Combinations of tocolytic drugs for inhibiting preterm labour

Preterm birth (birth before 37 weeks) is the single largest cause of deaths and ill health for newborn babies and a major cause of complications for pregnant women. Tocolytic agents include a wide range of drugs that can slow or stop labour contractions so as to prolong pregnancy and potentially improve the health outcomes for the baby. Using a combination of two or more tocolytic drugs may improve the length of time the pregnancy is prolonged over using a single tocolytic drug or no intervention, without adversely affecting the mother or baby or worsening drug side effects.

This review examined the effects of any combination of tocolytic drugs for the treatment of preterm labour, compared with any other treatment, no treatment or placebo. The results of the review are based on data from nine randomised controlled trials that examined seven different drug comparisons.

Three trials examined the betamimetic drug ritodrine plus magnesium compared with ritodrine alone. The trials reported on adverse side effects, with inconsistency between the trials as to which treatment gave fewer severe side effects. Other outcomes were either not reported or not clearly different between treatment groups.

One trial looked at ritodrine plus indomethacin versus ritodrine alone. There were no clear differences between groups for serious newborn ill health. Results for other outcomes were not clearly different. There were no clear differences between groups receiving ritodrine plus progesterone compared with ritodrine alone for most outcomes reported, although the time between giving the drugs and the birth was increased in the group receiving the combination of tocolytics. For other combinations of tocolytic agents, results did not demonstrate differences between groups. There were no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine) and oxytocin receptor antagonists (atosiban).

Due to insufficient evidence, it is unclear if combination tocolytic regimens are more or less effective than using a single tocolytic drug, or if they have more adverse effects. Some widely used tocolytic drugs have not been examined in trials as part of combination regimens, so further research is needed.

Authors' conclusions: 

It is unclear whether a combination of tocolytic drugs for preterm labour is more advantageous for women and/or newborns due to a lack of large, well-designed trials including the outcomes of interest. There are no trials of combination regimens using widely used tocolytic agents, such as calcium channel blockers (nifedipine) and/or oxytocin receptor antagonists (atosiban). Further trials are needed before specific conclusions on use of combination tocolytic therapy for preterm labour can be made.

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Background: 

Preterm birth represents the single largest cause of mortality and morbidity for newborns and a major cause of morbidity for pregnant women. Tocolytic agents include a wide range of drugs that can inhibit labour to prolong pregnancy. This may gain time to allow the fetus to mature further before being born, permit antenatal corticosteroid administration for lung maturation, and allow time for intra-uterine transfer to a hospital with neonatal intensive care facilities. However, some tocolytic drugs are associated with severe side effects. Combinations of tocolytic drugs may be more effective over single tocolytic agents or no intervention, without adversely affecting the mother or neonate.

Objectives: 

To assess the effects on maternal, fetal and neonatal outcomes of any combination of tocolytic drugs for the treatment of preterm labour when compared with any other treatment, no treatment or placebo.

Search strategy: 

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 January 2014) and reference lists of retrieved studies.

Selection criteria: 

We included randomised controlled trials comparing a combination of tocolytic agents, administered by any route or any dose, for inhibiting preterm labour versus any other treatment (including other combinations of tocolytics or single tocolytics), no intervention or placebo.

Data collection and analysis: 

Two review authors independently assessed study reports for eligibility, carried out data extraction and assessed risk of bias.

Main results: 

Eleven studies met our inclusion criteria. Two studies did not report any outcome data relevant to the review, so the results of the review are based on nine trials that contributed data. Primary outcomes were perinatal mortality, serious maternal or infant outcomes, adverse drug reactions, birth before 48 hours of trial entry, birth before 34 weeks' gestation and preterm neonates delivered without a full course of antenatal steroids completed 24 hours before birth. The quality of evidence in included trials was mixed; only three of the trials were placebo controlled.

The included trials examined seven different comparisons: intravenous (IV) ritodrine plus oral or IV magnesium (sulphate or gluconate) versus IV ritodrine alone (three trials, 231 women); IV ritodrine plus indomethacin suppositories versus IV ritodrine alone (one trial, 208 women); IV ritodrine plus vaginal progesterone versus IV ritodrine alone (one trial, 83 women); IV hexoprenaline sulphate plus IV magnesium hydrochloride versus IV hexoprenaline sulphate alone (one trial, 24 women); IV fenoterol plus oral naproxen versus IV fenoterol alone (one trial, 72 women); oral pentoxifylline plus IV magnesium sulphate plus IV fenoterol versus IV magnesium sulphate plus IV fenoterol (one trial, 125 women); and, IV terbutaline plus oral metoprolol versus IV terbutaline alone (one trial, 17 women). Few studies with small numbers of women were available for each comparison, hence very little data were pooled in meta-analysis. In all trials, not many of the primary outcomes were reported.

Three trials examined intravenous (IV) ritodrine plus IV or oral magnesium (sulphate or gluconate) compared with IV ritodrine alone. One study, with 41 women, reported more adverse drug reactions in the group receiving the combined tocolytics (risk ratio (RR) 7.79, 95% confidence interval (CI) 1.11 to 54.80). Two trials reported discontinuation of therapy due to severe side effects (results were not combined due to high statistical heterogeneity, I² = 83%); one trial reported increased severe side effects in the group receiving IV ritodrine alone (RR 7.79, 95% CI 1.11 to 54.80, 41 women); in the other trial there was no clear difference between groups (RR 0.23, 95% CI 0.03 to 1.97, 107 women). Other primary outcomes were not reported.

One trial assessed IV ritodrine plus indomethacin suppositories versus IV ritodrine alone. There were no significant differences between groups for perinatal mortality or serious neonatal morbidity. Results for other primary outcomes were not reported.

There were no significant differences between groups receiving IV ritodrine plus vaginal progesterone compared with IV ritodrine alone for most outcomes reported, although the latency period (time from recruitment to delivery) was increased in the group receiving the combination of tocolytics.

For other combinations of tocolytic agents, primary outcomes were rarely reported and for secondary outcomes results did not demonstrate differences between groups.

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