Neonatal hyperbilirubinemia
JFK pediatric core curriculum
MGH Center for Global Health
Pediatric Global Health Leadership Fellowship
Brett Nelson, MD, MPH
Rachel Siegel, MD
Susan O’Brien, MD
Discussion outline
• Bilirubin pathophysiology
• Physiologic and non-physiologic jaundice
• Causes of non-physiologic jaundice
– Unconjugated hyperbilirubinemia
– Conjugated hyperbilirubinemia
• Workup
• Treatment
Bilirubin pathophysiology
• Bilirubin is breakdown product of heme,
from circulating RBCs
• Carried by albumin to hepatocytes, where
processed for excretion
• In hepatocytes, uridine
glucuronosyltransferase (UGT) catalyzes
conjugation of bilirubin with glucuronic acid
• Conjugated bilirubin is now more water
soluble and can be excreted in bile (and
Bilirubin pathophysiology
Epidemiology: neonatal jaundice
• Neonatal jaundice is quite common
– >50% of normal newborns and
– 80% of preterm infants have some degree of
• Two types of neonatal jaundice:
– Normal / physiological
– Abnormal / non-physiological
Reasons for physiologic jaundice
• In term newborns, bilirubin production is 2-3
times higher than in adults
– Hematocrit of 50-60%, shorter RBC life span (90
days), and increased turnover of RBCs
• Bilirubin clearance decreased in newborns,
mainly due to deficiency of enzyme UGT
– UGT activity in term infants at 7 days is ~1% of adult
liver and doesn’t reach adult levels until 14 weeks
• Increase enterohepatic circulation of bilirubin,
further increasing bilirubin load
Greater concerns in preterm infants
• Even more RBC turnover and destruction
• Physiologically impaired conjugation and
elimination of bilirubin
– An even less mature liver
– Reduced bowel motility due to inadequate
oral intake
– Delayed elimination of meconium
– Increased enterohepatic circulation
Physiologic jaundice
Jaundice appears around 72 hrs of life
Bilirubin peaks <14 mg/dl
Direct bilirubin <10% of total bilirubin
Rate of rise <5mg/dL/day
Jaundice resolves in 1-2 weeks in term
infants, 2 weeks in preterm infants
• Otherwise the jaundice is abnormal…
Two forms of hyperbilirubinemia
• Unconjugated / indirect hyperbilirubinemia:
– Pre-hepatic cause, or impairment in conjugation
• Conjugated / direct hyperbilirubinemia:
– Injury at the level of the hepatocytes, or post-hepatic
– Consider diagnosis of conjugated hyperbilirubinemia
if direct bilirubin is >3mg/dL, or is >10% of total
Non-physiologic jaundice
• Early jaundice
– Starts on first day of life
• Jaundice of long duration
– >14 days in term or >21 days in preterm
• Deep jaundice
– Palms and soles deep yellow
– Objectively, high bilirubin lab levels
• Jaundice with fever
Differential diagnosis:
Unconjugated hyperbilirubinemia
Breastfeeding jaundice
Breast milk jaundice
ABO/Rh incompatibility
RBC membrane defects
Alpha thalassemia
G6PD deficiency
Occurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by
temporary switch to formula)
Occurs at 1-3 days of age; due to dehydration and lack of stooling (treat by increasing
feeding frequency)
impaired conjugation, associated with stress, no overt hemolysis
absent (type 1) or diminished (type 2) UDP-glucoronyl transferase
Differential diagnosis:
Conjugated hyperbilirubinemia
• Biliary atresia
– ~60% of cases; an obliterative process of bile ducts; diagnosed by U/S
or biopsy
• Infection
– Hepatitis B, TORCH
• Metabolic
– Galactosemia
– Alpha-1-antitrypsin deficiency: most common genetic cause
– Dubin Johnson or Rotor’s syndrome: defective liver secretion of bilirubin
• Iatrogenic
– Drug-mediated
– TPN-related: occurs in ~2/3 of infants given TPN over 2 weeks of
duration; unknown mechanism, possibly mediated by bacterial
endotoxins, oxidative stress, glutathione depletion
• Idiopathic
– neonatal non-infectious hepatitis (diagnosis of exclusion)
The concern: Kernicterus
• Bilirubin exceeds albuminbinding capacity, crosses BBB,
and deposits on basal ganglia
and brainstem nuclei
• Risks increase with levels >20
– Or lower levels in setting of sepsis,
meningitis, hemolysis, hypothermia,
hypoglycemia, or prematurity
Signs of kernicterus
• Acute sequelae:
– Poor suck, lethargy, hypotonia, seizure
– Then hypertonia (opisthotonus, retrocollis),
fever, high-pitched cry
• Chronic sequelae:
– Choreoathetoid CP, gaze paresis,
sensorineural hearing loss, mental retardation
Cause analysis of kernicterus
• Early discharge <48hrs without follow-up
within 48hrs
• Failure to check bilirubin level when
jaundice within 24hrs of life
• Failure to recognize risk factors
• Underestimating severity by visual
• Delay in initiating treatment
• Failure to respond to parental concerns
AAP Subcommittee on Neonatal Hyperbilirubinemia. Pediatrics 2001; 108: 763-765.
