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Neonatal Jaundice
M. Jeffrey Maisels, MB,
Objectives After reviewing this article, readers should be able to:
BCh*
1. Understand the metabolism of bilirubin.
2. Describe the factors that place an infant at risk for developing severe
Author Disclosure hyperbilirubinemia.
Dr Maisels did not 3. Describe the physiologic mechanisms that result in neonatal jaundice.
disclose any financial 4. List the common causes of indirect hyperbilirubinemia in the newborn.
relationships relevant 5. Delineate the criteria for diagnosing ABO hemolytic disease.
to this article. 6. Discuss the major clinical features of acute bilirubin encephalopathy and chronic
bilirubin encephalopathy (kernicterus).
7. List the key elements of the American Academy of Pediatrics guidelines for the
management of hyperbilirubinemia.
To view additional 8. Describe the factors that affect the dosage and efficacy of phototherapy.
figures and tables for
this article, visit
pedsinreview.org and
click on the title of this
article. Case Report
A 23-year-old primiparous mother delivered a 36 weeks’ gestation male infant following an
uncomplicated pregnancy. The infant initially had some difficulty latching on for breastfeed-
ing, but subsequently appeared to nurse adequately, although his nursing quality was consid-
ered “fair.” At age 25 hours, he appeared slightly jaundiced, and his bilirubin concentration
was 7.5 mg/dL (128.3 mcmol/L). He was discharged at age 30 hours, with a follow-up visit
scheduled for 1 week after discharge. On postnatal day 5, at about 4:30 PM, the mother called
the pediatrician’s office because her infant was not nursing well and was becoming increas-
ingly sleepy. On questioning, she also reported that he had become more jaundiced over the
previous 2 days. The mother was given an appointment to see the pediatrician the following
morning. Examination in the office revealed a markedly jaundiced infant who had a
high-pitched cry and intermittently arched his back. His total serum bilirubin (TSB) concen-
tration was 36.5 mg/dL (624.2 mcmol/L). He was admitted to the hospital, and an
immediate exchange transfusion was performed. Neurologic evaluation at age 18 months
showed profound neuromotor delay, choreoathetoid movements, an upward gaze paresis, and
a sensorineural hearing loss.
This infant had acute bilirubin encephalopathy and eventually developed chronic
bilirubin encephalopathy or kernicterus. Kernicterus, although rare, is one of the known
causes of cerebral palsy. Unlike other causes of cerebral palsy, kernicterus almost always can
be prevented through a relatively straightforward process of identification, monitoring,
follow-up, and treatment of the jaundiced newborn. Because kernicterus is uncommon,
pediatricians are required to monitor and treat many jaundiced infants—most of whom will
be healthy—to prevent substantial harm to a few.
Jaundice in the newborn is a unique problem because elevation of serum bilirubin is
potentially toxic to the infant’s developing central nervous system. Although it was
considered almost extinct, kernicterus still occurs in the United States and western Europe.
To prevent kernicterus, clinicians need to understand the physiology of bilirubin produc-
tion and excretion and develop a consistent, systematic approach to the management of
jaundice in the infant.
Physiologic Mechanisms
Table 1.
of Neonatal Jaundice
Increased Bilirubin Load on Liver Cell
● Increased erythrocyte volume
● Decreased erythrocyte survival
● Increased early-labeled bilirubin*
● Increased enterohepatic circulation of bilirubin
Decreased Hepatic Uptake of Bilirubin From Plasma
● Decreased ligandin
Decreased Bilirubin Conjugation
● Decreased uridine diphosphoglucuronosyl transferase
activity
Defective Bilirubin Excretion
● Excretion impaired but not rate limiting
*Early-labeled bilirubin refers to the bilirubin that does not come from
the turnover of effete red blood cells. This bilirubin is derived from
ineffective erythropoiesis and the turnover of nonhemoglobin heme,
primarily in the liver.
Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald
MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and
Management of the Newborn. Philadelphia, Pa: Lippincott Co;
2005:768 – 846.
