Neonatal Unconjugated Hyperbilirubinemia

Background

• More than 80% of newborn infants will appear clinically jaundiced during the first weeks of life.
• Most cases of neonatal jaundice are nonpathologic and may be due to physiologic reduction in bilirubin conjugating and excreting mechanisms and/or increased bilirubin production.
• Hyperbilirubinemia significant enough to require phototherapy has been reported in approximately 10% of term and 25% of near preterm infants.
• Major risk factors for developing severe hyperbilirubinemia include jaundice observed in the first 24 hours of life, lower gestational age, known or suspected hemolytic disease, scalp hematoma or significant bruising, need for phototherapy prior to discharge, family history or genetic ancestry suggestive of inherited erythrocyte disorder, Down syndrome, macrosomia and maternal history of diabetes during pregnancy, and exclusive breastfeeding with suboptimal intake.
• Pathologic causes of neonatal jaundice include hemolysis, enzyme deficiencies, or liver and biliary tract abnormalities.
• Total serum bilirubin levels > 25-30 mg/dL (428-513 mcmol/L) in term infants (lower levels in premature infants) are associated with the highest risk of kernicterus, or permanent sequela from bilirubin accumulation in the brain.

Evaluation

• If maternal antibody status is positive or unknown at the time of delivery, strongly consider obtaining a direct antibody test (DAT) and determining the neonate's blood type using either cord or peripheral blood as soon as possible (Weak recommendation).
• Visual estimation of the degree of jaundice should not be used for predicting serum bilirubin level. Absence of jaundice may predict low risk of developing severe hyperbilirubinemia.
• Visually assess all infants for jaundice at least every 12 hours from delivery until discharge (Strong recommendation).
• Measure transcutaneous bilirubin (TcB) or total serum bilirubin (TSB) as soon as possible in any neonate with jaundice < 24 hours after birth (Strong recommendation)
• Strongly consider TcB or TSB measurement in all neonates between 24 and 48 hours of life, or prior to discharge if that occurs earlier.
• Transcutaneous bilirubin measurement can be used to monitor for hyperbilirubinemia but should not be used when deciding to start phototherapy or when further escalating care. Specifically, TcB measurements above 15 mg/dL (257 mcmol/L) or those that exceeds or are within 3 mg/dL (51 mcmol/L) of the phototherapy threshold value should be verified with a TSB measurement.
• If phototherapy is indicated, strongly consider investigating cause of hyperbilirubinemia with (Weak recommendation):
  • blood testing for hemolysis (hemoglobin, hematocrit, or complete blood count)
  • direct antibody test if mother had a positive antibody screen, is blood group O (regardless of RhD status), or is RhD negative
  • gluose-6-phosphate dehydrogenase (G6PD) activity measurement in cases of rapidly increasing TSB.

Management

• Preventing significant hyperbilirubinemia
  • Breastfed infants should be fed > 8 times/day to help prevent hyperbilirubinemia from dehydration.
  • Consider supplementation with expressed breast milk or formula if the infant has weight loss > 10% of birth weight, poor urine output, poor caloric intake, or delayed stooling.
  • Do not use oral supplementation with water or dextrose water to prevent hyperbilirubinemia or to decrease bilirubin concentrations (Strong recommendation).
• Starting phototherapy
  • TSB thresholds for starting intensive phototherapy in infants ≥ 35 weeks gestation depend on gestational age, infant age in hours, and presence of hyperbilirubinemia neurotoxicity risk factors.
  • American Academy of Pediatrics (AAP) provides 2 nomograms for starting intensive phototherapy in infants ≥ 35 weeks gestation (with and without hyperbilirubinemia neurotoxicity risk factors). They can be found at (AAP 2022 Aug 5). A clinical decision support tool to operationalize the AAP nomograms can be found at bilitool.org.
  • Expert consensus-based recommendations for lower TSB thresholds may be considered for starting phototherapy in infants < 35 weeks gestation.
• Stopping phototherapy
  • Consider discontinuing phototherapy when TSB has decreased by at least 2 mg/dL (34.2 mcmol/L) below the hour-specific threshold at the start of treatment (Weak recommendation).
  • Strongly consider repeat bilirubin measurement following discontinuation of phototherapy based on risk of rebound hyperbilirubinemia (Weak recommendation).
• Escalating therapy
  • Infants with TSB levels within 2 mg/dL (34.2 mcmol/L) of the exchange transfusion threshold require escalation of care. AAP nomograms for exchange transfusion in infants ≥ 35 weeks gestation (with and without hyperbilirubinemia neurotoxicity risk factors) can be found at (AAP 2022 Aug 5). A clinical decision support tool to operationalize the AAP nomograms can be found at bilitool.org.
    • Strongly consider sending immediate blood work including total and direct-reacting serum bilirubin, complete blood cell count, serum albumin, serum chemistries, and type and crossmatch (Weak recommendation).
    • Strongly consider IV hydration and intensive phototherapy (Weak recommendation).
    • Strongly consider increased monitoring of TSB (at least every 2 hours) from initiation of escalation of care until TSB is less than escalation of care threshold (Weak recommendation).
    • Consider IV immunoglobulin (IVIG) for infants with isoimmune hemolytic disease (positive direct antibody test) (Weak recommendation).
  • Strongly consider exchange transfusion in infants ≥ 35 weeks with signs of intermediate or advanced stages of acute bilirubin encephalopathy or with TSB ≥ exchange transfusion threshold (Weak recommendation).