A Cochrane review [Abstract] 1 included 38 studies with a total of 3 550 subjects. Nifedipine showed a significant reduction in birth less than 48 hours after trial entry compared with placebo or no treatment (RR 0.30, 95% CI 0.21 to 0.43; 2 trials, n=173) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02; 1 trial, n=89). Data for preterm birth (less than 37 weeks) were not combined; one placebo controlled trial showed no difference (RR 0.96, 95% CI 0.89 to 1.03) while the other (non-placebo controlled trial) reported a reduction (RR 0.44, 95% CI 0.31 to 0.62). No other outcomes were reported.
Comparing calcium channel blockers (CCBs, mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and oxytocin receptor antagonists (e.g. atosiban), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment (CCB versus betamimetics RR 0.86, 95% CI 0.67 to 1.10; 19 trials, n=1505) or perinatal mortality.
Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53; 15 trials, n=1305) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48; 16 trials, n=1217). Calcium channel blockers resulted in a non-significant increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52; 10 trials, n=830), while decreasing preterm and very preterm birth (RR 0.89, 95% CI 0.80 to 0.98 and RR 0.78, 95% CI 0.66 to 0.93); respiratory distress syndrome (RR 0.64, 95% CI 0.48 to 0.86); necrotising enterocolitis (RR 0.21, 95% CI 0.05 to 0.96); intraventricular haemorrhage (RR 0.53, 95% CI 0.34 to 0.84); neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92); and admissions to neonatal intensive care unit (average RR 0.74, 95% CI 0.63 to 0.87).
Comparing CCBs with oxytocin receptor antagonist atosiban, data from one study (which did blind the intervention) showed an increase in gestational age at birth (MD 1.20 completed weeks, 95% CI 0.25 to 2.15) and reductions in preterm birth (RR 0.64, 95% CI 0.47 to 0.89); admissions to the neonatal intensive care unit (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the neonatal intensive care unit (MD -5.40 days,95% CI -10.84 to 0.04). Maternal adverse effects were increased in the CCB group (average RR 2.61, 95% CI 1.43 to 4.74).
A meta-analysis 4 included 7 studies with 992 patients comparing atosiban witt nifedipine. There was no significant difference between atosiban and nifedipine for pregnancy prolongation of 48 hours or more regarding efficacy (RR 1.06, 95% CI 0.92 to 1.22; P=0.440) or effectiveness (0.93, 0.84 to 1.03; P=0.177). Pregnancy prolongation for 7 days or more also did not differ between groups for efficacy (RR 1.04, 95% CI 0.89 to1.21; P=0.656) or effectiveness (0.91, 0.79 to 1.05; P=0.177). Atosiban was associated with fewer maternal side-effects than nifedipine.
A multicentre, randomised controlled trial 2 (the APOSTEL III study) included 500 women with threatened preterm birth (gestational age 25-34 weeks). The primary outcome was a composite of adverse perinatal outcomes, which included perinatal mortality, bronchopulmonary dysplasia, sepsis, intraventricular haemorrhage, periventricular leukomalacia, and necrotising enterocolitis. There was no difference in primary outcome (RR 0.91, 95% CI 0.61 to 1.37). 16 (5%) babies died in the nifedipine group and 7 (2%) died in the atosiban group (RR 2.20, 95% CI 0.91 to 5.33); all deaths were deemed unlikely to be related to the study drug. Maternal adverse events did not differ between groups.
An economic analysis 3 alongside the APOSTEL III study showed the mean costs per patients were significantly lower in the nifedipine vs atosiban group: singleton pregnancies: €34,897 vs €43,376, mean difference (MD) -€8479, 95% CI -€14,327 to -€2016); multiple pregnancies: €90,248 vs €102,292, MD -€12,044, 95% CI -€21,607 to € -1671. There was a non-significantly higher death rate in the nifedipine group. The difference in costs was mainly driven by a lower neonatal intensive care unit admission (NICU) rate in the nifedipine group.
A Cochrane network meta-analysis[Abstract]5assessing different tocolytic drugs included 122 trials with a total of 13 697 women (table T1). Nitric oxide donors ranked highest for delaying preterm birth by 48 hours and 7 days followed by calcium channel blockers, oxytocin receptor antagonists and combinations of tocolytics.
| Outcome | Network evidence | Anticipated absolute effects for network estimate | ||
|---|---|---|---|---|
| RR (95% CI) Certainty | Risk with placebo or no treatment | Risk with tocolytic agent | Risk difference with tocolytic agent | |
| Betamimetics | 1.12(1.05 to 1.20) Low | 645 per 1000 | 722 per 1000 | 77 more per 1000(from 32 to 129 more) |
| Calcium channel blockers | 1.16(1.07 to 1.24)Low | 645 per 1000 | 748 per 1000 | 103 per 1000(from 45 to 155 more) |
| Magnesium sulphate | 1.12(1.02 to 1.23) Moderate | 645 per 1000 | 722 per 1000 | 77 more per 1000(from 13 to 148 more) |
| Oxytocin receptor antagonists | 1.13(1.05 to 1.22) Moderate | 645 per 1000 | 729 per 1000 | 84 more per 1000(from 32 to 142 more) |
| Nitric oxide donors | 1.17(1.05 to 1.31) Moderate | 645 per 1000 | 755 per 1000 | 110 per 1000(from 32 to 200 more) |
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