Study design, and stunning results
PROLONG (Progestin's Role in Optimizing Neonatal Gestation) was a randomized (2:1), double-blind, vehicle-controlled, multicenter international trial (2009-2018) conducted to assess the safety and efficacy of 17P injection in 1,708 women with a singleton pregnancy and one or more prior spontaneous PTBs.7 Women in the active treatment group (n = 1,130) received weekly intramuscular injections of 17P, while those in the control group (n = 578) received weekly injections of inert oil vehicle.
Results of the trial showed no significant reduction in the co-primary end points, which were PTB < 35 weeks (11.0% in the 17P group vs 11.5% in the placebo group; RR, 0.95; 95% CI, 0.71-1.26) and neonatal morbidity index (5.6% in the 17P group vs 5.0% in the placebo group; RR, 1.12; 95% CI, 0.68-1.61). There was no evidence of benefit for any subpopulation (geographic region, race, or other PTB risk factor). Maternal outcomes also were similar between the groups. No significant safety concerns were identified.
Important differences between MFMU and PROLONG trials
Strengths of the PROLONG trial include its randomized, placebo-controlled design, excellent follow-up rate, and use of a protocol that mirrored that of the MFMU trial. The primary limitation of PROLONG is that participants experienced a lower rate of PTB compared with those in the MFMU trial. The rate of PTB < 37 weeks was 54.9% in the control group of the MFMU trial compared with 21.9% in PROLONG.
Given the low rate of PTB in PROLONG, the study was underpowered for the co-primary outcomes. In addition, lower rates of PTB in PROLONG compared with in the MFMU trial likely reflected different patient populations.8 Moreover, PROLONG was an international trial. Of the 1,708 participants, most were recruited in Russia (36%) and Ukraine (25%); only 23% were from the United States. By contrast, participants in the MFMU trial were recruited from US academic medical centers. Also, participants in the MFMU trial were significantly more likely to have a short cervix, to have a history of more than one PTB, and to be African American.
Discrepant trial results create clinical quandary
In October 2019, the FDA's Bone, Reproductive and Urologic Drugs Advisory Committee voted 9-7 to withdraw approval for 17P. Committee members struggled with the conflicting data between the 2 trials and hesitated to remove a medication whose use has become standard practice. Ultimately, however, it was lack of substantial evidence of effectiveness of 17P that swayed the committee's vote. While the FDA generally follows the recommendation of an advisory committee, it is not bound to do so.
Societies' perspectives
So what are physicians and patients to do? It is possible that a small subgroup of women at extremely high risk for early PTB may benefit from 17P administration. SMFM stated: "...it is reasonable for providers to use 17-OHPC [17P] in women with a profile more representative of the very high-risk population reported in the Meis [MFMU] trial."8 Further, the American College of Obstetricians and Gynecologists (ACOG) stated in a Practice Advisory dated October 25, 2019, that "ACOG is not changing our clinical recommendations at this time... [We] will be reviewing subsequent forthcoming analyses and will issue updated clinical guidance as appropriate."9
Where we stand on 17P use going forward
17P should be available to women who previously may have benefited from its use. However, 17P should not be recommended routinely to prevent recurrent spontaneous PTB in women with one prior PTB and no other risk factors. Of note, the PROLONG trial does not change recommendations for cervical length screening. Women with a history of a prior spontaneous PTB should undergo cervical length screening to identify those individuals who may benefit from an ultrasound-indicated cerclage.