This document discusses neonatal jaundice. It begins by outlining the objectives of understanding bilirubin metabolism, risk factors for hyperbilirubinemia, causes of jaundice, and guidelines for managing jaundice. It then presents a case study of a infant who developed acute and chronic bilirubin encephalopathy (kernicterus). The document explains the physiologic mechanisms that cause neonatal jaundice, including increased bilirubin load, decreased hepatic uptake and conjugation, and impaired excretion. It emphasizes that kernicterus is preventable but clinicians must understand bilirubin physiology and have a consistent approach to managing jaundiced newborns.

1. Article neonatology
Neonatal Jaundice
M. Jeffrey Maisels, MB,
Objectives After reviewing this article, readers should be able to:
BCh*
1. Understand the metabolism of bilirubin.
2. Describe the factors that place an infant at risk for developing severe
Author Disclosure hyperbilirubinemia.
Dr Maisels did not 3. Describe the physiologic mechanisms that result in neonatal jaundice.
disclose any financial 4. List the common causes of indirect hyperbilirubinemia in the newborn.
relationships relevant 5. Delineate the criteria for diagnosing ABO hemolytic disease.
to this article. 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.
To view additional 8. Describe the factors that affect the dosage and efficacy of phototherapy.
figures and tables for
this article, visit
pedsinreview.org and
click on the title of this
article. 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 breastfeed-
ing, but subsequently appeared to nurse adequately, although his nursing quality was consid-
ered “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 increas-
ingly 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) concen-
tration 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 produc-
tion 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.
Pediatrics in Review Vol.27 No.12 December 2006 443

2. neonatology neonatal jaundice
Physiologic Mechanisms
Table 1.
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.
nal mucosa. The unconjugated bilirubin is reabsorbed
into the blood stream by way of the enterohepatic circu-
Figure 1. Neonatal bile pigment metabolism. RBC erythro-
lation, adding an additional bilirubin load to the already
cytes, R.E. reticuloendothelial. Reprinted with permission overstressed liver. This enterohepatic circulation of bili-
from Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK, rubin is an important contributor to neonatal jaundice.
Mullett MD, eds. Neonatology: Pathophysiology and Manage- By contrast, in the adult, conjugated bilirubin is reduced
ment of the Newborn. Philadelphia, Pa: Lippincott Co; 2005: rapidly by the action of colonic bacteria to urobilinogens,
768 – 846. and very little enterohepatic circulation occurs.
Bilirubin Metabolism Physiologic Jaundice
Bilirubin is produced from the catabolism of heme in the
Following ligation of the umbilical cord, the neonate
reticuloendothelial system (Fig. 1). This unconjugated
must dispose of the bilirubin load that previously was
bilirubin is released into the circulation where it is revers-
cleared through the placenta. Because neonatal hyperbi-
ibly but tightly bound to albumin. When the bilirubin-
lirubinemia is an almost universal finding during the first
albumin complex reaches the liver cell, it is transported
into the hepatocyte where it combines enzymatically postnatal week, this transient elevation of the serum
with glucuronic acid, producing bilirubin mono- and bilirubin has been termed physiologic jaundice. The
diglucuronides. The conjugation reaction is catalyzed by mechanisms responsible for physiologic jaundice are
uridine diphosphate glucuronosyl transferase (UGT- summarized in Table 1.
1A1). The mono- and diglucuronides are excreted into The TSB concentration reflects a combination of the
the bile and the gut. In the newborn, much of the effects of bilirubin production, conjugation, and entero-
conjugated bilirubin in the intestine is hydrolyzed back hepatic circulation. The factors that affect these processes
to unconjugated bilirubin, a reaction catalyzed by the account for the bilirubinemia that occurs in virtually all
enzyme beta glucuronidase that is present in the intesti- newborns.
