17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial

Am J Perinatol. 2020 Jan;37(2):127-136. doi: 10.1055/s-0039-3400227. Epub 2019 Oct 25.


Background: Women with a history of spontaneous preterm birth (SPTB) are at a significantly increased risk for recurrent preterm birth (PTB). To date, only one large U.S. clinical trial comparing 17-OHPC (17-α-hydroxyprogesterone caproate or "17P") to placebo has been published, and this trial was stopped early due to a large treatment benefit.

Objective: This study aimed to assess whether 17-OHPC decreases recurrent PTB and neonatal morbidity in women with a prior SPTB in a singleton gestation.

Study design: This was a double-blind, placebo-controlled international trial involving women with a previous singleton SPTB (clinicaltrials.gov: NCT01004029). Women were enrolled at 93 clinical centers (41 in the United States and 52 outside the United States) between 160/7 to 206/7 weeks in a 2:1 ratio, to receive either weekly intramuscular (IM) injections of 250 mg of 17-OHPC or an inert oil placebo; treatment was continued until delivery or 36 weeks. Co-primary outcomes were PTB < 35 weeks and a neonatal morbidity composite index. The composite included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, or proven sepsis. A planned sample size of 1,707 patients was estimated to provide 98% power to detect a 30% reduction in PTB < 35 weeks (30% to 21%) and 90% power to detect a 35% reduction in neonatal composite index (17%-11%) using a two-sided type-I error of 5%. Finally, this sample size would also provide 82.8% power to rule out a doubling in the risk of fetal/early infant death assuming a 4% fetal/early infant death rate. Analysis was performed according to the intention-to-treat principle.

Results: Baseline characteristics between the 1,130 women who received 17-OHPC and 578 women who received placebo were similar. Overall, 87% of enrolled women were Caucasian, 12% had >1 prior SPTB, 7% smoked cigarettes, and 89% were married/lived with partner. Prior to receiving study drug, 73% women had a transvaginal cervical length measurement performed and <2% had cervical shortening <25 mm. There were no significant differences in the frequency of PTB < 35 weeks (17-OHPC 11.0% vs. placebo 11.5%; relative risk = 0.95 [95% confidence interval (CI): 0.71-1.26]) or neonatal morbidity index (17-OHPC 5.6% vs. placebo 5.0%; relative risk = 1.12 [95% CI: 0.68-1.61]). There were also no differences in frequency of fetal/early infant death (17-OHPC 1.7% vs. placebo 1.9%; relative risk = 0.87 [95% CI: 0.4-1.81]. Maternal outcomes were also similar. In the subgroup of women enrolled in the United States (n = 391; 23% of all patients), although the rate of PTB < 35 weeks was higher than the overall study population, there were no statistically significant differences between groups (15.6% vs. 17.6%; relative risk = 0.88 [95% CI: 0.55, 1.40].

Conclusion: In this study population, 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 17 alpha-Hydroxyprogesterone Caproate / adverse effects
  • 17 alpha-Hydroxyprogesterone Caproate / therapeutic use*
  • Double-Blind Method
  • Female
  • Gestational Age
  • Humans
  • Infant, Newborn
  • Infant, Newborn, Diseases / epidemiology
  • Infant, Newborn, Diseases / prevention & control*
  • Injections, Intramuscular
  • Perinatal Death
  • Pregnancy
  • Pregnancy Complications / epidemiology
  • Pregnancy Outcome*
  • Premature Birth / prevention & control*
  • Progestins / adverse effects
  • Progestins / therapeutic use*
  • Secondary Prevention
  • Treatment Failure


  • Progestins
  • 17 alpha-Hydroxyprogesterone Caproate

Associated data

  • ClinicalTrials.gov/NCT01004029