Neonatal Jaundice M. Jeffrey Maisels Pediatr. Rev. 2006;27;443-454 DOI: 10.1542/pir.

27-12-443

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/cgi/content/full/27/12/443

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2006 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601. Online ISSN: 1526-3347.

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Article

neonatology

Neonatal Jaundice
M. Jeffrey Maisels, MB, BCh*

Objectives

After reviewing this article, readers should be able to:

Author Disclosure Dr Maisels did not disclose any nancial relationships relevant to this article.

To view additional gures and tables for this article, visit pedsinreview.org and click on the title of this article.

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 efcacy 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 difculty 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 pediatricians ofce 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 ofce 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 identication, monitoring, follow-up, and treatment of the jaundiced newborn. Because kernicterus is uncommon, pediatricians are required to monitor and treat many jaundiced infantsmost of whom will be healthyto prevent substantial harm to a few. Jaundice in the newborn is a unique problem because elevation of serum bilirubin is potentially toxic to the infants 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

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Physiologic Mechanisms of Neonatal Jaundice

Table 1.

Increased Bilirubin Load on Liver Cell

Increased erythrocyte volume Decreased erythrocyte survival Increased early-labeled bilirubin* Increased enterohepatic circulation of bilirubin Decreased ligandin Decreased uridine diphosphoglucuronosyl transferase activity Excretion impaired but not rate limiting

Decreased Hepatic Uptake of Bilirubin From Plasma

Decreased Bilirubin Conjugation

Defective Bilirubin Excretion

*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.

cytes, 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.

Figure 1. Neonatal bile pigment metabolism. RBCerythro-

nal 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.

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 (UGT1A1). 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 intesti444 Pediatrics in Review Vol.27 No.12 December 2006

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 nding during the rst 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 reects 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 rst 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 rst few days after birth appears to be related to an increase in the enterohepatic circulation of bilirubin. This occurs in the rst 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.

Table 2.

Causes of Indirect Hyperbilirubinemia in Newborns

Increased Production or Bilirubin Load on the Liver

Pathologic Causes of Jaundice

Table 2 lists the causes of pathologic indirect-reacting hyperbilirubinemia in the neonate.

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 deciencies: Glucose-6phosphate dehydrogenase deciency,a pyruvate kinase deciency, and other erythrocyte enzyme deciencies Hemoglobinopathies: Alpha thalassemia, beta thalassemia Unstable hemoglobins: Congenital Heinz body hemolytic anemia Other Causes of Increased Production a, b Sepsis 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 a Pyloric stenosis Small or large bowel obstruction or ileus
Decreased Clearance Prematurity Glucose-6-phosphate dehydrogenase deciency Inborn Errors of Metabolism Crigler-Najjar syndrome, types I and II Gilbert syndrome Galactosemiab Tyrosinemiab Hypermethioninemiab Metabolic Hypothyroidism Hypopituitarismb
a b

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.

Decreased clearance also part of pathogenesis. 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

Table 4.

Major Clinical Features of Acute Bilirubin Encephalopathy

Slight stupor (lethargic, sleepy) Slight hypotonia, paucity of movement Poor sucking, slightly high-pitched cry Moderate stuporirritable Tone variable, usually increased; some have retrocollis-opisthotonos Minimal feeding, high-pitched cry Deep stupor to coma Tone usually increased; some have retrocollisopisthotonos No feeding, shrill cry

Initial Phase

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.

Intermediate Phase

Advanced Phase

increase in TSB concentrations within the rst 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.

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.

Glucose-6-phosphate Dehydrogenase (G-6PD) Deciency

G-6PD deciency is the most common and clinically signicant 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 deciency 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 deciency is found in 11% to 13% of African-American newborns. This translates to 32,000 to
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39,000 African-American male G-6PD-decient 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-decient. The G-6PD gene is located on the X chromosome, and hemizygous males have the full enzyme deciency, although female heterozygotes are also at risk for hyperbilirubinemia. G-6PD-decient 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 decits, but minority in mentally retarded range

Table 6.

Risk Factors for Development of Severe Hyperbilirubinemia in Infants >35 Weeks Gestation (In Approximate Order of Importance)
Predischarge TSB or TcB level in the high-risk zone (Fig. 2) Jaundice observed in the rst 24 h Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (eg, G-6PD deciency), elevated ETCOc Gestational age 35 to 36 wk Previous sibling received phototherapy Cephalhematoma or signicant bruising Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive East Asian race* 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

Major Risk Factors

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 livers conjugating system in the preterm newborn makes it much more difcult for the infants to clear bilirubin effectively. Thus, it is not surprising that they become more jaundiced. In addition, the infants 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 doctors ofce 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 rst stage of acute bilirubin encephalopathy (Table 4).

Minor Risk Factors

Decreased Risk (These factors are associated with decreased risk of signicant 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 dened by mothers 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;114:297316.

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), signicant jaundice certainly would have been noted, bilirubin would have been measured, and he would have been treated with phototherapy, thus preventing the disastrous outcome

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 physicians order. 3. Measure the TSB or TcB concentrations of infants jaundiced in the rst 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 infants 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: 4154, with permission. Adapted from Pediatrics. 2004;114:297316.

2 and Fig. 1-E). (The latter gure 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 identied 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 infants 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.

