Neonatal Jaundice - Associates in Newborn Medicine

Neonatal Jaundice
M. Jeffrey Maisels
Pediatr. Rev. 2006;27;443-454
DOI: 10.1542/pir.27-12-443
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Article neonatology
Neonatal Jaundice
M. Jeffrey Maisels, MB,
BCh*
Author Disclosure
Dr Maisels did not
disclose any financial
relationships relevant
to this article.
To view additional
figures and tables for
this article, visit
pedsinreview.org and
click on the title of this
article.
Objectives After reviewing this article, readers should be able to:
1. Understand the metabolism of bilirubin.
2. Describe the factors that place an infant at risk for developing severe
hyperbilirubinemia.
3. Describe the physiologic mechanisms that result in neonatal jaundice.
4. List the common causes of indirect hyperbilirubinemia in the newborn.
5. Delineate the criteria for diagnosing ABO hemolytic disease.
6. Discuss the major clinical features of acute bilirubin encephalopathy and chronic
bilirubin encephalopathy (kernicterus).
7. List the key elements of the American Academy of Pediatrics guidelines for the
management of hyperbilirubinemia.
8. Describe the factors that affect the dosage and efficacy of phototherapy.
Case Report
A 23-year-old primiparous mother delivered a 36 weeks’ gestation male infant following an
uncomplicated pregnancy. The infant initially had some difficulty latching on for breastfeeding,
but subsequently appeared to nurse adequately, although his nursing quality was considered
“fair.” At age 25 hours, he appeared slightly jaundiced, and his bilirubin concentration
was 7.5 mg/dL (128.3 mcmol/L). He was discharged at age 30 hours, with a follow-up visit
scheduled for 1 week after discharge. On postnatal day 5, at about 4:30 PM, the mother called
the pediatrician’s office because her infant was not nursing well and was becoming increasingly
sleepy. On questioning, she also reported that he had become more jaundiced over the
previous 2 days. The mother was given an appointment to see the pediatrician the following
morning. Examination in the office revealed a markedly jaundiced infant who had a
high-pitched cry and intermittently arched his back. His total serum bilirubin (TSB) concentration
was 36.5 mg/dL (624.2 mcmol/L). He was admitted to the hospital, and an
immediate exchange transfusion was performed. Neurologic evaluation at age 18 months
showed profound neuromotor delay, choreoathetoid movements, an upward gaze paresis, and
a sensorineural hearing loss.
This infant had acute bilirubin encephalopathy and eventually developed chronic
bilirubin encephalopathy or kernicterus. Kernicterus, although rare, is one of the known
causes of cerebral palsy. Unlike other causes of cerebral palsy, kernicterus almost always can
be prevented through a relatively straightforward process of identification, monitoring,
follow-up, and treatment of the jaundiced newborn. Because kernicterus is uncommon,
pediatricians are required to monitor and treat many jaundiced infants—most of whom will
be healthy—to prevent substantial harm to a few.
Jaundice in the newborn is a unique problem because elevation of serum bilirubin is
potentially toxic to the infant’s developing central nervous system. Although it was
considered almost extinct, kernicterus still occurs in the United States and western Europe.
To prevent kernicterus, clinicians need to understand the physiology of bilirubin production
and excretion and develop a consistent, systematic approach to the management of
jaundice in the infant.
*Department of Pediatrics, William Beaumont Hospital, Royal Oak, Mich.
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neonatology
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Table 1. Physiologic Mechanisms
of Neonatal Jaundice
Increased Bilirubin Load on Liver Cell
● Increased erythrocyte volume
● Decreased erythrocyte survival
● Increased early-labeled bilirubin*
● Increased enterohepatic circulation of bilirubin
Decreased Hepatic Uptake of Bilirubin From Plasma
● Decreased ligandin
Decreased Bilirubin Conjugation
● Decreased uridine diphosphoglucuronosyl transferase
activity
Defective Bilirubin Excretion
● Excretion impaired but not rate limiting
*Early-labeled bilirubin refers to the bilirubin that does not come from
the turnover of effete red blood cells. This bilirubin is derived from
ineffective erythropoiesis and the turnover of nonhemoglobin heme,
primarily in the liver.
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co;
2005:768–846.
Figure 1. Neonatal bile pigment metabolism. RBCerythrocytes,
R.E.reticuloendothelial. Reprinted with permission
from Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK,
Mullett MD, eds. Neonatology: Pathophysiology and Management
of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:
768–846.
