Hyperbilirubinemia in the Newborn

After completing this article, readers should be able to: For centuries, neonatal jaundice (icterus neonatorum) has been observed in newborns. As early as 1724, Juncker, in the Conspectus Medicinae Theoreticopraticae, began distinguishing between “true jaundice” and “the icteric tinge which may be observed in infants, immediately after birth.” In 1875, Orth noticed during autopsies the presence of bilirubin in the basal ganglia of infants who had severe jaundice, which was labeled kernicterus by Schmorl in 1903. (1) In 1958, however, a nurse in the nursery of the General Hospital in Rothford, Essex, Great Britain, reported “an apparent fading away of the yellow pigmentation in the skin of the jaundiced babies when they had been a short time in sunlight.” (2)Icterus neonatorum occurs in approximately two thirds of all newborns in the first postnatal week. Jaundice results from bilirubin deposition in the skin and mucous membranes. For most newborns, such deposition is of little consequence, but the potential remains for kernicterus from high bilirubin concentrations or lower bilirubin concentrations in preterm infants. (3) Although rare, kernicterus is a preventable cause of cerebral palsy.Hyperbilirubinemia was treated aggressively in the 1950s to 1970s because of a high rate of Rh hemolytic disease and kernicterus. However, data from the 1980s and 1990s showed that pediatricians may have been too aggressive in their approach, almost making kernicterus a disease of the past. Pediatricians subsequently became less aggressive, discharging newborns earlier from nurseries before bilirubin concentrations peaked. These factors helped lead to an increase in kernicterus in the 1990s. (4) Because of these events, an American Academy of Pediatrics (AAP) Subcommittee on Hyperbilirubinemia established guidelines for the approach to neonatal jaundice. (5)When red blood cells undergo hemolysis, hemoglobin is released. Within the reticuloendothelial system, heme oxygenase degrades heme into biliverdin and carbon monoxide. Biliverdin reductase reduces biliverdin to unconjugated (indirect) bilirubin. Unconjugated bilirubin binds to albumin and is transported to the liver. Unconjugated bilirubin can become unbound if albumin is saturated or if bilirubin is displaced from albumin by medications (eg, sulfisoxazole, streptomycin, chloramphenicol, ceftriaxone, ibuprofen). The unbound unconjugated bilirubin can cross the blood-brain barrier and is toxic to the central nervous system. (5)(6) Once unconjugated bilirubin reaches the liver, it is conjugated by uridine diphosphate glucuronosyl transferase (UGT1A1). Hepatic UGT1A1 increases dramatically in the first few weeks after birth. At 30 to 40 weeks' gestation, UGT1A1 values are approximately 1% of adult values, rising to adult concentrations by 14 weeks of age. (7) Conjugated (direct) bilirubin is excreted into the intestine via the gallbladder and bile duct. Bacteria in the intestine can deconjugate bilirubin, allowing it to be reabsorbed into the blood. The rest of the bilirubin is excreted with the stool. (5)(6)Physiologic jaundice is an unconjugated hyperbilirubinemia that occurs after the first postnatal day and can last up to 1 week. Total serum bilirubin (TSB) concentrations peak in the first 3 to 5 postnatal days and decline to adult values over the next several weeks. The TSB concentrations vary greatly in infants, depending on race, type of feeding, and genetic factors. (8) Initially, the cord TSB concentration in term newborns is approximately 1.5 mg/dL (25.7 μmol/L). The TSB concentration peaks at approximately 5.5 mg/dL (94.1 μmol/L) by the third postnatal day in white and African American infants. The mean TSB concentration peaks are higher in Asian infants at approximately 10 mg/dL (171.0 μmol/L). (9) By 96 hours of age, 95% of infants have TSB concentrations of less than 17 mg/dL (290.8 μmol/L). Therefore, bilirubinemia above this value is no longer considered physiologic jaundice.Physiologic jaundice occurs in infants for a number of reasons. They have a high rate of bilirubin production and an impaired ability to extract bilirubin from the body. Bilirubin production also is increased as a result of elevated hematocrit and red blood cell volume per body weight and a shorter life span of the red blood cells (70 to 90 days). (10) Finally, infants