Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter III.2. Neonatal Hyperbilirubinemia
Carol Hirai, MD
June 2003

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Case 1

This is a jaundiced, 4 day old, 3.1 kg, appropriate for gestational age (AGA) Asian female infant born at term to a 25 year old A+ primiparous woman with gestational diabetes. The pregnancy was otherwise uneventful. Labor was augmented with Pitocin. The baby was discharged home on day of life 2 at which time her weight was down 4% from birth weight and she had mild facial jaundice. In the hospital, she was breast fed every 3 hours and had 2 wet diapers and one meconium stool over a 24 hour period. On day 3, her parents gave her water on two occasions as she appeared hungry despite regular and frequent breast feeding attempts. In addition, they noted an increase in the degree of jaundice, but failed to address it after being reassured by family members that jaundice is common. They also had an appointment to see their pediatrician the following day. In the office, on day 4, mother reports that she is breastfeeding the baby every three hours and that there have been 2 wet diapers per day. The urine is described as dark yellow in color and the stools appear dark green.

Exam: VS T 37.8, P 162, RR 55, BP 63/45. Weight 2.7 kg (25%ile), length 50 cm (75%ile), head circumference 34 cm (75%ile). The infant is jaundiced and irritable. The anterior fontanel is slightly sunken, the oral mucosa is tacky, and there is jaundice to the lower extremities. No cephalohematoma or bruising is present. The sclera of both eyes are icteric. Muscle tone and activity are normal. The remainder of the physical exam is normal.

The total bilirubin is 20 mg% with a direct fraction of 0.7 mg%. She is admitted to the hospital for phototherapy, supplementary formula feedings, and lactation consultation. By the following day, the bilirubin has decreased to 12 mg% and she is discharged home on breast milk feedings. She baby is scheduled for follow-up with both the pediatrician and the lactation consultant.

Case 2

A 4 day old, 36 week gestation male presents to his primary care physician with worsening jaundice. The maternal blood type is 0+. He was discharged home on day 2 of life after successfully breastfeeding for a 24 hour period. At the time of discharge, his physical exam was remarkable for mild jaundice and a cephalohematoma. At today's visit there is an 8% weight loss from birth and a history of "fair" urine output and yellow stools. He is markedly jaundiced and has a resolving cephalohematoma. Other physical exam findings are remarkable for a normal cry, flat anterior fontanelle, moist oral mucosa and a normal neurologic examination. The total bilirubin is 27 mg% with a direct fraction of 1 mg%. He is admitted to the hospital where phototherapy is initiated. His blood type is A+ with a positive direct Coombs. The hematocrit is 42% with a reticulocyte count of 12% and the pathologist identifies spherocytes on the blood smear. The G6PD is pending. After 12 hours of phototherapy, a repeat bilirubin is 25 mg%. The G6PD is normal. The decision is made to perform a double volume exchange transfusion. The infant remains on phototherapy for an additional 2 days and is discharged home after being off phototherapy for 1 day. The serum bilirubin on the day of discharge is 12 mg% and he passes an auditory brainstem response test.

More than 50% of term neonates become jaundiced (1). In this community (Hawaii), hyperbilirubinemia is one of the major reasons for re-hospitalization within the first two weeks of life. The primary reason for the level of concern over jaundice and hyperbilirubinemia in the newborn is the association of hyperbilirubinemia with kernicterus, which is a rare, but devastating neurologic complication of hyperbilirubinemia. Kernicterus can occur without signs and symptoms (2), but acute kernicterus in term babies is usually characterized by changes in muscle tone, drowsiness, poor feeding, a high pitched cry, apnea, possible seizures, fever, and death (3). Neurologic sequelae include dystonia and athetosis, upward gaze abnormalities, sensorineural hearing loss, intellectual deficits and tooth enamel dysplasia (3). In term patients, the MRI has increased signal intensity in the globus pallidus on T2 images (2). Although kernicterus is rare, it is potentially preventable and it is being seen with increasing frequency. This has prompted a recent Joint Commission on Accreditation of Healthcare Organizations Sentinel Event Alert (4).