Bilirubin Metabolism
Bilirubin is produced from the catabolism of heme in the
reticuloendothelial system (Fig. 1). This unconjugated
bilirubin is released into the circulation where it is reversibly
but tightly bound to albumin. When the bilirubinalbumin
complex reaches the liver cell, it is transported
into the hepatocyte where it combines enzymatically
with glucuronic acid, producing bilirubin mono- and
diglucuronides. The conjugation reaction is catalyzed by
uridine diphosphate glucuronosyl transferase (UGT-
1A1). The mono- and diglucuronides are excreted into
the bile and the gut. In the newborn, much of the
conjugated bilirubin in the intestine is hydrolyzed back
to unconjugated bilirubin, a reaction catalyzed by the
enzyme beta glucuronidase that is present in the intestinal
mucosa. The unconjugated bilirubin is reabsorbed
into the blood stream by way of the enterohepatic circulation,
adding an additional bilirubin load to the already
overstressed liver. This enterohepatic circulation of bilirubin
is an important contributor to neonatal jaundice.
By contrast, in the adult, conjugated bilirubin is reduced
rapidly by the action of colonic bacteria to urobilinogens,
and very little enterohepatic circulation occurs.
Physiologic Jaundice
Following ligation of the umbilical cord, the neonate
must dispose of the bilirubin load that previously was
cleared through the placenta. Because neonatal hyperbilirubinemia
is an almost universal finding during the first
postnatal week, this transient elevation of the serum
bilirubin has been termed physiologic jaundice. The
mechanisms responsible for physiologic jaundice are
summarized in Table 1.
The TSB concentration reflects a combination of the
effects of bilirubin production, conjugation, and enterohepatic
circulation. The factors that affect these processes
account for the bilirubinemia that occurs in virtually all
newborns.
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Breastfeeding and Jaundice
An important change in the United States population has
been the dramatic increase in breastfeeding at hospital
discharge from 30% in the 1960s to almost 70% today. In
some hospitals, 85% or more of infants are breastfed.
Multiple studies have found a strong association between
breastfeeding and an increased incidence of neonatal
hyperbilirubinemia. The jaundice associated with breastfeeding
in the first 2 to 4 postnatal days has been called
“breastfeeding jaundice” or “breastfeeding-associated
jaundice”; that which appears later (onset at 4 to 7 d with
prolonged jaundice) has been called “the human milk
jaundice syndrome,” although there is considerable
overlap between the two entities.
Prolonged indirect-reacting hyperbilirubinemia (beyond
age 2 to 3 wk) occurs in 20% to 30% of all breastfeeding
infants and may persist for up to 3 months in
some infants. Such infants have an increased incidence of
Gilbert syndrome (diagnosed by UGT-1A1 genotyping
from a peripheral blood sample).
The jaundice associated with breastfeeding in the first
few days after birth appears to be related to an increase in
the enterohepatic circulation of bilirubin. This occurs in
the first few days because until the milk has “come in,”
breastfed infants receive fewer calories, and the decrease
in caloric intake is an important stimulus to increasing
the enterohepatic circulation.
Pathologic Causes of Jaundice
Table 2 lists the causes of pathologic indirect-reacting
hyperbilirubinemia in the neonate.
ABO Hemolytic Disease
The use of Rh immunoglobin has dramatically decreased
the incidence of Rh erythroblastosis fetalis, and hemolysis
from ABO incompatibility is by far the most common
cause of isoimmune hemolytic disease in newborns. In
about 15% of pregnancies, an infant who has blood type
A or B is carried by a mother who is type O. About one
third of such infants have a positive direct antiglobulin
test (DAT or Coombs test), indicating that they have
anti-A or anti-B antibodies attached to the red cells. Of
these infants, only 20% develop a peak TSB of more than
12.8 mg/dL (219 mcmol/L). Consequently, although
ABO-incompatible, DAT-positive infants are about
twice as likely as their compatible peers to have moderate
hyperbilirubinemia (TSB 13 mg/dL [222.3 mcmol/
L]), severe jaundice (TSB 20 mg/dL [ [342 mcmol/
L]) in the infants is uncommon. Nevertheless, ABO
hemolytic disease can cause severe hyperbilirubinemia
and kernicterus.
