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 


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. 

Pediatrics in Review Vol.27 No.12 December 2006 443 


neonatology 

neonatal jaundice 

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. 

444 Pediatrics in Review Vol.27 No.12 December 2006 


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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. 




2005:768–846. 

Diagnosing ABO Hemolytic Disease 

ABO hemolytic disease has a highly variable clinical 

presentation. Most affected infants present with a rapid 



neonatology 


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 




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 




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 



neonatology 


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 



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 



neonatology 


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), 



neonatology 


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 



neonatology 


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 



neonatology 


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 



neonatology 


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- 



neonatology 


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 

jaundice. J Perinatol. 2001;21:S21–S24 



neonatology 


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. 




M. Jeffrey Maisels 

Pediatr. Rev. 2006;27;443-454 

DOI: 10.1542/pir.27-12-443 

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