Hyperbilirubinemia in the Term Newborn MEREDITH L
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COVER ARTICLE Hyperbilirubinemia in the Term Newborn MEREDITH L. PORTER, CPT, MC, USA, and BETH L. DENNIS, MAJ, MC, USA Dewitt Army Community Hospital, Fort Belvoir, Virginia Hyperbilirubinemia is one of the most common problems encountered in term newborns. Historically, management guidelines were derived from studies on bilirubin toxicity in O A patient informa- infants with hemolytic disease. More recent recommendations support the use of less tion handout on jaun- intensive therapy in healthy term newborns with jaundice. Phototherapy should be insti- dice in infants, written by the authors of this tuted when the total serum bilirubin level is at or above 15 mg per dL (257 µmol per L) in article, is provided on infants 25 to 48 hours old, 18 mg per dL (308 µmol per L) in infants 49 to 72 hours old, and page 613. 20 mg per dL (342 µmol per L) in infants older than 72 hours. Few term newborns with hyperbilirubinemia have serious underlying pathology. Jaundice is considered pathologic if it presents within the first 24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL (86 µmol per L) per day or is higher than 17 mg per dL (290 µmol per L), or an infant has signs and symptoms suggestive of serious illness. The management goals are to exclude pathologic causes of hyperbilirubinemia and initiate treatment to prevent bilirubin neurotoxicity. (Am Fam Physician 2002;65:599-606,613-4. Copyright© 2002 Ameri- can Academy of Family Physicians.) eonatal hyperbilirubin- form of jaundice encountered by family emia, defined as a total physicians. The separate topic of conju- serum bilirubin level gated hyperbilirubinemia is beyond the above 5 mg per dL (86 scope of this article. µmol per L), is a fre- Nquently encountered problem. Although Risk Factors for Hyperbilirubinemia up to 60 percent of term newborns have Infants without identified risk factors clinical jaundice in the first week of life, rarely have total serum bilirubin levels few have significant underlying dis- above 12 mg per dL (205 µmol per L). As ease.1,2 However, hyperbilirubinemia in the number of risk factors increases, the the newborn period can be associated potential to develop markedly elevated with severe illnesses such as hemolytic bilirubin levels also increases.2 disease, metabolic and endocrine disor- Common risk factors for hyper- ders, anatomic abnormalities of the liver, bilirubinemia include fetal-maternal and infections. blood group incompatibility, prematu- Jaundice typically results from the rity, and a previously affected sibling deposition of unconjugated bilirubin (Table 1).2-4 Cephalohematomas, bruis- pigment in the skin and mucus mem- ing, and trauma from instrumented branes. Depending on the underlying delivery may increase the risk for serum etiology, this condition may present bilirubin elevation. Delayed meconium throughout the neonatal period. Uncon- passage also increases the risk. Infants jugated hyperbilirubinemia, the primary with risk factors should be monitored focus of this article, is the most common closely during the first days to weeks of life. Bilirubin Production and Newborns Up to 60 percent of term newborns have clinical jaundice in the Bilirubin is the final product of first week of life. heme degradation. At physiologic pH, bilirubin is insoluble in plasma and FEBRUARY 15, 2002 / VOLUME 65, NUMBER 4 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 599 cally declines to the adult level within 10 to 14 TABLE 1 days after birth.2 Risk Factors for Hyperbilirubinemia in Newborns Bilirubin Toxicity Maternal factors Neonatal factors “Kernicterus” refers to the neurologic con- Blood type ABO or Birth trauma: cephalohematoma, cutaneous sequences of the deposition of unconjugated Rh incompatibility bruising, instrumented delivery bilirubin in brain tissue. Subsequent damage Breastfeeding Drugs: sulfisoxazole acetyl with erythromycin and scarring of the basal ganglia and brain- ethylsuccinate (Pediazole), chloramphenicol Drugs: diazepam stem nuclei may occur.5 (Valium), oxytocin (Chloromycetin) (Pitocin) Excessive weight loss after birth The precise role of bilirubin in the develop- Ethnicity: Asian, Infections: TORCH ment of kernicterus is not completely under- Native American Infrequent feedings stood. If the serum unconjugated bilirubin Maternal illness: Male gender level exceeds the binding capacity of albumin, gestational diabetes Polycythemia unbound lipid-soluble bilirubin crosses the Prematurity blood-brain barrier. Albumin-bound biliru- Previous sibling with hyperbilirubinemia bin may also cross the blood-brain barrier if damage has occurred because of asphyxia, TORCH = toxoplasmosis, other viruses, rubella, cytomegalovirus, herpes (sim- acidosis, hypoxia, hypoperfusion, hyper- plex) viruses. osmolality, or sepsis in the newborn.3,8 Information from references 2, 3, and 4. The exact bilirubin concentration associ- ated with kernicterus in the healthy term infant is unpredictable.1 Toxicity levels may requires protein binding with albumin. vary among ethnic groups, with maturation of After conjugation in the liver, it is excreted an infant, and in the presence of hemolytic in bile.3,5-7 disease. Although the risk of bilirubin toxicity Newborns produce bilirubin at a rate of is probably negligible in a healthy term new- approximately 6 to 8 mg per kg per day. This born without hemolysis,9 the physician is more than twice the production rate in should become concerned if the bilirubin level adults, primarily because of relative poly- is above 25 mg per dL (428 µmol per L).1,3,10 cythemia and increased red blood cell turn- In the term newborn with hemolysis, a biliru- over in neonates.7 Bilirubin production typi- bin level above 20 mg per dL (342 µmol per L) is a concern.1,3 The effects of bilirubin toxicity are often devastating and irreversible (Table 2).3,9 TABLE 2 Early signs of kernicterus are subtle and Effects of Bilirubin Toxicity in Newborns nonspecific, typically appearing three to four days after birth. However, hyperbiliru- Early Late Chronic binemia may lead to kernicterus at any time Lethargy Irritability Athetoid cerebral palsy during the neonatal period.2 After the first Poor feeding Opisthotonos High-frequency hearing loss High-pitched cry Seizures Paralysis of upward gaze week of life, the affected newborn begins to Hypotonia Apnea Dental dysplasia demonstrate late effects of bilirubin toxicity. Oculogyric crisis Mild mental retardation If the infant survives the initial severe neu- Hypertonia rologic insult, chronic bilirubin enceph- Fever alopathy (evident by three years of age) leads to developmental and motor delays, Information from references 3 and 9. sensorineural deafness, and mild mental retardation. 600 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 65, NUMBER 4 / FEBRUARY 15, 2002 Hyperbilirubinemia Classification of Neonatal Infants without identified risk factors rarely have total serum Hyperbilirubinemia bilirubin levels above 12 mg per dL (205 µmol per L). The causes of neonatal hyperbilirubinemia can be classified into three groups based on mechanism of accumulation: bilirubin over- production, decreased bilirubin conjugation, over the first week after birth.2 Bilirubin eleva- and impaired bilirubin excretion (Table 3).11 tions of up to 12 mg per dL, with less than 2 mg per dL (34 µmol per L) of the conjugated PHYSIOLOGIC JAUNDICE form, can sometimes occur. Infants with mul- Physiologic jaundice in healthy term new- tiple risk factors may develop an exaggerated borns follows a typical pattern. The average form of physiologic jaundice in which the total serum bilirubin level usually peaks at 5 to total serum bilirubin level may rise as high as 6 mg per dL (86 to 103 µmol per L) on the 17 mg per dL (291 µmol per L).3 third to fourth day of life and then declines Factors that contribute to the development TABLE 3 Classification of Neonatal Hyperbilirubinemia Based on Mechanism of Accumulation Increased bilirubin load Decreased bilirubin conjugation Impaired bilirubin excretion Hemolytic causes Characteristics: increased Characteristics: increased unconjugated Characteristics: increased unconjugated bilirubin unconjugated bilirubin level, and conjugated bilirubin level, negative level, >6 percent reticulocytes, hemoglobin normal percentage of Coombs’ test, conjugated bilirubin level concentration of <13 g per dL (130 g per L) reticulocytes of >2 mg per dL (34 µmol per L) or Coombs’ test positive: Rh factor incompatibility, Physiologic jaundice >20% of total serum bilirubin level, ABO incompatibility, minor antigens Crigler-Najjar syndrome types 1 conjugated bilirubin in urine Coombs’ test negative: red blood cell membrane and 2 Biliary obstruction: biliary atresia, defects (spherocytosis, elliptocytosis), red blood Gilbert syndrome choledochal cyst, primary sclerosing cell enzyme defects (G6PD deficiency, pyruvate Hypothyroidism cholangitis, gallstones, neoplasm, kinase deficiency), drugs (e.g., sulfisoxazole acetyl Breast milk jaundice Dubin-Johnson syndrome, Rotor’s with erythromycin ethylsuccinate (Pediazole), syndrome streptomycin, vitamin K), abnormal red blood Infection: sepsis, urinary tract infection, cells (hemoglobinopathies), sepsis syphilis, toxoplasmosis, tuberculosis, Nonhemolytic causes hepatitis, rubella, herpes Characteristics: increased unconjugated bilirubin Metabolic disorder: alpha1 antitrypsin level, normal percentage of reticulocytes deficiency, cystic fibrosis, galactosemia, Extravascular sources: cephalohematoma, bruising, glycogen storage disease,