Neonatal 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

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 table Causes of Neonatal Hyperbilirubinemia).

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

• Physiologic hyperbilirubinemia

• Breastfeeding (chestfeeding) jaundice

• Human milk jaundice

• Pathologic hyperbilirubinemia due to hemolytic disease

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

Physiologic hyperbilirubinemia occurs in almost all neonates. Shorter neonatal red blood cell life span increases bilirubin production, deficient conjugation due to the deficiency of uridine diphosphate-glucuronosyltransferase (UGT) decreases clearance, and low bacterial levels in the intestine combined with increased hydrolysis of conjugated bilirubin increase enterohepatic circulation. Bilirubin levels typically rise over the first 3 to 4 days of life (7 days in East Asian infants, who have higher bilirubin levels at birth) and fall thereafter (1).

Breastfeeding (chestfeeding) jaundice develops in one-sixth of breast-fed 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.

Human milk jaundice is different from breastfeeding jaundice. It develops after the first 5 to 7 days of life and peaks at about 2 weeks. It is thought to be caused by an increased concentration of beta-glucuronidase in human 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 hours, after the first week of life, or lasts > 2 weeks

• Total serum bilirubin rises by > 5 mg/dL/day (> 86 micromol/L/day)

• Infant shows symptoms or signs of a serious illness

Some of the most common pathologic causes are

• Immune and nonimmune hemolytic anemia

• Hematoma resorption

• Sepsis

• Hypothyroidism

1. 1. Bentz MG, Carmona N, Bhagwat MM, et al. Beyond "Asian": Specific East and Southeast Asian Races or Ethnicities Associated With Jaundice Readmission. Hosp Pediatr. 2018;8(5):269-273. doi:10.1542/hpeds.2017-0234

History of present illness should note age of onset (in hours) and duration of jaundice. Important associated symptoms include lethargy and poor feeding (suggesting possible CBE), which may progress to stupor, hypotonia, or seizures and eventually to hypertonia. Patterns of feeding can be suggestive of possible breastfeeding jaundice or underfeeding. Therefore, history should include what the infant is being fed, how much and how frequently, urine and stool production (possible breastfeeding jaundice or underfeeding), how well the infant is latching on to the breast or chest or taking the nipple of the bottle, whether the parent feels that their 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 glucose-6-phosphate dehydrogenase (G6PD) deficiency, or other red cell enzyme deficiencies, thalassemias, and spherocytosis, and also any history of siblings who have had jaundice.

Medication history should specifically note medications that may promote jaundice (eg, ceftriaxone, antimalarials, sulfonamides [sulfonamides do not promote jaundice; they instead lead to potentially more harm at lower measured bilirubin levels because they displace bilirubin from albumin, increasing the free bilirubin fraction]).

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.

The physical examination should focus on signs of causative disorders.

The general appearance is inspected for plethora (due to maternofetal transfusion), macrosomia (due to maternal diabetes), and lethargy or extreme irritability (due to sepsis or infection) and for any dysmorphic features such as macroglossia (with hypothyroidism) and flat nasal bridge or bilateral epicanthal folds (in 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 perceived pain (intestinal obstruction).

Neurologic examination should focus on signs of hypotonia or weakness (metabolic disorder, hypothyroidism, sepsis).

The following findings are of particular concern:

• Jaundice in the first day of life

• Total serum bilirubin near hour-specific exchange transfusion levels

• Rate of rise of total serum bilirubin > 0.2 mg/dL/hour (> 3.4 micromol/L/hour) or > 5 mg/dL/day (> 86 micromol/L/day)

• Conjugated bilirubin concentration > 1 mg/dL (> 17 micromol/L) if total serum bilirubin is < 5 mg/dL (< 86 micromol/L) or > 20% of total serum bilirubin (suggests neonatal cholestasis)

• Jaundice after 2 weeks of age

• Lethargy, irritability, respiratory distress

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

Jaundice that develops in the first 24 to 48 hours, or that persists > 2 weeks, is most likely pathologic. Jaundice that does not become evident until after 2 to 3 days is more consistent with physiologic, breastfeeding, or human milk jaundice. An exception is undersecretion of bilirubin due to metabolic factors (eg, Crigler-Najjar syndrome, hypothyroidism, and medications), 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 (< 86 micromol/L), and can remain evident for a prolonged period. Because most neonates are now discharged from the hospital or nursery within 48 hours, many cases of hyperbilirubinemia are detected only after discharge.

