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Neonatal Hyperbilirubinemia

by Nicholas Jospe, MD

Jaundice is a yellow discoloration of the skin and eyes caused by hyperbilirubinemia (elevated serum bilirubin concentration). The serum bilirubin level required to cause jaundice varies with skin tone and body region, but jaundice usually becomes visible on the sclera at a level of 2 to 3 mg/dL (34 to 51 μmol/L) and on the face at about 4 to 5 mg/dL (68 to 86 μmol/L). With increasing bilirubin levels, jaundice seems to advance in a head-to-foot direction, appearing at the umbilicus at about 15 mg/dL (258 μmol/L) and at the feet at about 20 mg/dL (340 μmol/L). Slightly more than half of all neonates become visibly jaundiced in the first week of life.

Consequences of hyperbilirubinemia

Hyperbilirubinemia may be harmless or harmful depending on its cause and the degree of elevation. Some causes of jaundice are intrinsically dangerous whatever the bilirubin level. But hyperbilirubinemia of any etiology is a concern once the level is high enough. The threshold for concern varies by age (see see Figure: Risk of hyperbilirubinemia in neonates = 35 wk gestation.), degree of prematurity, and health status; however, among term infants, the threshold typically is considered to be a level > 18 mg/dL (> 308 μmol/L).

Kernicterus (see Kernicterus) is the major consequence of neonatal hyperbilirubinemia. Although it is now rare, kernicterus still occurs and can nearly always be prevented. Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei, caused by either acute or chronic hyperbilirubinemia. Normally, bilirubin bound to serum albumin stays in the intravascular space. However, bilirubin can cross the blood-brain barrier and cause kernicterus in certain situations:

  • When serum bilirubin concentration is markedly elevated

  • When serum albumin concentration is markedly low (eg, in preterm infants)

  • When bilirubin is displaced from albumin by competitive binders

Competitive binders include drugs (eg, sulfisoxazole, ceftriaxone, aspirin) and free fatty acids and hydrogen ions (eg, in fasting, septic, or acidotic infants).

Risk of hyperbilirubinemia in neonates ≥ 35 wk gestation.

Risk is based on total serum bilirubin levels. (Adapted from Bhutani VK, Johnson L, Sivieri EM: Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics 103 (1):6–14, 1999.)

Pathophysiology

The majority of bilirubin is produced from the breakdown of Hb into unconjugated bilirubin (and other substances). Unconjugated bilirubin binds to albumin in the blood for transport to the liver, where it is taken up by hepatocytes and conjugated with glucuronic acid by the enzyme uridine diphosphogluconurate glucuronosyltransferase (UGT) to make it water-soluble. The conjugated bilirubin is excreted in bile into the duodenum. In adults, conjugated bilirubin is reduced by gut bacteria to urobilin and excreted. Neonates, however, have sterile digestive tracts. They do have the enzyme β-glucuronidase, which deconjugates the conjugated bilirubin, which is then reabsorbed by the intestines and recycled into the circulation. This is called enterohepatic circulation of bilirubin (see Bilirubin metabolism).

Mechanisms of hyperbilirubinemia

Hyperbilirubinemia can be caused by one or more of the following processes:

  • Increased production

  • Decreased hepatic uptake

  • Decreased conjugation

  • Impaired excretion

  • Impaired bile flow (cholestasis)

  • Increased enterohepatic circulation


Etiology

Classification

There are several ways to classify and discuss causes of hyperbilirubinemia. Because transient jaundice is common among healthy neonates (unlike adults, in whom jaundice always signifies a disorder), hyperbilirubinemia can be classified as physiologic or pathologic. It can be classified by whether the hyperbilirubinemia is unconjugated, conjugated, or both. It also can be classified by mechanism (see Causes of Neonatal Hyperbilirubinemia).


Causes

Most cases involve unconjugated hyperbilirubinemia. Some of the most common causes of neonatal jaundice include

  • Physiologic hyperbilirubinemia

  • Breastfeeding jaundice

  • Breast milk jaundice

  • Pathologic hyperbilirubinemia due to hemolytic disease

Liver dysfunction (eg, caused by parenteral alimentation causing cholestasis, neonatal sepsis, neonatal hepatitis) may cause a conjugated or mixed hyperbilirubinemia.

