Neonatal Jaundice M. Jeffrey Maisels Pediatr. Rev. 2006;27...

DOI: 10.1542/pir.27-12-443 2006;27;443-454 Pediatr. Rev.

M. Jeffrey Maisels Neonatal Jaundice

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Neonatal JaundiceM. Jeffrey Maisels, MB,

BCh*

Author Disclosure

Dr Maisels did not

disclose any financial

relationships relevant

to this article.

To view additionalfigures and tables forthis article, visitpedsinreview.org andclick on the title of thisarticle.

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 ReportA 23-year-old primiparous mother delivered a 36 weeks’ gestation male infant following anuncomplicated 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 concentrationwas 7.5 mg/dL (128.3 mcmol/L). He was discharged at age 30 hours, with a follow-up visitscheduled for 1 week after discharge. On postnatal day 5, at about 4:30 PM, the mother calledthe 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 theprevious 2 days. The mother was given an appointment to see the pediatrician the followingmorning. Examination in the office revealed a markedly jaundiced infant who had ahigh-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 animmediate exchange transfusion was performed. Neurologic evaluation at age 18 monthsshowed profound neuromotor delay, choreoathetoid movements, an upward gaze paresis, anda sensorineural hearing loss.

This infant had acute bilirubin encephalopathy and eventually developed chronicbilirubin encephalopathy or kernicterus. Kernicterus, although rare, is one of the knowncauses of cerebral palsy. Unlike other causes of cerebral palsy, kernicterus almost always canbe 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 willbe healthy—to prevent substantial harm to a few.

Jaundice in the newborn is a unique problem because elevation of serum bilirubin ispotentially toxic to the infant’s developing central nervous system. Although it wasconsidered 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 ofjaundice in the infant.

*Department of Pediatrics, William Beaumont Hospital, Royal Oak, Mich.

Article neonatology

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Bilirubin MetabolismBilirubin is produced from the catabolism of heme in thereticuloendothelial system (Fig. 1). This unconjugatedbilirubin is released into the circulation where it is revers-ibly but tightly bound to albumin. When the bilirubin-albumin complex reaches the liver cell, it is transportedinto the hepatocyte where it combines enzymaticallywith glucuronic acid, producing bilirubin mono- anddiglucuronides. The conjugation reaction is catalyzed byuridine diphosphate glucuronosyl transferase (UGT-1A1). The mono- and diglucuronides are excreted intothe bile and the gut. In the newborn, much of theconjugated bilirubin in the intestine is hydrolyzed backto unconjugated bilirubin, a reaction catalyzed by theenzyme beta glucuronidase that is present in the intesti-

nal mucosa. The unconjugated bilirubin is reabsorbedinto the blood stream by way of the enterohepatic circu-lation, adding an additional bilirubin load to the alreadyoverstressed liver. This enterohepatic circulation of bili-rubin is an important contributor to neonatal jaundice.By contrast, in the adult, conjugated bilirubin is reducedrapidly by the action of colonic bacteria to urobilinogens,and very little enterohepatic circulation occurs.

Physiologic JaundiceFollowing ligation of the umbilical cord, the neonatemust dispose of the bilirubin load that previously wascleared through the placenta. Because neonatal hyperbi-lirubinemia is an almost universal finding during the firstpostnatal week, this transient elevation of the serumbilirubin has been termed physiologic jaundice. Themechanisms responsible for physiologic jaundice aresummarized in Table 1.

The TSB concentration reflects a combination of theeffects of bilirubin production, conjugation, and entero-hepatic circulation. The factors that affect these processesaccount for the bilirubinemia that occurs in virtually allnewborns.

Figure 1. Neonatal bile pigment metabolism. RBC�erythro-cytes, R.E.�reticuloendothelial. Reprinted with permissionfrom Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK,Mullett MD, eds. Neonatology: Pathophysiology and Manage-ment of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:768–846.

