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21. Jaundice*
Beena D. Kamath, Elizabeth H. Thilo and Jacinto A. Hernandez
Jaundice, or hyperbilirubinemia, is an almost universal occurrence in neonates. All infants have a rise in their bilirubin levels after birth because of excessive bilirubin formation and an immature liver that cannot clear the bilirubin from the blood. Sixty percent of normal newborns become noticeably jaundiced sometime during the first week of life. 19
Severe hyperbilirubinemia, defined as total serum bilirubin above the 95th percentile for age in hours, occurs in 8% to 9% of infants during the first week of life.5 Experiences have shown the dangers of excessive levels of unconjugated bilirubin, such as the development of bilirubin encephalopathy and the devastating and irreversible effects of kernicterus. Although the severe sequelae remain rare, a resurgence of kernicterus was seen in the 1990s. 8,14 The increasing incidence of kernicterus was attributed to several causes: the advent of early postnatal discharge before establishment of effective breast feeding, a lack of recognition for the signs of bilirubin encephalopathy, a lack of appropriate follow-up for discharged infants, and a delay in the measurement of bilirubin levels. Therefore an understanding of the pathophysiology and clinical significance of hyperbilirubinemia is critical in the care of newborn infants.
This chapter provides the reader with a basic overview of the multiple causes and contributing factors in the development of hyperbilirubinemia; describes the diagnosis, clinical significance, and complications of hyperbilirubinemia; and discusses current treatment modalities and their complications.


To understand the pathophysiology and clinical significance of hyperbilirubinemia, normal bilirubin metabolism in the newborn must be reviewed (Figure 21-1). A newborn has a rate of bilirubin production of 8 to 10 mg/kg/24 hr, which is 2 to 2½ times the production rate in adults. Red blood cells in newborns have a shortened life span of 70 to 90 days, compared with 120 days in adults. As the catabolism of 1 g of hemoglobin yields 35 mg of bilirubin, this accelerated red blood cell breakdown produces most of the bilirubin (75% to 85%) in newborns. The remaining 15% to 25% of bilirubin is derived from non-erythroid heme proteins found principally in the liver and heme precursors in the marrow and extramedullary hematopoietic areas that do not go on to form red blood cells (early peak or shunt bilirubin).
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(From Gartner LM, Hollander M: Disorders of bilirubin metabolism. In Assali NS, editor: Pathophysiology of gestation, vol 3, New York, 1972, Academic Press.)
Bilirubin metabolism is initiated in the reticuloendothelial system, principally in the liver and spleen, as old or abnormal red blood cells are removed from the circulation. The enzyme microsomal heme oxygenase will act on heme to produce biliverdin, and biliverdin reductase will convert this biliverdin into bilirubin. This bilirubin, in its unconjugated or indirect-reacting form, is released into the plasma. Exhaled carbon monoxide is an end product of these pathways.
At a normal plasma pH, bilirubin is very poorly soluble and binds tightly to circulating albumin, which serves as a carrier protein. Albumin contains one high-affinity site for bilirubin and one or more sites of lower affinity. Bilirubin binds to albumin in a molar ratio of between 0.5 and 1 mole of bilirubin per mole of albumin. A bilirubin/albumin molar ratio of 1 corresponds to approximately 8.5 mg bilirubin/g of albumin. This ratio may be somewhat lower in a sick very-low-birth-weight (VLBW) infant.7
Bilirubin bound to albumin is carried to the liver and transported into the hepatocyte by carrier-mediated diffusion. Intracellularly, bilirubin is bound to ligandin (Y protein) and, to a lesser extent, the Z protein. Conjugation occurs within the smooth endoplasmic reticulum of the cell. This reaction, catalyzed by the enzyme bilirubin uridine diphosphate glucuronosyl transferase (UDPGT), leads to the formation of water-soluble compounds called bilirubin glucuronides. In addition to UDPGT, conjugation requires glucuronic acid synthesized from glucose. Conjugated bilirubin is then actively secreted into bile and passes into the small intestine.
Conjugated bilirubin is not reabsorbed from the intestine, but the bowel lumen of the newborn contains the enzyme beta-glucuronidase, which can convert conjugated bilirubin back into glucuronic acid and unconjugated bilirubin, which may be absorbed. This pathway constitutes the enterohepatic circulation of bilirubin and contributes significantly to an infant’s bilirubin load.22