Physiologic hyperbilirubinemia occurs in almost all neonates. Shorter neonatal RBC life span increases bilirubin production; deficient conjugation due to the deficiency of UGT decreases clearance; and low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation. Bilirubin levels can rise up to 18 mg/dL by 3 to 4 days of life (7 days in Asian infants) and fall thereafter.

Breastfeeding jaundice develops in one sixth of breastfed infants during the first week of life. Breastfeeding increases enterohepatic circulation of bilirubin in some infants who have decreased milk intake and who also have dehydration or low caloric intake. The increased enterohepatic circulation also may result from reduced intestinal bacteria that convert bilirubin to nonresorbed metabolites.

Breast milk jaundice is different from breastfeeding jaundice. It develops after the first 5 to 7 days of life and peaks at about 2 wk. It is thought to be caused by an increased concentration of β-glucuronidase in breast milk, causing an increase in the deconjugation and reabsorption of bilirubin.

Pathologic hyperbilirubinemia in term infants is diagnosed if

  • Jaundice appears in the first 24 h, after the first week of life, or lasts > 2 wk

  • Total serum bilirubin (TSB) rises by > 5 mg/dL/day

  • TSB is > 18 mg/dL

  • Infant shows symptoms or signs of a serious illness

Some of the most common pathologic causes are

  • Immune and nonimmune hemolytic anemia

  • G6PD deficiency

  • Hematoma resorption

  • Sepsis

  • Hypothyroidism

Causes of Neonatal Hyperbilirubinemia

Mechanism

Causes

Increased enterohepatic circulation

Breast milk (breast milk jaundice)

Breastfeeding failure (breastfeeding jaundice)

Drug-induced paralytic ileus (Mg sulfate or morphine)

Fasting or other cause for hypoperistalsis

Hirschsprung’s disease

Intestinal atresia or stenosis, including annular pancreas

Meconium ileus or meconium plug syndrome

Pyloric stenosis*

Swallowed blood

Overproduction

Breakdown of extravascular blood (eg, hematomas; petechiae; pulmonary, cerebral, or occult hemorrhage)

Polycythemia due to maternofetal or fetofetal transfusion or delayed umbilical cord clamping

Overproduction due to hemolytic anemia

Certain drugs and agents in neonates with G6PD deficiency (eg, acetaminophen, alcohol, antimalarials, aspirin, bupivacaine, corticosteroids, diazepam, nitrofurantoin, oxytocin, penicillin, phenothiazine, sulfonamides)

Maternofetal blood group incompatibility (eg, Rh, ABO)

RBC enzyme deficiencies (eg, of G6PD or pyruvate kinase)

Spherocytosis

Thalassemias (α, βγ)

Undersecretion due to biliary obstruction

α 1 -Antitrypsin deficiency*

Biliary atresia*

Choledochal cyst*

Cystic fibrosis* (inspissated bile)

Dubin-Johnson syndrome and Rotor’s syndrome* (see Dubin-Johnson syndrome)

Parenteral nutrition

Tumor or band* (extrinsic obstruction)

Undersecretion due to metabolic-endocrine conditions

Crigler-Najjar syndrome (familial nonhemolytic jaundice types 1 and 2—see Crigler-Najjar Syndrome)

Drugs and hormones

Gilbert syndrome (see Gilbert Syndrome)

Hypermethioninemia

Hypopituitarism and anencephaly

Hypothyroidism

Lucey-Driscoll syndrome

Maternal diabetes

Prematurity

Tyrosinosis

Mixed overproduction and undersecretion

Asphyxia

Intrauterine infections

Maternal diabetes

Respiratory distress syndrome

Sepsis

Severe erythroblastosis fetalis

Syphilis

TORCH infections

*Jaundice may also occur outside the neonatal period.

TORCH = toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex.

Adapted from Poland RL, Ostrea EM Jr: Neonatal hyperbilirubinemia. In Care of the High-Risk Neonate , ed. 3, edited by MH Klaus and AA Fanaroff. Philadelphia, WB Saunders Company, 1986.


