Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn

Authors
Ronald J Wong, BA
Vinod K Bhutani, MD, FAAP
Section Editors
Steven A Abrams, MD
Elizabeth B Rand, MD
Deputy Editor
Melanie S Kim, MD
Disclosures: Ronald J Wong, BA Nothing to disclose. Vinod K Bhutani, MD, FAAP Nothing to disclose. Steven A
Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson (infant nutrition [specialized formulas for preterm
infants]). Elizabeth B Rand, MD Nothing to disclose. Melanie S Kim, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Apr 2014. | This topic last updated: Mar 04, 2014.
INTRODUCTION Almost all newborn infants develop a total serum or plasma bilirubin (TB) level
greater than 1 mg/dL (17 micromol/L), which is the upper limit of normal for adults. As the TB
increases, it produces neonatal jaundice, the yellowish discoloration of the skin and/or conjunctiva
caused by bilirubin deposition [1].
Hyperbilirubinemia in infants 35 weeks gestation is defined as a TB >95
th
percentile on the hour-
specific Bhutani nomogram [2]. Hyperbilirubinemia with a TB >25 to 30mg/dL (428 to
513 micromol/L) is associated with an increased risk for bilirubin-induced neurologic dysfunction
(BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. The
term "acute bilirubin encephalopathy" (ABE) is used to describe the acute manifestations of BIND.
The term "kernicterus" is used to describe the chronic and permanent sequelae of BIND.
Appropriate intervention is important to consider in every infant with severe hyperbilirubinemia.
However, even if these infants are adequately treated, long-term neurologic sequelae (kernicterus)
can sometimes develop.
The pathogenesis and etiology of neonatal unconjugated hyperbilirubinemia is reviewed here. The
clinical features, evaluation, and treatment of this disorder are discussed separately. (See "Clinical
manifestations of unconjugated hyperbilirubinemia in term and late preterm infants" and "Evaluation
of unconjugated hyperbilirubinemia in term and late preterm infants" and "Treatment of
unconjugated hyperbilirubinemia in term and late preterm infants".)
BILIRUBIN METABOLISM Knowledge of the basic steps in bilirubin metabolism is essential to
the understanding of the pathogenesis of neonatal hyperbilirubinemia. Bilirubin metabolism is briefly
reviewed here and is discussed in detail separately. (See "Bilirubin metabolism".)
Bilirubin production Bilirubin is a product of heme catabolism. Approximately 80 to 90 percent
of bilirubin is produced during the breakdown of hemoglobin from red blood cells or from ineffective
erythropoiesis. The remaining 10 to 20 percent is derived from the breakdown of other heme-
containing proteins, such as cytochromes and catalase.
Bilirubin is formed in two steps. The enzyme heme oxygenase (HO), located in the spleen and liver
as well as all nucleated cells, catalyzes the breakdown of heme, resulting in the formation of
equimolar quantities of carbon monoxide (CO) and biliverdin. Biliverdin then is converted to bilirubin
by the enzyme biliverdin reductase. Measurements of CO production, such as end-tidal CO (ETCO)
or carboxyhemoglobin (COHb), both corrected for ambient CO (ETCOc and COHbc, respectively),
can be used as indices of in vivo bilirubin production. (See "Evaluation of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'End-tidal carbon monoxide
concentration'.)
Bilirubin clearance and excretion Clearance and excretion of bilirubin occurs in the following
steps (figure 1):
Hepatic uptake Circulating bilirubin, which is bound to albumin, is transported to the liver.
Bilirubin dissociates from albumin and is taken up by hepatocytes, where it is processed for
excretion.
Conjugation In hepatocytes, uridine diphosphogluconurate glucuronosyltransferase
(UGT1A1) catalyzes the conjugation of bilirubin with glucuronic acid, producing bilirubin
diglucuronides and, to a lesser degree, bilirubin monoglucuronides. Conjugated bilirubin,
which is more water-soluble than unconjugated bilirubin, is excreted in bile.
Biliary excretion Conjugated bilirubin is secreted into the bile in an active process that
depends upon canalicular transporters, and then excreted into the digestive tract (figure 1).
Conjugated bilirubin cannot be reabsorbed by the intestinal epithelial cells. It is broken down in
the intestine by bacterial enzymes and, in the adult it is reduced to urobilin by bacterial
enzymes. But at birth the infant's gut is sterile and, subsequently, infants have far fewer
bacteria in the gut, so very little, if any, conjugated bilirubin is reduced to urobilin. Infants have
beta-glucuronidase in the intestinal mucosa, which deconjugates the conjugated bilirubin. The
unconjugated bilirubin can now be reabsorbed through the intestinal wall and recycled into the
circulation, a process known as the "enterohepatic circulation of bilirubin".
NEONATAL JAUNDICE Nonpathologic jaundice is caused by normal neonatal changes in
bilirubin metabolism resulting in increased bilirubin production, decreased bilirubin clearance, and
increased enterohepatic circulation.
In term newborn infants, bilirubin production is two to three times higher than in adults. This
occurs because newborns have more red blood cells (hematocrit between 50 to 60 percent)
and fetal red blood cells have a shorter life span (approximately 85 days) than those in adults.
The increased turnover of more red blood cells produces more bilirubin.
Bilirubin clearance is decreased in newborns, mainly due to the deficiency of the enzyme
uridine diphosphogluconurate glucuronosyltransferase (UGT1A1). UGT activity in term infants
at seven days of age is approximately 1 percent of that of the adult liver and does not reach
adult levels until 14 weeks of age [3,4].
There is an increase in the enterohepatic circulation of bilirubin, further increasing the
bilirubin load in the infant. (See 'Bilirubin clearance and excretion' above.)
These normal physiologic alterations generally result in the mild unconjugated (indirect-reacting)
bilirubinemia that occurs in nearly all newborns [1].
In Caucasian and African-American infants, the mean peak total serum or plasma bilirubin
(TB) occurs at 48 to 96 hours of age and is 7 to 9 mg/dL (120 to 154micromol/L). The
95
th
percentile ranges from 13 to 18 mg/dL (222 to 308 micromol/L) [5].
In some Asian infants, mean TB levels can reach 10 to 14 mg/dL (171 to
239 micromol/L) and can occur later, between 72 and 120 hours of age.
Primary neonatal jaundice resolves within the first one to two weeks after birth.
Peak TB is also later in infants born at 35 to 37 weeks gestational age. Physiologic jaundice
resolves within the first one to two weeks after birth, usually by the fifth day in Caucasian and
African-American infants, and by the 10
th
day in Asian infants.
Ethnic variation in conjugation ability Differences in TB levels among races may result from
specific genetic variations in conjugating ability [1]. As an example, polymorphisms in the UGT1A1
gene, due to differences in the number of thymine-adenine (TA) repeats in the promoter region of
the gene, vary among individuals of Asian, African, and Caucasian ancestry [6]. These
polymorphisms correlate with decreases in UGT1A1 enzyme activity resulting in increased TB
levels.
Another cause of racial variation in the development of neonatal jaundice results from a common
mutation in the UGT1A1 gene at Gly71Arg that occurs in Eastern Asians. This mutation leads to an
increased incidence of severe neonatal hyperbilirubinemia (approximately 20 percent) in Asians
[7,8]. The increased frequency of this polymorphism increases the risk of hyperbilirubinemia in
infants born to mothers who are Eastern Asian. (See "Clinical manifestations of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Risk factors'.)
HYPERBILIRUBINEMIA Hyperbilirubinemia (defined as a total serum or plasma bilirubin [TB]
>95
th
percentile on the hour-specific Bhutani nomogram [2]) can be caused by certain pathologic
conditions or by exaggeration of the mechanisms responsible for neonatal jaundice. Identification of
the cause of neonatal hyperbilirubinemia is useful in determining whether therapeutic interventions
can prevent severe hyperbilirubinemia. (See "Treatment of unconjugated hyperbilirubinemia in term
and late preterm infants".)
The following features suggest severe hyperbilirubinemia [9]:
Jaundice in the first 24 hours (usually caused by increased bilirubin production due to
hemolysis).