Factors That Affect Bilirubin Levels

The ability of albumin to bind bilirubin is affected by a number of different factors, including plasma pH, free fatty acid levels, and certain drugs (Table 21-1). Albumin binding of unconjugated bilirubin may be important in the prevention of toxicity (bilirubin encephalopathy or kernicterus). Once the high-affinity site is saturated, there is a rapid increase in potentially toxic free (nonbound) unconjugated bilirubin. Kernicterus has been clinically associated with administration of sulfisoxazole to newborns as a result of displacement of bilirubin from the primary binding site on albumin. Other drugs, such as ceftriaxone, also appear to displace bilirubin from this binding site. The effect on bilirubin-albumin binding of some but not all drugs used in newborn medicine has been studied in vitro. 23
TABLE 21-1 Factors Affecting Bilirubin-Albumin Binding
*From Hargreaves T: Effects of fatty acids on bilirubin conjugation, Arch Dis Child 48:446, 1973.
Factor Mechanism
pH (acidosis) Decreases binding by decreasing affinity at the binding site and increasing tissue affinity
Hematin Competitively inhibits binding at primary site
Free fatty acid (intralipid) * Competitively inhibits binding at primary site
Infection Mechanism not established
Drugs such as sulfa compounds, sodium salicylate, phenylbutazone, and ceftriaxone Primarily competitive binding; principally at secondary site; and best established for sulfisoxazole
Stabilizers for albumin preparations Competitively inhibit binding at primary site
X-ray contrast media for cholangiography Competitively inhibit binding at primary site
Newborn monkeys have been shown to be deficient in the intracellular Y and Z proteins for the first few days of life, and this also may occur in the human newborn. The hormonal (estrogen) environment of the infant may inhibit liver function and bilirubin secretion. A rise in bilirubin levels shortly after birth is also partially attributable to a relative deficiency of UDPGT activity (0.1% of adult levels at 30 weeks’ gestation). Enzyme activity increases rapidly after birth independent of the infant’s gestational age.
Certain ethnic groups, including Eskimo, Asian, and Native American, have an increased incidence and severity of hyperbilirubinemia for reasons that are not clearly understood. In a hypoglycemic infant, glucuronide production may be limited and thus conjugation is impaired. The presence of beta-glucuronidase in the bowel lumen during fetal life enables bilirubin to be reabsorbed and transported across the placenta for excretion by the maternal liver.


Bilirubin levels rise in newborn infants by three main mechanisms: increased production (accelerated red blood cell breakdown), decreased removal (transient liver enzyme insufficiency), and increased reabsorption (enterohepatic circulation) (Box 21-1). The normal pathways of bilirubin metabolism described earlier account for much of the increase in bilirubin levels in newborn infants; however, the following circumstances deserve special attention for infants who have prolonged or marked increases in bilirubin levels than would otherwise be expected.
BOX 21-1


• Hemolytic disease of the newborn
• Hereditary hemolytic anemias
• Membrane defects
• Hemoglobinopathies
• Enzyme defects
• Polycythemia
• Extravascular blood
• Swallowed
• Bruising or enclosed hemorrhage (e.g., cephalohematoma)
• Increased enterohepatic circulation

Slow Excretion

• Decreased hepatic uptake
• Decreased sinusoidal perfusion
• Ligandin deficiency
• Decreased conjugation
• Enzyme deficiency
• Enzyme inhibition, such as the Lucey-Driscoll syndrome
• Inadequate transport out of hepatocyte
• Biliary obstruction

Combined (Overproduction and Slow Excretion)

• Bacterial infection
• Congenital intrauterine infection

Breast Feeding

• Breast feeding jaundice
• Breast milk jaundice



• Hypothyroidism
• Galactosemia
• Infant of diabetic mother
From a management perspective, it is helpful to describe severe hyperbilirubinemia according to its time of onset, early or late, to determine its specific etiology. In general, early-onset severe hyperbilirubinemia is associated with increased bilirubin production, whereas late-onset hyperbilirubinemia is often associated with delayed bilirubin elimination with or without increased bilirubin production (Figure 21-2). 25
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(Modified from Smitherman H, Stark AR, Bhutani VK: Early recognition of neonatal hyperbilirubinemia and its emergent management, Semin Fetal Neonatal Med 11:214, 2006.)

