91.

3 Jaundice and Hyperbilirubinemia in the Newborn

Hyperbilirubinemia is a common and, in most cases, benign problem in neonates. Nonetheless,
untreated, severe indirect hyperbilirubinemia is potentially neurotoxic, and conjugated-direct
hyperbilirubinemia often signifies a serious hepatic or systemic illness. Jaundice is observed
during the 1st wk of life in approximately 60% of term infants and 80% of preterm infants. The
color usually results from the accumulation in skin of unconjugated, nonpolar, lipid-soluble
bilirubin pigment (indirect reacting) formed from hemoglobin by the action of heme oxygenase,
biliverdin reductase, and nonenzymatic reducing agents in the reticuloendothelial cells; it may
also be due in part to deposition of the pigment after it has been converted in the liver cell
microsome by the enzyme uridine diphosphoglucuronic acid (UDP)-glucuronyl transferase to the
polar, water-soluble ester glucuronide of bilirubin (direct reacting). The unconjugated form is
neurotoxic in infants at certain concentrations and under various conditions. Conjugated bilirubin
is not neurotoxic but indicates a potentially serious disorder.

Etiology.
A newborn infant's metabolism of bilirubin is in transition from the fetal stage, during which the
placenta is the principal route of elimination of the lipid-soluble bilirubin, to the adult stage,
during which the water-soluble conjugated form is excreted from hepatic cells into the biliary
system and then into the gastrointestinal tract.
Unconjugated hyperbilirubinemia may be caused or increased by any factor that
(1) increases the load of bilirubin to be metabolized by the liver (hemolytic anemias,
polycythemia, shortened red cell life as a result of immaturity or transfused cells, increased
enterohepatic circulation, infection),
(2) damages or reduces the activity of the transferase enzyme (genetic deficiency, hypoxia,
infection, possibly hypothermia and thyroid deficiency),
(3) competes for or blocks the transferase enzyme (drugs and other substances requiring
glucuronic acid conjugation for excretion), or
(4) leads to an absence or decreased amounts of the enzyme or to reduction of bilirubin uptake
by liver cells (genetic defect, prematurity).
The toxic effects of elevated levels of unconjugated bilirubin in serum are increased by factors
that reduce the retention of bilirubin in the circulation (hypoproteinemia, displacement of
bilirubin from its binding sites on albumin by competitive binding of drugs such as sulfisoxazole
and moxalactam, Chuen-Lin herbal tea, acidosis, increased free fatty acid concentration
secondary to hypoglycemia, starvation, or hypothermia) or by factors that increase the
permeability of the blood-brain barrier or nerve cell membranes to bilirubin or increase the
susceptibility of brain cells to its toxicity, such as asphyxia, prematurity, hyperosmolality, and
infection. Early feeding decreases whereas breast-feeding and dehydration increase serum levels
of bilirubin. Meconium has 1 mg bilirubin/dL and may contribute to jaundice by the
enterohepatic circulation after deconjugation by intestinal glucuronidase (Fig. 91-6). Drugs such
as oxytocin and chemicals used in the nursery such as phenolic detergents may also produce
unconjugated hyperbilirubinemia. The mnemonic JAUNDICE can be helpful in recalling risk
factors for unconjugated hyperbilirubinemia (see Box 91-2).
Clinical Manifestations.

