Neonatal hyperbilirubinemia is common, but bilirubin-induced neurologic dysfunction (BIND) remains an important cause of preventable morbidity, particularly in preterm infants. Japan has developed a distinctive approach centered on unbound bilirubin (UB), the biologically active fraction. Nakamura and colleagues pioneered neonatal UB measurement in the 1970s and incorporated UB measurements into the Kobe University (Nakamura) criteria in 1991. With improved survival of extremely preterm infants, bilirubin encephalopathy was still observed despite modest total serum bilirubin (TSB) levels that persisted beyond the first postnatal week. These observations led Morioka to revise the criteria in 2017, incorporating gestational age (GA), corrected GA, UB levels, and staged treatment throughout the prolonged neonatal course. Clinical experience suggests that this approach may reduce phototherapy exposure without increasing UB levels or exchange transfusion, although multicenter evidence with long-term neurodevelopmental outcomes remains limited. The Japanese experience emphasizes longitudinal monitoring and bilirubin-albumin binding characteristics beyond TSB levels alone. Transcutaneous bilirubin, albumin, and bilirubin-albumin molar ratio may facilitate screening, while emerging fluorescence-based methods may improve UB accessibility. UB measurement should be viewed as a framework for individualized risk assessment, with principles adaptable to diverse populations and clinical settings.
Every clinical decision to start or discontinue phototherapy ultimately depends on a single laboratory value of a total serum bilirubin (TSB) level. Yet that value is neither the biologically most relevant marker of bilirubin neurotoxicity nor necessarily measured with sufficient analytical accuracy. Although TSB remains the most widely used clinically available marker to guide phototherapy, it is an indirect measure of bilirubin neurotoxicity. Unbound bilirubin (UB) levels are considered biologically more relevant, representing the fraction of bilirubin that can cross the blood-brain barrier and potentially cause neurotoxicity. However, UB measurements are not routinely available, technically demanding, and lacks broad standardization for clinical use. The bilirubin-to-albumin (B/A) ratio may provide a pragmatic intermediate marker, as it partly reflects bilirubin-binding capacity, but its clinical value is limited by variability in albumin binding and the influence of illness severity, acidosis, and competing substances. Therefore, despite its limitations, TSB levels remain the practical standard for treatment decisions. But clinically relevant analytical bias remains an important limitation of TSB measurements, emphasizing that the reliability of the assay is as important as the choice of biomarker.