TB greater than the hour-specific 95
th
percentile (figure 2). The risk for severe
hyperbilirubinemia and the threshold for intervention based upon the hour-specific bilirubin
value may be determined using the newborn hyperbilirubinemia assessment calculator
(calculator 1). (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and
late preterm infants".)
Rate of TB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour.
Jaundice in a term newborn after two weeks of age.
Direct (conjugated) bilirubin concentration >1 mg/dL (17 micromol/L) if the total bilirubin is
<5 mg/dL (86 micromol/L), or more than 20 percent of the total bilirubin if the total bilirubin is
>5 mg/dL (86 micromol/L) [10]. An increase in direct (conjugated) bilirubin is suggestive of
cholestasis. (See "Approach to neonatal cholestasis".)
CAUSES OF HYPERBILIRUBINEMIA
Increased production The most common cause of pathologic indirect hyperbilirubinemia is
increased bilirubin production due to hemolytic disease processes that include the following [5-7,11-
15]:
Isoimmune-mediated hemolysis (eg, ABO or Rh(D) incompatibility). (See "Hemolytic disease
of the newborn: RBC alloantibodies in pregnancy and associated serologic issues" and "Red
cell transfusion in infants and children: Selection of blood products", section on 'Hemolytic
disease of the fetus and newborn'.)
Inherited red blood cell membrane defects (eg, hereditary spherocytosis and elliptocytosis).
(See "Hereditary spherocytosis: Clinical features, diagnosis, and treatment" and "Hereditary
elliptocytosis: Clinical features and diagnosis".)
Erythrocyte enzymatic defects (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency
[16], pyruvate kinase deficiency, and congenital erythropoietic porphyria). (See "Clinical
manifestations of glucose-6-phosphate dehydrogenase deficiency" and "Pyruvate kinase
deficiency" and "Congenital erythropoietic porphyria".)
Sepsis is a known cause of hemolysis. The mechanism is not known; however, one theory
suggests that increased oxidative stress due to sepsis damages neonatal red blood cells that
are susceptible to cell injury [5].
Other causes of increased bilirubin production due to increased red blood cell breakdown include
polycythemia or sequestration of blood within a closed space, which occurs in cephalohematoma.
Macrosomic infants of diabetic mothers (IDM) also have increased bilirubin production due to either
polycythemia or ineffective erythropoiesis. (See "Neonatal polycythemia" and "Infant of a diabetic
mother".)
Decreased clearance Inherited defects in the gene that encodes UGT1A1, which catalyzes the
conjugation of bilirubin with glucuronic acid, decrease bilirubin conjugation. This reduces hepatic
bilirubin clearance and increases total serum or plasma bilirubin (TB) levels [17]. These disorders
include Crigler-Najjar syndrome types I and II and Gilbert syndrome, which are briefly summarized
below and discussed in detail separately. (See "Crigler-Najjar syndrome" and "Gilbert syndrome
and unconjugated hyperbilirubinemia due to bilirubin overproduction".)
Crigler-Najjar syndrome There are two variants of Crigler-Najjar syndrome. (See "Crigler-Najjar
syndrome".)
Crigler-Najjar syndrome type I (CN-I) Crigler-Najjar syndrome type I (CN-I) is the most
severe form of inherited UGT1A1 disorders. UGT activity is essentially absent, and severe
hyperbilirubinemia develops in the first two to three days after birth. Lifelong phototherapy is
required to avoid bilirubin-induced neurologic dysfunction (BIND) unless liver transplantation is
performed. The mode of inheritance is autosomal recessive.
Crigler-Najjar syndrome type II Crigler-Najjar syndrome type II (CN-II) is less severe than is
CN-I. UGT activity in this disorder is low, but detectable. Although some affected children
develop severe jaundice, the hyperbilirubinemia often responds to phenobarbital treatment.
CN-II usually is inherited in an autosomal recessive manner, although autosomal dominant
transmission occurs in some cases.
Gilbert syndrome Gilbert syndrome is the most common inherited disorder of bilirubin
glucuronidation. It results from a mutation in the promoter region of the UGT1A1 gene [18]. The
mutation causes a reduced production of UGT, leading to unconjugated hyperbilirubinemia. Breast
milk jaundice during the second week after birth may be due to the concurrent neonatal
manifestation of Gilbert syndrome.
In the United States, 9 percent of the population is homozygous and 42 percent heterozygous for
the Gilbert mutation [19]. Newborns who are homozygous for the gene mutation have a higher
incidence of jaundice during the first two days after birth than normal infants or those who are
heterozygous [20]. Similar findings have been noted in other parts of the world, especially in Asian
countries [8,21].
The Gilbert genotype is particularly clinically apparent when affected newborns have increased
bilirubin production or enhanced enterohepatic circulation. As an example, in one study, infants with
the normal Gilbert genotype did not produce an increase in the incidence of hyperbilirubinemia; 9.7
percent of the deficient infants and 9.9 percent of the G6PD-sufficient normal infants had a TB
15 mg/dL (257 micromol/L) [22]. However, hyperbilirubinemia was more frequent in G6PD-
deficient infants who were homozygous or heterozygous for the Gilbert mutation (50 and 32
percent, respectively). In another study of male infants with G6PD deficiency, mean TB was highest
in patients who were homozygotes (11.1 mg/dL [190 micromol/L]), followed by heterozygotes for the
Gilbert mutation (9.1 mg/dL [156 micromol/L]), and those without the mutation
(8.8 mg/dL [150 micromol/L]) [23].
The combination of a usually benign polymorphism of Gilbert genotype coupled with another factor
that increases TB may be the underlying cause of some of the rare cases of infants with extremely
high TB levels (>25 mg/dL [428 micromol/L]) [24]. (See "Gilbert syndrome and unconjugated
hyperbilirubinemia due to bilirubin overproduction".)
OATP-2 polymorphism In addition to the polymorphisms of the UGT gene discussed above, a
study of Taiwanese newborns reported that those with a polymorphic variant of the organic anion
transporter protein OATP-2 (also known as OATP-C or solute carrier organic anion transporter 1B1
[SLCO1B1]) were more likely to develop severe hyperbilirubinemia [25]. Furthermore, the
combination of the OATP-2 polymorphism with a UGT1A1 gene mutation increased this risk.
Other causes Other causes of decreased bilirubin clearance include maternal diabetes [26],
congenital hypothyroidism, and galactosemia, although in the latter case, infants typically present
with elevated conjugated hyperbilirubinemia. These conditions usually are identified by metabolic
screening programs; however, infants may develop severe and prolonged jaundice before
screening results become available. (See "Clinical features and detection of congenital
hypothyroidism" and "Galactosemia: Clinical features and diagnosis".)
Increased enterohepatic circulation The major causes of increased enterohepatic circulation
of bilirubin are breastfeeding failure jaundice, breast milk jaundice, or impaired intestinal motility
caused by functional or anatomic obstruction.
Breast milk jaundice Breast milk jaundice is defined as the persistence of physiologic jaundice
beyond the first week of age. It typically begins after the first three to five days of life, peaks within
two weeks after birth, and progressively declines to normal levels over 3 to 12 weeks [27]. Breast
milk jaundice, a benign condition, needs to be distinguished from breastfeeding failure jaundice that
occurs within the first seven days of life, which is caused by decreased intake resulting in excessive
weight and fluid loss. (See 'Breastfeeding failure jaundice' below.)
In breast milk jaundice, infants commonly have TB levels >5 mg/dL (86 micromol/L) for several
weeks after delivery. Although the hyperbilirubinemia is generally mild and does not require
intervention, it should be monitored to ensure that it remains unconjugated and does not increase. If
TB levels begin to increase or there is a significant component of conjugated bilirubin, evaluation for
other causes of hyperbilirubinemia should be performed including neonatal cholestasis. If after
evaluation, the clinical diagnosis of breast milk jaundice is made, breast feeding can continue with
the expectation of resolution by 12 weeks of age [28]. (See "Evaluation of unconjugated
hyperbilirubinemia in term and late preterm infants" and "Causes of neonatal
cholestasis" and "Approach to neonatal cholestasis".)
