Pocket Pediatrics: The Massachusetts General Hospital for Children Handbook of Pediatrics (Pocket Notebook Series), 2 Ed.


Introduction (Pediatr Rev 2011;32:341; Pediatrics 2004;114:297)

• Jaundice = yellowing of skin, sclera, and mucous membranes 2/2 deposition of bilirubin, which is produced from the breakdown of hemoglobin (Hgb)

• Occurs in 2/3 of healthy FT infants; 10% develop severe jaundice (>17 mg/dL)

• Cephalocaudal progression with increasing bilirubin level (face to trunk to palms and soles): Estimate of level from visual assessment; face = 5 mg/dL, chest = 10 mg/dL, abdomen = 12 mg/dL, and palms/soles >15 mg/dL. Not visible if <4 mg/dL. If above nipple line, level likely <12 mg/dL

• Need confirmation via transcutaneous or serum bilirubin measurement

• Acute bilirubin encephalopathy (ABE) is the acute manifestation of bilirubin toxicity during the first postnatal weeks

• Phase 1 (early, first few d): Lethargy, poor feeding, high-pitched cry, hypotonia

• Phase 2 (intermed, first wk) irritability alternat w/ lethargy; high pitched cry; may see ↑’d extensor tone; backward arching of neck (retrocollis) & trunk (opisthotonos); fever

• Phase 3 (advanced, after first wk): Stupor to coma; no feeding; shrill cry; hypertonia; retrocollis–opisthotonos; apnea; fever; seizures

• Kernicterus: Chronic/permanent sequelae of bili deposition in basal ganglia & brainstem

• Athetoid CP, upward gaze paralysis, hi-freq hearing loss/deafness, enamel dysplasia

Bilirubin Metabolism (Pediatr Rev 2006;27:443)

• Reticuloendothelial system: Hgb degraded by heme oxygenase and biliverdin reductase to unconj bilirubin, which binds albumin. Unconj bili fat soluble; able to cross the blood–brain barrier, can be neurotoxic

• Liver: Uridine diphosphate glucuronosyltransferase (UGT 1A1) converst unconj bili to conj bilirubin, conj bile excreted into bile, water soluble, does not cross blood–brain barrier

• Intestine: Much of conj bili hydrolyzed back to unconj form and absorbed into enterohepatic circulation (EH), rest is excreted in stool. Intestinal bacteria reduce conj bili to urobilinogen, reducing EH circulation but newborn gut initially sterile

Pathophysiology (Pediatr Rev 2006;27:443; Pediatr Rev 2011;32:341)

• Hyperbilirubinemia 2/2 ↑ production, ↓ conjugation, or impaired excretion of bilirubin

• ↑ Bili production (unconjugated)

• Hemolytic (>6% reticulocyte count, hemoglobin < 13, hepatosplenomegaly)

• Coombs (+): ABO, Rh, and minor antigen incompatibility

• Coombs (−): RBC memb defects (spherocytosis), enzyme def (pyruvate kinase, G6PD), Hgb defects (SCD, thal), drugs (streptomycin, Vit K)

• Nonhemolytic (normal reticulocyte count and hemoglobin)

• Extravascular blood: Cephalohematoma, bruising, CNS bleed

• Intravascular blood = polycythemia (high Hb/HCT): 2/2 delayed cord clamping, fetal–maternal xfusion, twin–twin xfusion, maternal DM or smoking, high altitude

• Intestinal = ↑ EH circ; ↓ stooling, CF, Hirschsprung, pyloric stenosis, obstruct

• ↓ bili conj (unconj): Breast milk jaundice, hypothyroid, Gilbert and Crigler–Najjar

• Impaired bilirubin excretion (conjugated)

• Biliary obstruction: Biliary atresia, choledochal cyst, 1° sclerosing cholangitis, gallstones, Dubin–Johnson, and Rotor syndromes

• Metabolic disease: α-1 antitrypsin def, CF, galactosemia, glycogen storage dz, Gaucher, Wilson, Niemann–Pick, genetic dz, Trisomy 21 and 18, Turner

• Infection: UTI, sepsis, idiopathic neonatal hepatitis, Hep B, TORCH

• ↓ Albumin binding (unconj): Low albumin, meds (CTX, sulfa, steroids), acidosis

Physiologic Jaundice (Pediatr Rev 2006;27:443; Pediatr Rev 2011;32:341)

• Transient elevation of unconj bili after 24 hr of life but w/i first wk 2/2 multi factors

• Newborn relatively polycythemic, which is resolved by hemolysis

• Neonatal erythrocytes larger w/ shorter lifespan (70–90 vs. 120 d for adult)

• Immature liver: ↓ glucuronyl transferase activity and ↓ uptake of unconj bilirubin

• ↑ EH circ: Sterile neonatal gut does not degrade conj bili, reverts and is reabsorbed

• Colostrum: Small vol leads to weight loss and slow passage of bili-rich meconium

• Breast-feeding jaundice

• Early onset; peaks DOL 3–5: 2/2 relative caloric depriv, mild dehyd, and delayed passage of mec; Rx: Inc freq feeds (10×/d w/ formula suppl as needed)

