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Should we stop prescribing IM progesterone to women with a history of preterm labor?

The Journal of Family Practice. 2022 January;71(1):E15-E17 | doi: 10.12788/jfp.0334
January 21, 2022|Family Medicine
Lee Dresang, MD;Lia Vellardita, MA
Author and Disclosure Information

Lee Dresang, MD
University of Wisconsin Department of Family Medicine and Community Health, Madison

Lia Vellardita, MA
Ebling Library, University of Wisconsin School of Medicine and Public Health, Madison

DEPUTY EDITOR
Richard Guthmann, MD, MPH
Advocate Illinois Masonic Family Medicine Residency, Chicago

EVIDENCE-BASED REVIEW:

YES, we should stop the routine prescribing of IM progesterone to prevent preterm delivery. A 2003 randomized controlled trial (RCT) found that weekly intramuscular (IM) 17 hydroxyprogesterone (17-OHP) for women with a singleton pregnancy and a history of spontaneous preterm delivery decreased the preterm delivery rate by 34% (strength of recommendation [SOR]: B, single RCT). However, the follow-up 2020 PROLONG RCT did not find that 17-OHP prevents preterm birth or improves neonatal outcomes. This held true for subgroup analyses (SOR: B, single larger RCT). (Notably, though, the PROLONG study had very few Black participants when compared with the 2003 study.)

The US Food and Drug Administration (FDA) has recommended withdrawing 17-OHP from the market. The American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have released statements supporting shared decision-making with women regarding the prescribing of 17-OHP for preterm delivery prevention (SOR: C, expert opinion).

Recommendations from others

In 2008, a joint ACOG/SMFM statement said, “Progesterone supplementation for the prevention of recurrent preterm birth should be offered to women with a singleton pregnancy and prior spontaneous preterm birth.”7 A 2012 ACOG Practice Bulletin stated that, “A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16 to 24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth.”8

In 2011, Makena (hydroxyprogesterone caproate injection) received accelerated approval from the FDA. In October 2020, the FDA Advisory Committee recommended that Makena be withdrawn from the market (9 to 7 vote).9 On October 5, 2020, the FDA’s Center for Drug Evaluation and Research (CDER) proposed that Makena be withdrawn from the market “because the required postmarket study failed to verify clinical benefit and we have concluded that the available evidence does not show Makena is effective for its approved use.”10 A subgroup analysis by CDER did not find benefit for any subgroup, including high-risk women.10 However, Makena will remain on the market unless its manufacturer withdraws it or the FDA Commissioner mandates its removal.

In response to the FDA’s proposal, both ACOG and SMFM recommended that “obstetric health care professionals discuss Makena’s benefits, risks, and uncertainties with their patients”11 as part of “a shared ­decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit.”12 Both organizations reiterated their position on shared decision-making after the EPPPIC meta-analysis was published.13

Studies comparing the 2 routes of administration (vaginal and IM) are underway.13

Editor’s takeaway

Our best evidence does not support routine IM progesterone use to prevent preterm delivery. However, therapeutic inertia, uncertainty, and defensive medicine may slow down adoption of this newer evidence. Shared decision-making can assist treatment decisions, but it is not a substitute for following the best evidence.

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