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The New England Journal of Medicine (Editorial)

Volume 348:2453-2455
June 12, 2003
Number 24

Progesterone and Preterm Delivery- Deja Vu All Over Again

Michael F. Greene, M.D.

It has become almost a platitude to lament the complexity and intractability of the problem of preterm delivery, the poor predictive value of screening tests for its occurrence, its resistance to attempted interventions, and its increasing rate. (1) Preterm delivery is more common among blacks, the poor, the unmarried, cigarette smokers, underweight women, women with multiple gestations, women with uterine anomalies, women with a history of previous preterm delivery, and women without prenatal care. Although the perinatal mortality rate due to prematurity has decreased dramatically during the past three decades, this reduction has resulted from improvements in perinatal and pediatric care for premature babies and has occurred in spite of the increasing incidence of premature delivery. Outcomes have improved for all racial and ethnic groups, but the racial disparity in the rate of premature delivery has been stubbornly persistent. (2) The health care system of the United States is second to none in the achievement of better outcomes for tiny babies, but because it is burdened with such large numbers of these babies, our perinatal mortality rate is among the highest in the developed world.

A minority of preterm deliveries are "indicated" deliveries that result from obstetrical interventions to end pregnancies whose continuation is perceived as placing the fetus or the mother in jeopardy. With regard to these deliveries, the news is not all bad. The increasing rate of preterm delivery in such pregnancies has been associated with a reduction in fetal mortality. (3)

The majority of preterm deliveries, however, are spontaneous and result primarily from premature labor, with or without premature rupture of the fetal membranes. For such cases, the news has been disappointing. Scoring systems have been developed to estimate the risk of preterm delivery on the basis of historical risk factors. These scoring systems have been successful in identifying women with a risk of premature delivery that is two to three times as high as that for a woman in the general population (as high as 35 percent). (4) But the majority of women identified as having an increased risk do not delivery prematurely. Furthermore, efforts to provide these "high-risk" women with early care, universal provision of care, or enhanced prenatal services have generally failed to improve perinatal outcomes. (5) Physiological measures (the monitoring of uterine contractions), anatomical measures (the ultrasonographic measurement of cervical length), and biochemical measures (the assessment of fetal fibronectin in cervicovaginal secretions) are also poorly predictive of the risk of preterm delivery. (6) Efforts to treat women with tocolytic agents for premature labor after it has been diagnosed have had minimal success and have not resulted in improved perinatal outcomes. (7)

The report by Meis et al. (8) in this issue of the Journal provides some encouraging news. Inspired in part by the positive results of a small trial of 17alpha-hydroxyprogesterone caproate (17P), published in the Journal nearly 30 years ago, (9) the current study takes another look at the efficacy of this agent in preventing preterm delivery. 17P is a wakly active, naturally occurring progesterone that has been isolated from both adrenal glands and corpora lutea. The synthetic caproate ester is virtually inactive when given by mouth but works as a long-acting progestin when administered intramuscularly. Subjects in the study by Meis et al. had a history of at least one preterm delivery and were randomly assigned to a double-blind treatment with weekly intramuscular injections of 17P or placebo in a 2:1 ratio. Treatment began at 16 to 20 weeks of gestation and continued until delivery or 36 weeks of gestation. The primary outcome measure was preterm delivery. The rate of delivery before 37 weeks of gestation was 36.3 percent in the treatment group and 54.9 percent in the control group- an absolute risk reduction of 18.6 percent in the treatment group. Similarly impressive reductions in the rates of preterm delivery before 35 weeks of gestation and before 32 weeks of gestation were also achieved.

In addition to the dramatic treatment effects observed, the study has several notable features. It was large, with 310 treated subjects and 153 control subjects. The incidence of preterm delivery in the control group was strikingly high. The treatment and control groups were very similar in randomization. Compliance with the study protocol was excellent. Less than 1 percent of subjects were lost to follow-up. Nearly 60 percent of the subjects were black, and they derived the same benefit from the treatment as the white subjects.

