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

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doi:doi: 10.12788/jfp.0334

Clinical Inquiries

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

J Fam Pract. 2022 January;71(1):E15-E17 | doi: 10.12788/jfp.0334

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References

1. Meis P, Klebanoff M, Thom E, et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med. 2003;348:2379-2385. doi: 10.1056/NEJMoa035140

2. Dodd J, Jones L, Flenady V, et al. Prenatal administration of progesterone for preventing preterm birth in women considered to be at risk of preterm birth. Cochrane Database Syst Rev. 2013;(7):CD004947. doi: 10.1002/14651858.CD004947.pub3

3. Blackell S, Gyamfi-Bannerman C, Biggio JJ, et al. 17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG study): a multicenter, international, randomized double-blind trial. Am J Perinatol. 2020;37:127-136. doi: 10.1055/s-0039-3400227

4. Greene M, Klebanoff M, Harrington D. Preterm birth and 17OHP—why the FDA should not withdraw approval. N Engl J Med. 2020;383:e130. doi: 10.1056/NEJMp2031727

5. Schlenker T, Dresang L, Ndiaye M, et al. The effect of prenatal support on birth outcomes in an urban Midwestern county. WMJ. 2012;111:267-273.

6. EPPPIC Group. Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC): meta-analysis of individual participant data from randomised controlled trials. Lancet. 2021;397:1183-1194. doi: 10.1016/S0140-6736(21)00217-8

7. Society for Maternal Fetal Medicine Publications Committee. ACOG Committee Opinion number 419 October 2008 (replaces no. 291, November 2003). Use of progesterone to reduce preterm birth. Obstet Gynecol. 2008;112:963-965. doi: 10.1097/AOG.0b013e31818b1ff6

8. Committee on Practice Bulletins—Obstetrics, The American College of Obstetricians and Gynecologists. Practice Bulletin no. 130: prediction and prevention of preterm birth. Obstet Gynecol. 2012;120:964-973. doi: 10.1097/AOG.0b013e3182723b1b

9. Chang C, Nguyen C, Wesley B, et al. Withdrawing approval of Makena—a proposal from the FDA Center for Drug Evaluation and Research. N Engl J Med. 2020;383:e131. doi: 10.1056/NEJMp2031055

10. US Food and Drug Administration. CDER proposes withdrawal of approval for Makena. Published October 5, 2020. Accessed December 10, 2021. www.fda.gov/drugs/drug-safety-and-availability/cder-proposes-withdrawal-approval-makena

11. Zahn CM. ACOG statement on FDA proposal to withdraw 17p hydroxyprogesterone caproate. Published October 7, 2020. Accessed December 10, 2021. www.acog.org/en/News/News%20Releases/2020/10/ACOG%20Statement%20on%20FDA%20Proposal%20to%20Withdraw%2017p%20Hydroxyprogesterone%20Caproate

12. Society for Maternal-Fetal Medicine Publications Committee. SMFM Statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth. Published October 5, 2021. Accessed December 10, 2021. https://s3.amazonaws.com/cdn.smfm.org/media/2543/Makena,_10.5.pdf

13. Society for Maternal-Fetal Medicine. SMFM Statement: Response to EPPPIC and considerations of the use of progestogens for the prevention of preterm birth. Published March 2021. Accessed December 10, 2021. www.smfm.org/publications/383-smfm-statement-response-to-epppic-and-considerations-of-the-use-of-progestogens-for-the-prevention-of-preterm-birth

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.”⁷A 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.¹⁰However, 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.”¹²Both 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.

Evidence-based answers from the Family Physicians Inquiries Network