Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate

Paul J Meis; Mark Klebanoff; Elizabeth Thom; Mitchell P Dombrowski; Baha Sibai; Atef H Moawad; Catherine Y Spong; John C Hauth; Menachem Miodovnik; Michael W Varner; Kenneth J Leveno; Steve N Caritis; Jay D Iams; Ronald J Wapner; Deborah Conway; Mary J O'Sullivan; Marshall Carpenter; Brian Mercer; Susan M Ramin; John M Thorp; Alan M Peaceman; Steven Gabbe; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

doi:10.1056/NEJMoa035140

Pregnancy · Preterm Birth

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate

Meis PJ, Klebanoff M, Thom E, Dombrowski MP, Sibai B, Moawad AH, Spong CY, Hauth JC, Miodovnik M, Varner MW, Leveno KJ, Caritis SN, Iams JD, Wapner RJ, Conway D, O'Sullivan MJ, Carpenter M, Mercer B, Ramin SM, Thorp JM, Peaceman AM, Gabbe S, National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network

Published June 12, 2003 The New England Journal of Medicine, 348(24), 2379-2385

DOI 10.1056/NEJMoa035140 PMID 12802023

RRM Academy Synopsis

17P injections lowered repeat preterm birth in high-risk women

Weekly 17P injections lowered the risk of repeat preterm birth in women with earlier spontaneous preterm delivery. In a 2003 placebo-controlled trial of 463 women, about 36 out of 100 on 17P (17 alpha-hydroxyprogesterone caproate) delivered before 37 weeks. About 55 out of 100 on placebo did.

Key Findings

Delivery before 37 weeks occurred in 111 of 306 women on 17P (36.3 percent) and 84 of 153 on placebo (54.9 percent); relative risk 0.66 (95 percent CI 0.54 to 0.81).
Delivery before 35 weeks occurred in 20.6 percent on 17P and 30.7 percent on placebo; relative risk 0.67 (95 percent confidence interval 0.48 to 0.93).
Delivery before 32 weeks occurred in 11.4 percent on 17P and 19.6 percent on placebo; relative risk 0.58 (95 percent confidence interval 0.37 to 0.91).
Infants needed supplemental oxygen in 14.9 percent of the 17P group and 23.8 percent of the placebo group; relative risk 0.62 (95 percent confidence interval 0.42 to 0.92).
Injection-site swelling occurred in 17.2 percent of women on 17P and 7.8 percent on placebo (P=0.007). Congenital malformations were 2.0 percent in each group.

Interpretation

This randomized, double-blind, placebo-controlled trial enrolled 463 women at 19 centers. The trial stopped early, after an interim analysis crossed its prespecified boundary with outcome data on 70 percent of the planned sample. Each woman had a documented earlier spontaneous preterm delivery. Women with multiple pregnancy or a cervical cerclage were excluded. The authors say the result may not apply to women at lower risk. Delivery before 37 weeks still occurred in 36.3 percent of women on 17P. The placebo group had more earlier preterm deliveries, and the adjusted relative risk was 0.70 (95 percent confidence interval 0.57 to 0.85).

RRM Context

Restorative reproductive medicine treats preterm risk as a question about cause. The authors write that preterm delivery has multiple causes. They add that finding other causes and other ways to prevent it remains a pressing need. Entry to the trial depended on a documented earlier spontaneous preterm delivery, and the trial tested one injected drug.

Our editorial summary of this paper, not the article's abstract.

Abstract

Background

Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies. The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate (17P) may reduce the risk of preterm delivery.

Methods

We conducted a double-blind, placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery. Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and randomly assigned by a central data center, in a 2:1 ratio, to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo; injections were continued until delivery or to 36 weeks of gestation. The primary outcome was preterm delivery before 37 weeks of gestation. Analysis was performed according to the intention-to-treat principle.

Results

Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar. Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation (incidence, 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group; relative risk, 0.66 [95 percent confidence interval, 0.54 to 0.81]), delivery at less than 35 weeks of gestation (incidence, 20.6 percent vs. 30.7 percent; relative risk, 0.67 [95 percent confidence interval, 0.48 to 0.93]), and delivery at less than 32 weeks of gestation (11.4 percent vs. 19.6 percent; relative risk, 0.58 [95 percent confidence interval, 0.37 to 0.91]). Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis, intraventricular hemorrhage, and need for supplemental oxygen.

Conclusions

Weekly injections of 17P resulted in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants.

Responses

Preterm Birth · Progesterone Prophylaxis

Progesterone and preterm delivery--deja vu all over again

Greene MF, 2003

Topics

Pregnancy › Preterm Birth › Progesterone Prophylaxis · Birth and Delivery › Birth Outcomes › Maternal Morbidity · Therapeutics › Hormonal Agents › Progesterone and Progestins

Paul J Meis, Mark Klebanoff, Elizabeth Thom, Mitchell P Dombrowski, Baha Sibai, Atef H Moawad, Catherine Y Spong, John C Hauth, Menachem Miodovnik, Michael W Varner, Kenneth J Leveno, Steve N Caritis, Jay D Iams, Ronald J Wapner, Deborah Conway, Mary J O'Sullivan, Marshall Carpenter, Brian Mercer, Susan M Ramin, John M Thorp, Alan M Peaceman, Steven Gabbe

P Meis, M Klebanoff, Liz Thom, Beth Thom, Betsy Thom, E Thom, M Dombrowski, B Sibai, A Moawad, Cathy Spong, Kate Spong, C Spong, Jack Hauth, J Hauth, M Miodovnik, Mike Varner, M Varner, Ken Leveno, K Leveno, Stephen Caritis, Steven Caritis, S Caritis, J Iams, Ron Wapner, R Wapner, Debbie Conway, Deb Conway, D Conway, M O'Sullivan, M Carpenter, B Mercer, Sue Ramin, S Ramin, Jack Thorp, J Thorp, A Peaceman, Steve Gabbe, S Gabbe

PMID 12802023 12802023 DOI 10.1056/NEJMoa035140 10.1056/NEJMoa035140 Meis et al. 2003, Meis 2003

Keywords

17 alpha-Hydroxyprogesterone Caproate, Adult, Birth Weight, Cerebral Hemorrhage/epidemiology, Double-Blind Method, Enterocolitis, Necrotizing/epidemiology, Female, Humans, Hydroxyprogesterones/adverse Effects/therapeutic Use, Infant, Newborn, Infant, Premature, Obstetric Labor, Premature/prevention & Control, Oxygen Inhalation Therapy, Pregnancy, Pregnancy Outcome, Progesterone Congeners/adverse Effects/therapeutic Use, Risk, Survival Analysis, Hydroxyprogesterones, Progesterone Congeners, 17 alpha-Hydroxyprogesterone Caproate

Prevention of recurrent preterm delivery by 17 alpha-hydroxyprogesterone caproate

17P injections lowered repeat preterm birth in high-risk women

Key Findings

Interpretation

RRM Context

Abstract

Responses

Topics

By this author

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Keywords