Clinical Inquiries

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

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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).


 

References

Evidence summary

Early evidence suggested benefit from IM progesterone

A 2003 RCT compared weekly IM progesterone (n = 310) and placebo (n = 153) injections in women with a history of spontaneous preterm delivery. Participants were at 15w0d to 20w3d of a singleton pregnancy with no fetal abnormality. The 17-OHP group, compared to the placebo group, had significantly fewer deliveries at < 37 weeks (36.3% vs 54.9%; relative risk [RR] = 0.66; 95% CI, 0.54 to 0.81; number needed to treat [NNT] = 6), at < 35 weeks (20.6% vs 30.7%; RR = 0.67; 95% CI, 0.48 to 0.93; NNT = 10), and at < 32 weeks (11.4% vs 19.6%; RR = 0.58; 95% CI, 0.37 to 0.91; NNT = 13).1 There were significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen in infants of women in the treatment group.1 The study was underpowered to detect neonatal morbidity.

A 2013 Cochrane Review (5 studies including the 2003 RCT; 602 women) found that 17-OHP led to a decreased risk of birth at < 34 weeks (RR = 0.31; 95% CI, 0.14-0.69). It also led to a significant reduction in perinatal and neonatal mortality, birth at < 37 weeks, birthweight < 2500 g, use of assisted ventilation, incidence of necrotizing enterocolitis, and admission to the neonatal ICU.2

In a large follow-up study, progesterone did not demonstrate benefit

The PROLONG study was a double-blind, placebo-controlled international RCT of women with a previous singleton spontaneous preterm birth. The study involved 93 clinical centers in 9 countries: 41 in the United States and 52 outside the United States. The ­PROLONG study was much larger than the 2003 study: 1139 active treatment (vs 310) and 578 placebo (vs 153) participants. Women were randomized 2:1 to receive either 250 mg 17-OHP or inert oil placebo weekly from 16w0d-20w6d until 36 weeks. The outcome measures were: (1) delivery at < 35 weeks and (2) a neonatal morbidity composite index. This composite index included any of the following: neonatal death, grade 3 or 4 intraventricular hemorrhage, respiratory distress syndrome, bronchopulmonary dysplasia, necrotizing enterocolitis, and proven sepsis.3

Our best evidence does not support routine IM progesterone use to prevent preterm delivery.

Progesterone did not improve any of the studied outcomes: there were no significant differences in the frequency of birth at < 35 weeks (17-OHP 11% vs placebo 11.5%; RR = 0.95; 95% CI, 0.71-1.26), in neonatal morbidity index (17-OHP 5.6% vs placebo 5%; RR = 1.12; 95% CI, 0.68-1.61), and in frequency of fetal/early infant death (17-OHP 1.7% vs placebo 1.9%; RR = 0.87; 95% CI, 0.4-1.81).3 In the United States subgroup (n = 391; 23% of all patients), there was no significant difference in rate of birth at < 35 weeks (17-OHP 15.6% vs placebo 17.6%; RR = 0.88; 95% CI, 0.55-1.40).3

However, PROLONG had some limitations. Importantly, the 2003 RCT included 183 (59%) non-Hispanic Black women in the experimental group and 90 (58.5%) in the control group, whereas the 2020 PROLONG study had only 6.6% non-Hispanic Black participants. The neonatal outcome data for the PROLONG study only included 6 Black women in the experimental arm and 3 in the control arm.3,4 Black women have prematurity rates that are 2 to 3 times higher than those in White women.5

Additionally, the PROLONG study had fewer smokers and more women who were married/living with a partner. Compared with prior studies, the PROLONG study had a lower proportion of women with > 1 spontaneous preterm birth and fewer with a shortened cervix (< 2%).3 As a result of having lower risk participants, PROLONG may have been underpowered to detect improvements in outcome.3

A subsequent meta-analysis suggests some benefit for high-risk women

The 2021 Evaluating Progestogens for Preventing Preterm birth International Collaborative (EPPPIC) meta-analysis of individual data from 31 RCTs—involving 11,644 women and 16,185 babies—found that, compared with placebo, 17-OHP for women with a history of preterm delivery or short cervix did not significantly decrease the number of babies born before 34 weeks (5 trials [including the 2003 RCT and PROLONG studies]; 3053 women; RR = 0.83; 95% CI, 0.68–1.01).6 However, it found that vaginal progesterone significantly decreased birth prior to 34 weeks (9 trials; 3769 women; RR = 0.78, 95% CI, 0.68-0.90).6 The authors concluded that both IM and vaginal progesterone decreased preterm delivery in high-risk women. The effect was stronger for women with a short cervix than for women with a history of preterm delivery.6

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