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Network meta-analysis of tocolytics in preterm labor: Establishing an evidence-based treatment hierarchy
Barbara Gardella1,2, Chiara Cassani1,2, Vittoria Morteo1,2
1Department of Clinical, Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.
Background:
The choice of tocolytic drugs is one of the most debated aspects of preterm birth management.
Objective:
This network meta-analysis aimed to establish an evidence-based hierarchy for tocolytics used in preterm labor by evaluating their efficacy in delaying delivery, safety, and neonatal outcomes. Advanced metrics were applied, including ranking against average efficacy, minimal clinically important difference, and simultaneous evaluation of multiple outcomes.
Search Strategy:
A comprehensive search of randomized controlled trials was conducted across databases such as Cochrane, PubMed, Scopus, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and European Clinical Trials Register (PROSPERO no. CRD420251006201) from inception to March 15, 2025.
Selection Criteria:
Randomized trials assessing acute tocolytic therapy for preterm labor (24-36 weeks). Seven drug classes and placebo/no-treatment were analyzed: calcium channel blockers, oxytocin receptor antagonists, magnesium sulfate, COX inhibitors, nitric oxide donors, betamimetics, and combination therapies.
Data Collection And Analysis:
Risk of bias and confidence in results were assessed using ROB-2 and CINeMA. Network meta-analysis was performed using the netmeta package in R. Treatments were ranked using P-scores, surface under the cumulative ranking curve (SUCRA), minimal clinically important difference and simultaneous ranking on efficacy, maternal adverse effects and neonatal mortality.
Main Results:
The analysis included 164 studies (18 802 participants). All tocolytics delayed delivery by 48 h more effectively than placebo, with no significant differences among drugs (low to moderate confidence). Calcium channel blockers ranked highest (SUCRA score: 0.99; ranking score vs. average efficacy: 0.998) and were optimal when combining efficacy and safety (P-score: 0.46). Oxytocin receptor antagonists followed, particularly when accounting for minimal clinically important difference (score = 0.42). For 7-day delay, calcium channel blockers and oxytocin receptor antagonists outperformed magnesium sulfate (odds ratio [OR] = 1.83, 95% confidence interval [CI]: 1.15-2.94, and OR = 2.02, 95% CI: 1.17-3.4) and betamimetics (OR = 1.26, 95% CI: 1-1.61, and OR = 1.39, 95% CI: 1-1.88). Oxytocin receptor antagonists ranked highest in multiple outcomes at 7 days, while betamimetics ranked lowest due to adverse maternal effects. Precision of hierarchies ranged from moderate (0.62) to high (0.82).
Conclusions:
Calcium channel blockers are the most effective and safest tocolytics for short-term delay, supporting current WHO guidelines. Oxytocin receptor antagonists are also highly effective, especially for prolongation beyond 48 h.
Registration:
PROSPERO registration number CRD420251006201, March 16, 2025.
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