Jaundice: Newborn to Age 2 Months

Neonatal jaundice is a common clinical sign that indicates hyperbilirubinemia. Clinicians should become familiar with the differential diagnoses of hyperbilirubinemia in newborns and young infants and the importance of early referral of all patients with cholestatic jaundice to a pediatric gastroenterologist or hepatologist.After completing this article, readers should be able to:The term jaundice, derived from the French word jaune, meaning yellow, is a yellowish discoloration of the skin, sclerae, and mucous membranes that is caused by tissue deposition of pigmented bilirubin. Jaundice is also known as icterus, from the ancient Greek word ikteros, signifying jaundice. Jaundice is a common clinical sign in newborns, especially during the first 2 weeks after birth. The first description of neonatal jaundice and bilirubin staining of the newborn brain goes back to the eighteenth century. The finding of jaundice on physical examination is an indicator of hyperbilirubinemia. This differs from carotenemia, which can also manifest as a pale yellow-red skin color and is caused by a high level of carotene in the blood.Older children and adults have a normal total serum bilirubin level less than 1.5 mg/dL (26 μmol/L), with the conjugated fraction accounting for less than 5%. (1) Hyperbilirubinemia is defined as a total serum bilirubin level greater than 1.5 mg/dL (26 μmol/L). In newborns, serum bilirubin universally exceeds this level for physiological reasons during the transitional period after birth. Jaundice becomes evident when the total serum bilirubin level reaches 5 mg/dL (86 μmol/L). More than 60% of healthy newborns develop neonatal jaundice and receive diagnoses of neonatal hyperbilirubinemia during the first week after birth. (2) In a more recent study, neonatal jaundice affected 84% of neonates born at at least 35 weeks of gestation. (3) Jaundice usually begins on the face and progresses in a cephalocaudate fashion, for unknown reasons. The total bilirubin level roughly correlates with progression of jaundice (face, 4–8 mg/dL [68–137 μmol/L]; upper trunk, 5–12 mg/dL [86–205 μmol/L]; lower trunk, 8–16 mg/dL [137–274 μmol/L]; soles of the feet, >15 mg/dL [>257 μmol/L]). (4)It is important to understand the metabolism of bilirubin to be able to identify the factors that lead to hyperbilirubinemia in the newborn (Fig 1). Bilirubin is the end product of heme degradation. (1)(5) Heme is produced by the breakdown of hemoglobin (70%–80%) and other hemoproteins (20%–30%). The conversion from heme to bilirubin occurs mainly in the reticuloendothelial system of the spleen, liver, and bone marrow. Heme is first converted to biliverdin by the microsomal enzyme heme oxygenase and then to unconjugated bilirubin by the cytosolic enzyme biliverdin reductase. (6) The unconjugated bilirubin is tightly bound to serum albumin and transported to the liver for conjugation and clearance. Once inside the hepatocyte, unconjugated bilirubin binds to a cytosolic binding protein and is then conjugated with glucuronic acids in the endoplasmic reticulum by the enzyme bilirubin uridine diphosphate-glucuronosyltransferase (BUGT) to form bilirubin mono- and diglucuronides, known as conjugated bilirubin. (7) The conjugated bilirubin is then excreted into the bile through the canalicular membrane, a process mediated by an adenosine triphosphate–dependent transporter system. This excreted bilirubin is further metabolized by intestinal bacterial flora to form urobilinoids, which are then eliminated in the feces. The conjugated bilirubin can also be deconjugated by bacterial or tissue β-glucuronidase converting back to unconjugated bilirubin, which is reabsorbed in the intestine, a process known as enterohepatic circulation. (8)Jaundice is quantified by measuring transcutaneous and/or serum bilirubin levels. The transcutaneous bilirubin measurement is a quick and noninvasive tool to measure total bilirubin levels in newborns, and it can be used in the initial screening and follow-up. (9) This measurement has generally correlated well with the serum bilirubin level in both term and preterm newborns. (10)(11) However, clinicians should be aware that there are discrepancies between transcutaneous and serum bilirubin measurements, especially in African-American newborns. (12) When in doubt, clinicians should confirm the result by obtaining a serum bilirubin level. Serum bilirubin is conventionally measured in the clinical laboratory as total