Prophylactic Indomethacin Compared with Delayed Conservative Management of the Patent Ductus Arteriosus in Extremely Preterm Infants: Effects on Neonatal Outcomes

Abstract

To determine whether prophylactic indomethacin (PINDO) has more or less morbidity than delayed conservative management of the moderate-to-large patent ductus arteriosus (PDA). We performed a prospective double cohort controlled study of infants delivered at ≤276/7 weeks gestation (n = 397). From January 2005 through April 2011, all infants were treated with PINDO (n = 247). From May 2011 through August 2016, no infant was treated with indomethacin until at least 8 postnatal days (conservative epoch, n = 150). Echocardiograms were performed on day 7 and at planned intervals until the PDA was small or closed. A single neonatologist prospectively collected all data. The incidence of moderate-to-large PDA on day 7 and duration of exposure to moderate-to-large PDA were significantly less in the PINDO epoch (incidence = 10%, median = 2 days) than the conservative epoch (incidence = 67%, median = 14 days). Ligation rates were low in both epochs (PINDO = 14%, conservative = 5%). In multivariate analyses, PINDO infants had a significantly lower incidence of bronchopulmonary dysplasia (BPD) (risk ratio = 0.68, CI: 0.46-0.89) and BPD or death (risk ratio= 0.78, CI: 0.62-0.95) than conservative infants. There were no differences between the epochs in death, intraventricular hemorrhage grades 3 and 4, necrotizing enterocolitis, or retinopathy of prematurity receiving treatment. The effects of PINDO on BPD and BPD or death were no longer significant when analyses were adjusted for presence of a moderate-to-large PDA on day 7. The significant effects of PINDO were independent of whether or not a ligation was performed. PINDO decreases BPD and BPD or death compared with delayed conservative PDA management. These effects are mediated by closure of the PDA.