Intraventricular hemorrhage (IVH), or hemorrhage into the germinal matrix tissues of the developing brain, remains a major problem of preterm neonates. We enrolled 505 neonates of 600 - 1250 g birth weight in a prospective, randomized, placebo- controlled multicenter trial to test the hypothesis that indomethacin would lower the incidence of IVH. This study demonstrated that indomethacin both lowered the incidence and decreased the severity of IVH in preterm infants with no evidence for hemorrhage at 6 - 11 hours (p = 0.03, trend test). Infants randomized to indomethacin had less parenchymal hemorrhage (p = 0.01), less cerebral ventriculomegaly at term (p = 0.04), and improved survival (p = 0.08) compared to placebo infants. At 54 months corrected age (C.A.) categorical analysis demonstrated a modest benefit on both the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) full scale IQ (p= 0.035) and the Peabody Picture Vocabulary - Revised (PPVT-R, p =0.02). At 72 months C.A., indomethacin children were found to perform significantly better on the WPPSI-R verbal IQ (p = 0.04), the PPVT-R (p = 0.009), and the Vineland Communication Score (p = 0.009) when compared to placebo children; the Child Behavior Check List showed they had better social skills. We hypothesize that at 96 and 144 months C.A. children randomized to indomethacin will score significantly better on measures of cognitive function and achievement than placebo children. These are ages when and the educational demands are great. In addition, based on ultrasound data demonstrating less ventriculomegaly in indomethacin children, we hypothesize that indomethacin subjects will have significantly less cerebral volumetric abnormalities than placebo subjects when the entire cohort is assessed by volume magnetic resonance imaging. Because our indomethacin subjects appear to have significantly better verbal skills than placebo children, we will perform a verbal activation task using functional magnetic resonance imaging to test the hypothesis that indomethacin children will show significantly better patterns of fMRI activation than placebo children. Study subjects will undergo structured, systematic assessments for neuropsychiatric disorders and adaptive capacities in the social domain to test the hypothesis that indomethacin children will have less neuropsychiatric disorders, anxiety symptoms and socialization difficulties than placebo subjects. Finally, multivariate statistical analyses will be performed to determine the independent and important predictors of cognitive outcome and function at 8 and 12 years C.A.
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