Tocolytic therapy for preterm delivery: systematic review and network meta-analysis

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Abstract

Objective To determine the most effective tocolytic agent at delaying delivery.

Design Systematic review and network meta-analysis.

Data sources Cochrane Central Register of Controlled Trials, Medline, Medline In-Process, Embase, and CINAHL up to 17 February 2012.

Study selection Randomised controlled trials of tocolytic therapy in women at risk of preterm delivery.

Data extraction At least two reviewers extracted data on study design, characteristics, number of participants, and outcomes reported (neonatal and maternal). A network meta-analysis was done using a random effects model with drug class effect. Two sensitivity analyses were carried out for the primary outcome; restricted to studies at low risk of bias and restricted to studies excluding women at high risk of preterm delivery (those with multiple gestation and ruptured membranes).

Results Of the 3263 titles initially identified, 95 randomized controlled trials of tocolytic therapy were reviewed. Compared with placebo, the probability of delivery being delayed by 48 hours was highest with prostaglandin inhibitors (odds ratio 5.39, 95% credible interval 2.14 to 12.34) followed by magnesium sulfate (2.76, 1.58 to 4.94), calcium channel blockers (2.71, 1.17 to 5.91), beta mimetics (2.41, 1.27 to 4.55), and the oxytocin receptor blocker atosiban (2.02, 1.10 to 3.80). No class of tocolytic was significantly superior to placebo in reducing neonatal respiratory distress syndrome. Compared with placebo, side effects requiring a change of medication were significantly higher for beta mimetics (22.68, 7.51 to 73.67), magnesium sulfate (8.15, 2.47 to 27.70), and calcium channel blockers (3.80, 1.02 to 16.92). Prostaglandin inhibitors and calcium channel blockers were the tocolytics with the best probability of being ranked in the top three medication classes for the outcomes of 48 hour delay in delivery, respiratory distress syndrome, neonatal mortality, and maternal side effects (all cause).

Conclusions Prostaglandin inhibitors and calcium channel blockers had the highest probability of delaying delivery and improving neonatal and maternal outcomes.

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Most cited references 99

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The hazards of scoring the quality of clinical trials for meta-analysis.

Peter Jüni (1999)

Although it is widely recommended that clinical trials undergo some type of quality review, the number and variety of quality assessment scales that exist make it unclear how to achieve the best assessment. To determine whether the type of quality assessment scale used affects the conclusions of meta-analytic studies. Meta-analysis of 17 trials comparing low-molecular-weight heparin (LMWH) with standard heparin for prevention of postoperative thrombosis using 25 different scales to identify high-quality trials. The association between treatment effect and summary scores and the association with 3 key domains (concealment of treatment allocation, blinding of outcome assessment, and handling of withdrawals) were examined in regression models. Pooled relative risks of deep vein thrombosis with LMWH vs standard heparin in high-quality vs low-quality trials as determined by 25 quality scales. Pooled relative risks from high-quality trials ranged from 0.63 (95% confidence interval [CI], 0.44-0.90) to 0.90 (95% CI, 0.67-1.21) vs 0.52 (95% CI, 0.24-1.09) to 1.13 (95% CI, 0.70-1.82) for low-quality trials. For 6 scales, relative risks of high-quality trials were close to unity, indicating that LMWH was not significantly superior to standard heparin, whereas low-quality trials showed better protection with LMWH (P<.05). Seven scales showed the opposite: high quality trials showed an effect whereas low quality trials did not. For the remaining 12 scales, effect estimates were similar in the 2 quality strata. In regression analysis, summary quality scores were not significantly associated with treatment effects. There was no significant association of treatment effects with allocation concealment and handling of withdrawals. Open outcome assessment, however, influenced effect size with the effect of LMWH, on average, being exaggerated by 35% (95% CI, 1%-57%; P= .046). Our data indicate that the use of summary scores to identify trials of high quality is problematic. Relevant methodological aspects should be assessed individually and their influence on effect sizes explored.

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Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.

