- M. Jeffrey Maisels, MB, BCh*
After reviewing this article, readers should be able to:
Understand the metabolism of bilirubin.
Describe the factors that place an infant at risk for developing severe hyperbilirubinemia.
Describe the physiologic mechanisms that result in neonatal jaundice.
List the common causes of indirect hyperbilirubinemia in the newborn.
Delineate the criteria for diagnosing ABO hemolytic disease.
Discuss the major clinical features of acute bilirubin encephalopathy and chronic bilirubin encephalopathy (kernicterus).
List the key elements of the American Academy of Pediatrics guidelines for the management of hyperbilirubinemia.
Describe the factors that affect the dosage and efficacy of phototherapy.
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.
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 bilirubin-albumin 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.
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.
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 ↵* 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.
Increased Bilirubin Load on Liver Cell Decreased Hepatic Uptake of Bilirubin From Plasma Decreased Bilirubin Conjugation Defective Bilirubin Excretion
Increased erythrocyte volume
Decreased erythrocyte survival
Increased early-labeled bilirubin*
Increased enterohepatic circulation of bilirubin
Decreased uridine diphosphoglucuronosyl transferase activity
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.
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.
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 2lists the causes of pathologic indirect-reacting hyperbilirubinemia in the neonate.
|Increased Production or Bilirubin Load on the Liver|
|Hemolytic Disease |
|Other Causes of Increased Production|
|Increased Enterohepatic Circulation of Bilirubin |
|Inborn Errors of Metabolism|
↵ a Decreased clearance also part of pathogenesis.
↵ b Elevation of direct-reading bilirubin also occurs.
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and Management of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:768–846.
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.
Diagnosing ABO Hemolytic Disease
ABO hemolytic disease has a highly variable clinical presentation. Most affected infants present with a rapid 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 ABO-incompatible infant who has a negative DAT and nevertheless develops early hyperbilirubinemia.
|Mother group O, infant group A or B AND |
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 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.
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).
|Intermediate Phase |
|Advanced Phase |
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.
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 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.
|Major Risk Factors|
|Minor Risk Factors|
|(These factors are associated with decreased risk of significant jaundice, listed in order of decreasing importance.)|
↵* Race as defined by mother’s description. TSB=total serum bilirubin, TcB=transcutaneous bilirubin, G-6PD=glucose-6-phosphate dehydrogenase, ETCOc=end 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.
TSB=total serum bilirubin, TcB=transcutaneous 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.
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 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 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).
|When there is a finding of:||Obtain:|
|Jaundice in first 24 h||Total serum bilirubin (TSB)|
|Jaundice that appears excessive for the infant’s age||TSB|
|An infant receiving phototherapy or having a TSB that is above the 75th percentile or rising rapidly (ie, crossing percentiles) and unexplained by history or findings on physical examination||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|
|A TSB approaching exchange level or not responding to phototherapy||Reticulocyte count, G-6PD test, albumin|
|An elevated direct (or conjugated) bilirubin level||Urinalysis and urine culture; evaluate for sepsis if indicated by history and physical examination|
|Jaundice present at or beyond age 3 wk or the infant is sick||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.
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), 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 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).
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.
|Risk Category||Bilirubin/Albumin Ratio at Which Exchange Transfusion Should be Considered|
|TSB (mg/dL)-to-Albumin (dL)||TSB (mcmol/L)-to-Albumin (mcmol/L)|
|nfants ≥38 0/7 wk||8.0||0.94|
|Infants 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 or isoimmune 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.
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 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 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 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 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 newborns. For infants who have isoimmune hemolytic disease, the administration of intravenous immunoglobulin significantly reduces the need for exchange transfusion.
Dr Maisels did not disclose any financial relationships relevant to this article.
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- Copyright © 2006 by the American Academy of Pediatrics