Neonatal Hyperbilirubinemia
William J. Cashore
Jaundice is one of the most common conditions found in newborn infants, and the measurement of the serum bilirubin concentration is probably the diagnostic laboratory test most often performed in the newborn nursery. Although most neonatal jaundice is caused by a maturational delay in bilirubin conjugation and excretion, the outcome is nearly always benign. However, physicians must be alert for the minority of cases in which the cause of hyperbilirubinemia is pathologic or the clinical course is atypical, with exaggerated and possibly harmful levels of hyperbilirubinemia. The observation and follow-up of the newborn infant must be planned and arranged to identify such cases early enough in the clinical course to ensure timely evaluation and treatment.
DEFINITION
The term hyperbilirubinemia implies an excessive level of serum bilirubin, potentially associated with a pathologic cause or outcome. During their first few days of postnatal life, most newborns have maximum serum bilirubin levels that exceed the upper limits of normal for adults, even when no disease is present. The reason for this “physiologic” hyperbilirubinemia is a developmental delay in the conjugation and excretion of bilirubin as the infant achieves a postnatal transition from dependence on placental clearance of fetal bilirubin to the maturation of self-contained hepatic uptake and enzymatic and excretory pathways for bilirubin conjugation and elimination.
Because mild, transient jaundice is part of the normal physiologic transition for many newborns, we prefer to reserve the term “neonatal hyperbilirubinemia” for cases in which jaundice appears earlier, persists longer, or reaches higher bilirubin levels than expected for age during the neonatal and postnatal periods. Some cases of neonatal hyperbilirubinemia represent an exaggeration of the physiologic pattern, whereas others have detectable causes, usually increased red-cell breakdown leading to increased bilirubin production or an exaggerated delay or inhibition of conjugating enzyme (glucuronyl transferase) activity. Typical neonatal hyperbilirubinemia is predominantly unconjugated or indirect-reacting. A minority of infants present with conjugated (direct-reacting) hyperbilirubinemia, a condition with a different pathogenesis than the more common indirect hyperbilirubinemia.
EPIDEMIOLOGY
In 2,416 well, term infants at 3 to 4 days of age, Maisels and Gifford (1986) found peak bilirubin levels (mean ± S.D.) of 5.7± 3.3 mg/dL in formula-fed and 7.3 ± 3.9 mg/dL in breast-fed newborns, respectively. In most babies, bilirubin levels spontaneously declined after day 4. Of their patients, 6.1% had peak bilirubin values of greater than or equal to 13.0 mg/dL, with more breast-fed babies in the upper percentiles (9% of breast-fed versus 2.2% of formula-fed babies). Other surveys have shown similar differences between breast- and formula-fed newborns. Bhutani et al. found a 95th percentile value of 17 mg/dL and a 40th percentile value of 11.5 mg/dL at age 4 days in a largely breast-fed newborn population. In several large surveys of jaundiced infants without prior treatment, approximately 1 in 100 had peak bilirubin levels of greater than or equal to 20 mg/dL, and about 1 in 700 had levels of greater than or equal to 25 mg/dL at readmission.
Mean postnatal bilirubin levels and the incidence of “severe” hyperbilirubinemia vary with race and ethnicity. Within the population of the United States, newborns of Asian Pacific and Central American ethnic origin have average bilirubin levels which are slightly higher, and newborns of African-American origin slightly lower, than those of white newborns. Within-group variation is generally larger than between-group differences. The extent to which these intergroup differences reflect differences in diet, environment, and genetic control of bilirubin production and excretion is undetermined.
Because visible cutaneous and scleral jaundice in newborns is usually noted only when the serum bilirubin level exceeds 7 to 8 mg/dL, most self-limited developmental jaundice with a maximum bilirubin level at or below the mean value for newborns remains undetected. Visible jaundice develops in about 25% to 40% of newborns with bilirubin levels in the range of 10 to 12 mg/dL or greater. Many term newborns have a length of nursery stay less than or equal to 48 hours, so that some infants not visibly jaundiced in the nursery may become severely jaundiced by 4 to 5 days of age. The early identification and differential diagnosis of jaundice (Table 26.1) in these infants may be assisted by a system-based approach of regular visual or instrumental screening for jaundice before discharge, noting the age of onset and the progression of the baby’s jaundice by age in hours. Other helpful observations include evidence of maternal–fetal major or minor blood group incompatibility; family history; associated findings, such as hematomas or evidence of infection; the method of feeding; and the duration, intensity, and clinical course of the jaundice beyond the third day.
