I. BACKGROUND. Almost all newborn infants have a serum or plasma total bilirubin (TB) level >1 mg/dL in contrast to normal adults in whom the normal TB level is <1 mg/dL. Approximately 85% of all term newborns and most preterm infants develop clinical jaundice. Also, 6.1% of well term newborns have a peak TB level >12.9 mg/dL. A TB level >15 mg/dL is found in 3% of normal term infants.

II. BILIRUBIN METABOLISM. The TB level results from the balance of bilirubin production and excretion.

A. Bilirubin production. Bilirubin is derived from the breakdown of hemecontaining proteins in the reticuloendothelial system. A normal newborn produces 6 to 10 mg of bilirubin/kg/day, greater than the adult production of 3 to 4 mg/kg/day.

1. Red blood cell (RBC) hemoglobin is the major heme-containing protein. Hemoglobin released from senescent RBCs in the reticuloendothelial system or from ineffective erythropoiesis accounts for 80% to 90% of bilirubin production. One gram of hemoglobin produces 34 mg of bilirubin. Breakdown of other heme-containing proteins such as cytochromes and catalase contributes the remaining 10% to 20% of bilirubin.

2. Bilirubin metabolism. The microsomal enzyme heme oxygenase located in the liver, spleen, and nucleated cells oxidizes the heme ring from heme-containing proteins to biliverdin and carbon monoxide (CO)
(excreted from the lung); the iron that is released is reused. The enzyme biliverdin reductase reduces biliverdin to bilirubin. Because heme breakdown yields equimolar amounts of CO and biliverdin, bilirubin production can be indirectly assessed by measuring CO production.

1. Transport. Bilirubin is nonpolar, insoluble in water, and is transported to liver cells bound to serum albumin. Bilirubin bound to albumin does not usually enter the central nervous system (CNS) and is thought to be nontoxic. Displacement of bilirubin from albumin by acidosis, drugs, such as ceftriaxone, or by free fatty acids (FFAs) at high molar ratios of FFA:albumin may increase bilirubin toxicity.

2. Hepatic uptake. Nonpolar, fat-soluble bilirubin (dissociated from albumin) crosses the hepatocyte plasma membrane and is bound mainly to cytoplasmic ligandin (Y protein) for transport to the smooth endoplasmic reticulum.

3. Conjugation. In hepatocytes, the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT1A1) catalyzes the conjugation of bilirubin with glucuronic acid, resulting in mostly bilirubin diglucuronides and some monoglucuronides that are more water-soluble than unconjugated bilirubin. Both forms of conjugated bilirubin are excreted into the bile canaliculi against a concentration gradient.

Inherited deficiencies and polymorphisms of the conjugating enzyme gene can cause severe hyperbilirubinemia in newborns. Polymorphisms in the UGT1A gene due to differences in the number of thymineadenine repeats in the promotor gene diminish the expression of the UGT1A1 enzyme and result in increased TB levels (Gilbert syndrome). Differences in these polymorphisms in individuals of different ancestry contribute to the racial variation in conjugating ability and neonatal hyperbilirubinemia among Caucasian, Asian, and African populations. In addition, a mutation in the UGT1A1 gene that is common in East Asians contributes to an increased risk of severe neonatal hyperbilirubinemia in that population.

4. Excretion. Conjugated bilirubin is secreted into the bile and then excreted into the gastrointestinal (GI) tract where it is eliminated in the stool. Conjugated bilirubin is not reabsorbed from the bowel unless it is deconjugated by the intestinal enzyme β-glucuronidase, present in the neonatal intestinal mucosa. Resorption of bilirubin from the GI tract and delivery back to the liver for reconjugation is called the enterohepatic circulation. Intestinal bacteria, present in adults but to a limited extent in newborns, can prevent enterohepatic circulation of bilirubin by reducing conjugated bilirubin to urobilin, which is not a substrate for β-glucuronidase.