444 Pediatrics in Review Vol.27 No.12 December 2006

3. neonatology neonatal jaundice
Breastfeeding and Jaundice
An important change in the United States population has Causes of Indirect
Table 2.
been the dramatic increase in breastfeeding at hospital
discharge from 30% in the 1960s to almost 70% today. In
Hyperbilirubinemia in
some hospitals, 85% or more of infants are breastfed. Newborns
Multiple studies have found a strong association between
breastfeeding and an increased incidence of neonatal Increased Production or Bilirubin Load on the Liver
hyperbilirubinemia. The jaundice associated with breast- Hemolytic Disease
● Immune-mediated
feeding in the first 2 to 4 postnatal days has been called
—Rh alloimmunization, ABO and other blood group
“breastfeeding jaundice” or “breastfeeding-associated incompatibilities
jaundice”; that which appears later (onset at 4 to 7 d with ● Heritable
prolonged jaundice) has been called “the human milk —Red cell membrane defects: Hereditary
jaundice syndrome,” although there is considerable spherocytosis, elliptocytosis, pyropoikilocytosis,
overlap between the two entities. stomatocytosis
—Red cell enzyme deficiencies: Glucose-6-
Prolonged indirect-reacting hyperbilirubinemia (be- phosphate dehydrogenase deficiency,a pyruvate
yond age 2 to 3 wk) occurs in 20% to 30% of all breast- kinase deficiency, and other erythrocyte enzyme
feeding infants and may persist for up to 3 months in deficiencies
some infants. Such infants have an increased incidence of —Hemoglobinopathies: Alpha thalassemia, beta
Gilbert syndrome (diagnosed by UGT-1A1 genotyping thalassemia
—Unstable hemoglobins: Congenital Heinz body
from a peripheral blood sample). hemolytic anemia
The jaundice associated with breastfeeding in the first Other Causes of Increased Production
a, b
few days after birth appears to be related to an increase in ● Sepsis
the enterohepatic circulation of bilirubin. This occurs in ● Disseminated intravascular coagulation
● Extravasation of blood: Hematomas; pulmonary,
the first few days because until the milk has “come in,”
abdominal, cerebral, or other occult hemorrhage
breastfed infants receive fewer calories, and the decrease ● Polycythemia
in caloric intake is an important stimulus to increasing ● Macrosomia in infants of diabetic mothers
the enterohepatic circulation. Increased Enterohepatic Circulation of Bilirubin
● Breast milk jaundice
a
● Pyloric stenosis
Pathologic Causes of Jaundice
● Small or large bowel obstruction or ileus
Table 2 lists the causes of pathologic indirect-reacting
hyperbilirubinemia in the neonate. Decreased Clearance
●
Prematurity
ABO Hemolytic Disease ●
Glucose-6-phosphate dehydrogenase deficiency
The use of Rh immunoglobin has dramatically decreased Inborn Errors of Metabolism
—Crigler-Najjar syndrome, types I and II
the incidence of Rh erythroblastosis fetalis, and hemoly- —Gilbert syndrome
sis from ABO incompatibility is by far the most common —Galactosemiab
cause of isoimmune hemolytic disease in newborns. In —Tyrosinemiab
about 15% of pregnancies, an infant who has blood type —Hypermethioninemiab
A or B is carried by a mother who is type O. About one Metabolic
—Hypothyroidism
third of such infants have a positive direct antiglobulin —Hypopituitarismb
test (DAT or Coombs test), indicating that they have
a
Decreased clearance also part of pathogenesis.
anti-A or anti-B antibodies attached to the red cells. Of b
Elevation of direct-reading bilirubin also occurs.
these infants, only 20% develop a peak TSB of more than Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
12.8 mg/dL (219 mcmol/L). Consequently, although Management of the Newborn. Philadelphia, Pa: Lippincott Co;
ABO-incompatible, DAT-positive infants are about 2005:768 – 846.
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 Diagnosing ABO Hemolytic Disease
hemolytic disease can cause severe hyperbilirubinemia ABO hemolytic disease has a highly variable clinical
and kernicterus. presentation. Most affected infants present with a rapid
Pediatrics in Review Vol.27 No.12 December 2006 445

4. neonatology neonatal jaundice
Criteria for Diagnosing
Table 3. Major Clinical Features
Table 4.
ABO Hemolytic Disease as the of Acute Bilirubin
Cause of Neonatal Encephalopathy
Hyperbilirubinemia Initial Phase
Mother group O, infant group A or B ● Slight stupor (“lethargic,” “sleepy”)
AND ● Slight hypotonia, paucity of movement
● Positive DAT ● Poor sucking, slightly high-pitched cry
● Jaundice appearing within 12 to 24 h after birth Intermediate Phase
● Microspherocytes on blood smear
● Negative DAT but homozygous for Gilbert ● Moderate stupor—irritable
syndrome ● Tone variable, usually increased; some have
retrocollis-opisthotonos
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald ● Minimal feeding, high-pitched cry
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co; Advanced Phase
2005:768 – 846.
