A Prospective Randomised Trial of Nifedipine Versus Placebo in Preterm Labour

Abstract

Introduction:Preterm labour is defined as the presence of uterine contractions of sufficient frequency and intensity to effect progressive effacement and dilatation prior to term gestation. Preterm labour and preterm births occur in approximately 12 % of all pregnancies and is the leading cause of neonatal death in the United States as well in the developing countries 1 . In addition, preterm birth accounts for 70% of neonatal morbidity, and mortality, and health care spent on the neonate 2 .Despite the current use of material, effort and money in perinatal medical technology neonatal mortality rates continue to remain high. Implementation of effective risk identification, strategies and programms for the prevention of preterm labour may lead to successful reduction of perinatal morbidity and mortality associated with prematurity. This in turn requires both an improved understanding of the psychosocial risk factors, etiology, mechanisms of preterm labour, and programmes for accurate identification of pregnant women at risk of premature labour and delivery 3 .Until an etiological treatment is found for preterm labour, treatment is based on preventing unwanted uterine contractions. Several therapeutic attempts have been made to inhibit uterine activity such as ethanol, prostaglandin synthetase inhibitors, magnesium sulphate, ritordine and beta-sympathomimetics. The side effects as well as the limited success have stimulated the investigators to search for new drugs such as oxytocin antagonists, calcium channel openers and calcium channel blockers 4 .Nifedipine, a calcium channel blocking agent inhibits smooth muscle contraction by impeding the flow of calcium across the muscle cell membrane.The aim of the study was to evaluate the tocolytic efficacy of nifedipine in preventing preterm labour and to evaluate the side effects. Material and MethodsThe study was conducted in the Institute of Child & Mother Health Matuail Dhaka & a private hospital, between January 2005 till December 2008. Eighty nine patients presenting with preterm labour between 30-34 weeks with singleton pregnancy and intact membrane were included in the study. Preterm labour was diagnosed by minimum of four contractions in 30 min. and cervical dilatation less than 3 cm. The subjects who met the inclusion criteria were randomized to receive either oral nifedipine or placebo by lottery method. There were 45 patients in the nifedipine group and 44 in the placebo group. Written consent was obtained from them. Women were considered to enroll for the study if preterm labour occurred between 30 and 34 weeks of singleton pregnancy and intact membrane. Exclusion criteria A Prospective Randomised Trial of Nifedipine Versus Placebo in Preterm Labour

Nifedipine for Acute Tocolysis of Preterm Labor

“…Of the two trials, the nonplacebo trial by Zhang, which included nifedipine maintenance tocolysis at two dosages compared with no treatment until 35 weeks of gestation, revealed a significant reduction in preterm birth before 37 weeks of gestation, 5,6 whereas the placebo-controlled trial by Ara failed to demonstrate a difference in preterm birth before 37 weeks. 5,7 Although not powered for neonatal outcomes, our second finding regarding neonatal outcomes comports with the ACOG statement that, although tocolysis may result in short-term pregnancy prolongation, there is no evidence that such therapy translates into significant neonatal benefit. 2 The report by Flenady, 5 which compared nifedipine with other tocolytics, found beta adrenergic-receptor agonists compared with nifedipine resulted in a reduction of short-term adverse neonatal outcomes but failed to affect perinatal mortality.…”

“…Of the two trials, the nonplacebo trial by Zhang, which included nifedipine maintenance tocolysis at two dosages compared with no treatment until 35 weeks of gestation, revealed a significant reduction in preterm birth before 37 weeks of gestation, 5,6 whereas the placebo-controlled trial by Ara failed to demonstrate a difference in preterm birth before 37 weeks. 5,7…”

Repurposing existing drugs as a therapeutic approach for the prevention of preterm birth

“…The review included 38 trials of 3550 patients; nifedipine was assessed in 35 of these trials and nicardipine in three. In the two studies that compared nifedipine to placebo or no treatment, there was a delay in delivery and a reduction in birth less than 48 h after trial entry with nifedipine use (Zhang & Liu 2002, Ara & Banu 2008. This supports the use of nifedipine to prolong pregnancies in the short term, to provide time for corticosteroid administration and to transfer to higher level care.…”

“…However, in terms of the outcome of reducing the incidence of preterm birth, the two trials found conflicting results. The placebocontrolled trial showed nifedipine was no different to placebo (Ara & Banu 2008), while the non-placebo controlled trial showed nifedipine reduced the occurrence of preterm birth (Zhang & Liu 2002). These different findings may be attributable to the fundamental differences between the two trials, particularly regarding doses and blinding to the intervention.…”

Tocolysis for Acute Preterm Labor: Where Have We Been, Where Are We Now, and Where are We Going?

“…Comparing calcium channel blockers (mainly nifedipine) with other tocolytics (betamimetics, nonsteroidal antiinflammatories, and oxytocin receptor antagonists), there was no significant reduction in delivery within 48 hours of treatment or perinatal mortality. 35 Due to substantial heterogeneity, outcome data for PTB < 37 weeks were not combined; one placebo-controlled trial showed no difference, 36 while the other (non-placebo-controlled trial) reported a reduction in PTB < 37 weeks (►Table 1). 37 Calcium channel blockers have a favorable side-effect profile when compared with the betamimetics, with the most common side effect being hypotension-related.…”