Breast milk jaundice appears to be caused by a factor, which has not yet been identified, in human
milk that promotes an increase in intestinal absorption of bilirubin. Beta-glucuronidase is one
proposed substance as it deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie,
increasing enterohepatic circulation) [29]. Approximately 20 to 40 percent of women have high
levels of beta-glucuronidase in their breast milk. Blocking the deconjugation of bilirubin through
beta-glucuronidase inhibition may provide a mechanism to reduce intestinal absorption of bilirubin
in breastfed infants [30]. Although some studies have found elevated fecal levels of beta-
glucuronidase in breastfed infants with hyperbilirubinemia, this has not been a consistent finding.
Beta-glucuronidase inhibitors such as enzymatically-hydrolyzed casein or L-aspartic acid have been
used prophylactically in breastfed newborns [30]. However, further studies are needed to determine
whether these agents are effective and safe in promoting increased fecal bilirubin excretion, thereby
resulting in lower TB. We do not currently recommend these agents for breast milk jaundice.
Intestinal obstruction Ileus or anatomic causes of intestinal obstruction increase the
enterohepatic circulation of bilirubin and result in jaundice. TB levels are frequently higher with small
bowel than with large bowel obstruction. As an example, jaundice occurs in 10 to 25 percent of
infants with pyloric stenosis when vomiting begins.
Breastfeeding failure jaundice Breastfeeding compared with formula feeding is associated with
an increased risk of jaundice and kernicterus.
In a review of cases from the Pilot Kernicterus Registry, 59 of 61 infants with kernicterus
were breastfed. Of the two infants who were formula-fed, both were found to have G6PD
deficiency [31].
In one report, infants who were breastfed compared with bottle-fed infants at day three of life
were more likely to have TB concentrations >13 mg/dL (222 micromol/L),(8.9 versus 2.2
percent) [32].
In another report, infants fed human milk compared with those fed formula had higher TB on
day three of life and lower volumes of stool and urine output during the first week of life [33].
The primary mechanism for the increased likelihood of kernicterus and jaundice with breast versus
formula feeding is the failure to successfully initiate breastfeeding rather than a direct effect of
breast milk itself, as is seen in breast milk jaundice. A population-based study demonstrated that TB
was only marginally higher in successfully breastfed compared with formula-fed infants [2].
Breastfeeding failure jaundice typically occurs within the first week of life, as lactation failure leads
to inadequate intake with significant weight and fluid loss resulting in hypovolemia. This causes
hyperbilirubinemia (jaundice) and in some cases, hypernatremia defined as a serum sodium
>150 mEq/L. Decreased intake also causes slower bilirubin elimination and increased enterohepatic
circulation that contribute to elevated TB. (See "Initiation of breastfeeding", section on 'Weight
loss'.)
A root cause analysis identified the following as predictors of lactation failure in infants with
kernicterus [34]. (See "Initiation of breastfeeding".)
Inadequate education from clinicians and lactation consultants
Inadequate documentation of infant latching
Inadequate measurement of milk transfer
Inadequate recording of urine output and stool pattern changes
In addition, maternal breastfeeding complications, such as engorgement, cracked nipples, and
fatigue, and neonatal factors, such as ineffective suck, may not be properly addressed prior to
hospital discharge and result in ineffective breastfeeding. (See "Common problems of breastfeeding
and weaning".)
Although late preterm infants (defined as gestational age between 34 weeks, and 36 weeks and 6
days) are usually able to breastfeed, they are more likely to experience difficulty in establishing
successful breastfeeding than term infants. Late preterm infants may not fully empty the breast
because of increased sleepiness, fatigue, and/ordifficulty maintaining a latch because their oro-
buccal coordination and swallowing mechanisms are not fully matured. (See "Breastfeeding the
preterm infant", section on 'Late preterm infants'.)
Prevention Initiation of successful breastfeeding, one of the mainstays of preventing
hyperbilirubinemia, has become an increasing problem due to shortened postpartum length of stay
for newborn infants and their mothers. Postnatal education, support, and care should be provided to
the infant-mother dyad during the birth hospitalization and after discharge. The overall approach is
briefly summarized here and is discussed in greater detail separately. (See "Breastfeeding: Parental
education and support" and "Initiation of breastfeeding".)
During the first postpartum week while breastfeeding is being established, mothers should
nurse whenever the infant shows signs of hunger or when four hours have elapsed since the
last feeding. This will usually result in 8 to 12 feedings in 24 hours, which is usually sufficient
to prevent significant hyperbilirubinemia that requires intervention [35].
During the birth hospitalization, monitoring and assessment of breastfeeding are crucial.
Problems identified in the hospital should be addressed at that time, and a documented plan
for management after discharge should be communicated to both the parents and primary
care provider.
At discharge, a primary care appointment should be scheduled so that the infant-mother
dyad is evaluated 24 to 48 hours after discharge, and post-discharge lactation resources
provided.
At the follow-up appointment, supplementation with banked human milk or commercial infant
formula is recommended when the infant has lost more than 7 percent ofhis/her birth weight or
exhibits signs of dehydration (eg, decreased urine output), stool output is less than three small
stools a day, and mother's milk supply remains limited. Glucose water or sterile water feedings
should not be used, as they do not provide adequate nutrition.
Severe hyperbilirubinemia Although genetic factors may contribute to an increase in TB,
clinical factors are the major contributors to the pathogenesis of severe hyperbilirubinemia defined
as a TB >95
th
percentile. This was illustrated in a case-control study of term infants that compared
genetic and clinical factors between infants with TB levels >95
th
percentile and those with TB levels
<40
th
percentile [15]. There were no differences in the frequency of G6PD, UGT1A1, and SCLO1B1
(liver transport protein) genetic variants between the two groups. Among the group with severe
hyperbilirubinemia, the most common cause of an elevated TB was hemolysis due to ABO
incompatibility (31 percent) followed by breastfeeding failure (22 percent), although no cause was
identified in 39 percent of the cases.
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SUMMARY
Total serum or plasma bilirubin (TB) levels >1 mg/dL (17 micromol/L) occur in almost all term
and near-term newborn infants. Infants with severe hyperbilirubinemia (TB >25 to
30 mg/dL [428 to 513 micromol/L]) are at risk for bilirubin-induced neurologic dysfunction
(BIND), presenting acutely as acute bilirubin encephalopathy (ABE) and, if inadequately
treated, long-term neurologic sequelae or kernicterus.
Neonatal jaundice is primarily caused by normal neonatal alterations in bilirubin metabolism
including increased bilirubin production, decreased bilirubin clearance, and increased
enterohepatic circulation. These alterations generally result in mild unconjugated (indirect-
reacting) hyperbilirubinemia with peak TB of 7 to 9 mg/dL (120 to 154 micromol/L) in
Caucasian and African-American infants and higher values in Asian infants, 10 to
14 mg/L (171 to 239 micromol/L). (See 'Neonatal jaundice' above.)
Hyperbilirubinemia is caused by exaggeration of mechanisms that cause neonatal jaundice
or by pathologic conditions that increase bilirubin production, decrease bilirubin clearance, or
increase the enterohepatic circulation. Identification of the cause of neonatal
hyperbilirubinemia is useful in determining whether therapeutic interventions can prevent
severe hyperbilirubinemia. (See 'Hyperbilirubinemia' above and "Treatment of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Prevention of
hyperbilirubinemia'.)
The following clinical findings are predictors for hyperbilirubinemia:
Jaundice in the first 24 hours of life.
TB greater than the hour-specific 95
th
percentile (figure 2).
Conjugated bilirubin concentration >1 mg/dL (17 micromol/L) if the total bilirubin is
<5 mg/dL (86 micromol/L), or more than 20 percent of the total bilirubin if the total
bilirubin is >5 mg/dL (86 micromol/L). Conjugated bilirubinemia suggests neonatal
cholestasis. (See "Approach to neonatal cholestasis".)
Rate of TB rise greater than 0.2 mg/dL (3.4 micromol/L) per hour.
Jaundice in a term newborn after two weeks of age.
Causes of hyperbilirubinemia can be classified by pathogenesis as follows:
Increased production Hemolytic disease, polycythemia, and sequestration of blood
within a closed space increase bilirubin production because of increased red cell
breakdown. (See 'Increased production' above.)
