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Nifedipine for Preterm Labor
Abstract & Commentary
By John C. Hobbins, MD, Professor, Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Denver, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationships to this field of study.
Source: Conde-Agudelo A, et al. Nifedipine in the management of preterm labor: A systematic review and meta-analysis. Am J Obstet Gynecol2011;204:134.e1-20.
Over the years, different tocolytics have been in vogue, only to be discarded later because meta-analyses showed that the agent simply did not work. This month's review will focus on nifedipine, a medication that has been in and out of favor for more than 20 years. Conde-Agudelo et al just published a review of nifedipine that may now tip the scales regarding therapy for preterm labor.1
The group scoured the literature from 1960, looking for clinical trials involving nifedipine as a tocolytic. They found 26 studies that met their stringent quality criteria. Of the 23 studies evaluating nifedipine as an acute tocolytic, 16 were pitted against beta-adrenergic receptor agonists (BARA) such as ritodrine, terbutaline, or isoxsuprine. Eleven of these studies involved ritrodrine the only tocolytic approved by the FDA. Five studies involved magnesium sulfate, and one study each compared nifedipine with antosiban and nitric oxide donors. No good studies were available in which nefidipine was compared against a placebo or no treatment for acute tocolysis. There were three additional studies in which nifedipine was used as a maintenance tocolytic against either placebo or no treatment.
Pooled data comparing nifedipine with BARA showed a significant decrease in deliveries occurring within 7 days of treatment (37.1% vs 45, relative risk [RR] = 0.82, 95% confidence interval [CI] 0.70-0.97), with 12 patients needing to be treated to prevent one case of delivery before 7 days. In addition, the use of nifedipine was associated with less chance of delivering before 34 weeks (48.4% vs 62.2%). The greatest differences between the two agents were in maternal adverse events, which occurred in 48.4% with nifedipine and 62% with BARA. In comparing the two agents, there was only a 0.6% need to stop treatment with the nifedipine and 8.8% with BARA. On the neonatal side, nifedipine was associated with statistically significant reductions in respiratory distress syndrome (RR = 0.63), necrotizing enterocolitis (RR = 0.21), and intraventricular hemorrhage (RR = 0.53).
When compared with magnesium sulfate, there were no significant differences in the ability to prolong labor or to prevent immediate neonatal complications. However, there was a significant decrease in maternal adverse events (23.5% vs 35.6%) with the use of nifedipine.
Finally, three trials evaluated the use of nifedipine as a maintenance tocolytic. Although this analysis only contained a total of 215 patients, there were no differences noted in any maternal or fetal outcome compared with either no treatment or placebo, except the ability to prolong pregnancy by an average of 6.3 days with nifedipine.
To summarize the findings, nifedipine was better at prolonging pregnancy, while decreasing neonatal complications and maternal morbidity, compared with BARA, but it did not seem to be any more effective than magnesium sulfate in prolonging pregnancy. However, significantly fewer maternal side effects were noted with nifedipine. The benefit of maintenance tocolysis with nifedipine only showed up in one, perhaps significant, category a prolongation of pregnancy by an average of 6 days. Nevertheless, this did not translate into any neonatal benefit.
Virtually every tocolytic that has been used over the last 20 years has been shown by meta-analysis to be ineffective in preventing preterm labor while potentially increasing neonatal or maternal morbidity. If prolonging pregnancy were as simple as stopping contractions, then possibly all tocolytic therapies would be effective. However, in many cases the etiologic process starts long before there is a hint of preterm labor, and attempting tocolysis with any agent is like standing in front of a runaway train with a stop sign. However, if we are going to make an attempt at all, it should be with the safest agent. The current meta-analysis points toward nifedipine as the winner.
The use of nifedipine previously has been questioned because of its potential effect on the heart (reduces cardiac after-load and negative ianotropic effect). This, in turn, may decrease utero-placental perfusion. To the contrary, a very recent study in normotensive pregnant women showed that, despite significant after-load reduction with nifedipine, the compensatory increase in cardiac output maintained blood pressures, resulting in no ill effects on the utero-placental or fetal circulations.2
Finally, I need to comment on an article that was featured in the March 2010 OB/GYN Clinical Alert that dealt with a possible relationship between BARA use in pregnancy and autism in the children exposed to this type of medication.3,4 This month a rather pointed editorial emerged in the American Journal of Obstetrics and Gynecology that strongly challenges the previous authors' hypothesis that such a relationship exists.5 However, as shown in the Conde-Agudelo meta-analysis, there is now enough evidence to indicate that there is now little reason to use BARA.