Vaginal progesterone versus Intramuscular 17-hydroxyprogesterone caproate for Prevention of recurrent preterm birth (VIP): a randomized controlled trial

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Background: Preterm birth is the leading cause of neonatal morbidity and mortality, and prior preterm birth is one of the strongest risk factors for preterm birth. National and international obstetric societies have different recommendations regarding progesterone formulation for prevention of recurrent preterm birth.

Objective: To determine whether vaginal progesterone is superior to 17OHPC in prevention of recurrent preterm birth (PTB) in singletons with prior spontaneous preterm birth (sPTB).

Design: This was an open-label multi-center pragmatic randomized controlled trial at five United States centers of singleton pregnancies <24 weeks' with a prior sPTB randomized 1:1 to either 200mg vaginal progesterone suppository nightly or 250mg intramuscular 17OHPC weekly from 16 weeks' until 36 weeks'. Based on estimated recurrent PTB rate of 36% with 17OHPC, 95 participants needed in each arm to detect a 50% reduction in PTB rate with vaginal progesterone, with 80% power and 2-sided alpha 0.05. Primary outcome was PTB <37 weeks. Pre-specified secondary outcomes included PTB<34 and <28 weeks, mean gestational age at delivery, neonatal morbidity/mortality, and measures of adherence. Analysis was by intention to treat. Chi square and student t-test were used as appropriate. P<0.05 was considered significant.

Results: 205 participants were randomized; n=94 in vaginal progesterone and n=94 in 17OHPC were included. Although gestational age at enrollment was similar, those assigned to vaginal progesterone initiated therapy earlier (16.9 ±1.4 vs 17.8±2.5wks, p=0.001). Overall continuation of assigned formulation until delivery was similar (73% vs 69%, p=0.61). There was no significant difference in PTB<37wks (31% vs 38%, p=0.28, RR 0.81 (0.54-1.20)), <34 weeks (9.6% vs 14.9%, p=0.26, RR 0.64 (0.29-1.41)), or <28 weeks (1.1% vs 4.3%, p=0.37, RR 0.25 (0.03-2.20)). Those in the vaginal progesterone group had a later mean gestational age at delivery than 17OHPC (37.36±2.72 vs 36.34±4.10 weeks, MD 1.02 (0.01-2.01), p=0.047).

Conclusions: Vaginal progesterone did not reduce the risk of recurrent preterm birth by 50% compared to 17OHPC, but may lead to increased latency to delivery. This trial is underpowered to detect a smaller, although still clinically significant, difference in preterm birth prevention efficacy. Patient factors that impact adherence and ability to obtain medication in a timely fashion should be included in counseling on progesterone selection.

Keywords: 17-hydroxyprogesterone caproate; preterm birth; preterm birth prevention; prior preterm birth; progesterone.