Design of the trial
PROLONG was a multicenter (93 sites), randomized, placebo-controlled, double-blind study conducted in 9 countries (23% of participants were in the United States, 60% were in Russia and Ukraine). The co-primary outcome was PTB < 35 weeks and a composite neonatal morbidity and mortality index. The primary safety outcome was fetal/early infant death.
The study was designed to have 98% power to detect a 30% reduction in PTB < 35 weeks, and 90% power to detect a 35% reduction in the neonatal composite index. It included 1,708 participants (1,130 were treated with 17-OHPC, and 578 received placebo).
Trial outcomes. There was no difference in PTB < 35 weeks between the 17-OHPC and the placebo groups (11.0% vs 11.5%; relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There was no difference in PTB < 32 or < 37 weeks.
The study revealed also that there was no difference between groups in the neonatal composite index (5.6% for 17-OHPC vs 5.0% for placebo; RR, 1.12; 95% CI, 0.68-1.61). In addition, there was no difference in fetal/early infant death between the 17-OHPC and placebo groups (1.7% vs 1.9%; RR, 0.87; 95% CI, 0.4-1.81).
Conclusions. The trial investigators concluded that 17-OHPC did not demonstrate a reduction in recurrent PTB and did not decrease neonatal morbidity.
Study limitations included underpowering and selection bias
The investigators noted that the PTB rate in PROLONG was unexpectedly almost 50% lower than that in the Meis trial, and that therefore the PROLONG trial was underpowered to assess the primary outcomes.
Further, the study populations of the 2 trials were very different: The Meis trial included women at higher baseline risk for PTB (> 1 prior PTB and at least 1 other risk factor for PTB). Additionally, while the PROLONG trial included mostly white (90%), married (90%), nonsmoking women (8% smoked), the Meis trial population was 59% black and 50% married, and 20% were smokers.
The availability and common use of 17-OHPC in the United States likely led to a selection bias for the PROLONG trial population, as the highest-risk patients were most likely already receiving treatment and were therefore excluded from the PROLONG trial.
Society, and FDA, responses to the new data
The results of the PROLONG trial call into question what has become standard practice for patients with a history of spontaneous PTB in the United States. While the safety profile of 17-OHPC has not been cited as a concern, whether or not the drug should be used at all has—as has its current FDA-approved status.
In response to the publication of the PROLONG trial results, ACOG released a Practice Advisory that acknowledged the study's findings but did not alter the current recommendations to continue to offer progesterone for the prevention of preterm birth, upholding ACOG's current Practice Bulletin guidance.2,4 Additional considerations for offering 17-OHPC use include the patients' preferences, available resources, and the setting for the intervention.
SMFM's response was more specific, stating that it is reasonable to continue to use 17-OHPC in high-risk patient populations consistent with those in the Meis trial.5 In the rest of the general population at risk for recurrent PTB, SMFM recommends that, due to uncertain benefit with 17-OHPC, the high cost, patient discomfort, and increased visits should be taken into account.
Four days after the publication of the PROLONG study, the FDA Bone, Reproductive, and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17-OHPC.6 In response, SMFM released a statement supporting continued access to 17-OHPC.7 The FDA's final decision on the status of the drug is expected within the next several months from this writing.
17-OHPC continues to be considered safe and still is recommended by both ACOG and SMFM for the prevention of recurrent preterm birth in high-risk patients. The high-risk patient population who may benefit most from this therapy is still not certain, but hopefully future studies will better delineate this. The landscape for 17-OHPC use may change dramatically if FDA approval is not upheld in the future. In my current practice, I am continuing to offer 17-OHPC to patients per the current ACOG guidelines, but I am counseling patients in a shared decision-making model regarding the findings of the PROLONG trial and the potential change in FDA approval.
Continue to: ACOG updates guidance on preventing early-onset GBS disease...