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Definition

More than 80% of newborns will exhibit jaundice, the clinical sign of hyperbilirubinemia, in the first few days of life. Hyperbilirubinemia can be benign at low levels but is harmful to the brain at higher levels.  All newborns will have a serum bilirubin level that is higher than the adult norm, but the level of hyperbilirubinemia requiring treatment is determined by age in hours and risk factors for developing severe jaundice.

Physiology

Bilirubin is the product of red blood cell breakdown, specifically heme degradation. Bilirubin in this state is not water-soluble, and must become water-soluble to be excreted in bile. Bilirubin binds with albumin, and is then conjugated in the liver by the enzyme uridine diphosphogluconurate (UDP) glucuronyltransferase.

Several factors specific to the neonate’s physiology contribute to physiologic hyperbilirubinemia:

  • Increased production: Fetal erythrocytes have a higher rate of turnover; per kilogram, newborn infants produce twice the daily adult amount of bilirubin.
  • Decreased clearance: Newborns have relatively low UDP-glucuronyltransferase activity (increases until approximately 14 weeks). They also have slow intestinal motility in the first few days as feeding becomes established, and this increases small amounts of bilirubin reuptake by the enterohepatic circulation.

Etiology and pathophysiology of pathologic hyperbilirubinemia

Causes of pathologic hyperbilirubinemia can be classified as due to (1) increased bilirubin load (i.e., pre-hepatic; either hemolytic or non-hemolytic processes), (2) impaired bilirubin conjugation (i.e., hepatic) or (3) impaired bilirubin excretion (i.e., post-hepatic).

 

Approach to neonatal jaundice

1) Increased bilirubin load – hemolytic

Hemolysis, either by immune or nonimmune mechanisms, results in greater levels of bilirubin than hepatic conjugation is able to keep pace with. In this case, total and unconjugated bilirubin levels are increased, but conjugated levels remain normal. Because of the excessive red blood cell breakdown, hemoglobin levels may be low or normal and reticulocyte (immature erythrocyte) count may be elevated. In immune-mediated hemolysis, a Coombs test is positive.  Important causes of hemolysis in newborns include:

  • Immune mediated hemolysis:
    • Rh factor incompatibility: Rh is an antigen carried only on red blood cells. Most women are Rh-positive, however certain populations have a higher prevalence of Rh-negative women (i.e., Basques 30-35%, Caucasians 15%, African American 8%). When an Rh-negative woman carries an Rh-positive fetus, she may develop antibodies to the Rh antigen on fetal red blood cells that enter maternal circulation during pregnancy on occasion or during labour. These maternal anti-Rh antibodies cross the placenta and induce lysis of fetal red blood cells in utero and/or postnatally. With the use of Rho(D) immune globulin, the risk of maternal sensitization (antibody production) is substantially decreased. In utero, Rh sensitization can lead to hydrops fetalis.
    • ABO incompatibility: Like Rh, A and B are two major erythrocyte membrane antigens. If a mother carries a fetus whose erythrocytes bear an antigen that is foreign to her immune system (e.g. if mother is blood type O [neither A or B antigen is expressed on her RBCs], and fetus is A, B or AB), she may develop antibodies to those antigens, which will cross the placenta. Hemolysis due to these antibodies is generally not problematic in utero, but can cause significant hyperbilirubinemia in the newborn period.
  • RBC enzyme defects: These are caused by a defect in the formation of RBCs.
    • G6PD deficiency: X-linked enzymopathy due to enzyme deficiency in NADPH production. This defect makes RBCs more vulnerable to lysing under oxidative stress.
    • Pyruvate kinase deficiency: A deficiency in this enzyme prevents ATP formation, causing cellular death and hemolysis.
  • RBC membrane defects: In hereditary spherocytosis and elliptocytosis, the spleen recognizes these RBCs as abnormal and thus destroys the misshapen cells.
  • Hemoglobinopathies: Thalassemia and sickle cell disease involve the production of abnormal globin chains that destroy the RBC.

