Indomethacin Prophylaxis Is Associated with Reduced Risk of Intraventricular Hemorrhage in Extremely Preterm Infants Born in the Context of Amniotic Infection Syndrome

<b><i>Background:</i></b> Amniotic infection syndrome (AIS) with perinatal inflammation may increase the susceptibility to intraventricular hemorrhage (IVH) in preterm infants. Given its anti-inflammatory and ductus arteriosus constricting capacities, we hypothesized that prophylactic administration of indomethacin reduces the incidence, severity, and consequences of IVH in the context of perinatal inflammation. <b><i>Methods:</i></b> We evaluated data of infants born between 2009 and 2020 of 22 + 0–25+6 weeks of gestation from 68 German Neonatal Network centers. The effect of indomethacin prophylaxis on outcomes was analyzed in univariate analyses and multivariate regression models including a subgroup of infants with available data on 5-year follow-up. <b><i>Results:</i></b> 4760 infants were included with a median gestational age of 24.6 SSW [interquartile range (IQR) 24.1w–25.2w] and a birth weight of 640 g [IQR 550–750 g]. 1767/4760 (37.1%) preterm infants were born in the context of AIS and 527/4760 (11.1%) received indomethacin prophylaxis. AIS infants receiving prophylactic indomethacin had lower rates of IVH (32.7% vs. 36.9%, <i>p</i> = 0.04), IVH III/IV (9.7% vs. 16.0%, <i>p</i> = 0.02) and the combined outcome of severe IVH or death (15.9% vs. 23.2%, <i>p</i> = 0.01) as compared to infants without prophylaxis. Multivariate logistic regression analyses confirmed our observations. In a subgroup analysis of 730 preterm infants at 5 years of age, we did not find any correlation between prophylactic indomethacin and intelligence quotient &lt;70 or cerebral palsy. <b><i>Conclusions:</i></b> Our observational data demonstrate that prophylactic indomethacin is associated with a reduced risk of IVH in the highly vulnerable subgroup of preterm infants &lt;26 weeks of gestation born from AIS.