Hyperbilirubinemia in Preterm Infants and Neurodevelopmental Outcome at 2 Years of Age: Results of a National Collaborative Survey

As part of a prospective national survey of preterm and small for gestational age infants in the Netherlands, the relationship between maximal serum total bilirubin concentration in the neonatal period and neurodevelopmental outcome at the corrected age of 2 years was studied. Initially, 1,338 infants with a gestational age of less than 32 completed weeks and/or a birth weight of less than 1,500 g were enrolled in the study; 146 were subsequently excluded because of congenital malformations and 361 died during the study period. At the corrected age of 2 years, 831 children were available for follow-up. Children with minor and major handicaps had significantly greater maximal serum total bilirubin concentrations than children with a normal neurodevelopmental outcome (P = .02). A consistent increase in prevalence of handicaps was found for each 50-µmol/L (2.9 mg/dL) increase of maximal serum total bilirubin concentration. The handicaps consisted mainly of cerebral palsy. Logistic regression analysis involving seven suspected confounding factors (gestational age, birth weight, seizures, intracranial hemorrhage, respiratory distress syndrome, ventriculomegaly, and bronchopulmonary dysplasia) revealed that the odds ratio was 1.3. This indicates that, on a multiplicative scale, the risk of a handicap increased by 30% for each 50-µmol/L (2.9 mg/dL) increase of maximal serum total bilirubin concentration (P = .02). Further analysis treated bilirubin as a categorized exposure. A striking systematic increase was found, suggesting a causal relationship between maximal serum total bilirubin concentration and neurodevelopmental outcome.