Table 2. Causes of Indirect
Hyperbilirubinemia in
Newborns
Increased Production or Bilirubin Load on the Liver
Hemolytic Disease
● Immune-mediated
—Rh alloimmunization, ABO and other blood group
incompatibilities
● Heritable
—Red cell membrane defects: Hereditary
spherocytosis, elliptocytosis, pyropoikilocytosis,
stomatocytosis
—Red cell enzyme deficiencies: Glucose-6-
phosphate dehydrogenase deficiency, a pyruvate
kinase deficiency, and other erythrocyte enzyme
deficiencies
—Hemoglobinopathies: Alpha thalassemia, beta
thalassemia
—Unstable hemoglobins: Congenital Heinz body
hemolytic anemia
Other Causes of Increased Production
● Sepsis a, b
● Disseminated intravascular coagulation
● Extravasation of blood: Hematomas; pulmonary,
abdominal, cerebral, or other occult hemorrhage
● Polycythemia
● Macrosomia in infants of diabetic mothers
Increased Enterohepatic Circulation of Bilirubin
● Breast milk jaundice
● Pyloric stenosis a
● Small or large bowel obstruction or ileus
Decreased Clearance
● Prematurity
● Glucose-6-phosphate dehydrogenase deficiency
Inborn Errors of Metabolism
—Crigler-Najjar syndrome, types I and II
—Gilbert syndrome
—Galactosemia b
—Tyrosinemia b
—Hypermethioninemia b
Metabolic
—Hypothyroidism
—Hypopituitarism b
a Decreased clearance also part of pathogenesis.
b Elevation of direct-reading bilirubin also occurs.
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co;
2005:768–846.
Diagnosing ABO Hemolytic Disease
ABO hemolytic disease has a highly variable clinical
presentation. Most affected infants present with a rapid
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Table 3. Criteria for Diagnosing
ABO Hemolytic Disease as the
Cause of Neonatal
Hyperbilirubinemia
Mother group O, infant group A or B
AND
● Positive DAT
● Jaundice appearing within 12 to 24 h after birth
● Microspherocytes on blood smear
● Negative DAT but homozygous for Gilbert
syndrome
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co;
2005:768–846.
increase in TSB concentrations within the first 24 hours,
but the TSB subsequently declines, in many infants,
often without any intervention. ABO hemolytic disease is
a relatively common cause of early hyperbilirubinemia
(before the infant leaves the nursery), but it is a relatively
rare cause of hyperbilirubinemia in infants who have been
discharged and readmitted. The criteria for diagnosing
ABO hemolytic disease as the cause of neonatal hyperbilirubinemia
are listed in Table 3. Recently, it has been
shown that DAT-negative, ABO-incompatible infants
who also have Gilbert syndrome are at risk for hyperbilirubinemia.
This may explain the occasional ABOincompatible
infant who has a negative DAT and nevertheless
develops early hyperbilirubinemia.
Glucose-6-phosphate Dehydrogenase (G-6PD)
Deficiency
G-6PD deficiency is the most common and clinically
significant red cell enzyme defect, affecting as many as
4,500,000 newborns worldwide each year. Although
known for its prevalence in the populations of the Mediterranean,
Middle East, Arabian Peninsula, southeast
Asia, and Africa, G-6PD has been transformed by immigration
and intermarriage into a global problem. Nevertheless,
most pediatricians in the United States do not
think of G-6PD deficiency when confronted with a jaundiced
infant. This possibility should be considered,
though, particularly when seeing African-American infants.
Although African-American newborns, as a group,
tend to have lower TSB concentrations than do caucasian
newborns, G-6PD deficiency is found in 11% to 13% of
African-American newborns. This translates to 32,000 to
Table 4. Major Clinical Features
of Acute Bilirubin
Encephalopathy
Initial Phase
● Slight stupor (“lethargic,” “sleepy”)
● Slight hypotonia, paucity of movement
● Poor sucking, slightly high-pitched cry
Intermediate Phase
● Moderate stupor—irritable
● Tone variable, usually increased; some have
retrocollis-opisthotonos
● Minimal feeding, high-pitched cry
Advanced Phase
● Deep stupor to coma
● Tone usually increased; some have retrocollisopisthotonos
● No feeding, shrill cry
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co;
2005:768–846.
39,000 African-American male G-6PD-deficient hemizygous
newborns born annually in the United States. As
many as 30% of infants in the United States who have
kernicterus have been found to be G-6PD-deficient.
The G-6PD gene is located on the X chromosome,
and hemizygous males have the full enzyme deficiency,
although female heterozygotes are also at risk for hyperbilirubinemia.
G-6PD-deficient neonates have an increase
in heme turnover, although overt evidence of
hemolysis often is not present. In addition, affected
infants have an impaired ability to conjugate bilirubin.
Bilirubin Encephalopathy
In the case described at the beginning of this article, the
infant developed extreme hyperbilirubinemia and the
classic signs of acute bilirubin encephalopathy (Table 4).
He also developed the typical features of chronic bilirubin
encephalopathy or kernicterus (Table 5).