Table 1. Physiologic Mechanismsof Neonatal JaundiceIncreased 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 transferaseactivity

Defective Bilirubin Excretion

● Excretion impaired but not rate limiting

*Early-labeled bilirubin refers to the bilirubin that does not come fromthe turnover of effete red blood cells. This bilirubin is derived fromineffective erythropoiesis and the turnover of nonhemoglobin heme,primarily in the liver.Reprinted with permission from Maisels MJ. Jaundice. In: MacDonaldMG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology andManagement of the Newborn. Philadelphia, Pa: Lippincott Co;2005:768–846.

neonatology neonatal jaundice

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Breastfeeding and JaundiceAn important change in the United States population hasbeen the dramatic increase in breastfeeding at hospitaldischarge from 30% in the 1960s to almost 70% today. Insome hospitals, 85% or more of infants are breastfed.Multiple studies have found a strong association betweenbreastfeeding and an increased incidence of neonatalhyperbilirubinemia. The jaundice associated with breast-feeding in the first 2 to 4 postnatal days has been called“breastfeeding jaundice” or “breastfeeding-associatedjaundice”; that which appears later (onset at 4 to 7 d withprolonged jaundice) has been called “the human milkjaundice syndrome,” although there is considerableoverlap between the two entities.

Prolonged indirect-reacting hyperbilirubinemia (be-yond age 2 to 3 wk) occurs in 20% to 30% of all breast-feeding infants and may persist for up to 3 months insome infants. Such infants have an increased incidence ofGilbert syndrome (diagnosed by UGT-1A1 genotypingfrom a peripheral blood sample).

The jaundice associated with breastfeeding in the firstfew days after birth appears to be related to an increase inthe enterohepatic circulation of bilirubin. This occurs inthe first few days because until the milk has “come in,”breastfed infants receive fewer calories, and the decreasein caloric intake is an important stimulus to increasingthe enterohepatic circulation.

Pathologic Causes of JaundiceTable 2 lists the causes of pathologic indirect-reactinghyperbilirubinemia in the neonate.

ABO Hemolytic DiseaseThe use of Rh immunoglobin has dramatically decreasedthe incidence of Rh erythroblastosis fetalis, and hemoly-sis from ABO incompatibility is by far the most commoncause of isoimmune hemolytic disease in newborns. Inabout 15% of pregnancies, an infant who has blood typeA or B is carried by a mother who is type O. About onethird of such infants have a positive direct antiglobulintest (DAT or Coombs test), indicating that they haveanti-A or anti-B antibodies attached to the red cells. Ofthese infants, only 20% develop a peak TSB of more than12.8 mg/dL (219 mcmol/L). Consequently, althoughABO-incompatible, DAT-positive infants are abouttwice as likely as their compatible peers to have moderatehyperbilirubinemia (TSB �13 mg/dL [222.3 mcmol/L]), severe jaundice (TSB �20 mg/dL [ [342 mcmol/L]) in the infants is uncommon. Nevertheless, ABOhemolytic disease can cause severe hyperbilirubinemiaand kernicterus.

Diagnosing ABO Hemolytic DiseaseABO hemolytic disease has a highly variable clinicalpresentation. Most affected infants present with a rapid

Table 2. Causes of IndirectHyperbilirubinemia inNewbornsIncreased Production or Bilirubin Load on the Liver

Hemolytic Disease● Immune-mediated

—Rh alloimmunization, ABO and other blood groupincompatibilities

● Heritable—Red cell membrane defects: Hereditary

spherocytosis, elliptocytosis, pyropoikilocytosis,stomatocytosis

—Red cell enzyme deficiencies: Glucose-6-phosphate dehydrogenase deficiency,a pyruvatekinase deficiency, and other erythrocyte enzymedeficiencies

—Hemoglobinopathies: Alpha thalassemia, betathalassemia

—Unstable hemoglobins: Congenital Heinz bodyhemolytic anemia

Other Causes of Increased Production● Sepsisa, 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 stenosisa

● 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—Galactosemiab

—Tyrosinemiab

—Hypermethioninemiab

Metabolic—Hypothyroidism—Hypopituitarismb

aDecreased clearance also part of pathogenesis.bElevation of direct-reading bilirubin also occurs.Reprinted with permission from Maisels MJ. Jaundice. In: MacDonaldMG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology andManagement of the Newborn. Philadelphia, Pa: Lippincott Co;2005:768–846.




increase in TSB concentrations within the first 24 hours,but the TSB subsequently declines, in many infants,often without any intervention. ABO hemolytic disease isa relatively common cause of early hyperbilirubinemia(before the infant leaves the nursery), but it is a relativelyrare cause of hyperbilirubinemia in infants who have beendischarged and readmitted. The criteria for diagnosingABO hemolytic disease as the cause of neonatal hyperbi-lirubinemia are listed in Table 3. Recently, it has beenshown that DAT-negative, ABO-incompatible infantswho also have Gilbert syndrome are at risk for hyperbil-irubinemia. This may explain the occasional ABO-incompatible infant who has a negative DAT and never-theless develops early hyperbilirubinemia.