Decreased clearance Inherited defects in uridine diphosphogluconurate
glucuronosyltransferase (UGT1A1), such as Crigler-Najjar syndrome types I and II and
Gilbert's syndrome. In addition, metabolic disorders, such as congenital hypothyroidism,
galactosemia, and infants of diabetic mothers, can decrease bilirubin clearance.
(See 'Decreased clearance' above.)
Increased enterohepatic circulation of bilirubin.
Breast milk jaundice, and impaired intestinal motility caused by functional or anatomic
obstruction increase enterohepatic circulation of bilirubin. (See 'Increased enterohepatic
circulation' above and 'Breastfeeding failure jaundice' above.)

Treatment of unconjugated hyperbilirubinemia in term and late preterm infants
Authors
Ronald J Wong, BA
Vinod K Bhutani, MD, FAAP
Section Editor
Steven A Abrams, MD
Deputy Editor
Melanie S Kim, MD
Disclosures: Ronald J Wong, BA Nothing to disclose. Vinod K Bhutani, MD, FAAP Nothing to disclose. Steven A
Abrams, MD Grant/Research/Clinical Trial Support: Mead-Johnson (infant nutrition [specialized formulas for preterm
infants]). Melanie S Kim, MD Employee of UpToDate, Inc.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed
by vetting through a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.
Conflict of interest policy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2014. | This topic last updated: Sep 04, 2013.
INTRODUCTION Almost all newborn infants develop a total serum or plasma bilirubin (TB) value
greater than 1 mg/dL (17.1 micromol/L), which is the upper limit of normal for adults. As TB
increases, it causes neonatal jaundice, the yellowish discoloration of the skin and/or sclerae caused
by bilirubin deposition in half of all newborn infants [1].
Hyperbilirubinemia in infants 35 weeks gestational age (GA) is defined as TB >95th percentile on
the hour-specific Bhutani nomogram [2]. Hyperbilirubinemia with a TB >25 to 32 mg/dL (428 to
547 micromol/L) is associated with an increased risk for bilirubin-induced neurologic dysfunction
(BIND), which occurs when bilirubin crosses the blood-brain barrier and binds to brain tissue. The
term "acute bilirubin encephalopathy" (ABE) is used to describe the acute manifestations of BIND.
The term "kernicterus" is used to describe the chronic and permanent sequelae of BIND.
Appropriate intervention is important to consider in every infant with severe hyperbilirubinemia.
However, even if these infants are adequately treated, long-term neurologic sequelae (kernicterus)
can sometimes develop.
The treatment of neonatal unconjugated hyperbilirubinemia is reviewed here. The clinical
manifestations, evaluation, pathogenesis, and etiology of this disorder are discussed separately.
(See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm
infants" and "Evaluation of unconjugated hyperbilirubinemia in term and late preterm
infants" and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".)
OVERVIEW Two advances in medical care had a significant impact on the need for treatment
and the way in which hyperbilirubinemia is managed. The administration of Rh (D) immunoglobulin
to Rh-negative mothers in the late 1960s decreased dramatically the incidence of neonatal Rh
isoimmune hemolytic disease. At about the same time, the introduction of phototherapy in the
United States reduced significantly the need for exchange transfusions and the risk of severe
hyperbilirubinemia. Thus, the risk of kernicterus was significantly reduced from its peak incidence in
the 1950s to the 1970s. Nevertheless, isolated cases of kernicterus, a preventable condition,
continue to be reported. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late
preterm infants", section on 'Overview'.)
Limited data based upon case reports suggest that kernicterus occurs in term or late preterm infants
with hyperbilirubinemia, defined as total serum or plasma bilirubin (TB) >95th percentile on the
hour-specific Bhutani nomogram [2]. In order to prevent future cases of kernicterus, the
management of unconjugated hyperbilirubinemia focuses on two key elements:
Prevention of hyperbilirubinemia by identifying at-risk infants and initiation of preventive
therapeutic interventions (eg, phototherapy) as needed
Reduction of TB in infants with severe hyperbilirubinemia
Prevention of hyperbilirubinemia Universal screening of all term and late preterm infants
identifies at-risk infants for hyperbilirubinemia. In these patients, phototherapy is initiated to prevent
hyperbilirubinemia when TB exceeds a threshold level based upon a nomogram of TB levels
adjusted by the infant's age-in-hours [3] and the presence or absence of additional risk factors [2,3].
(See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants" and 'Phototherapy
indications' below.)
Treatment of severe hyperbilirubinemia Therapeutic interventions for infants with
hyperbilirubinemia include:
Phototherapy
Exchange transfusion
Improving the frequency and efficacy of breastfeeding or supplementing inadequate
breastfeeding with formula
PHOTOTHERAPY Phototherapy is the most commonly used intervention to treat and prevent
severe hyperbilirubinemia. In term and large preterm infants, phototherapy is safe based upon its
extensive use in millions of infants over 30 years and only rare reports of significant toxicity [2].
(See 'Adverse effects' below.)
Phototherapy reduces the risk that total bilirubin (TB) concentration will reach the level at which
exchange transfusion is recommended [4,5]. It decreases or blunts the rise of TB in almost all cases
of hyperbilirubinemia regardless of the patient's ethnicity or the etiology of hyperbilirubinemia. It is
estimated that 5 to 10 infants with TB between 15 and 20 mg/dL (257 to 342 micromol/L) must
receive phototherapy to prevent one patient from developing a TB >20 mg/dL (342 micromol/L) [2].
(See 'Efficacy' below and'Exchange transfusion' below.)
Mechanisms Phototherapy exposes the infant's skin to light of a specific wavelength, which
reduces TB by the following three mechanisms:
Structural isomerization to lumirubin Phototherapy converts bilirubin into lumirubin via
structural isomerization that is not reversible [6]. Lumirubin, a more soluble substance than
bilirubin, is excreted without conjugation into bile and urine. This is the principal mechanism
by which phototherapy reduces TB concentration.
Photoisomerization to a less toxic bilirubin isomer Phototherapy converts the stable
4Z,15Z bilirubin isomer to the 4Z,15E isomer, which is more polar and less toxic than the
4Z,15Z form. Like lumirubin, 4Z,15E isomer is excreted into bile without conjugation. Unlike
structural isomerization to lumirubin, photoisomerization is reversible; however, clearance
of the 4Z,15E isomer is very slow and the photoisomerization is reversible. Thus, some of
the 4Z,15E isomer in bile is converted back to the stable 4Z,15Z isomer. As a result, this
pathway may have little effect on TB values. In addition, standard laboratory measurements
do not distinguish among the isomers, so these measurements do not reflect these
changes. Nevertheless, photoisomerization does reduce the amount of potentially toxic
bilirubin by rapidly converting 15 percent of it to a non-toxic form.
Photo-oxidation to polar molecules Photo-oxidation reactions convert bilirubin to
colorless, polar compounds that are excreted primarily in the urine. This is a slow process
and accounts for a small proportion of bilirubin elimination.
Technique The dose of phototherapy, known as irradiance (measured
in microW/cm
2
/nm), determines its efficacy. Irradiance depends upon the type of the light used,
distance between the light and infant (except with light emitting diodes), and the exposed surface
area of the infant. Irradiance usually is expressed for a certain wavelength band (spectral
irradiance) [7]. In conventional phototherapy, the irradiance dosing is typically 6 to
12 microW/cm
2
of body surface area exposed per nm of wavelength (425 to 475 nm) and with
intensive phototherapy it is 30 microW/cm
2
/nm.
For TB levels 20 mg/dL (342 micromol/L), phototherapy should be administered continuously, until
the TB falls below 20 mg/dL (342 micromol/L). Once this occurs, phototherapy can be interrupted
for feeding and parental visits.
During phototherapy, the area covered by the diaper should be minimized. The eyes should be
shielded with an opaque blindfold and care should be taken to prevent the blindfold from covering
the nose. With fluorescent lights, the infant should be placed in an open crib, bassinet, or on a
warmer, rather than in an incubator (the top of the incubator prevents the light from being brought
sufficiently close to the infant). Lining the sides of the bassinet or warmer with aluminum foil or white
material increases the exposed surface area of the infant and the efficiency of phototherapy [8,9].
