Familial hyperbilirubinemia in ABO-incompatible neonates – Letters to the Editor – Letter to the Editor
To the Editor. —
We read with interest the report of Sarici et al (1) on their success in predicting subsequent hyperbilirubinemia by performing first-day serum bilirubin determinations in ABO-incompatible neonates. Although the incidence of hyperbilirubinemia of 21.3% is perhaps not surprising in an ABO-incompatible cohort, the authors also note that, in a previous study in the same population group, the incidence of hyperbilirubinemia in their general neonatal population was as high as 12.05%. (2) Of note was the observation that a significant risk factor for hyperbilirubinemia among the ABO-incompatible neonates was a sibling with neonatal jaundice.
It is surprising that although in both studies ghicose-6-phosphate dehydrogenase (G-6-PD) deficiency was screened for routinely, the results of this screening were not provided. G-6-PD deficiency may result in an incidence of neonatal hyperbilirubinemia several times higher that of G-6-PD-normai counterparts. (3) Furthermore, G-6-PD deficiency may result in rates of neonatal bilirubin production and conjugation that are sigrfificantly different from that of G-6-PD-normal neonates. (4) Female G-6-PD-deficient heterozygotes may also be at risk for hyperbilirubinemia but may not be detected by biochemical screening tests or quantitative enzyme assay. (5) For these reasons, it has been suggested that the condition be taken into account in populations with a high incidence of G-6-PD deficiency, and that data from G-6-PD-deficient and -normal cohorts not be pooled.
As the incidence of G-6-PD deficiency in Turkish males (hemizygotes) may be as high as 11%, (6) according to the Hardy-Weinberg equation, the frequency of heterozygous females in the same population may be 19.6%, and that of homozygous-deficient females 1.2%. (6) Presuming equal distribution of males and females, a total of 16% of the neonatal population studied may have been affected by G-6-PD deficiency in one of these forms. It is therefore possible that this condition may have contributed considerably both to the high incidence of neonatal hyperbilirubinemia in general, and also to the familial factor in the ABO-incompatible subgroup.
MICHAEL KAPLAN, MB, CHB CATHY HAMMERMAN, MD Department of Neonatology Shaare Zedek Medical Center Faculty of Medicine of the Hebrew University Jerusalem 91031 Israel Faculty of Health Sciences Ben Gurion University of the Negev Beer Sheva 84105, Israel
(1.) Sarici SU, Yurdakok M, Serdar MA, et al. An early (sixth-hour) serum bflirubin measurement is useful in predicting the development of significant hyperbilirubinemia and severe ABO hemolytic disease in a selective high-risk population of newborns with ABO incompatibility Pediatrics. 2002;109(4). Available at: http://www.pediatrics.org/cgi/ content/full/lOg/4/e53
(2.) Alpay F, Sarici SU, Tosuncuk D, Serder MA, Inane N, Gokcay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics. 2000;106. Available at: http://www.pediatrics.org/cgi/content/full/ 106/2/e16
(3.) Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia. A potential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol. 1998;25:575-590
(4.) Kaplan M, Hammerman C, Renbaum P, Levy-Lahad E, Vreman HJ, Stevenson DK. Differing pathogenesis of perinatai bilirubinernia in glucose-6-phosphate dehydrogenase-deficient versus normal neonates. Pediatr Res. 2001;50:532-537
(5.) Kaplan M, Beutler E, Vreman HJ, et al. Neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. Pediatrics. 1999;104:68-74
(6.) Oner R, Gumruk F, Acar C, Oner C, Gurgey A, Altay C. Molecular characterization of glucose-6-ptiosphate dehydrogenase deficiency in Turkey. Haematologica. 2000;85:320-321
(7.) Piomelli S. G6PD deficiency and related disorders of the pentose pathway. In: Nathan DG, Oskl FA, eds. Hematology of Infancy and Childhood. Philadelphia, PA: WB Saunders Co; 1987:588
We thank Drs Kaplan and Hammerman for their comments regarding our articles in which we investigated the value of early serum bilirubin measurements in predicting the development of subsequent significant hyperbilirubinemia in term newborns),2 Although glucose-6-phosphate dehydrogenase (G-6-PD) deficiency was screened for routinely in both our studies, (1,2) the numbers of cases with G-6-PD deficiency (1/150 and 2/525, respectively) were not given because the primary aims of these studies were different from the issue of G-6-PD deficiency and it was, on the contrary, an exclusion criterion. The statement that the incidence of G-6-PD deficiency may be as high as 11% is valid for the Mediterranean and southeastern regions of Turkey, where G-6-PD deficiency is more prevalent. (3,4) However, the incidences of G-6-PD deficiency (0.66% and 0.38%) in studies we conducted in Ankara are in accordance with those of the previously published studies, as the overall incidence of G-6-PD deficiency in central Anatolia in general is low at 0.5%. (3,4)
Although the authors state that G-6-PD deficiency may result inrates of neonatal biliruhin production and conjugation that are significantly different from that of G-6-PD-normal newborns, it is also known that ABO-incompatible and G-6-PD-deficient newborns, compared with those with either condition alone, are not at increased risk for hemolysis or hyperbilirubinemia. (5)Furthermore, in most cases of marked hyperbilirubinemia in G-6-PD-deficient newborns, there is also no overt evidence of hemolysis. (6) It should be noted that 6 ABO-incompatible newborns in our study (1) who developed significant (and hemolytic) hyperbilirubinemia not only had a sibling with neonatal jaundice but also had a positive direct antiglobulin test and higher reticulocyte counts. Thus, to define such cases as “familial” without demonstrating a hereditary or genetic basis may be confusing and misleading.