Overproduction of Bilirubin


Hemolytic disease of the newborn may occur when blood group incompatibilities such as Rh, ABO, or minor blood groups exist between a mother and her fetus. The classic example of hemolytic disease of the newborn has been erythroblastosis fetalis occurring as a result of Rh incompatibility. Fifteen percent of the white population is Rh negative. When an Rh-negative mother is sensitized to the Rh antigen by an improperly matched blood transfusion or the occurrence of fetal-maternal blood transfusion during pregnancy, delivery, abortion, or amniocentesis, the presence of the Rh antigen induces maternal antibody production. Because prior sensitization with the Rh antigen is necessary for antibody production, the first Rh-positive infant usually is not affected. Once a mother is sensitized, maternal immunoglobulin G (IgG) crosses the placenta into the fetal circulation where it reacts with the Rh antigen on fetal erythrocytes. These antibody-coated cells are recognized as abnormal and destroyed by the spleen. This results in increased amounts of hemoglobin, requiring metabolic degradation. As the destruction of erythrocytes and production of bilirubin progress, the ability of the fetus to compensate may be surpassed. Fortunately, the use of anti-D gamma globulin (RhoGAM), particularly antenatal administration at 26 to 28 weeks’ gestation to non-sensitized pregnant women, has markedly decreased the incidence of Rh isoimmunization and the resulting hyperbilirubinemia in newborn infants.
With the widespread use of RhoGAM, the most frequent cause of hemolytic disease of the newborn is now ABO blood group incompatibility. ABO incompatibility is limited to mothers of blood group O and affects infants of blood group A or B. All group O individuals have naturally occurring anti-A and anti-B (IgG) antibodies, so specific sensitization is not necessary. The resulting hyperbilirubinemia in the newborn is very variable and generally milder than that seen with Rh incompatibility.


Erythrocytes with abnormal membranes or containing abnormal hemoglobin variants have increased rates of red blood cell destruction. Individuals with enzyme defects, such as spherocytosis and elliptocytosis, cannot maintain the integrity of red blood cells because of abnormal osmotic fragility (generally increased) and an increased rate of splenic destruction. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect and is more commonly found in certain racial and ethnic groups, including Chinese, Greeks, and blacks. Pyruvate kinase deficiency is less common.
Individuals with hemoglobinopathies, which can be diagnosed by hemoglobin electrophoresis, also have increased splenic destruction. Often, the precipitating factor for the hemolysis cannot be found in infants. A family history is important, however, since it may be positive in as many as 80% of cases.


Polycythemia (with a central venous hematocrit value >65) is the condition in which an increased red blood cell mass, coupled with the shortened life span of these cells found in all newborns, results in an increased bilirubin load. Polycythemia may be idiopathic or may occur as a result of a maternal-fetal transfusion, twin-to-twin transfusion, chronic in utero hypoxia, or delayed clamping of the umbilical cord at the time of delivery.


Enclosed hemorrhage includes cephalohematoma, subgaleal hemorrhage, cerebral hemorrhage, intraabdominal bleeding, and any occult internal bleeding, as well as extensive bruising. As these enclosed hemorrhages resolve, red blood cells trapped within are broken down and add to bilirubin production. Swallowed maternal blood is another possible source of increased bilirubin load.


As mentioned, the intestinal brush border contains the enzyme beta-glucuronidase, which can convert conjugated bilirubin back into its unconjugated (absorbable) form and glucuronic acid. Meconium contains a substantial amount of bilirubin, estimated at 1 mg of bilirubin per 1 g of meconium, or a total load of 100 to 200 mg. Any delay in the passage of meconium, as can occur with prematurity or bowel obstruction, increases the bilirubin load that must be metabolized. Hyperbilirubinemia requiring treatment due to these causes is rarely evident in the first 24 to 48 hours of life.

Slow Excretion of Bilirubin

Infants with normal bilirubin production rates may be unable to remove this load for a variety of reasons, as described in the following conditions.


Diminished hepatic uptake of bilirubin may be a result of inadequate perfusion of hepatic sinusoids or deficient carrier proteins (Y and Z). Certain drugs and compounds (e.g., steroid hormones, free fatty acids, chloramphenicol) may competitively bind to these proteins, creating a functional deficiency.
Inadequate perfusion of hepatic sinusoids occurs when there is a shunt through a persistent ductus venosus or extrahepatic portal vein thrombosis or with hyperviscosity and hypovolemia, as seen in infants with severe congestive heart failure. Although Y and Z proteins are decreased in some newborn primates, no actual deficiency has yet been demonstrated in the human newborn.