The assessment and management of hyperbilirubinemia can be confusing. For instance, a bilirubin of 11 mg% has a different significance under different circumstances. It would be considered physiologic (not pathologic) in a 4 day old term breast fed baby, while the same level would be pathologic on day 1. A serum bilirubin of 11 mg% would also be concerning in a sick, two day old, 27 week gestation premature infant. Clinical decision-making is based on serum bilirubin values which are not directly reflective of risk for neurotoxicity (3). In an attempt to assist physicians with this common problem, the AAP released a practice parameter in 1994 on the Management of Hyperbilirubinemia in the Healthy Term Newborn (5). According to the commentary from the AAP Subcommittee on Neonatal Hyperbilirubinemia in 2001, this practice parameter is currently being revised (6).

Hyperbilirubinemia is more common in neonates due to the shortened life span of their red blood cells, declining hematocrit, immature liver uptake and conjugation of bilirubin, and increased intestinal reabsorption of bilirubin. Hemoglobin breakdown releases iron, carbon monoxide, and biliverdin. The latter is reduced to bilirubin, which enters the liver. Uridine diphosphate glucuronyltransferase (UDPGT) conjugates bilirubin into an excretable form. Intestinal bacteria can deconjugate bilirubin allowing for reabsorption of bilirubin into the circulation. This increased enterohepatic circulation occurs particularly in preterm neonates with diminished stool passage. In Asians, a variant in the UDPGT has been associated with hyperbilirubinemia.

Infants with red blood cell membrane G6PD (glucose-6-phosphate dehydrogenase) deficiency have a tendency for hemolysis and hyperbilirubinemia. In G6PD deficiency, hyperbilirubinemia can occur despite minimal evidence for hemolysis. Also, decreased conjugation of bilirubin has been described in G6PD deficiency.

Most unconjugated bilirubin is bound to albumin, but free unconjugated bilirubin (a form unbound to albumin) can enter the brain (i.e., it can cross the blood brain barrier). Sulfonamides are contraindicated in the neonatal period because they displace bilirubin from albumin. Conditions that disrupt the integrity of the blood brain barrier, such as infection (e.g., sepsis, meningitis, congenital viral infections), acidosis, prematurity, and hyperosmolarity, place the infant at increased risk for kernicterus. Hemolytic causes of hyperbilirubinemia (Rh incompatibility and G6PD deficiency) have higher risks of kernicterus compared to other causes of jaundice at comparable bilirubin levels.

Bilirubin may be the toxic substances responsible for kernicterus, but this is not a certainty. Very high bilirubin levels (in the 30 mg% range) most often do not result in kernicterus if no hemolytic disease is present. However, bilirubins in the 20 mg% range due to Rh incompatibility or G6PD deficiency, often result in kernicterus. The paradox that a very high bilirubin due to non-hemolytic causes has a lower kernicterus risk while a moderately high bilirubin due to Rh incompatibility or G6PD deficiency has a higher kernicterus risk, suggests that bilirubin itself may not be the direct cause of kernicterus. Bilirubin may only be a marker of the true toxic substance that causes kernicterus. This phenomenon may explain why the risk of kernicterus is not determined by bilirubin levels alone.

Jaundice can be detected clinically with tactile blanching of the skin revealing an underlying yellow color. The examination should be done in a well-lit, neutral light. Jaundice usually begins on the face and progresses caudally. The presence of scleral icterus should be assessed. Generally, the farther the jaundice progresses down the body, the higher the total serum bilirubin (3). The more intense the color (which can approach a yellow-orange) also suggests a higher total serum bilirubin. Jaundice may be clinically detected with a total serum bilirubin of 5 mg%. The presence of jaundice in particularly dark skinned newborns can be difficult to assess. Any time there is uncertainty, the recommendation is to check a total serum or transcutaneous bilirubin. Universal screening has been recently recommended, perhaps simultaneously with the newborn screen. If a patient is under phototherapy, jaundice is difficult to visually assess because phototherapy preferentially reduces bilirubin concentrations near the skin. If assessing a patient under phototherapy, jaundice severity is best determined by examining unexposed sites (e.g., under the eye shield) and phototherapy should be interrupted during the exam. If the skin is green or bronze colored, this suggests an elevated direct (conjugated) bilirubin fraction, so a fractionated bilirubin should be obtained. The patient should also be assessed for pallor, plethora and hepatosplenomegaly.