5. Fetal bilirubin metabolism. Most unconjugated bilirubin formed by the fetus is cleared by the placenta into the maternal circulation. Formation of conjugated bilirubin is limited in the fetus because of decreased fetal hepatic blood flow, decreased hepatic ligandin, and decreased UGT1A1 activity. The small amount of conjugated bilirubin excreted into the fetal gut is usually hydrolyzed by β-glucuronidase and resorbed.
Bilirubin is normally found in amniotic fluid by 12 weeks’ gestation and is usually absent by 37 weeks’ gestation. Increased amniotic fluid bilirubin is found in hemolytic disease of the newborn and in fetal intestinal obstruction below the bile ducts.

III. NONPATHOLOGIC HYPERBILIRUBINEMIA. The serum TB level of most newborn infants rises to >2 mg/dL in the first week after birth. This level usually rises in full-term infants to a peak of 6 to 8 mg/dL by 3 to 5 days of age and then falls. A rise to 12 mg/dL is in the physiologic range. In preterm infants, the peak may be 10 to 12 mg/dL on the fifth day after birth, and can rise further in the absence of treatment without any specific abnormality of bilirubin metabolism, and may not be benign based on the infant’s gestational age. Levels <2 mg/dL may not be seen until 1 month of age in both full-term and preterm infants. This nonpathologic jaundice is attributed to the following mechanisms:

1. Increased RBC volume per kilogram and decreased RBC survival (90 days vs. 120 days) in infants compared to adults

2. Increased ineffective erythropoiesis and increased turnover of nonhemoglobin heme proteins

B. Defective uptake of bilirubin from plasma caused by decreased ligandin and binding of ligandin by other anions

C. Decreased clearance due to decreased UGT1A1 activity. In term infants at 7 days of age, UGT activity is approximately 1% that of adults and does not reach adult levels until at least 3 months of age.

D. Decreased hepatic excretion of bilirubin. Increased enterohepatic circulation caused by high levels of intestinal β-glucuronidase, preponderance of bilirubin monoglucuronide rather than diglucuronide, decreased intestinal bacteria, and decreased gut motility with poor evacuation of bilirubin-laden meconium

IV. HYPERBILIRUBINEMIA is defined as a TB >95th percentile on the hourspecific Bhutani nomogram (Fig. 26.1).

A. The following situations suggest severe hyperbilirubinemia and require evaluation:

1. Onset of jaundice before 24 hours of age

2. An elevation of TB that requires phototherapy (Fig. 26.2)

3. Rate of rise in total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) level of >0.2 mg/dL/hour

4. Associated signs of illness such as vomiting, lethargy, poor feeding, excessive weight loss, apnea, tachypnea, or temperature instability

5. Jaundice persisting after 14 days in a term infant

1. Increased bilirubin production. Hemolytic disease is the most common cause of hyperbilirubinemia (see Chapter 45). This includes
RBC disorders such as isoimmunization (e.g., Rh ABO and minor blood group incompatibility), erythrocyte biochemical abnormalities such as glucose-6-phosphate dehydrogenase or pyruvate kinase deficiencies, or abnormal erythrocyte morphology such as hereditary spherocytosis (HS). Other causes of increased RBC breakdown are sepsis, sequestered blood due to bruising or cephalohematoma, and polycythemia.

a. Mutations in the gene that encodes UGT1A1 decrease bilirubin conjugation, reducing hepatic clearance and increasing serum TB levels.

b. Crigler-Najjar syndrome due to either absent UGT activity (type I) or reduced UGT activity (type II) results in severe hyperbilirubinemia.

c. Gilbert syndrome results from a mutation in the promoter region of the UGT1A1 gene, reducing production of UGT, and is the most common inherited disorder of bilirubin glucuronidation. Although the

Gilbert genotype alone is not associated with increased hyperbilirubinemia, severe hyperbilirubinemia can result when an affected newborn also has increased bilirubin production or increased enterohepatic circulation.

d. Polymorphisms of the organic anion transporter protein OATP-2 may lead to severe hyperbilirubinemia, especially when combined with a UGT1A1 mutation.

e. Decreased clearance may occur in infants of diabetic mothers and with congenital hypothyroidism, galactosemia, and other inherited metabolic disorders.

