Cause Neonatal Jaundice

  • 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 African Americans.
    • Geography: Incidence is higher in populations living at high altitudes. Greeks living in Greece 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.
    • Nutrition: Incidence is higher in infants who are breastfed or who receive inadequate nutrition. 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.
    • Birthweight and gestational age: Incidence is higher in premature infants and in infants with low birthweight.
    • Congenital infection
  • Causes of Indirect Hyperbilirubinemia in Newborns

    Increased Production or Bilirubin Load on the Liver

    Hemolytic Disease

    • Immune-mediated
      —Rh alloimmunization, ABO and other blood group incompatibilities
    • Heritable
      —Red cell membrane defects: Hereditary spherocytosis, elliptocytosis, pyropoikilocytosis, stomatocytosis
      —Red cell enzyme deficiencies: Glucose-6-phosphate dehydrogenase deficiency,a pyruvate kinase deficiency, and other erythrocyte enzyme deficiencies
      —Hemoglobinopathies: Alpha thalassemia, beta thalassemia
      —Unstable hemoglobins: Congenital Heinz body hemolytic anemia
    Other Causes of Increased Production

    • Sepsisa, b
    • Disseminated intravascular coagulation
    • Extravasation of blood: Hematomas; pulmonary, abdominal, cerebral, or other occult hemorrhage
    • Polycythemia
    • Macrosomia in infants of diabetic mothers
    Increased Enterohepatic Circulation of Bilirubin

    • Breast milk jaundice
    • Pyloric stenosisa
    • Small or large bowel obstruction or ileus
    Decreased Clearance

    • Prematurity
    • Glucose-6-phosphate dehydrogenase deficiency
    Inborn Errors of Metabolism

    —Crigler-Najjar syndrome, types I and II
    —Gilbert syndrome


    a Decreased clearance also part of pathogenesis.

    b Elevation of direct-reading bilirubin also occurs.

    Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and Management of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:768–846.


         ABO Hemolytic Disease
    The use of Rh immunoglobin has dramatically decreased the incidence of Rh erythroblastosis fetalis, and hemolysis from ABO incompatibility is by far the most common cause of isoimmune hemolytic disease in newborns. In about 15% of pregnancies, an infant who has blood type A or B is carried by a mother who is type O. About one third of such infants have a positive direct antiglobulin test (DAT or Coombs test), indicating that they have anti-A or anti-B antibodies attached to the red cells. Of these infants, only 20% develop a peak TSB of more than 12.8 mg/dL (219 mcmol/L). Consequently, although ABO-incompatible, DAT-positive infants are about twice as likely as their compatible peers to have moderate hyperbilirubinemia (TSB >13 mg/dL [222.3 mcmol/L]), severe jaundice (TSB >20 mg/dL [[342 mcmol/L]) in the infants is uncommon. Nevertheless, ABO hemolytic disease can cause severe hyperbilirubinemia and kernicterus.

         Diagnosing ABO Hemolytic Disease
    ABO hemolytic disease has a highly variable clinical presentation. Most affected infants present with a rapid increase in TSB concentrations within the first 24 hours, but the TSB subsequently declines, in many infants, often without any intervention. ABO hemolytic disease is a relatively common cause of early hyperbilirubinemia (before the infant leaves the nursery), but it is a relatively rare cause of hyperbilirubinemia in infants who have been discharged and readmitted. The criteria for diagnosing ABO hemolytic disease as the cause of neonatal hyperbilirubinemia are listed in Table 3. Recently, it has been shown that DAT-negative, ABO-incompatible infants who also have Gilbert syndrome are at risk for hyperbilirubinemia. This may explain the occasional ABO-incompatible infant who has a negative DAT and nevertheless develops early hyperbilirubinemia.
    Table 3. Criteria for Diagnosing ABO Hemolytic Disease as the Cause of Neonatal Hyperbilirubinemia

    Mother group O, infant group A or B AND

    • Positive DAT
    • Jaundice appearing within 12 to 24 h after birth
    • Microspherocytes on blood smear
    • Negative DAT but homozygous for Gilbert syndrome

    Reprinted with permission from Maisels MJ. Jaundice. In: MacDonald MG, Seshia MMK, Mullett MD, eds. Neonatology: Pathophysiology and Management of the Newborn. Philadelphia, Pa: Lippincott Co; 2005:768–846.


         Glucose-6-phosphate Dehydrogenase (G-6PD) Deficiency
    G-6PD deficiency is the most common and clinically significant red cell enzyme defect, affecting as many as 4,500,000 newborns worldwide each year. Although known for its prevalence in the populations of the Mediterranean, Middle East, Arabian Peninsula, southeast Asia, and Africa, G-6PD has been transformed by immigration and intermarriage into a global problem. Nevertheless, most pediatricians in the United States do not think of G-6PD deficiency when confronted with a jaundiced infant. This possibility should be considered, though, particularly when seeing African-American infants. Although African-American newborns, as a group, tend to have lower TSB concentrations than do caucasian newborns, G-6PD deficiency is found in 11% to 13% of African-American newborns. This translates to 32,000 to 39,000 African-American male G-6PD-deficient hemizygous newborns born annually in the United States. As many as 30% of infants in the United States who have kernicterus have been found to be G-6PD-deficient.

