SUMMARY:

The results of the PROLONG Study (Progestin’s Role in Optimizing Neonatal Gestation) are now available. The authors conclude that

In this study population, 250 mg 17-OHPC did not decrease recurrent PTB and was not associated with increased fetal/early infant death

On October 29, 2019, the FDA advisory committee recommended that the drug be withdrawn from the market (9 to 7 vote). Although the recommendation is not binding, it does become part of the overall assessment process when the FDA makes its final decision.

Background

• A previous study, on behalf of the NICHD, demonstrated success of IM 17-OHCP in preventing PTB (see ‘Learn More – Primary Sources)
  • Meis et al. (NEJM, 2003): 250 mg IM 17-OHPC reduced recurrent preterm birth (PTB) in women with a prior spontaneous PTB (SPTB)
    • Relative risk [RR] 0.66 (95% CI, 0.54–0.81)
• The current PROLONG study was a ‘confirmatory trial’, performed with FDA input as a requirement for the FDA accelerated approval pathway

Methods

• Double blind randomized controlled trial (RCT)
• Participants
  • ≥18 years
  • Singleton pregnancy
  • Currently 16w0d to 20w6d
  • Previous history of singleton SPTB (birth between 20w0d and 36w6d following preterm labor or PROM)
• Groups (IM injection 1 in upper outer quadrant of the gluteus maximus)
  • 17-OHPC
  • Placebo
• Stratified by
  • Study site
  • GA at randomization
• Primary outcomes
  • PTB < 35 weeks
  • Composite neonatal morbidity and mortality index

Results

• PTB < 35w0d (p=0.72)
  • 17-OHPC: 11.0%
  • Placebo: 11.5%
  • Relative risk (RR) 0.95 (95% CI, 0.71–1.26)
• Neonatal composite index (p=0.73)
  • 17-OHPC 5.6%
  • Placebo 5.0%
  • RR 1.12 (95% CI, 0.70–1.66)
  • Note: No differences seen in any of the individual components that were part of the composite index

KEY POINTS:

SMFM Response

SMFM has responded to the PROLONG trial results and makes the following substantive points comparing current data to Meis et. al. study

• Difference in population when analyzing Meis et al., vs PROLONG
  • Higher rate of black women: 59% vs 7%
  • Smoking (tobacco): >20% vs 8%
  • >1 prior PTB: 32% vs 12%
  • Additional PTB risk factors aside from prior history: 91% vs 48%
• Difference in results may be a result of high vs average risk but “population differences do not completely explain the discrepancy” due to complexity of PTB
• Concerns related to 17-OHPC include
  • Health care costs
  • Injection-site pain
  • Additional patient visits
• Additional research required to (1) determine long-term maternal and neonatal side effects (2) “identify populations in which administration of 17-OHPC may provide needed benefit in the reduction of recurrent sPTB”
• SMFM states that

…it is reasonable for providers to use 17-OHPC in women with a profile more representative of the very high-risk population reported in the Meis trial. For all women at risk of recurrent sPTB, the risk/benefit discussion should incorporate a shared decision-making approach, taking into account the lack of short-term safety concerns but uncertainty regarding benefit

ACOG Response

ACOG has likewise responded to the PROLONG trial with a Practice Advisory

• Similar to SMFM, ACOG notes that while eligibility criteria were similar between the Meis trial and PROLONG, the populations are different and preterm birth rate in the current study is approximately 50% lower than the earlier study
• The study authors acknowledge that
  • PROLONG may be underpowered for the population under study
  • Selection bias may have played a role, as women at higher risk would not have agreed to possibility of receiving placebo
• Additional studies, including a meta-analysis, are planned
• ACOG Guidance (Practice Bulletin 130) states

A woman with a singleton gestation and a prior spontaneous preterm singleton birth should be offered progesterone supplementation starting at 16–24 weeks of gestation, regardless of transvaginal ultrasound cervical length, to reduce the risk of recurrent spontaneous preterm birth

• The Practice Advisory response to the PROLONG trial states that ACOG

is not changing our clinical recommendations at this time and continues to recommend offering hydroxyprogesterone caproate as outlined in Practice Bulletin # 130

Learn More – Primary Sources:

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

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. (NEJM, 2003)

SMFM Statement: Use of 17-alpha hydroxyprogesterone caproate for prevention of recurrent preterm birth

ACOG Practice Advisory: Clinical guidance for integration of the findings of the PROLONG study: Progestin’s Role in Optimizing Neonatal Gestation

ACOG Practice Bulletin 130: Prediction and Prevention of Preterm Birth

Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee Meeting Announcement: MAKENA supplemental new drug application

WSJ: FDA Committee Recommends Withdrawing Makena

Related ObG Topics:

Progesterone, Cerclage or Pessary for Prevention of Preterm Birth: A Comparison

Does Use of Progestogen Prolong Labor in PPROM Pregnancies?

Does a Weekly Dose of 17-OHPC Improve Outcomes in the Setting of Preterm Ruptured Membranes?

17-OHPC Treatment and Prevention of Preterm Birth: Does Timing Matter?

Do Progestogens Prevent Preterm Birth in Symptomatic Pregnancies with a Short Cervix?

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