Evaluation

History

History of present illness should note age of onset and duration of jaundice. Important associated symptoms include lethargy and poor feeding (suggesting possible kernicterus), which may progress to stupor, hypotonia, or seizures and eventually to hypertonia. Patterns of feeding can be suggestive of possible breastfeeding failure or underfeeding. Therefore, history should include what the infant is being fed, how much and how frequently, urine and stool production (possible breastfeeding failure or underfeeding), how well the infant is latching on to the breast or taking the nipple of the bottle, whether the mother feels that her milk has come in, and whether the infant is swallowing during feedings and seems satiated after feedings.

Review of systems should seek symptoms of causes, including respiratory distress, fever, and irritability or lethargy (sepsis); hypotonia and poor feeding (hypothyroidism, metabolic disorder); and repeated episodes of vomiting (intestinal obstruction).

Past medical history should focus on maternal infections (toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex [TORCH] infections), disorders that can cause early hyperbilirubinemia (maternal diabetes), maternal Rh factor and blood group (maternofetal blood group incompatibility), and a history of a prolonged or difficult birth (hematoma or forceps trauma).

Family history should note known inherited disorders that can cause jaundice, including G6PD deficiency, thalassemias, and spherocytosis, and also any history of siblings who have had jaundice.

Drug history should specifically note drugs that may promote jaundice (eg, ceftriaxone, sulfonamides, antimalarials).


Physical examination

Overall clinical appearance and vital signs are reviewed.

The skin is inspected for extent of jaundice. Gentle pressure on the skin can help reveal the presence of jaundice. Also, ecchymoses or petechiae (suggestive of hemolytic anemia) are noted.

The physical examination should focus on signs of causative disorders.

The general appearance is inspected for plethora (maternofetal transfusion); macrosomia (maternal diabetes); lethargy or extreme irritability (sepsis or infection); and any dysmorphic features such as macroglossia (hypothyroidism) and flat nasal bridge or bilateral epicanthal folds (Down syndrome).

For the head and neck examination, any bruising and swelling of the scalp consistent with a cephalohematoma are noted. Lungs are examined for crackles (rales), rhonchi, and decreased breath sounds (pneumonia). The abdomen is examined for distention, mass (hepatosplenomegaly), or pain (intestinal obstruction). Neurologic examination should focus on signs of hypotonia or weakness (metabolic disorder, hypothyroidism, sepsis).


Red flags

The following findings are of particular concern:

  • Jaundice in the first day of life

  • TSB > 18 mg/dL

  • Rate of rise of TSB > 0.2 mg/dL/h (> 3.4 μmol/L/h) or > 5 mg/dL/day

  • Conjugated bilirubin concentration > 1 mg/dL (> 17 μmol/L) if TSB is < 5 mg/dL or > 20% of TSB (suggests neonatal cholestasis)

  • Jaundice after 2 wk of age

  • Lethargy, irritability, respiratory distress


Interpretation of findings

Evaluation should focus on distinguishing physiologic from pathologic jaundice. History, physical examination, and timing can help (see Physical Findings in Neonatal Jaundice), but typically TSB and conjugated serum bilirubin levels are measured.


Timing

Jaundice that develops in the first 24 to 48 h, or that persists > 2 wk, is most likely pathologic. Jaundice that does not become evident until after 2 to 3 days is more consistent with physiologic, breastfeeding, or breast milk jaundice. An exception is undersecretion of bilirubin due to metabolic factors (eg, Crigler-Najjar syndrome, hypothyroidism, drugs), which may take 2 to 3 days to become evident. In such cases, bilirubin typically peaks in the first week, accumulates at a rate of < 5 mg/dL/day, and can remain evident for a prolonged period. Because most neonates are now discharged from the hospital or nursery within 48 h, many cases of hyperbilirubinemia are detected only after discharge.