have immature hepatic glucuronosyl transferase, a key enzyme involved in the conjugation of bilirubin that facilitates excretion from the body. (5)(10)Early-onset breastfeeding jaundice is the most common cause of unconjugated hyperbilirubinemia. (6)(8) Breastfeeding exaggerates physiologic jaundice in the first postnatal week because of caloric deprivation, leading to an increase in enterohepatic circulation. Mild dehydration and delayed passage of meconium also play roles. Successful breastfeeding decreases the risk of hyperbilirubinemia. Infants need to be fed at least 8 to 12 times in the first few days after birth to help improve the mother's milk supply. The best way to judge successful breastfeeding is to monitor infant urine output, stool output, and weight. Newborns should have four to six wet diapers and three to four yellow, seedy stools per day by the fourth day after birth. Breastfed infants should lose no more than 10% of their body weight by the third or fourth postnatal day. Formula supplementation may be necessary if the infant has significant weight loss, poor urine output, poor caloric intake, or delayed stooling. (4)(7) Water and dextrose solutions should not be used to supplement breastfeeding because they do not prevent hyperbilirubinemia and may lead to hyponatremia.Late-onset human milk jaundice usually occurs from the sixth through the fourteenth day after birth and may persist for 1 to 3 months. A few theories hypothesize the cause of human milk jaundice, but the exact mechanism is not entirely clear. It is believed that human milk contains beta-glucuronidases and nonesterified fatty acids that inhibit enzymes that conjugate bilirubin in the liver. Human milk jaundice is the most likely cause of unconjugated hyperbilirubinemia in this age group, but rarely, conjugation defects can occur. If the diagnosis is in question, breastfeeding can be discontinued for 48 hours to observe whether a decrease in TSB concentration occurs. During this time, the mother should continue to express milk to maintain her supply and supplement the infant with formula. TSB concentrations usually peak between 12 and 20 mg/dL (205.2 and 342.1 μmol/L) and should decrease 3 mg/dL (51.3 μmol/L) per day. If this decrease occurs, breastfeeding should be restarted. (6)Although preterm infants develop hyperbilirubinemia by the same mechanisms as term infants, it is more common and more severe in preterm infants and lasts longer. This outcome is related to the relative immaturity of the red blood cells, hepatic cells, and gastrointestinal tract. Sick preterm newborns are more likely to have a delay in initiating enteral nutrition, resulting in an increase in enterohepatic circulation. Despite the prevalence of hyperbilirubinemia in preterm newborns, kernicterus is extremely uncommon. However, kernicterus does occur at lower TSB concentrations, even without acute neurologic signs. (11) It is unclear, however, at what value of bilirubin central nervous system injury occurs. TSB values as low as 10 to 14 mg/dL (171.0 to 239.5 μmol/L) have resulted in milder forms of bilirubin-induced neurologic dysfunction (BIND) in preterm infants. (11)(12)Pathologic hyperbilirubinemia in a newborn can be separated into four categories: increased bilirubin production, deficiency of hepatic uptake, impaired conjugation of bilirubin, and increased enterohepatic circulation (Table 1). (5) Increased production occurs in infants who have erythrocyte-enzyme deficiencies, blood group incompatibility, or structural defects in erythrocytes. ABO incompatibility may cause anemia in the first-born child, but Rh incompatibility rarely does. Pediatricians also should consider glucose-6-phosphate dehydrogenase (G6PD) deficiency, especially in African American infants. G6PD deficiency is a sex-linked disorder occurring in 11% to 13% of African American newborns in the United States and is a significant risk factor for kernicterus. (8)Multiple conditions can cause hyperbilirubinemia through impaired bilirubin conjugation. Gilbert syndrome is an autosomal recessive condition in which UGT1A1 activity decreases mildly in hepatocytes, typically resulting in a benign unconjugated hyperbilirubinemia. The likelihood of severe hyperbilirubinemia is increased if the infant also has G6PD deficiency. In Crigler-Najjar syndrome type I, severe deficiency of UGT1A1 results in