How Could This Have Been Prevented
The infant in the case report had many of the factors that
increase the risk of severe hyperbilirubinemia (Table 6).
A key recommendation in the American Academy of
Pediatrics (AAP) clinical practice guideline (Table 7) is
that every infant be assessed for the risk of subsequent
severe hyperbilirubinemia before discharge, particularly
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Table 5. Major Clinical Features
of Chronic Postkernicteric
Bilirubin Encephalopathy
● Extrapyramidal abnormalities, especially athetosis
● Gaze abnormalities, especially of upward gaze
● Auditory disturbance, especially sensorineural hearing
loss
● Intellectual deficits, but minority in mentally
retarded range
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:
768–846.
infants discharged before age 72 hours. The infant described
in the case was a 36 weeks’ gestation, breastfed
male who was discharged at age 30 hours. Two of the risk
factors that have been shown repeatedly to be very important
are a gestational age less than 38 weeks and
breastfeeding, particularly if nursing is not going well.
Almost every recently described case of kernicterus has
occurred in a breastfed infant, and infants of 35 to
36 weeks’ gestation are about 13 times more likely than
those at 40 weeks’ gestation to be readmitted for severe
jaundice. These so called “near-term” infants receive care
in well-baby nurseries, but unlike their term peers, they
are much more likely to nurse ineffectively, receive fewer
calories, and have greater weight loss. In addition, the
immaturity of the liver’s conjugating system in the preterm
newborn makes it much more difficult for the
infants to clear bilirubin effectively. Thus, it is not surprising
that they become more jaundiced.
In addition, the infant’s TSB was 7.5 mg/dL
(128.3 mcmol/L) at age 25 hours, a value very close to
the 95th percentile (Fig. 2). Another TSB measurement
should have been obtained within 24 hours and a
follow-up visit scheduled no less than 48 hours after
discharge. In addition, when the doctor’s office was told
that the infant was not nursing well, was sleepy, and was
jaundiced, the infant should have been seen immediately.
The mother was describing the first stage of acute bilirubin
encephalopathy (Table 4).
Appropriate Follow-up is Essential
If the infant in the case had been seen within 48 hours of
discharge (before he was 4 days old), significant jaundice
certainly would have been noted, bilirubin would have
been measured, and he would have been treated with
phototherapy, thus preventing the disastrous outcome
Table 6. Risk Factors for
Development of Severe
Hyperbilirubinemia in Infants
>35 Weeks’ Gestation (In
Approximate Order of
Importance)
Major Risk Factors
● Predischarge TSB or TcB level in the high-risk zone
(Fig. 2)
● Jaundice observed in the first 24 h
● Blood group incompatibility with positive direct
antiglobulin test, other known hemolytic disease (eg,
G-6PD deficiency), elevated ETCOc
● Gestational age 35 to 36 wk
● Previous sibling received phototherapy
● Cephalhematoma or significant bruising
● Exclusive breastfeeding, particularly if nursing is not
going well and weight loss is excessive
● East Asian race*
Minor Risk Factors
● Predischarge TSB or TcB in the high- to
intermediate-risk zone (Fig. 2)
● Gestational age 37 to 38 wk
● Jaundice observed before discharge
● Previous sibling had jaundice
● Macrosomia in an infant of a diabetic mother
● Maternal age >25 y
● Male sex
Decreased Risk
(These factors are associated with decreased risk of
significant jaundice, listed in order of decreasing
importance.)
● TSB or TcB in the low-risk zone (Fig. 2)
● Gestational age >41 wk
● Exclusive formula feeding
● Black race*
● Discharge from hospital after 72 h
*Race as defined by mother’s description. TSBtotal serum bilirubin,
TcBtranscutaneous bilirubin, G-6PDglucose-6-phosphate dehydrogenase,
ETCOcend tidal carbon monoxide concentration corrected
for ambient carbon monoxide
Reprinted with permission from Maisels MJ, Baltz RD, Bhutani V, et
al. Management of hyperbilirubinemia in the newborn infant 35 or
more weeks of gestation. Pediatrics. 2004;114:297–316.
that occurred. The AAP now recommends that any infant
discharged at less than 72 hours of age should be
seen within 2 days of discharge. Infants who have many
risk factors might need to be seen earlier (within 24 h of
discharge), which would have been appropriate for this
infant. Such follow-up is critical to protect infants from
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Table 7. The Ten Commandments
for Preventing and Managing
Hyperbilirubinemia
1. Promote and support successful breastfeeding.
2. Establish nursery protocols for the jaundiced
newborn and permit nurses to obtain TSB levels
without a physician’s order.
