Clinical Guidance for the Integration of the Findings of the EPPPIC Meta-Analysis: Evaluating Progestogens for Preventing Preterm Birth International Collaborative

  • Practice Advisory PA
  • March 2021

The findings of an individual patient data meta-analysis of 31 randomized trials including 11,644 pregnant women and 16,185 offspring comparing vaginal progesterone, intramuscular 17-hydroxyprogesterone caproate (17-OHPC), or oral progesterone with control, or with each other, in asymptomatic women at risk of preterm birth due to prior preterm birth or short cervix were published on March 27, 2021.1 The analysis found evidence for a reduction in the risk of preterm birth with progesterone treatment (preterm birth less than 34 weeks of gestation: vaginal progesterone, nine trials, 3,769 women relative risk [RR] 0.78, 95% CI, 0.68-0.90; 17-OHPC, 5 trials, 3,053 women RR 0.83, 95% CI, 0.68-1.01). Although the findings for 17-OHPC compared to placebo did not reach statistical significance, the authors concluded that there was not clear evidence of a difference in effect of progesterone based on indication for treatment or route of administration; the authors acknowledge that there was little evidence comparing vaginal progesterone and 17-OHPC directly. The most consistent evidence was for vaginal progesterone, and due to the increased underlying risk, the absolute risk reduction was greatest for women with a short cervix.

Current guidelines in the United States recommend the use of progesterone supplementation in pregnant patients with prior spontaneous preterm birth.2 Consideration for offering 17-OHPC to individuals at risk of recurrent preterm birth should take into account the body of evidence for progesterone supplementation, the values and preferences of the pregnant patient, the resources available, and the practicalities of the intervention. Patients with a singleton pregnancy and a prior spontaneous preterm birth should be offered progesterone supplementation (either vaginal or intramuscular) in the context of a shared-decision making process with the patient incorporating the available evidence and the patient’s preferences. With regard to multiple gestations, the Evaluating Progestogens for Preventing Preterm Birth International Collaborative (EPPPIC) findings support the current recommendation that progesterone supplementation is not indicated for the indication of multiple gestation alone as there is no evidence of benefit.

There are ongoing trials directly comparing vaginal progesterone with 17-OHPC. This guidance will be updated as additional data become available. 


  1. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. EPPPIC Group. Lancet 2021;397:1183-94.
  2. Prediction and prevention of preterm birth. Practice Bulletin No. 130. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:964-73.

Click here to access the Society for Maternal-Fetal Medicine response to EPPPIC and considerations of the use of progestogens for the prevention of preterm birth.

This Practice Advisory was developed by the American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics in collaboration with Anjali J. Kaimal, MD, MAS; Hyagriv N. Simhan, MD, MS; Manisha Ghandi, MD; and Megan McReynolds.

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