Work up: assess risk factors
• Maternal:
– Race or ethnic group
(Asian, Mediterranean)
– ABO, Rh incompatibility
– Previous jaundiced infant
– Advanced maternal age
– Diabetes
• Infant:
Gestation <38 weeks
Bruising, cephalohematoma
G6PD deficiency
Male gender
• Nutritional:
– Breastfeeding
– Weight loss
– Decreased feeding
– Decreased stooling
– Decreased urine output
Work up: laboratory studies
• Where possible, confirm clinical jaundice with
bilirubin levels
• Possible additional investigations, depending on
likely diagnoses and lab availability:
Hemoglobin/hematocrit (PCV) to look for hemolysis
Blood smear
Reticulocyte count
WBC to look for signs of infection (WBC <5, WBC>20, or I:T ratio
– Blood type of baby and mother, and Coombs test
– Syphilis serology (e.g. VDRL)
– G6PD screen, thyroid function tests, liver ultrasound
Treatment options:
Unconjugated hyperbilirubinemia
• Hydration / feeding
– Consider formula supplementation with temporary
interruption of breastfeeding
• Phototherapy… (see next slide)
• Antibiotics if suspected infection
• Antimalarials if fever and positive smear
• (Exchange transfusion)
• (IVIG in immune-mediated red cell destruction)
Diagnosis of jaundice can be
very difficult in dark-skinned
Scleral icterus may be more
sensitive marker but is a later
High level of suspicion is
• Clinical indications1:
– Jaundice on day 1
– Jaundice in premature infant
– Deep jaundice involving palms and soles
of the feet
• Laboratory indications:
– In full-term infants, bilirubin levels per
Bhutani curves
– In premature infants, when bilirubin level
≥5x weight (e.g. threshold for 3kg
newborn = 3kg x 5 = 15mg/dl)
1. Pocket Book of Hospital Care for Children. WHO. 2005.
Bhutani curve: identifying risk
Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age with
birth weight of 2000 g or more or 35 or more weeks' gestational age and birth weight of 2500 g or more
based on the hour-specific serum bilirubin values. (Subcommittee on Hyperbilirubinemia, Pediatrics
Bhutani curve: phototherapy
Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation.
(Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316)
WHO guidelines: phototherapy
Pocket Book of Hospital Care for Children. WHO. 2005.
Key points regarding treatment:
• Bilirubin levels above 20 are an emergency that
need to be treated emergently
• Multiple unit phototherapy, up to 6-8 lights, if
they are available, can and should be used
• If bilirubin is high, need to provide multi-unit
therapy, encouragement of frequent feeding and
possibly IV fluids as well
Conjugated hyperbilirubinemia
• Phototherapy is contraindicated
• Treat underlying cause
• Phenobarbital
– increases conjugation and excretion of bilirubin;
however, could affect cognitive development,
therefore used cautiously
• Ursodiol
– increases biliary flow and improves cholestatic
• Neonatal jaundice is a very common condition
• Important to prevent kernicterus
• Pathologic jaundice is early, deep, quickly
progressing, or of long duration
• Assess jaundice through identifying risk factors
and laboratory analysis
• Bhutani curves guide phototherapy treatment for
unconjugated hyperbilirubinemia
• Treat underlying cause of conjugated
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