● Deep stupor to coma
● Tone usually increased; some have retrocollis-
opisthotonos
● No feeding, shrill cry
increase in TSB concentrations within the first 24 hours,
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
but the TSB subsequently declines, in many infants, MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
often without any intervention. ABO hemolytic disease is Management of the Newborn. Philadelphia, Pa: Lippincott Co;
2005:768 – 846.
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 39,000 African-American male G-6PD-deficient hemi-
ABO hemolytic disease as the cause of neonatal hyperbi- zygous newborns born annually in the United States. As
lirubinemia are listed in Table 3. Recently, it has been many as 30% of infants in the United States who have
shown that DAT-negative, ABO-incompatible infants kernicterus have been found to be G-6PD-deficient.
who also have Gilbert syndrome are at risk for hyperbil- The G-6PD gene is located on the X chromosome,
irubinemia. This may explain the occasional ABO- and hemizygous males have the full enzyme deficiency,
incompatible infant who has a negative DAT and never- although female heterozygotes are also at risk for hyper-
theless develops early hyperbilirubinemia. bilirubinemia. G-6PD-deficient neonates have an in-
crease in heme turnover, although overt evidence of
Glucose-6-phosphate Dehydrogenase (G-6PD) hemolysis often is not present. In addition, affected
Deficiency infants have an impaired ability to conjugate bilirubin.
G-6PD deficiency is the most common and clinically
significant red cell enzyme defect, affecting as many as Bilirubin Encephalopathy
4,500,000 newborns worldwide each year. Although In the case described at the beginning of this article, the
known for its prevalence in the populations of the Med- infant developed extreme hyperbilirubinemia and the
iterranean, Middle East, Arabian Peninsula, southeast classic signs of acute bilirubin encephalopathy (Table 4).
Asia, and Africa, G-6PD has been transformed by immi- He also developed the typical features of chronic biliru-
gration and intermarriage into a global problem. Never- bin encephalopathy or kernicterus (Table 5).
theless, most pediatricians in the United States do not
think of G-6PD deficiency when confronted with a jaun- How Could This Have Been Prevented?
diced infant. This possibility should be considered, The infant in the case report had many of the factors that
though, particularly when seeing African-American in- increase the risk of severe hyperbilirubinemia (Table 6).
fants. Although African-American newborns, as a group, A key recommendation in the American Academy of
tend to have lower TSB concentrations than do caucasian Pediatrics (AAP) clinical practice guideline (Table 7) is
newborns, G-6PD deficiency is found in 11% to 13% of that every infant be assessed for the risk of subsequent
African-American newborns. This translates to 32,000 to severe hyperbilirubinemia before discharge, particularly
446 Pediatrics in Review Vol.27 No.12 December 2006

5. neonatology neonatal jaundice
Major Clinical Features
Table 5. Risk Factors for
Table 6.
of Chronic Postkernicteric Development of Severe
Bilirubin Encephalopathy Hyperbilirubinemia in Infants
● Extrapyramidal abnormalities, especially athetosis >35 Weeks’ Gestation (In
●
●
Gaze abnormalities, especially of upward gaze
Auditory disturbance, especially sensorineural hearing
Approximate Order of
loss Importance)
● Intellectual deficits, but minority in mentally
retarded range Major Risk Factors
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald ● Predischarge TSB or TcB level in the high-risk zone
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and (Fig. 2)
Management of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:
● Jaundice observed in the first 24 h
768 – 846.
● Blood group incompatibility with positive direct
antiglobulin test, other known hemolytic disease (eg,
G-6PD deficiency), elevated ETCOc
infants discharged before age 72 hours. The infant de- ● Gestational age 35 to 36 wk
scribed in the case was a 36 weeks’ gestation, breastfed ● Previous sibling received phototherapy
male who was discharged at age 30 hours. Two of the risk ● Cephalhematoma or significant bruising
● Exclusive breastfeeding, particularly if nursing is not
factors that have been shown repeatedly to be very im-
going well and weight loss is excessive
portant are a gestational age less than 38 weeks and ● East Asian race*
breastfeeding, particularly if nursing is not going well.
