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Hyperbilirubinemia and Kernicterus: 50 Years Later

2004; American Academy of Pediatrics; Volume: 114; Issue: 1 Linguagem: Inglês

10.1542/peds.114.1.263

1098-4275

Stanley Ip, Joseph Lau, Mei Chung, John W. Kulig, Robert Sege, Stephan Glicken, Rebecca O’Brien,

Methemoglobinemia and Tumor Lysis Syndrome

In 1952, Hsia et al1 reported that 50% of infants with erythroblastosis fetalis in whom the total serum bilirubin (TSB) was >30 mg/dL developed kernicterus. The authors further reported that kernicterus did not occur in >200 consecutive cases of erythroblastosis fetalis when the hospital policy was to keep the serum bilirubin level 50 years after the report by Hsia et al, the premise that hyperbilirubinemia alone is sufficient to explain kernicterus is still not entirely satisfactory.In our review of 123 cases of kernicterus in infants ≥34 weeks’ gestation published between 1955 and 2001, 88 had comorbid factors such as hemolysis, sepsis, and other neonatal complications.8 It was not possible to separate the effects of these comorbid factors from hyperbilirubinemia to further elucidate the chain of events leading to kernicterus. We concluded that hyperbilirubinemia, in most cases, is a necessary but not sufficient condition to explain kernicterus. Epidemiologic studies are useful to evaluate factors associated with disease outcome, but they offer inadequate proof for causation.Additional understanding of bilirubin neurotoxicity is clearly needed and may be forthcoming from basic science investigations. Ostrow et al9 have proffered new concepts in bilirubin pathophysiology based on studies of bilirubin toxicity in cultured cells from the central nervous system and in jaundiced Gunn rats and measurement of the free fraction of unconjugated bilirubin by using a new peroxidase-diazo assay. These investigators advocate the use of this assay and brainstem auditory evoked potential to improve the prediction of those jaundiced newborns at risk for neurotoxicity. As a cautionary note, it remains to be demonstrated if there exists a meaningful relationship between abnormal brainstem auditory evoked potential and permanent neurologic damage.In this era of low prevalence of erythroblastosis fetalis, measurement of TSB remains invaluable in the management of infants with jaundice. Treating hyperbilirubinemia will likely prevent kernicterus in most instances. However, this also implies that we need to treat many jaundiced infants to prevent 1 from developing kernicterus. To illustrate, let us assume for the moment that the incidence of kernicterus is somewhere between 1 in 100 000 to 1 in 1 000 000 newborns and that 2% of the ∼4 million newborns per year have TSB levels of ≥20 mg/dL. If we further assume that kernicterus only occurs with a TSB level of ≥20 mg/dL, then we will treat anywhere between 2000 and 20 000 newborns to prevent 1 case of kernicterus. TSB alone is a poor indicator of kernicterus risk. We need to explore the use of newer tools in conjunction with TSB to target infants at higher risk. Kernicterus is rare, but it is not extinct. As a preventable tragedy, it remains a highly controversial issue. Much work remains to be done to understand its pathophysiology and optimize its prevention.