It is essential to distinguish whether the jaundice is physiologic or pathologic. Jaundice noted within the first 24 hours is pathologic and a total serum bilirubin should be drawn. Early jaundice is usually related to hemolysis, infection, drug effect, neonatal hepatitis or liver enzyme defects (e.g., Crigler-Najjar-deficiency of UDPGT) (7). A total bilirubin greater than 17 mg% in a full term neonate is pathologic (2). Jaundice that persists beyond 2 weeks should be evaluated beginning with a fractionated bilirubin (5). Direct hyperbilirubinemia is also considered pathologic, (i.e., direct bilirubin >1.5-2 mg% or > 20% of the total bilirubin) (8).

Direct (conjugated) hyperbilirubinemia cases are relatively uncommon. The differential diagnosis includes neonatal hepatitis, biliary atresia, sepsis, metabolic disorders (e.g., galactosemia), and hepatotoxicity from hyperalimentation. A detailed discussion of direct hyperbilirubinemia is beyond the scope of this chapter. One of the principal diagnoses to exclude is biliary atresia which is associated with dark urine or light colored stool. Early surgical intervention done prior to 2 months of age reduces mortality and the probability of future liver transplantation (refer to the chapter on biliary atresia).

Indirect (unconjugated) hyperbilirubinemia, is more common and presents a risk for kernicterus. The most common causes of indirect hyperbilirubinemia are physiologic, breast milk, breast feeding with a large postnatal weight loss (3), ABO incompatibility, cephalohematoma, bruising, G6PD deficiency, and East Asian ethnicity. Of these, G6PD deficiency poses a higher risk of kernicterus, but ABO incompatibility is a more common reason for exchange transfusion. Rh incompatibility is less common, but represents a high risk of kernicterus. Breastfeeding jaundice is related to inadequate intake by the newborn (i.e., components of poor feeding and dehydration are contributory). Breast milk jaundice (i.e., due to breast milk itself) has its onset later than breastfeeding jaundice. It is related to increased enterohepatic circulation and is relatively uncommon. Uncommon causes of indirect hyperbilirubinemia include other RBC membrane defects (e.g., hereditary spherocytosis) and hemoglobinopathies. In the pilot kernicterus registry, 31% of the cases were idiopathic (no identified cause), approximately equal to the incidence associated with G6PD deficiency (3).

A rise in bilirubin of greater than 0.5 mg% per hour and failure to control hyperbilirubinemia despite phototherapy are suggestive of hemolytic disease. ABO incompatibility occurs in approximately 20% to 25% of pregnancies of which significant hemolysis occurs in 10%. G6PD deficiency (X-linked recessive) occurs in African, Mediterranean, and Southeast Asian ethnic groups. In our community, some pediatricians routinely screen for G6PD in males delivered to mothers of high risk ethnic groups (e.g., Filipino).

Prenatal testing includes maternal blood typing and screening for antibodies to major RBC antigens (1). Rh incompatibility occurs with an Rh negative mother (usually not a primigravida) and an Rh positive baby. The routine use of RhoGAM at 28 weeks gestation and following delivery or pregnancy termination is generally effective in preventing maternal Rh sensitization (i.e., the production of anti-Rh antibodies by the mother). An adequate amount of RhoGAM must be given to neutralize the amount of Rh Ag or the volume of blood from a feto-maternal transfusion. Thus, the incidence of Rh isoimmunization and Rh incompatibility is uncommon. The Rh antigen is markedly more antigenic than the A or B antigen. In situations where the maternal blood type and antibody screening results are unknown, an Rh and Coombs test should be performed on the baby's blood (1).

In ABO incompatibility, the mother's blood type is O. More commonly, the babies blood type is A rather than B. Hemolysis in ABO isoimmunization usually has a positive direct antiglobulin testing (DAT), also known as a direct Coombs test. Clinically significant hemolysis is associated with a decreasing hemoglobin, hematocrit and an elevated reticulocyte count. Due to phagocytic removal of antibody and portions of the RBC membrane, the smear in ABO incompatibility may have spherocytes, mimicking spherocytosis. Therefore, a CBC with differential, reticulocyte count and a smear should be requested with suspected hemolysis. Nucleated RBCs may also be present with more severe causes of hemolysis, but is classically associated with Rh incompatibility.

