Progesterone for the prevention of preterm birth among women at increased risk

Preterm birth is one of the main causes of perinatal and neonatal mortality, neonatal morbidity, and long-term neurodevelopmental problems. In particular, the risk of mortality and morbidity is influenced by gestational age at delivery, birth weight, and multiple pregnancies. Moreover, the cost of neonatal intensive and long-term care for premature infants is very high. Spontaneous preterm birth represents approximately 75% of all preterm births. Among all treatments evaluated for the prevention of spontaneous preterm birth, progestational agents are the most promising. Although the exact mechanism of progesterone in the prevention of preterm birth is not known, this drug could prevent the formation of gap junctions, could have an inhibitory effect on myometrial contractions, and, noticeably, could prevent spontaneous abortion in women in early pregnancy after excision of the corpus luteum.
The first randomized controlled trial of progestational agents for the prevention of preterm birth in women at increased risk was published in 1970. This trial demonstrated efficacy in a group of 99 women who received 17 alpha-hydroxyprogesterone caproate (17P) or placebo in the third trimester. A subsequent trial reported a significant reduction in the preterm birth rate among a small sample of high-risk women when 17P treatment was initiated in the second trimester. Only two other randomized controlled trials have been published concering the use of progestational agents in women at risk of spontaneous preterm during the second semester.
Metanalysis of these trials can therefore provide some new evidence on the potential use of progestational agents in this class of women. In total, 648 women and 643 infants were considered in these three analyses; 399 subjects received progestational agents and 249 received placebo. The mean gestational age at enrollment varied between 14.0 and 26.2 weeks’ gestation. Overall results show that the risk of delivery less than 37 weeks’ gestation is significantly lower with treatment with a progestational agent versus placebo [relative risk (RR)=0.57], as well as the risks of delivery before 35 weeks’ (RR=0.67), 34 weeks’ (RR=0.15), and 32 weeks’ gestation (R=0.58). The treatment with progestational agent is also associated to a lower risk of birth weight less than 2500 g (RR=0.66) and to an higher mean birth weight with respect to placebo. However, progestational agents had no significant effect on the risk of congenital anomalies, spontaneous abortion, perinatal death or on measures of serious neonatal morbidity. These results are consistent, although it can be shown a trend toward reductions in risk for perinatal death and for serious morbidity such as respiratory distress syndrome, ventilatory support, and necrotizing enterocolitis.
In summary, review of results from specific clinical trials has found that progestational agents, initiated in the second trimester of pregnancy, could reduce the risk of delivery less than 37 weeks’ gestation for women at increased risk of spontaneous preterm birth, but their effect on spontaneous abortion, perinatal mortality, or neonatal morbidity is, at present, still uncertain. Therefore, present evidence suggest that treatment of women with progestational agents to reduce the complications of preterm birth should continue to be confined to women enrolled in well-designed randomized controlled trials.

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