The use of reflective white curtains around the phototherapy light source has also been shown to
increase phototherapy efficiency [10].
Light sources and devices Bilirubin absorbs light most strongly in the blue region of the
spectrum near 460 nm. Several light sources, utilizing different wavelengths of light and varying
degrees of irradiance, and devices are available for phototherapy.
Fluorescent blue light Fluorescent special blue light, F20 T12/BB and TL52 tubes (Philips,
The Netherlands), should be used. They are the most effective light source in lowering TB
because they deliver light in the blue-green spectrum, which penetrates the skin well and is
absorbed maximally. Fluorescent special blue light should not be confused with regular blue
light or blue light-emitting diodes (LEDs).
Halogen white light Halogen white lamps are hot and can cause thermal injury. They
should be placed at the distance from the patient recommended by the manufacturer.
Fiberoptic blankets or pads Fiberoptic blankets or pads generate little heat and can be
placed close to the infant, providing higher irradiance than do fluorescent lights [11].
However, blankets are small and rarely cover sufficient surface area to be effective when
used alone in term infants. They can be used as an adjunct to overhead fluorescent or
halogen lights. Fiberoptic blankets also can be used during feedings when overhead
fluorescent or halogen lights are discontinued. This is particularly helpful for infants with
severe hyperbilirubinemia.
Blue LEDs LEDs use high-intensity blue gallium nitride and are commercially available as
both overhead and underneath devices [7,12,13]. These devices, which deliver high
intensity narrow band light in the absorption spectrum of bilirubin, are as effective as
conventional fluorescent blue light [14,15]. The mattress LED device is preferable to the
fiberoptic pad because it is large enough to cover the entire surface (in contact with the
mattress) of a term infant.
For effective (intensive) phototherapy, high levels of irradiance (usually 30 microW/cm
2
/nm) are
delivered to as much of an infant's surface area as possible [2]. The necessary irradiance can be
achieved using a phototherapy light placed at a distance of 10 to 30 cm from the infant's body
depending on the manufacturers recommendation in combination with a fiberoptic pad, LED
mattress, or special blue lights below the infant [16]. LEDs at the distance dictated by the device
also provide an irradiance of 30 microW/cm
2
/nm.
Although there are no trials comparing the efficacy of phototherapy devices in term and late preterm
infants, a trial in extremely low birth weight preterm infants (birth weight 1000 g) found that the
absolute and relative decrease of TB during the first 24 hours of life was greatest for LEDs, followed
by spotlights, bank of lights, and blankets [17]. (See "Hyperbilirubinemia in the premature infant (less
than 35 weeks gestation)", section on 'Light source and devices'.)
Home phototherapy As an alternative to readmission to the hospital, phototherapy can be
administered to term infants at home. Home phototherapy is less disruptive to the family and can be
considered for otherwise healthy term infants (>38 weeks gestational age [GA]) without hemolysis
or other risk factors who have TB levels 2 to 3 mg/dL (34 to 51 micromol/L) below the
recommended threshold level for initiation of hospital phototherapy, are feeding well, and can be
closely followed [2]. (See'Phototherapy indications' below.)
Sunlight exposure Although exposure to sunlight provides sufficient irradiance in the 425 to 475
nm band and is known to lower the TB [18], exposure to sunlight is not recommended to prevent
severe hyperbilirubinemia [2]. The difficulties of avoiding sunburn while exposing a naked infant to
sunlight preclude the use of sunlight exposure as a reliable therapeutic option.
Selection of light source Although there is a wide selection of commercially available
phototherapy devices, there are no standardized methods of reporting and measuring phototherapy
devices. (See 'Light sources and devices' above.)
In order to help guide clinicians and hospitals to provide the most effective phototherapy, a
technical report from the American Academy of Pediatrics (AAP) summarized the key features to
consider in the selection of a device to treat neonatal hyperbilirubinemia [16]. After review of the
available literature, the report concluded that the most effective devices displayed the following
characteristics:
Emission of light in the blue-to-green range (460 to 490 nm). Lights with broader emission
also will work, but not as effectively.
Irradiance of at least 30 microW/cm
2
/nm (confirmed by an appropriate irradiance meter
calibrated over the appropriate wavelength range).
Ability to illuminate maximal body surface. Blocking the light source or reducing the
exposed body surface area should be avoided.
Demonstration of a decrease in TB during the first four to six hours of exposure.
Phototherapy indications The following discussion on the indications for phototherapy for term
and late preterm infants (35 weeks GA) is based upon the practice guideline developed by the
AAP [2]. Similar guidelines for term infants based on TB and postnatal age have been developed by
the United Kingdoms National Institute for Health and Clinical Excellence (NICE guideline for
Neonatal Jaundice). National guidelines have also been developed in Norway, which are based on TB
values, birth weight (BW), and postnatal age [19].
Initiation of phototherapy is based upon hour-specific TB values [3], GA, and the presence or
absence of risk factors that include isoimmune hemolytic disease, glucose-6-phosphate
dehydrogenase (G6PD) deficiency, asphyxia, lethargy, temperature instability, sepsis, acidosis, or
albumin <3 g/dL (if measured) (figure 1). These are conditions that increase the risk of brain
damage because of their negative effects on albumin binding of bilirubin, the blood-brain barrier,
and the susceptibility of the brain cells to damage by bilirubin. (See "Evaluation of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Risk assessment' and "Evaluation of
unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Bilirubin/albumin ratio'.)
The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-
specific bilirubin value may be determined using the newborn hyperbilirubinemia assessment
calculator (calculator 1). In general, the guidelines for phototherapy are as follows:
For infants at low risk (38 weeks GA and without risk factors), phototherapy is started at
the following TB values.
24 hours of age: >12 mg/dL (205 micromol/L)
48 hours of age: >15 mg/dL (257 micromol/L)
72 hours of age: >18 mg/dL (308 micromol/L)

Infants in this category who have TB levels 2 to 3 mg/dL (34 to 51 micromol/L) below
the recommended levels may be treated with fiberoptic or conventional phototherapy at
home.
For infants at medium risk (38 weeks GA with risk factors or 35 to 37 6/7 weeks gestation
without risk factors), phototherapy is started at the following TB values.
24 hours of age: >10 mg/dL (171 micromol/L)
48 hours of age: >13 mg/dL (222 micromol/L)
72 hours of age: >15 mg/dL (257 micromol/L)

The threshold for intervention may be lowered for infants closer to 35 weeks GA and
raised for those closer to 37 6/7 weeks GA.
For infants at high risk (35 to 37 6/7 weeks GA with risk factors), phototherapy is initiated at
the following TB values.
24 hours of age: >8 mg/dL (137 micromol/L)
48 hours of age: >11 mg/dL (188 micromol/L)
72 hours of age: >13.5 mg/dL (231 micromol/L)
Special circumstances Infants with clinical jaundice within the first 24 hours frequently have
hemolysis. They require immediate evaluation and close surveillance to assess the need for
phototherapy.
In infants with other causes of increased bilirubin production, such as cephalohematoma or
extensive bruising, or in infants suspected of having genetic disorder of bilirubin conjugation (eg,
Crigler-Najjar or Gilbert's syndromes), we start phototherapy when the hour-specific TB
concentration is in the high intermediate risk zone (>75th percentile) (figure 2). The risk for severe
hyperbilirubinemia and the threshold for intervention based upon the hour-specific TB value may be
determined using the newborn hyperbilirubinemia assessment calculator (calculator 1).
(See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".)
Efficacy of phototherapy Although there are no data showing that phototherapy improves
neurodevelopmental outcome, phototherapy does reduce the likelihood that TB reaches a level
associated with an increased risk of kernicterus or at which exchange transfusion is recommended
[20,21]. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and late preterm infants",
section on 'Overview'.)