The study raises a number of important questions. How does this drug work? In many mammals, progesterone is chiefly responsible for maintaining uterine quiescense during pregnancy; a drop in the progesterone level, is normal to the initiation of parturations at term. There is substantial evidence, however, that preterm labor is not simply the early initiation of otherwise normal labor through these same physiological mechanisms. Data suggest that preterm labor and preterm rupture of the membranes before labor frequently result from an exuberant, and often inappropriate, inflammatory response, with elaboration of cytokines and matrix metalloproteinases. These mediators appear to incite a paracrine cascade, resulting in pathologic labor. Could progesterone treatment suppress the final common pathway to labor, and could such suppression be maladaptive in cases of infection with virulent organisms? It is reassuring that treatment did not increase the incidence of either maternal chorioamnionitis or neonatal sepsis. Although exposure to 17P during the first trimester was avoided, the experience of late sequelae from exposure to the potent sex steroid diethylstilbestrol in utero casts a long shadow. Could there be some long-term consequenses of this treatment that would not be obvious during the brief follow-up period reported in this trial? Longer-term follow-up of this cohort would help to provide reassurance in this regard.

Can these results be generalized to other populations of patients? The 54.9 percent incidence of preterm delivery in the placebo group is so much higher than the rates reported in other high-risk cohorts that it calls into question whether these women are representative of the U.S. population at large. To what extent can the results obtained in these subjects be extrapolated to women who are at risk for preterm delivery for other reasons? Metronidazole, for example, successfully reduced the risk of preterm delivery among women with bacterial vaginosis who were at very high risk for preterm delivery because of other factors (10) but failed to reduce the risk among women with bacterial vaginosis who did not have other risk factors. (11) A small trial of 17P in women with twin gestations was unsuccessful more than 20 years ago. (12) In view of the current epidemic of multiple gestations, perhaps another trial of 17P should be undertaken in such women. The progesterone preparation used in the current study is not readily and generally available. Will adequate supplies of 17P be available to doctors and patients who might want to use it? Might other gestational agents administered by less invasive routes be equally efficacious and more tolerable? (13)

Despite treatment, more than a third of the subjects studied by Meis et al. still delivered prematurely. The study does, however, demonstrate that at least some preterm deliveries can be prevented. 17P may be only the first in a series of successful interventions to reduce the rate or preterm delivery.

References
1.Goldenberg RL, Rouse DJ. Prevention of premature birth.
N Engl J Med 1998;339:313-320.

2. Infant mortality and low birth weight among black and white infants -- United States, 1980-2000. MMWR Morb Mortal Wkly Rep 2002;51:589-592

3.Joseph KS, Kramer MS, Marcoux S, et al. Determinants of preterm birth rates in Canada from 1981 through 1983 and from 1992 through 1994. N Engl J Med 1998;339:1434-1439.

4.Main DM, Gabbe SG. Risk scoring for preterm labor: where do we go from here? Am J Obstet Gynecol 1987;157:789-793.

5. Collaborative Group on Preterm Birth Prevention. Multicenter randomized, controlled trial of a preterm birth prevention program. Am J Obstet Gynecol 1993;169:352-366.

6. Iams JD, Newman RB, Thom EA, et al. Frequency of uterine contractions and the risk of spontaneous preterm delivery.
N Engl J Med 2002;346:250-255.

7. The Canadian Preterm Labor Investigators Group. Treatment of preterm labor with the beta-adrenergic agonist ritodrine.
N Engl J Med 1992;327:308-312

8. 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.

9. Johnson JWC, Austin KL, Jones GS, Davis GH, King TM. Efficacy of 17alpha-hydroxyprogesterone caproate in the prevention of premature labor. N Engl J Med 1975; 293:675-680.

10. Hauth JC, Goldenberg RL, Andrews WW, DuBard MB, Cooper RL. Reduced incidence of preterm delivery with metronidazole and erythromycin in women with bacterial vaginosis.
N Engl J Med 1995; 333:1732-1736.

11. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. N Engl J Med 2000; 342:534-540.

12. Hartikainen-Sorri A-L, Kauppila A, Tuimala R. Inefficacy of 17 alpha-hydroxyprogesterone caproate in the prevention of prematurity in twin pregnancy. Obstet Gynecol 1980; 56:692-695.

13. da Fonseca EB, Bittar RE, Carvalho MHB, Zugaib M. Prophylactic administration of progesterone by vaginal suppository to reduce the incidence of spontaneous preterm birth in women at increased risk: a randomized placebo-controlled double-blind study. Am J Obstet Gynecol 2003; 188:419-424.