Vaginal Progesterone Prophylaxis for Preterm Birth (the OPPTIMUM Study): A Multicentre, Randomized, Double-Blind Trial

Administration of vaginal progesterone or intramuscular 17[alpha]-hydroxyprogesterone caproate has been found to prevent preterm birth in women with a short cervix and to reduce neonatal mortality as reported by the Cochrane Library meta-analysis. However, data on medium and long-term outcomes after the neonatal period are lacking. To this end, a double-blind randomized trial, OPPTIMUM (dOes Progesterone Prophylaxis To prevent preterm labour IMprove oUtcoMe?) was performed to determine the effect of vaginal progesterone prophylaxis on neonatal and childhood outcomes. A screening phase at 18 to 24 weeks' gestation, and a treatment phase commencing at between 22 and 24 weeks of gestation were conducted. The eligibility criteria for women included in the study were that they were 16 years or older, had a singleton pregnancy, displayed clinical risk factors for preterm birth and were fibronectin-positive at 22 to 24 weeks of gestation, or were fibronectin negative at 34 or less weeks of gestation, or had a cervical length of 25 mm or less at any time between 18 and 24 weeks' and 0 day gestation. The participants were randomly assigned through a Web portal to treatment, which comprised administration of either progesterone, 200 mg soft capsules or a placebo, beginning from approximately 22 to 24 weeks of gestation until 34 weeks or delivery of the baby, whichever was earlier. Data collection was done during screening, randomization, 34 weeks of gestation, labor and delivery, neonatal stay, and at 1 and 2 years after delivery to assess clinical outcomes. The assessment included the parent-completed structured clinical history, a parent-completed behavioral measure (the Strengths and Difficulties Questionnaire) and the cognitive scale of the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). Three primary outcomes (obstetric, neonatal, and childhood), secondary outcomes and safety outcomes were determined. Statistical analyses were undertaken by C-MM and AM as per the intention-to-treat principle. Of a total of 1228 women, 618 were randomly assigned to progesterone treatment and 610 to placebo between the years 2009 and 2013. Data on the obstetric, neonatal, and childhood primary outcomes were available for 597, 587, and 439 participants in the placebo group, and for 600, 589, and 430 participants in the progesterone group, respectively. Based on the odds ratio (OR), it was found that progesterone administration did not significantly change primary outcomes (OR, 0.86 [95% confidence interval [CI], 0.61–1.22] for the obstetric outcome; OR, 0.62 [95% CI, 0.38–1.03] for the neonatal outcome; and mean [SD] cognitive score, 97.7 [17.5] for placebo and 97.3 [17.9] for progesterone; difference in mean values, -0.48; adjusted 95% CI, -2.77 to 1.81). There was no statistical significance in differences between the progesterone and placebo groups recorded for secondary and safety outcomes. OPPTIMUM showed that progesterone did not have an effect on either preterm birth rates or neonatal composite outcomes, and neurodevelopmental outcomes for 2 years, thereby implying that progesterone treatment was safe at least until the child completed 2 years of age