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

G-6PD deficiency is the most common and clinicallysignificant red cell enzyme defect, affecting as many as4,500,000 newborns worldwide each year. Althoughknown for its prevalence in the populations of the Med-iterranean, Middle East, Arabian Peninsula, southeastAsia, and Africa, G-6PD has been transformed by immi-gration and intermarriage into a global problem. Never-theless, most pediatricians in the United States do notthink of G-6PD deficiency when confronted with a jaun-diced infant. This possibility should be considered,though, particularly when seeing African-American in-fants. Although African-American newborns, as a group,tend to have lower TSB concentrations than do caucasiannewborns, G-6PD deficiency is found in 11% to 13% ofAfrican-American newborns. This translates to 32,000 to

39,000 African-American male G-6PD-deficient hemi-zygous newborns born annually in the United States. Asmany as 30% of infants in the United States who havekernicterus 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 hyper-bilirubinemia. G-6PD-deficient neonates have an in-crease in heme turnover, although overt evidence ofhemolysis often is not present. In addition, affectedinfants have an impaired ability to conjugate bilirubin.

Bilirubin EncephalopathyIn the case described at the beginning of this article, theinfant developed extreme hyperbilirubinemia and theclassic signs of acute bilirubin encephalopathy (Table 4).He also developed the typical features of chronic biliru-bin encephalopathy or kernicterus (Table 5).

How Could This Have Been Prevented?The infant in the case report had many of the factors thatincrease the risk of severe hyperbilirubinemia (Table 6).A key recommendation in the American Academy ofPediatrics (AAP) clinical practice guideline (Table 7) isthat every infant be assessed for the risk of subsequentsevere hyperbilirubinemia before discharge, particularly

Table 3. Criteria for DiagnosingABO Hemolytic Disease as theCause of NeonatalHyperbilirubinemiaMother 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: MacDonaldMG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology andManagement of the Newborn. Philadelphia, Pa: Lippincott Co;2005:768–846.

Table 4. Major Clinical Featuresof Acute BilirubinEncephalopathyInitial 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 retrocollis-

opisthotonos● No feeding, shrill cry

Reprinted with permission from Maisels MJ. Jaundice. In: MacDonaldMG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology andManagement of the Newborn. Philadelphia, Pa: Lippincott Co;2005:768–846.




infants discharged before age 72 hours. The infant de-scribed in the case was a 36 weeks’ gestation, breastfedmale who was discharged at age 30 hours. Two of the riskfactors that have been shown repeatedly to be very im-portant are a gestational age less than 38 weeks andbreastfeeding, particularly if nursing is not going well.Almost every recently described case of kernicterus hasoccurred in a breastfed infant, and infants of 35 to36 weeks’ gestation are about 13 times more likely thanthose at 40 weeks’ gestation to be readmitted for severejaundice. These so called “near-term” infants receive carein well-baby nurseries, but unlike their term peers, theyare much more likely to nurse ineffectively, receive fewercalories, and have greater weight loss. In addition, theimmaturity of the liver’s conjugating system in the pre-term newborn makes it much more difficult for theinfants to clear bilirubin effectively. Thus, it is not sur-prising 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 tothe 95th percentile (Fig. 2). Another TSB measurementshould have been obtained within 24 hours and afollow-up visit scheduled no less than 48 hours afterdischarge. In addition, when the doctor’s office was toldthat the infant was not nursing well, was sleepy, and wasjaundiced, the infant should have been seen immediately.The mother was describing the first stage of acute biliru-bin encephalopathy (Table 4).