Decreased bilirubin conjugation may be a result of UDPGT deficiency, as in the Crigler-Najjar syndromes or Gilbert syndrome. These disorders are caused by defects in the UDPGT1 gene complex recently identified on chromosome 2. Crigler-Najjar syndrome is rare and exists in two forms with either complete (type I) or partial (type II) absence of enzymatic activity. Type I is an autosomal recessive disorder. Phototherapy becomes ineffective in preventing excessive bilirubin levels, and liver transplantation is the only possible cure. Type II is inherited as an autosomal dominant disorder and responds to enzyme induction with phenobarbital. Gilbert syndrome is a milder and very common autosomal dominant disorder with partial enzyme activity generally becoming apparent beyond the newborn period with mild bilirubin elevation during times of stress or intercurrent illness. It may well be an important contributing factor, however, in cases of late-onset severe hyperbilirubinemia.


Dubin-Johnson and Rotor syndromes are genetically inherited conditions (autosomal recessive and dominant, respectively) in which individuals can conjugate bilirubin normally but cannot excrete it, resulting in direct (conjugated) hyperbilirubinemia. These conditions, in addition to causing generalized hepatocellular damage, require specialized evaluation, including liver biopsy.


Biliary obstruction often is seen as a diagnostic dilemma requiring differentiation between generalized hepatocellular damage and mechanical obstruction.
A variety of disorders can cause hepatocellular damage, including infections such as hepatitis and metabolic disorders such as galactosemia. In the neonatal intensive care unit (NICU), the most common cause of hepatocellular damage is the use of parenteral nutrition. The mechanism is not well established, but the damage takes at least 2 weeks to develop and is especially prominent in VLBW infants. Biliary atresia or, much less frequently, a choledochal cyst can cause mechanical obstruction to bile flow, resulting in a conjugated hyperbilirubinemia with light-colored stools.

Combined Overproduction and Slow Excretion


Bacterial infections (sepsis neonatorum, especially necrotizing enterocolitis [NEC] caused by toxin-producing organisms such as certain strains of Escherichia coli [E. coli]) or intrauterine viral infections can result in increased bilirubin production and decreased hepatic clearance.
Intrauterine infections, including syphilis, toxoplasmosis, rubella, cytomegalovirus, herpes simplex, Coxsackie B virus, and hepatitis virus, cause clinical jaundice with evidence for hepatocellular damage. Infants with these infections often have additional clinical stigmata of their infection such as thrombocytopenia and rash.


The cause of hyperbilirubinemia in an infant of a diabetic mother (IDM) appears to be multifactorial. In addition to prematurity and a tendency to feed poorly, an IDM may have an increased bilirubin load as a result of an expanded red blood cell mass. Erythrocyte membrane composition may be altered, and macrosomic infants often are bruised during labor and delivery.

Jaundice Associated with Breast Feeding

Ideally, a trained observer should evaluate all breast-fed infants within 48 to 72 hours of discharge in either a home or office setting. 6 Early discharge of breast-fed infants with inadequate follow-up may result in excessive levels of bilirubin and the possibility of kernicterus. Thus promotion and support of successful breast feeding constitutes a key element of the American Academy of Pediatrics (AAP) clinical practice guideline on the management of hyperbilirubinemia. 1


In general, breast-fed infants have higher bilirubin levels than bottle-fed infants, especially in the first days of life. It has been postulated that this early jaundice is related to decreased caloric and fluid intake from colostrum and increased enterohepatic circulation resulting from low stool output and breast milk beta-glucuronidase. 1 Many studies show a relationship between the degree of hyperbilirubinemia and the amount of weight lost by the infant after birth.
Because of concern for breast-fed infants being underfed, it once was common practice in some institutions to supplement with glucose water or electrolyte solutions after nursing. Such supplementation should be avoided because it reduces breast-feeding frequency and maternal milk production, without improving the infant’s intestinal motility, leading to higher peak bilirubin levels. Optimal management of a breast-feeding mother and infant includes early and frequent nursing: 8 to 12 times each day. If the infant is unable to feed this frequently, the mother should be instructed in the use of a mechanical breast pump, and the infant supplemented with expressed breast milk or formula to improve both the milk supply and the infant’s nutritional status and intestinal motility.


