Vaginal progesterone decreases preterm birth and neonatal morbidity and mortality in women with a twin gestation and a short cervix: An updated meta-analysis of individual patient data

OBJECTIVE: To assess the efficacy of vaginal progesterone for the prevention of preterm birth and neonatal morbidity and mortality in asymptomatic women with a twin gestation and a sonographic short cervix (cervical length ≤25 mm) in the midtrimester.

METHODS: Updated systematic review and meta-analysis of individual patient data from randomized controlled trials comparing vaginal progesterone with placebo/no treatment in women with a twin gestation and a midtrimester sonographic cervical length ≤25 mm. MEDLINE, EMBASE, POPLINE, CINAHL, and LILACS (all from inception to December 20, 2016), bibliographies, the Cochrane Central Register of Controlled Trials, Research Registers of ongoing trials, Google scholar, and conference proceedings were searched. The primary outcome measure was preterm birth <33 weeks of gestation. Two reviewers independently selected studies, assessed the risk of bias, and extracted the data. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated.

RESULTS: Individual patient data were available from 303 women (159 assigned to vaginal progesterone, 144 assigned to placebo/no treatment) and their 606 infants from six randomized controlled trials. One study including women with a CL between 20-25 mm provided 74% of total sample size of the IPD meta-analysis. Vaginal progesterone, compared with placebo/no treatment, was associated with a statistically significant reduction in the risk of preterm birth <33 weeks of gestation (31.4% vs. 43.1%; RR 0.69, 95% CI 0.51-0.93; moderate-quality evidence). Moreover, vaginal progesterone administration was associated with a significant decrease in the risk of preterm birth <35, <34, <32 and <30 weeks of gestation (RRs from 0.47 to 0.83), neonatal death (RR 0.53, 95% CI 0.35-0.81), respiratory distress syndrome (RR 0.70, 95% CI 0.56-0.89), composite neonatal morbidity and mortality (RR 0.61, 95% CI 0.34-0.98), use of mechanical ventilation (RR 0.54, 95% CI 0.36-0.81), and birthweight <1500 g (RR 0.53, 95% CI 0.35-0.80) (all moderate-quality evidence). There were no significant differences in neurodevelopmental outcomes at 4-5 years of age between the vaginal progesterone and placebo groups.

CONCLUSION: The administration of vaginal progesterone to asymptomatic women with a twin gestation and a sonographic short cervix in the midtrimester reduces the risk of preterm birth occurring at <30 to <35 gestational weeks, neonatal mortality and some measures of neonatal morbidity, without any demonstrable deleterious effects on childhood neurodevelopment.