Appropriate Follow-up is EssentialIf the infant in the case had been seen within 48 hours ofdischarge (before he was 4 days old), significant jaundicecertainly would have been noted, bilirubin would havebeen measured, and he would have been treated withphototherapy, thus preventing the disastrous outcome

that occurred. The AAP now recommends that any in-fant discharged at less than 72 hours of age should beseen within 2 days of discharge. Infants who have manyrisk factors might need to be seen earlier (within 24 h ofdischarge), which would have been appropriate for thisinfant. Such follow-up is critical to protect infants from

Table 5. Major Clinical Featuresof Chronic PostkernictericBilirubin Encephalopathy● Extrapyramidal abnormalities, especially athetosis● Gaze abnormalities, especially of upward gaze● Auditory disturbance, especially sensorineural hearing

loss● Intellectual deficits, but minority in mentally

retarded range

Reprinted with permission from Maisels MJ. Jaundice. In: MacDonaldMG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology andManagement of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:768–846.

Table 6. Risk Factors forDevelopment of SevereHyperbilirubinemia in Infants>35 Weeks’ Gestation (InApproximate Order ofImportance)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- tointermediate-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 ofsignificant jaundice, listed in order of decreasingimportance.)● 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. TSB�total serum bilirubin,TcB�transcutaneous bilirubin, G-6PD�glucose-6-phosphate dehy-drogenase, ETCOc�end tidal carbon monoxide concentration cor-rected for ambient carbon monoxideReprinted with permission from Maisels MJ, Baltz RD, Bhutani V, etal. Management of hyperbilirubinemia in the newborn infant 35 ormore weeks of gestation. Pediatrics. 2004;114:297–316.




severe hyperbilirubinemia and kernicterus. Nevertheless,clinical judgment is required at the time of discharge. If a41-weeks’ gestation, formula-fed, nonjaundiced infant isdischarged and has no significant risk factors (Table 6), afollow-up visit after 3 or 4 days is acceptable. The absenceof risk factors and any decision for a later follow upshould be documented in the chart. If, on the otherhand, a 36-weeks’ gestation breastfed newborn is dis-charged on a Friday, he or she should be seen no laterthan Sunday.

If follow-up cannot be assured and there is a signifi-cant risk of severe hyperbilirubinemia, the clinician mayneed to delay discharge. If weekend follow-up is difficultor impossible, a reasonable option is to have the infantbrought to a laboratory for a bilirubin measurement (or atranscutaneous bilirubin measurement).

Management of Jaundice in the InfantInterpreting Serum Bilirubin Levels

TSB (or transcutaneous bilirubin [TcB]) concentrationsgenerally peak by the third to fifth day after birth (Fig.

2 and Fig. 1-E). (The latter figure is available only in theonline edition of this article.) In the past, when newbornsremained in the hospital for 3 or 4 days, jaundiced babiescould be identified before discharge and appropriatelyevaluated and treated. Today, because almost all infantsdelivered vaginally leave the hospital before they are48 hours old, the bilirubin concentration peaks afterdischarge. Because the TSB has not yet peaked at thetime of discharge, the AAP provides stringent guidelinesfor follow-up of all infants discharged before 72 hours ofage: They should be seen within 2 days of discharge.

In addition, it is essential that all TSB values beinterpreted in terms of the infant’s age in hours and notin days. Although clinicians often talk about a TSBconcentration on day 2 or day 3, Figure 2 (and Figure1-E in the online edition) shows how misleading thisthought process can be. A TSB of 8 mg/dL (136.8mcmol/L) at 24.1 hours is above the 95th percentile andcalls for evaluation and close follow-up, whereas the samelevel at 47.9 hours is in the low-risk zone (Fig. 2) andprobably warrants no further concern. Yet, both valuesoccur on postnatal day 2. In the case, the TSB value at25 hours was 7.5 mg/dL (128.3 mcmol/L), very closeto the 95th percentile. Consideration should have beengiven to additional investigations to try to determine whythe infant was jaundiced, a subsequent TSB should havebeen measured within 24 hours, and follow-up shouldhave been scheduled no later than 48 hours after dis-charge.

When to Seek a Cause for JaundiceIn some infants, the cause of hyperbilirubinemia is appar-ent from the history and physical examination findings.For example, jaundice in a severely bruised infant needsno further explanation, nor is there a need to investigatewhy a 5-day-old breastfed infant has a TSB value of15 mg/dL (256.5 mcmol/L). On the other hand, if theTSB concentration is above the 95th percentile or risingrapidly and crossing percentiles (Fig. 2 and Fig.1-E in theonline edition), and this cannot be readily explained bythe history and physical examination results, certain lab-oratory tests should be performed (Table 8).