and direct bilirubin levels. Indirect bilirubin is calculated as the difference between the total bilirubin level and the direct bilirubin fraction. The terms “indirect” and “direct” are used interchangeably with unconjugated and conjugated bilirubin, respectively. Hyperbilirubinemia is classified as unconjugated or indirect and conjugated or direct hyperbilirubinemia. Neonatal unconjugated hyperbilirubinemia is often transient and benign; less frequently, it can be a manifestation of an underlying disorder. Furthermore, severe unconjugated hyperbilirubinemia can cause acute bilirubin encephalopathy and chronic irreversible neurological damage (kernicterus). Conjugated hyperbilirubinemia or cholestasis, on the other hand, is always pathologic and refers to a direct bilirubin level greater than 2 mg/dL (34 μmol/L) or greater than 20% of the total bilirubin level. The term neonatal cholestasis is defined as cholestasis or conjugated hyperbilirubinemia occurring within the first 3 months after birth.Unconjugated and conjugated hyperbilirubinemia in newborns and young infants differ in their etiologic origins and management approaches. A brief list of the differential diagnoses of jaundice in newborns and young infants is presented in the Table.It is important to distinguish between benign transient neonatal jaundice and pathologic jaundice caused by underlying conditions on the basis of the newborn’s age, risk factors, and laboratory findings. It is also important to monitor the development of severe hyperbilirubinemia, which could potentially lead to acute and chronic bilirubin encephalopathy (kernicterus). Risk factors for severe hyperbilirubinemia include prematurity, maternal diabetes, race (Asians and Native Americans), male sex, trisomy 21, cephalohematoma, oxytocin induction, breastfeeding, delayed passage of meconium, and a history of siblings who had neonatal jaundice. (3)(13) All term or near-term newborns are screened by using an hour-specific total serum or transcutaneous bilirubin nomogram (Fig 2). (14) This tool allows physicians to identify newborns at low (<40th percentile), intermediate (40th–95th percentiles), or high (>95th percentile for age) risk for developing severe hyperbilirubinemia and potential kernicterus. The nomogram is not designed for infants with hemolysis or other illness that requires intensive care.Mild, unconjugated hyperbilirubinemia, also known as physiological jaundice, is common in the first few days after birth. It develops in newborns who are otherwise healthy, without any underlying conditions, and their total serum bilirubin levels rarely exceed 12 mg/dL (205 μmol/L). Multiple factors can lead to physiological jaundice, including (a) increased bilirubin production from breakdown of red blood cells, which have a higher concentration and shorter lifespan at birth; (b) relatively low BUGT enzyme activity, so more bilirubin monoglucuronides than bilirubin diglucuronides are excreted into the bile; the bilirubin monoglucuronides are easily deconjugated and reabsorbed in the intestine; (15) and (c) lack of intestinal bacterial flora at birth to metabolize bilirubin to nonabsorbable urobilinoids. This type of jaundice typically does not appear in the first 24 hours after birth. It develops between the second and fourth days after birth, reaches its peak between the fourth and fifth days, and resolves within the first 2 weeks after birth. During the first week after birth, physiological jaundice often overlaps with breastfeeding jaundice, a phenomenon of indirect hyperbilirubinemia in breastfed infants caused mainly by inadequate breast milk intake and dehydration. (16)(17) In contrast, breast milk jaundice typically develops after the first week after birth and lasts longer than breastfeeding jaundice. The mechanism of breast milk jaundice is thought to be inhibition of BUGT enzyme activity and increased enterohepatic circulation caused by compounds in breast milk. (16) More recent data from Japan showed a variation in the gene encoding BUGT as a genetic basis of breast milk jaundice. (18) Breastfeeding interruption is no longer recommended for breast milk jaundice because of its low specificity as a diagnostic procedure. (19)Nonphysiological jaundice should always be considered in the differential diagnosis of neonatal jaundice. Features such as early onset of jaundice, rapid progression, persistent jaundice beyond 2 weeks after birth, or association with other signs or symptoms suggest a pathologic