Appropriate Follow-up is Essential that occurred. The AAP now recommends that any in-
If the infant in the case had been seen within 48 hours of fant discharged at less than 72 hours of age should be
discharge (before he was 4 days old), significant jaundice seen within 2 days of discharge. Infants who have many
certainly would have been noted, bilirubin would have risk factors might need to be seen earlier (within 24 h of
been measured, and he would have been treated with discharge), which would have been appropriate for this
phototherapy, thus preventing the disastrous outcome infant. Such follow-up is critical to protect infants from
severe hyperbilirubinemia and kernicterus. Nevertheless, When to Seek a Cause for Jaundice
clinical judgment is required at the time of discharge. If a In some infants, the cause of hyperbilirubinemia is appar-
41-weeks’ gestation, formula-fed, nonjaundiced infant is ent from the history and physical examination findings.
discharged and has no significant risk factors (Table 6), a For example, jaundice in a severely bruised infant needs
follow-up visit after 3 or 4 days is acceptable. The absence no further explanation, nor is there a need to investigate
of risk factors and any decision for a later follow up why a 5-day-old breastfed infant has a TSB value of
should be documented in the chart. If, on the other 15 mg/dL (256.5 mcmol/L). On the other hand, if the
hand, a 36-weeks’ gestation breastfed newborn is dis- TSB concentration is above the 95th percentile or rising
charged on a Friday, he or she should be seen no later rapidly and crossing percentiles (Fig. 2 and Fig.1-E in the
than Sunday. online edition), and this cannot be readily explained by
If follow-up cannot be assured and there is a signifi- the history and physical examination results, certain lab-
cant risk of severe hyperbilirubinemia, the clinician may oratory tests should be performed (Table 8).
need to delay discharge. If weekend follow-up is difficult
or impossible, a reasonable option is to have the infant Predicting the Risk of Hyperbilirubinemia
brought to a laboratory for a bilirubin measurement (or a Before discharge, every newborn needs to be assessed for
transcutaneous bilirubin measurement). the risk of subsequent severe hyperbilirubinemia. This
can be accomplished by using clinical criteria (Table 6) or
Management of Jaundice in the Infant measuring a TSB or TcB concentration prior to dis-
Interpreting Serum Bilirubin Levels charge. In the case described, the infant had several risk
TSB (or transcutaneous bilirubin [TcB]) concentrations factors for hyperbilirubinemia, and his TSB measured at
generally peak by the third to fifth day after birth (Fig. 26 hours was in the high intermediate-risk zone (Fig. 2),
Figure 2. Establishing “risk zones” for the prediction of hyperbilirubinemia in newborns. This nomogram is based on hour-specific
bilirubin values obtained from 2,840 well newborns >36 weeks gestational age whose birthweights were >2,000 g or >35 weeks
gestational age whose birthweights were >2,500 g. The serum bilirubin concentration was measured before discharge. The risk zone
in which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile. Reprinted with
permission from Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent
significant hyperbilirubinemia in healthy-term and near-term newborns. Pediatrics. 1999;103:6 –14.
placing him at significant risk for subsequent develop- same time as the metabolic screen, sparing the infant an
ment of hyperbilirubinemia. additional heel stick.
other risk factors) always should be one above which a products that can bypass the liver’s conjugating system
TSB value always will be obtained. In our nursery, we and be excreted without further metabolism. Some
routinely evaluate infants via a TcB measurement and photo products also are excreted in the urine.
obtain a TSB whenever the TcB is above the 75th per- Phototherapy displays a clear dose-response effect,
centile (Fig. 2) (or the 95th percentile in Fig. 1-E). and a number of variables influence how light works to
lower the TSB level. (In the online edition of this article,
Treatment Table 1-E shows the radiometric units used to measure
Hyperbilirubinemia can be treated via: 1) exchange the dose of phototherapy and Tables 2-E and 3-E show
transfusion to remove bilirubin mechanically; 2) photo- the factors that affect the dose and efficacy of photother-
therapy to convert bilirubin to products that can bypass apy, including type of light source, the infant’s distance
the liver’s conjugating system and be excreted in the bile from the light, and the surface area exposed.) Because of
or in the urine without further metabolism; and 3) phar- the optical properties of bilirubin and skin, the most
macologic agents to interfere with heme degradation and effective lights are those that have wavelengths predom-
bilirubin production, accelerate the normal metabolic inately in the blue-green spectrum (425 to 490 nm). At
pathways for bilirubin appearance, or inhibit the entero- these wavelengths, light penetrates the skin well and is
hepatic circulation of bilirubin. Guidelines for the use of absorbed maximally by bilirubin.
