Hyperbilirubinemia

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Chapter 25 HYPERBILIRUBINEMIA

Jonathan M. Wong and Theodore X. O’Connell

General Discussion

This discussion focuses on neonatal hyperbilirubinemia in infants 35 or more weeks of gestation.

Neonatal hyperbilirubinemia is defined as a total serum bilirubin greater than 5 mg/dL. Jaundice results from the deposition of unconjugated bilirubin pigment in the skin and mucus membranes. Up to 60% of term newborns have clinical jaundice in the first week of life, yet few have significant underlying disease. However, neonatal hyperbilirubinemia can be associated with hemolytic disease, metabolic and endocrine disorders, infections, and anatomic abnormalities of the liver.

Bilirubin is the final product of heme degradation. Newborns produce bilirubin at twice the rate of adults because of relative polycythemia and increased red blood cell (RBC) turnover. Bilirubin production typically declines to adult levels within 10-14 days after birth. Neonatal hyperbilirubinemia results from a predisposition to the production in newborn infants and their limited ability to excrete it.

The term kernicterus has come to be used interchangeably with both the acute and chronic findings of bilirubin encephalopathy. Bilirubin encephalopathy describes the clinical central nervous system (CNS) findings caused by bilirubin toxicity to the basal ganglia and various brainstem nuclei. It is unclear what level of total serum bilirubin is associated with kernicterus, although most experts agree that bilirubin levels greater than 20 mg/dL in the term infant warrant concern. Early signs of kernicterus are subtle and nonspecific, but bilirubin encephalopathy may be more evident by 3 years of age and leads to developmental and motor delays, sensorineural deafness, and mild mental retardation.

Physiologic jaundice in the healthy term newborn usually peaks at 5 to 6 mg/dL on the third to fourth day of life and then declines over the first week after birth. Bilirubin elevations up to 12 mg/dL can sometimes occur. Infants with multiple risk factors may develop an exaggerated form of physiologic jaundice. Breastfed newborns may be at increased risk for exaggerated physiologic jaundice because of relative caloric deprivation and mild dehydration with resulting delayed passage of meconium in the first few days of life. Formula supplementation may be necessary, but breastfeeding should be continued to maintain breast milk production. Serum bilirubin concentrations higher than 17 mg/dL in full-term infants are no longer considered physiologic, and a cause of pathologic jaundice can usually be identified in these infants.

Breast milk jaundice occurs later in the newborn period, with the bilirubin level usually peaking between 6 and 14 days of life. Breast milk jaundice may occur in up to one third of healthy breastfed infants and is believed to be the result of substances in maternal milk which may inhibit normal bilirubin metabolism. The bilirubin level usually falls after the infant is 2 weeks old but may remain elevated for 1 to 3 months. Breastfeeding may be temporarily interrupted if the diagnosis of breast milk jaundice is in doubt or the total serum bilirubin level becomes markedly elevated.

Any jaundice beyond physiologic and breast milk jaundice is considered pathologic. Features of pathologic jaundice include the appearance of jaundice within 24 hours after birth, an increase of total serum bilirubin greater than 5 mg/dL per day, and a total serum bilirubin level higher than 17 mg/dL in a full-term newborn. Other features suggesting pathologic jaundice include prolonged jaundice, evidence of underlying illness, and elevation of the serum conjugated bilirubin to greater than 2 mg/dL or more than 20% of the total serum bilirubin concentration.

Risk factors for neonatal hyperbilirubinemia are outlined below.

