Commentary On : Flenady V, Wojcieszek AM, Papatsonis DN, Stock OM, Murray L,
Jardine LA, Carbonne B. Calcium channel blockers for inhibiting preterm birth.
Cochrane database Syst Rev. 2014 Jun 5;6:CD002255
Declarative Title- Calcium channel blockers as first line for tocolysis in the
management of preterm labour?
Richard G Brown1 and David MacIntyre1,*
1Imperial
College Parturition Research Group, Division of the Institute of Reproduction and
Developmental Biology, Imperial College London, UK
*Correspondence to: Dr David MacIntyre, Imperial College Parturition Research Group,
Division of the Institute of Reproduction and Developmental Biology, Imperial College London,
Hammersmith Campus, London, W12 0NN, UK
Context (word count 799)
Preterm birth (PTB) remains the leading cause of neonatal morbidity and mortality. Although
tocolytics do not reduce the risk of PTB they effectively delay delivery by 48 hours (1). This
creates a window of opportunity for corticosteroid administration and transfer to units with
neonatal intensive care facilities, which improves neonatal mortality and morbidity (2).
However a consensus on the most effective tocolytic does not exist. This study aimed to
assess the effects of calcium channel blockers (CCBs) on maternal, fetal and neonatal
outcomes when administered to women in preterm labour.
Methods
This was an updated review of randomised trials using CCBs as tocolytics for PTB
management. Maternal, fetal and neonatal outcomes were compared between CCBs (mainly
nifedipine), no treatment, placebo and other tocolytics. High and low dose Nifedipine regimes
and long-term childhood outcomes were also reviewed. Six core outcomes were identified
across all trials; birth <48 hours after trial entry, PTB <34 weeks, serious maternal and infant
outcomes, perinatal mortality, and maternal adverse effects (MAE). Results were presented
using risk ratio (RR), number needed to treat to benefit (NNTB) and number needed to treat
to harm (NNTH) for categorical data and mean difference with 95% confidence intervals (CI)
for continuous data.
Findings
Twenty-six additional trials were included in the update providing a combined total of 38 trials,
involving 3550 women. Two trials comparing CCBs with placebo or no treatment showed that
CCBs significantly reduced birth <48hrs after trial entry (RR 0.3, 95% CI 0.21 to 0.43) and
increased MAE (RR 49.89, 95% CI 3.13 to 795.02). Primary birth and perinatal mortality
outcomes were unchanged <48 hours post-treatment, however CCBs performed better than
betamimetics with fewer MAEs (RR 0.36, 95% CI 0.24 to 0.53), longer interval between trial
entry and birth (4.38 days, 95% CI 0.25 to 8.52), increased gestational age at birth (0.71
weeks, 95% CI 0.34 to 1.09), reduced respiratory distress syndrome (RR 0.64, 95% CI 0.48
to 0.86), necrotizing enterocolitis (RR 0.21, 95% CI 0.05 to 0.96), intraventricular
haemorrhage (RR 0.53, 95% CI 0.34-0.84), neonatal jaundice (RR 0.72, 95% CI 0.57 to 0.92)
and neonatal intensive care (NICU) admissions (RR 0.74, 95% CI 0.63 to 0.87). CCBs were
also associated with fewer MAEs (RR 0.52, 95% CI 0.40 to 0.68) and NICU stays (RR -4.55
days, 95% CI -8.17 to -0.92) compared to magnesium sulphate (MgSO4). In comparison to
oxytocin receptor antagonists (ORA), CCBs showed reduced PTB rates (RR 0.64, 95% CI
0.47 to 0.89), reduced admission (RR 0.59, 95% CI 0.41 to 0.85) and length of NICU stay
(RR -5.4 days, 95% CI -10.84 to 0.04) plus increased gestational age at birth (1.2 weeks,
95% CI 0.25 to 2.15). However, MAEs were comparatively higher in the CCBs group (RR
2.61, 95% CI 1.43 to 4.74). Using limited data from small trials, no differences were seen
between CCBs and other tocolytics (e.g. NSAIDs, GTN), high vs low dose nifedipine or longterm childhood outcomes.
Commentary
This study provides a timely review and assessment of CCBs for inhibiting preterm labour and
birth. The findings suggest that despite increased minor and potentially modifiable MAEs,
nifedipine is an effective first line tocolytic. No serious maternal or infant outcomes were
recorded in this review. Previous safety concerns regarding CCBs stem primarily from their
use in combination with other tocolytics (3). As acknowledged by the authors, findings are
limited by lack of blinding in reported trials, raising the possibility of bias particularly for
subjective outcomes of maternal and neonatal morbidity. Inconsistent, suboptimal reporting
limits definitive conclusions being drawn in key areas including tocolytic use in twin
pregnancies and following preterm prelabour rupture of membranes (PPROM).
The updated review is strengthened by the inclusion of 26 additional trials, allowing some
assessment of efficacy. Two small trials (173 women) indicate that CCBs exhibit superior
efficacy compared to placebo or no treatment.
Nifedipine is affordable, accessible, orally administered, delays labour for >48 hours and
appears beneficial compared to Atosiban and MgSO4, consistent with a recent network metaanalysis identifying prostaglandin inhibitors and CCBs as having the highest likelihood of
delaying delivery by 48 hours and improving neonatal outcomes(1).
Further randomised, blinded trials with high quality reporting are required to improve the
evidence that CCBs be used first line. There remains the need to clarify; optimum dosage and
preparation, long-term childhood outcomes, use in combination with MgSO4 (increasingly
used in PTB for fetal neuroprotection) and suitability for tocolysis in PPROM and multiple
gestations.
References
1. Haas DM, Caldwell DM, Kirkpatrick P, McIntosh JJ, Welton NJ. Tocolytic therapy for
preterm delivery:systematic review and network meta-analysis. BMJ.345;2012
2. Crowley P. Prophylactic corticosteroids for preterm birth (Cochrane Review) In: The
Cochrane Library. ChichesterUK:Wiley;2004
3. Oei SG. Calcium channel blockers for tocolysis: a review of their role and safety
following reports of serious adverse events. Eur J Obstet Gynecol Reprod Biol.Jun
1;126(2):137-45.2006