Figure 91-6 The neonatal production rate of bilirubin is 6-8 mg/kg/24 hr (in contrast to 3-4
mg/kg/24 hr in adults). Water-insoluble bilirubin is bound to albumin. At the plasma-hepatocyte
interface, a liver membrane carrier (bilitranslocase) transports bilirubin to a cytosolic binding
protein (ligandin or Y protein, now known to be glutathione S-transferase), which prevents back-
absorption to plasma. Bilirubin is converted to bilirubin monoglucuronide (BMG) or
diglucuronide (BDG) by several classes of the enzyme bilirubin glucuronyl transferase. Neonates
excrete more BMG than adults do. In the fetus, conjugated lipid-insoluble BMG and BDG must
be deconjugated by tissue -glucuronidases to facilitate placental transfer of lipid-soluble
unconjugated bilirubin across the placental lipid membranes. After birth, intestinal or milk-
containing glucuronidases contribute to the enterohepatic recirculation of bilirubin and possibly
to the development of hyperbilirubinemia.
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Jaundice may be present at birth or may appear at any time during the neonatal period,
depending on the cause. Jaundice usually begins on the face and, as serum levels increase,
progresses to the abdomen and then the feet. Dermal pressure may reveal the anatomic
progression of jaundice (face, [ap ]5 mg/dL; mid-abdomen, [ap ]15 mg/dL; soles, [ap ]20
mg/dL), but clinical examination cannot be depended on to estimate blood levels. Jaundice to the
mid-abdomen, signs or symptoms, high-risk factors that suggest nonphysiologic jaundice (Box
91-2), or hemolysis must be evaluated further. Noninvasive techniques for transcutaneous
measurement of bilirubin that correlate well with serum levels may be used to screen infants, but
determination of a serum bilirubin level is indicated for patients with progressing jaundice,
symptoms, or a risk for hemolysis or sepsis. Jaundice resulting from deposition of indirect
bilirubin in the skin tends to appear bright yellow or orange, and jaundice of the obstructive type
(direct bilirubin) has a greenish or muddy yellow cast. This difference is usually apparent only in
severe jaundice. Affected infants may be lethargic and may feed poorly. Signs of kernicterus
rarely appear on the 1st day of jaundice (Chapter 91.4).

Differential Diagnosis.
Jaundice, consisting of either indirect or direct bilirubin, that is present at birth or appears within
the 1st 24 hr of life requires immediate attention and may be due to erythroblastosis fetalis,
concealed hemorrhage, sepsis, or intrauterine infections, including syphilis, cytomegalic
inclusion disease, rubella, and congenital toxoplasmosis. Hemolysis is suggested by a rapid rise
in serum bilirubin (>0.5 mg/dL/hr), anemia, pallor, reticulocytosis, hepatosplenomegaly, and a
positive family history. An unusually high proportion of direct-reacting bilirubin may
characterize jaundice in infants who have received intrauterine transfusions. Jaundice that first
appears on the 2nd or 3rd day is usually "physiologic" but may represent a more severe form.
Familial nonhemolytic icterus (Crigler-Najjar syndrome) and early-onset breast-feeding jaundice
are seen initially on the 2nd or 3rd day. Jaundice appearing after the 3rd day and within the 1st
wk should suggest bacterial sepsis or urinary tract infection; it may be due to other infections,
notably syphilis, toxoplasmosis, cytomegalovirus, or enterovirus. Jaundice secondary to
extensive ecchymosis or hematoma may occur during the 1st day or later, especially in
premature infants. Polycythemia may lead to early jaundice.
Jaundice that is noted initially after the 1st wk of life suggests breast milk jaundice, septicemia,
congenital atresia or paucity of the bile ducts, hepatitis, galactosemia, hypothyroidism, CF,
congenital hemolytic anemia (spherocytosis), or possibly the crises of other hemolytic anemias
(such as pyruvate kinase and other glycolytic enzyme deficiencies or hereditary nonspherocytic
anemia) or hemolytic anemia related to drugs (as in congenital deficiencies of the enzymes
glucose-6-phosphate dehydrogenase [G6PD] or glutathione synthetase, reductase, or peroxidase)
(Fig. 91-7).

