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New England Journal of Medicine Abstract

Volume 348:2379-2385
June 12, 2003
Number 24

Prevention of Recurrent Preterm Delivery by 17 Alpha-Hydroxyprogesterone Caproate

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

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.

Preterm delivery — that is, delivery before 37 completed weeks of gestation — is the major determinant of infant mortality in developed countries.1 Preterm delivery is more common in the United States than in many other developed countries and is the factor most responsible for the relatively high infant mortality in this country.1 The rate of preterm delivery in the United States has increased progressively from 9 percent to 12 percent over the past two decades.2 Despite many trials of reduced activity, tocolytic therapy, antibiotic therapy, and other strategies for prevention, no effective and reproducible method of preventing preterm delivery has been demonstrated.3

One treatment that showed promise in small trials was prophylactic treatment with progestational compounds.4,5,6,7 Not all trials reported positive results.8,9 One meta-analysis found no evidence of effectiveness of progestational compounds in the prevention of preterm delivery or the prevention of recurrent miscarriage.10 Another meta-analysis, restricted to trials of 17 alpha-hydroxyprogesterone caproate (17P), a natural metabolite of progesterone, showed, in composite, a significant reduction in the rate of preterm delivery.11 We therefore chose this pharmacologic agent as the active drug for our study.

Women who have had a preterm delivery are at especially high risk for preterm delivery in a subsequent pregnancy.12 We therefore conducted a multicenter trial to test the effectiveness of 17P as compared with placebo in the prevention of recurrent preterm delivery in this group of women.

http://www.bsc.gwu.edu/mfmu/PROJECTS/progest.html

MFMU Network Randomized Clinical Trial of 17 alpha-Hydroxyprogesterone Caproate for Prevention of Preterm Birth in High Risk Women

Objective:
To test the hypothesis that administration of 17 alpha-hydroxyprogesterone caproate for initiated before 21 weeks gestation will reduce the risk of preterm birth in women who have previously experienced an early spontaneous preterm delivery.

Conclusion:
To be determined.

Clinical Centers:
Magee Womens, Tennessee, Alabama, Wayne State, Cincinnati, Wake Forest, Chicago, Ohio State, Miami, UT-San Antonio, UT-Dallas, Utah, Thomas Jefferson, Brown, Columbia, UT-Houston, Case Western, UNC, Northwestern

Major Eligibility Criteria:
Documented previous SPTD
16,0 to 20,6 weeks gestation
Informed consent

Groups:
Experimental = 1 ml IM with 250 17 a-hydroxyprogesterone caproate weekly
Placebo = 1 ml IM inert oil weekly
Sample size: Goal = 500 (334 active; 166 placebo)
Management Protocols

Coded medication:
1 ml IM with 250 mg 17 a-hydroxyprogesterone caproate weekly until 36,6 weeks gestation
1 ml IM inert oil weekly until 36,6 weeks gestation
Outcome Measures

Primary:
Preterm delivery (<37 weeks gestation)

Secondary:
Tocolytic therapy
Cerclage placement
Salivary esteriol and progesterone trends
Neonatal morbidity and mortality
Timetable
As designed: Randomization: 12/97-03/99
Data collection: 12/97-11/99
Closeout/final analysis: 11/99-05/00

17 ALPHA HYDROXYPROGESTERONE CAPROATE, (17P), PREVENTS PRETERM BIRTH IN WOMEN AT HIGH RISK

PAUL J. MEIS FOR THE NICHD MFMU NETWORK, BETHESDA MD

OBJECTIVE:
Although early small studies suggested a benefit for 17P therapy in preventing preterm birth, no large rigorous trial has confirmed these data. The current study was undertaken to answer this question.

STUDY DESIGN:
Women with a documented history of a previous spontaneous preterm birth at less that 37 weeks gestational age were enrolled at 19 Centers at 16 to 20 weeks gestation and randomly assigned by a central data center using a 2 to 1 ratio to weekly injections of 17P or to a placebo injection, with treatment continuing to 36 weeks gestation.

RESULTS:
The predominant race of the subjects was African-American, (59%). Mean gestational age at birth of the qualifying delivery was 30.7 weeks. Baseline characteristics of the treatment group, n=306, and the placebo group, n=153, were similar. Treatment with 17P significantly reduced the risk of preterm birth at <37 weeks, <35 weeks and <32 weeks gestation. Treatment with 17P was equally effective in African American and non-African American subjects.

CONCLUSIONS:
Weekly injections of 17P can provide a significant and powerful protection to prevent recurrent preterm birth in women at high risk.