3. Measure the TSB or TcB concentrations of infants
jaundiced in the first 24 h after birth.
4. Recognize that visual diagnosis of jaundice is
unreliable, particularly in darkly pigmented infants.
5. Interpret all TSB levels according to the infant’s
age in hours, not days.
6. Do not treat a near-term (35 to 38 wk) infant as
a term infant; a near-term infant is at much
higher risk of hyperbilirubinemia.
7. Perform a predischarge systematic assessment on
all infants for the risk of severe
hyperbilirubinemia.
8. Provide parents with information about newborn
jaundice.
9. Provide follow-up based on the time of discharge
and the risk assessment.
10. When indicated, treat the newborn with
phototherapy or exchange transfusion.
TSBtotal serum bilirubin, TcBtranscutaneous bilirubin
Reprinted with permission from Maisels MJ. Jaundice in a newborn.
How to head off an urgent situation. Contemp Pediatr. 2005;22:
41–54, with permission. Adapted from Pediatrics. 2004;114:297–316.
severe hyperbilirubinemia and kernicterus. Nevertheless,
clinical judgment is required at the time of discharge. If a
41-weeks’ gestation, formula-fed, nonjaundiced infant is
discharged and has no significant risk factors (Table 6), a
follow-up visit after 3 or 4 days is acceptable. The absence
of risk factors and any decision for a later follow up
should be documented in the chart. If, on the other
hand, a 36-weeks’ gestation breastfed newborn is discharged
on a Friday, he or she should be seen no later
than Sunday.
If follow-up cannot be assured and there is a significant
risk of severe hyperbilirubinemia, the clinician may
need to delay discharge. If weekend follow-up is difficult
or impossible, a reasonable option is to have the infant
brought to a laboratory for a bilirubin measurement (or a
transcutaneous bilirubin measurement).
Management of Jaundice in the Infant
Interpreting Serum Bilirubin Levels
TSB (or transcutaneous bilirubin [TcB]) concentrations
generally peak by the third to fifth day after birth (Fig.
2 and Fig. 1-E). (The latter figure is available only in the
online edition of this article.) In the past, when newborns
remained in the hospital for 3 or 4 days, jaundiced babies
could be identified before discharge and appropriately
evaluated and treated. Today, because almost all infants
delivered vaginally leave the hospital before they are
48 hours old, the bilirubin concentration peaks after
discharge. Because the TSB has not yet peaked at the
time of discharge, the AAP provides stringent guidelines
for follow-up of all infants discharged before 72 hours of
age: They should be seen within 2 days of discharge.
In addition, it is essential that all TSB values be
interpreted in terms of the infant’s age in hours and not
in days. Although clinicians often talk about a TSB
concentration on day 2 or day 3, Figure 2 (and Figure
1-E in the online edition) shows how misleading this
thought process can be. A TSB of 8 mg/dL (136.8
mcmol/L) at 24.1 hours is above the 95th percentile and
calls for evaluation and close follow-up, whereas the same
level at 47.9 hours is in the low-risk zone (Fig. 2) and
probably warrants no further concern. Yet, both values
occur on postnatal day 2. In the case, the TSB value at
25 hours was 7.5 mg/dL (128.3 mcmol/L), very close
to the 95th percentile. Consideration should have been
given to additional investigations to try to determine why
the infant was jaundiced, a subsequent TSB should have
been measured within 24 hours, and follow-up should
have been scheduled no later than 48 hours after discharge.
When to Seek a Cause for Jaundice
In some infants, the cause of hyperbilirubinemia is apparent
from the history and physical examination findings.
For example, jaundice in a severely bruised infant needs
no further explanation, nor is there a need to investigate
why a 5-day-old breastfed infant has a TSB value of
15 mg/dL (256.5 mcmol/L). On the other hand, if the
TSB concentration is above the 95th percentile or rising
rapidly and crossing percentiles (Fig. 2 and Fig.1-E in the
online edition), and this cannot be readily explained by
the history and physical examination results, certain laboratory
tests should be performed (Table 8).
Predicting the Risk of Hyperbilirubinemia
Before discharge, every newborn needs to be assessed for
the risk of subsequent severe hyperbilirubinemia. This
can be accomplished by using clinical criteria (Table 6) or
measuring a TSB or TcB concentration prior to discharge.