Minor Risk Factors
Almost every recently described case of kernicterus has
occurred in a breastfed infant, and infants of 35 to ● Predischarge TSB or TcB in the high- to
36 weeks’ gestation are about 13 times more likely than intermediate-risk zone (Fig. 2)
● Gestational age 37 to 38 wk
those at 40 weeks’ gestation to be readmitted for severe ● Jaundice observed before discharge
jaundice. These so called “near-term” infants receive care ● Previous sibling had jaundice
in well-baby nurseries, but unlike their term peers, they ● Macrosomia in an infant of a diabetic mother
are much more likely to nurse ineffectively, receive fewer ● Maternal age >25 y
● Male sex
calories, and have greater weight loss. In addition, the
immaturity of the liver’s conjugating system in the pre- Decreased Risk
term newborn makes it much more difficult for the (These factors are associated with decreased risk of
infants to clear bilirubin effectively. Thus, it is not sur- significant jaundice, listed in order of decreasing
prising that they become more jaundiced. importance.)
● TSB or TcB in the low-risk zone (Fig. 2)
In addition, the infant’s TSB was 7.5 mg/dL
● Gestational age >41 wk
(128.3 mcmol/L) at age 25 hours, a value very close to ● Exclusive formula feeding
the 95th percentile (Fig. 2). Another TSB measurement ● Black race*
should have been obtained within 24 hours and a ● Discharge from hospital after 72 h
follow-up visit scheduled no less than 48 hours after *Race as defined by mother’s description. TSB total serum bilirubin,
discharge. In addition, when the doctor’s office was told TcB transcutaneous bilirubin, G-6PD glucose-6-phosphate dehy-
drogenase, ETCOc end tidal carbon monoxide concentration cor-
that the infant was not nursing well, was sleepy, and was rected for ambient carbon monoxide
jaundiced, the infant should have been seen immediately. Reprinted with permission from Maisels MJ, Baltz RD, Bhutani V, et
al. Management of hyperbilirubinemia in the newborn infant 35 or
The mother was describing the first stage of acute biliru- more weeks of gestation. Pediatrics. 2004;114:297–316.
bin encephalopathy (Table 4).
Appropriate Follow-up is Essential that occurred. The AAP now recommends that any in-
If the infant in the case had been seen within 48 hours of fant discharged at less than 72 hours of age should be
discharge (before he was 4 days old), significant jaundice seen within 2 days of discharge. Infants who have many
certainly would have been noted, bilirubin would have risk factors might need to be seen earlier (within 24 h of
been measured, and he would have been treated with discharge), which would have been appropriate for this
phototherapy, thus preventing the disastrous outcome infant. Such follow-up is critical to protect infants from
Pediatrics in Review Vol.27 No.12 December 2006 447

6. neonatology neonatal jaundice
2 and Fig. 1-E). (The latter figure is available only in the
The Ten Commandments
Table 7. online edition of this article.) In the past, when newborns
remained in the hospital for 3 or 4 days, jaundiced babies
for Preventing and Managing could be identified before discharge and appropriately
Hyperbilirubinemia evaluated and treated. Today, because almost all infants
delivered vaginally leave the hospital before they are
1. Promote and support successful breastfeeding. 48 hours old, the bilirubin concentration peaks after
2. Establish nursery protocols for the jaundiced
newborn and permit nurses to obtain TSB levels discharge. Because the TSB has not yet peaked at the
without a physician’s order. time of discharge, the AAP provides stringent guidelines
3. Measure the TSB or TcB concentrations of infants for follow-up of all infants discharged before 72 hours of
jaundiced in the first 24 h after birth. age: They should be seen within 2 days of discharge.
4. Recognize that visual diagnosis of jaundice is In addition, it is essential that all TSB values be
unreliable, particularly in darkly pigmented infants.
