Prevention of Preterm Delivery in Twin Pregnancies by 17 Alpha-hydroxyprogesterone Caproate

Preterm birth remains the leading public health problem in obstetrics. A recent analysis of neonatal mortality (death at age < 28 days) in the United States between 1989 and 2001 revealed that preterm delivery (< 37 weeks) accounted for 70% of neonatal deaths.9 In addition to being at risk for neonatal death, preterm infants are at increased risk for long-term neurologic and developmental morbidity, with an estimated risk of significant handicaps in up to 15% of the survivors. These statistics have led many investigators to identify those women at greatest risk (e.g., those with prior preterm delivery, multiple gestations, maternal weight <50 kg, African-American race, bleeding, and concurrent sexually transmitted diseases). Despite identification of these risk factors, no reproducible and effective method of preventing preterm delivery has been demonstrated. On the contrary, preterm birth rates has risen 27% since 1981.1 A significant contributor to this tremendous rise is the increase in the rate of multiple gestations observed in over the past years. This is partly due to the advances in assisted reproductive technologies with twin gestations accounting for around a quarter of pregnancies conceived following these procedures.

One modality that showed promise for prevention of preterm labor in small trials was treatment with progestational agents. Two separate meta-analyses assessing the effects of progesterone on preterm labor arrived at contradictory conclusions. Goldstein found no evidence of effectiveness of progestational compounds in the prevention of preterm delivery. Daya, on the other hand, showed a beneficial effect. A third meta-analysis, restricted to trials of 17-alpha Hydroxyprogesterone Caproate showed, in composite, a significant reduction in the rate of preterm delivery. A recently reported trial comparing 17-alpha Hydroxyprogesterone Caproate therapy with placebo to prevent preterm birth in a select, high-risk group of women (documented history of a previous spontaneous preterm birth <37 weeks of gestation) was terminated prematurely when results showed a significant protection against recurrent preterm birth for women who received 17-alpha Hydroxyprogesterone Caproate. Other studies, using the same form of progesterone, did not demonstrate such a beneficial effect. A study in 1980 has failed to show any benefit of 17-alpha Hydroxyprogesterone Caproate in women with twin gestations. In that study, 77 women with twin gestations were treated during the last trimester with weekly injections of either 17-alpha Hydroxyprogesterone Caproate or a placebo. The study was limited by the small sample size. In addition, the progesterone therapy was started late in the third trimester of gestation which could partly explain the inability to detect a beneficial effect of progesterone in this group of patients using that particular regimen. Most reported trials on other progesterone compounds have failed to demonstrate a substantial effect in reducing the risk of preterm delivery. However, a recent small randomized placebo-controlled trial of supplemental vaginal progesterone in women at high risk for preterm birth revealed that the preterm birth rate at less than 34 weeks of gestation was significantly lower among women receiving progesterone than among those receiving placebo.8 The results of this study and that of the National Institute of Child Health and Human Development7 support the hypothesis that progesterone supplementation reduces preterm birth in a select very high-risk group of women. In fact, the American College of Obstetricians and Gynecologists Committee on Obstetric Practice believes that further studies are needed to evaluate the use of progesterone in patients with other high-risk obstetric factors, such as multiple gestations, short cervical length, or positive test results for cervicovaginal fetal fibronectin.

The mechanisms of action of 17-alpha Hydroxyprogesterone Caproate in prolonging gestation are not entirely known. They include relaxation of myometrial smooth muscle, blocking of the action of oxytocin, and inhibition of the formation of gap junctions. There is also evidence that local changes in the progesterone level or the ratio of progesterone to estrogen in the placenta, decidua, or fetal membranes may be important in the initiation of labor in humans. As for its safety profile, aside from local injection-site reactions like soreness, swelling, itching and bruising, 17-alpha Hydroxyprogesterone Caproate appears to be safe during pregnancy with absence of teratogenic effects. The safety of 17-alpha Hydroxyprogesterone Caproate administration in pregnancy is well documented by animal and clinical studies. Reviews of this topic by knowledgeable authors have uniformly concluded that no evidence exists that administration of 17-alpha Hydroxyprogesterone Caproate in pregnancy represents a significant risk to mother, fetus or newborn.

SPECIFIC AIM(S):

To test the effectiveness of weekly injections of 250 mg of 17-alpha Hydroxyprogesterone Caproate as compared with placebo in the prevention of preterm delivery in patients with twin gestations, when given from 16-20 weeks of gestation until 36 weeks.