If the baby is at risk for G6PD deficiency or other hemolytic diseases, appropriate testing should be done. When a G6PD level is obtained, it is important to realize that false negatives may occur in the face of active hemolysis because G6PD is increased in nucleated red blood cells.

An evaluation should be done for newborns with feeding intolerance, behavioral changes, hepatosplenomegaly, excessive weight loss, and instability of vital signs regardless of clinical detection of jaundice. Urine that is positive for reducing substances, but negative for glucose is suggestive of galactosemia. Galactosemia, a cause of direct hyperbilirubinemia, is one of the over 30 metabolic disorders included in the expanded newborn screen.

Educating parents about proper infant feeding practices (both breast and bottle), detecting their infant's hydration status, observing changes in behavior, and how to detect and report worsening jaundice, are extremely important anticipatory guidance measures. Parents should also be counseled that jaundice is common, but in rare instances, it can lead to severe morbidity and mortality which is largely preventable. At follow-up, the primary care physician should document the presence/absence of jaundice and/or the serum bilirubin level. The pediatrician's goal is to discharge a functional maternal-infant dyad with early follow up (in 1-2 days) if the infant is discharged from the hospital at less than 48 hours of age. If certain risk factors exist such as blood group incompatibility or prematurity, or if early follow-up cannot be scheduled, discharge should be delayed until after the infant has been monitored for an appropriate period of time. Some of the patients with kernicterus had a bilirubin of less than 25 mg% and did not have predictable risk factors (9). Potential separation of the parent and newborn needs to be minimized and weighed against the risks of hyperbilirubinemia complications. In this community, most mothers are discharged within 48 hours of a vaginal delivery and 3-4 days post C-section. Discharging the mother prior to the newborn can affect bonding and breastfeeding. This needs to be weighed against the risk for significant hyperbilirubinemia and compliance with follow up.

The clinician should be responsive to parents who are concerned about their child's degree of jaundice, feeding frequency or volume, drowsiness, and/or irritability (3). Caution should be used when sending patients home while awaiting lab results. Never presume that a lab value is falsely elevated. Parents should also be counseled to seek medical attention for jaundice that persists beyond 2 weeks of age.

Bhutani developed an hour specific bilirubin nomogram in healthy term and near term newborns with a negative direct Coombs (12). The patient population consisted of term and near-term appropriate for gestational age (AGA) newborns. Total serum bilirubins (TSB) of greater than or equal to 8 mg% at 24 hours, greater than or equal to 14 mg% at 48 hours, and greater than or equal to 16 mg% at 72 hours were above the 95th percentile. A TSB of greater than or equal to 17 mg% during the first week of life was above the 95th percentile. This group is at higher risk for bilirubin-induced neurologic dysfunction (BIND), including kernicterus. Bhutani advocates universal bilirubin screening with early follow up to also catch neonates who may move up from the lower percentiles.

The 1994 AAP Practice parameter (5) is an appropriate guideline for managing jaundice in the healthy term newborn without hemolysis. The guideline has age-based recommendations for therapy. At 25 to 48 hours, phototherapy is recommended at a bilirubin of greater than or equal to 15 mg%. At 49 to 72 hours, the threshold increases to 18 mg%. From greater than 72 hours, the threshold is 20 mg%. If G6PD deficiency or other kernicterus risk factors are present, it is advisable to have a lower threshold to begin phototherapy. The AAP Practice parameter also contains recommendations for exchange transfusion. Table 1 below describes hyperbilirubinemia treatment guidelines for preterm infants. Table 2 below describes hyperbilirubinemia treatment guidelines for term infants.

Table 1 - Suggested Maximum Indirect Serum Bilirubin Concentrations (mg%) in Preterm Infants (10)

Birthweight (g)

For table 1 above, phototherapy is usually started at 50% to 70% of the maximum indirect levels. If values greatly exceed this level, if phototherapy is unsuccessful in reducing the maximum bilirubin level, or if there are signs of kernicterus, exchange transfusion is indicated. *Complicated cases include those associated with perinatal asphyxia, acidosis, hypoxia, hypothermia, hypoalbuminemia, meningitis, intraventricular hemorrhage, hemolysis, hypoglycemia, or signs of kernicterus (10).