bilirubin encephalopathy in the first few days or month after birth. In Crigler-Najjar syndrome type II, the incidence of bilirubin encephalopathy is low. (5)Conjugated hyperbilirubinemia is defined by a conjugated bilirubin concentration greater than 1 mg/dL (17.1 μmol/L) when the TSB concentration is 5 mg/dL (85.6 μmol/L) or less. If the TSB concentration is greater than 5 mg/dL (85.6 μmol/L), conjugated hyperbilirubinemia is defined when the value is 20% or greater of the TSB concentration. Elevated conjugated hyperbilirubinemia may be related to a urinary tract infection or sepsis. In an infant older than 3 weeks of age, total and conjugated bilirubin should be measured to rule out cholestasis and biliary atresia, which are associated with elevated conjugated bilirubin concentrations. The newborn screen also should be reviewed because thyroid abnormalities and galactosemia are additional causes of conjugated hyperbilirubinemia.The term kernicterus was used originally for staining of the brainstem nuclei and cerebellum. Acute bilirubin encephalopathy describes the neurologic changes that occur in the first postnatal weeks from bilirubin toxicity. Kernicterus is the chronic or permanent neurologic sequela of bilirubin toxicity. (13) The level at which bilirubin toxicity occurs is not completely known, and multiple factors influence whether bilirubin toxicity does occur. Bilirubin can cross the blood-brain barrier and enter the brain tissue if it is unconjugated and unbound to albumin or if there is damage to the blood-brain barrier. Asphyxia, acidosis, hypoxia, hypoperfusion, hyperosmolarity, and sepsis can damage the blood-brain barrier, allowing bilirubin bound to albumin to enter the brain tissue. Pediatricians should consider acute bilirubin toxicity in a term infant if there are no signs of hemolysis and the TSB concentration is greater than 25 mg/dL (427.6 μmol/L). If the TSB concentration is above 20 mg/dL (342.1 μmol/L) in a term infant who has hemolysis, the physician should be concerned. (6)Acute bilirubin toxicity occurs in three phases during the first few weeks after birth. Phase 1 occurs during the first 1 to 2 days and results in poor suck, high-pitched cry, stupor, hypotonia, and seizures. Phase 2 occurs during the middle of the first postnatal week and results in hypertonia of extensor muscles, opisthotonus, retrocollis, and fever. Phase 3 occurs after the first postnatal week and presents with hypertonia. If bilirubin concentrations are not reduced, long-term morbidity can result in BIND. Neuronal injury occurs primarily in the basal ganglia and brainstem nuclei, but the hippocampus and cerebellum also may be affected. (12) BIND or kernicterus occurs in two phases. The first phase is seen during the first postnatal year and is characterized by hypotonia, active deep-tendon reflexes, obligatory tonic neck reflexes, and delayed motor skills. The second phase, which occurs after the first postnatal year, results in choreoathetotic cerebral palsy, ballismus, tremor, upward gaze, dental dysplasia, sensorineural hearing loss, and cognitive impairment. (6)The following recommendations are based on information from the AAP Subcommittee on Hyperbilirubinemia. Evaluation for hyperbilirubinemia should occur before birth and extend through the first few postnatal weeks. Hemolytic anemia caused by isoantibodies in the infant is a major risk factor for severe hyperbilirubinemia and bilirubin neurotoxicity. (13) ABO incompatibility may occur if the mother’s blood type is O and the infant’s blood type is A or B. (13) Mother-infant ABO incompatibility occurs in approximately 15% of all pregnancies, but symptomatic hemolytic disease occurs in only 5% of these infants. Hyperbilirubinemia in infants who have symptomatic ABO hemolytic disease usually is detected within the first 12 to 24 hours after birth. (14) Hence, ABO and Rh (D) blood types and a screen for unusual isoimmune antibodies should be evaluated for all pregnant women. If such testing is not performed or if the mother is Rh-negative, the infant’s cord blood should be evaluated for a direct antibody (Coombs) test, blood type, and Rh determination. If the newborn is assessed adequately and the mother’s blood type is not O and is Rh positive, cord blood does not need to be tested. (13)After birth, the infant should be assessed for jaundice at a minimum of every 8 