phototherapy and exchange transfusion in term and
near-term infants are provided in Figs. 3 and 4 and Table Using Phototherapy Effectively
9. Phototherapy was used initially in low-birthweight and
term infants primarily to prevent slowly rising bilirubin
Phototherapy concentrations from reaching levels that might require
Phototherapy works by infusing discrete photons of en- exchange transfusion. Today, phototherapy often is used
ergy similar to the molecules of a drug. These photons in term and near-term infants who have left the hospital
are absorbed by bilirubin molecules in the skin and and are readmitted on days 4 to 7 for treatment of TSB
subcutaneous tissue, just as drug molecules bind to a concentrations of 20 mg/dL (342 mcmol/L) or more.
receptor. The bilirubin then undergoes photochemical Such infants require a full therapeutic dose of photother-
reactions to form excretable isomers and breakdown apy (now termed intensive phototherapy) to reduce the
Figure 3. The risk factors listed for this figure increase the likelihood of brain damage at different bilirubin concentrations. Infants
are designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of bilirubin, the
blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin. “Intensive phototherapy” implies irradiance in
the blue-green spectrum (wavelengths of approximately 430 to 490 nm) of at least 30 mcW/cm2 per nanometer (measured at the
infant’s skin directly below the center of the phototherapy unit) and delivered to as much of the infant’s surface area as possible.
Note that irradiance measured below the center of the light source is much greater than that measured at the periphery.
Measurements should be made with a radiometer specified by the manufacturer of the phototherapy system. If total serum bilirubin
values approach or exceed the exchange transfusion line, the sides of the bassinet, incubator, or warmer should be lined with
aluminum foil or white material to increase the surface area of the infant exposed and increase the efficacy of phototherapy. If the
total serum bilirubin value does not decrease or continues to rise in an infant who is receiving intensive phototherapy, this strongly
suggests the presence of hemolysis. Infants who receive phototherapy and have an elevated direct-reacting or conjugated bilirubin
level (cholestatic jaundice) may develop the bronze baby syndrome. Reprinted with permission from Maisels MJ, Baltz RD, Bhutani
V, et al. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.
bilirubin concentration as soon as possible. Intensive improves the therapy’s efficacy significantly. This is ac-
phototherapy implies the use of irradiance in the 430 to complished by placing fiberoptic pads or a light-emitting
490-nm band of at least 30 mcW/cm2 per nanometer diode (LED) mattress below the infant or using a pho-
delivered to as much of the infant’s surface area as possi- totherapy device that delivers phototherapy from special
ble (Table 2-E in the online edition of this article). blue fluorescent tubes both above and below the infant.
Increasing the surface area exposed to phototherapy When intensive phototherapy is applied appropriately, a
Figure 4. The risk factors listed for this figure are factors that increase the likelihood of brain damage at different bilirubin levels.
Infants are designated as “higher risk” because of the potential negative effects of the conditions listed on albumin binding of
bilirubin, the blood-brain barrier, and the susceptibility of the brain cells to damage by bilirubin.
30% to 40% decrement in the bilirubin concentration can heme oxygenase and, therefore, the production of bili-
be expected in the first 24 hours, with the most signifi- rubin (Fig. 1). To date, more than 500 newborns have
cant decline occurring in the first 4 to 6 hours. received tin mesoporphyrin in control trials, but the drug
still is awaiting United States Food and Drug Adminis-
Pharmacologic Treatment tration approval. Other drugs have been used to inhibit
Pharmacologic agents such as phenobarbital and ursode- the enterohepatic circulation of bilirubin. A recent con-
oxycholic acid improve bile flow and can help to lower trolled trial showed that agents that inhibit beta glucu-
bilirubin concentrations. Tin mesoporphyrin inhibits ronidase can decrease bilirubin levels in breastfed new-
borns. For infants who have isoimmune hemolytic jaundice in newborns by inhibiting the production of bilirubin.
disease, the administration of intravenous immunoglob- Pediatrics. 2004;113:119 –123
Maisels MJ. A primer on phototherapy for the jaundiced newborn.