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 signicant 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 signicant risk of severe hyperbilirubinemia, the clinician may need to delay discharge. If weekend follow-up is difcult or impossible, a reasonable option is to have the infant brought to a laboratory for a bilirubin measurement (or a transcutaneous bilirubin measurement).

When to Seek a Cause for Jaundice

In some infants, the cause of hyperbilirubinemia is apparent from the history and physical examination ndings. 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),

Management of Jaundice in the Infant

Interpreting Serum Bilirubin Levels
TSB (or transcutaneous bilirubin [TcB]) concentrations generally peak by the third to fth day after birth (Fig.
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Figure 2. Establishing risk zones for the prediction of hyperbilirubinemia in newborns. This nomogram is based on hour-specic

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-specic serum bilirubin for subsequent signicant hyperbilirubinemia in healthy-term and near-term newborns. Pediatrics. 1999;103:6 14.

placing him at signicant risk for subsequent development of hyperbilirubinemia.

same time as the metabolic screen, sparing the infant an additional heel stick.

Visual Assessment of Jaundice

Traditional identication 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

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 signicantly elevated TSB value, the value for the TcB measurement (based on the infants age in hours and
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Table 8.

Laboratory Tests for the Jaundiced Infant

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 infants age and TSB level) Consider the possibility of glucose-6-phosphate dehydrogenase (G-6PD) deciency, particularly in AfricanAmerican 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)

When there is a nding of: Jaundice in rst 24 h Jaundice that appears excessive for the infants 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 ndings 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

Reprinted with permission from Maisels MJ. Jaundice in a newborn. How to head off an urgent situation. Contemp Pediatr. 2005;22:4154. Adapted with permission from Pediatrics. 2004;14:297316.

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 livers 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.

products that can bypass the livers 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 inuence 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 efcacy of phototherapy, including type of light source, the infants 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

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
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Figure 3. The risk factors listed for this gure 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 infants skin directly below the center of the phototherapy unit) and delivered to as much of the infants 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 specied 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 efcacy 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;114:297316.

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/cm2 per nanometer delivered to as much of the infants surface area as possible (Table 2-E in the online edition of this article). Increasing the surface area exposed to phototherapy

improves the therapys efcacy signicantly. This is accomplished by placing beroptic pads or a light-emitting diode (LED) mattress below the infant or using a phototherapy device that delivers phototherapy from special blue uorescent tubes both above and below the infant. When intensive phototherapy is applied appropriately, a
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Figure 4. The risk factors listed for this gure 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 rst 24 hours, with the most signicant decline occurring in the rst 4 to 6 hours.

Pharmacologic Treatment
Pharmacologic agents such as phenobarbital and ursodeoxycholic acid improve bile ow and can help to lower bilirubin concentrations. Tin mesoporphyrin inhibits
452 Pediatrics in Review Vol.27 No.12 December 2006

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

Bilirubin/Albumin Ratio at Which Exchange Transfusion Should be Considered

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 Infants >38 0/7 wk Infants 35 0/7 to 37 6/7 wk and well or >38 0/7 wk if higher risk or isoimmune hemolytic disease or G6PD deciency Infants 35 0/7 to 37 6/7 wk if higher risk or isoimmune hemolytic disease or G-6PD deciency

TSB (mg/dL)-to-Albumin (dL) 8.0 7.2 6.8

TSB (mcmol/L)-to-Albumin (mcmol/L) 0.94 0.84 0.80

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;114:297316.

borns. For infants who have isoimmune hemolytic disease, the administration of intravenous immunoglobulin signicantly 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-specic serum bilirubin for subsequent signicant 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 deciency. Clin Perinatol. 1998;25:575590 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;22:4154 Maisels MJ. Why use homeopathic doses of phototherapy? Pediatrics. 1996;98:283287 Maisels MJ, Baltz RD, Bhutani V, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297316 Maisels MJ, Kring EA. Transcutaneous bilirubin levels in the rst 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:S21S24

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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 rst postnatal week results from an increase in the enterohepatic circulation due primarily to: A. B. C. D. E. Decreased caloric intake. Gilbert syndrome. Increased protein binding. Insufcient free water. 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. B. C. D. E. 24. 36. 48. 72. 96.

3. Almost all infants experience a transient increase in bilirubin concentrations known as physiologic jaundice during the rst week after birth. Among the following, which is most likely to contribute to the development of this condition? A. B. C. D. E. Decreased enterohepatic circulation. Decreased erythrocyte survival. Decreased erythrocyte volume. Increased bilirubin conjugation. 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. B. C. D. E. Advise the mother to increase the frequency of breastfeeding. Check the mothers and the babys blood groups. Obtain a complete blood count and differential count. Obtain a serum bilirubin measurement. 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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including high-resolution figures, can be found at: http://pedsinreview.aappublications.org/cgi/content/full/27/12/44 3 Supplementary material can be found at: http://pedsinreview.aappublications.org/cgi/content/full/27/12/44 3/DC1 This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://pedsinreview.aappublications.org/cgi/collection/fetus_new born_infant Gastrointestinal Disorders http://pedsinreview.aappublications.org/cgi/collection/gastrointe stinal_disorders Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pedsinreview.aappublications.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://pedsinreview.aappublications.org/misc/reprints.shtml

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