Predicting the Risk of HyperbilirubinemiaBefore discharge, every newborn needs to be assessed forthe risk of subsequent severe hyperbilirubinemia. Thiscan be accomplished by using clinical criteria (Table 6) ormeasuring a TSB or TcB concentration prior to dis-charge. In the case described, the infant had several riskfactors for hyperbilirubinemia, and his TSB measured at26 hours was in the high intermediate-risk zone (Fig. 2),

Table 7. The Ten Commandmentsfor Preventing and ManagingHyperbilirubinemia1. Promote and support successful breastfeeding.2. Establish nursery protocols for the jaundiced

newborn and permit nurses to obtain TSB levelswithout a physician’s order.

3. Measure the TSB or TcB concentrations of infantsjaundiced in the first 24 h after birth.

4. Recognize that visual diagnosis of jaundice isunreliable, particularly in darkly pigmented infants.

5. Interpret all TSB levels according to the infant’sage in hours, not days.

6. Do not treat a near-term (35 to 38 wk) infant asa term infant; a near-term infant is at muchhigher risk of hyperbilirubinemia.

7. Perform a predischarge systematic assessment onall infants for the risk of severehyperbilirubinemia.

8. Provide parents with information about newbornjaundice.

9. Provide follow-up based on the time of dischargeand the risk assessment.

10. When indicated, treat the newborn withphototherapy or exchange transfusion.

TSB�total serum bilirubin, TcB�transcutaneous bilirubinReprinted 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.




placing him at significant risk for subsequent develop-ment of hyperbilirubinemia.

Visual Assessment of JaundiceTraditional identification of jaundice relied on blanchingthe skin with digital pressure to reveal the underlyingcolor of the skin and subcutaneous tissue. Although thisremains a fundamentally important clinical sign, it haslimitations and can be unreliable, particularly in darklypigmented infants. The difference between a TSB valueof 5 mg/dL (85.5 mcmol/L) and 8 mg/dL (136.8mcmol/L) cannot be perceived by the eye, but thisrepresents the difference between the 50th and the 95thpercentiles at 24 hours (Fig. 2). The potential errorsassociated with visual diagnosis have led some experts torecommend that all newborns have a TSB or TcB mea-sured prior to discharge. The TSB can be obtained at the

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

Noninvasive Bilirubin MeasurementTwo hand-held electronic devices are available in theUnited States for measuring TcB. They provide an esti-mate of the TSB concentration, and a close correlationhas been found between TcB and TSB measurements indifferent racial populations.

TcB measurement (Fig. 1-E in the online edition) isnot a substitute for TSB measurement, but TcB can bevery helpful. When used as a screening tool, TcB mea-surement can help to answer the questions, “Should Iworry about this infant?” and “Should I obtain a TSB onthis infant?” Because the goal is to avoid missing asignificantly elevated TSB value, the value for the TcBmeasurement (based on the infant’s age in hours and

Figure 2. Establishing “risk zones” for the prediction of hyperbilirubinemia in newborns. This nomogram is based on hour-specificbilirubin values obtained from 2,840 well newborns >36 weeks gestational age whose birthweights were >2,000 g or >35 weeksgestational age whose birthweights were >2,500 g. The serum bilirubin concentration was measured before discharge. The risk zonein which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile. Reprinted withpermission from Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequentsignificant hyperbilirubinemia in healthy-term and near-term newborns. Pediatrics. 1999;103:6–14.




other risk factors) always should be one above which aTSB value always will be obtained. In our nursery, weroutinely evaluate infants via a TcB measurement andobtain a TSB whenever the TcB is above the 75th per-centile (Fig. 2) (or the 95th percentile in Fig. 1-E).

TreatmentHyperbilirubinemia can be treated via: 1) exchangetransfusion to remove bilirubin mechanically; 2) photo-therapy to convert bilirubin to products that can bypassthe liver’s conjugating system and be excreted in the bileor in the urine without further metabolism; and 3) phar-macologic agents to interfere with heme degradation andbilirubin production, accelerate the normal metabolicpathways for bilirubin appearance, or inhibit the entero-hepatic circulation of bilirubin. Guidelines for the use ofphototherapy and exchange transfusion in term andnear-term infants are provided in Figs. 3 and 4 and Table9.

