Protective effects of early neonatal methylxanthine treatment on cognitive and language outcomes in premature infants with and without high-risk perinatal factors.

Abstract

Caffeine and theophylline are methylxanthines and non-selective adenosine antagonists commonly used to treat apnea of prematurity. Both human and animal data suggest that xanthines also have clinically important long-term neuroprotective effects in the presence of inflammation in the perinatal period as seen following hypoxic-ischemic brain insults. Moreover, these protective effects appear to be more robust when administered shortly (< 48 hrs) after preterm birth. To evaluate the importance of the post-delivery therapeutic window, we collected and analyzed medical data from preterm infants meeting criteria (23 - 30 weeks gestational age (GA)), born at the University of Connecticut Health Center (UCHC) and cared for at the UCHC/Connecticut Children's Medical Center (CCMC) NICU from 1991 - 2017 (n=858). Eighteen-month follow-up data included cognitive and language scores from the Neonatal Neurodevelopmental Follow-Up Clinic records, with a retention of 81% of subjects (n=696). Differences were analyzed via multivariate ANOVA and ANCOVA. Analyses showed that infants who received xanthine treatment within the first 48 hours after preterm birth showed significantly better 18-month behavioral outcomes than those treated later than 48 hours, despite a lack of a priori differences in GA, birth, or length of stay. The positive effect of early xanthine therapy was particularly robust for infants exposed prenatally to the inflammatory conditions of chorioamnionitis and/or preeclampsia. Current findings are consistent with human and animal data showing that caffeine exerts protective effects, at least in part via attenuation of inflammation. Results add to the evidence supporting routine immediate prophylactic neuroprotective xanthine therapy (i.e., caffeine) in preterm infants. Findings also add important new evidence of the augmented value of caffeine specifically for infants with inflammatory risk including mothers with pre-eclampsia or chorioamnionitis.