Diagnosis of hyperbilirubinemia is suspected by the infant’s color and is confirmed by measurement of serum bilirubin. Noninvasive techniques for measuring bilirubin in infants, including transcutaneous and digital photography–based techniques, are being used increasingly and correlate well with serum bilirubin measurements. Risk of hyperbilirubinemia is based on age-specific (in hours) total serum bilirubin levels.

A bilirubin concentration > 10 mg/dL (> 171 micromol/L) in preterm infants or > 18 mg/dL (> 308 micromol/L) in term infants warrants additional testing, including hematocrit, blood smear, reticulocyte count, direct Coombs test, total serum bilirubin and direct serum bilirubin concentrations, and blood type and Rh group of the infant and mother.

Other tests, such as blood, urine, and cerebrospinal fluid cultures to detect sepsis and other serious infections and measurement of red blood cell enzyme levels to detect unusual causes of hemolysis, may be indicated by the history and physical examination. Such tests are also indicated for any neonates with an initial bilirubin level > 25 mg/dL (> 428 micromol/L).

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 CBE (1). Phototherapy remains the standard of care, most commonly using fluorescent white light. (Blue light, wavelength 425 to 475 nm, is most effective for intensive phototherapy.)

For neonates born at ≥ 35 weeks gestation, there are gestational age-specific phototherapy guidelines that also depend on the presence of additional risk factors for neurotoxicity (2). Phototherapy is not indicated for conjugated hyperbilirubinemia.

For neonates born at < 35 weeks gestation, threshold bilirubin levels for treatment are lower because preterm infants are at a greater risk of neurotoxicity. The more preterm the infant, the lower the threshold (see table Suggested Thresholds for Starting Phototherapy or Exchange Transfusion in Infants < 35 Weeks Gestation).

Because visible jaundice may disappear during phototherapy even 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.

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, or other access as available, to remove partially hemolyzed and antibody-coated red blood cells (RBCs) as well as circulating immunoglobulins. The blood is replaced with uncoated donor RBCs that do not have the RBC membrane antigen that binds the circulating antibodies. That is, type O blood is used if the neonate is sensitized to AB antigens and Rh-negative blood is used if the neonate is sensitized to Rh antigen. Because adult donor RBCs have more ABO antigen sites than fetal cells, type-specific transfusion will intensify the hemolysis. Only unconjugated hyperbilirubinemia can cause CBE, so if conjugated bilirubin is elevated, the level of unconjugated rather than total bilirubin is used to determine the need for exchange transfusion.

For infants ≥ 35 weeks gestational age, guidelines with week-specific values for each hour of life are available for infants with and without risk factors for neurotoxicity (2). If the serum bilirubin level is > 25 mg/dL (≥ 428 micromol/L) when the neonate is initially examined, preparation for an exchange transfusion should be made in case intensive phototherapy fails to lower the bilirubin level.

Thresholds have been suggested for neonates born at < 35 weeks gestation (see table Suggested Thresholds for Starting Phototherapy or Exchange Transfusion in Infants 35 Weeks Gestation). Previously, some clinicians used criteria based solely on patient weight, but these criteria have been replaced by the more specific guidelines described above.

In term infants, most often, 160 mL/kg (twice the infant’s total blood volume) of packed RBCs is exchanged over 2 to 4 hours; an alternative is to give 2 successive exchanges of 80 mL/kg each over 1 to 2 hours (3). To do an exchange, a volume of blood is withdrawn and then immediately replaced by transfused blood. The volume of each can vary depending on the infant's size, but volumes are typically near 20 mL for the average term infant. This procedure is repeated until the total desired volume is exchanged. For critically ill or preterm 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 the pretransfusion level within 1 to 2 hours. It is also customary to lower the target level by 1 to 2 mg/dL (17 to 34 micromol/L) in infants who have conditions that increase the risk of CBE (eg, sepsis, acidosis). Exchange transfusions may need to be repeated if bilirubin levels remain high.

There are risks and complications associated with exchange transfusion, and the success of phototherapy has reduced the frequency of this procedure.

1. 1. Bhutani VK; Committee on Fetus and Newborn; American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2011;128(4):e1046-e1052. doi:10.1542/peds.2011-1494

2. 2. Kemper AR, Newman TB, Slaughter JL, et al. Clinical Practice Guideline Revision: Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics. 2022;150(3):e2022058859. doi:10.1542/peds.2022-058859

3. 3. Falciglia HS, Greenwood C. Double Volume Exchange Transfusion: A Review of the “Ins and Outs”. Neoreviews 2013; 14 (10): e513–e520. https://doi.org/10.1542/neo.14-10-e513