Bilirubin neurotoxicity in preterm infants: Risk and prevention

Abstract

Hemolytic conditions in preterm neonates, including Rhesus (Rh) disease, can lead to mortality and long-term impairments due to bilirubin neurotoxicity. Universal access to Rh immunoprophylaxis, coordinated perinatal-neonatal care, and effective phototherapy has virtually eliminated the risk of kernicterus in many countries. In the absence of jaundice due to isoimmunization and without access to phototherapy or exchange transfusion (in 1955), kernicterus was reported at 10.1%, 5.5%, and 1.2% in babies <30, 31-32, and 33-34 wks gestational age, respectively. Phototherapy initiated at 24±12 hr effectively prevented hyperbilirubinemia in infants <2,000 g even in the presence of hemolysis. This approach (in 1985) reduced exchange transfusions from 23.9% to 4.8%. Now with 3 decades of experience in implementing effective phototherapy, the need for exchange transfusions has virtually been eliminated. However, bilirubin neurotoxicity continues to be associated with prematurity alone. The ability to better predict this risk, other than birthweight and gestation, has been elusive. Objective tests such as total bilirubin, unbound or free bilirubin, albumin levels, and albumin-bilirubin binding, together with observations of concurrent hemolysis, sepsis, and rapid rate of bilirubin rise have been considered, but their individual or combined predictive utility has yet to be refined. The disruptive effects of immaturity, concurrent neonatal disease, cholestasis, use of total parenteral nutrition or drugs that alter bilirubin-binding abilities augment the clinical risk of neurotoxicity. Current management options rely on the “fine-tuning” of each infant's exposure to beneficial antioxidants and avoidance of silent neurotoxic properties of bilirubin navigated within the safe spectrum of operational thresholds demarcated by experts.

Hyperbilirubinemia in Preterm Neonates

“…BIND is a wider spectrum of disorders that excludes classic (chronic) kernicterus. 8,29 Clinical evidence of damage confined to more narrow neural pathways may result in isolated, less severe clinical signs, such as auditory or visual deficits. Auditory neuropathy (or auditory "dys"-synchrony) defined by characteristic clinical criteria and distinctive findings on the auditory brainstem-evoked response (ABR) and normal cochlear function (normal cochlear microphonic, normal otoacoustic emissions [OAE]) without severe hearing loss or by similar auditory neuropathy associated with minimal fine and/or gross motor disability.…”

Inflammatory signature of cerebellar neurodegeneration during neonatal hyperbilirubinemia in Ugt1 -/- mouse model

“…It is the result of the increased bilirubin production, mainly due to the high turnover of erythrocytes occurring after birth, and the delayed induction of the Ugt1a1 enzyme. It is usually considered a benign condition, but other concomitant causes may lead to uncontrolled acute hyperbilirubinemia [4, 5]. Prolonged high bilirubin levels are life threatening and often lead to permanent brain damage and death by kernicterus [6].…”

Neonatal Jaundice in Low- and Middle-Income Countries: Lessons and Future Directions from the 2015 Don Ostrow Trieste Yellow Retreat

“…The importance of Rh disease varies widely with the prevalence of Rh-negative maternal status, but the issue of affordable prophylaxis is clearly a priority for many LMICs. The lack of routine maternal and neonatal blood testing in many LMICs is also a barrier, and also impacts the management of ABO incompatibility as a risk factor for serious NNJ [7,32,53,56,57,58,59]. …”