2) Increased bilirubin load – nonhemolytic

The nonhemolytic causes are miscellaneous, and include breakdown of extravascular blood, polycythemia and exaggerated enterohepatic circulation. In nonhemolytic processes, a normal reticulocyte count, and normal or increased hemoglobin level are expected. A large volume of extravasated blood is the exception, where increased reticulocytes and decreased hemoglobin may be observed.

  • Extravascular blood: Examples include extensive bruising from birth, cephalohematoma or subgaleal hematoma, or swallowed blood.
  • Polycythemia: Defined as a hematocrit (RBC volume percentage in blood) of greater than 65%. Of the many etiologies, the most common are erythrocyte transfusion (fetal-maternal transfusion, delayed cord clamping or twin-twin transfusion) and increased intrauterine erythropoiesis usually caused by placental insufficiency and/or chronic intrauterine hypoxia (e.g. from preeclampsia, or heavy maternal cigarette consumption).
  • Exaggerated enterohepatic circulation: A common cause is breast milk jaundice (see below), however other less likely causes are disease states such as cystic fibrosis, pyloric stenosis and Hirschsprung’s disease.

3) Decreased/impaired bilirubin conjugation

  • Physiologic hyperbilirubinemia: This normal process occurs when the neonatal liver is not able to conjugate the amount of bilirubin being produced. Total bilirubin level usually peaks on the 3rd day of life with values of 86-103 umol/L and then slowly declines over the first week.
  • Crigler-Najjar syndromes type 1 and 2: These rare syndromes are caused by autosomal recessive mutations that result in total UDP-glucoronyltransferase deficiency (type 1), or significantly reduced activity (type 2).
  • Gilbert syndrome: Caused by only mildly reduced activity of UDP-glucoronyltransferase, Gilbert’s is a benign condition and may only manifest as subtle jaundice during periods of illness or stress, and may exacerbate neonatal jaundice.
  • Congenital hypothyroidism: Hypothyroidism causes decreased rate of bilirubin conjugation, slows gut motility and impairs feeding, all contributing to jaundice.
  • Breastfeeding jaundice: Infants who are breastfed receive only small volumes of colostrum in the first days of life, which leads to dehydration and increased uptake of conjugated bilirubin from the intestines, both of which worsen hyperbilirubinemia. Breastfed infants generally lose 6-8% of their birth weight by day 3 of life.
    • Breastfed babies are at higher risk of developing hyperbilirubinemia as compared to those that are formula-fed, however, the proven benefits of breastfeeding substantially outweigh the risks of hyperbilirubinemia, and thus should continue if possible.
  • Breast milk jaundice: Distinct from breastfeeding jaundice, breast milk jaundice develops in the second week of life, lasts longer than physiologic jaundice, and has no other identifiable cause. Pathophysiology is not well understood, but it is thought that substances in breast milk, such as beta-glucuronidases and nonesterified fatty acids, may inhibit normal bilirubin metabolism (e.g. via unconjugation and reabsorption of conjugated bilirubin excreted in bile).

4) Impaired bilirubin excretion

Anatomical abnormalities or disease processes that prevent bilirubin from being normally excreted in bile can cause a conjugated hyperbilirubinemia, defined as >17 umol/L if total is 85.6umol/L or less, or a conjugated component >20% of total, if total is greater than 85.6umol/L.