Intensive phototherapy results in a decline of TB of at least 2 to 3 mg/dL (34 to
51 micromol/L) within four to six hours. A decrease in TB can be measured as soon as two hours
after initiation of treatment. In infants 35 weeks GA, 24 hours of intensive phototherapy can result
in a 30 to 40 percent decrease in the initial TB [22]. With conventional phototherapy, a decline of 6
to 20 percent can be expected in the first 18 to 24 hours [11,23,24].
The efficacy of phototherapy in preventing a rise in TB to the exchange transfusion threshold was
demonstrated in a large retrospective cohort study of 281,898 infants born 35 weeks GA [25].
Overall, 23 percent of patients received phototherapy within eight hours after reaching a TB within
3 mg/dL (51 micromol/L) of the AAP phototherapy threshold (figure 1). Only 1.6 percent (354
infants) ever exceeded the AAP exchange threshold (figure 3) and only three received exchange
transfusions. Multivariate analysis demonstrated that lower GA and birth weight, younger age at the
time TB level reached the phototherapy threshold, and a positive direct antiglobulin test (DAT) were
associated with an increased risk in reaching the AAP exchange transfusion threshold. Based upon
these results, phototherapy was found to be highly effective in preventing TB from rising to the AAP
exchange transfusion threshold, especially in full-term infants who are appropriate size for GA, older
than 48 hours at the time TB level reached the phototherapy threshold, and are not DAT positive.
The rate of decline of TB during phototherapy is affected by a number of factors [2].
Increased irradiance increases the rate of TB decline
Greater surface area exposure to phototherapy increases the rate of TB reduction
The higher the initial TB, the more rapid is the rate of decline (as much as
10 mg/dL [171 micromol/L] within a few hours)
Phototherapy is less effective in infants whose hyperbilirubinemia is due to cholestasis or
hemolysis with a DAT than in infants with other causes
Monitoring During phototherapy, the dose of phototherapy (irradiance) and the infant's
temperature, hydration status, time of exposure, and TB are monitored. Phototherapy may increase
both the body and environmental temperature resulting in increased insensible fluid loss. LED-
based devices emit low levels of heat, and thus fluid loss is less of a concern with these devices [8].
(See 'Hydration' below.)
The frequency of TB measurements depends upon the initial TB value. When infants are
discharged and readmitted with TB values exceeding the 95th percentile for hour-specific TB levels
[3] (figure 2), the TB measurement should be repeated two to three hours after initiation of
phototherapy to assess the response. When phototherapy is started for a rising TB, TB should be
measured after 4 to 6 hours and then within 8 to 12 hours, if TB continues to fall.
If, despite intensive phototherapy, the TB is at or approaches the threshold for exchange
transfusion, blood should be sent for immediate type and cross-match. In addition, if exchange
transfusion is being considered, the serum albumin level should be measured so that the
serum bilirubin/albumin (B/A) ratio can be used in conjunction with the TB level and other factors to
determine the need for exchange transfusion. (See 'Exchange transfusion' below.)
Hydration It is important to maintain adequate hydration and urine output during phototherapy
since urinary excretion of lumirubin is the principal mechanism by which phototherapy reduces TB.
Thus, during phototherapy, infants should continue oral feedings by breast or bottle. For TB levels
that approach the exchange transfusion level, phototherapy should be continuous until the TB has
declined to about 20 mg/dL (342 micromol/L). Thereafter phototherapy can be interrupted for
feeding. (See 'Technique'above.)
Intravenous hydration may be necessary to correct hypovolemia in infants with significant volume
depletion whose oral intake is inadequate; otherwise, intravenous fluid is not recommended [2].
Breastfeeding Breastfed infants whose intake is inadequate, with excessive weight loss (>12
percent of BW), or who have evidence of hypovolemia, should receive supplementation with
expressed breast milk or formula [2]. The temporary interruption of breastfeeding with the
substitution of formula may enhance the efficacy of phototherapy by decreasing the enterohepatic
circulation of bilirubin [4,26,27]. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the
newborn", section on 'Breastfeeding failure jaundice' and "Evaluation of unconjugated hyperbilirubinemia in
term and late preterm infants", section on 'Breastfed infants'.)
If breastfeeding is interrupted, it should be resumed as soon as possible. (See "Infant benefits of
breastfeeding".)
Discontinuation For infants who have been readmitted for phototherapy, we discontinue the
phototherapy when the TB has reached 12 to 14 mg/dL (205 to 239micromol/L). For those who
required phototherapy during the birth hospitalization, phototherapy is started at a significantly lower
level and, therefore, is stopped at a lower level. For these infants, we generally discontinue
phototherapy when the TB has fallen to, or below, the level at which phototherapy was initiated
because, by this time, the infant is significantly older and the level for initiation of phototherapy has,
consequently, increased.
TB is measured 18 to 24 hours after phototherapy is terminated. This is important in infants who
need phototherapy during their birth hospitalization, but might not be necessary in those who have
been readmitted where the risk of rebound is much lower. The readmitted infant should not be kept
in the hospital pending measurement of rebound. If necessary, this can be done as an outpatient.
Although the value following discontinuation is known as the rebound bilirubin, typically it is lower
than the TB value before the initiation of phototherapy.
In one study of 161 infants with BW >1800 g, TB was significantly lower 17 hours after termination
of phototherapy compared with TB at the time of termination (11.5 versus 12.2 mg/dL [197 versus
209 micromol/L]) [28].
However, in another study of 226 infants, which included 110 neonates with a positive DAT
(Coombs test), 13 percent had rebound TB levels >15 mg/dL (257 micromol/L)[29]. Risk factors for
significant rebound (TB levels >15 mg/dL [257 micromol/L]) were initial phototherapy beginning <72
hours of age (odds ratio [OR] 3.61, 95% CI 1.21-10.77), GA <37 weeks (OR 3.21, 95% CI 1.29-
7.96), and a positive DAT test (OR 2.44, 95% CI 1.25-4.74).
Adverse effects Phototherapy is considered safe. Side effects include transient erythematous
rashes, loose stools, and hyperthermia. Increased insensible water loss may lead to dehydration.
Phototherapy is not associated with an increase in nevus count [30]. (See 'Hydration' above.)
The "bronze baby syndrome" is an uncommon complication of phototherapy that occurs in some
infants with cholestatic jaundice. It is manifested by a dark, grayish-brown discoloration of the skin,
serum, and urine [31]. Although the etiology of the bronze appearance remains unknown, it is
proposed that the color is a result of impaired biliary excretion of bile pigment photoproducts due to
cholestasis [31,32]. The condition gradually resolves without sequelae within several weeks after
discontinuation of phototherapy [33]. It remains controversial whether the bronze pigments have
potential neurotoxic consequences.
Although the effect of phototherapy on the eyes of infants is not known, animal studies indicate that
retinal degeneration may occur after 24 hours of continuous exposure [34]. As a result, it is essential
that the eyes of all neonates treated with phototherapy are sufficiently covered to eliminate any
potential eye exposure.
Limited data on long-term effects are conflicting, with some studies suggesting that blue light
phototherapy (using broadband light emitting light in the UV region) increases the risk of
melanocytic nevi in children and adolescents [35]. (See "Acquired melanocytic nevi (moles)".)
EXCHANGE TRANSFUSION Exchange transfusion is used to remove bilirubin from the
circulation when intensive phototherapy fails or in infants with signs of bilirubin-induced neurologic
dysfunction (BIND). The term ABE, or "acute bilirubin encephalopathy," is used to describe the
acute manifestations of overt BIND. The term "kernicterus" is used to describe the chronic and
permanent sequelae of overt BIND and differentiate these from the subtle signs observed in the
syndrome of BIND [36]. Exchange transfusion is especially useful for infants with increased bilirubin
production resulting from isoimmune hemolysis because circulating antibodies and sensitized red
blood cells also are removed.
Although exchange transfusion is both expensive and time consuming, it is the most effective
method for removing bilirubin rapidly. Exchange transfusion is indicated when intensive
phototherapy cannot prevent a continued rise in the total bilirubin (TB) or in infants who already
display signs indicative of BIND. Exchange transfusions should be performed only by trained
personnel in a neonatal or pediatric intensive care unit equipped with full monitoring and
resuscitation capabilities [2]. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term
and late preterm infants", section on 'Neurologic manifestations'.)
