Update on the controversies of tocolytic therapy for the prevention of preterm birth

Dear Sir, We read with interest the article by Ingemarsson and Lamont (1). We do not agree with their conclusion that the use of calcium channel blockers (CCBs) for the management of preterm labor will increase the risk of cardiovascular mortality, malignancy and gastro-intestinal bleeding, as this are inferences from observations in nonpregnant (often elderly) patients. We are aware that the issue of cardiovascular safety of CCBs is quite controversial. For example, in a study of 11 575 patients with chronic arterial disease, Braun et al. (2) reported no difference in mortality between users and nonusers of CCBs after an average follow up of more than 3 years. Furthermore, a recent review of the scientific literature of cellular, animal and human evidence concerning the effect of CCBs on apoptosis showed that the use of CCBs did not increase the risk for cancer development (3). Sorensen et al. (4) found no increased risk of cancer or cancer mortality in a large population-based cohort study of 23 167 patients using CCBs. We challenge the extrapolation of these equivocal findings, derived from elderly patients with cardiovascular disease, to the use of nifedipine in ‘healthy’ pregnant women in preterm labor. The risk for myocardial ischemia with nifedipine in otherwise healthy pregnant women is extremely low, and our ‘guestimate’ is that this risk is substantially lower than the cardiovascular risks of betamimetics. In our personal experience at the Free University Hospital Amsterdam in the past 10 years (more than 1000 patients), we have not seen any patient develop myocardial ischemia as a result of tocolytic treatment with nifedipine. The supposition that nifedipine treatment may precipitate pulmonary edema is mainly based on theoretical considerations because, to our knowledge, no such case has been reported to date with nifedipine alone. On the other hand, betamimetics are notorious for causing massive fluid retention with increased cardiac output by 40–60% greater than baseline and their use is known to be associated with an increased risk of pulmonary edema (estimated incidence of 1 : 400). More than 130 cases of pulmonary edema and 25 maternal deaths have been reported with the use of betamimetics for tocolysis (5). Ferguson et al. (6) investigated the cardiovascular and metabolic effects of nifedipine or ritodrine use for preterm labor in pregnant women and found no adverse side-effects with the use of nifedipine; this in sharp contrast with the use of ritodrine. We have conducted a Cochrane systematic review of CCBs vs. other tocolytics (7), which demonstrates that CCBs, especially nifedipine, compared with any other tocolytic agent (mainly betamimetics) were associated with better tocolytic efficacy and improved neonatal outcome (7). We acknowledge that the oxytocin antagonist atosiban for preterm labor is associated with a better outcome for delivery within 24 h, 48 h or within 1 week when compared with placebo (8). However perinatal outcomes were not improved. Atosiban compared with betamimetics showed a similar tocolytic efficacy with no improvement in perinatal outcome (9). Atosiban is a very expensive agent which must be administered intravenously, whereas nifedipine is inexpensive and easy to administer. We draw the authors’ attention to persuasive evidence that nifedipine is a safe and effective tocolytic agent for the management of preterm labor with improved perinatal outcomes. Until there is reliable evidence to indicate otherwise, nifedipine (which is inexpensive and easy to administer) should therefore be considered the agent of first choice when tocolysis is indicated for preterm labor.