Does progesterone prophylaxis to prevent preterm labour improve outcome? A randomised double-blind placebo-controlled trial (OPPTIMUM)

Background: Progesterone prophylaxis is widely used to prevent preterm birth but is not licensed and there is little information on long-term outcome. Objective: To determine the effect of progesterone prophylaxis in women at high risk of preterm birth on obstetric, neonatal and childhood outcomes. Design: Double-blind, randomised placebo-controlled trial. Setting: Obstetric units in the UK and Europe between February 2009 and April 2013. Participants: Women with a singleton pregnancy who are at high risk of preterm birth because of either a positive fibronectin test or a negative fibronectin test, and either previous spontaneous birth at ≤ 34 weeks+0 of gestation or a cervical length of ≤ 25 mm. Interventions: Fibronectin test at 18+0 to 23+0 weeks of pregnancy to determine risk of preterm birth. Eligible women were allocated (using a web-based randomisation portal) to 200 mg of progesterone or placebo, taken vaginally daily from 22+0 to 24+0 until 34+0 weeks’ gestation. Participants, caregivers and those assessing the outcomes were blinded to group assignment until data collection was complete. Main outcome measures: There were three primary outcomes, as follows: (1) obstetric – fetal death or delivery before 34+0 weeks’ gestation; (2) neonatal – a composite of death, brain injury on ultrasound scan (according to specific criteria in the protocol) and bronchopulmonary dysplasia; and (3) childhood – the Bayley-III cognitive composite score at 22–26 months of age. Results: In total, 96 out of 600 (16%) women in the progesterone group and 108 out of 597 (18%) women in the placebo group had the primary obstetric outcome [odds ratio (OR) 0.86, 95% confidence interval (CI) 0.61 to 1.22]. Thirty-nine out of 589 (7%) babies of women in the progesterone group and 60 out of 587 (10%) babies of women in the placebo group experienced the primary neonatal outcome [OR 0.62, 95% CI 0.38 to 1.03]. The mean Bayley-III cognitive composite score of the children at 2 years of age was 97.3 points [standard deviation (SD) 17.9 points; n = 430] in the progesterone group and 97.7 points (SD 17.5 points; n = 439) in the placebo group (difference in means –0.48, 95% CI –2.77 to 1.81). Limitations: Overall compliance with the intervention was 69%. Harms: There were no major harms, although there was a trend of more deaths from trial entry to 2 years in the progesterone group (20/600) than in the placebo group (16/598) (OR 1.26, 95% CI 0.65 to 2.42). Conclusions: In this study, progesterone had no significant beneficial or harmful effects on the primary obstetric, neonatal or childhood outcomes.The OPPTIMUM trial is now complete. We intend to participate in a comprehensive individual patient-level data meta-analysis examining women with a singleton pregnancy with a variety of risk factors for preterm birth. Trial registration: Current Controlled Trials ISRCTN14568373. Funding: This trial was funded by the Medical Research Council (MRC) and managed by the National Institute for Health Research (NIHR) on behalf of the MRC–NIHR partnership