Progesterone Injections Don't Reduce Preterm Twin Births

BIRMINGHAM, Ala., Aug. 1 -- Weekly progesterone injections don't reduce the risk of preterm births of twins they way they do for singletons in high-risk pregnancies, a multicenter team found.

In a randomized placebo-controlled trial, there were no significant differences in the rate of adverse fetal or neonatal events between women who received weekly injections of 17 alpha-hydroxyprogesterone caproate (17P) and those who received placebo injections, reported Dwight J. Rouse, M.D., of the University of Alabama here, and colleagues.

"Why 17P has been effective in women with singleton gestations and a history of spontaneous preterm birth but was not effective in the present trial in women carrying twins is a question that will be answered only when the mechanisms underlying preterm birth and the actions of 17P are better understood," they wrote in the Aug. 2 issue of the New England Journal of Medicine.

There was better news, however, for women with short cervixes. In a separate study in the same issue, Kypros H. Nicolaides, M.D., of King's College Hospital London, and colleagues, reported that among women with cervixes 15 mm or shorter, nightly vaginal progesterone cut the risk for preterm delivery nearly in half.

"The mechanisms that lead to preterm birth are complex, and I think our current study shows they may not be amenable to a single solution," said co-author John Thorp, M.D. of the University of North Carolina at Chapel Hill.

Nearly 25% of all very-low-birth-weight infants (1,500 g or less) are twins, and one in six children who die within the first month of life is a twin, the authors wrote.

Along with colleagues in the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, Dr. Rouse had previously shown that weekly 17P injections reduced the risk of preterm singleton births by one third. They designed the current study to determine whether there would be a similar benefit in twin pregnancies. They conducted a multicenter, randomized, double-blind study in 14 US centers.

They enrolled 661 healthy women who were pregnant with twins and randomly assigned them to intramuscular injections of 17P 250 mg beginning at 16 to 20 weeks gestation, and continuing through week 35.

The primary study outcome was delivery or fetal death before gestation week 35.

A total of 325 in the 17P group and 330 in the placebo group completed the study. The authors found that 41.5% of pregnancies in those assigned to 17P met the composite outcome of fetal death or preterm delivery, compared with 37.3% of placebo controls.

The relative risk for women who received the 17P injections was 1.1 (95% confidence interval 0.9 to 1.3).

There were no significant differences between the groups in either mean gestational age at delivery or in the proportion of deliveries occurring before 37, 32, or 28 weeks.

"From the time of randomization, the estimated distributions of time to first miscarriage, fetal death, or delivery for the two groups were very similar," the authors wrote.

There were also no significant differences in injection-related side effects, which occurred in 65.9% of women on 17P, and 64.4% of women on placebo (P=0.69). Adverse reactions were generally mild and limited to the injection site.

The discrepancy in the results between the twins study and the earlier study suggests a take-it-slow approach to the use of progesterone in women at risk for premature delivery, said Jim G. Thornton, M.D., of the University of Nottingham in England, in an accompanying editorial.

"Even if progesterone therapy is effective for some women who are at risk of preterm labor, reliable evidence is needed about long-term effects on the children before it could be widely recommended," he wrote. "In this regard, experience with a previous hormonal treatment intended to reduce preterm delivery, diethylstilbestrol, which later was shown to cause vaginal cancers in female offspring, has made many cautious."

Dr. Rouse and colleagues noted that fewer than 10% of the women in the study had a previous preterm birth, and that there might be an effect of 17P in women with a history of spontaneous preterm birth that could not be evaluated in this study. It's also possible that the 250 mg dose used in the single study was too low for the twin study, but if that had been the case they would likely have seen an attenuated effect of the drug rather than none, they wrote.

In the cervix study by Dr. Nicolaides and colleagues, 250 women were randomly assigned to vaginal progesterone (200 mg each night) or placebo from 24 to 34 weeks of gestation. The primary outcome was spontaneous delivery before 34 weeks.

They found that women given the progesterone vaginal capsules had a 19.2% rate of delivery before 34 weeks, versus 34.4% of women on placebo. The relative risk was 0.56 (95% confidence interval, 0.36 to 0.86) for women on the active hormone.

Progesterone was also associated with a reduction in neonatal morbidity (8.1% versus 13.8%, relative risk, 0.59, 95% CI 0.26 to 1.25) but this reduction was not significant (P=0.17). There were no serious adverse events associated with the use of progesterone, the authors reported.

Dr. Thornton pointed out that more information concerning the value of progesterone will be forthcoming.

"There are at least 14 ongoing trials involving women with high-risk pregnancies (both singleton and twin)" he wrote. "These should have ample power to test the effect of progesterone on important fetal outcomes. In the meantime. The remaining uncertaincies about both efficacy and fetal safety mean that even women at high risk for preterm delivery should join one of the ongoing randomized trials, rather than take a treatment for which the efficacy and safety have not been proved," he concluded.