PhototherapyPhototherapy works by infusing discrete photons of en-ergy similar to the molecules of a drug. These photonsare absorbed by bilirubin molecules in the skin andsubcutaneous tissue, just as drug molecules bind to areceptor. The bilirubin then undergoes photochemicalreactions to form excretable isomers and breakdown

products that can bypass the liver’s conjugating systemand be excreted without further metabolism. Somephoto products also are excreted in the urine.

Phototherapy displays a clear dose-response effect,and a number of variables influence how light works tolower the TSB level. (In the online edition of this article,Table 1-E shows the radiometric units used to measurethe dose of phototherapy and Tables 2-E and 3-E showthe factors that affect the dose and efficacy of photother-apy, including type of light source, the infant’s distancefrom the light, and the surface area exposed.) Because ofthe optical properties of bilirubin and skin, the mosteffective lights are those that have wavelengths predom-inately in the blue-green spectrum (425 to 490 nm). Atthese wavelengths, light penetrates the skin well and isabsorbed maximally by bilirubin.

Using Phototherapy EffectivelyPhototherapy was used initially in low-birthweight andterm infants primarily to prevent slowly rising bilirubinconcentrations from reaching levels that might requireexchange transfusion. Today, phototherapy often is usedin term and near-term infants who have left the hospitaland are readmitted on days 4 to 7 for treatment of TSBconcentrations of 20 mg/dL (342 mcmol/L) or more.Such infants require a full therapeutic dose of photother-apy (now termed intensive phototherapy) to reduce the

Table 8. Laboratory Tests for the Jaundiced InfantWhen there is a finding of: Obtain:

Jaundice in first 24 h Total serum bilirubin (TSB)Jaundice that appears excessive for the infant’s age TSBAn infant receiving phototherapy or having a TSB that is

above the 75th percentile or rising rapidly (ie, crossingpercentiles) and unexplained by history or findings onphysical examination

Blood type; also, perform a Coombs test, if not obtained withcord blood

Complete blood count, smear, and reticulocyte countDirect (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 tophototherapy

Reticulocyte count, G-6PD test, albumin

An elevated direct (or conjugated) bilirubin level Urinalysis and urine culture; evaluate for sepsis if indicatedby history and physical examination

Jaundice present at or beyond age 3 wk or the infantis sick

Total and direct bilirubin concentration; if direct bilirubin iselevated, evaluate for causes of cholestasis

(Also check results of newborn thyroid and galactosemiascreen and evaluate infant for signs or symptoms ofhypothyroidism)

Reprinted with permission from Maisels MJ. Jaundice in a newborn. How to head off an urgent situation. Contemp Pediatr. 2005;22:41–54. Adapted withpermission from Pediatrics. 2004;14:297–316.




bilirubin concentration as soon as possible. Intensivephototherapy implies the use of irradiance in the 430 to490-nm band of at least 30 mcW/cm2 per nanometerdelivered to as much of the infant’s surface area as possi-ble (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 ac-complished by placing fiberoptic pads or a light-emittingdiode (LED) mattress below the infant or using a pho-totherapy device that delivers phototherapy from specialblue fluorescent tubes both above and below the infant.When intensive phototherapy is applied appropriately, a

Figure 3. The risk factors listed for this figure increase the likelihood of brain damage at different bilirubin concentrations. Infantsare designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of bilirubin, theblood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin. “Intensive phototherapy” implies irradiance inthe blue-green spectrum (wavelengths of approximately 430 to 490 nm) of at least 30 mcW/cm2 per nanometer (measured at theinfant’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 bilirubinvalues approach or exceed the exchange transfusion line, the sides of the bassinet, incubator, or warmer should be lined withaluminum foil or white material to increase the surface area of the infant exposed and increase the efficacy of phototherapy. If thetotal serum bilirubin value does not decrease or continues to rise in an infant who is receiving intensive phototherapy, this stronglysuggests the presence of hemolysis. Infants who receive phototherapy and have an elevated direct-reacting or conjugated bilirubinlevel (cholestatic jaundice) may develop the bronze baby syndrome. Reprinted with permission from Maisels MJ, Baltz RD, BhutaniV, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.




30% to 40% decrement in the bilirubin concentration canbe expected in the first 24 hours, with the most signifi-cant decline occurring in the first 4 to 6 hours.

