Calcium channel blockers for inhibiting preterm labour and birth

Abstract

Background: 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.

Objectives: To assess the effects on maternal, fetal and neonatal outcomes of CCBs, administered as a tocolytic agent, to women in preterm labour.

Search methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (12 November 2013).

Selection criteria: All published and unpublished randomised trials in which CCBs were used for tocolysis for women in labour between 20 and 36 completed weeks' gestation.

Data collection and analysis: 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.

Main results: 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.

Authors' conclusions: 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.

Conflict of interest statement

Vicki Flenady: nothing to declare.

Aleena M Wojcieszek: nothing to declare.

Dimitri NM Papatsonis: D Papatsonis is a co‐author on a non‐Cochrane systematic review of nifedipine and beta‐agonists (Tsatsaris 2001) and was a co‐author of a randomised trial of nifedipine and ritodrine for preterm labour (Papatsonis 1997).

Owen M Stock: I am supported by an NHMRC Medical/Dental Postgraduate Scholarship as I am currently undertaking a PhD.

Linda Murray: nothing to declare.

Luke A Jardine: nothing to declare.

Bruno Carbonne: B Carbonne is a co‐author on a non‐Cochrane systematic review of nifedipine and beta‐agonists (Tsatsaris 2001). B Carbonne assisted in the organisation of a symposium with Ferring laboratories and has also participated as a speaker in meetings/symposia organised by Ferring. Funds in relation to these activities were provided by Ferring to B Carbonne’s institution.

Figures

1

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

2

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

3

Funnel plot of comparison: 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), outcome: 2.1 Birth less than 48 hours after trial entry.

4

Funnel plot of comparison: 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by agent), outcome: 2.3 Perinatal mortality.

5

Funnel plot of comparison: 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), outcome: 2.9 Preterm birth (before completion of 37 weeks of gestation).

1.1. Analysis

Comparison 1 Calcium channel blockers compared with placebo or no treatment, Outcome 1 Birth within 48 hours after trial entry.

1.2. Analysis

Comparison 1 Calcium channel blockers compared with placebo or no treatment, Outcome 2 Preterm birth (before completion of 37 weeks of gestation).

1.3. Analysis

Comparison 1 Calcium channel blockers compared with placebo or no treatment, Outcome 3 Maternal adverse effects.

2.1. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 1 Birth less than 48 hours after trial entry.

2.2. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).

2.3. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 3 Perinatal mortality (stillbirth and neonatal death up to 28 days).

2.4. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 4 Stillbirth.

2.5. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 5 Neonatal death.

2.6. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 6 Maternal death.

2.7. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 7 Interval between trial entry and birth (days).

2.8. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 8 Gestational age at birth (completed weeks).

2.9. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 9 Preterm birth (before completion of 37 weeks of gestation).

2.10. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 10 Extremely preterm birth (before completion of 28 weeks of gestation).

2.11. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 11 Apgar score

2.12. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 12 Admission to NICU.

2.13. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 13 Respiratory distress syndrome.

2.14. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 14 Chronic lung disease.

2.15. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 15 Necrotising enterocolitis.

2.16. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 16 Neonatal sepsis.

2.17. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 17 Neonatal jaundice.

2.18. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 18 Intraventricular haemorrhage.

2.19. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 19 Intraventricular haemorrhage grades 3 or 4.

2.20. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 20 Periventricular leukomalacia (PVL).

2.21. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 21 Retinopathy of prematurity.

2.22. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 22 Maternal adverse effects.

2.23. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 23 Discontinuation of therapy for maternal adverse effects.

2.24. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 24 Caesarean section.

2.25. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 25 Duration of stay in NICU (days).

2.26. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 26 Duration of maternal hospital stay (days).

2.27. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 27 Behavioural‐emotional problems at 9‐12 years.

2.28. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 28 Special education at 9‐12 years.

2.29. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 29 Motor quality at 9‐12 years.

2.30. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 30 Quality of life at 9‐12 years: physical.

2.31. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 31 Quality of life at 9‐12 years: motor.

2.32. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 32 Quality of life at 9‐12 years: autonomy.

2.33. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 33 Quality of life at 9‐12 years: cognitive.

2.34. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 34 Quality of life at 9‐12 years: social.

2.35. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 35 Quality of life at 9‐12 years: positive emotion.

2.36. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 36 Quality of life at 9‐12 years: negative emotion.

2.37. Analysis

Comparison 2 Calcium channel blockers compared with any other tocolytic agent (subgrouped by other tocolytic), Outcome 37 Parent distress scores at 9‐12 years.

3.1. Analysis

Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 1 Birth within 48 hours after trial entry.

3.2. Analysis

Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).

3.3. Analysis

Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 3 Perinatal mortality (fetal death and neonatal death up to 28 days).

3.4. Analysis

Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 4 Interval between trial entry and birth (days).

3.5. Analysis

Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 5 Respiratory distress syndrome.

3.6. Analysis

Comparison 3 Calcium channel blockers compared with betamimetics (subgrouped by type of CCB), Outcome 6 Discontinuation of therapy for maternal adverse effects.

4.1. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 1 Birth within 48 hours after trial entry.

4.2. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).

4.3. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 3 Perinatal mortality (fetal death and neonatal death up to 28 days).

4.4. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 4 Maternal death.

4.5. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 5 Interval between trial entry and birth (days).

4.6. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 6 Respiratory distress syndrome.

4.7. Analysis

Comparison 4 Calcium channel blockers compared with magnesium sulphate (subgrouped by type of CCB), Outcome 7 Discontinuation of therapy for maternal adverse effects.

5.1. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 1 Birth within 48 hours after trial entry.

5.2. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 2 Very preterm birth (before completion of 34 weeks of gestation).

5.3. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 3 Extremely preterm birth (before completion of 28 weeks of gestation).

5.4. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 4 Perinatal mortality (stillbirth and neonatal death up to 28 days).

5.5. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 5 Stillbirth.

5.6. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 6 Neonatal death.

5.7. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 7 Maternal death.

5.8. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 8 Interval between trial entry and birth (days).

5.9. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 9 Gestational age at birth (completed weeks).

5.10. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 10 Preterm birth (before completion of 37 weeks of gestation).

5.11. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 11 Apgar score

5.12. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 12 Admission to NICU.

5.13. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 13 Respiratory distress syndrome.

5.14. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 14 Necrotising enterocolitis.

5.15. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 15 Neonatal sepsis.

5.16. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 16 Neonatal jaundice.

5.17. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 17 Intraventricular haemorrhage.

5.18. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 18 Maternal adverse effects.

5.19. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 19 Discontinuation of therapy for maternal adverse effects.

5.20. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 20 Duration of stay in NICU (days).

5.21. Analysis

Comparison 5 Higher dose calcium channel blockers compared with lower dose calcium channel blockers, Outcome 21 Duration of maternal hospital stay (days).