Table 2 - Treatment Strategies for Indirect Hyperbilirubinemia in Healthy Term Infants Without Hemolysis (10)

Age (hrs)
Intensive phototherapy and preparation for exchange transfusion if phototherapy fails
Exchange transfusion

If the initial bilirubin on presentation is high, intense phototherapy should be initiated and preparation made for exchange transfusion. If the phototherapy fails to reduce the bilirubin level to the levels noted on the column to the right (table 2), an exchange transfusion should be initiated. Intensive phototherapy usually reduces serum bilirubin levels 1 to 2 mg% in 4 to 6 hours. This is often done with IV fluid administration at 1 to 1.5 times maintenance and oral alimentation should continue (10).

Jaundice in the 1st 24 hours of life is not seen in " healthy" infants. Hyperbilirubinemia of this degree noted in the 24-48 hours line of table 2, is unusual and should suggest hemolysis, concealed hemorrhage, or causes of conjugated (direct) hyperbilirubinemia (10).

Jaundice suddenly appearing in the second week of life or continuing beyond the second week of life with significant hyperbilirubinemia levels to warrant therapy should be investigated in detail, as it most probably is due to a serious underlying cause such as biliary atresia, galactosemia, hypothyroidism, or neonatal hepatitis (10).

Supplementing feeds with water or dextrose has been associated with higher bilirubin levels. Use of metalloporphyrins which inhibit bilirubin production has been limited to study trials in newborns. The mainstay of treatment is phototherapy with a wavelength of 450 nm. It induces photoisomerization of bilirubin, forming lumirubin which is water soluble and excreted in the urine. Phototherapy is generally delivered by fluorescent lights, spot lights, or fiberoptics, the latter generating less heat. Unless there is a high risk for an exchange transfusion, phototherapy can usually be discontinued for an hour to allow for neonatal care. Discontinuation of phototherapy in a term baby without hemolysis generally is not associated with rebound hyperbilirubinemia, i.e., a significant increase in bilirubin.

Although phototherapy may be commonly thought of to prevent kernicterus, this is less than accurate, since if the patient is at significant risk of kernicterus, an exchange transfusion should be done. Phototherapy's major role is to avoid an exchange transfusion. By implementing phototherapy, the belief is that this will reduce the likelihood that bilirubin levels will reach these exchange transfusion levels, thus avoiding an exchange transfusion.

In term neonates with hemolytic disease, if the bilirubin approaches 20 mg% despite medical management, informed consent should be obtained for an exchange transfusion. In preterm neonates less than 37 weeks gestation, most neonatologists will await serum bilirubin levels of 15-20 mg% before considering an exchange (11). Exchange transfusion removes bilirubin and antibodies causing hemolysis. Twice the patient's blood volume is exchanged (i.e., double volume exchange) while monitoring cardiovascular stability. Risk factors include those related to catheters, electrolyte imbalance and blood products superimposed onto preexisting medical problems. Thrombocytopenia is common. Necrotizing enterocolitis, graft versus host disease, and death have also been reported as complications of exchange transfusion.

Does phototherapy reduce the need for an exchange transfusion? In ABO incompatibility, prophylactic phototherapy was not shown to be superior to no therapy at all in this regard (13). However, phototherapy intensities have increased since the time of that study and anecdotally, it appears that fewer exchange transfusions are being done, possibly due to more routine use of phototherapy. Additionally, phototherapy appears to be harmless, so its utilization is reasonable to treat moderately high bilirubin levels.

Although extreme bilirubin levels are associated with kernicterus, the adverse effects of moderate hyperbilirubinemia may be more difficult to identify. For example, subclinical adverse effects, learning disabilities or behavioral disorders would be more difficult to causally link to moderate hyperbilirubinemia, since this would only be manifested in later childhood.

Most cases of hyperbilirubinemia resolve without sequelae. However, there may be impairment of auditory nerve conduction (2). After significant hyperbilirubinemia, the patient should undergo auditory brainstem response testing (6).