5. Interpret all TSB levels according to the infant’s interpreted in terms of the infant’s age in hours and not
age in hours, not days. in days. Although clinicians often talk about a TSB
6. Do not treat a near-term (35 to 38 wk) infant as concentration on day 2 or day 3, Figure 2 (and Figure
a term infant; a near-term infant is at much 1-E in the online edition) shows how misleading this
higher risk of hyperbilirubinemia. thought process can be. A TSB of 8 mg/dL (136.8
7. Perform a predischarge systematic assessment on
all infants for the risk of severe mcmol/L) at 24.1 hours is above the 95th percentile and
hyperbilirubinemia. calls for evaluation and close follow-up, whereas the same
8. Provide parents with information about newborn level at 47.9 hours is in the low-risk zone (Fig. 2) and
jaundice. probably warrants no further concern. Yet, both values
9. Provide follow-up based on the time of discharge occur on postnatal day 2. In the case, the TSB value at
and the risk assessment.
10. When indicated, treat the newborn with 25 hours was 7.5 mg/dL (128.3 mcmol/L), very close
phototherapy or exchange transfusion. to the 95th percentile. Consideration should have been
given to additional investigations to try to determine why
TSB total serum bilirubin, TcB transcutaneous bilirubin
Reprinted with permission from Maisels MJ. Jaundice in a newborn. the infant was jaundiced, a subsequent TSB should have
How to head off an urgent situation. Contemp Pediatr. 2005;22: been measured within 24 hours, and follow-up should
41–54, with permission. Adapted from Pediatrics. 2004;114:297–316.
have been scheduled no later than 48 hours after dis-
charge.
severe hyperbilirubinemia and kernicterus. Nevertheless, When to Seek a Cause for Jaundice
clinical judgment is required at the time of discharge. If a In some infants, the cause of hyperbilirubinemia is appar-
41-weeks’ gestation, formula-fed, nonjaundiced infant is ent from the history and physical examination findings.
discharged and has no significant risk factors (Table 6), a For example, jaundice in a severely bruised infant needs
follow-up visit after 3 or 4 days is acceptable. The absence no further explanation, nor is there a need to investigate
of risk factors and any decision for a later follow up why a 5-day-old breastfed infant has a TSB value of
should be documented in the chart. If, on the other 15 mg/dL (256.5 mcmol/L). On the other hand, if the
hand, a 36-weeks’ gestation breastfed newborn is dis- TSB concentration is above the 95th percentile or rising
charged on a Friday, he or she should be seen no later rapidly and crossing percentiles (Fig. 2 and Fig.1-E in the
than Sunday. online edition), and this cannot be readily explained by
If follow-up cannot be assured and there is a signifi- the history and physical examination results, certain lab-
cant risk of severe hyperbilirubinemia, the clinician may oratory tests should be performed (Table 8).
need to delay discharge. If weekend follow-up is difficult
or impossible, a reasonable option is to have the infant Predicting the Risk of Hyperbilirubinemia
brought to a laboratory for a bilirubin measurement (or a Before discharge, every newborn needs to be assessed for
transcutaneous bilirubin measurement). the risk of subsequent severe hyperbilirubinemia. This
can be accomplished by using clinical criteria (Table 6) or
Management of Jaundice in the Infant measuring a TSB or TcB concentration prior to dis-
Interpreting Serum Bilirubin Levels charge. In the case described, the infant had several risk
TSB (or transcutaneous bilirubin [TcB]) concentrations factors for hyperbilirubinemia, and his TSB measured at
generally peak by the third to fifth day after birth (Fig. 26 hours was in the high intermediate-risk zone (Fig. 2),
448 Pediatrics in Review Vol.27 No.12 December 2006

7. neonatology neonatal jaundice
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 develop- same time as the metabolic screen, sparing the infant an
ment of hyperbilirubinemia. additional heel stick.
Visual Assessment of Jaundice Noninvasive Bilirubin Measurement
Traditional identification of jaundice relied on blanching Two hand-held electronic devices are available in the
the skin with digital pressure to reveal the underlying United States for measuring TcB. They provide an esti-
color of the skin and subcutaneous tissue. Although this mate of the TSB concentration, and a close correlation
remains a fundamentally important clinical sign, it has has been found between TcB and TSB measurements in
limitations and can be unreliable, particularly in darkly different racial populations.