The need for exchange transfusions has decreased with the prevention of Rh isoimmune hemolytic
disease and the systemic application of the 2004 American Academy of Pediatrics (AAP) Guideline
for identification and treatment of infants at risk for severe hyperbilirubinemia with phototherapy [37-
39].
This was best illustrated in a study from a large Northern California health maintenance
organization of over 18,000 neonates with a gestational age (GA) 35 weeks born between 2005
and 2007 following the initiation of universal screening. In this cohort, only 22 patients (0.1 percent)
had a TB level that exceeded the AAP recommended threshold for exchange transfusion [39].
Fourteen of these infants were <38 weeks GA. Only one exchange transfusion was performed and
there were no reported sequelae.
A similar incidence was reported from a single institution with an exchange transfusion rate of 0.015
percent (8 of 55,128 inborn infants) between 1988 and 1997 [37]. (See"Evaluation of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Systematic approach' and 'Phototherapy
indications' above.)
Morbidity and mortality Because exchange transfusions are rarely performed, it is difficult to
assess the current risks of morbidity and mortality associated with this procedure. Studies published
in 1985 reported mortality rates of 0.3 percent associated with the procedure [40,41] and a
significant complication rate of 1 percent [41]. Subsequent studies are limited by the number of
patients due to the infrequency of the procedure.
In the previously mentioned retrospective 21-year review, 5 of the 141 patients died within
seven days of the exchange transfusion; however, none of the deaths appeared to be
related to the procedure [38]. In this study, the most common complications were
thrombocytopenia (38 percent of patients) and hypocalcemia (38 percent).
In a retrospective study of 55 infants cared for at two neonatal intensive care units between
1992 and 2002, there was only one death, which was a critically ill preterm infant [42].
There was a high rate of complications including thrombocytopenia (44 percent),
hypocalcemia (29 percent), and metabolic acidosis (24 percent).
In another retrospective study published in 1997, which reviewed 106 patients who
underwent exchange transfusion over 15 years from two neonatal intensive care units
(NICUs), two patients died because of complications attributed to exchange transfusions.
These two deaths occurred in patients classified as "ill," having other existing comorbidities
[43].
Procedure The infant's circulating blood volume is approximately 80 to 90 mL/kg. A double-
volume exchange transfusion (160 to 180 mL/kg) replaces approximately 85 percent of the infant's
circulating red blood cells with appropriately cross-matched reconstituted (from packed red blood
cells and fresh frozen plasma) blood.
Irradiated blood products should be used to reduce the risk of graft versus host disease. In infants
born to cytomegalovirus (CMV) seronegative mothers, CMV-safe blood products should be used.
(See "Red cell transfusion in infants and children: Selection of blood products".)
The procedure involves placement of at least a central catheter and removing and replacing blood
in aliquots that are approximately 10 percent or less of the infant's blood volume. Exchange
transfusion usually reduces TB by approximately 50 percent [44]. Infusion of albumin (1 g/kg) one to
two hours before the procedure shifts more extravascular bilirubin into the circulation, allowing
removal of more bilirubin, although this has not been shown to decrease the need for repeat
exchange transfusion.
Indications The following discussion on the indications for exchange transfusions for term and
late preterm infants (35 weeks GA) is based upon the clinical practice guideline developed by the
AAP [2]. Similar guidelines for term infants based on TB and postnatal age have been developed by
the United Kingdoms National Institute for Health and Clinical Excellence (NICE guideline for
Neonatal Jaundice). National guidelines have also been developed in Norway, which are based on TB
values, birth weight (BW), and postnatal age [19].
Exchange transfusions are indicated in the following settings [2]:
Jaundiced infants with signs of ABE, such as significant lethargy, hypotonia, poor sucking,
or high-pitched cry, irrespective of the TB level. (See "Clinical manifestations of unconjugated
hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'.)
or
Infants with a TB greater than threshold values established by the AAP (figure 3).
For infants who have not yet been discharged from the birth hospital, exchange transfusion
is recommended if the TB reaches the threshold level despite intensive phototherapy [2].
Infants who have been discharged from the nursery to home and have TB concentrations
that are approaching or exceed threshold values for exchange transfusion are initially
treated with phototherapy. If TB remains above the threshold TB after about six hours of
phototherapy, then exchange transfusion is indicated. This approach reduces the number of
infants requiring an invasive therapy that has significant morbidity and mortality.
(See 'Phototherapy' above.)
The risk for severe hyperbilirubinemia and the threshold for intervention based upon the hour-
specific TB value may be determined using the newborn hyperbilirubinemia assessment calculator
(calculator 1).
The following are general age-in-hours specific TB threshold values for exchange transfusion
recommended by the AAP based upon gestational age and the presence or absence of risk factors
(isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase [G6PD] deficiency, asphyxia,
significant lethargy, temperature instability, sepsis, acidosis, or albumin <3 g/dL [if measured]) [2]:
For infants at low risk (38 weeks GA and without risk factors), exchange transfusion is
indicated for the following TB values.
24 hours of age: >19 mg/dL (325 micromol/L)
48 hours of age: >22 mg/dL (376 micromol/L)
72 hours of age: >24 mg/dL (410 micromol/L)
Any age greater than 72 hours: 25 mg/dL (428 micromol/L)
For infants at medium risk (38 weeks GA with risk factors or 35 to 37 6/7 weeks GA
without risk factors), exchange transfusion is indicated for the following TB values.
24 hours of age: >16.5 mg/dL (282 micromol/L)
48 hours of age: >19 mg/dL (325 micromol/L)
72 hours of age: >21 mg/dL (359 micromol/L)

The threshold for intervention may be lowered for infants closer to 35 weeks GA and
raised for those closer to 37 6/7 weeks GA.
For infants at high risk (35 to 37 6/7 weeks GA with risk factors), exchange transfusion is
indicated for the following TB values.
24 hours of age: >15 mg/dL (257 micromol/L)
48 hours of age: >17 mg/dL (291 micromol/L)
72 hours of age: >18.5 mg/dL (316 micromol/L)
Infants who are close or meet the criteria for exchange transfusion should be directly admitted or
transferred to the neonatal or pediatric intensive care unit. Referral should not be through an
emergency department, because this delays the initiation of treatment [45]. Upon admission, a type
and cross-match of the infants blood and placement of umbilical catheter are performed promptly,
so that exchange transfusion can be started as quickly as possible. (See 'Technique' above.)
Special circumstances In infants with isoimmune hemolytic disease and rising TB despite
intensive phototherapy, administration of intravenous immunoglobulin (IVIG) is recommended since
it may avoid the need for exchange transfusion. (See 'Intravenous immunoglobulin' below.)
Exchange transfusion should be considered in infants receiving phototherapy who develop the
"bronze baby" syndrome, if phototherapy has been ineffective in reducing TB below the threshold
range for intensive phototherapy [2]. (See 'Adverse effects' above.)
Bilirubin/albumin ratio The bilirubin/albumin (B/A) ratio can be used as an additional factor in
determining the need for exchange transfusion; it should not be used alone, but in conjunction with
TB values [2,46]. (See "Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants",
section on 'Bilirubin/albumin ratio'.)
For infants 38 weeks GA, consider exchange transfusion when
TB (mg/dL)/albumin (g/dL) ratio is >8 or TB (micromol/L)/albumin (micromol/L) is >0.94.
For infants 35 to 37 6/7 weeks GA and well, or 38 weeks with high risk (eg, isoimmune
hemolytic disease or G6PD deficiency), consider exchange transfusion when
TB (mg/dL)/albumin (g/dL) ratio is >7.2 or TB (micromol/L)/albumin (micromol/L) is >0.84.
For infants 35 to 37 6/7 weeks GA with high risk (eg, isoimmune hemolytic disease or
G6PD deficiency), consider exchange transfusion when TB (mg/dL)/albumin(g/dL) ratio is
>6.8 or TB (micromol/L)/albumin (micromol/L) is >0.8.
Efficacy After a successful procedure, TB typically falls to approximately one-half of the pre-
exchange value, then increases to approximately two-thirds of that of the pre-exchange
concentration because there is re-equilibration between extravascular and vascular bilirubin.