CAUSES
Bilirubin is the breakdown product of heme, derived via heme oxygenase and biliverdin reductase, with release of 1 mole of carbon monoxide for each mole of heme metabolized. Circulating bilirubin is transported on albumin to receptor sites in the liver, and then is conjugated by bilirubin uridine disphosphate-glucuronyl transferase to its water-soluble form, also called “conjugated” or “direct-reacting” bilirubin. The products of conjugation include bilirubin monoglucuronide and diglucuronide, the latter being the predominant conjugated form in humans.
Bilirubin conjugates enter the small bowel via canalicular transport and bile excretion. In the course of normal metabolism, they are oxidized further by the intestinal brush border and bacterial enzymes (mainly the latter) and excreted in the stool. Because the bowel is not colonized and does not fully function during fetal life, the hepatic conjugation and transport system is relatively inactive in the fetus, so that bilirubin produced from fetal red cells in utero mostly circulates in the unconjugated form.
This unconjugated or “indirect reacting” bilirubin is albumin-bound, relatively lipophilic, and can be transferred across the placenta again to the maternal circulation for conjugation and excretion by the maternal liver. At birth, as the maternal excretory pathway is removed, the development of normal conjugating capacity, canalicular transport, and metabolism and excretion of conjugated bilirubin in the small and large bowel require several days before this disposal pathway becomes adequate for the quantitative conjugation and excretion of bilirubin. Associated with the gradual maturation of bilirubin conjugation and excretion is the accumulation of unconjugated or indirect-reacting bilirubin in the plasma until the pathways mature.
Factors Associated with Hyperbiliruinemia
Classically, neonatal unconjugated hyperbilirubinemia has been attributed primarily to low levels of bilirubin glucuronyl transferase activity in the fetal and neonatal liver. The specific roles of inhibitors of glucuronyl transferase activity, such as maternal steroids, as well as postulated activators of enzyme expression, remain unclear. Other factors in the genesis of physiologic jaundice (unconjugated hyperbilirubinemia) include:
Discontinuation of placental mechanisms for fetal bilirubin transfer and detoxification.
Persistent patency of the ductus venosus, which diverts some blood flow away from the hepatic sinusoidal bed, shunting some unconjugated bilirubin past the loci of uptake and conjugation in the hepatocytes.
A greater rate of bilirubin production in the infant (6 to 8 mg/kg every 24 hours) than in the adult, secondary to a larger red blood cell mass and shortened survival time of fetal red cells.
Diminished binding of unconjugated bilirubin to neonatal serum albumin.
Diminished levels of intracellular bilirubin binding (Y) protein.
TABLE 26.1. DIFFERENTIAL DIAGNOSIS OF NEONATAL HYPERBILIRUBINEMIA
Cause
Associated Findings
Unconjugated (“Indirect”) Hyperbilirubinemia
Hemolytic Disease (Isoimmune)
ABO incompatibility
Positive Coombs’ antiglobulin test (anti-A or anti-B); microspherocytes
Rh incompatibility
Maternal anti-Rh titer; positive Coombs’ test; nucleated RBCs
Other minor blood group incompatibility
Positive Coombs’ test; RBC morphology variable
Structural or Metabolic Abnormalities of RBCs*
Hereditary spherocytosis
Family history; splenomegaly; microspherocytes
Glucose-6-phosphate dehydrogenase (G6PD) deficiency
Family history; recent exposure to an oxidant in food or drug; with or without splenomegaly
Hereditary Defects in Bilirubin Conjugation
Crigler-Najjar syndrome–Type I
Complete lack of glucuronyl transferase; severe, lifelong, unconjugated hyperbilirubinemia
Crigler-Najjar syndrome–Type II
Defective glucuronyl transferase with recurrent or chronic moderate hyperbilirubinemia; phenobarbital usually increases conjugating enzyme activity
Gilbert disease (Arias syndrome)
Family history; mild, recurrent hyperbilirubinemia due to a promoter region defect or structural polymorphism in glucuronyl transferase; usually responds to phenobarbital
Bacterial sepsis
History and findings compatible with neonatal infection; often an increase in direct bilirubin as well
Breast-milk jaundice
Mild to moderate, but persistent, hyperbilirubinemia; usually improves when breast milk is discontinued
Physiologic jaundice
Usually mild to moderate; no predisposing factors; self-limited (duration <1 week)