Physical Findings in Neonatal Jaundice

Findings

Timing of Jaundice

Cause

General examination

Fever, tachycardia, respiratory distress

First 24 h

Accumulates > 5 mg/dL/day (> 86 μmol/L/day)

Pneumonia, TORCH infection, sepsis

Lethargy, hypotonia

May appear in the first 24–48 h

Can be prolonged (> 2 wk)

Hypothyroidism, metabolic disorder

Macrosomia

24–48 h

Can accumulate > 5 mg/dL

Maternal diabetes

Petechiae

First 24 h

Accumulates > 5 mg/dL

Hemolytic states (eg, maternofetal blood group incompatibility, RBC enzyme deficiencies, hereditary spherocytosis, thalassemias, sepsis)

Plethora

First 24 h

Accumulates > 5 mg/dL

Maternofetal or fetofetal transfusion, delayed umbilical cord clamping

Head and neck examination

Bilateral slanting palpebral fissures, flat nasal bridge, macroglossia, flattened occiput

First 2–3 days

Down syndrome (possible duodenal atresia, Hirschsprung’s disease, intestinal obstruction, wide spacing between 1st and 2nd toes)

Cephalohematoma

24–48 h

Can accumulate > 5 mg/dL

Birth trauma

Macroglossia

24–48 h

Can be prolonged (> 2 wk)

Hypothyroidism

Abdominal examination

Abdominal distention, decreased bowel sounds

Possible delayed manifestation (2–3 days or later)

Intestinal obstruction (eg, cystic fibrosis, Hirschsprung’s disease, intestinal atresia or stenosis, pyloric stenosis, biliary atresia)

TORCH = toxoplasmosis, other pathogens, rubella, cytomegalovirus, and herpes simplex.


Testing

Diagnosis is suspected by the infant’s color and is confirmed by measurement of serum bilirubin. Noninvasive techniques for transcutaneous measurement of bilirubin levels in infants are being used increasingly, with good correlation with serum bilirubin measurements. Risk of hyperbilirubinemia is based on age-specific TSB levels.

A bilirubin concentration> 10 mg/dL (> 170 μmol/L) in preterm infants or > 18 mg/dL in term infants warrants additional testing, including Hct, blood smear, reticulocyte count, direct Coombs’ test, TSB and direct serum bilirubin concentrations, and blood type and Rh group of the infant and mother.

Other tests, such as blood, urine, and CSF cultures to detect sepsis and measurement of RBC enzyme levels to detect unusual causes of hemolysis, may be indicated by the history and physical examination. Such tests also may be indicated for any neonates with an initial bilirubin level > 25 mg/dL (> 428 μmol/L).


Treatment

Treatment is directed at the underlying disorder. In addition, treatment for hyperbilirubinemia itself may be necessary.

Physiologic jaundice usually is not clinically significant and resolves within 1 wk. Frequent formula feedings can reduce the incidence and severity of hyperbilirubinemia by increasing GI motility and frequency of stools, thereby minimizing the enterohepatic circulation of bilirubin. The type of formula does not seem important in increasing bilirubin excretion.

Breastfeeding jaundice may be prevented or reduced by increasing the frequency of feedings. If the bilirubin level continues to increase > 18 mg/dL in a term infant with early breastfeeding jaundice, a temporary change from breast milk to formula may be appropriate; phototherapy also may be indicated at higher levels. Stopping breastfeeding is necessary for only 1 or 2 days, and the mother should be encouraged to continue expressing breast milk regularly so she can resume nursing as soon as the infant’s bilirubin level starts to decline. She also should be assured that the hyperbilirubinemia has not caused any harm and that she may safely resume breastfeeding. It is not advisable to supplement with water or dextrose because that may disrupt the mother’s production of milk.

Definitive treatment involves

  • Phototherapy

  • Exchange transfusion

Phototherapy

This treatment remains the standard of care, most commonly using fluorescent white light. (Blue light is most effective for intensive phototherapy.) Phototherapy is the use of light to photoisomerize unconjugated bilirubin into forms that are more water-soluble and can be excreted rapidly by the liver and kidney without glucuronidation. It provides definitive treatment of neonatal hyperbilirubinemia and prevention of kernicterus. Phototherapy is an option when unconjugated bilirubin is > 12 mg/dL (> 205.2 μmol/L) and may be indicated when unconjugated bilirubin is > 15 mg/dL at 25 to 48 h, 18 mg/dL at 49 to 72 h, and 20 mg/dL at> 72 h (see see Figure: Risk of hyperbilirubinemia in neonates = 35 wk gestation.). Phototherapy is not indicated for conjugated hyperbilirubinemia. Because visible jaundice may disappear during phototherapy though serum bilirubin remains elevated, skin color cannot be used to evaluate jaundice severity. Blood taken for bilirubin determinations should be shielded from bright light, because bilirubin in the collection tubes may rapidly photo-oxidize.