to 12 hours. Jaundice can be detected on a physical examination, but darker skin makes for a harder assessment. Jaundice has a cephalocaudal progression, but visual assessment has been shown to predict the TSB concentration unreliably. Jaundice in an infant is best assessed by a window in daylight; otherwise, a well-lit room is adequate. The sclera and mucous membranes are assessed for icterus, and the color of the skin and subcutaneous tissues can be revealed by blanching the skin with digital pressure.For any infants who develop jaundice in the first 24 hours after birth, the clinician should assess whether it seems excessive for gestational age. If there is any doubt in the visual evaluation, transcutaneous bilirubin (TcB) or TSB should be assessed. Newer devices used to detect TcB have been shown to correlate well with TSB. (15) Once a TcB or TSB has been measured, the result should be interpreted based on the nomogram in Figure 1. Reassessment should be based on the zone in which the bilirubin falls on the nomogram. It is important to realize that the nomogram is based on infants of greater than 35 weeks' gestation who had no evidence of hemolytic disease. Preterm infants or infants who have risk factors for bilirubin toxicity are at higher risk of bilirubin toxicity at lower TSB concentrations. Therefore, the nomogram may not accurately predict the infant's risk based solely on the degree of hyperbilirubinemia in these high-risk infants. (13)Sometimes further laboratory evaluation is required to determine the cause of hyperbilirubinemia. If the cause is not evident after a thorough history assessing current risk factors or significant hyperbilirubinemia occurred in siblings, evaluation is appropriate for any infant who is receiving phototherapy or when the TSB crosses percentiles on the nomogram. A complete blood count with smear and direct bilirubin concentration should be checked in these instances. A reticulocyte count, G6PD measurement, and end-tidal carbon monoxide (ETCO) determination (if available) can be considered. (12) ETCO is a good indicator of ongoing bilirubin production. As noted previously, biliverdin and carbon monoxide are the byproducts of bilirubin breakdown. Measuring the ETCO allows identification of infants experiencing increased bilirubin production and possibly infants who have hemolytic disease. (5) The TSB concentration should be rechecked in 4 to 24 hours, depending on the infant's age, TSB value, and risk factors. If the TSB is increasing despite phototherapy or if the infant is being considered for a reticulocyte count, G6PD and ETCO should be and urine are appropriate if the infant has an elevated direct bilirubin If by the history and physical examination, a sepsis evaluation should be human milk jaundice is a common cause of jaundice in infants, more conditions should be out Total and direct bilirubin should be measured for the infant who jaundice or when jaundice after 3 weeks of age. In the newborn screen should be reviewed to rule out galactosemia and elevated direct bilirubin value should an evaluation for TSB concentrations peak at 3 to 5 days of age, after infants have the it is important to a risk assessment on all infants before they the and appropriate should be Although and risk based on the AAP Subcommittee has assessing TSB or TcB on all newborns before The value should be on the nomogram to assess the risk (13) a TSB on all newborns when the newborn screen is that data are to all infants at phototherapy in a gestational age less than jaundice in the first 24 hours, hemolytic Asian race, or significant and a TSB or TcB in the high risk zone before are the most common risk factors for severe hyperbilirubinemia. risk factor has little value, but the greater the number of risk the greater the likelihood of the severe hyperbilirubinemia. In a term infant who is fed has a low likelihood of severe hyperbilirubinemia. for following up with a infants are from the on the age at the time of A newborn at 48 to hours of age should be evaluated for jaundice, weight or loss, stool and of by hours of age. The should be evaluated at 96 hours of age if between 24 to 48 hours and at hours if before 24 hours of age. Infants before 48 hours of age may need a second to evaluation during the time when the TSB Infants who have more risk factors may need more if be is appropriate is or the infant