The review assessed the effects of tocolysis with CCB in women in preterm labour on maternal, fetal and neonatal outcomes compared to no treatment or placebo and to other tocolytic agent.
When comparing CCB to no treatment or placebo
- CCB showed significant reduction in birth less than 48 hours after trial entry
- CCB showed significant increase in maternal adverse effects
- No pooled data for the outcome preterm birth, with significant reduction in preterm birth with CCB in one trial and no differences in the second study reporting this outcome
- No other outcomes reported
When comparing CCB with other tocolytic agents
- CCB showed significant less preterm birth, increase in the interval between trial entry and birth and in gestational age at birth and significant reduction in admission to neonatal intensive care unit (NICU) when compared to betamimetics and to atosiban
- No differences in birth less than 48 hours after trial entry
- No differences in perinatal mortality and long-term effects
- CCB showed significant reduction in very preterm birth, respiratory distress syndrome, necrotizing enterocolitis, intraventricular haemorrhage and neonatal jaundice when compared to betamimetics
- CCB showed significant less adverse effects and reduction in discontinuation of treatment due to side effects than betamimetics and magnesium sulphate but more adverse effects than atosiban
- No differences in the comparisons with glyceryl trinitrate and indomethacin, though the numbers were small
- CCB showed significant reduction in NICU stay when compared with magnesium sulphate
- No differences in perinatal mortality and long-term outcomes
- No differences when comparing different nifedipine dosages
- No data on maternal serious morbidity and mortality
Evidence included in this review
The review included 38 trials involving 3550 women in labour between 20 and 36 completed weeks of gestation. Two trials compared CCB with placebo or no treatment. Thirty-five trials used other tocolytic agent in the comparison group (betamimetics, atosiban, indomethacin, magnesium sulphate, glyceryl trinitrate). Most trials used nifedipine as the CCB and three trials used nicardipine.
Overall, the quality of included trials was considered fair using GRADE approach. All but one trial did not use blinding of the intervention or outcomes assessment hence the possibility of bias was high for subjective outcome measures. Most trials were assessed as having low risk of selection and attrition bias.
Giving CCB as a tocolytic agent in preterm labour showed a significant reduction in preterm birth compared to placebo, betamimetics and atosiban and some short-term reduction in neonatal morbidity. However, no differences in perinatal mortality and in long-term outcomes were seen. Available data and the lack of blinding in the majority of the included trials limit firm conclusions to be drawn from this review.
The review highlights the need for further well-designed tocolytic trials to determine short- and longer-term infant benefits of CCB over placebo, no treatment and other tocolytics.
Citation: Flenady V, Wojcieszek AM, Papatsonis DNM, Stock OM, Murray L, Jardine LA, Carbonne B. Calcium ch annel blockers for inhibiting preterm labour and birth. Cochrane Database of Systematic Reviews 2014, Issue 6. Art. No.: CD002255. DOI:10.1002/14651858.CD002255.pub2.
Preterm birth is a major contributor to perinatal mortality and morbidity, affecting around 9% of births in high-income countries and an estimated 13% of births in low- and middle-income countries. Tocolytics are drugs used to suppress uterine contractions for women in preterm labour. The most widely used tocolytic are the betamimetics, however, these are associated with a high frequency of unpleasant and sometimes severe maternal side effects. Calcium channel blockers (CCBs) (such as nifedipine) may have similar tocolytic efficacy with less side effects than betamimetics. Oxytocin receptor antagonists (ORAs) (e.g. atosiban) also have a low side-effect profile.
To assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour.
We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register (12 November 2013).
All published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation.
Two review authors independently assessed trial eligibility, undertook quality assessment and data extraction. Results are presented using risk ratio (RR) for categorical data and mean difference (MD) for data measured on a continuous scale with the 95% confidence interval (CI). The number needed to treat to benefit (NNTB) and the number needed to treat to harm (NNTH) were calculated for categorical outcomes that were statistically significantly different.
This update includes 26 additional trials involving 2511 women, giving a total of 38 included trials (3550 women). Thirty-five trials used nifedipine as the CCB and three trials used nicardipine. Blinding of intervention and outcome assessment was undertaken in only one of the trials (a placebo controlled trial). However, objective outcomes defined according to timing of birth and perinatal mortality were considered to have low risk of detection bias.
Two small trials comparing CCBs with placebo or no treatment showed a significant reduction in birth less than 48 hours after trial entry (RR 0.30, 95% CI 0.21 to 0.43) and an increase in maternal adverse effects (RR 49.89, 95% CI 3.13 to 795.02, one trial of 89 women). Due to substantial heterogeneity, outcome 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 CCBs (mainly nifedipine) with other tocolytics by type (including betamimetics, glyceryl trinitrate (GTN) patch, non-steriodal anti inflammatories (NSAID), magnesium sulphate and ORAs), no significant reductions were shown in primary outcome measures of birth within 48 hours of treatment or perinatal mortality.
Comparing CCBs with betamimetics, there were fewer maternal adverse effects (average RR 0.36, 95% CI 0.24 to 0.53) and fewer maternal adverse effects requiring discontinuation of therapy (average RR 0.22, 95% CI 0.10 to 0.48). Calcium channel blockers resulted in an increase in the interval between trial entry and birth (average MD 4.38 days, 95% CI 0.25 to 8.52) and gestational age (MD 0.71 weeks, 95% CI 0.34 to 1.09), 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 (NICU) (average RR 0.74, 95% CI 0.63 to 0.87). No difference was shown in one trial of outcomes at nine to twelve years of age.
Comparing CCBs with ORA, 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 NICU (RR 0.59, 95% CI 0.41 to 0.85); and duration of stay in the NICU (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).
Comparing CCBs with magnesium sulphate, maternal adverse effects were reduced (average RR 0.52, 95% CI 0.40 to 0.68), as was duration of stay in the NICU (days) (MD -4.55, 95% CI -8.17 to -0.92). No differences were shown in the comparisons with GTN patch or NSAID, although numbers were small.
No differences in outcomes were shown in trials comparing nicardipine with other tocolytics, although with limited data no strong conclusions can be drawn. No differences were evident in a small trial that compared higher- versus lower-dose nifedipine, though findings tended to favour a high dose on some measures of neonatal morbidity.
Calcium channel blockers (mainly nifedipine) for women in preterm labour have benefits over placebo or no treatment in terms of postponement of birth thus, theoretically, allowing time for administration of antenatal corticosteroids and transfer to higher level care. Calcium channel blockers were shown to have benefits over betamimetics with respect to prolongation of pregnancy, serious neonatal morbidity, and maternal adverse effects. Calcium channel blockers may also have some benefits over ORAs and magnesium sulphate, although ORAs results in fewer maternal adverse effects. However, it must be noted that no difference was shown in perinatal mortality, and data on longer-term outcomes were limited. Further, the lack of blinding of the intervention diminishes the strength of this body of evidence. Further well-designed tocolytic trials are required to determine short- and longer-term infant benefit of CCBs over placebo or no treatment and other tocolytics, particularly ORAs. Another important focus for future trials is identifying optimal dosage regimens of different types of CCBs (high versus low, particularly addressing speed of onset of uterine quiescence) and formulation (capsules versus tablets). All future trials on tocolytics for women in preterm labour should employ blinding of the intervention and outcome assessment, include measurement of longer-term effects into early childhood, and also costs.
This RHL summary should be cited as: WHO Reproductive Health Library: Calcium channel blockers for inhibiting preterm labour and birth: RHL summary (last revised 6 May 2016). The WHO Reproductive Health Library; Geneva: World Health Organization.