17-OHPC to Prevent Recurrent Preterm Birth in Singleton Gestations (PROLONG Study): A Multicenter, International, Randomized Double-Blind Trial
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In women with a history of spontaneous preterm birth, weekly 17-OHPC injections did not significantly reduce the risk of recurrent preterm birth or neonatal morbidity compared to placebo.
Key Findings
Study Design
Study Limitations
Clinical Significance
The PROLONG trial failed to confirm the clinical benefits of 17-OHPC (Makena) that were previously reported in earlier research. Demonstrating no efficacy in preventing recurrent preterm birth or improving neonatal morbidity, this pivotal negative result prompted a critical re-evaluation of progestogen use for this indication and ultimately led the FDA to withdraw the drug's approval.
Historical Context
In 2003, the Meis trial (conducted by the MFMU Network) reported that 17-OHPC significantly reduced recurrent preterm birth, which led to the FDA granting accelerated approval to the drug (marketed as Makena) in 2011. As a condition of that accelerated approval, the FDA mandated a confirmatory Phase 3 trial, which became the PROLONG study. When PROLONG failed to replicate the original efficacy findings, it ignited intense debate within the maternal-fetal medicine community regarding study design, demographic differences, and drug efficacy, culminating in the FDA officially withdrawing Makena from the US market in 2023.
Guided Discussion
High-yield insights from every perspective
Physiologically, why was 17-alpha hydroxyprogesterone caproate (17-OHPC) initially hypothesized to prevent preterm birth, and what role does endogenous progesterone normally play in maintaining pregnancy?
Key Response
Endogenous progesterone is essential for maintaining early pregnancy and later promotes uterine quiescence by suppressing myometrial contractility, inhibiting gap junction formation, and preventing cervical ripening. 17-OHPC, a synthetic progestin, was hypothesized to supplement these effects in women at risk for premature delivery, though the PROLONG trial ultimately questioned its clinical efficacy in preventing recurrent preterm birth.
A pregnant patient at 14 weeks gestation with a history of a prior spontaneous preterm birth at 28 weeks asks if she should start weekly progesterone injections. Based on the findings of the PROLONG trial and subsequent FDA actions, how should you counsel her, and what alternative management should be offered?
Key Response
Residents must know that due to the negative findings of the PROLONG trial, the FDA withdrew approval for 17-OHPC (Makena) in 2023. The patient should be counseled that 17-OHPC is no longer recommended or available. Instead, management should focus on serial transvaginal ultrasound cervical length monitoring between 16 and 24 weeks, with the potential use of vaginal progesterone or cervical cerclage if a short cervix is identified.
The results of the PROLONG trial directly contradicted the landmark 2003 Meis trial. What were the critical demographic, epidemiological, and baseline risk differences between the populations in these two studies that might explain the divergent outcomes?
Key Response
The Meis trial consisted of a predominantly US, high-risk, largely African American population with a very high placebo preterm birth rate (approx. 55%). In contrast, PROLONG was an international study, heavily reliant on Eastern European sites, with a much lower placebo preterm birth rate (11.5%). Fellows must understand how baseline population risk profoundly impacts the observed efficacy of an intervention and complicates cross-trial comparisons.
How does the 15-year trajectory of 17-OHPC—from its widespread adoption following the Meis trial to the PROLONG study and subsequent FDA withdrawal—serve as a teaching model for 'medical reversal' and the limitations of accelerated drug approvals based on single trials?
Key Response
Attendings must lead practice changes and teach critical appraisal. The 17-OHPC story is a classic example of medical reversal, highlighting the danger of entrenching a standard of care based on a single trial with unusually high event rates in the control group. It emphasizes to learners the necessity of robust, adequately powered confirmatory trials before universally adopting a therapy.
Scholarly Review
Critical appraisal through the lens of expert reviewers and guideline development
The PROLONG trial observed a placebo event rate of 11.5% for preterm birth before 35 weeks, which was significantly lower than anticipated. How does a lower-than-expected baseline event rate impact statistical power, and how could future global obstetric trials use adaptive designs to mitigate background rate heterogeneity?
Key Response
A drastically lower baseline event rate severely reduces a trial's power to detect a hypothesized relative risk reduction, raising the question of whether the trial became underpowered or if the drug truly lacks efficacy. Methodologists would argue for adaptive trial designs that allow for sample size re-estimation based on interim, blinded event rates, or stratified randomization by baseline risk to ensure adequate power across diverse geographical sites.
As a peer reviewer evaluating the PROLONG manuscript, what concerns would you raise regarding the 'standard of care paradox' and selection bias introduced by the difficulty of enrolling US patients, given that 17-OHPC was already the established standard of care in the US at the time of the trial?
Key Response
Because 17-OHPC was ACOG standard of care in the US during enrollment, high-risk US patients were unlikely to consent to randomization where they might receive a placebo. Consequently, the trial had to enroll primarily in countries where 17-OHPC was not standard of care. A critical reviewer would flag this as a major threat to external validity, questioning whether the enrolled cohort accurately represented the high-risk US populations most targeted by the drug.
In light of the PROLONG trial and the FDA's withdrawal of Makena, how must SMFM and ACOG guidelines for the prevention of recurrent spontaneous preterm birth be rewritten regarding the algorithm for patients with a prior preterm birth, and what level of evidence now supports these changes?
Key Response
Guidelines previously gave a strong recommendation (Level A evidence based on Meis) for 17-OHPC in all women with a history of spontaneous preterm birth. Following PROLONG (Level A evidence contradicting Meis), guidelines must shift from universally recommending prophylactic 17-OHPC to recommending risk stratification via serial cervical length screening, reserving interventions like vaginal progesterone or cerclage only for those who develop a shortened cervix.
Clinical Landscape
Noteworthy Related Trials
Meis Trial
Tested
17-alpha hydroxyprogesterone caproate weekly injection
Population
Women with a history of spontaneous preterm delivery
Comparator
Placebo
Endpoint
Preterm delivery before 37 weeks
PREGNANT Trial
Tested
Vaginal progesterone gel 90mg daily
Population
Asymptomatic women with a short cervix mid-trimester
Comparator
Placebo
Endpoint
Preterm birth before 33 weeks
OPPTIMUM Trial
Tested
Vaginal progesterone 200mg daily
Population
Women at high risk for preterm birth due to history or short cervix
Comparator
Placebo
Endpoint
Delivery before 34 weeks and composite neonatal morbidity
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