage plus progesterone) or the control group (progesterone alone).

The incidence of multiple pregnancies has increased rapidly over the years mainly due to the resultant widespread use of assisted reproduction techniques. The twin birth rate in the USA has risen 70%, from 19 per 1000 live births in 1980 to 31 per 1000 live births in 2020. Twin pregnancies have a high risk on preterm birth (PTB) which is associated with increased risk of neonatal mortality and long-term morbidity. Around 60% of twin pregnancies deliver prior to 37 weeks and 12% before 34 weeks of gestation, with rates 5 and 8 times higher than the equivalent rates for a singleton pregnancy, respectively. Children born at an early gestational age are at increased risk of short-term morbidities affecting vital organ systems such as lungs, brain, bowels and are at increased risk of severe infection and sepsis. Perinatal mortality is strongly associated with extreme PTB. Survivors are at increased risk for developmental and behavioral disorders. In Vietnam, the rate of twin pregnancies deliver at \< 28 weeks was about 11% in 2019. Caring for extremely premature infants is a significant burden for families and society. Therefore, obstetricians have a need for high-quality evidence for effective treatments. Cervical length measurement (ideally transvaginal) is the preferred method of screening for preterm birth in twins; 25mm is a pragmatic cut-off between 18 and 24 gestational weeks (Grade of recommendation: C). Majority of the studies conducted previously has taken the cut-off cervical length as ≤ 25 mm. A systematic review and meta-analysis (13 retrospective studies and 3 RCTs) showed that cervical cerclage may reduce preterm birth in twin pregnancies with a cervical length \<25 mm; however, preterm birth before 37, 34, and 28 weeks remained high (56.7%, 38.8%, and 11.7%, respectively)5, compared with much lower rates in singleton pregnancies (6.2%, 4.7%, and 0.4%). These findings support the need for further studies on preterm birth prevention in twin pregnancies with a cervical length \>25 mm. In 2025, Yen et al. showed that cervical cerclage was more effective than pessary in twin pregnancies with a cervical length ≤28 mm, particularly in reducing preterm birth \<28 weeks, with benefit observed at 25-28 mm. However, preterm birth rates remained high, suggesting that intervention at a higher cervical length threshold may be justified. Given gestational age-related cervical shortening and the substantially higher preterm birth risk in twins, a higher threshold corresponding to the 10th percentile (≤30 mm) has been proposed. Accordingly, we selected ≤30 mm as the intervention threshold in twin pregnancies. In singleton pregnancies, vaginal progesterone is recommended as the primary intervention for pregnant women with a cervical length less than 25mm with consistently demonstrated effectiveness in preventing premature labor. In cases with a prior spontaneous preterm delivery and a short cervix, the placement of a vaginal cerclage should be considered. Conversely, there is less evidence on the optimal strategy for preventing PTB in twin pregnancies. In twins, IM 17- OHPC and cervical pessary are not indicated in order to prevent PTB. Evidence regarding the effectiveness of vaginal progesterone and cerclage remains unclear. Several randomized trials and systematic reviews reported little or no benefit of cerclage in twin pregnancies. However, these studies were limited by small sample size and large heterogeneity in their inclusion criteria, study populations, and outcomes observed. The data are insufficient to recommend for or against these interventions in the clinical circumstances. Moreover, in the a last few years, an increasing number of studies reporting a potential beneficial role of cerclage in reducing the risk of PTB and adverse outcomes in twin pregnancies have been published. The latest ISUOG practice guidelines (2025) stated that a combined strategy of physical-exam-indicated cerclage, antibiotics, and tocolytics may be considered in asymptomatic twin pregnancy with dilated cervix before 24 weeks of gestation and a cervical cerclage may be considered when the cervical length is ≤ 15 mm before 24 weeks of gestation (grade of recommendation: C). However, these findings are mainly based on observational studies and require confirmation in large and adequately powered RCTs. In conclusion, there is a lack of well-designed RCT's on the effect of vaginal cerclage in asymptomatic twin pregnancies. We propose a multi-center randomized trial on the effectiveness of vaginal cerclage in women with a twin pregnancy and a short cervix (less than 30mm) in the second trimester with relevant outcomes assessing not only PTB at different cut-offs but also adverse maternal and neonatal