Neonatal jaundice is yellowish discoloration of the skin, conjunctiva and the sclera from elevated serum or plasma bilirubin in the newborn period. The term jaundice is from the French word "jaune," which means yellow. Neonatal jaundice in most newborns is a mild and transient event. It is, however imperative to identify newborns with jaundice that do not follow this pattern as failure to do so may lead to long-term sequelae.

Unconjugated hyperbilirubinemia in neonates is due to either physiologic or pathologic causes. Over 75% of neonatal unconjugated hyperbilirubinemia is due to physiologic causes. Physiologic jaundice is also referred to as non-pathologic jaundice, and it is mild and transient. This occurs because of differences in the metabolism of bilirubin in the neonatal period leading to an increased bilirubin load. The increased bilirubin load in the newborn arises from increased production of bilirubin due to a higher mass of red blood cells with a decreased lifespan in the neonate, a decreased bilirubin clearance from a deficiency of the uridine diphosphate glucuronosyltransferase (UGT) enzyme, which in the newborn has the activity of about 1% of the adult liver,[1] and increased enterohepatic circulation.

Physiologic jaundice usually occurs on days 2 to 4, peaks between 4 to 5 days, and resolves in 2two weeks. Physiologic jaundice never occurs in the first 24 hours.[2]

Similarly, the causes of pathologic unconjugated hyperbilirubinemia are also due to increased bilirubin production, decreased bilirubin clearance, and increased enterohepatic circulation. Pathologic jaundice may occur in the first 24 hours of life and is characterized by a rapid rate of rising in the bilirubin level more than 0.2 mg/dl per hour or 5 mg/dl per day.

Causes of increased bilirubin production in pathologic jaundice are immune-mediated hemolysis such as ABO and Rhesus incompatibility, non-immune mediated causes such as cephalhematoma, red blood cell membrane defects like hereditary spherocytosis and elliptocytosis, enzyme defects like glucose-6-phosphate dehydrogenase (G6PD) deficiency and pyruvate kinase.

ABO incompatibility occurs in mother’s with blood group O who have anti-A and anti-B IgG antibodies that cross the placenta and cause hemolysis in newborns with blood group A or B. In Rhesus (Rh) incompatibility, an Rh-negative mother who has been exposed to Rh-positive blood from a previous pregnancy becomes sensitized, causing hemolysis in the fetus with Rh-positive blood. Using Rhogam (anti-D gamma globulin) as prophylaxis in a mother with prior exposure has decreased the incidence of Rh hemolysis, which, although less common than ABO incompatibility, is more severe.[3]

The G6PD enzyme, found in red blood cells (RBCs), protects against oxidative injury by the production of NADPH (nicotinamide adenine dinucleotide phosphate hydrogenase) from NADP (nicotinamide adenine dinucleotide phosphate). With its deficiency, and in the presence of oxidant stressors like illness, certain drugs, dyes, and foods like fava beans, there is hemolysis of RBCs. The clinical presentation is varied depending on the variant of the GGPD, and some newborns may present with neonatal jaundice with severe hyperbilirubinemia or kernicterus. G6PD is an X-linked disorder leading to males mostly being affected and females mostly being asymptomatic carriers

Decreased bilirubin clearance occurs in inherited disorders such as Crigler-Najjar and Gilbert syndrome, as well as maternal diabetes and congenital hypothyroidism.

In Crigler-Najjar syndrome, there is either an absence of UGT activity (type 1) or low UGT activity (type 2), which leads to severe hyperbilirubinemia in the first days of life or less severe disease respectively. Neonates with Crigler-Najar 1 need liver transplantation or long-term use of phototherapy. Phenobarbital may be used in type 2 Crigler-Najjar.

There is a mutation of the UGT1A1 gene in Gilbert syndrome[4], causing decreased UGT production and unconjugated hyperbilirubinemia. Gilbert is usually diagnosed in the adolescent period, although presentation in the neonatal period may occur and is mostly inherited as an autosomal dominant condition. It can be diagnosed with genetic testing.

Decreased intestinal activity leads to increased enterohepatic circulation. Breastfeeding jaundice, breast milk jaundice, and intestinal obstruction are common conditions associated with increased enterohepatic circulation, leading to unconjugated hyperbilirubinemia.

Breastfeeding jaundice, also known as breastfeeding failure jaundice, occurs in the first week of life and is due to failure of adequate intake of breast milk leading to dehydration and sometimes hypernatremia.[1] Breastfeeding failure leads to decreased intestinal motility and decreases the elimination of bilirubin in the stool or meconium. 

Breast milk jaundice occurs late in the first week, peaks in the second, and usually resolves by 12 weeks of age. It is due to inhibition of  UGT activity and a factor in breast milk with a beta-glucuronidase-like activity that deconjugates conjugated bilirubin in the intestines leading to increased enterohepatic circulation.[5][6]

Conjugated hyperbilirubinemia is always pathologic and is due to defects in bile formation or transport, obstruction to its flow, or to systemic conditions that may affect the liver.

Conditions causing conjugated hyperbilirubinemia due to hepatobiliary disease include biliary atresia, choledochal cysts, idiopathic neonatal hepatitis, and Alagille syndrome.