In the case described, the infant had several risk
factors for hyperbilirubinemia, and his TSB measured at
26 hours was in the high intermediate-risk zone (Fig. 2),
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Figure 2. Establishing “risk zones” for the prediction of hyperbilirubinemia in newborns. This nomogram is based on hour-specific
bilirubin values obtained from 2,840 well newborns >36 weeks gestational age whose birthweights were >2,000 g or >35 weeks
gestational age whose birthweights were >2,500 g. The serum bilirubin concentration was measured before discharge. The risk zone
in which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile. Reprinted with
permission 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;103:6–14.
placing him at significant risk for subsequent development
of hyperbilirubinemia.
Visual Assessment of Jaundice
Traditional identification of jaundice relied on blanching
the skin with digital pressure to reveal the underlying
color of the skin and subcutaneous tissue. Although this
remains a fundamentally important clinical sign, it has
limitations and can be unreliable, particularly in darkly
pigmented infants. The difference between a TSB value
of 5 mg/dL (85.5 mcmol/L) and 8 mg/dL (136.8
mcmol/L) cannot be perceived by the eye, but this
represents the difference between the 50th and the 95th
percentiles at 24 hours (Fig. 2). The potential errors
associated with visual diagnosis have led some experts to
recommend that all newborns have a TSB or TcB measured
prior to discharge. The TSB can be obtained at the
same time as the metabolic screen, sparing the infant an
additional heel stick.
Noninvasive Bilirubin Measurement
Two hand-held electronic devices are available in the
United States for measuring TcB. They provide an estimate
of the TSB concentration, and a close correlation
has been found between TcB and TSB measurements in
different racial populations.
TcB measurement (Fig. 1-E in the online edition) is
not a substitute for TSB measurement, but TcB can be
very helpful. When used as a screening tool, TcB measurement
can help to answer the questions, “Should I
worry about this infant” and “Should I obtain a TSB on
this infant” Because the goal is to avoid missing a
significantly elevated TSB value, the value for the TcB
measurement (based on the infant’s age in hours and
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Table 8. Laboratory Tests for the Jaundiced Infant
When there is a finding of:
Jaundice in first 24 h
Jaundice that appears excessive for the infant’s age
An infant receiving phototherapy or having a TSB that is
above the 75th percentile or rising rapidly (ie, crossing
percentiles) and unexplained by history or findings on
physical examination
A TSB approaching exchange level or not responding to
phototherapy
An elevated direct (or conjugated) bilirubin level
Jaundice present at or beyond age 3 wk or the infant
is sick
Obtain:
Total serum bilirubin (TSB)
TSB
Blood type; also, perform a Coombs test, if not obtained with
cord blood
Complete blood count, smear, and reticulocyte count
Direct (or conjugated) bilirubin
(Repeat TSB in 4 to 24 hours, depending on infant’s age and
TSB level)
Consider the possibility of glucose-6-phosphate
dehydrogenase (G-6PD) deficiency, particularly in African-
American infants
Reticulocyte count, G-6PD test, albumin
Urinalysis and urine culture; evaluate for sepsis if indicated
by history and physical examination
Total and direct bilirubin concentration; if direct bilirubin is
elevated, evaluate for causes of cholestasis
(Also check results of newborn thyroid and galactosemia
screen and evaluate infant for signs or symptoms of
hypothyroidism)
Reprinted with permission from Maisels MJ. Jaundice in a newborn. How to head off an urgent situation. Contemp Pediatr. 2005;22:41–54. Adapted with
permission from Pediatrics. 2004;14:297–316.
other risk factors) always should be one above which a
TSB value always will be obtained. In our nursery, we
routinely evaluate infants via a TcB measurement and
obtain a TSB whenever the TcB is above the 75th percentile
(Fig. 2) (or the 95th percentile in Fig. 1-E).
Treatment
Hyperbilirubinemia can be treated via: 1) exchange
transfusion to remove bilirubin mechanically; 2) phototherapy
to convert bilirubin to products that can bypass
the liver’s conjugating system and be excreted in the bile
or in the urine without further metabolism; and 3) pharmacologic
agents to interfere with heme degradation and
bilirubin production, accelerate the normal metabolic
pathways for bilirubin appearance, or inhibit the enterohepatic
circulation of bilirubin. Guidelines for the use of
phototherapy and exchange transfusion in term and
near-term infants are provided in Figs. 3 and 4 and Table
9.
Phototherapy
Phototherapy works by infusing discrete photons of energy
similar to the molecules of a drug. These photons
are absorbed by bilirubin molecules in the skin and
subcutaneous tissue, just as drug molecules bind to a
receptor. The bilirubin then undergoes photochemical
reactions to form excretable isomers and breakdown
products that can bypass the liver’s conjugating system
and be excreted without further metabolism. Some
photo products also are excreted in the urine.
