SAN FRANCISCO – A large randomized, double-blind placebo-controlled study in the Netherlands supports earlier studies that found no benefit from routine maintenance tocolysis using nifedipine in women with arrested preterm labor.
What to do when preterm labor stops is "a million dollar question that many of us have faced," Dr. Deirdre J. Lyell said at a meeting on antepartum and intrapartum management sponsored by the University of California, San Francisco. Surveys suggest that more than a quarter of maternal-fetal medicine specialists routinely use maintenance tocolysis, most often with nifedipine, despite its questionable utility.
Dr. Deirdre J. Lyell
The Dutch study of 406 women "puts the question to bed," said Dr. Lyell, a maternal-fetal medicine ob.gyn. at Stanford (Calif.) University. She was not involved in the study.
The multicenter trial in these women was underpowered to show a statistically significant difference in its primary outcome – a composite of perinatal adverse outcomes – because of a lower-than-expected rate of adverse events in the control group, so it couldn’t exclude a possible benefit from nifedipine. However, "its use for maintenance tocolysis does not appear beneficial at this time," the investigators wrote (JAMA 2013;309:41-7).
Women in the study had arrested preterm labor at 24-34 weeks’ gestation. They were randomized to maintenance tocolysis with 20 mg nifedipine or placebo every 4-6 hours. Delivery occurred at 35 weeks in the nifedipine group and at 35 weeks and 2 days in the control group. The number of days of pregnancy after starting treatment was 34 and 33, respectively, and the two groups had similar rates of recurrent preterm labor. Twelve percent in the nifedipine group and 14% in the control group developed one of the problems in the primary composite outcome: perinatal death, chronic lung disease, neonatal sepsis, intraventricular hemorrhage greater than grade 2, periventricular leukomalacia greater than grade 1, or necrotizing enterocolitis.
"There’s no evidence these medications were able to delay delivery," Dr. Lyell said.
Three previous randomized trials also found no benefit from maintenance tocolysis with nifedipine. One nonblinded study of 74 U.S. women found no difference in outcomes (Am. J. Obstet. Gynecol. 1999;181:822-7). Neither did a nonblinded Iranian study that randomized 73 women but did not report how the randomization was conducted (J. Perinat. Med. 2004;32:220-4). Dr. Lyell and her associates then conducted a double-blind placebo-controlled trial in 68 women, which again was negative (Obstet. Gynecol. 2008;112:1221-6).
These studies were small, "but we still haven’t seen anything robust to say this is something we should do," Dr. Lyell said.
Nifedipine can produce maternal side effects. In a trial comparing intravenous magnesium sulfate with oral nifedipine for acute tocolysis, nifedipine caused headache in 24% of women who received the drug, vomiting in 5%, hypotension in 5%, shortness of breath in 5%, and lethargy in 5% (Obstet. Gynecol. 2007;110:61-7).
Beta-mimetics such as terbutaline have a much longer list of maternal, fetal, and neonatal side effects, and two randomized controlled trials have shown that maintenance tocolysis using a terbutaline pump was not more effective than giving saline to prevent recurrent preterm labor, Dr. Lyell said.
A 2008 survey of 827 members of the Society of Maternal-Fetal Medicine found that 29% routinely use maintenance tocolysis and 31% will use it if the patient desires. Among members who employ maintenance tocolysis, nifedipine was the first choice of 79% (Obstet. Gynecol. 2008;112:42-7).
In an informal electronic survey of the physicians, nurses, and midwives at the meeting, 6% said they routinely use maintenance tocolysis, 67% occasionally use it, and 26% never use it. In a repeat survey after Dr. Lyell’s talk, none favored routine maintenance tocolysis, 53% said they would use it occasionally, and 47% said they would no longer use it.
The Netherlands Organization for Health Research and Development funded the study. Dr. Lyell reported having no relevant financial disclosures.
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