Bilirubin Thresholds in Preterm Infants on Neonatal Intensive CarE Units: the B-NICE Trial

RATIONALE Very preterm infants frequently develop neonatal hyperbilirubinemia due toimmature hepatic conjugation and increased red blood cell turnover. When rising bilirubinlevels are left untreated, unbound bilirubin can cross the immature blood‐brain barrier,potentially causing bilirubin‐induced neurologic dysfunction (BIND) and, in severe cases,kernicterus.Phototherapy is effective in lowering bilirubin concentrations and prevention of exchangetransfusions, and is very frequently applied in very preterm infants. However,phototherapy is not without drawbacks. Phototherapy exposure is associated with highermortality (especially in sick, mechanically ventilated extremely low birth weight infants< 1000 g), and some studies report increased oxidative stress, disturbedthermoregulation, elektrolyte imbalance, cardiovascular and gastrointestinal effects. Inaddition, exposure to intense light during phototherapy, together with prolonged eyeshielding, may affect the development of circadian rhythms and sleep‐wake organization.Conflicting data exist on few long‐term adverse effects of neonatal phototherapy, such asa modestly increased risk of childhood cancer and seizures. Phototherapy requiresfrequent blood sampling with risk of anemia and increases nursing workload in alreadyresource‐constrained NICUs. Moreover, prolonged phototherapy exposure can reduceopportunities for skin‐to‐skin care and negatively affect early parent‐infant bonding.When phototherapy fails, escalation of care to an exchange transfusion is indicated,being an invasive procedure with well‐known complications.In the Netherlands, uniform phototherapy and exchange thresholds for preterm infants havebeen used since 2008. These thresholds are consensus‐based, relatively strict and lead tophototherapy in >80% of infants born <32 weeks. International variation is substantial;notably, the UK NICE guideline uses higher thresholds. Given the potential burdens andpossible adverse effects of phototherapy, minimizing unnecessary treatment is in the bestinterest of both the preterm infant and the parents. Yet, there is currently no robustRCT evidence to support any specific threshold strategy in very preterm infants.The B‐NICE trial addresses this evidence gap by comparing Dutch and NICE thresholdstrategies in a nationwide multicenter randomized non‐inferiority design, focusing onlong‐term safety (survival without neurodevelopmental impairment (NDI) at the correctedage of two years) and short‐term reductions in treatment burden, including fewer hoursand days of phototherapy, fewer bilirubin measurements and heel pricks, less handling ofthe infant, and more opportunities for uninterrupted skin‐to‐skin care and parent‐infantbonding. By tailoring phototherapy more closely to the bilirubin level needed to remainbelow a presumed safe threshold, the study aims to minimize unnecessary exposure tophototherapy and reduce its associated burden and potential adverse effects, whilepreserving its clinical benefits and maintaining patient safety.