Jaundice is the most common condition that requires 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.
Neonatal jaundice may have first been described in a Chinese textbook 1000 years ago. Medical theses, essays, and textbooks from the 18th and 19th centuries contain discussions about the causes and treatment of neonatal jaundice. Several of these texts also describe a lethal course in infants who probably had Rh isoimmunization. In 1875, Orth first described yellow staining of the brain, in a pattern later referred to by Schmorl as kernicterus.
Neonatal physiologic jaundice results from simultaneous occurrence of the following two phenomena  :
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, whereas 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 IXα Z,Z). Because of 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. In fetal life, free bilirubin crosses the placenta, possibly by a carrier-mediated process,  and excretion of bilirubin from the fetus occurs primarily through the maternal organism.
When it reaches the liver, bilirubin is transported into liver cells, where it binds to ligandin. Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin concentrations are low at birth but rapidly increase 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 conjugated bilirubin to be excreted into bile. UDPGT activity 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.
Infants who have Gilbert syndrome or who are compound heterozygotes for the Gilbert promoter and structural mutations of the UDPGT1A1 coding region are at an increased risk of significant hyperbilirubinemia. Interactions between the Gilbert genotype and hemolytic anemias such as glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency, hereditary spherocytosis, or ABO hemolytic disease also appear to increase the risk of severe neonatal jaundice.
Further, the observation of jaundice in some infants with hypertrophic pyloric stenosis may also be related to a Gilbert-type variant. Genetic polymorphism for the organic anion transporter protein OATP-2 correlates with a 3-fold increased risk for developing marked neonatal jaundice. Combination of the OATP-2 gene polymorphism with a variant UDPGT1A1 gene further increases this risk to 22-fold.  Studies also suggest that polymorphisms in the gene for glutathione-S-transferase (ligandin) may contribute to higher levels of total serum bilirubin.
Thus, some interindividual variations in the course and severity of neonatal jaundice may be explained genetically.  As the impact of these genetic variants is more fully understood, development of a genetic test panel for risk of severe and/or prolonged neonatal jaundice may become feasible. 
Once excreted into bile and transferred to the intestines, bilirubin is eventually reduced to colorless tetrapyrroles by microbes in the colon. However, some deconjugation occurs in the proximal small intestine through the action of B-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 '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.
In mother-infant dyads who are experiencing difficulties with the establishment of breast feeding, inadequate fluid and nutrient intake often leads to significant postnatal weight loss in the infant. Such infants have an increased risk of developing jaundice through increased enterohepatic circulation, as described above. This phenomenon is often referred to as breastfeeding jaundice and is different from the breast milk jaundice described below.
Certain factors present in the breast milk of some mothers may also contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice). β-glucuronidase may play a role by uncoupling bilirubin from its binding to glucuronic acid, thus making it available for reabsorption. Data suggest that the risk of breast milk jaundice is significantly increased in infants who have genetic polymorphisms in the coding sequences of the UDPGT1A1  or OATP2 genes. Although the mechanism that causes this phenomenon is not yet agreed on, evidence suggests that supplementation with certain breast milk substitutes may reduce the degree of breast milk jaundice (see Other therapies).
Neonatal jaundice, although a normal transitional phenomenon in most infants, can occasionally become more pronounced. Blood group incompatibilities (eg, Rh, ABO) may increase bilirubin production through increased hemolysis. Historically, Rh isoimmunization was an important cause of severe jaundice, often resulting in the development of kernicterus. Although this condition has become relatively rare in industrialized countries following the use of Rh prophylaxis in Rh-negative women, Rh isoimmunization remains common in low- and middle-income countries (LMICs).
Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased jaundice, and increased hemolysis appears to have been present in some of the infants reported to have developed kernicterus in the United States in the past 15-20 years. The possible interaction between such conditions and genetic variants of the Gilbert and UDPGT1A1 genes, as well as genetic variants of several other proteins and enzymes involved in bilirubin metabolism, is discussed above.
These discoveries also highlight the challenges involved in the common use of the terms physiologic jaundice and pathologic jaundice. Although physiologic jaundice is a helpful concept from a didactic perspective, applying it to an actual neonate with jaundice is more difficult.
Consider the following metaphor: Think of total serum bilirubin in neonatal jaundice as a mountain covered by a glacier. If a measurement of the height of the mountain is taken when standing on the summit, the amount of rock and the amount of ice that comprise this measurement is unclear. The same is true for many total serum bilirubin values obtained in neonatal jaundice. An underpinning of physiologic processes and pathological process (eg, Rhesus incompatibility) may clearly contribute to the measurement. However, how much of the measured total value comes from each of these components is unclear. Also, because genetic variants in bilirubin metabolism are only exceptionally pursued in the diagnostic work-up of infants with jaundice, their possible contribution to the measured total serum bilirubin is usually unknown.
Physiologic jaundice is caused by a combination of increased bilirubin production secondary to accelerated destruction of erythrocytes, decreased excretory capacity secondary to low levels of ligandin in hepatocytes, and low activity of the bilirubin-conjugating enzyme uridine diphosphoglucuronyltransferase (UDPGT).
Pathologic neonatal jaundice occurs when additional factors accompany the basic mechanisms described above. Examples include immune or nonimmune hemolytic anemia, polycythemia, and the presence of bruising or other extravasation of blood.
Decreased clearance of bilirubin may play a role in breast feeding jaundice, breast milk jaundice, and in several metabolic and endocrine disorders.