1. Which of the following factors leads to neonatal hyperbilirubinemia?
. . . . . a. Shortened neonatal red cell life span.
. . . . . b. Impaired excretion of unconjugated bilirubin.
. . . . . c. Limited conjugation of bilirubin in the liver.
. . . . . d. Increased enterohepatic circulation.
. . . . . e. All of the above.

2. True/False: Hemoglobin degradation results in the formation of biliverdin and carbon monoxide.

3. A total serum bilirubin >17 mg% in a term neonate is:
. . . . . a. physiologic
. . . . . b. pathologic

4. In G6PD deficiency, there is hyperbilirubinemia on the basis of:
. . . . . a. hemolysis
. . . . . b. decreased conjugation
. . . . . c. both
. . . . . d. neither

5. True/False: In Asians, a variant in UDPGT is associated with neonatal hyperbilirubinemia.

6. True/False: Systemic sulfonamide medications are avoided in the newborn because they displace bilirubin from albumin and increase free bilirubin.

7. True/False: Breast milk jaundice is more common than breast feeding jaundice.

8. True/False: Supplementation of breast feeding with water or dextrose lowers the serum bilirubin.

9. True/False: Discontinuation of phototherapy in a healthy, term neonate is usually associated with rebound hyperbilirubinemia.

10. Which of the following factors should be strongly considered in determining whether an exchange transfusion is indicated in a term neonate with an indirect bilirubin of 21 mg%.
. . . . . a. Age of the neonate (time since birth).
. . . . . b. Whether the cause is hemolytic or non-hemolytic.
. . . . . c. The presence of other clinical factors such as intraventricular hemorrhage or meningitis.
. . . . . d. All of the above.
. . . . . e. None of the above.


1. Nazarian LF. Personal Reflections on the AAP Practice Parameter on Management of Hyperbilirubinemia in the Healthy Term Newborn. Pediatr Rev 1998;19(3):75-77.

2. Dennery PA, Seidman DS, Stevenson DK. Neonatal Hyperbilirubinemia. N Engl J Med 2001;344(8):581-590.

3. Johnson LH, Bhutani VK, Brown AK. System-based Approach to Management of Neonatal Jaundice and Prevention of Kernicterus. J Pediatr 2002;140(4):396-403.

4. JCAHO Sentinel Event Alert: Kernicterus Threatens Healthy Newborns. JCAHO website, 2001. 5. American Academy of Pediatrics. Practice Parameter: Management of Hyperbilirubinemia in the Healthy Term Newborn. Pediatrics 1994;94(4):558-565.

6. AAP Subcommittee on Neonatal Hyperbilirubinemia: Neonatal Jaundice and Kernicterus. Pediatrics 2001;108(3):763-765.

7. Jain SK. Index of suspicion. Case 3. Diagnosis: jaundice. Pediatr Rev 2001;22(8):271-276.

8. Bisgard L. Visual diagnosis: a 10-week-old infant who has jaundice. Pediatr Rev 2001;22(12):408-412.

9. Poland RL. Preventing kernicterus: almost there. J Pediatr 2002;140(4):385-386.

10. Stoll BJ, Kliegman RM. Chapter 98.3. Jaundice and Hyperbilirubinemia in the Newborn. In: Behrman RE, Kliegman RM, Jenson HB (eds.). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: WB Saunders, pp. 513-517.

11. Chapter 8. Neonatal Complications. In: American Academy of Pediatrics and American College of Obstetricians and Gynecologists. Guidelines for Perinatal Care, 5th edition. 2002, Elk Grove Village, IL: AAP, pp. 239-240.

12. Bhutani VK. Predictive Ability of a Predischarge Hour-specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near Term Newborns. Pediatrics 1999;103(1):6-14

13. Maurer HM, Kirkpatrick BV, McWilliams NB, et al. Phototherapy for Hyperbilirubinemia of Hemolytic Disease of the Newborn. Pediatrics 1985;75(2-Supp):407-412.

Answers to questions

1.e, 2.True, 3.b, 4.c, 5.True, 6.True, 7.False, 8.False, 9.False, 10.d

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