  • Biliary obstruction (biliary atresia, gallstones, neoplasm, bile duct abnormalities): Biliary atresia is the most common cause of biliary obstruction in the newborn, accounting for 40-50% of cases. This can be congenital (~15-20%) and is associated with other anomalies. The acquired form is more common, and pathophysiology has not been fully elucidated. One hypothesis is the presence of an inflammatory response postnatally that affects the intra- and extrahepatic bile ducts, with postinflammatory scarring and duct obliteration. Infants with biliary atresia require a Kasai procedure (portoenterostomy). One third of patients will ultimately require liver transplantation. Bile duct abnormalities include Alagille syndrome, Caroli syndrome, choledochal cyst, and other rare entities.
  • Infection: Sepsis, meningitis, TORCH infections and others can all cause liver impairment. Liver dysfunction disrupts normal bile flow from hepatocytes through the biliary tree to the duodenum (i.e. cholestasis). Cytomegalovirus (CMV) is one of the most common infectious causes of neonatal cholestasis.
  • Chromosomal abnormalities (including Turner’s syndrome, trisomy 18, trisomy 21): Certain chromosomal abnormalities are associated with a paucity of intrahepatic bile ducts, resulting in cholestasis. Cholestasis decreases bile flow and excretion, and allows conjugated bilirubin to be reabsorbed into the blood stream.
  • Metabolic disorders: A long list of inborn errors of metabolism can cause cholestasis.

Presentation

The most notable signs of hyperbilirubinemia are jaundice and scleral icterus. Jaundice refers to yellowing of the skin, which can be seen by blanching the skin with digital pressure. This should be done centrally, and at multiple levels, since jaundice develops in a cephalocaudal fashion. Roughly, the following serum levels have been observed to correlate with clinical findings:

  • 34-51 umol/L – scleral icterus
  • 68-86 umol/L – jaundice on face
  • 258 umol/L – jaundice from face to umbilicus, upper chest 171 umol/L, abdomen 205 umol/L
  • 340 umol/L – jaundice from head to toe (palms and soles >257umol/L)

However assessing jaundice by skin appearance is inaccurate, especially in darker skinned infants, and serum bilirubin should be measured to assess for hyperbilirubinemia.

Infants do not exhibit symptoms of mild hyperbilirubinemia, but with higher levels signs and symptoms of toxicity occur, and are related to the degree to which the central nervous system (CNS) is affected.  Albumin binds unconjugated bilirubin in the blood, and high levels exceed albumin carriage capacity. Unbound unconjugated bilirubin is fat-soluble and crosses the blood-brain barrier, causing damage to neurons. The basal ganglia are preferentially affected, but the cranial nerves, central and peripheral auditory and visual pathways, the hippocampus, diencephalon, subthalamic nuclei, midbrain and cerebellum may all be involved. CNS toxicity has acute and chronic phases.

Acute bilirubin encephalopathy (ABE) develops at the time of severe hyperbilirubinemia. At early stages of ABE, infants display sleepiness, slight hypotonia, and poor suck. A high-pitched cry is heard. Untreated, this can progress to deep stupor or coma, seizures, apnea, and increased tone (retrocollis-opisthotonus [extreme arching of the neck and back]).

Kernicterus refers to the longterm effects of bilirubin toxicity. This term was initially used to describe the histologic finding of bilirubin staining of the basal ganglia, which usually occurs at total bilirubin levels of 425-510umol/L, but is now also used as a synonym for chronic bilirubin encephalopathy. Symptoms of kernicterus include dystonia, choreoathetoid cerebral palsy, gaze abnormalities, and sensorineural hearing loss. These usually develop over the first year after birth. The sparing of cognitive function is highly debated.

 

Table 1: Mechanism of Presenting Signs and Symptoms based on Disease Process

Disease Process/Mechanism Sign/Symptom Mechanism
Hemolytic State Jaundice Accumulation of unconjugated bilirubin
Petechiae Concomitant thrombocytopenia occurs in some cases
Increased reticulocyte count Hemolysis causing increased production of RBC and release of immature reticulocytes.
Pallor Anemia
Hepatosplenomegaly Extravascular hemolysis occurs in the spleen and liver, which sequesters damaged RBCs. Extramedullary hematopoiesis also occurs in these organs in response to anemia.
Dark urine Hemolysis resulting in hemoglobin entering urine + increased urobilin from increased amount of bilirubin
Nonhemolytic State Jaundice Accumulation of unconjugated bilirubin
Ecchymosis/hemorrhage Birthing trauma
Ruddy complexion, hepatomegaly Polycythemia
Metabolic (Impaired conjugation) Jaundice Accumulation of unconjugated bilirubin
Lethargy