Observational studies report that exchange transfusions decreased the risk for prominent
neurologic abnormalities in term infants with TB >20 mg/dL (342 micromol/L) [47] and improved
abnormal brainstem auditory-evoked response (BAER) in infants with severe hyperbilirubinemia [48-
51]
Risks The risks of exchange transfusion result from the use of blood products and from the
procedure itself. Complications include:
Blood-borne infection
Thrombocytopenia and coagulopathy
Graft versus host disease
Necrotizing enterocolitis (NEC)
Portal vein thrombosis
Electrolyte abnormalities (eg, hypocalcemia and hyperkalemia)
Cardiac arrhythmias
(See "Administration and complications of red cell transfusion in infants and children".)
As previously mentioned, the current morbidity and mortality rates associated with exchange
transfusions are not known because the procedure is rarely performed [37]. Studies published in
1985 reported mortality rates of 0.3 percent associated with exchange transfusions [40,41] and a
significant complication rate of 1 percent [41]. In a retrospective review of 15 years experience from
1981 to 1995 at two academic medical centers, 1 of 81 healthy infants developed necrotizing
enterocolitis after exchange transfusion and none died [52].
PHARMACOLOGIC AGENTS Pharmacologic agents, including intravenous immunoglobulin
(IVIG), phenobarbital, ursodeoxycholic acid, and metalloporphyrins can be used to inhibit hemolysis,
increase conjugation and excretion of bilirubin, increase bile flow, or inhibit the formation of bilirubin,
respectively. However, currently only IVIG is used to treat unconjugated hyperbilirubinemia.
Intravenous immunoglobulin IVIG can reduce the need for exchange transfusion in infants
with hemolytic disease caused by Rh or ABO incompatibility [53-55]. Several systematic reviews
and meta-analyses have shown that infants who received IVIG compared with the control group
had lower rates of exchange transfusions [53-57]. Avoiding exchange transfusion reduces the risk of
any of its potential adverse effects; as a result, the administration of IVIG should be considered
based on the relative benefits and risks of the two interventions.
IVIG (dose 0.5 to 1 g/kg over two hours) is recommended in infants with isoimmune hemolytic
disease if the total bilirubin (TB) is rising despite intensive phototherapy or is within 2 or 3 mg/dL (34
to 51 micromol/L) of the threshold for exchange transfusion [2,56]. The dose may be repeated in 12
hours if necessary [2]. (See 'Exchange transfusion' above.)
The mechanism is uncertain, but IVIG is thought to inhibit hemolysis by blocking antibody receptors
on red blood cells. (See "Overview of Rhesus (Rh) alloimmunization in pregnancy".)
Phenobarbital Phenobarbital increases the conjugation and excretion of bilirubin and decreases
postnatal TB levels when given to pregnant women or infants. However, prenatal administration of
phenobarbital may adversely affect cognitive development and reproduction [58,59]. As a result,
phenobarbital is not routinely used to treat indirect neonatal hyperbilirubinemia.
Ursodeoxycholic acid Ursodeoxycholic acid increases bile flow and helps to lower TB levels. It is
also useful in the treatment of cholestatic jaundice.
Metalloporphyrins Synthetic metalloporphyrins, such as tin mesoporphyrin (SnMP), reduce
bilirubin production by competitive inhibition of heme oxygenase [60-67]. There are limited data
upon the safety of SnMP [67], and SnMP is not available for general use.
In one report, term infants with glucose-6-phosphate dehydrogenase (G6PD) deficiency given
SnMP at approximately 27 hours of age had lower and earlier peak TB values than did control
infants with and without G6PD deficiency [60]. No treated infant required phototherapy, compared
with 31 and 15 percent in the controls with and without G6PD deficiency, respectively.
In a systematic review of three randomized trials including 170 infants, short-term benefits of
metalloporphyrin therapy included lower maximum TB, lower frequency of severe
hyperbilirubinemia, decreased need for phototherapy, and shorter duration of hospitalization
[61,62,66]. None of the enrolled infants required exchange transfusion. None of the studies reported
on kernicterus, death, or long-term neurodevelopmental outcome.
SnMP is not approved for use in the United States.
OUTCOME When infants with hyperbilirubinemia are identified and treated appropriately, the
outcome is excellent with minimal or no additional risk for adverse neurodevelopmental sequelae
[68-70]. This was illustrated in a prospective cohort control study of 140 infants with total bilirubin
(TB) levels 25 mg/dL (428 micromol/L)identified from a cohort of 106,627 term or late preterm
infants [68]. The study group also included 10 infants with TB
30 mg/dL (513 micromol/L). Treatment of hyperbilirubinemia included phototherapy in 136 cases
and exchange transfusions in five cases. The hyperbilirubinemic infants compared with the control
group had a greater proportion of infants who were born <38 weeks gestational age (GA), Asian,
and were exclusively breastfed during birth hospitalization. At two-year follow-up, results were as
follows:
There were no reports of kernicterus in either the hyperbilirubinemic or control group.
Formal cognitive testing was performed in 82 children with neonatal hyperbilirubinemia and
168 control children at two and six years of age. There was no difference between patients
with hyperbilirubinemia and matched controls in cognitive testing, reported behavioral
problems, and frequency of parental concerns.
On physical examination, patients with hyperbilirubinemia compared with control patients
had a lower prevalence of abnormal neurologic findings (14 versus 29 percent). The degree
and duration of hyperbilirubinemia had no effect on these outcomes.
In a subset analysis, nine patients with hyperbilirubinemia and a positive direct antiglobulin
test (DAT, Coombs test) had lower scores on cognitive testing than other patients with
hyperbilirubinemia with a negative DAT. There was no difference between these two
hyperbilirubinemic groups regarding the presence of an abnormal neurologic finding.
Similar findings were noted in a follow-up study from the Collaborative Perinatal Project of children
(n = 46,872) at seven and eight years of age who were born 36 weeks GA with a birth weight
2000 g between 1959 and 1966 [69]. Results showed an adverse effect on cognitive testing was
only seen in children who had a TB 25 mg/dL (428micromol/L) and a positive DAT result as
neonates. TB in the absence of a positive DAT had no effect on cognitive testing.
Population-based studies have also reported observing no or limited chronic neurologic effects of
severe hyperbilirubinemia:
In a report of all live-born births in Denmark from 2004 to 2007, results based on parental
survey demonstrated no difference in development at one to five years of age between
infants with at least one neonatal measurement of TB 25 mg/dL (428 micromol/L) from
controls matched by gender, age, gestational age, and municipality of residency [71].
In a study from Nova Scotia of 61,238 infants born between 1994 and 2000, there were no
reported cases of kernicterus after implementation of treatment guidelines for
hyperbilirubinemia in term and late preterm infants [70]. There were no differences in the
overall neurologic composite outcome (cerebral palsy, developmental delay, hearing and
vision abnormalities, attention-deficit disorder, and autism) in infants with severe (TB
19 mg/dL [325 mmol/L]) or moderate (TB 19 mg/dL [325mmol/L]) hyperbilirubinemia
compared with those without hyperbilirubinemia. However, subset analysis for each
neurologic outcome suggested that some neurologic impairment might be associated with
hyperbilirubinemia. (See "Clinical manifestations of unconjugated hyperbilirubinemia in term and
late preterm infants", section on 'Neurologic dysfunction'.)
These results support the American Academy of Pediatrics (AAP) treatment guidelines for the
management of hyperbilirubinemia in term and late preterm infants, especially the use of lower
threshold values for intervention in infants with a positive DAT.
INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The
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Here are the patient education articles that are relevant to this topic. We encourage you to print or
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subjects by searching on patient info and the keyword(s) of interest.)
Basics topics (see "Patient information: Jaundice in babies (The Basics)")
Beyond the Basics topics (see "Patient information: Jaundice in newborn infants (Beyond the
Basics)")
A list of frequently asked questions and answers for parents is available through the American
Academy of Pediatrics (AAP):http://www.healthychildren.org/English/news/Pages/Jaundice-in-
Newborns.aspx
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