Medications Associated with Hyperbilirubinemia

• Acetaminophen

• Aspirin

• Chloramphenicol

• Corticosteroids

• Diazepam (maternal use)

• Erythromycin

• Pitocin (maternal use)

• Rifampin

• Streptomycin

• Sulfa

• Sulfisoxazole acetyl with erythromycin ethylsuccinate

• Tetracycline

Causes of Hyperbilirubinemia

Increased Bilirubin Load

Hemolytic Causes (increased unconjugated bilirubin level, >6% reticulocytes, hemoglobin concentration of <13 g/dL)

• Positive Coombs’ test
image Rh factor incompatibility
image ABO incompatibility
image Minor antigens
• Negative Coombs’ test
image Drugs
image Elliptocytosis
image Glucose-6-phosphate dehydrogenase (G6PD) deficiency
image Hemoglobinopathies
image Pyruvate kinase deficiency
image Sepsis
image Spherocytosis

Nonhemolytic causes (increased unconjugated bilirubin level, normal percentage of reticulocytes)

• Exaggerated enterohepatic circulation
image Breast milk jaundice
image Cystic fibrosis
image Hirschsprung disease
image Ileal atresia
image Pyloric stenosis
• Extravascular sources
image Bruising
image CNS hemorrhage
image Cephalohematoma
image Swallowed blood
• Polycythemia
image Delayed cord clamping
image Fetal-maternal transfusion
image Twin-twin transfusion

Decreased Bilirubin Conjugation

Characterized by increased unconjugated bilirubin level, normal percentage of reticulocytes

• Breast milk jaundice
• Crigler-Najjar syndrome types 1 and 2
• Gilbert syndrome
• Hypothyroidism
• Physiologic jaundice

Impaired Bilirubin Excretion

Characterized by increased unconjugated and conjugated bilirubin levels, negative Coombs’ test, conjugated bilirubin level greater than 2 mg/dL or more than 20% of total serum bilirubin level, and conjugated bilirubin in the urine

• Biliary obstruction
image Biliary atresia
image Choledochal cyst
image Dubin-Johnson syndrome
image Gallstones
image Neoplasm
image Primary sclerosing cholangitis
image Rotor syndrome
• Chromosomal abnormality
image Trisomy 18
image Trisomy 21
image Turner syndrome
• Infection
image Hepatitis
image Herpes simplex
image Rubella
image Sepsis
image Syphilis
image Toxoplasmosis
image Tuberculosis
image Urinary tract infection (UTI)
• Medications
image Acetaminophen
image Alcohol
image Aspirin
image Corticosteroids
image Erythromycin
image Rifampin
image Sulfa
image Tetracycline
• Metabolic disorder
image α1-antitrypsin deficiency
image Cystic fibrosis
image Galactosemia
image Gaucher disease
image Glycogen storage disease
image Hypothyroidism
image Niemann-Pick disease
image Wilson disease

Key Historical Features

Risk Factors for Hyperbilirubinemia in Newborns

Maternal factors

Blood type ABO or Rh incompatibility

Ethnicity (Asian, Native American)

Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive

Medications (see page 172)

Maternal age > 25 years

Neonatal factors

Birth trauma (cephalohematoma, cutaneous bruising, instrumented delivery)

Excessive weight loss after birth

Gestational age (age 35-36 weeks is a major risk factor; age 37-38 weeks is a minor risk factor)

Infections: toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex (TORCH)

Jaundice observed before hospital discharge

Macrosomic infant of a diabetic mother

Male gender

Medications (see page 172)

Polycythemia

Previous sibling with hyperbilirubinemia

Key Physical Findings

Weight measurement with comparison to birth weight

General examination for evidence of infection

Evaluation for dehydration

Skin examination for jaundice, pallor, petechiae, extravasated blood, or excessive bruising

Abdominal examination for hepatosplenomegaly

Suggested Work-Up

The suggested work-up for the jaundiced infant of 35 or more weeks’ gestation depends on the clinical picture and is outlined below. A transcutaneous bilirubin or total serum bilirubin measurement, or both, should be performed on every infant who is jaundiced in the first 24 hours after birth and in all infants in whom jaundice appears excessive for the infant’s age. If there is any doubt about the degree of jaundice, the transcutaneous bilirubin or total serum bilirubin should be measured. All bilirubin levels should be interpreted on a nomogram according to the infant’s age in hours (Figures 25-1 and 25-2). An algorithm for the management of jaundice is presented in Figure 25-3.

image

Figure 25-1 Bilirubin levels and risk of significant hyperbilirubinemia. Nomogram for designation of risk in 2840 well newborns at ≥ 36 weeks’ gestational age with birth weight of 2000 g or more or ≥ 35 weeks’ gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin values. The serum bilirubin level was obtained before discharge, and the zone in which the value fell predicted the likelihood of a subsequent bilirubin level exceeding the 95th percentile (high-risk zone). This nomogram should not be used to represent the natural history of neonatal hyperbilirubinemia.

