Oral progesterone for the prevention of recurrent preterm birth: systematic review and metaanalysis

Objective The purpose of this study was to perform a systematic review and metaanalysis of randomized controlled trials on oral progesterone compared with placebo or other interventions for preterm birth prevention in singleton pregnancies with previous spontaneous preterm birth. The primary outcome was preterm birth at <37 weeks gestation; the secondary outcomes included preterm birth rate at <34 weeks gestation, neonatal morbidity/death, and maternal side-effects. Study Searches were performed in PubMed, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, and the Cochrane Register with the use of a combination of words related to “preterm birth,” “preterm delivery,” “progesterone,” “progestogens,” and “oral” from inception of each database to April 2018. Additionally, systematic reviews on progesterone for preterm birth prevention that were identified in our search were also reviewed for additional studies. We included all randomized trials of asymptomatic singleton gestations with previous spontaneous singleton preterm birth that had been randomized to prophylactic treatment with oral progesterone vs placebo, no treatment, or other preterm birth intervention. Exclusion criteria included quasirandomized trials, trials that involved women with preterm labor/membrane rupture at the time of randomization or multiple gestations. Study Appraisal and Synthesis Methods The risk of bias and quality of evidence were assessed for each study. All analyses were done with an intention-to-treat approach. The primary outcome was incidence of preterm birth at <37 weeks gestation; the secondary outcomes included preterm birth at <34 and <28 weeks gestation, maternal adverse events, maternal serum progesterone level, and neonatal morbidity and death. Summary measures were reported as relative risk or mean difference. I2 >30% was used to identify heterogeneity. Results The search strategy identified 79 distinct studies. Three trials on oral progesterone vs placebo (involved 386 patients: 196 in oral progesterone and 190 in placebo) met the inclusion criteria; there were no studies on oral progesterone vs other intervention that met inclusion criteria. Metaanalysis demonstrated a significantly decreased risk of preterm birth at <37 weeks gestation (42% vs 63%; P=.0005; relative risk, 0.68; 95% confidence interval, 0.55–0.84), preterm birth at <34 weeks gestation (29% vs 53%; P<.00001; relative risk, 0.55; 95% confidence interval, 0.43–0.71), and increased gestational age of delivery (mean difference, 1.71 weeks; 95% confidence interval, 1.11–2.30) with oral progesterone compared with placebo. There was a significantly lower rate of perinatal death (5% vs 17%; P=.001; relative risk 0.32; 95% confidence interval, 0.16–0.63), neonatal intensive care admission (relative risk, 0.39; 95% confidence interval, 0.25–0.61), respiratory distress syndrome (relative risk, 0.21; 95% confidence interval, 0.05–0.93), and higher birthweight (mean difference, 435.06 g; 95% confidence interval, 324.59–545.52) with oral progesterone. There was a higher rate of maternal adverse effects with oral progesterone that included dizziness (relative risk, 2.95; 95% confidence interval, 1.47–5.90), somnolence (relative risk, 2.06; 95% confidence interval, 1.29–3.30), and vaginal dryness (relative risk, 2.37; 95% confidence interval, 1.10–5.11); no serious adverse effects were noted. Conclusion Oral progesterone appears to be effective for the prevention of recurrent preterm birth and a reduction in perinatal morbidity and mortality rates in asymptomatic singleton gestations with a history of previous spontaneous preterm birth compared with placebo. There were also increased adverse effects with oral progesterone therapy compared with placebo, although none were serious. Further randomized study on oral progesterone compared with other established therapies for the prevention of recurrent preterm birth are warranted.