    The G-6PD gene is located on the X chromosome, and hemizygous males have the full enzyme deficiency, although female heterozygotes are also at risk for hyperbilirubinemia. G-6PD-deficient neonates have an increase in heme turnover, although overt evidence of hemolysis often is not present. In addition, affected infants have an impaired ability to conjugate bilirubin.

    In neonates, beginning jaundice tends to develop because of two factors – the breakdown of fetal hemoglobin as it is replaced with adult hemoglobin and the relatively immature hepatic metabolic pathways which are unable to conjugate and so excrete bilirubin as quickly as an adult. This causes an accumulation of bilirubin in the blood (hyperbilirubinemia), leading to the symptoms of jaundice.

    If the neonatal jaundice does not clear up with simple phototherapy, other causes such as biliary atresia, PFIC, bile duct paucity, Alagille’s syndrome, alpha 1 and other pediatric liver diseases should be considered. The evaluation for these will include blood work and a variety of diagnostic tests. Prolonged neonatal jaundice is serious and should be followed up promptly.

    Severe neonatal jaundice may indicate the presence of other conditions contributing to the elevated bilirubin levels, of which there are a large variety of possibilities (see below). These should be detected or excluded as part of the differential diagnosis to prevent the development of complications. They can be grouped into the following categories:

    Neonatal jaundice
    Unconjugated bilirubin
    Conjugated bilirubin
    Physiological jaundice of Neonates
    Intrinsic causes
    Extrinsic causes

    [edit] Intrinsic causes of hemolysis

    [edit] Extrinsic causes of hemolysis

    [edit] Non-hemolytic causes

    [edit] Hepatic causes

    [edit] Post-hepatic

    [edit] Non-organic causes

    [edit] Breast feeding jaundice

    “Breastfeeding jaundice or “lack of breastfeeding jaundice,” is caused by insufficient breast milk intake, resulting in inadequate quantities of bowel movements to remove bilirubin from the body. This can usually be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate milk production. Passage of the baby through the vagina during birth helps stimulate milk production in the mother’s body, so infants born by cesarean section are at higher risk for this condition.

    [edit] Breast milk jaundice

    Whereas breast feeding jaundice is a mechanical problem, breast milk jaundice is more of a biochemical problem. The term applies to jaundice in a newborn baby who is exclusively breastfed and in whom other causes of jaundice have been ruled out. The jaundice appears at the end of the first week of life and hence overlaps physiological jaundice. It can last for up to two months. Several factors are thought to be responsible for this condition.

    First, in exclusively breastfed babies the establishment of normal gut flora is delayed. The bacteria in the adult gut convert conjugated bilirubin to stercobilinogen which is then oxidized to stercobilin and excreted in the stool. In the absence of sufficient bacteria the bilirubin is de-conjugated and reabsorbed. This process of re-absorption is called entero-hepatic circulation.

    Second, the breast-milk of some women contains a metabolite of progesterone called 3-alpha-20-beta pregnanediol. This substance inhibits the action of the enzyme uridine diphosphoglucuronic acid (UDPGA) glucuronyl transferase responsible for conjugation and subsequent excretion of bilirubin. Reduced conjugation of bilirubin leads to increased level of bilirubin in the blood.

    Third, an enzyme in breast milk called lipoprotein lipase produces increased concentration of nonesterified free fatty acids that inhibit hepatic glucuronyl transferase which again leads to decreased conjugation and subsequent excretion of bilirubin.

    Breast-milk jaundice does not usually cause any complication (like kernicterus) if the baby is otherwise healthy. The serum bilirubin level rarely goes above 20 mg /dL. It is usually not necessary to discontinue breast-feeding as the condition resolves spontaneously. Adequate hydration should be maintained by giving extra fluids if necessary.

    [edit] Non-invasive measurement of jaundice

    This method is more accurate and less subjective in estimating jaundice.

    Ingram icterometer: In this method a piece of transparent plastic known as Ingram icterometer is used. Ingram icterometer is painted in five transverse strips of graded yellow lines. The instrument is pressed against the nose and the yellow colour of the blanched skin is matched with the graded yellow lines and biluribin level is assigned.

    Transcutaneous bilirubinometer: This is hand held, portable and rechargable but expensive and sophisticated. When pressure is applied to the photoprobe, a xenon tube generates a strobe light; And this light passes through the subcutaneous tissue. The reflected light returns through the second fiber optic bundle to the spectrophotometric module. The intensity of the yellow color in this light, after correcting for the hemoglobin, is measured and instantly displayed in arbitrary units.

    Supported  by

    Yudhasmara Foundation 

    JL Taman Bendungan Asahan 5 Jakarta Indonesia 102010

    phone : 62(021) 70081995 – 5703646 

    email :,


    Clinical and Editor in Chief :



    Copyright © 2009, Clinical Pediatric Online Information Education Network. All rights reserved.


    Leave a Reply

    Fill in your details below or click an icon to log in: Logo

    You are commenting using your account. Log Out /  Change )

    Google+ photo

    You are commenting using your Google+ account. Log Out /  Change )

    Twitter picture

    You are commenting using your Twitter account. Log Out /  Change )

    Facebook photo

    You are commenting using your Facebook account. Log Out /  Change )


    Connecting to %s