A small percentage (1% to 2%) of breast-fed infants exhibit prolonged and exaggerated jaundice possibly related to an inhibitor or inhibitory substance found in their mother’s breast milk that prolongs and increases enterohepatic circulation. The rate of recurrence in families approaches 70%.
Such infants have an unconjugated hyperbilirubinemia (>12 mg/dL) that becomes exaggerated and persistent toward the end of the first week of life. 10 Other causes of excessive hyperbilirubinemia should be ruled out. Elevated bilirubin levels may persist for 4 to 14 days, followed by a very gradual decline. For the vast majority of infants, it is not necessary to interrupt breast feeding, even if the bilirubin increases to a level that may require phototherapy.

Miscellaneous Causes

The following causes of hyperbilirubinemia are uncommon but important to consider in infants who have no other clear etiology to explain their elevated bilirubin levels. These conditions include hypothyroidism and galactosemia. States now require routine screening for these conditions, since early detection allows intervention before permanent adverse neurologic outcomes. Hyperbilirubinemia, unconjugated or mixed, may be the initial sign of these conditions.


A prolonged period of unconjugated hyperbilirubinemia can be seen in infants with hypothyroidism. The mechanism of hyperbilirubinemia in hypothyroidism is not well understood, but in some animal studies, thyroxine was needed for the hepatic clearance of bilirubin.


Galactosemia is an autosomal recessive disorder characterized by increased jaundice in infants fed breast milk or lactose-containing formulas. The mechanism of hyperbilirubinemia in galactosemia may be related to a lack of substrate for glucuronidation and the accumulation of abnormal hepatotoxic by-products. The presence of non–glucose-reducing substances in the urine suggests galactosemia.


Identification of those infants at risk for hyperbilirubinemia enables clinicians to provide timely treatment to prevent neuronal injury. The AAP has described risk factors for hyperbilirubinemia, which can be seen in Box 21-2.
BOX 21-2

Major Risk Factors

• Pre-discharge TSB or TcB level in the high-risk zone
• Jaundice observed in the first 24 hours of life
• Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (e.g., G6PD deficiency), elevated ET coc
• Gestational age 35 to 36 weeks
• Previous sibling received phototherapy
• Cephalohematoma or significant bruising
• Exclusive breast feeding, especially if nursing is not going well and weight loss is excessive

Minor Risk Factors

• Pre-discharge TSB or TcB level in the high intermediate-risk zone
• Gestational age 37 to 38 weeks
• Jaundice observed before discharge
• Previous sibling with jaundice
• Macrosomic infant of a diabetic mother
• Maternal age ≥25 years
• Male gender

Decreased Risk (these factors are associated with decreased risk for significant jaundice, listed in order of decreasing importance)

• TSB or TcB level in the low-risk zone
• Gestational age ≥41 weeks
• Exclusive bottle feeding
• Black race*
• Discharge from the hospital after 72 hours
ET coc, End-tidal carbon monoxide corrected; G6PD, glucose-6-phosphate dehydrogenase; TcB, transcutaneous bilirubin; TSB, Total serum bilirubin.
From American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia: Clinical Practice Guideline: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation, Pediatrics 114:297, 2004.
The most important determinants of brain injury caused by hyperbilirubinemia are the concentrations of unconjugated bilirubin and free bilirubin, the concentration of serum albumin and its ability to bind unconjugated bilirubin, the concentration of hydrogen ion (pH), and neuronal susceptibility.24 The blood-brain barrier allows free bilirubin to pass; however, the blood-brain interface, consisting of capillary endothelium and astrocytic foot processes, and the choroid plexus have specific transporters that can pump free bilirubin out of the central nervous system, thereby protecting the brain from exposure to high bilirubin. Timing of exposure to excess bilirubin during neurodevelopment is important in determining the pattern of the neurologic damage; for example, because auditory pathways mature earlier than motor pathways, patterns of damage in premature infants may differ from those in mature infants. 24 Unconjugated bilirubin is fat soluble and can cross cell membranes; however, because most unconjugated bilirubin is bound to albumin, toxicity is avoided. 25 Therefore development of toxicity may also depend on albumin-bilirubin binding. Factors that interfere with albumin-bilirubin binding appear to predispose to the development of kernicterus (see Table 21-1). Once toxicity has occurred, it appears to be irreversible.
Although elevated levels of bilirubin occur in virtually all newborns, precise identification of what constitutes a “safe” level for an individual newborn, especially if sick or premature, remains elusive and is the subject of much ongoing investigation. A “pathologic” level for one infant may be a “physiologic” level for another infant; therefore it has been suggested that these terms be done away with altogether.
All bilirubin levels should be interpreted according to the infant’s age in hours.

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