Conjugated (direct) hyperbilirubinemia
Congenital biliary atresia
Dilated intrahepatic ducts; no bile excretion
Extrahepatic biliary obstruction
Extrahepatic cyst or mass; dilated main or common bile ducts
Neonatal Hepatitis
Bacterial
Findings compatible with neonatal sepsis
Viral
Inflammatory changes; other systemic signs of specific viral infection
Nonspecific
Inflammatory changes without a specific infectious etiology
TPN-related
Hepatocellular cholestasis with variable fatty and inflammatory changes; usually reversible, but occasionally progresses to cirrhosis
Short-bowel related
Hepatocellular inflammation and small bile duct proliferation due to bile acid recirculation and bacterial overgrowth in the small bowel
Inspissated bile syndrome
Persistent direct hyperbilirubinemia associated with isoimmune hemolytic disease
Post-asphyxia
Compatible history, plus increased hepatocellular enzyme concentrations
Alpha1-antitrypsin deficiency
Decreased alpha1-antitrypsin levels; recurrent or “chronic” lung disease
Neonatal hemosiderosis
Hemosiderin-filled macrophages on biopsy
RBCs, red blood cells.
*Only the two most common disorders are listed, as examples.
Impaired canalicular excretion of organic anions in the developing liver.
In addition, bilirubin appears to undergo a significant entero-hepatic circulation in the newborn. Conjugated bilirubin in the adult intestinal tract is reduced by (predominantly) anaerobic intestinal flora to poorly absorbable urobilinogen. These flora are not all present in the fetal and neonatal intestine. Instead, beta-glucuronidase present in the neonatal intestine hydrolyzes bilirubin mono-or diglucuronide back to unconjugated bilirubin, which is subsequently reabsorbed into the portal circulation, thus contributing to the “bilirubin overload” and further taxing already stressed metabolic and excretory pathways. Thus, the delayed passage of meconium can cause an elevation in the serum bilirubin level.
Some newborns who show an unusually early onset, exaggerated and sustained level, or uncommonly long duration of hyperbilirubinemia may require medical attention. In Maisels and Gifford’s patients, noted above, and in similar large series, a definite cause for exaggerated hyperbilirubinemia was found in only 45% to 50% of the infants evaluated. Therefore, about 3% of term newborns may have exaggerated or sustained hyperbilirubinemia as part of their “normal” development, whereas another 3% to 5% may have clinically significant hyperbilirubinemia associated with some other identifiable cause. Therefore, although hyperbilirubinemia is a frequent observation in the nursery, the term by itself indicates only that the level of jaundice observed is greater than expected for a normal healthy infant of the same age. Further observation and diagnostic studies are needed to establish a cause for the hyperbilirubinemia.
Associated Conditions
Infants of Diabetic Mothers
The infants of diabetic mothers often have polycythemia, with an increased red cell mass that leads to an increased daily rate of
bilirubin formation. They may have some acquired structural or metabolic instability of their red cells (e.g., increased glycohemoglobin) related to their glucose metabolism. In general, they follow a less mature pattern of physiologic development (including bilirubin conjugation) than do term infants of similar birth weight, whose mothers are not diabetic.
bilirubin formation. They may have some acquired structural or metabolic instability of their red cells (e.g., increased glycohemoglobin) related to their glucose metabolism. In general, they follow a less mature pattern of physiologic development (including bilirubin conjugation) than do term infants of similar birth weight, whose mothers are not diabetic.
Immaturity
Delay in the conjugation and excretion of bilirubin varies between individuals, but some infants may have predisposing factors to delayed excretion. The most common underlying condition is immaturity. Otherwise healthy preterm infants (<37 weeks gestation) tend to have maximum serum bilirubin levels 30% to 50% higher than their term counterparts, with increasing serum unconjugated bilirubin continuing until as late as the sixth or seventh postnatal day, and sometimes persisting into the second week. If heavier and physiologically stable preterm infants are cared for and discharged from well-baby nurseries, their pediatricians must keep in mind the possibility of prolonged or late jaundice.
