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  • Jaundice within the first 24 hours of life is NEVER normal.

  • Urinary tract infections and sepsis can be associated with the onset of hyperbilirubinemia after a week of age.

  • Consider hemolytic disease in case of unconjugated hyperbilirubinemia beyond the neonatal period.

  • Conjugated hyperbilirubinemia in the neonate indicates hepatobiliary dysfunction, most commonly due to biliary atresia.

  • Acute cholangitis should be suspected in any patient with fever and jaundice who has had surgical correction of biliary atresia.


Hemoglobin released from red blood cells (RBCs) is broken down into heme and reduced to unconjugated (indirect) bilirubin, which is then bound to serum albumin. Unconjugated bilirubin is converted to water-soluble conjugated (direct) bilirubin in the liver and stored in the gallbladder as bile. Bile is released into the intestines to assist in digestion and cholesterol metabolism as well as absorption of lipids and fat-soluble vitamins. Hyperbilirubinemia can be due to an increase in either unconjugated bilirubin or conjugated bilirubin levels. Conditions causing increased RBC destruction or decreased conjugation lead to unconjugated hyperbilirubinemia. Conditions that impair secretion of bile from liver or gallbladder result in conjugated hyperbilirubinemia.

The patient’s age and the type of hyperbilirubinemia, whether direct or indirect, are important factors in determining the cause and treatment.


The most common causes of indirect/unconjugated hyperbilirubinemia in the first week of life are physiologic jaundice and breast milk jaundice.

Physiologic neonatal jaundice becomes visible by the second or third day, peaking by the fourth day and decreasing by seventh day of life. Physiologic jaundice is due to increased production of bilirubin following breakdown of fetal RBCs combined with limited conjugation of bilirubin by the liver. Sixty percent of full-term and 80% of preterm infants will be jaundiced in the first week after birth. In full-term infants, hyperbilirubinemia appears by the second or third day of life, peaks to around 10 to 12 mg/dL and disappears by four to five days. Six to seven percent of full-term infants have indirect bilirubin levels greater than 12.9 mg/dL, and less than 3% have levels greater than 15 mg/dL. In preterm infants, hyperbilirubinemia appears slower at around 3 to 5 days of life, peaks around 15 mg/dL, and disappears by 7 to 9 days.1

Breast milk jaundice is a common cause of neonatal unconjugated hyperbilirubinemia. It is due to beta-glucuronidases and nonesterified fatty acids in breast milk that inhibit enzymes which conjugate bilirubin. Bilirubin levels peak at 2 to 3 weeks of life and may remain elevated for 3 weeks to 2 months and then resolve.

Other causes of unconjugated hyperbilirubinemia are birth trauma resulting in cephalhematomas/bruising and maternal–fetal blood group incompatibility such as ABO/Rh incompatibility that can cause excessive red blood cell breakdown.1 Erythrocyte enzymatic defects such as G6PD and pyruvate kinase deficiency decrease RBC ...

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