process. In general, pathologic, unconjugated hyperbilirubinemia results from excessive production and/or abnormal hepatic clearance of bilirubin. To screen newborns for pathologic jaundice, the initial diagnostic tests should include a total and direct bilirubin level, complete blood cell count, reticulocyte count, blood grouping, and Coombs test. Laboratory findings to support the diagnosis of hemolysis include anemia, a positive direct Coombs test result, a high reticulocyte count, an increased unconjugated bilirubin level, and presence of fragmented red blood cells on the blood smear. Severe, unconjugated hyperbilirubinemia can lead to acute or chronic bilirubin encephalopathy. Under normal circumstances, unconjugated bilirubin is hydrophobic and is albumin-bound. When an excessive amount of unconjugated bilirubin is produced, the unbound bilirubin can cross the brain-blood barrier, resulting in brain toxicity. Affected infants can present with symptoms such as lethargy, hypotonia, and decreased suck, known as acute bilirubin encephalopathy. This process can be reversible if treated promptly. However, it may progress to kernicterus, an irreversible brain damage with cerebral palsy, sensorineural hearing loss, posturing, arching, and seizures. (20)(21)Hemolysis can cause rapid and excessive bilirubin production, which can result in neonatal jaundice. This type of hyperbilirubinemia usually starts within the first 24 hours after birth and often requires intensive phototherapy and exchange transfusion to prevent kernicterus. Hemolysis is often seen in association with immune-mediated maternal-fetal blood type incompatibility or non–immune-mediated conditions such as hemoglobinopathies, erythrocyte membrane defects, and enzyme deficiencies. ABO and Rh incompatibility are the two most common types of immune-mediated maternal-fetal blood type incompatibility that can lead to hemolysis in the newborn. ABO incompatibility occurs in approximately 15% of all pregnancies but results in hemolytic disease in only 3% of newborns, with less than 0.1% of infants needing exchange transfusion. (22) Hemolysis secondary to ABO incompatibility is usually seen in newborns with blood type A or B who are born to with blood type who have or which can through the disease in Rh incompatibility can also develop after an has become after to blood during a Rh incompatibility is less but it is usually more severe than ABO In the the of the is approximately 15% in in African-American and less than in Rh incompatibility occurs in approximately neonates usually present with jaundice in the first hours after birth, anemia, and In severe neonates may be born with as the result of The of in has decreased the of hemolytic disease of the newborn to less than of of hemolysis that can lead to neonatal jaundice and unconjugated hyperbilirubinemia include hemoglobinopathies, erythrocyte membrane defects, enzyme and such as should be in newborns with jaundice and a hemolytic a red blood cell membrane should be if there is a positive and the diagnosis can be with an test. enzyme defects, such as or may cause hemolysis in the newborn A newborn screening for is screening for this occurs in only a few is neonatal hyperbilirubinemia with potential may develop in the presence of such as All newborns with should be for the development of severe jaundice and after Neonatal can lead to increased bilirubin production to an in red blood cell It occurs in to of newborns and results in unconjugated hyperbilirubinemia in to of affected can result in increased bilirubin production from rapid breakdown of red blood cells in the or conjugation of bilirubin is mechanism that can lead to unconjugated hyperbilirubinemia. such as and can bilirubin by has to of bilirubin. In a of clinical conditions, such as physiological jaundice, breast milk jaundice, and unconjugated hyperbilirubinemia is at least in with decreased conjugation of bilirubin, as a result of decreased or delayed of BUGT enzyme and are 2 types of unconjugated hyperbilirubinemia caused by a of in the gene encoding for is a common by unconjugated hyperbilirubinemia and caused by a level of of the This is a benign that of the It is as an an has also is usually during or after it can present as transient neonatal hyperbilirubinemia. is to is a form of unconjugated hyperbilirubinemia as and it is caused by or decreased BUGT enzyme type with severe jaundice in the first hours after birth. 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