Identification of Neonates at Risk for Hazardous Hyperbilirubinemia: Emerging Clinical Insights

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Late preterm gestation

Late preterm (340/7–366/7 weeks' gestation) and full-term infants become jaundiced by similar mechanisms, including (1) an increased bilirubin load on the hepatocyte as a result of decreased erythrocyte survival, increased erythrocyte volume, and the enterohepatic circulation of bilirubin; and (2) defective hepatic bilirubin conjugation.17 Late preterm infants evidence a similar degree of red blood cell turnover and heme degradation as their full-term counterparts;18 however, they differ from

Exclusive breast milk feeding

It is likely no coincidence that almost every reported case of kernicterus over the past 2.5 decades has been in breastfed infants.4 As such, exclusive breast milk feeding, particularly if nursing is not going well and weight loss is excessive, is listed as a major hyperbilirubinemia risk factor in the 2004 AAP practice guideline.15 What does the association between exclusive breast milk feeding and kernicterus imply with respect to the etiopathogenesis of marked neonatal jaundice? Numerous

Glucose-6-phosphate dehydrogenase deficiency

G6PD deficiency is an X-linked enzymopathy affecting hemizygous males, homozygous females, and a subset of heterozygous females (by way of nonrandom X chromosome inactivation) and is an important cause of severe neonatal hyperbilirubinemia and kernicterus worldwide.52, 53, 54, 55 Although most prevalent in Africa, the Middle East, East Asia, and the Mediterranean, G6PD deficiency has evolved into a global problem as a result of centuries of immigration and intermarriage.52, 53, 54, 55 It is a

ABO hemolytic disease

Hemolytic disease related to ABO incompatibility is a major risk factor for severe hyperbilirubinemia in the 2004 AAP practice guideline15 and, for all intents and purposes, is limited to infants of blood group A or B born to mothers who are blood group O.72, 73 Although this association exists in approximately 15% of pregnancies, only a small fraction of such infants develop significant hyperbilirubinemia.72, 73 More specifically, of type A or B infants born to mothers who are blood group O,

East Asian ethnicity

Neonates of East Asian ethnicity encompassing the populations of mainland China, Hong Kong, Japan, Macau, Korea, and Taiwan evidence a higher incidence of hyperbilirubinemia than other ethnicities (see Fig. 3)67 and an overall increased risk for a TSB level of 20 mg/dL (342 μmol/L) or greater (odds ratio: 3.1; 95% CI: 1.5–6.3).11 As such, East Asian ancestry is listed as a major risk factor for severe hyperbilirubinemia in the 2004 AAP clinical practice guideline.15 Investigators have

Jaundice observed in the first 24 hours of life

Jaundice appearing in the first 24 hours of life has long been regarded as an abnormal clinical finding and an indication for a bilirubin measurement.15 Approximately 2.8% of newborns evidence jaundice within 18 hours of life and 6.7% within 24 hours (Fig. 4).91 As contrasted with nonjaundiced newborns on the first day of life, newborns who have overt jaundice in the first 24 hours of life are more likely to receive phototherapy (18.9% versus 1.7%; relative risk: 10.1; 95% CI: 4.2–24.4)91 and

Cephalohematoma or significant bruising

Internal hemorrhage, ecchymoses, and other extravascular blood collections enhance the bilirubin load on the liver. Extravascular red cells have a markedly shortened life span, and their heme fraction is quickly catabolized to bilirubin by tissue macrophages that contain heme oxygenase and biliverdin reductase.92 Thus, cephalohematoma, subdural hemorrhage, massive adrenal hemorrhage, and marked bruising can be associated with increased serum bilirubin levels and typically manifest 48 to 72

Previous sibling treated with phototherapy

A history of a previous sibling treated with phototherapy is an identified risk factor for hyperbilirubinemia,11, 95 most notable at higher TSB levels (>15 mg/dL [257 μmol/L]).96 This relationship may reflect recurrent ABO or Rh hemolytic disease97 or exposure to a common environmental factor in addition to a shared genetic background.95 It is known that the recurrence rate of ABO hemolytic disease is high; 88% in infants of the same blood type as their index sibling, with almost two thirds of

Combining clinical risk factor assessment with predischarge bilirubin measurement

Three recent clinical studies suggest that combining clinical risk factor analysis with a birth hospitalization predischarge measurement of TSB or TcB will improve the prediction of subsequent hyperbilirubinemia risk.13, 14, 16 An hour-specific predischarge TSB or TcB level in the high risk zone (>95%) using the percentile-based bilirubin nomogram described by Bhutani and colleagues21 is itself a major risk factor (see Box 1) for severe hyperbilirubinemia.21, 100 Not surprisingly, the clinical

Summary

A myriad of demographic, environmental, and genetic factors have been identified as risks for developing severe hyperbilirubinemia. Late preterm gestational age, exclusive breastfeeding, G6PD deficiency, ABO hemolytic disease, East Asian ethnicity, jaundice observed in the first 24 hours of life, cephalohematoma or significant bruising, and a previous sibling treated with phototherapy are highlighted as major risk factors in the 2004 AAP guideline15 and reviewed herein. It increasingly appears

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