Breast-fed Infants
Breast-fed infants can have a combined inefficiency of hepatic conjugation and gastrointestinal excretion of bilirubin, mediated by factors in breast milk that may suppress hepatic function, increase reabsorption of bilirubin from the small bowel, or both. As noted earlier, their mean bilirubin concentration is slightly higher, duration of jaundice somewhat longer, and the incidence of clinically detectable hyperbilirubinemia during the first week is more frequent in breast-fed than in formula-fed infants.
About 2% of breast-fed infants have a longer (2- to 8-week) course of moderate hyperbilirubinemia, usually in the range of 10 to 15 mg/dL, while feeding adequately on breast milk and gaining weight, with no other abnormal clinical findings. Arias et al. showed that high levels of 3-alpha, 20-beta-pregnanediol in mothers’ milk were associated with decreased bilirubin conjugation and persistent hyperbilirubinemia. However, subsequent studies have not found the association to be consistent. Multiple hormonal or enzymatic factors may be involved in suppressing the hepatic conjugation of bilirubin or cleaving bilirubin conjugates in the neonatal small bowel in certain mother–baby pairs, thereby promoting the reabsorption and enterohepatic recirculation of unconjugated bilirubin. Although the pathogenesis of breast-milk jaundice is controversial, most babies have only mild hyperbilirubinemia. Refractory, severe cases usually respond to cessation of breast-feeding for 36 to 48 hours, with a prompt decrease in serum bilirubin.
Hospital feeding schedules and practices may abet jaundice in breast-fed infants by delaying the initial breast feedings during a prescribed observation period and by adherence to feeding intervals of once every 4 hours, rather than early nursing patterns of 8 to 10 times daily. Delay in feeding and suboptimal intake also delay and decrease meconium output and delay the transition to normal stools rich in bile pigments.
Delayed Intestinal Transit
Infants who are not fed or have high intestinal obstructions (e.g., pyloric stenosis or duodenal atresia) may have exaggerated levels of jaundice from the combined effects of lack of nutritional substrate for conjugation, lack of peristalsis for excretion, and consequent reabsorption of bilirubin from an obstructed or nonfunctioning bowel.
Genetic Variations in Conjugation
Genetic variations in the conjugating enzyme, bilirubin glucuronyl transferase, may act independently to impair and delay conjugation or may act in concert with other genetic or environmental influences to cause early or severe persistent neonatal hyperbilirubinemia. To date, more than 50 mutations or polymorphisms in UDPGT-A1, the gene encoding hepatic bilirubin glucuronyl transferase, have been identified. With substantial individual variation, several clinical phenotypes have been associated with specific classes of mutations (see Table 26.1).
Crigler-Najjar Syndrome, Type I, is caused by an absence of glucuronyl transferase activity with severe, persistent unconjugated hyperbilirubinemia. An autosomal recessive nonsense or “stop” mutation terminates protein synthesis proximal to the C-terminal of the enzyme, precluding glucuronidation of any substrates that enter this pathway. Patients with this disorder have severe, persistent hyperbilirubinemia of 20 to 35 mg/dL or higher, beginning in the newborn period. Liver histology is normal, and usually no other findings of liver disease or hemolytic anemia are present.
Nearly all patients with Type I Crigler-Najjar syndrome eventually develop bilirubin-related neurologic impairment, even if early recognition and aggressive treatment with exchange transfusion and phototherapy averts (or postpones) neonatal kernicterus. Patients treated with daily phototherapy, oral administration of bilirubin binding or solubilizing agents, or suppression of bilirubin formation via inhibition of heme oxygenase (experimental at present) often “escape” from control. This may occur during an intercurrent illness (e.g., a viral infection), with an abrupt increase in unconjugated bilirubin years or decades after neonatal survival. Hepatic transplantation, which provides the missing enzyme, is curative and should be attempted before irreversible neurologic damage occurs.
Type II Crigler-Najjar Syndrome is caused by substitution mutations in UDPGT-A1, generally autosomal recessive, with variable penetrance. Neonatal jaundice may be severe and lead to kernicterus. Subsequent unconjugated bilirubin levels may vary from 6 to 20 mg/dL, sometimes increasing during acute illnesses. In Type II Crigler-Najjar Syndrome, increased enzyme activity can be induced with low-dose phenobarbital (3 to 5 mg/kg/day), sometimes with clinical resolution of the hyperbilirubinemia. The clinical course is generally milder than Type I, and amenable to pharmacologic treatment as noted for Type I.