Inborn errors of metabolism like galactosemia, metabolic disorders such as tyrosinemia and genetic disorders like a-1 antitrypsin deficiency present as conjugated hyperbilirubinemia.

Systemic infections like “TORCH” (toxoplasmosis, other-syphilis, varicella-zoster, rubella, cytomegalovirus, and herpes simplex) infections and systemic conditions like sepsis, shock, and birth asphyxia may also present with conjugated hyperbilirubinemia. Urinary tract infections in the neonatal period and prolonged use of parenteral nutrition in premature newborns are also known causes of conjugated hyperbilirubinemia.

Biliary atresia is the most common cause of conjugated neonatal hyperbilirubinemia.[2] It involves both intra-hepatic and extra-hepatic bile ducts and classically presents around 2 to 4 weeks of life with pale stools. The initial evaluation is by ultrasonography that may show an absent gallbladder and the classic "triangular cord" sign.[7] The absence of pale stools and ultrasonographic findings or the presence of the gallbladder, however, do not rule out biliary atresia. Ultrasonography is followed by percutaneous liver biopsy, which gives additional information and supports the diagnosis of biliary atresia or helps to differentiate biliary atresia from other causes. If the liver biopsy supports a diagnosis of biliary atresia, an open cholangiogram should be performed, followed by the definitive surgical intervention, the Kasai procedure (hepatoportoenterostomy) should be performed. For a better outcome, the Kasai procedure should be performed before eight weeks. Newborns suspected of biliary atresia should, therefore, be promptly referred for evaluation and management.

Choledochal cysts involve dilation of the intrahepatic and extra-hepatic bile duct. Ultrasonography can detect the cysts with normal or dilated intrahepatic bile ducts as opposed to sclerosed ducts in biliary atresia, although cystic biliary atresia may resemble choledochal cysts.[8]

Alagille syndrome is caused by a genetic mutation leading to a paucity of interlobular bile ducts and hepatic manifestations, including jaundice and cirrhosis. Other clinical features are butterfly vertebrae, peripheral pulmonic stenosis, renal involvement, dysmorphic features, and posterior embryotoxon of the eye. Alagille syndrome is inherited in an autosomal dominant pattern.[9]

Alpha-1-antitrypsin deficiency is a common genetic disorder that presents with cholestatic jaundice in infants who are homozygous for the PiZZ genotype. Accumulation of anti-trypsin polymers in the endoplasmic reticulum of hepatocytes of a patient with the PiZZ genotype leads to apoptosis, neonatal cholestasis, and cirrhosis later in childhood.[10]

Newborns with galactosemia present with jaundice, cataracts, hepatomegaly, failure to thrive, renal tubular acidosis, and Escherichia coli sepsis after the ingestion of milk.[11] Galactosemia is due to galactose-1-phosphate uridyl transferase (GALT) deficiency leading to the accumulation of toxic metabolites in multiple organs. The presence of reducing substances in urine suggests galactosemia, and GALT activity in the liver or erythrocytes confirms the diagnosis.

Almost all newborns will develop a total bilirubin level above the upper limit of normal for adults and older children bilirubin of 1.5 mg/dl with less than 5% of the total bilirubin conjugated.[2] Up to 60% of term infants[12] and 80% of newborns with a  gestational age of 35 weeks or more[13] will develop jaundice, which occurs when serum bilirubin reaches and exceeds 5 mg/dl.

Neonatal jaundice appears to be more common in people living at high altitudes and those living around the mediterranean sea, especially Greece.

Bilirubin comes from the breakdown in heme, which is produced from the breakdown of hemoglobin. Heme is converted to biliverdin, iron, and carbon monoxide by the enzyme heme oxygenase[14]; biliverdin is then converted to bilirubin by biliverdin reductase. The conversion of heme to bilirubin takes place in the reticuloendothelial system. The unconjugated bilirubin is hydrophobic and is transported to the liver bound to albumin where it is conjugated by the enzyme uridine diphosphate-glucuronosyltransferase (UGT). Conjugated bilirubin, which is water-soluble, is excreted in bile and into the gastrointestinal (GI) tract and mostly excreted in feces after being metabolized by bacterial flora. Some conjugated bilirubin is deconjugated to unconjugated bilirubin and reabsorbed through the enterohepatic circulation.[15]

Hyperbilirubinemia is total serum bilirubin more than the 95% on the Bhutani nomogram[16] or above 1.5 mg/dl.[17] Neonatal hyperbilirubinemia is classified as unconjugated/indirect hyperbilirubinemia, which is usually benign or conjugated/direct hyperbilirubinemia when the direct bilirubin is more than 20% of the total bilirubin with the total bilirubin above 5 mg/dl. Conjugated hyperbilirubinemia is always pathologic.

Severe neonatal hyperbilirubinemia is associated with neurologic dysfunction known as bilirubin-induced neurologic dysfunction (BIND). In severe hyperbilirubinemia, unconjugated bilirubin crosses the blood-brain barrier. It binds to the basal ganglia and brainstem nuclei, presenting either as an acute bilirubin encephalopathy or progresses to become a permanent neurologic dysfunction known as kernicterus.