Preterm labor: Diagnostic and therapeutic options are not all alike

Preventing preterm labor

Progestational agents

Many authors have advocated the use of progestational agents to inhibit premature labor. Progesterone’s presumed mechanisms are inhibition of the oxytocin effect of prostaglandin F2a and stimulation of α-adrenergic receptors, thereby increasing the α-adrenergic tocolytic response.^15,16 Natural progesterone appears to be free of any untoward teratogenic, metabolic, or hemodynamic effects.¹⁷

Studies favoring progesterone. Two double-blind, placebo-controlled studies assessed the use of 17 α-hydroxyprogesterone caproate in preventing premature labor in high-risk populations. These patients had histories of preterm deliveries or spontaneous abortions.

Weekly intramuscular (IM) injections of 250 mg were started at 12 to 16 weeks gestation and given until 37 weeks or delivery, whichever came first. In both studies, the rate of premature deliveries was significantly lower in the treated group than the control group (number needed to treat [NNT]=2.4 and 4.6). In addition, neither mothers nor infants experienced adverse effects attributable to 17 α-hydroxyprogesterone caproate (LOE: 2).^18,19 However, these studies were small—43 and 79 patients.

A large double-blind, placebo-controlled, randomized study established the effectiveness of 17 α-hydroxyprogesterone caproate in preventing preterm delivery.²³ Four hundred fifty-nine pregnant women with a history of preterm delivery were randomized to receive weekly injections of 17 α-hydroxyprogesterone caproate 250 mg or placebo beginning at 16 to 20 weeks gestation and continuing to 36 weeks. Significantly fewer women in the treated group than the control group gave birth before 37 weeks, 36.3% v 54.9%, respectively (NNT=6; LOE: 1). Perhaps more importantly, treatment resulted in significant reductions in birth weight <2500 g (NNT=7), necrotizing enterocolitis (NNT=38), need for supplemental oxygen (NNT=11), and intraventricular hemorrhage (NNT=26). Swelling, bruising, or rash at the injection site were the most common adverse effects of 17 α-hydroxyprogesterone caproate administration.

Vaginal progesterone suppositories have also been shown to decrease the rate of preterm birth in patients at increased risk.¹⁷ da Fonseca et al noted that among 142 women who had 1 prior preterm birth, prophylactic cerclage, or uterine malformation, daily use of a 100-mg vaginal progesterone suppository compared with placebo significantly decreased the likelihood of delivery prior to 37 weeks, 14% v 28% (NNT=7; LOE: 1). Adverse effects of progesterone suppositories were not mentioned.

Studies lacking clear benefit. Another investigator enrolled 168 active-duty military women into a randomized double-blind study that evaluated weekly IM injections of 1000 mg 17 α-hydroxyprogesterone caproate or placebo beginning between 16 and 20 weeks gestation.²⁰ The study population was chosen based on a report that active-duty pregnant military personnel had an increased number of pregnancy complications including low birth-weight infants and increased premature delivery.²¹ In contrast to the previous studies, no significant difference in premature labor or perinatal mortality was seen between the 2 groups (LOE: 2). Perhaps although active-duty personnel are at a higher risk for preterm labor, the risk is not as high as it is with previous preterm birth, prior spontaneous abortion, and so forth.

An additional small study of 77 women with twin pregnancies investigated the use of 17 α-hydroxyprogesterone caproate to prevent preterm delivery.²² Patients were randomized to receive weekly injections of 17 α-hydroxyprogesterone caproate 250 mg or placebo from the 28th gestational week until the 37th week or delivery. The mean duration of pregnancy did not differ between the two groups of women, nor did perinatal mortality (LOE: 2).

Evidence generally supports use of progesterone. Based on available data, consider administering progesterone to women at high risk for preterm delivery to prevent recurrent preterm birth (SOR: A). These data are summarized in Table 2 .

Hydroxyprogesterone caproate in oil is commercially available in the United States in 125 mg/mL and 250 mg/mL strengths. It is not, however, approved by the Food and Drug Administration (FDA) for the prevention of preterm labor.

Progesterone suppositories are also not FDA approved, and they are commercially unavailable in the US. Therefore, they have to be extemporaneously compounded.

TABLE 2
Evidence generally supports progesterone in prevention of preterm labor

Treating bacterial vaginosis may not prevent preterm labor

Bacterial vaginosis (BV) during pregnancy has been associated with preterm birth, and antibiotics have been thought perhaps to reduce this risk. A systematic review of 10 trials including 4249 pregnant women with BV showed that, although antibiotics eradicated BV, they did not significantly reduce the risk of birth before 32, 34, or 37 weeks (LOE: 1).²⁴ This was true even for women with a history of preterm delivery. However, antibiotics did decrease the risk of PPROM. The authors concluded that evidence does not support screening all pregnant women for asymptomatic BV to prevent preterm birth.