Assessing the neonatal safety of indomethacin tocolysis - A systematic review with meta-analysis

Objective: To systematically review and summarize the medical literature regarding the effects of tocolysis with indomethacin on neonatal outcome. Data Sources: We supplemented a search of entries in electronic databases with references cited in original studies and review articles to identify studies pertaining to indomethacin tocolysis and neonatal outcome. Methods of Study Selection: We evaluated, abstracted data, and performed quantitative analyses in studies assessing the neonatal outcomes of patients undergoing tocolysis with indomethacin. Observational studies and randomized trials were included in this systematic review. Tabulation, Integration, and Results: Forty-six studies were identified, 28 of which met criteria for systematic review and meta-analysis. These 28 studies included 6,008 infants. Of these infants, 1,621 were exposed to indomethacin for tocolysis antenatally; 4,387 infants not exposed to indomethacin served as the comparison group. An estimate of pooled odds ratios with 95% confidence intervals was calculated for dichotomous outcomes using random- and fixed-effects models. Observational studies and randomized trials were analyzed separately. Pooled estimates from observational studies and randomized trials revealed no significant differences in the rates of intraventricular hemorrhage, patent ductus arteriosus, necrotizing enterocolitis, or neonatal mortality between infants exposed to indomethacin antenatally and those not exposed. Meta-analysis of randomized trials revealed increased risk of bronchopulmonary dysplasia. However, the meta-analysis included only 3 randomized clinical trials, one of which showed increased risk. An association of bronchopulmonary dysplasia and indomethacin use was not noted in our analysis of observational studies. Conclusion: Although our pooled results did not identify significantly increased risks of adverse effects, the limited statistical power of published randomized trials does not allow us to exclude the possibility that indomethacin tocolysis increases the risk of adverse neonatal outcomes.