(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, with permission.)

image

Figure 25-2 AAP Phototherapy Guidelines for Infants ≥35 weeks’ gestation.

(From Subcommittee on Hyperbilirubinemia, American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316, with permission.)

image

Figure 25-3 Algorithm for the management of jaundice in the newborn nursery.

(From Subcommittee on Hyperbilirubinemia, American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297–316, with permission.)

Jaundice in the First 24 Hours  
Measurement of transcutaneous bilirubin and/or total serum bilirubin To determine bilirubin level and interpret on a nomogram according to the infant’s age in hours
Jaundice Appears Excessive for Infant’s Age
Measurement of transcutaneous bilirubin and/or total serum bilirubin To determine bilirubin level and interpret on a nomogram according to the infant’s age in hours
Infant Receiving Phototherapy or Total Serum Bilirubin is Rising Rapidly and Unexplained by History and Physical Examination
Blood type and Coombs’ test if not obtained with cord blood To evaluate for isoimmune hemolysis
Complete blood count (CBC) and smear To evaluate for infection, evidence of hemolysis, or polycythemia
Direct (conjugated) bilirubin To evaluate for causes of impaired bilirubin excretion
Consider:  
Reticulocyte count To evaluate for hemolysis
G6PD assay To evaluate for G6PD deficiency in infants whose family history or ethnic or geographic origin suggest the likelihood of G6PD deficiency
End Tidol Co (ETCO) if available To evaluate for hemolysis
Repeat total serum bilirubin in 4 to 24 hours depending on infant’s age and total serum bilirubin level  
Total Serum Bilirubin Concentration Approaching Exchange Levels or Responding to Phototherapy
Reticulocyte count To evaluate for hemolysis
G6PD assay To evaluate for G6PD deficiency
Albumin To evaluate for hypoalbuminemia
ETCO if available To evaluate for hemolysis
Elevated Direct (Conjugated) Bilirubin Level
Urinalysis and urine culture Evaluate for sepsis if indicated by history and physical examination To evaluate for UTI
Jaundice Present at or Beyond Age 3 Weeks, or Sick Infant
Total and direct (conjugated) bilirubin level To determine bilirubin level and evaluate for cholestasis
Check results of newborn thyroid and galactosemia screen To evaluate for hypothyroidism and galactosemia

Additional Work-Up

Peripheral blood smear If hemolysis is suspected
Red cell enzyme studies If G6PD deficiency or pyruvate kinase deficiency is suspected
Hemoglobin electrophoresis If hemoglobinopathy is suspected
Thyroid-stimulating hormong (TSH) If hypothyroidism is suspected
Toxicology screen If the history is suggestive of toxin exposure
Purified protein derivative (PPD) If tuberculosis infection is suspected
Toxoplasmosis titers If toxoplasmosis is suspected
Syphilis titers If syphilis is suspected
Chromosomal analysis If a chromosomal abnormality is suspected

References

1. Bhutani V.K., Johnson L., Sivieri E.M. 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.

2. Dennery P.A., Seidman D.S., Stevenson D.K. Neonatal hyperbilirubinemia. N Engl J Med. 2001;344:581–590.

3. Porter M.L., Dennis B.L. Hyperbilirubinemia in the term newborn. Am Fam Physician. 2002;65:599–606.

4. Subcommittee on Hyperbilirubinemia. American Academy of Pediatrics. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.

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