excreted in feces, while 10% is reabsorbed into the liver via enterohepatic circulation Newborn infants inherently possess multiple factors which contribute to the development of physiologic hyperbilirubinemia: increased red blood cell (RBC) volume, decreased RBC life span, immature hepatic uptake and conjugation, and increased enterohepatic circulation Hyperbilirubinemia is considered pathologic when it is present in the first day of life, when the level exceeds the age-specific 95th percentile or has a concerning rate of rise (greater than 0.2 mg/dL/hr), when the conjugated fraction is high, or in the presence of concerning physical examination or laboratory findings DIFFERENTIAL DIAGNOSIS The causes of unconjugated hyperbilirubinemia may be classified into three groups, based on mechanism of accumulation: excess bilirubin production, decreased bilirubin conjugation, impaired bilirubin excretion ( Table 45.1 ) Excess Bilirubin Production The numerous causes of hemolysis may be categorized as intravascular or extravascular Intravascular hemolysis may be further divided into intrinsic and extrinsic RBC defects Inherited RBC enzyme deficiencies include glucose-6phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase deficiency G6PD is common in children of African, Asian, and Mediterranean descent; patients with this disorder who are exposed to oxidant stress (e.g., fava beans, sulfa drugs) may present with acute rapid hemolysis (see Chapter 93 Hematologic Emergencies ) Children with hemoglobinopathies, such as sickle cell disease and thalassemias, are prone to hemolysis Congenital defects in the RBC membrane found in hereditary spherocytosis and hereditary elliptocytosis increase the fragility of the corpuscles, which predisposes patients to hemolytic episodes Maternal–fetal blood group incompatibility is critical to recognize early When maternal antibodies are produced against fetal RBC antigens, the neonate can develop a Coombs positive isoimmune hemolytic anemia ABO incompatibility generally occurs in infants with A or B blood groups whose mothers have type O blood group; maternal anti-A and anti-B antibodies are produced and can result in hemolysis with a positive direct Coombs test Rh-negative mothers may become sensitized to an Rh-positive fetus during pregnancy and mount an antibody response during a subsequent pregnancy leading to Rh disease of the newborn Administration of Rho (D) immune globulin (RhoGAM) to Rh-negative mothers who have not yet developed anti-Rh antibodies can prevent Rh isoimmunization Infections such as sepsis, urinary tract infection (UTI), and malaria are also