Management of Neonatal Jaundice

Educational Objectives

The goal of this program is to improve diagnosis and management of hyperbilirubinemia. After hearing and assimilating this program, clinician will be better able to:

1. Distinguish among different causes of elevated bilirubin levels in infants.

2. Identify possible causes of pathologic jaundice.

3. Adopt measures to prevent progression of bilirubin toxicity.

Summary

Bilirubin (BIL): total (TBIL) is BIL production minus elimination (conjugation); unconjugated BIL is indirect reacting BIL; a BIL level >2 mg/dL is indirect hyperbilirubinemia (normal is <0.8 mg/dL in individuals ≥3 yr of age); an unconjugated level >2 mg/dL in a newborn is considered unconjugated hyperbilirubinemia; in conjugated hyperbilirubinemia, the direct component is >1.5 mg/dL and must be >10% of TBIL production

Elimination of BIL: unconjugated BIL becomes water soluble when conjugated with a carbohydrate, allowing removal through urine or stool; in the fetus, elimination occurs via the placenta; uridine diphosphoglucoronosyltransferase (UDP) — the rate-limiting enzyme in the liver (catalyzes binding of glucuronic acid to BIL, creating a polar [conjugated] form that can be excreted); during the first few hours of life, the activity of UDP is only 1% that in adults; infants develop jaundice because of their inability to rapidly conjugate BIL; enzyme activity dramatically increases over the first 3 mo of life

BIL synthesis: red blood cells (RBCs) are produced by bone marrow; when RBCs break down, hemoglobin is converted to biliverdin, which is converted to unconjugated BIL and accounts for 75% of serum unconjugated BIL; the shunt pathway, which involves heme precursors, myoglobin, and nonhemoglobin heme proteins, accounts for the remaining 25%; degradation of erythrocytes during the third trimester and neonatal period leads to a 150% increase in BIL production per unit of body weight

BIL transport: unconjugated BIL that is bound to albumin cannot cross the blood-brain barrier; serum BIL binds to albumin and is transported to the liver, where it is broken down and conjugated; if the BIL level is high, there may be insufficient albumin for binding, allowing it to cross the blood-brain barrier

Role of albumin: can bind ≥2 molecules of BIL (has a high-affinity site and a low-affinity site); at a molar ratio of 1, 1 g of albumin can bind 7 to 8 mg of BIL; if the albumin level is 3.5 mg/dL, almost 29.4 mg of BIL can be bound (at the high-affinity site); there is a direct relationship between albumin level and risk for jaundice

Elimination of BIL (continued): BIL bound to albumin enters the liver and binds to ligandin; this allows UDP to conjugate BIL, after which it is eventually excreted into the small intestine; bacteria convert BIL into urobilinoids, which are excreted in stool

Conjugated (direct) hyperbilirubinemia: failure of elimination causes high levels of conjugated BIL (>10% of TBIL); differential diagnosis — neonatal or viral hepatitis; choledochal cysts; biliary atresia, urinary tract infection; Alagille syndrome (a genetic condition that results in a paucity of bile ducts)

Enterohepatic circulation (EHC): neonates have a high concentration of unconjugated BIL in the intestine owing to exaggerated hydrolysis of BIL glucuronide; concentrations of BIL are high in meconium, but flora (needed for conversion to urobilinogen) are lacking; 25% of TBIL that enters the intestine in the first few days of life is reabsorbed as unconjugated BIL, which may account for jaundice in breastfed infants

Jaundice: Accumulation of serum BIL; visible to the naked eye in the sclera or skin; visible scleral icterus or jaundice indicates a BIL level of at least 5 to 6 mg/dL; 60% of newborns have unconjugated BIL levels >1.8 mg/dL during the first week of life; elevated RBC counts, elevated hemoglobin, breakdown of RBCs, breastfeeding, increased EHC, and low UDP levels combine to create unconjugated hyperbilirubinemia (physiologic jaundice)

Nonphysiologic jaundice: implies that an additional source of stress on this system (eg, hemolytic anemia, immune-mediated hemolysis, red cell disorders, enzyme defects, membrane defects, extravasation of blood, cephalohematomas, caput succedaneum) is causing a pathologic elevation in catabolism of RBCs; other causes — genetic defects in UDP (resulting in absence of enzyme activity); liver and biliary disease; exaggerated EHC to, eg, bowel atresia, other gastrointestinal diseases

Distinguishing physiologic from pathologic hyperbilirubinemia: physiologic — in White and Black infants, BIL level is 5 to 6 mg/dL between 48 and 120 hr of age and peaks by 72 to 96 hr; Asian infants have levels between 10 and 14 mg/dL, with lower levels of GDP; pathologic — BIL level >6 mg/dL in the first 24 hr of life; the rate of rise is >0.5 mg/dL/hr or an underlying disease is present

Differential diagnosis for pathologic jaundice: increased catabolism of heme — hemolytic disease (eg, ABO or Rh disease); enzyme deficiencies (eg, glucose-6-phosphate dehydrogenase [G6PD]), pyruvate kinase); membrane defects (eg, spherocytosis, elliptocytosis); sepsis; sequestered blood; polycythemia; disorders of hepatic uptake — Gilbert syndrome; disorders of conjugation — Crigler-Najjar syndrome; Lucy-Driscoll syndrome; intestinal obstruction; hypothyroidism; others — disorders of excretion; disorders of EHC

Gilbert syndrome: a benign disorder that affects ≤6% of the population; caused by defective uptake of BIL and low UDP activity; may present in the second decade of life, but affected infants are typically jaundiced as newborns; responds to phototherapy