Figure 91-7 Schematic approach to the diagnosis of neonatal jaundice. G6PD = glucose-6-
phosphate dehydrogenase; PK = pyruvate kinase. (From Oski FA: Differential diagnosis of
jaundice. In Taeusch HW, Ballard RA, Avery MA [editors]: Schaffer and Avery's Diseases of the
Newborn, 6th ed. Philadelphia, WB Saunders, 1991.)
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Persistent jaundice during the 1st mo of life suggests inspissated bile syndrome (which may
follow hemolytic disease of the newborn), hyperalimentation-associated cholestasis, hepatitis,
cytomegalic inclusion disease, syphilis, toxoplasmosis, familial nonhemolytic icterus, congenital
atresia of the bile ducts, or galactosemia. Rarely, physiologic jaundice may be prolonged for
several weeks, as in infants with hypothyroidism or pyloric stenosis.
Low-risk jaundiced infants who are full term and asymptomatic may be evaluated by monitoring
serum total bilirubin levels. Regardless of the gestational age or time of appearance of jaundice,
those with significant hyperbilirubinemia and all patients with symptoms or signs require a
complete diagnostic evaluation, which should include determination of the direct and indirect
bilirubin fractions, hemoglobin, reticulocyte count, and blood type, a Coombs test, and
examination of a peripheral blood smear. Indirect-reacting bilirubinemia, reticulocytosis, and a
smear demonstrating evidence of red blood cell destruction suggest hemolysis; in the absence of
blood group incompatibility, non-immunologically induced hemolysis should be considered. If
direct-reacting hyperbilirubinemia is present, hepatitis, congenital bile duct disorders (atresia,
paucity, Byler disease), cholestasis, inborn errors of metabolism, CF, and sepsis are diagnostic
possibilities. If the reticulocyte count, Coombs test, and direct bilirubin are normal, physiologic
or pathologic indirect hyperbilirubinemia may be present (see Fig. 91-7).
Physiologic Jaundice (Icterus Neonatorum).
Under normal circumstances, the level of indirect-reacting bilirubin in umbilical cord serum is 1-
3 mg/dL and rises at a rate of less than 5 mg/dL/24 hr; thus, jaundice becomes visible on the 2nd-
3rd day, usually peaking between the 2nd and 4th days at 5-6 mg/dL and decreasing to below 2
mg/dL between the 5th and 7th days of life. Jaundice associated with these changes is designated
"physiologic" and is believed to be the result of increased bilirubin production after the
breakdown of fetal red blood cells combined with transient limitation in the conjugation of
bilirubin by the liver.
Overall, 6-7% 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. Risk factors for indirect hyperbilirubinemia include
maternal diabetes, race (Chinese, Japanese, Korean, and Native American), prematurity, drugs
(vitamin K3, novobiocin), altitude, polycythemia, male sex, trisomy 21, cutaneous bruising,
cephalohematoma, oxytocin induction, breast-feeding, weight loss (dehydration or caloric
deprivation), delayed bowel movement, and a sibling who had physiologic jaundice (see Box 91-
2). A family history of neonatal jaundice, exclusive breast-feeding, bruising, cephalohematoma,
Asian race, and maternal age older than 25 yr identify approximately 60% of cases of extreme
hyperbilirubinemia. In infants without these variables, indirect bilirubin levels rarely rise above
12 mg/dL, whereas infants with several risk factors are more likely to have higher bilirubin
levels. Indirect bilirubin levels in full-term infants decline to adult levels (1 mg/dL) by 10-14
days of life.
Prediction of which neonatal infants are at risk for exaggerated physiologic jaundice can be
based on hour-specific bilirubin levels in the 1st 24-72 hr of life (Fig. 91-8).
Persistent indirect hyperbilirubinemia beyond 2 wk suggests hemolysis, hereditary glucuronyl
transferase deficiency, breast milk jaundice, hypothyroidism, or intestinal obstruction. Jaundice
associated with pyloric stenosis may be due to caloric deprivation, deficiency of hepatic UDP-
glucuronyl transferase, or ileus-induced increased enterohepatic circulation of bilirubin.