outcomes. This open label, multi-center, randomized controlled trial aims to compare the effectiveness of cervical cerclage combined with progesterone versus progesterone alone in preventing preterm birth among women with twin pregnancies with a cervix ≤ 30 mm. Cervical length will be measured routinely in twin pregnancies between 16 and 24 weeks of gestation by qualified doctors via transvaginal ultrasound. Women with a cervical length ≤30 mm will be eligible for the study. Eligible participants will receive a Participant Information Sheet and provide written informed consent after discussion with the investigators. All eligible women will be invited to participate in the study. Six centers are involved in the study and patients will be stratified by center. Patients will be randomly assigned in a 1:1 ratio to receive either cerclage plus progesterone or progesterone alone, using block randomization with a variable block size of 4, 6. To ensure allocation concealment, the random lists will be generated by www.sealedenvelope.com. Upon identification of an eligible participant, randomization data will be sequentially accessed an administrative staff who does not involve in clinical intervention. The random allocation will be conveyed to responsible clinicians. Due to the nature of interventions, the obstetricians and patients will not be blinded. Apart from randomization, patients will be managed and treated preterm birth (if present) according to local protocol. In participants allocated to cerclage plus progesterone group, a Mersilene suture (Ethicon, LLC, United State) will be placed around the cervix in a purse-string fashion and securely tied anteriorly, following the McDonald technique under spinal anesthesia. The intervention needs to be performed before 24+0 weeks of gestation, by a team of dedicated obstetricians in our hospitals (2 to 3 obstetricians in each centers) to ensure the quality of the surgical procedure. For standardization of the cervical cerclage technique, all participating physicians received standardized training before study initiation. Prophylactic antibiotic: First/Second - generation Cephalosporin will be administered intravenously 1 hour before the procedure. In case of reporting an allergy to Cephalosporin, Clindamycin (Dalacin C® 600mg/4ml Pfizer, Belgium) will be used. Additional vaginal micronized progesterone will be administered at a total daily dose of 400 mg, given as Utrogestan® 200 mg (Besins Healthcare, France) twice daily, in the morning and at bedtime, from 2 days after receiving cerclage to 37+0/7 week of gestation or preterm birth whatever comes first. In participants allocated to progesterone alone group, vaginal micronized progesterone will be administered at a total daily dose of 400 mg, given as Utrogestan® 200 mg (Besins Healthcare, France) twice daily, in the morning and at bedtime, from after randomization to 37+0/7 week of gestation or in case of preterm birth whatever comes first. In both group, participants will be asked to record their vaginal progesterone application in a patient diary sheet for up to 140 days. At every visit, their compliance was documented by checking the diary and drug purchasing records from the hospital pharmacy. Compliance rate was calculated by dividing the number of progesterone doses used by the number of progesterone doses that should have been used since the last visit. Participants were considered compliant when their drugs used-to-prescribed rate was 80%. Follow-up examination will be 7 days after randomization and then 2 weeks apart until delivery. At every exam, we perform routine antenatal care and CL measurement, record drug compliance and reveal any adverse events or complications. In case of premature rupture of the membranes, active vaginal bleeding, other signs of preterm labor, or severe discomfort of the participant, the use of cerclage and/or progesterone will be discontinued. Further treatment was indicated per local protocol. All interventions were terminated at 37 weeks or at delivery, whichever came first. Delivery will take place by either spontaneous onset of labor, induction of labor, or elective cesarean section according to national guidelines for twin pregnancies. In cases where the patient delivers at hospitals that are not among the six study sites, data on neonatal and obstetric outcomes will be collected through telephone follow-up and medical record summaries obtained from the respective healthcare facilities. The selected outcome measures correspond to the core outcome set established for studies on preterm birth prevention by GONet and the Core Outcomes in Women's Health initiative. Hospital costs will be measured from hospital costs of patients and neonates.

Conditions

Interventions

Eligibility

Locations (6)

Outcomes

Central Contacts