The issue of what is a critical threshold of bilirubin for the neonate in terms of long-term morbidity, however, remains unanswered. The recent large prospective study carried out in the Netherlands by Van de Bor et al. to evaluate the effect of bilirubin on 2-year neurodevelopmental outcome of premature infants with a birthweight less than 1500 gm identified a consistent increase in handicap rate for each 2.9 mg/dl (50 microns mol/L) increase in maximum bilirubin concentration. The percentage of children with both minor and major handicaps increased consistently with increased bilirubin concentration. Logistic regression analysis with the maximum serum bilirubin concentration as the continuous variable and controlling for seven other risk factors identified an odds ratio for handicap of 1.3 with a 95% confidence interval between 1.03 and 1.62, (P less than 0.02). These data suggest that a relationship exists between mild and moderate levels of bilirubin and neurodevelopmental handicap at 2 years of age in premature infants. Van de Bor's study is important because it suggests that we must continue to investigate the risk of low to moderate levels of bilirubin in both premature and full-term infants. The study of neonatal alterations of behavior, BAER conduction time, and cry characteristics in infants with hyperbilirubinemia lends support to the hypothesis that low levels of bilirubin result in neonatal neurobehavioral changes that can be easily measured and recorded by these techniques. BAER changes are mediated by the eighth cranial nerve pathway, and cry characteristics are mediated by the vagal complex cranial nerves. The nuclei of these cranial nerves are located in close proximity to one another in the brainstem, and therefore the insult imposed by bilirubin is reflected not only in changes of these two parameters but by behavioral manifestations (i.e., specifically orientation). Finally, however, evidence exists that reversals of these measured changes do occur after treatment modalities such as exchange transfusion or phototherapy are used. The question of a safe level of bilirubin concentration, and safe duration of exposure relative to long-term minor or soft neurodevelopmental handicaps remains unanswered. Large, controlled, prospective, epidemiologic studies are needed to provide these answers.