Phototherapy displays a clear dose-response effect,
and a number of variables influence how light works to
lower the TSB level. (In the online edition of this article,
Table 1-E shows the radiometric units used to measure
the dose of phototherapy and Tables 2-E and 3-E show
the factors that affect the dose and efficacy of phototherapy,
including type of light source, the infant’s distance
from the light, and the surface area exposed.) Because of
the optical properties of bilirubin and skin, the most
effective lights are those that have wavelengths predominately
in the blue-green spectrum (425 to 490 nm). At
these wavelengths, light penetrates the skin well and is
absorbed maximally by bilirubin.
Using Phototherapy Effectively
Phototherapy was used initially in low-birthweight and
term infants primarily to prevent slowly rising bilirubin
concentrations from reaching levels that might require
exchange transfusion. Today, phototherapy often is used
in term and near-term infants who have left the hospital
and are readmitted on days 4 to 7 for treatment of TSB
concentrations of 20 mg/dL (342 mcmol/L) or more.
Such infants require a full therapeutic dose of phototherapy
(now termed intensive phototherapy) to reduce the
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Figure 3. The risk factors listed for this figure increase the likelihood of brain damage at different bilirubin concentrations. Infants
are designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of bilirubin, the
blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin. “Intensive phototherapy” implies irradiance in
the blue-green spectrum (wavelengths of approximately 430 to 490 nm) of at least 30 mcW/cm 2 per nanometer (measured at the
infant’s skin directly below the center of the phototherapy unit) and delivered to as much of the infant’s surface area as possible.
Note that irradiance measured below the center of the light source is much greater than that measured at the periphery.
Measurements should be made with a radiometer specified by the manufacturer of the phototherapy system. If total serum bilirubin
values approach or exceed the exchange transfusion line, the sides of the bassinet, incubator, or warmer should be lined with
aluminum foil or white material to increase the surface area of the infant exposed and increase the efficacy of phototherapy. If the
total serum bilirubin value does not decrease or continues to rise in an infant who is receiving intensive phototherapy, this strongly
suggests the presence of hemolysis. Infants who receive phototherapy and have an elevated direct-reacting or conjugated bilirubin
level (cholestatic jaundice) may develop the bronze baby syndrome. Reprinted with permission from Maisels MJ, Baltz RD, Bhutani
V, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.
bilirubin concentration as soon as possible. Intensive
phototherapy implies the use of irradiance in the 430 to
490-nm band of at least 30 mcW/cm 2 per nanometer
delivered to as much of the infant’s surface area as possible
(Table 2-E in the online edition of this article).
Increasing the surface area exposed to phototherapy
improves the therapy’s efficacy significantly. This is accomplished
by placing fiberoptic pads or a light-emitting
diode (LED) mattress below the infant or using a phototherapy
device that delivers phototherapy from special
blue fluorescent tubes both above and below the infant.
When intensive phototherapy is applied appropriately, a
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neonatal jaundice
Figure 4. The risk factors listed for this figure are factors that increase the likelihood of brain damage at different bilirubin levels.
Infants are designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of
bilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin.
30% to 40% decrement in the bilirubin concentration can
be expected in the first 24 hours, with the most significant
decline occurring in the first 4 to 6 hours.
Pharmacologic Treatment
Pharmacologic agents such as phenobarbital and ursodeoxycholic
acid improve bile flow and can help to lower
bilirubin concentrations. Tin mesoporphyrin inhibits
heme oxygenase and, therefore, the production of bilirubin
(Fig. 1). To date, more than 500 newborns have
received tin mesoporphyrin in control trials, but the drug
still is awaiting United States Food and Drug Administration
approval. Other drugs have been used to inhibit
the enterohepatic circulation of bilirubin. A recent controlled
trial showed that agents that inhibit beta glucuronidase
can decrease bilirubin levels in breastfed new-
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Table 9. Additional Guidelines for Exchange Transfusion
These ratios can be used together with but not in lieu of the TSB concentration as an additional factor in determining the need
for exchange transfusion.
Risk Category
Bilirubin/Albumin Ratio at Which Exchange Transfusion
Should be Considered
TSB (mg/dL)-to-Albumin
(dL)
Infants >38 0/7 wk 8.0 0.94
Infants 35 0/7 to 37 6/7 wk and well or >38 0/7 wk 7.2 0.84
if higher risk or isoimmune hemolytic disease or G-
6PD deficiency
Infants 35 0/7 to 37 6/7 wk if higher risk or
isoimmune hemolytic disease or G-6PD deficiency
6.8 0.80
TSB (mcmol/L)-to-Albumin
(mcmol/L)
TSBtotal serum bilirubin, G-6PDglucose–6–phosphate dehydrogenase. Reprinted with permission from Maisels MJ, Baltz RD, Bhutani V, et al.
Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.
borns. For infants who have isoimmune hemolytic
disease, the administration of intravenous immunoglobulin
significantly reduces the need for exchange transfusion.
Suggested Reading
Bhutani V, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson
LH. Noninvasive measurement of total serum bilirubin in a
multiracial predischarge newborn population to assess the risk of
severe hyperbilirubinemia. Pediatrics. 2000;106:e17. Available
at: http://pediatrics.aappublications.org/cgi/content/full/
106/2/e17
Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemiological
strategies for its prevention through systems-based
approaches. J Perinatol. 2004;24:650–662
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;103:6–14
Ennever JF. Blue light, green light, white light, more light: treatment
of neonatal jaundice. Clin Perinatol. 1990;17:467–481
Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: a
potential complication of glucose-6-phosphate dehydrogenase
deficiency. Clin Perinatol. 1998;25:575–590
Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the
nongeneticist: hereditary defects of neonatal bilirubin conjugation.
Pediatrics. 2003;111:886–893
Kappas A. A method for interdicting the development of severe
jaundice in newborns by inhibiting the production of bilirubin.
Pediatrics. 2004;113:119–123
Maisels MJ. A primer on phototherapy for the jaundiced newborn.
Contemp Pediatr. 2005;22:38–57
Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK, Mullett
MD, eds. Neonatology: Pathophysiology and Management of the
Newborn. Philadelphia, Pa: Lippincott Co; 2005:768–846
Maisels MJ. Jaundice in a newborn. Answers to questions about a
common clinical problem. Contemp Pediatr. 2005;22:34–40
Maisels MJ. Jaundice in a newborn. How to head off an urgent
situation. Contemp Pediatr. 2005;22:41–54
Maisels MJ. Why use homeopathic doses of phototherapy Pediatrics.
1996;98:283–287
Maisels MJ, Baltz RD, Bhutani V, et al. Management of hyperbilirubinemia
in the newborn infant 35 or more weeks of gestation.
Pediatrics. 2004;114:297–316
Maisels MJ, Kring EA. Transcutaneous bilirubin levels in the first
96 hours in a normal newborn population of 35 weeks’
gestation. Pediatrics. 2006;117:1169–1173
Maisels MJ. Ostrea EJ Jr, Touch S, et al. Evaluation of a new transcutaneous
bilirubinometer. Pediatrics. 2004;113:1628–1635
Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes among
newborns with total serum bilirubin levels of 25 mg per deciliter
or more. N Engl J Med. 2006;354:1889–1900
Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and
prevention of extreme neonatal hyperbilirubinemia in a mature
health maintenance organization. Arch Pediatr Adolesc Med.
2000;154:1140–1147
Stevenson DK, Dennery PA, Hintz SR. Understanding newborn
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PIR Quiz
Quiz also available online at www.pedsinreview.org.
1. In explaining breastfeeding-associated jaundice to the third-year students on your service, you note that
jaundice seen in the first postnatal week results from an increase in the enterohepatic circulation due
primarily to:
A. Decreased caloric intake.
B. Gilbert syndrome.
C. Increased protein binding.
D. Insufficient free water.
E. Polycythemia.
2. The American Academy of Pediatrics now recommends that any infant discharged before 72 hours of age
be seen for follow-up no longer than how many hours later
A. 24.
B. 36.
C. 48.
D. 72.
E. 96.
3. Almost all infants experience a transient increase in bilirubin concentrations known as physiologic jaundice
during the first week after birth. Among the following, which is most likely to contribute to the
development of this condition
A. Decreased enterohepatic circulation.
B. Decreased erythrocyte survival.
C. Decreased erythrocyte volume.
D. Increased bilirubin conjugation.
E. Increased ligandin levels.
4. A 36 weeks’ gestation breastfed African-American infant is being discharged at 36 hours of age. The
transcutaneous bilirubin level is above the 75th percentile. Of the following, the next most appropriate step
in the management of this infant is to:
A. Advise the mother to increase the frequency of breastfeeding.
B. Check the mother’s and the baby’s blood groups.
C. Obtain a complete blood count and differential count.
D. Obtain a serum bilirubin measurement.
E. Start phototherapy.
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Neonatal Jaundice
M. Jeffrey Maisels
Pediatr. Rev. 2006;27;443-454
DOI: 10.1542/pir.27-12-443
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