• Breast milk jaundice (“human milk jaundice”)

• Late onset; peaks DOL 6–14; can persist 1–3 mo

• 2/2 breast milk substances (B-glucuronidases and non-esterified fatty acids), which inhibit normal bilirubin metabolism; actual causal substance unknown

• Rx: Can interrupt breast-feeding 2 d (to  bili level, pump in btw), then resume

Pathologic Jaundice (Pediatrics 2004;114:297; Pediatr Rev 2011;32:341)

• Any jaundice w/i 1st 24 hr of life or beyond 21 d, rapid rise Tbili (crossing percentiles in risk nomogram below), Tbili >17 mg/dL in FT newborns, or any evidence of underlying illness should prompt further evaluation

Risk Factors for Development of Severe Hyperbilirubinemia (Pediatrics 2004;114:297; Pediatrics 2009;124:1193)

• Major: Predischarge bili level in high-risk zone (see nomogram below), jaundice in 1st 24 hr, isoimmune or other hemolytic dz, GA <37 wk, prev sibling Rx’d w/ phototherapy (PTX), cephalohematoma/bruising, exclusive breast-feeding, East Asian race

• Minor: Predischarge bili high intermediate-risk, GA 37–38 wk, jaundice seen before discharge, prev sib w/ jaundice, macrosomic infant of diabetic mother, mother >25 yo

• Nomogram for designation of risk (Pediatrics 1999;103:6)

Hyperbilirubinemia Neurotoxicity Risk Factors (Pediatrics 2004;114:297; Pediatrics 2009;124:1193)

• Isoimmune hemolytic dz, G6PD def, asphyxia, sepsis, acidosis, albumin <3mg/dL (gestational age considered separately)

• These risk factors, plus sig lethargy or temp instability, used in determining indications for treatment of hyperbilirubinemia (referred to as “risk factors” in PTX and exchange transfusion figures below)

Evaluation (Pediatr Rev 2011;32:341; Pediatrics 2004;114:297)

• Physical exam

• Assess for jaundice (cephalocaudal progression)

• Bruises, pallor, petechiae, hepatosplenomegaly, weight loss, and dehydration

• Labs: Tbili/Dbili, blood type, direct Ab test (Coomb), CBC/diff/smear

• Consider retic count, G6PD, ETCO2, CF screen, albumin

• If ↑ conj bili; U/A and cx, consider sepsis eval (blood cx and LP, as well)

• Persistent hyperbili (>3 wk): Tbili/Dbili review thyroid & galactosemia screen results, eval infant for clinical evidence of hypothyroidism

• Can use online calculators using Bhutani nomogram; www.bilitool.org

Rx of Unconjugated Hyperbili (N Engl J Med 2008;358:920; Pediatrics 2004;114:297)

• Phototherapy (PTX): Light in blue–green spectrum (wavelength 430–490 nm) convert unconj bili to more water-soluble form excreted in bile and urine w/o conjugation

• Congenital or family history of porphyria is absolute contraindication to PTX

• If bili does not fall or continues to rise despite PTX, hemolysis is likely

• Serum albumin <3 lowers threshold to start PTX

• Can stop PTX when bili is <13–14 mg/dL

• No need to delay discharge to check rebound bilirubin level (J Pediatr 1998;133:705; Arch Pediatr Adolesc Med 2002;156:669). Check 24 hr after d/c in cases of hemolytic dz, prematurity, or PTX started <72 hr of life (Arch Dis 2006;91:31)

Guidelines for Phototherapy in Hospitalized Infants ≥35 Wk (AAP Guidelines 2004)

• Exchange transfusion: Removes bilirubin and damaged erythrocytes from circulation

• Reaching exchange transfusion levels (bili ≥25 mg/dL) is a medical emergency

• In isoimmune hemolytic dz, may avoid exchange transfusion rx w/ IVIG (0.5–1 g/kg over 2 hr), should give if bili is rising despite intensive PTX or if bili level is w/i

2–3 mg/dL of the appropriate exchange level (see below), can repeat dose in 12 hr

• Immediate exchange transfusion if bili >5 mg/dL above these lines or infant has ABE, also if bili reaches these levels despite intensive PTX

• Consider exchange if T bili remains above exchange level after 6 hr of intensive PTX

• Can calculate “bilirubin/albumin” ratio to help determine need for exchange transfusion along w/ other risk factors

• Infants ≥38 wk: 8; if higher then concerning

• Infants 35–37.9 wk and well, or ≥38 wk if higher risk or hemolytic dz: 7.2

• Infants 35–37.9 wk and higher risk, or hemolytic disease: 6.8

Guidelines for Exchange Transfusion in Infants ≥35 Wk (AAP Guidelines 2004)

• Pharmacology

• Phenobarbital and ursodeoxycholic acid lower bili levels by facilitating bile flow

• Tin-mesoporphyrin – inhibits production of heme oxygenase (not FDA approved)


See GI section.