Prophylactic indomethacin in micropreemies : a retrospective cohort study

Background: In Canada, preterm birth is the leading cause of infant death. Micropreemies, classified as infants born <26 weeks’ gestation, are especially vulnerable and face devastating health complications such as severe intraventricular hemorrhage (sIVH). sIVH is strongly associated with overall neurodevelopmental disabilities among survivors and frequently influences decisions regarding withdrawal of life-sustaining therapy. Existing evidence shows that prophylactic intravenous indomethacin results in a significant reduction in sIVH, an outcome deemed critical by families. However, the use of indomethacin prophylaxis is highly variable among clinicians due to perceived adverse effects. Objectives: To determine the effectiveness of prophylactic indomethacin in reducing (1) mortality and morbidity at NICU discharge, and (2) significant neurodevelopmental impairment (NDI) at 18-24 months corrected age (CA) follow-up assessment in infants born <26 weeks gestational age (GA). Design/methods: We conducted a retrospective, multicenter cohort study using data from the Canadian Neonatal Network (CNN) and a sub-cohort from the Canadian Neonatal Follow-up Network (CNFUN) for preterm infants born < 26 weeks GA between 2010 and 2021. Outcomes included survival at NICU discharge and significant NDI at 18–24 months CA. We used three complementary multivariable statistical approaches to compare prophylactic indomethacin administered within 24 hours to no prophylaxis. Results: In the NICU cohort, multivariable analysis found that the risk of severe brain injury or death in the NICU was statistically significantly lower in the indomethacin group in Model 1 (aOR: 0.76, 95% Cl: 0.68-0.85) and Model 2 (aOR: 0.87, 95% CI: 0.79–0.96) compared to no treatment. Additionally, the risk of death (aOR: 0.77, 95% CI: 0.65–0.90), severe brain injury (aOR: 0.87, 95% CI: 0.78–0.98), severe IVH (aOR: 0.80, 95% CI: 0.68–0.94), and periventricular leukomalacia (aOR: 0.75, 95% CI: 0.62–0.91) was lower in the indomethacin group. Among the survivors followed up in the sub-cohort, we found no difference in overall neurodevelopmental outcomes. Conclusion: In infants born <26 weeks’ gestation, prophylactic indomethacin was associated with lower odds of severe brain injury or death in the NICU. However, no differences in long-term neurodevelopmental outcomes were observed among survivors that were followed up.