Fujian Song, Douglas G. Altman, Anne-Marie Glenny … (2003)

To determine the validity of adjusted indirect comparisons by using data from published meta-analyses of randomised trials. Direct comparison of different interventions in randomised trials and adjusted indirect comparison in which two interventions were compared through their relative effect versus a common comparator. The discrepancy between the direct and adjusted indirect comparison was measured by the difference between the two estimates. Database of abstracts of reviews of effectiveness (1994-8), the Cochrane database of systematic reviews, Medline, and references of retrieved articles. 44 published meta-analyses (from 28 systematic reviews) provided sufficient data. In most cases, results of adjusted indirect comparisons were not significantly different from those of direct comparisons. A significant discrepancy (P<0.05) was observed in three of the 44 comparisons between the direct and the adjusted indirect estimates. There was a moderate agreement between the statistical conclusions from the direct and adjusted indirect comparisons (kappa 0.51). The direction of discrepancy between the two estimates was inconsistent. Adjusted indirect comparisons usually but not always agree with the results of head to head randomised trials. When there is no or insufficient direct evidence from randomised trials, the adjusted indirect comparison may provide useful or supplementary information on the relative efficacy of competing interventions. The validity of the adjusted indirect comparisons depends on the internal validity and similarity of the included trials.

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Addressing between-study heterogeneity and inconsistency in mixed treatment comparisons: Application to stroke prevention treatments in individuals with non-rheumatic atrial fibrillation.

B. D. Cooper, Danielle Morris, Nicky Welton … (2009)

Mixed treatment comparison models extend meta-analysis methods to enable comparisons to be made between all relevant comparators in the clinical area of interest. In such modelling it is imperative that potential sources of variability are explored to explain both heterogeneity (variation in treatment effects between trials within pairwise contrasts) and inconsistency (variation in treatment effects between pairwise contrasts) to ensure the validity of the analysis.The objective of this paper is to extend the mixed treatment comparison framework to allow for the incorporation of study-level covariates in an attempt to explain between-study heterogeneity and reduce inconsistency. Three possible model specifications assuming different assumptions are described and applied to a 17-treatment network for stroke prevention treatments in individuals with non-rheumatic atrial fibrillation.The paper demonstrates the feasibility of incorporating covariates within a mixed treatment comparison framework and using model fit statistics to choose between alternative model specifications. Although such an approach may adjust for inconsistencies in networks, as for standard meta-regression, the analysis will suffer from low power if the number of trials is small compared with the number of treatment comparators. Copyright (c) 2009 John Wiley & Sons, Ltd.

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Author and article information

Contributors

David M Haas: Role: associate professor of obstetrics and gynecology

Deborah M Caldwell: Role: MRC fellow population health science

Page Kirkpatrick: Role: research associate

Jennifer J McIntosh: Role: medical resident

Nicky J Welton: Role: MRC research fellow

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): bmj

Title: BMJ : British Medical Journal

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2012

Publication date (Electronic): 09 October 2012

Volume: 345

Electronic Location Identifier: e6226

Affiliations

[1 ]Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN, USA

[2 ]School of Social and Community Medicine, University of Bristol, Bristol, UK

Author notes

Correspondence to: D M Haas Wishard Memorial Hospital, 1001 W 10th Street, F5102, Indianapolis, IN 46202, USA dahaas@ 123456iupui.edu

Article

Publisher ID: haad004821

DOI: 10.1136/bmj.e6226

PMC ID: 4688428

PubMed ID: 23048010

SO-VID: 964fea6c-25c2-4400-a17a-d1412c0deda3

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: http://creativecommons.org/licenses/by-nc/2.0/ and http://creativecommons.org/licenses/by-nc/2.0/legalcode.

Tocolytic therapy for preterm delivery: systematic review and network meta-analysis

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Most cited references 99

The hazards of scoring the quality of clinical trials for meta-analysis.

Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.

Addressing between-study heterogeneity and inconsistency in mixed treatment comparisons: Application to stroke prevention treatments in individuals with non-rheumatic atrial fibrillation.

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