Exchange transfusion

This treatment can rapidly remove bilirubin from circulation and is indicated for severe hyperbilirubinemia, which most often occurs with immune-mediated hemolysis. Small amounts of blood are withdrawn and replaced through an umbilical vein catheter to remove partially hemolyzed and antibody-coated RBCs as well as circulating Igs. The blood is replaced with uncoated donor RBCs. Only unconjugated hyperbilirubinemia can cause kernicterus, so if conjugated bilirubin is elevated, the level of unconjugated rather than total bilirubin is used to determine the need for exchange transfusion.

Specific indications are serum bilirubin 20 mg/dL at 24 to 48 h or 25 mg/dL at > 48 h and failure of phototherapy to result in a 1- to 2-mg/dL (17- to 34-μmol/L) decrease within 4 to 6 h of initiation or at the first clinical signs of kernicterus regardless of bilirubin levels. If the serum bilirubin level is > 25 mg/dL when the neonate is initially examined, preparation for an exchange transfusion should be made in case intensive phototherapy fails to lower the bilirubin level. An alternative approach uses the weight of the neonate in grams divided by 100 to determine the bilirubin level (in mg/dL) at which exchange transfusion is indicated. Thus, a 1000-g neonate would receive an exchange transfusion at a bilirubin level of 10 mg/dL, and a 1500-g neonate would receive an exchange transfusion at a bilirubin level of 15 mg/dL.

Most often, 160 mL/kg (twice the infant’s total blood volume) of packed RBCs is exchanged over 2 to 4 h; an alternative is to give 2 successive exchanges of 80 mL/kg each over 1 to 2 h. To do an exchange, 20 mL of blood is withdrawn and then immediately replaced by 20 mL of transfused blood. This procedure is repeated until the total desired volume is exchanged. For critically ill or premature infants, aliquots of 5 to 10 mL are used to avoid sudden major changes in blood volume. The goal is to reduce bilirubin by nearly 50%, with the knowledge that hyperbilirubinemia may rebound to about 60% of pretransfusion level within 1 to 2 h. It is also customary to lower the target level by 1 to 2 mg/dL in conditions that increase the risk of kernicterus (eg, fasting, sepsis, acidosis). Exchange transfusions may need to be repeated if bilirubin levels remain high. Finally, there are risks and complications with the procedure, and the success of phototherapy has reduced the frequency of exchange transfusion.


Key Points

  • Neonatal jaundice is caused by increased bilirubin production, decreased bilirubin clearance, or increased enterohepatic circulation.

  • Some jaundice is normal in neonates.

  • Risk varies with postnatal age, TSB value, prematurity, and health of the neonate.

  • Treatment depends on cause and degree of elevation.

  • Definitive treatments include phototherapy and exchange transfusion.

Kernicterus

(Bilirubin Encephalopathy)

Kernicterus is brain damage caused by unconjugated bilirubin deposition in basal ganglia and brain stem nuclei.

Normally, bilirubin bound to serum albumin stays in the intravascular space. However, bilirubin can cross the blood-brain barrier and cause kernicterus when serum bilirubin concentration is markedly elevated; serum albumin concentration is markedly low (eg, in preterm infants); or bilirubin is displaced from albumin by competitive binders (eg, sulfisoxazole, ceftriaxone, and aspirin; free fatty acids and hydrogen ions in fasting, septic, or acidotic infants).

In preterm infants, kernicterus may not cause recognizable clinical symptoms or signs. Early symptoms in term infants are lethargy, poor feeding, and vomiting. Opisthotonos, oculogyric crisis, seizures, and death may follow. Kernicterus may result in intellectual disability, choreoathetoid cerebral palsy, sensorineural hearing loss, and paralysis of upward gaze later in childhood. It is unknown whether minor degrees of kernicterus can cause less severe neurologic impairment (eg, perceptual-motor problems, learning disorders).

There is no reliable test to determine the risk of kernicterus, and the diagnosis is made presumptively. A definite diagnosis can be made only by autopsy.

There is no treatment once kernicterus develops; it can be prevented by treating hyperbilirubinemia (see Neonatal Hyperbilirubinemia).

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