pigmented infants. The difference between a TSB value TcB measurement (Fig. 1-E in the online edition) is
of 5 mg/dL (85.5 mcmol/L) and 8 mg/dL (136.8 not a substitute for TSB measurement, but TcB can be
mcmol/L) cannot be perceived by the eye, but this very helpful. When used as a screening tool, TcB mea-
represents the difference between the 50th and the 95th surement can help to answer the questions, “Should I
percentiles at 24 hours (Fig. 2). The potential errors worry about this infant?” and “Should I obtain a TSB on
associated with visual diagnosis have led some experts to this infant?” Because the goal is to avoid missing a
recommend that all newborns have a TSB or TcB mea- significantly elevated TSB value, the value for the TcB
sured prior to discharge. The TSB can be obtained at the measurement (based on the infant’s age in hours and
Pediatrics in Review Vol.27 No.12 December 2006 449

8. neonatology neonatal jaundice
Table 8. Laboratory Tests for the Jaundiced Infant
When there is a finding of: Obtain:
Jaundice in first 24 h Total serum bilirubin (TSB)
Jaundice that appears excessive for the infant’s age TSB
An infant receiving phototherapy or having a TSB that is Blood type; also, perform a Coombs test, if not obtained with
above the 75th percentile or rising rapidly (ie, crossing cord blood
percentiles) and unexplained by history or findings on Complete blood count, smear, and reticulocyte count
physical examination 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
A TSB approaching exchange level or not responding to Reticulocyte count, G-6PD test, albumin
phototherapy
An elevated direct (or conjugated) bilirubin level Urinalysis and urine culture; evaluate for sepsis if indicated
by history and physical examination
Jaundice present at or beyond age 3 wk or the infant Total and direct bilirubin concentration; if direct bilirubin is
is sick 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 products that can bypass the liver’s conjugating system
TSB value always will be obtained. In our nursery, we and be excreted without further metabolism. Some
routinely evaluate infants via a TcB measurement and photo products also are excreted in the urine.
obtain a TSB whenever the TcB is above the 75th per- Phototherapy displays a clear dose-response effect,
centile (Fig. 2) (or the 95th percentile in Fig. 1-E). and a number of variables influence how light works to
lower the TSB level. (In the online edition of this article,
Treatment Table 1-E shows the radiometric units used to measure
Hyperbilirubinemia can be treated via: 1) exchange the dose of phototherapy and Tables 2-E and 3-E show
transfusion to remove bilirubin mechanically; 2) photo- the factors that affect the dose and efficacy of photother-
therapy to convert bilirubin to products that can bypass apy, including type of light source, the infant’s distance
the liver’s conjugating system and be excreted in the bile from the light, and the surface area exposed.) Because of
or in the urine without further metabolism; and 3) phar- the optical properties of bilirubin and skin, the most
macologic agents to interfere with heme degradation and effective lights are those that have wavelengths predom-
bilirubin production, accelerate the normal metabolic inately in the blue-green spectrum (425 to 490 nm). At
pathways for bilirubin appearance, or inhibit the entero- these wavelengths, light penetrates the skin well and is
hepatic circulation of bilirubin. Guidelines for the use of absorbed maximally by bilirubin.
phototherapy and exchange transfusion in term and
near-term infants are provided in Figs. 3 and 4 and Table Using Phototherapy Effectively
9. Phototherapy was used initially in low-birthweight and
term infants primarily to prevent slowly rising bilirubin
Phototherapy concentrations from reaching levels that might require
Phototherapy works by infusing discrete photons of en- exchange transfusion. Today, phototherapy often is used
ergy similar to the molecules of a drug. These photons in term and near-term infants who have left the hospital
are absorbed by bilirubin molecules in the skin and and are readmitted on days 4 to 7 for treatment of TSB
subcutaneous tissue, just as drug molecules bind to a concentrations of 20 mg/dL (342 mcmol/L) or more.
receptor. The bilirubin then undergoes photochemical Such infants require a full therapeutic dose of photother-
reactions to form excretable isomers and breakdown apy (now termed intensive phototherapy) to reduce the
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9. neonatology neonatal jaundice
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/cm2 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 improves the therapy’s efficacy significantly. This is ac-
phototherapy implies the use of irradiance in the 430 to complished by placing fiberoptic pads or a light-emitting
490-nm band of at least 30 mcW/cm2 per nanometer diode (LED) mattress below the infant or using a pho-
delivered to as much of the infant’s surface area as possi- totherapy device that delivers phototherapy from special
ble (Table 2-E in the online edition of this article). blue fluorescent tubes both above and below the infant.