Pharmacologic TreatmentPharmacologic agents such as phenobarbital and ursode-oxycholic acid improve bile flow and can help to lowerbilirubin concentrations. Tin mesoporphyrin inhibits

heme oxygenase and, therefore, the production of bili-rubin (Fig. 1). To date, more than 500 newborns havereceived tin mesoporphyrin in control trials, but the drugstill is awaiting United States Food and Drug Adminis-tration approval. Other drugs have been used to inhibitthe enterohepatic circulation of bilirubin. A recent con-trolled trial showed that agents that inhibit beta glucu-ronidase can decrease bilirubin levels in breastfed new-

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 ofbilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin.




borns. For infants who have isoimmune hemolyticdisease, the administration of intravenous immunoglob-ulin significantly reduces the need for exchange transfu-sion.

Suggested ReadingBhutani V, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson

LH. Noninvasive measurement of total serum bilirubin in amultiracial predischarge newborn population to assess the risk ofsevere hyperbilirubinemia. Pediatrics. 2000;106:e17. Availableat: http://pediatrics.aappublications.org/cgi/content/full/106/2/e17

Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemi-ological strategies for its prevention through systems-basedapproaches. J Perinatol. 2004;24:650–662

Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predis-charge hour-specific serum bilirubin for subsequent significanthyperbilirubinemia in healthy term and near-term newborns.Pediatrics. 1999;103:6–14

Ennever JF. Blue light, green light, white light, more light: treat-ment of neonatal jaundice. Clin Perinatol. 1990;17:467–481

Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: apotential complication of glucose-6-phosphate dehydrogenasedeficiency. Clin Perinatol. 1998;25:575–590

Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for thenongeneticist: hereditary defects of neonatal bilirubin conjuga-tion. 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, MullettMD, eds. Neonatology: Pathophysiology and Management of theNewborn. Philadelphia, Pa: Lippincott Co; 2005:768–846

Maisels MJ. Jaundice in a newborn. Answers to questions about acommon clinical problem. Contemp Pediatr. 2005;22:34–40

Maisels MJ. Jaundice in a newborn. How to head off an urgentsituation. Contemp Pediatr. 2005;22:41–54

Maisels MJ. Why use homeopathic doses of phototherapy? Pediat-rics. 1996;98:283–287

Maisels MJ, Baltz RD, Bhutani V, et al. Management of hyperbil-irubinemia in the newborn infant 35 or more weeks of gestation.Pediatrics. 2004;114:297–316

Maisels MJ, Kring EA. Transcutaneous bilirubin levels in the first96 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 transcu-taneous bilirubinometer. Pediatrics. 2004;113:1628–1635

Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes amongnewborns with total serum bilirubin levels of 25 mg per deciliteror more. N Engl J Med. 2006;354:1889–1900

Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction andprevention of extreme neonatal hyperbilirubinemia in a maturehealth maintenance organization. Arch Pediatr Adolesc Med.2000;154:1140–1147

Stevenson DK, Dennery PA, Hintz SR. Understanding newbornjaundice. J Perinatol. 2001;21:S21–S24

Table 9. Additional Guidelines for Exchange TransfusionThese ratios can be used together with but not in lieu of the TSB concentration as an additional factor in determining the needfor exchange transfusion.

Risk Category

Bilirubin/Albumin Ratio at Which Exchange TransfusionShould be Considered

TSB (mg/dL)-to-Albumin(dL)

TSB (mcmol/L)-to-Albumin(mcmol/L)

Infants >38 0/7 wk 8.0 0.94Infants 35 0/7 to 37 6/7 wk and well or >38 0/7 wk

if higher risk or isoimmune hemolytic disease or G-6PD deficiency

7.2 0.84

Infants 35 0/7 to 37 6/7 wk if higher risk orisoimmune hemolytic disease or G-6PD deficiency

6.8 0.80

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.




PIR QuizQuiz also available online at www.pedsinreview.org.

1. In explaining breastfeeding-associated jaundice to the third-year students on your service, you note thatjaundice seen in the first postnatal week results from an increase in the enterohepatic circulation dueprimarily 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 agebe 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 jaundiceduring the first week after birth. Among the following, which is most likely to contribute to thedevelopment 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. Thetranscutaneous bilirubin level is above the 75th percentile. Of the following, the next most appropriate stepin 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.




DOI: 10.1542/pir.27-12-443 2006;27;443-454 Pediatr. Rev.

M. Jeffrey Maisels Neonatal Jaundice

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