Neonatal hyperbilirubinemia

JFK pediatric core curriculum

MGH Center for Global Health
Pediatric Global Health Leadership Fellowship
Credits:
Brett Nelson, MD, MPH
Rachel Siegel, MD
Susan OBrien, 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
diphosphogluconurate
glucuronosyltransferase (UGT) catalyzes
conjugation of bilirubin with glucuronic acid
Conjugated bilirubin is now more water
soluble and can be excreted in bile (and
urine)

Bilirubin pathophysiology

Epidemiology: neonatal jaundice

Neonatal jaundice is quite common
>50% of normal newborns and
80% of preterm infants have some degree of
jaundice

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 doesnt 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

VS.
Conjugated / direct hyperbilirubinemia:
Injury at the level of the hepatocytes, or post-hepatic
obstruction
Consider diagnosis of conjugated hyperbilirubinemia
if direct bilirubin is >3mg/dL, or is >10% of total
bilirubin

Non-physiologic jaundice
Early jaundice
Starts on first day of life

Jaundice of long duration

>14 days in term or >21 days in preterm
infants

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
Cephalohematoma
Polycythemia

Infection
Hypothyroidism
Gilberts

Occurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by
temporary switch to formula)

Hemolysis

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

Crigler-Najjars

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 Rotors 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

mg/dl
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
assessment
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
Infection
G6PD deficiency
Polycythemia
Male gender

Nutritional:
Breastfeeding
Weight loss
Decreased feeding
frequency
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
>20%)
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
babies
Scleral icterus may be more
sensitive marker but is a later
sign
High level of suspicion is
required!

Phototherapy
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
2004;114:297-316)

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

Treatment:

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
jaundice

Conclusion
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
hyperbilirubinemia