In addition to racial, sexual, ethnic, and geographic variations in epidemiology of G-6-PD deficiency, the presence of varying proportions of normal and G-6-PD-deficient red cell populations and enzyme activity differs according to heterozygocity/homozygocity and type (class) of mutants (7); Gilbert’s syndrome interacts with G-6-PD deficiency (8); and increase in bilirubin in G-6-1 deficient infants may occur later than in other types of hyperbilirubinemia. (9) Therefore, in the era of early discharge it would be more valuable to establish predictive nomograms to identify newborns at high risk for G-6-PD deficiency-associated severe neonatal hyperbilirubinemia not only on the basis of G-6-PD screeing, (10) but with respect to molecular characterization of heterozygous/homozygous states using DNA analysis and biochemical determination of uridine-diphosphogiucuronosyl transferase activity as well, rather than pooling all unidentified high risk minority subgroups in a single study.
S. U. SARICI, MD
Division of Neonatology
Department of Pediatrics
Gulhane Military Medical Academy
PK 660, Yenisehir-06445
(1.) Sarici SU, Yurdakok M, Serdar MA, et al. An early (sixth-hour) serum bilirubin measurement is useful in predicting the development of significant hyperbilirubinemia and severe ABO hemolytic disease in a selective high-risk population of newborns with ABO incompatibility Pediatrics. 2002;109(4). Available at: bttp://www.pediatrics.org/cgi/ content/full/109/4/e53
(2.) Alpay F, Sarici SU, Tosuncuk HD, Serdar MA, Inanc N, Gokcay E. The value of first-day bilirubin measurement in predicting the development of significant hyperbilirubinemia in healthy term newborns. Pediatrics 2000;106(2). Available at: http://www.pediatrics.org/cgi/content/ full/1O6/2/e16
(3.) Say B, Ozand P, Berkel I, Cevik N. Erythrocyte glucose-6-pbosphate dehydrogenase deficiency in Turkey. Acta Paediatr Scand. 1965;54: 319-324
(4.) Altay C, Yetgin S, Ozsoylu S, Kutsal A. Hemoglobin S and some other hemoglobinopathies in Eti-Turks. Hum Hered. 1978;28:56-61
(5.) Kaplan M, Vreman HJ, Hammerman C, et al. Combination of ABO blood group incompatibility and glucose-6-phosphate dehydrogenase deficiency: effect on hemolysis and neonatal hyperbilirubinemia. Acta Paediatr. 1998;87:455-457
(6.) Valaes T. Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl. 1994;394:58-76
(7.) Valaes T. Neonatal jaundice in glucose-6-phosphate dehydrogenase deficiency. In: Maisels MJ, Watechko JF, eds. Neonatal Jaundice. The Netherlands: Harwood Academic Publishers; 2000:67-72
(8.) Kaplan M, Renbaum P, Levi-Lahad E, Hammerman C, Lahad A, Beutler E. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci USA. 1997;94:12128-12132
(9.) Maisels MJ. Epidemiology of neonatal jaundice, in: Maisels MJ, Watchko JF, eds. Neonatal Jaundice. The Netherlands: Harwood Academic Publishers; 2000;37-49
(10.) Kaplan M, Hammerman C, Feldman R, Brisk R. Predischarge bilirubin screening in glucose-6-phosphate dehydrogenase-deficient neonates. Pediatrics. 2000;105:53:-537
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