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PEDIATRICS Vol. 114 No. 1 July 2004, pp. 263-264

COMMENTARY

Hyperbilirubinemia and Kernicterus: 50 Years Later

Stanley Ip, MD^*, Joseph Lau, MD, Mei Chung, MPH, John Kulig, MD^*, Robert Sege, MD^*, Stephan Glicken, MD^* and Rebecca O’Brien, MD^*

^* Department of Pediatrics
Tufts-New England Medical Center Evidence-Based Practice Center,
Tufts-New England Medical Center,
Boston, MA 02111

Abbreviations: TSB, total serum bilirubin

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 <20 mg/dL. They concluded that "although it has not been proved that bilirubin is the actual cause of brain damage, tests of serum bilirubin in infants with erythroblastosis fetalis serve as extremely valuable guides to treatment."

There is no doubt that bilirubin plays a major role in the development of central nervous system pathology. High-quality studies^2–7 have consistently demonstrated abnormal brainstem auditory evoked responses to elevated serum bilirubin levels. Indirect evidence from the decreasing prevalence of kernicterus since the introduction of Rhogam and prophylactic use of phototherapy also implicates hyperbilirubinemia as a major factor associated with kernicterus. However, >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.

	FOOTNOTES

 
Received for publication Jan 14, 2004; Accepted Jan 14, 2004.

Address correspondence to Stanley Ip, MD, Department of Pediatrics, Tufts-New England Medical Center, 750 Washington St, Box 63, Boston, MA 02111. E-mail: sip{at}0040tufts-nemc.org

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics

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