Figure 91-8 Risk designation of term and near-term well newborns based on their hour-specific
serum bilirubin values. The high-risk zone is designated by the 95th percentile track. The
intermediate-risk zone is subdivided into upper and lower risk zones by the 75th percentile track.
The low-risk zone has been electively and statistically defined by the 40th percentile track.
(Dotted extensions are based on less than 300 total serum bilirubin values/epoch.) (From Bhutani
VK, Johnson L, Sivieri EM: Predictive ability of a predischarge hour-specific serum bilirubin for
subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics
1999;103:9.)
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In premature infants, the rise in serum bilirubin tends to be the same or a little slower than that in
term infants, but it is of longer duration, which generally results in higher levels, the peak being
reached between the 4th and 7th days; the pattern depends on the time required for the
development of mature mechanisms for the metabolism and excretion of bilirubin. Peak levels of
8-12 mg/dL are not usually reached until the 5th-7th day, and jaundice is infrequently observed
after the 10th day.
The diagnosis of physiologic jaundice in term or preterm infants can be established only by
precluding known causes of jaundice on the basis of the history and clinical and laboratory
findings (Table 91-1). In general, a search to determine the cause of jaundice should be made if
(1) it appears in the 1st 24-36 hr of life, (2) serum bilirubin is rising at a rate faster than 5
mg/dL/24 hr, (3) serum bilirubin is greater than 12 mg/dL in full-term (especially in the absence
of risk factors) or 10-14 mg/dL in preterm infants, (4) jaundice persists after 10-14 days of life,
or (5) direct-reacting bilirubin is greater than 2 mg/dL at any time. Among other factors
suggesting a nonphysiologic cause of jaundice are a family history of hemolytic disease, pallor,
hepatomegaly, splenomegaly, failure of phototherapy to lower bilirubin, vomiting, lethargy, poor
feeding, excessive weight loss, apnea, bradycardia, abnormal vital signs (including
hypothermia), light-colored stools, dark urine positive for bilirubin, and signs of kernicterus
(Chapter 91.4).

Pathologic Hyperbilirubinemia.

Table 91-1. Diagnostic Features of the Various Types of Neonatal Jaundice

DiagnosisNature of Van den Bergh ReactionJaundicePeak Bilirubin
ConcentrationBilirubin Rate of Accumulation (mg/dL/day)Remarks
AppearsDisappearsmg/dLAge in Days
"Physiologic jaundice": Usually relates to degree of maturity
Full-termIndirect2-3 days4-5 days10-122-3<5
PrematureIndirect3-4 days7-9 days156-8<5
Hyperbilirubinemia due to metabolic factors Metabolic factors: hypoxia, respiratory distress,
lack of carbohydrate
Full-termIndirect2-3 daysVariable>121st wk<5Hormonal influences: cretinism, hormones,
Gilbert syndrome
PrematureIndirect3-4 daysVariable>151st wk<5Genetic factors: Crigler-Najjar syndrome,
Gilbert syndrome
Drugs: vitamin K, novobiocin
Hemolytic states and hematomaIndirectMay appear in 1st 24
hrVariableUnlimitedVariableUsually >5Erythroblastosis: Rh, ABO, Kell
Congenital hemolytic states: spherocytic, nonspherocytic
Infantile pyknocytosis
Drugs: vitamin K
Enclosed hemorrhage-hematoma
Mixed hemolytic and hepatotoxic factorsIndirect and directMay appear in 1st 24
hrVariableUnlimitedVariableUsually >5Infection: bacterial sepsis, pyelonephritis, hepatitis,
toxoplasmosis, cytomegalic inclusion disease, rubella, syphilis
Drugs: vitamin K
Hepatocellular damageIndirect and directUsually 2-3 days, may appear by 2nd
wkVariableUnlimitedVariableVariable, can be >5Biliary atresia; paucity of bile ducts, familial
cholestasis, galactosemia; hepatitis and infection

From Brown AK: Pediatr Clin North Am 1962;9:589.

