Association between prophylactic indomethacin and death or bronchopulmonary dysplasia: A systematic review and meta-analysis of observational studies

The use of prophylactic indomethacin in very preterm infants is controversial. The last randomized controlled trial (RCT) to study this therapy enrolled infants over 20 years ago. More recently, observational studies have investigated the association between exposure to prophylactic indomethacin and neonatal morbidities and mortality. We performed a systematic review and meta-analysis of these studies for the outcomes of death and bronchopulmonary dysplasia (BPD). Two observational studies involving a total of 11,289 very preterm infants were suitable for meta-analysis. The pooled data showed that prophylactic indomethacin was not associated with higher or lower risk-adjusted odds of death or BPD (0.93, 95% CI: 0.76-1.13) and of BPD among survivors (0.94, 95% CI: 0.78-1.12). However, there was a weak association between indomethacin prophylaxis and decreased risk-adjusted odds of mortality (0.81, 95% CI: 0.66-0.98). It is unknown whether this finding resulted from unmeasured confounding, chance, or represents a true benefit. To confirm the hypothesis that prophylactic indomethacin has a small effect on mortality in the current era, a contemporary RCT would need to enroll over 3500 very immature infants at high risk of death.