By Camille Hoffman, MD, MSc
Associate Professor, Maternal Fetal Medicine, University of Colorado Departments of Obstetrics and Gynecology
and Psychiatry, Wheat Ridge, CO
Dr. Hoffman reports no financial relationships relevant to this field of study.
SYNOPSIS: In this large, double-blind, placebo-controlled, international trial, pregnant women at risk for preterm birth (PTB) between 16-36 weeks gestational age were randomized to an intramuscular weekly injection of either 17-hydroxyprogesterone caproate (17P) or placebo. There was no difference in rates of PTB or neonatal morbidity between these two groups. In comparison to the Meis trial published in 2003, the findings of the PROLONG trial question the use of intramuscular 17P injection as the cornerstone of PTB prevention.
SOURCE: Blackwell SC, Gyamfi-Bannerman C, Biggio JR, 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.
The PROLONG study was a double-blind, placebo-controlled, international trial that enrolled women with a previous singleton spontaneous preterm birth. Forty-one of 93 enrollment sites were in the United States and 52 were outside the country. Women were enrolled between 16w0d and 20w6d to receive a weekly intramuscular injection of either 17-hydroxyprogesterone caproate (17P) or placebo. Participants were continued on either the study medication or placebo (in a 2:1 ratio of 17P: placebo) until either delivery or 36 weeks gestation. Co-primary outcomes were preterm birth (PTB) < 35 weeks and a composite neonatal morbidity measure.
Women were enrolled in a 2:1 ratio, with 1,130 women in the 17P group and 578 in the placebo group. Baseline characteristics between the 17P and placebo groups were similar. The racial composition of the PROLONG study group to the population in the Meis trial was different, with a higher proportion of Caucasian women in this study than in the Meis trial. Unlike the Meis study, the results of the PROLONG study did not show a significant reduction in preterm birth < 35 weeks (11.0% in the 17P group vs. 11.5% in the placebo group, relative risk [RR], 0.95; 95% confidence interval [CI], 0.71-1.26). There were no differences in the neonatal morbidity index (5.6% 17P vs. 5.0% placebo; RR, 1.12; 95% CI, 0.68-1.61) or fetal/early infant death (1.7% 17P vs. 1.9% placebo; RR, 0.87; 95% CI, 0.4-1.81) between groups. When subgroup analyses were done of only the women enrolled in the United States (391 total, or 23% of this study cohort), PTB < 35 weeks occurred in 15.6% of the 17P group vs. 17.6% of the placebo group (RR, 0.88; 95% CI, 0.55-1.40). In comparison, in the Meis trial, PTB < 35 weeks occurred in 20.6% of the 17P group vs. 30.7% of the placebo group (RR, 0.67; 95% CI, 0.48-0.93). Of note, the primary outcome of the Meis trial was PTB < 37 weeks, and the authors found a “34% reduction in the incidence of recurrent preterm birth” in the 17P group vs. placebo for PTB < 37 weeks.
The Meis study concluded that “weekly 17P injections result in a substantial reduction in the rate of recurrent PTB among women who were at particularly high risk for PTB and reduced the likelihood of several complications in their infants.” In comparison, the PROLONG study concluded that “in this study population, 17P did not decrease recurrent PTB and was not associated with increased fetal/early infant death.” This large difference in outcomes — and statistical significance — immediately led to media announcements and major organization proclamations.
Preterm birth is a major health issue. Since the Meis trial was published in 2003, 17P has been the mainstay of managing pregnancies complicated by a history of prior preterm birth.1 This medication is a weekly intramuscular injection that pregnant women with a history of prior spontaneous preterm birth receive between 16 to 36 weeks. As part of Food and Drug Administration (FDA) approval of the Makena (hydroxyprogesterone caproate) formulation of 17P, a product created by AMAG pharmaceuticals and that received FDA “orphan drug exclusivity status” in February 2011, a larger randomized, controlled trial was required. The Blackwell/PROLONG study is the result of this requirement.
When the Meis study was published in 2003, findings provided hope toward reducing the risk of PTB as a significant cause of neonatal morbidity and mortality. Thus, it is not surprising that the Meis study was published in the New England Journal of Medicine in 2003 and received some media attention. Then, in 2019, the PROLONG study, a potentially more robust trial, was published in the American Journal of Perinatology, a lesser-known journal. This may underscore the issue of publication bias and the public’s desire for only good news — where only positive results end up in high-impact journals and a bigger, albeit negative, primary outcome trial ends up in the American Journal of Perinatology. Nonetheless, within hours of the FDA’s advisory committee voting in favor of withdrawing 17P from the market on Oct. 30, 2019, all the major players (i.e., American College of Obstetricians and Gynecologists, Society for Maternal-Fetal Medicine [SMFM]) jumped in to underscore all the ways that the PROLONG study was different from the Meis trial.2,3
The excuses cited for the difference in study outcomes ranged from “it was unethical to enroll patients in a placebo-controlled trial when an ‘efficacious’ treatment already existed” to more data-driven excuses including the race/ethnic differences between study populations, with a much higher proportion of African-American women (who are at increased risk for PTB) in the Meis population than in the PROLONG population. Other data-driven differences were variation in the number of previous PTBs, marital status, and reported substance use.
Based on these results, and subsequent commentaries, the SMFM has recommended that obstetric care providers “use an individualized approach as they counsel patients regarding the use of 17P.” They also suggest that “it is reasonable to continue use of 17P in the context of a shared decision-making model that includes consideration of risk level for recurrent PTB.”
Considering both 2003 and 2019 data, our maternal-fetal medicine division has decided to recommend the following:
• Continue any patient already on 17P at the time of the FDA announcement on this medication through 36 weeks.
• Advise against new starts of 17P in women with a prior PTB unless they have used this medication in the past and have had a later gestational age at delivery ON 17P (and they desire to use it again in the index pregnancy).
• Take an individualized approach and use shared-decision making in African-American women, who are at higher risk for PTB and recurrent PTB.
• Be more consistent with serial cervical lengths and vaginal progesterone use in women with a history of prior PTB.
- Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate. N Engl J Med 2003;348:2379-2385.
- GlobalData Healthcare. FDA faces conundrum over future of AMAGʼs Makena following drug withdrawal. Clinical Trials Arena. Published Nov. 11, 2019. https://www.clinicaltrialsarena.com/comment/fda-faces-conundrum-over-future-of-amags-makena-following-a-negative-vote/
- Society for Maternal-Fetal Medicine. Experts in high-risk pregnancy respond to the published results of the PROLONG trial. American Association for the Advancement of Science. Published Oct. 25, 2019. https://www.eurekalert.org/pub_releases/2019-10/sfmm-eih102519.php