Gilbert disease is characterized by a mild elevation in serum bilirubin levels, typically of 2 to 6 mg/dL. Liver function and histology are normal, except for minor changes noted on electron microscopy. This disorder usually results from a mutation in the promoter region of UDPGT-A1. A different mutation in several Japanese kindreds is a single amino acid substitution (Arg 71 → Gly) in the enzyme protein. Mutations for Gilbert disease have a frequency of 2% to 10% in various human populations. Heterozygous individuals are sometimes mildly affected. Newborns can have more severe jaundice than older children or adults, sometimes exceeding 20 mg/dL. In newborns either homozygous or heterozygous for genes causing Gilbert disease, early jaundice is more severe in breast-fed infants or in those who also carry gene mutations for red cell G6-PD deficiency. Intercurrent illness or caloric deprivation may increase serum bilirubin levels two- to threefold in this disorder. Low-dose phenobarbital increases bilirubin conjugation and excretion in patients with mild, chronic jaundice or acute flare-ups of Gilbert disease.
Hypothyroidism
Hypothyroidism may cause persistent unconjugated hyperbilirubinemia, which is sometimes a presenting sign of neonatal thyroid hormone deficiency. Jaundice noted in newborns with hypopituitarism is presumably secondary to hypothyroidism. The typical presentation would be a newborn with nonhemolytic hyperbilirubinemia unresponsive to standard
therapy, and with a low T4 and high thyroid stimulating hormone (TSH) level on neonatal metabolic screening tests.
therapy, and with a low T4 and high thyroid stimulating hormone (TSH) level on neonatal metabolic screening tests.
Lucey-Driscoll Syndrome
Lucey-Driscoll syndrome, a condition of severe neonatal hyperbilirubinemia capable of causing kernicterus, is thought to be caused by the inhibition of glucuronyl transferase in the neonatal liver by an unidentified factor present in maternal serum and urine. After initial treatment with exchange transfusions, infants with this rare disorder have shown normal development without further episodes of jaundice.
Intravascular and Extravascular Hemolysis
Hemolysis or, more rarely, ineffective erythropoiesis, increases bilirubin production. The principal causes of hemolysis in newborns are antibody-mediated hemolytic anemias (e.g., Rh or ABO incompatibility); enclosed hemorrhage (e.g., cephalohematoma, intracranial hemorrhage, or skin bruising); hemolysis associated with group B streptococcal or Escherichia coli septicemia; or an abnormality of red-cell structure or metabolism (e.g., hereditary spherocytosis or glucose-6-phosphate dehydrogenase deficiency). Increased bilirubin production associated with hemolysis can be detected as an increase in pulmonary carbon monoxide excretion using sensitive equipment to detect small amounts of carbon monoxide in expired air. Jaundice from enclosed hemorrhage is generally evident by 3 to 5 days of postnatal life, because extravasated hemoglobin is metabolized slowly.
The most common causes of hemolysis in term infants are isoantibody-mediated hemolytic anemias resulting from maternal–fetal ABO or Rh incompatibility. Although not all susceptible infants are affected, 25% of normal pregnancies are ABO incompatible, and about 12% are Rh(D) incompatible.
Neonatal polycythemia (central hematocrit of greater than 65%) can be seen in infants of diabetic mothers, infants with adrenal hyperplasia, placental insufficiency, twin-to-twin transfusion, or aggressive “stripping” of the umbilical cord. When combined with shortened fetal red-cell survival time, polycythemia may increase the infant’s bilirubin load. Postnatal hemoconcentration and red-cell breakdown may be gradual, with hyperbilirubinemia becoming clinically evident after 48 hours. Partial exchange transfusion for symptomatic polycythemia/hyperviscosity will decrease the bilirubin load by lowering the hematocrit.
Drug-Associated Jaundice
Some drugs, such as vitamin K in excessive amounts, also may cause hemolysis. Maternal oxytocin has been associated with neonatal hyperbilirubinemia, but this appears to be secondary to osmotic changes in the fetal/neonatal circulation.
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