Jaundice and its underlying hyperbilirubinemia are considered pathologic if their time of
appearance, duration, or pattern of serially determined serum bilirubin concentrations varies
significantly from that of physiologic jaundice or if the course is compatible with physiologic
jaundice but other reasons exist to suspect that the infant is at special risk from the neurotoxicity
of unconjugated bilirubin. It may not be possible to precisely determine the cause of an abnormal
elevation of unconjugated bilirubin. Many of these infants have an associated risk factor such as
Asian race, prematurity, breast-feeding, or weight loss; hence, the terms exaggerated physiologic
jaundice and hyperbilirubinemia of the newborn are used for infants whose primary problem is
probably a deficiency or inactivity of bilirubin glucuronyl transferase (e.g., Gilbert syndrome)
rather than an excessive load of bilirubin for excretion (see Box 91-2). The combination of
G6PD deficiency and a mutation of the promoter region of UDP-glucuronyl transferase 1
produces indirect hyperbilirubinemia in the absence of signs of hemolysis. Nonphysiologic
hyperbilirubinemia may also be caused by mutations in the gene for bilirubin UDP-glucuronyl
transferase.
The greatest risk associated with hyperbilirubinemia is the development of kernicterus (bilirubin
encephalopathy) at high indirect serum bilirubin levels (Chapter 91.4). The level of serum
bilirubin associated with kernicterus is dependent in part on the cause of the jaundice.
Kernicterus develops at lower bilirubin levels in preterm infants and in the presence of asphyxia,
intraventricular hemorrhage, hemolysis, or drugs that displace bilirubin from albumin. The exact
serum bilirubin level that is harmful for VLBW infants is unclear. Kernicterus does occur in
patients with breast milk jaundice but is very uncommon. The duration of exposure to bilirubin
and the brain concentration of bilirubin are important factors for neurotoxicity.
Jaundice Associated with Breast-Feeding.
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Significant elevations in unconjugated bilirubin (breast milk jaundice) develop in an estimated
2% of breast-fed term infants after the 7th day of life, with maximal concentrations as high as
10-30 mg/dL reached during the 2nd-3rd wk. If breast-feeding is continued, the
hyperbilirubinemia gradually decreases and may then persist for 3-10 wk at lower levels. If
nursing is discontinued, the serum bilirubin level falls rapidly, usually reaching normal levels
within a few days. Cessation of breast-feeding for 1-2 days and substitution of formula for breast
milk results in a rapid decline in serum bilirubin, after which nursing can be resumed without a
return of the hyperbilirubinemia to its previously high levels. If indicated, phototherapy may be
of benefit (Chapter 91.4). These infants have no other sign of illness; nonetheless, kernicterus
has been reported. The cause is unclear, but in some the milk contains a glucuronidase that may
be responsible for jaundice.
This syndrome should be distinguished from an early-onset, accentuated unconjugated
hyperbilirubinemia (breast-feeding jaundice) in the 1st wk of life, when breast-fed infants have
higher bilirubin levels than formula-fed infants do (Fig. 91-9). Hyperbilirubinemia (>12 mg/dL)
develops in 13% of breast-fed infants in the 1st wk of life and may be due to decreased milk
intake with dehydration or reduced caloric intake. Giving supplements of glucose water to
breast-fed infants is associated with higher bilirubin levels, in part because of reduced intake of
the higher caloric density breast milk. Frequent breast-feeding (>10/24 hr), rooming-in with
night feeding, and discouraging 5% dextrose or water supplementation may reduce the incidence
of early breast-feeding jaundice.
Neonatal Hepatitis.
See Chapter 337.1.
Congenital Atresia of the Bile Ducts.
See Chapter 337.1. Jaundice persisting for more than 2 wk or associated with acholic stools and
dark urine suggests biliary atresia. All such infants should have an immediate diagnostic
evaluation, including determination of direct bilirubin.
Inspissated Bile Syndrome.