PEDIATRICS Vol. 122 No. 1 July 2008, pp. 216-217 (doi:10.1542/10.1542/peds.2008-0834)
LETTER TO THE EDITOR |
Neonatal Hyperbilirubinemia: Don't Let Glucose-6-phosphate Dehydrogenase Deficiency off the Hook
Michael Kaplan, MB, ChBCathy Hammerman, MD
Department of Neonatology
Shaare Zedek Medical Center
Faculty of Medicine of the Hebrew University
Jerusalem 91031, Israel
To the Editor.—
We read with great interest the recent article by Keren et al,1 in which factors predictive of neonatal hyperbilirubinemia were sought. We found it particularly surprising that glucose-6-phosphate dehydrogenase (G6PD) deficiency did not reach significance as a risk factor and seemed to be nonpredictive of jaundice. This finding is contrary to those of previous studies in which G6PD deficiency was found to be a major factor in the pathogenesis of hyperbilirubinemia and was highly associated with extreme hyperbilirubinemia and kernicterus. Recent examples of this association emanate from the United States, Canada, and the United Kingdom and Ireland, countries not usually associated with a high overall frequency of G6PD deficiency.2–4
Newborns are a group at particular risk of G6PD deficiency. Commonly, there is an increased risk of moderate hyperbilirubinemia that responds to phototherapy and should not endanger these newborns.5,6 Rarely, acute hemolytic crises may precipitate extreme and dangerous hyperbilirubinemia, with the devastating consequence of bilirubin encephalopathy and the long-term outcome of kernicterus. This form of extreme icterus is unpredictable, unfortunately, and may be the reason that kernicterus may not be completely eradicable.
What could be the reasons for the discrepancy between the Keren et al findings and those previously reported? One factor may be that a molecular screen, rather than customary biochemical testing, was used to identify G6PD deficiency. The particular screen used by these authors studies 5 G6PD mutations that are prevalent in the United States and is, by design, estimated to identify 
90% of G6PD-deficient individuals in the United States, including female heterozygotes who may be partially deficient.7 Had a simple biochemical screening test or a quantitative enzyme assay been used, virtually 100% of the G6PD-deficient boys should have been identified. Although the G6PD Mediterranean mutation has been predictive of hyperbilirubinemia, even in heterozygotes,5 this mutation accounts for only a portion of the US-based G6PD genotype. Because of possible differences between G6PD Mediterranean and other genotypes, we cannot be sure how many of the study subjects designated as G6PD deficient by the DNA method actually had low levels of G6PD enzyme activity. Pooling of boys and girls, thereby including many heterozygotes, may have resulted in dilution of the patient sample. Another difference between the present and past studies includes the definition of hyperbilirubinemia: the Keren et al definition was based on the criteria for commencing phototherapy from the 2004 American Academy of Pediatrics guidelines.8 Because these guidelines vary according to the presence or absence of risk factors, and because the G6PD status was available only 2 weeks after delivery, this important risk factor was not taken into account at the time of patient management.
The results of the study in question ought not to let G6PD deficiency off the hook. Until this molecular method of screening for G6PD deficiency is evaluated further and the definitions used for determining hyperbilirubinemia are put to scrutiny, G6PD deficiency should continue to be regarded as a risk factor associated with severe neonatal hyperbilirubinemia.
REFERENCES
- Keren R, Luan X, Friedman S, Saddlemire S, Cnaan A, Bhutani VK. A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants. Pediatrics.2008; 121 (1). Available at: www.pediatrics.org/cgi/content/full/121/1/e170
- Bhutani VK, Johnson LH, Maisels JM, et al. Kernicterus: epidemiological strategies for its prevention through systems-based approaches. J Perinatol.2004; 24 (10):650 –662[CrossRef][Medline]
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[Abstract/Free Full Text] - Manning D, Todd P, Maxwell M, Jane Platt M. Prospective surveillance study of severe hyperbilirubinaemia in the newborn in the UK and Ireland.
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[Abstract/Free Full Text] - Kaplan M, Beutler E, Vreman HJ, et al. Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes.
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[Abstract/Free Full Text] - Kaplan M, Herschel M, Hammerman C, Hoyer JD, Stevenson DK. Hyperbilirubinemia among African American, glucose-6-phosphate dehydrogenase-deficient neonates. Pediatrics.2004; 114 (2). Available at: www.pediatrics.org/cgi/content/full/114/2/e213[Web of Science][Medline]
- Lin Z, Fontaine JM, Freer DE, Naylor EW. Alternative DNA-based newborn screening for glucose-6-phosphate dehydrogenase deficiency. Mol Genet Metab.2005; 86 (1–2):212 –219[CrossRef][Web of Science][Medline]
- American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation [published correction appears in Pediatrics. 2004;114(4):1138].
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[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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