3. Increased enterohepatic circulation. Pathologic conditions leading to increased enterohepatic circulation include decreased enteral intake, including breastfeeding failure; breast milk jaundice; or impaired intestinal motility due to intestinal atresias, meconium ileus, or Hirschsprung disease.

a. Breastfeeding failure jaundice. Infants who are breastfed have higher bilirubin levels on day 3 of age compared to formula-fed infants. Breastfeeding failure jaundice typically occurs with lactation failure during the first postnatal week that leads to insufficient intake, with weight loss and sometimes hypernatremia. Hyperbilirubinemia is attributed mainly to the decreased intake of milk that leads to slower bilirubin elimination and increased enterohepatic circulation.

b. “Breast milk jaundice” (condition that may be due to genetic predisposition) occurs in about 2.4% of all infants. Typically, it begins after the first 3 to 5 postnatal days, peaks within 2 weeks of age, and if breastfeeding is continued, gradually returns to normal levels over 3 to 12 weeks. If breastfeeding is stopped, the bilirubin level may fall rapidly in 48 hours. If nursing is then resumed, the bilirubin may rise by 2 to 4 mg/dL but usually will not reach the previous high level. Affected infants have good weight gain, normal liver function test (LFT) results, and no evidence of hemolysis. The mechanism of breast milk jaundice is thought to be either associated with Gilbert disease or perhaps a factor in human milk, possibly β-glucuronidase, that deconjugates intestinal bilirubin and promotes its absorption.

V. PREVENTION OF HYPERBILIRUBINEMIA IN HEALTHY TERM AND LATE-PRETERM INFANTS. The American Academy of Pediatrics (AAP) practice guideline for the treatment of unconjugated hyperbilirubinemia in healthy newborn infants at 35 weeks’ gestation and greater is based on three general principles to reduce the occurrence of severe hyperbilirubinemia while also reducing unintended harm: universal systematic assessment before discharge, close follow-up, and prompt intervention when indicated.

A. Risk assessment is performed prior to discharge of otherwise healthy infants ≥35 weeks’ gestation to predict the development of severe hyperbilirubinemia that requires treatment. This is accomplished with a measurement of serum/plasma or TcB. Visual inspection is not a reliable measure of bilirubin level.

1. A screening TB collected by heelstick sampling at the time of the metabolic screen is plotted on an hour-specific bilirubin nomogram (Fig. 26.1) and combined with clinical risk factors (see section V.B),
especially lower gestational age, helps to identify infants at increased risk for developing hyperbilirubinemia and that require close follow-up.

2. TcB measurement is sometimes used to avoid blood sampling, and TcB hour-specific nomograms are available. However, TcB measurements are not reliable in certain circumstances such as during or after phototherapy, after sunlight exposure, or at TB levels ≥15 mg/dL. TcB can overestimate TB in darkly pigmented infants and underestimate TB in light-skinned infants. As a result, if TcB is used to screen infants, TB should be measured if TcB is ≥75th percentile on the TB nomogram for phototherapy, ≥95th percentile on the TcB nomogram, if the TcB is ≥13 mg/dL on follow-up after discharge, or if therapy is being considered.

3. End-tidal carbon monoxide (ETCO), corrected to ambient CO₂, does not improve the sensitivity or specificity of predicting severe hyperbilirubinemia over TB alone. However, it identifies infants with increased bilirubin production due to hemolytic conditions who need closer monitoring and earlier intervention.

B. Major risk factors for development of severe hyperbilirubinemia include the following:

1. Predischarge TB in a high-risk zone (>95th percentile for age in hours according to the Bhutani nomogram) or high intermediate risk zone (Fig. 26.1).

2. Jaundice within the first 24 hours after birth

3. Immune or other hemolytic disease

4. Gestational age 35 to 36 weeks

5. Previous sibling with jaundice