17-OHPC may not reduce recurrent preterm birth or decrease neonatal morbidity

Référence

Blackwell SC, Gyamfi-Bannerman C, Biggio JR, et al. 17-OHPC to prevent recurrent preterm birth in singleton gestations (PROLONG study): A multicenter, international, randomized double-blind trial. Am J Perinatol 2020;37(2):127-136.

Sommaire

The authors of this study, in consultation with the Federal Drug Administration, initiated this PROLONG trial for the purpose of serving as a confirmatory study for the National Institutes of Child and Human Development Maternal-Fetal Medicine Units trial that led to the current guidelines to offer 17-OHPC for the prevention of recurrent preterm birth. For the PROLONG trial, 1708 women from 93 centers across 9 countries (at least 10% of women from the United States) were enrolled and randomized in a 2:1 ratio to receive either weekly intramuscular injections of 250 mg 17-OHPC or an inert oil placebo. Participating women began treatment between 16 0/7 and 20 6/7 weeks' gestation, which was continued until delivery or 36 6/7 weeks'. Russian and Ukrainian women accounted for 60% of the enrollees. The included women were at least 18 years old with a singleton pregnancy and a prior spontaneous preterm birth, defined as birth at a gestational age between 20 0/7 and 36 6/7 weeks. Women were excluded for known major fetal anomaly, heparin treatment during pregnancy, cervical cerclage, hypertension requiring medication, seizure disorder, or progesterone use in any form during the current pregnancy. The study protocol did not dictate the content of prenatal care, other than use of the study drug and preclusion of cerclage. The primary outcome of preterm birth at less than 35 0/7 weeks' occurred in 11.0% (122/1113) of the 17-OHPC group and 11.5% (66/574) of the control group (relative risk [RR] 0.95; 95% CI 0.71 - 1.26 [NS]). The neonatal co-primary outcome was a composite of neonatal death (until 28 days after birth) and the following severe morbidities: grade 3 or grade 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. This composite outcome also did not differ between groups: 1.7% in the 17-OHPC group vs 1.9% in the control group (RR 0.87; 0.4 - 1.81). Interestingly, the rates of preterm birth were higher in US patients than in non-US patients, though they were not statistically significant. Despite PROLONG's large sample size, the study was underpowered to assess treatment efficacy because of lower-than-expected event rates of preterm birth within the control group (11.5% vs 21% to 30% expected). Among the subgroup of US women (n = 391, 23% of participants), there was also no difference in preterm birth (15.6% vs 17.6%; RR 0.88; 0.55 - 1.40). The authors account for possible selection biases, acknowledging that many physicians within the United States were already prescribing 17-OHPC as part of routine prenatal care when recruitment for PROLONG started in 2009, thereby limiting the number of US participants. The authors also acknowledge that women with a higher risk of recurrent preterm birth may not have been enrolled in PROLONG but rather steered toward open-label therapy in order to avoid the possibility of placebo thus enrolling a lower risk profile of women. The risk of bias toward lower-risk women seems likely.