is older than to 96 hours of age. of the most important is all on the and assessment of hyperbilirubinemia as well as necessary can decrease the likelihood of severe hyperbilirubinemia. should at least 8 to 12 times in the first few days after birth to in in the milk supply. should be any and involved when The stool and weight of newborns are good of whether the is receiving (6)(8) the of the of on bilirubin concentrations in the need for because of severe hyperbilirubinemia has by bilirubin into a which is excreted in the urine or bile without conjugation in the liver. The two factors in the of bilirubin to are the of and the total of Bilirubin is a yellow it most in the (5) a is seen only when the can tissue and bilirubin. with in the to are the most in hyperbilirubinemia. types of phototherapy are used that or or are also that in the The are the most and should be used when phototherapy is is not used for Although has been shown to decrease bilirubin concentrations, it is not because it is to determine a that is to a infant to without (13) The total or is by the the infant is from the and the to which or is Therefore, infants should be as as to the an infant in a than an allows the to be to the it is to the to within 10 of the infant without or can the the should be to determine the between the and the the infant as as or her results in a decline in bilirubin concentrations. It is to the the bilirubin concentrations are the level an The should be with or white when the of an In most it is to phototherapy to the infant or for phototherapy should be used if is an infant is receiving or her and should be Because bilirubin is excreted in the urine and the it is important to good urine If the infant is should be is for the infant who is not breastfeeding with is an to enterohepatic circulation and decrease the TSB of phototherapy should be based on the TSB age in hours, and risk as in guidelines from the AAP The TSB value should be and the direct bilirubin value should not be from the total when when to are no guidelines for infants earlier than 35 weeks' a decrease of mg/dL μmol/L) per can be in the first 4 to 8 hours. the TSB does not decline or during ongoing hemolysis is of phototherapy is not Therefore, is (5) the bilirubin decreases 4 to 5 mg/dL to μmol/L). (5) that the value should decrease to to 14 mg/dL to 239.5 μmol/L) if the is for hyperbilirubinemia. A common is that of phototherapy results in a hyperbilirubinemia. is a in an infant who more than and has no evidence of (5) this for infants or who have evidence of hemolysis is A bilirubin determination is not but if an infant is a TSB or in 24 hours is is performed for of infants, but do occur. The infant who has jaundice with elevated conjugated hyperbilirubinemia has the potential for infant infants develop a color of the and the syndrome is of little The only to phototherapy is or a history of in these result in severe and was the first successful for severe hyperbilirubinemia. These should be performed only in a neonatal by a for an infant is a and the should be to the neonatal the (9) the physician from the circulation bilirubin and any antibodies that may be to ongoing The of the infant's blood and with the same of red cells via to two central the infant's blood volume has been (5) of albumin 1 to 4 hours before the can increase the of bilirubin that is is for infants who have isoimmune hemolytic disease if the TSB is rising despite phototherapy or the TSB is within 2 to 3 mg/dL to μmol/L) of the level for an in of an can be in 12 hours, if (13) Figure 3 guidelines for initiating an should be immediately in a jaundiced infant signs of acute bilirubin even if the TSB value is factors for severe hyperbilirubinemia and the should be into when when to an are successful in infants who have severe there are and even The rate is reported to be approximately (5) Because of these risk phototherapy should be to the need for an a is a preventable cause of cerebral that infants are being at earlier it is important to consider with a TcB or TSB before because visual assessment is not It is important to for evaluation after within 48 hours, for additional should be to that the infants are receiving caloric and stool and urine can be checked at the bilirubin concentrations, can be used to of phototherapy and and can and the approach to the infant who has hyperbilirubinemia.