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Combination of tocolytic agents for inhibiting preterm labour.

Abstract

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 METHODS

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.

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.

Authors+Show Affiliations

UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research, World Health Organization, Avenue Appia 20, Geneva, Switzerland, CH-1211.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Review
Systematic Review

Language

eng

PubMed ID

25010869

Citation

Vogel, Joshua P., et al. "Combination of Tocolytic Agents for Inhibiting Preterm Labour." The Cochrane Database of Systematic Reviews, 2014, p. CD006169.
Vogel JP, Nardin JM, Dowswell T, et al. Combination of tocolytic agents for inhibiting preterm labour. Cochrane Database Syst Rev. 2014.
Vogel, J. P., Nardin, J. M., Dowswell, T., West, H. M., & Oladapo, O. T. (2014). Combination of tocolytic agents for inhibiting preterm labour. The Cochrane Database of Systematic Reviews, (7), CD006169. https://doi.org/10.1002/14651858.CD006169.pub2
Vogel JP, et al. Combination of Tocolytic Agents for Inhibiting Preterm Labour. Cochrane Database Syst Rev. 2014 Jul 11;(7)CD006169. PubMed PMID: 25010869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combination of tocolytic agents for inhibiting preterm labour. AU - Vogel,Joshua P, AU - Nardin,Juan Manuel, AU - Dowswell,Therese, AU - West,Helen M, AU - Oladapo,Olufemi T, Y1 - 2014/07/11/ PY - 2014/7/11/entrez PY - 2014/7/11/pubmed PY - 2015/1/13/medline SP - CD006169 EP - CD006169 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev IS - 7 N2 - 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 METHODS: 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. 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. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/25010869/Combination_of_tocolytic_agents_for_inhibiting_preterm_labour_ L2 - https://doi.org/10.1002/14651858.CD006169.pub2 DB - PRIME DP - Unbound Medicine ER -