Effectiveness of progestogens to improve perinatal outcome in twin pregnancies: an individual participant data meta-analysis

Abstract

Background: In twin pregnancies, the rates of adverse perinatal outcome and subsequent long-term morbidity are substantial, and mainly result from preterm birth (PTB).

Objectives: To assess the effectiveness of progestogen treatment in the prevention of neonatal morbidity or PTB in twin pregnancies using individual participant data meta-analysis (IPDMA).

Search strategy: We searched international scientific databases, trial registration websites, and references of identified articles.

Selection criteria: Randomised clinical trials (RCTs) of 17-hydroxyprogesterone caproate (17Pc) or vaginally administered natural progesterone, compared with placebo or no treatment.

Data collection and analysis: Investigators of identified RCTs were asked to share their IPD. The primary outcome was a composite of perinatal mortality and severe neonatal morbidity. Prespecified subgroup analyses were performed for chorionicity, cervical length, and prior spontaneous PTB.

Main results: Thirteen trials included 3768 women and their 7536 babies. Neither 17Pc nor vaginal progesterone reduced the incidence of adverse perinatal outcome (17Pc relative risk, RR 1.1; 95% confidence interval, 95% CI 0.97-1.4, vaginal progesterone RR 0.97; 95% CI 0.77-1.2). In a subgroup of women with a cervical length of ≤25 mm, vaginal progesterone reduced adverse perinatal outcome when cervical length was measured at randomisation (15/56 versus 22/60; RR 0.57; 95% CI 0.47-0.70) or before 24 weeks of gestation (14/52 versus 21/56; RR 0.56; 95% CI 0.42-0.75).

Author's conclusions: In unselected women with an uncomplicated twin gestation, treatment with progestogens (intramuscular 17Pc or vaginal natural progesterone) does not improve perinatal outcome. Vaginal progesterone may be effective in the reduction of adverse perinatal outcome in women with a cervical length of ≤25 mm; however, further research is warranted to confirm this finding.

Keywords: 17-Hydroxyprogesterone caproate; individual participant data meta-analysis; preterm birth; twin pregnancy; vaginal progesterone.

Conflict of interest statement

Contribution to authorship

ES, ACL, and BWJM were involved in the concept and the design of the study. ES performed the analyses in collaboration with NPAZ, RHHG, and BWJM. ES, SS, LR, DJR, ACL, JEN, AHN, VS, CAC, CV, SW, EÇ, CMB, EBF, EAT, SNC, KK, AT, JA, IMU, AP, JM, KM, TG, SR, CC, AKa, JCM, EFM, KHN, RHHG, KGMM, AKw, and BWJM participated in face-to-face meetings, teleconferences and/or e-mail conversations to discuss the article, the design of the meta-analysis, the choice of outcome measures, and analysis strategies. SS, LR, DJR, ACL, JEN, AHN, VS, CAC, CV, MMA, SW, EÇ, CMB, EBF, EAT, SNC, KK, AT, JA, IMU, AP, JM, KM, TG, MAA, YMA, SR, CC, AKa, JCM, EFM, KHN, and BWJM were involved in the construction and design of one of the trials included in the meta-analysis. ES wrote the initial article, with significant contributions by RHHG, AK, KGMM, and BWJM. All authors critically reviewed the subsequent versions of the article and approved the final version.

© 2014 Royal College of Obstetricians and Gynaecologists.

Figures

Figure 1

Flow of study identification.

Figure 2. Risk of bias for each included study

Risk of bias was judged as low (green, +), high (red, −), or unclear (yellow, ?), and was assessed based on the published paper/protocol and queries to the principal investigator of the included study.