Crigler-Najjar syndrome: type 1 — an autosomal recessive disorder resulting in almost complete absence of UDP activity; BIL levels are >20 mg/dL; liver transplantation is required; type 2 — similar but can be treated with phenobarbital

Increased EHC: type 1 (breastfeeding failure jaundice) — results from inexperience of parents with breastfeeding; infants are starving and dehydrated; intestines are not being colonized; instruct the mother to breastfeed every 1 to 2 hr to increase production of milk; colostrum provides the needed bacteria; type 2 (breast milk jaundice) — develops 3 to 5 days after birth and may persist into the third week of life; affects 10% to 30% infants; BIL levels may reach 10 to 30 mg/dL; may be caused by an enzyme that increases EHC or (alternatively) inhibits UDP; cured by discontinuation of breastfeeding

Clinical implications of unconjugated hyperbilirubinemia: unbound unconjugated BIL is free to cross the blood-brain barrier and may permanently damage the brain; the albumin level determines the “safe” BIL level; in a healthy, full-term infant without hemolysis, neurologic complications are unlikely at BIL levels <25 mg/dL; however, in the setting of hemolysis, albumin may be insufficient and BIL levels of 18 to 20 mg/dL must be aggressively managed to avoid BIL-induced neurologic dysfunction (BIND)

Acute BIL encephalopathy: central nervous system findings caused by BIL toxicity affecting, eg, the basal ganglia; phase 1 — lethargy, hypotonia, and poor feeding; reversible with treatment; phase 2 — stupor, irritability, and hypertonia; retrocollis, opisthotonos, fever, high-pitched cry, and hypotonia may develop; possibly reversible but damage may be occurring; advanced phase — pronounced retrocollis and opisthotonos; seizures are possible; the infant does not feed, has poor suck and a shrill cry, and is apneic; similar to a comatose state; damage is irreversible (kernicterus)

Risk factors for severe hyperbilirubinemia: high-risk or high intermediate-risk predischarge serum or transcutaneous BIL levels; low gestational age; exclusively breastfeeding and losing weight; jaundice in the first 24 hr; a known hemolytic disease; a previously born sibling with severe jaundice; significant cephalohematoma or bruising; east Asian ancestry

Risk factors for BIND: isoimmune hemolytic disease, G6PD deficiency; birth asphyxia; sepsis; albumin <3 mg/dL

Phototherapy: reduces risk of TBIL reaching levels that indicate double-volume exchange transfusion (DVET); mechanisms of action — geometric photoisomerization; intramolecular cyclization (major mechanism; converts BIL into lumirubin, which is excreted in bile and urine); oxidation of BIL (minor); effectiveness — influenced by quality and wavelength of bulbs used (should be 340-540 nm), irradiance (ie, intensity; should be ≥30W/cm2/nm for intensive phototherapy), and proportion of body surface area exposed (eyes and gonads should be covered; the infant should be otherwise naked); adverse effects — water loss; retinal damage; in infants with congenital erythropoietic porphyria (rare), reaction to blue light causes hemolysis, skin lesions, and severe bullous lesions

Double-volume exchange transfusion: admit infants with concerning BIL levels; in those with ABO or Rh disease and rising levels, treat with intravenous immunoglobulin and phototherapy; DVET replaces 85% of RBCs and reduces BIL by 50%; required for any infant in BIND stage 2 or 3; use fresh, irradiated, whole blood or blood reconstituted with fresh frozen plasma; complications — rates of mortality and morbidity are 0.003% and 5%, respectively; may cause thrombocytopenia, hypocalcemia, and acid-base imbalances; BIL-to-albumin ratios indicating DVET — ratio of 8 for term infants (≥38-wk gestation); ratio of 7.2 for 35- to 37-wk gestation infants who are well or ≥38 wk at higher risk; ratio of 6.8 for late preterm infants at higher risk

Readings

Hulzebos CV et al. Usefulness of the bilirubin/albumin ratio for predicting bilirubin-induced neurotoxicity in premature infants. Arch Dis Child Fetal Neonatal Ed. 2008 Sep;93(5):F384-8. doi: 10.1136/adc.2007.134056. Epub 2008 May 1. PMID: 18450807; Karimzadeh P et al. Bilirubin induced encephalopathy. Iran J Child Neurol. 2020 Winter;14(1):7-19. PMID: 32021624; PMCID: PMC6956966; Memon N et al. Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar;79(3):378-86. doi: 10.1038/pr.2015.247. Epub 2015 Nov 23. PMID: 26595536; PMCID: PMC4821713; Singh A, Jialal I. Unconjugated hyperbilirubinemia. 2020 Jun 25. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan–. PMID: 31747203; Ullah S et al. Hyperbilirubinemia in neonates: types, causes, clinical examinations, preventive measures and treatments: a narrative review article. Iran J Public Health. 2016 May;45(5):558-68. PMID: 27398328; PMCID: PMC4935699; Watchko JF. Emergency release uncross-matched packed red blood cells for immediate double volume exchange transfusion in neonates with intermediate to advanced acute bilirubin encephalopathy: timely but insufficient? J Perinatol. 2018 Aug;38(8):947-953. doi: 10.1038/s41372-018-0168-x. Epub 2018 Jul 12. PMID: 29997396.

Disclosures

For this program, members of the faculty and planning committee reported nothing to disclose.

Acknowledgements

Dr. Saxonhouse was recorded using video conferencing software on July 10, 2020, in compliance with social distancing guidelines during the COVID-19 pandemic. Audio Digest thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PD670401

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.