NEONATAL JAUNDICE IN THE NEWBORNS

Jaundice is the most common condition requiring medical attention in newborns. The yellow coloration of the skin and sclera in newborns with jaundice is the result of accumulation of unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively, which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus). For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation.

Physicians recognized neonatal jaundice as early as the 18th century. Supposedly, Morgagni described 15 infants with jaundice (all of them his). Descriptions of the clinical course and epidemiology of neonatal jaundice are found in a number of 19th-century theses and other publications.

Pathophysiology (neonatal jaundice):
Neonatal physiologic jaundice results from simultaneous occurrence of the following 2 phenomena:
• Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates.
• Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin water soluble (conjugation).

Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism and is formed through oxidation-reduction reactions. Approximately 75% of bilirubin is derived from hemoglobin, but degradation of myoglobin, cytochromes, and catalase also contributes. In the first oxidation step, biliverdin is formed from heme through the action of heme oxygenase, the rate-limiting step in the process, releasing iron and carbon monoxide. The iron is conserved for reuse, while carbon monoxide is excreted through the lungs and can be measured in the patient's breath to quantify bilirubin production.

Next, water-soluble biliverdin is reduced to bilirubin, which, because of the intramolecular hydrogen bonds, is almost insoluble in water in its most common isomeric form (bilirubin IX Z,Z). Due to its hydrophobic nature, unconjugated bilirubin is transported in the plasma tightly bound to albumin. Binding to other proteins and erythrocytes also occurs, but the physiologic role is probably limited. Binding of bilirubin to albumin increases postnatally with age and is reduced in infants who are ill. The presence of endogenous and exogenous binding competitors, such as certain drugs, also decreases the binding affinity of albumin for bilirubin. A minute fraction of unconjugated bilirubin in serum is not bound to albumin. This free bilirubin is able to cross lipid-containing membranes, including the blood-brain barrier, leading to neurotoxicity.

When the bilirubin-albumin complex reaches the hepatocyte, bilirubin is transported into the cell, where it partially binds to ligandin. Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin concentrations are low at birth, but they increase rapidly over the first few weeks of life. Ligandin concentrations may be increased by the administration of pharmacologic agents such as phenobarbital.

Bilirubin is bound to glucuronic acid (conjugated) in the hepatocyte endoplasmic reticulum in a reaction catalyzed by uridine diphosphoglucuronyltransferase (UDPGT). Monoconjugates are formed first and predominate in the newborn. Diconjugates appear to be formed at the cell membrane and may require the presence of the UDPGT tetramer.

Bilirubin conjugation is biologically critical because it transforms a water-insoluble bilirubin molecule into a water-soluble molecule. Water-solubility allows bilirubin to be excreted into bile. The activity of UDPGT is low at birth, but increases to adult values by age 4-8 weeks. In addition, certain drugs (phenobarbital, dexamethasone, clofibrate) can be administered to increase UDPGT activity.

Once excreted into bile and transferred to the intestines, bilirubin eventually is reduced to colorless tetrapyrroles by microbes in the colon. However, some deconjugation occurs in the proximal small intestine through the action of β-glucuronidases located in the brush border. This unconjugated bilirubin can be reabsorbed into the circulation, increasing the total plasma bilirubin pool. This cycle of uptake, conjugation, excretion, deconjugation, and reabsorption is termed the enterohepatic circulation. The process may be extensive in the neonate, partly because nutrient intake is limited in the first days of life, prolonging the intestinal transit time. Certain factors present in the breast milk of some mothers also may contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice), but the mechanism behind this phenomenon remains unelucidated.

Neonatal jaundice, while a normal transitional phenomenon in most infants, can occasionally become more pronounced. Blood group incompatibilities (Rh, ABO, and others) may increase bilirubin production through increased hemolysis. Historically, Rh isoimmunization was an important cause of severe jaundice, often resulting in the development of kernicterus. While this condition has become relatively rare in industrialized countries following the use of Rh prophylaxis in Rh-negative women, Rh isoimmunization remains common in developing countries. Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) also may cause increased jaundice through increased hemolysis.