Risk factors include the following:
Race: Incidence is higher in East Asians and American Indians and is lower in Africans/African Americans.
Geography: Incidence is higher in populations living at high altitudes. Greeks living in Greece appear to have a higher incidence than those living outside of Greece.
Genetics and familial risk: Incidence is higher in infants with siblings who had significant neonatal jaundice and particularly in infants whose older siblings were treated for neonatal jaundice. Incidence is also higher in infants with mutations/polymorphisms in the genes that code for enzymes and proteins involved in bilirubin metabolism, and in infants with homozygous or heterozygous glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency and other hereditary hemolytic anemias. Combinations of such genetic variants appear to exacerbate neonatal jaundice. [1, 5, 9, 10, 6]
Nutrition: Incidence is higher in infants who are breastfed or who receive inadequate nutrition. The mechanism for this phenomenon may not be fully understood. However, when inadequate feeding volume is involved, increased enterohepatic circulation of bilirubin probably contributes to prolonged jaundice. Recent data have shown that breast milk jaundice correlates with higher levels of epidermal growth factor, both in breast milk and in infants' serum.  Data suggest that the difference between breastfed and formula-fed infants may be less pronounced with some modern formulas. However, formulas containing protein hydrolysates have been shown to promote bilirubin excretion.
Maternal factors: Infants of mothers with diabetes have higher incidence. Use of some drugs may increase the incidence, whereas others decrease the incidence. Some herbal remedies taken by the lactating mother may apparently exacerbate jaundice in the infant.
Birthweight and gestational age: Incidence is higher in premature infants and in infants with low birthweight.
United States data
An estimated 50% of term and 80% of preterm infants develop jaundice, typically 2-4 days afer birth.  Neonatal hyperbilirubinemia is extremely common because almost every newborn develops an unconjugated serum bilirubin level of more 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 hyperbilirubinemia or jaundice. In addition, identification of infants to be tested depends on visual recognition of jaundice by health care providers, which varies widely 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 of more than 220 µmol/L (12.9 mg/dL).  In a 2003 study in the United States, 4.3% of 47,801 infants had total serum bilirubin levels in a range in which phototherapy was recommended by the 1994 American Academy of Pediatrics (AAP) guidelines, and 2.9% had values in a range in which the 1994 AAP guidelines suggest considering phototherapy.  In some LMICs, the incidence of severe neonatal jaundice may be as much as 100 times higher than in higher-income countries. 
Incidence varies with ethnicity and geography. Incidence is higher in East Asians and American Indians and lower in Africans. 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 of more than 205 µmol/L (12 mg/dL) at 3100 m of altitude. 
A study from Turkey reported significant jaundice in 10.5% of term infants and in 25.3% of near-term infants.  Significant jaundice was defined according to gestational and postnatal age and leveled off at 14 mg/dL (240 µmol/L) at 4 days in preterm infants and 17 mg/dL (290 µmol/L) in the term infants. Severe neonatal jaundice is 100-fold more frequent in Nigeria than in industrialized countries.  In Denmark, 24 in 100.000 infants met exchange transfusion criteria, while 9 in 100.000 developed acute bilirubin encephalopathy. 
Studies seem to suggest that some of the ethnic variability in the incidence and severity of neonatal jaundice may be related to differences in the distribution of the genetic variants in bilirubin metabolism discussed above. [1, 5]
The incidence of neonatal jaundice is increased in infants of East Asian, American Indian, and Greek descent, although the latter appears to apply only to infants born in Greece and thus may be environmental rather than ethnic in origin. African infants are affected less often than non-African infants. For this reason, significant jaundice in an African infant merits a closer evaluation of possible causes, including G-6-PD deficiency. In 1985, Linn et al reported on a series in which 49% of East Asian, 20% of white, and 12% of black infants had serum bilirubin levels of more than 170 µmol/L (10 mg/dL). 
The possible impact of genetic polymorphisms on ethnic variation in incidence and severity should be recognized. Thus, in a study of Taiwanese infants, Huang et al reported that neonates who carry the 211 and 388 variants in the UGT1A1 and OATP2 genes and who are breastfed are at particularly high risk for severe hyperbilirubinemia. 
Sex- and age-related demographics
Risk of developing significant neonatal jaundice is higher in male infants. This does not appear to be related to bilirubin production rates, which are similar to those in female infants.
The risk of significant neonatal jaundice is inversely proportional to gestational age.
Prognosis is excellent if the patient receives treatment according to accepted guidelines.
Brain damage due to kernicterus remains a true risk, and the apparent increased incidence of kernicterus in recent years may be due to the misconception that jaundice in the healthy full-term infant is not dangerous and can be disregarded.
Kernicterus is a complication of neonatal jaundice.
The incidence of kernicterus in North America and Europe ranges from 0.4-2.7 cases per 100,000 births.  Death from physiologic neonatal jaundice per se should not occur. Death from kernicterus may occur, particularly in countries with less developed medical care systems. In one small study from rural Nigeria, 31% of infants with clinical jaundice tested had G-6-PD deficiency, and 36% of the infants with G-6-PD deficiency died with presumed kernicterus compared with only 3% of the infants with a normal G-6-PD screening test result. 
Please see the Medscape Drugs & Diseases article Kernicterus for more information.
Parents should be educated about neonatal jaundice and receive written information prior to discharge from the birth hospital. The parent information leaflet should preferably be available in several languages.
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