Several factors increase the likelihood that an infant will incur hyperbilirubinemia, and they need to be taken into account when evaluating age-specific TSB measurements. Risk factors may be congenital and based on inborn biochemical factors, while others are contingent on the environment and care of the infant. The biochemical risk factors in turn may be broadly separated into those that are characterized by increased production of bilirubin and those that involve impaired mechanisms for elimination of bilirubin.


Biochemical Risk factors

Hemolytic diseases cause increased bilirubin production because of the increased breakdown of red cells and their hemoglobin.

Immune mediated hemolytic diseases are caused by blood-group incompatibilities between the mother and the child. The most important of these are Rh disease and ABO blood type incompatibility.

Rh Disease occurs when an Rh- mother has an Rh+ child. If any of the fetal red cells cross the placenta, she may develop antibodies to the RhD antigen present on the fetal red cell membrane. Usually, this is a problem for subsequent pregnancies and can almost always be prevented by a dose of anti-RhD immunoglobulin given to the mother soon after the first delivery. Historically, Rh disease was probably responsible for most cases of severe encephalopathy and resulting infant death. In westernized countries, the routine use of anti-RhD immunoglobulin has mostly eliminated Rh disease as a cause of extreme hyperbilirubinemia, although it may be quite common still in less developed countries.   

ABO incompatibility can occur when an O type mother is pregnant with an A or B type child and develops an IgG type antibody to the A or B antigen on the fetal red cells. It is the most common cause of immune mediated hemolytic disease in westernized countries, although it rarely causes the severe hyperbilirubinemia that is likely to lead to encephalopathy.

Red Cell Defects include membrane defects (e.g. hereditary spherocytosis) and defective forms of hemoglobin(e.g. thalassemias) which lead to increased or accelerated breakdown of red cells. The most common and important enzyme deficiency is Glucose-6-phosphate dehydrogenase deficiency (G6PDd) but this may also be associated with impairment of bilirubin clearance.

Defects of Bilirubin Clearance occur when the mechanism for conjugation of bilirubin with sugar-like compounds is impaired. There is a family of enzymes in the liver called uridine diphosphate glucuronosyltransferases (UGT) which catalyze the conjugation of many different substances with a sugar-like substance called glucuronide; one of these enzymes, called bilirubin-UGT and coded for by the UGT1A1 gene, is responsible for the specific reaction that conjugates bilirubin. Two different syndromes have been shown to be caused by mutations of the UGT1A1 gene.   

Crigler-Najjar syndrome is the result of mutations that affect the activity of the UGT1A1 enzyme. Crigler-Najjar Type I is a very rare condition resulting from mutations in part of the gene that is common to all of the UGT1A family of enzymes. These mutations cause the complete absence of UGT1A activity. It usually causes very severe hyperbilirubinemia and kernicterus, leading to death within eighteen months after birth. Crigler-Najjar Type II is caused by a single mutation that results in the production an enzyme with reduced functionality; it is generally benign after the neonatal period when moderate to severe hyperbilirubinemia may occur.

Gilbert Syndrome has very similar clinical characteristics to Crigler-Najjar Type II but is caused by a genetic variant of the promoter region of the gene. This leads to reduced production of a normally functioning enzyme. It is relatively common, and may affect up to 10% of the population. While it is a risk factor for severe neonatal hyperbilirubinemia, it is otherwise benign. The diagnosis of Gilbert Syndrome may also be made when an individual has just one copy of the altered gene responsible for Crigler-Najjar Type II syndrome.

Glucose-6-phosphate Dehydrogenase Deficiency
The association of hyperbilirubinemia with G6PD deficiency is clear: of the infants who develop the syndrome or go on to develop kernicterus there is a disproportionate number with G6PD deficiency — several times the percentage in the general population and rising in some studies to 20-30% of readmissions for hyperbilirubinemia. Nevertheless, it should be emphasized that not all infants with G6PD deficiency develop severe jaundice (the incidence is about 30%) and not all, or even the majority, of cases of neonatal hyperbilirubinemia are the result of G6PD deficiency.

In some cases, the cause of the hyperbilirubinemia may be traced to an exposure to the same kind of external trigger that causes a hemolytic crisis in adults with G6PD deficiency. These include drugs, infections and exposure to substances such as mothballs or henna. In most cases, however, hemolysis is not markedly greater in infants who develop jaundice compared to those who do not and anemia is not seen. Thus the primary defect seems to be the metabolism of bilirubin in the liver.

It has been proposed that the most severe cases of hyperbilirubinemia may be caused by the unfortunate concurrence of G6PD deficiency and Gilbert Syndrome, since both occur with a great enough frequency for this to happen; this has been disputed, however, as an explanation, for the unpredictable development of severe hyperbilirubinemia. If G6PD deficiency directly causes an impairment of liver function, which is a significant cause of hyperbilirubinemia, the mechanism by which this occurs has yet to be elucidated.

Other Risk Factors

Much effort has gone into the identification of clinical risk factors that can be readily assessed soon after birth as a way of identifying newborns who need extra vigilance against the threat of hyperbilirubinemia. Many studies using sophisticated statistical methods have attempted to identify a set of risk indicators that can either replace or enhance the use of frequent measurements of TSB. Factors that have been considered, in addition to the biochemical defects described above, include:

Gestational age 35 – 36 weeks

Significant Bruising — especially Cephalhematoma


Higher birth weight

Use of oxytocin or vacuum extraction during delivery

Risk factor models have generally not been found to be an improvement over the use of time-specific bilirubin measurements, although the gestational age is the next strongest predictor of later hyperbilirubinemia. When gestational age of less than 38 weeks is added as a risk factor to the use of the nomogram recommended by the AAP, a more accurate prediction of the risk of subsequent hyperbilirubinemia can be achieved.

Breastfeeding had long been known to be associated with jaundice in infants and the term “breastfeeding jaundice” has been used to describe the jaundice that occurs 2 – 4 days after birth. It seems to be related to the initially low caloric intake of exclusively breast fed infants. This stimulates the enterohepatic circulation which in turn leads to increased re-uptake of bilirubin.

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