Poor muscle tone

Direct cause of metabolic disease
Cholestasis (Impaired excretion) Jaundice Accumulation of conjugated bilirubin
Hepatomegaly Obstruction of hepatic outflow ducts
Pale stool Lack of stercobilin (which normally gives feces its dark colour)
Failure to thrive Multifactorial causes
Tachycardia, fever Infection causing cholestasis

 

Diagnosis

As discussed above in ‘Presentation,’ clinical signs of jaundice are not a reliable measure of bilirubin level due to differences in skin colour, delays in dermal deposition and interobserver variability. Instead of clinical assessment, laboratory values should be evaluated.

  • Transcutaneous bilirubin measurement provides more accurate information than clinical assessment. This is done through a device (e.g., Konica Minolta Drager Air-Shields JM-103 or the BiliChek) which measures the amount of yellow colour in subcutaneous tissue, converting it into an estimate of total serum bilirubin level. This is a non-invasive test that can be done at the bedside, and thus can be a useful screening tool to determine if serum measurement is necessary. However, most Canadian centers do not use this method; it can be unreliable following phototherapy, or with changes in skin colour or thickness.
  • Total serum bilirubin (TSB) measurements are the best method in predicting severe hyperbilirubinemia. These should be timed, plotted and analysed on a nomogram based on the infant’s gestational age and risk factors for developing severe hyperbilirubinemia (Figures 1 and 2).
  • Umbilical cord blood TSB can also be measured, and should be sent for evaluation at birth if the mother was not tested for ABO and Rh blood types. 

Screening

The first measurement of serum bilirubin should occur between 24-72h of life, or earlier if visible jaundice is observed. This initial screening value is plotted on a predictive nomogram that determines risk and specifies recommended actions based on this risk zone, gestational age, and any risk factors for developing severe jaundice (Figure 1). Recommended actions include degree of monitoring required, and when repeating a serum level is advisable.

The serum bilirubin is then plotted on the nomogram for initiation of phototherapy (Figure 2), which is also stratified by risk. On this nomogram, treatment threshold depends on gestational age and risk factors. Infants at higher risk for developing severe hyperbilirubinemia are treated at lower bilirubin levels.

Red flags for pathologic jaundice

  • Jaundice in first 24 hours
  • Rapidly rising total bilirubin concentration (>86umol/L/day)
  • Younger gestational age
  • Previous sibling with jaundice
  • Significant bruising
  • Jaundice persisting for more than 2-3 weeks
  • East Asian ethnicity

Of these risk factors, previous siblings with severe hyperbilirubinemia holds the highest odds ratio.

In an infant presenting with jaundice, total and conjugated bilirubin should be measured through capillary or a venous blood sample. Often, a complete blood count (CBC) is also obtained to evaluate hematocrit and hemoglobin. Detailed history, including family, antenatal and birth histories, as well as a thorough physical exam should be done. Taken together, these pieces of information help formulate a differential diagnosis, on which any further investigations are based.

An additional workup for hyperbilirubinemia may include:

  • Blood group and direct Coombs testing in babies who are at risk of Rh or ABO isoimmunization.
  • Evaluations for sepsis, congenital infection
  • Screening for metabolic disorders
  • Thyroid studies
  • Blood smear for cell morphology if the history suggests a red blood cell defect
  • Hemoglobin electrophoresis can be considered to investigate for hemoglobinopathy
  • G6PD assay can be considered if ethnicity or family history confers increase risk of G6PD deficiency (though an X-linked recessive disorder, females heterozygotes can have ~50% of their red blood cells deficient due to random X chromosome inactivation).