Increasing the surface area exposed to phototherapy When intensive phototherapy is applied appropriately, a
Pediatrics in Review Vol.27 No.12 December 2006 451

10. neonatology 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 heme oxygenase and, therefore, the production of bili-
be expected in the first 24 hours, with the most signifi- rubin (Fig. 1). To date, more than 500 newborns have
cant decline occurring in the first 4 to 6 hours. received tin mesoporphyrin in control trials, but the drug
still is awaiting United States Food and Drug Adminis-
Pharmacologic Treatment tration approval. Other drugs have been used to inhibit
Pharmacologic agents such as phenobarbital and ursode- the enterohepatic circulation of bilirubin. A recent con-
oxycholic acid improve bile flow and can help to lower trolled trial showed that agents that inhibit beta glucu-
bilirubin concentrations. Tin mesoporphyrin inhibits ronidase can decrease bilirubin levels in breastfed new-
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11. neonatology neonatal jaundice
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.
Bilirubin/Albumin Ratio at Which Exchange Transfusion
Should be Considered
TSB (mg/dL)-to-Albumin TSB (mcmol/L)-to-Albumin
Risk Category (dL) (mcmol/L)
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 6.8 0.80
isoimmune hemolytic disease or G-6PD deficiency
TSB total serum bilirubin, G-6PD glucose– 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 jaundice in newborns by inhibiting the production of bilirubin.
disease, the administration of intravenous immunoglob- Pediatrics. 2004;113:119 –123
Maisels MJ. A primer on phototherapy for the jaundiced newborn.
ulin significantly reduces the need for exchange transfu-
Contemp Pediatr. 2005;22:38 –57
sion. 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
Suggested Reading Maisels MJ. Jaundice in a newborn. Answers to questions about a
Bhutani V, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson common clinical problem. Contemp Pediatr. 2005;22:34 – 40
LH. Noninvasive measurement of total serum bilirubin in a Maisels MJ. Jaundice in a newborn. How to head off an urgent
multiracial predischarge newborn population to assess the risk of situation. Contemp Pediatr. 2005;22:41–54
severe hyperbilirubinemia. Pediatrics. 2000;106:e17. Available Maisels MJ. Why use homeopathic doses of phototherapy? Pediat-
at: http://pediatrics.aappublications.org/cgi/content/full/ rics. 1996;98:283–287
106/2/e17 Maisels MJ, Baltz RD, Bhutani V, et al. Management of hyperbil-
Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemi- irubinemia in the newborn infant 35 or more weeks of gestation.
ological strategies for its prevention through systems-based Pediatrics. 2004;114:297–316
approaches. J Perinatol. 2004;24:650 – 662 Maisels MJ, Kring EA. Transcutaneous bilirubin levels in the first
Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predis- 96 hours in a normal newborn population of 35 weeks’
charge hour-specific serum bilirubin for subsequent significant gestation. Pediatrics. 2006;117:1169 –1173
hyperbilirubinemia in healthy term and near-term newborns. Maisels MJ. Ostrea EJ Jr, Touch S, et al. Evaluation of a new transcu-
Pediatrics. 1999;103:6 –14 taneous bilirubinometer. Pediatrics. 2004;113:1628 –1635
Ennever JF. Blue light, green light, white light, more light: treat- Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes among
ment of neonatal jaundice. Clin Perinatol. 1990;17:467– 481 newborns with total serum bilirubin levels of 25 mg per deciliter
Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: a or more. N Engl J Med. 2006;354:1889 –1900
potential complication of glucose-6-phosphate dehydrogenase Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and
deficiency. Clin Perinatol. 1998;25:575–590 prevention of extreme neonatal hyperbilirubinemia in a mature
Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the health maintenance organization. Arch Pediatr Adolesc Med.
nongeneticist: hereditary defects of neonatal bilirubin conjuga- 2000;154:1140 –1147
tion. Pediatrics. 2003;111:886 – 893 Stevenson DK, Dennery PA, Hintz SR. Understanding newborn
Kappas A. A method for interdicting the development of severe jaundice. J Perinatol. 2001;21:S21–S24
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12. neonatology neonatal jaundice
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.
454 Pediatrics in Review Vol.27 No.12 December 2006