A number of other nonhemolytic processes can increase serum bilirubin levels. Accumulation of blood in extravascular compartments (cephalhematomas, bruising, occult bleeding) may increase bilirubin production as the blood is absorbed and degraded. Increased bilirubin production also is seen in patients with polycythemia and in infants of mothers with diabetes. Increased enterohepatic circulation leading to elevated bilirubin levels is seen in patients with bowel obstruction or ileus and when infants are not fed for other reasons.

Decreased clearance of bilirubin is seen in certain inborn errors of metabolism, such as Crigler-Najjar syndrome, Gilbert syndrome, galactosemia, tyrosinemia, and hypermethioninemia. In the latter 3 conditions, elevations of conjugated serum bilirubin occur frequently. Hormone deficiencies, such as hypothyroidism and hypopituitarism, also can decrease bilirubin clearance. Finally, decreased clearance may play a role in breast milk jaundice. Compared to unconjugated hyperbilirubinemia, conjugated (direct) hyperbilirubinemia is rare in neonates.

Conjugated hyperbilirubinemia can be broadly classified into the following 2 groups:
• Obstructed bile flow with or without hepatocellular injury
• Hepatocyte injury with normal bile ducts

Obstructed bile flow with or without hepatocellular injury may result from biliary atresia or choledochal cyst. Hepatocyte injury with normal bile ducts may be due to iatrogenic, infectious, or metabolic causes. Iatrogenic causes include intravenous hyperalimentation. Infectious causes may be viral (cytomegalovirus, hepatitis B, other viruses), bacterial (septicemia), or parasitic (toxoplasmosis). Metabolic disorders include enzyme deficiencies (α1-antitrypsin deficiency, galactosemia, cystic fibrosis, tyrosinemia, fructosemia, hypermethioninemia), storage diseases, Rotor syndrome, Dubin-Johnson syndrome, Byler disease, Zellweger syndrome, and Aagenaes syndrome.

Frequency (neonatal jaundice):
• In the US: Neonatal hyperbilirubinemia is extremely common because almost every newborn develops an unconjugated serum bilirubin level greater than 30 μmol/L (1.8 mg/dL) during the first week of life. Incidence figures are difficult to compare because authors of different studies do not use the same definitions for significant neonatal jaundice. In addition, identification of infants to be tested depends on visual recognition of jaundice by health care providers, which is subject to great variability and depends both on observer attention and on infant characteristics such as race and gestational age. With the above caveats, epidemiologic studies provide a frame of reference for estimated incidence. In 1986, Maisels and Gifford reported 6.1% of infants with serum bilirubin levels greater than 220 μmol/L (12.9 mg/dL). In 1983, Palmer and Drew reported 10.7% of infants with serum bilirubin levels greater than 154 μmol/L (9 mg/dL).
• Internationally: Incidence varies with ethnicity and geography. Incidence is higher in East Asians and American Indians and lower in African Americans. Greeks living in Greece have a higher incidence than those of Greek descent living outside of Greece. Incidence is higher in populations living at high altitudes. In 1984, Moore et al reported 32.7% of infants with serum bilirubin levels greater than 205 μmol/L (12 mg/dL) at 3100 m of altitude.

Mortality/Morbidity (neonatal jaundice):
• Death from physiologic neonatal jaundice per se should not occur.
• Death from kernicterus may occur, particularly in countries with less developed medical care systems. Mortality figures in this setting are not available.

Race:
• Incidence of neonatal jaundice is increased in infants of East Asian, American Indian, and Greek descent, although the latter applies only to infants born in Greece and thus may be environmental rather than ethnic in origin.
• African American infants are affected less often than white infants.
• In 1985, Linn et al reported on a series in which 49% of East Asian, 20% of white, and 12% of African American infants had serum bilirubin levels greater than 170 μmol/L (10 mg/dL).

Sex: Risk of developing significant neonatal jaundice is higher in male infants. This does not appear to be related to bilirubin production rates, which appear to be similar to those in female infants.