A finding of conjugated hyperbilirubinemia is always pathologic, and pediatric gastroenterology +/- surgical referral is advised for expert workup of the possible etiologies.

Treatment

Treatment depends on the severity of hyperbilirubinemia, its etiology, and the risk of developing serious neurological complications.

Phototherapy

The mainstay of treatment for hyperbilirubinemia is phototherapy. Phototherapy within the first 24-36 hours of life is effective in decreasing rates of exchange transfusion (see below) and in preventing progression to severe hyperbilirubinemia in infants with moderately elevated levels.

Mechanism: Phototherapy involves exposing the skin to blue wavelengths of light. At this frequency, light induces a conformational change in the fat-soluble unconjugated bilirubin deposited in the skin and subcutaneous tissues, rendering it water soluble. This form of bilirubin can be then excreted in bile and urine without needing to be conjugated by hepatocytes.

Indications for starting and stopping treatment: Phototherapy is initiated based on the individual risk of developing severe hyperbilirubinemia. In low risk infants the threshold to begin phototherapy is at serum total bilirubin above the 95th percentile (see Figure 2, a nomogram issued by the Canadian Pediatric Society). Treatment should be stopped once total bilirubin is below the treatment threshold.

Phototherapy is usually able to decrease bilirubin by 17-34 umol/L within 4-6 hours. If levels continue to rise without improvement from intensive phototherapy (defined as at least 30µW/cm2 per nm as measured at the baby’s skin below the center of the phototherapy, compared with lower intensity conventional phototherapy), exchange transfusion may be indicated (see below). In this scenario, transfer to a Level III Neonatal Intensive Care unit is indicated.

  • Phototherapy is generally quite safe and complications are very rare, but include burns, retinal damage, thermoregulatory instability, loose stools, dehydration, skin rash and tanning of the skin.
  • Phototherapy should not be used in infants with conjugated hyperbilirubinemia, since excretion is the issue and not conjugation. ‘Bronze baby syndrome’ occurs in these cases.

Exchange transfusion

In an exchange transfusion, aliquots of the infant’s blood are removed, and equal amounts of donor whole blood are transfused. This process aims to remove bilirubin in the serum, as well as partially hemolyzed and antibody-coated red blood cells.  This treatment is considered in infants with total bilirubin concentration between 375 umol/L and 425 umol/L, without response to intensive phototherapy, in the presence of severe anemia or hemolytic disease or rapid rise in total bilirubin (> 17umol/L in less than 6 hours). See Figure 3, a nomogram for treatment with exchange transfusion.

  • All infants presenting with symptoms and signs of ABE should receive immediate exchange transfusion.
  • Additional investigations (as mentioned above, in ‘Diagnosis’) should be completed prior to exchange transfusion, since any blood tests for metabolic conditions, chromosomal analysis etc. will not be valid after transfusion.
  • Exchange transfusion is associated with significant morbidity. Complications include air embolism, vasospasm, infarction, infection and death.

Pharmacologic interventions

Intravenous immunoglobulin G (IVIG) can be used in Rh and ABO hemolytic disease, and has been demonstrated to significantly reduce the need for exchange transfusion. There may be multiple mechanisms involved, but the major one is competitive inhibition of hemolysis-inducing antibodies.

Currently there are no other pharmacologic interventions that have been shown to improve hyperbilirubinemia and reduce progression to exchange transfusion and/or ABE.

Other

Breastfeeding should continue, with lactation support as necessary. Stopping breastfeeding, despite its potential to exacerbate hyperbilirubinemia, is not associated with adverse outcomes. Interrupting breastfeeding is, however, associated with markedly reduced rates of breastfeeding continuation after 1 month.

Only infants who are at higher risk for requiring exchange transfusion should receive supplemental fluids, either orally (formula) or intravenously (D10W).