ulin significantly reduces the need for exchange transfu-
Contemp Pediatr. 2005;22:38 –57
sion. Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK, Mullett
MD, eds. Neonatology: Pathophysiology and Management of the
Newborn. Philadelphia, Pa: Lippincott Co; 2005:768 – 846
Suggested Reading Maisels MJ. Jaundice in a newborn. Answers to questions about a
Bhutani V, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson common clinical problem. Contemp Pediatr. 2005;22:34 – 40
LH. Noninvasive measurement of total serum bilirubin in a Maisels MJ. Jaundice in a newborn. How to head off an urgent
multiracial predischarge newborn population to assess the risk of situation. Contemp Pediatr. 2005;22:41–54
severe hyperbilirubinemia. Pediatrics. 2000;106:e17. Available Maisels MJ. Why use homeopathic doses of phototherapy? Pediat-
at: http://pediatrics.aappublications.org/cgi/content/full/ rics. 1996;98:283–287
106/2/e17 Maisels MJ, Baltz RD, Bhutani V, et al. Management of hyperbil-
Bhutani VK, Johnson LH, Maisels MJ, et al. Kernicterus: epidemi- irubinemia in the newborn infant 35 or more weeks of gestation.
ological strategies for its prevention through systems-based Pediatrics. 2004;114:297–316
approaches. J Perinatol. 2004;24:650 – 662 Maisels MJ, Kring EA. Transcutaneous bilirubin levels in the first
Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predis- 96 hours in a normal newborn population of ⬎⫽ 35 weeks’
charge hour-specific serum bilirubin for subsequent significant gestation. Pediatrics. 2006;117:1169 –1173
hyperbilirubinemia in healthy term and near-term newborns. Maisels MJ. Ostrea EJ Jr, Touch S, et al. Evaluation of a new transcu-
Pediatrics. 1999;103:6 –14 taneous bilirubinometer. Pediatrics. 2004;113:1628 –1635
Ennever JF. Blue light, green light, white light, more light: treat- Newman TB, Liljestrand P, Jeremy RJ, et al. Outcomes among
ment of neonatal jaundice. Clin Perinatol. 1990;17:467– 481 newborns with total serum bilirubin levels of 25 mg per deciliter
Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia: a or more. N Engl J Med. 2006;354:1889 –1900
potential complication of glucose-6-phosphate dehydrogenase Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and
deficiency. Clin Perinatol. 1998;25:575–590 prevention of extreme neonatal hyperbilirubinemia in a mature
Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the health maintenance organization. Arch Pediatr Adolesc Med.
nongeneticist: hereditary defects of neonatal bilirubin conjuga- 2000;154:1140 –1147
tion. Pediatrics. 2003;111:886 – 893 Stevenson DK, Dennery PA, Hintz SR. Understanding newborn
Kappas A. A method for interdicting the development of severe jaundice. J Perinatol. 2001;21:S21–S24
PIR Quiz
Quiz also available online at www.pedsinreview.org.
1. In explaining breastfeeding-associated jaundice to the third-year students on your service, you note that
jaundice seen in the first postnatal week results from an increase in the enterohepatic circulation due
primarily to:
A. Decreased caloric intake.
B. Gilbert syndrome.
C. Increased protein binding.
D. Insufficient free water.
E. Polycythemia.
2. The American Academy of Pediatrics now recommends that any infant discharged before 72 hours of age
be seen for follow-up no longer than how many hours later?
A. 24.
B. 36.
C. 48.
D. 72.
E. 96.
3. Almost all infants experience a transient increase in bilirubin concentrations known as physiologic jaundice
during the first week after birth. Among the following, which is most likely to contribute to the
development of this condition?
A. Decreased enterohepatic circulation.
B. Decreased erythrocyte survival.
C. Decreased erythrocyte volume.
D. Increased bilirubin conjugation.
E. Increased ligandin levels.
4. A 36 weeks’ gestation breastfed African-American infant is being discharged at 36 hours of age. The
transcutaneous bilirubin level is above the 75th percentile. Of the following, the next most appropriate step
in the management of this infant is to:
A. Advise the mother to increase the frequency of breastfeeding.
B. Check the mother’s and the baby’s blood groups.
C. Obtain a complete blood count and differential count.
D. Obtain a serum bilirubin measurement.
E. Start phototherapy.
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References This article cites 17 articles, 8 of which you can access for free at:
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