1. 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 O’Brien, MD

2. Discussion outline Bilirubin pathophysiology
Physiologic and non-physiologic jaundice
Causes of non-physiologic jaundice
Unconjugated hyperbilirubinemia
Conjugated hyperbilirubinemia
Workup
Treatment

3. 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)

4. Bilirubin pathophysiology

5. 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

6. 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

7. 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

8. 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…

9. 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

10. 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

11. Differential diagnosis: Unconjugated hyperbilirubinemia
Breastfeeding jaundice
Occurs at 1-3 days of age; due to dehydration and lack of stooling (treat by increasing feeding frequency)
Breast milk jaundice
Occurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by temporary switch to formula)
Hemolysis
ABO/Rh incompatibility
RBC membrane defects
Alpha thalassemia
G6PD deficiency
Cephalohematoma
Polycythemia
Infection
Hypothyroidism
Gilbert’s
impaired conjugation, associated with stress, no overt hemolysis
Crigler-Najjar’s
absent (type 1) or diminished (type 2) UDP-glucoronyl transferase

12. 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)

13. The concern: Kernicterus
Bilirubin exceeds albumin-binding 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
Kernicterus is yellow staining of the basal ganglia and brainstem nuclei.
Bilirubin encephalopathy is the clinical term to describe the condition that results from accumulation of bilirubin in the brain.
Acute phase: infant is severely jaundiced, has a poor suck, lethargy, hypotonia
If not treated, the infant may become hypertonic (opisthotonus, retrocollis), develop a fever and a high pitched cry.
The chronic form: includes choreoathetoid cerebral palsy, upward gaze paresis, hearing loss, and mental retardation.
Kernicterus is a devastating usually completely preventable effect of severe hyperbilirubinemia.

14. Signs of kernicterus Acute sequelae: Chronic 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

15. 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
A root cause analysis of these recent cases identified the following concerns:
Early d/c <48 hrs with no f/u within 48 hrs of d/c.
Failure to respond to parental concerns regarding jaundice, poor feeding or lethargy.
AAP Subcommittee on Neonatal Hyperbilirubinemia. Pediatrics 2001; 108:

16. 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
These are some of the common maternal clinical risk factors:
East Asian, Native American, Mediteranean
Black infants have lower bilirubin levels than white infants but both peak at about 5-6 mg/dl on the 3rd day of life.
Asian infants peak on the 4th or fifth day of life at mean levels of 9-12 mg/dl and sustain higher bilirubin levels for longer period of time..
Mechanism is not clear but may be due to an increase in bilirubin production or enterohepatic circulation rates in Asian infants.
And these are some common infant risk factors
G6PD Deficiency occurs in 11%- to 13% of blacks and is more common among immigrants from the Mediterranean countries and Southeast Asia. It has been associated with kernicterus. Screening of G6PD Deficiency is not routinely performed in most hospitals. (other enzyme, RBC structural defects)
(Genetics- Less common- Gilbert’s disease, Crigler-Najaar)
Examine infants in well lit area.
Look for bruising, cephalohematomas, petechiae, hepatosplenomegaly and other signs of sepsis.
Don’t get bili’s on babies who aren’t jaundiced.
Normal bili= 5-6 mg/dl
Clinical jaundice appears when the serum bilirubin levels reach >7 mg/dl.
Breastfeeding infants who aren’t feeding well have low levels of intestinal bacteria that are capable of converting bilirubin to to it’s non-resorbable form increases enterohepatic circulation
ALSO, WHEN DECIDING WHETHER TO TREAT OR DISCHARGE, CONSIDER SOCIAL RISK FACTORS:
Parity
Maternal age
Access to medical care
Phone
Language
Maternal depression
Single parent
Overwhelmed household
need to be considered in planning whether or not to send a family home and in deciding how much support they will require.

17. 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
Additional laboratories:
Reticulocyte to evaluate degree of hemolysis
consider G6PD screen
Once starting:
We follow bilirubin values at hour intervals.
Frequent feeds
Maintain hydration and nutrition
Keep parents informed
Document
Consider stopping when:
underlying issues are under control
bili trend indicates rebound would be lower than that which requires phototherapy
So, it seems straightforward but for many infants the question of who should get phototherapy and for how long still leaves a lot of clinicians biting their fingernails.

18. 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)

19. 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!

20. Phototherapy Clinical indications1: Laboratory indications:
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

21. Bhutani curve: identifying risk
Another excellent resource resource we use for guidance in treatment decision-making is a percentile-based bilirubin nomogram developed by Bhutani and published in Pediatrics in 1999.
This normogram was developed using:
13,000 term and near term infants > 36 weeks
no risk factors for hyperbilirubinemia
TSB pre-discharge at hours of life at the time of routine metabolic screening
Racially diverse
60% were breastfed
Follow-up TSB was obtained 2-4 days after discharge to determine the probability of subsequent, moderately severe hyperbilirubinemia (>17 mg/dl)
(F/U on 2976/13,000)
Using the nomogram, newborns can be designated as
high risk (serum bilirubin concentrations >95 %ile)
high or low intermediate risk
and low risk (serum bilirubin concentrations below 40th % ile)
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: )

22. Bhutani curve: phototherapy
Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation. (Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114: )

23. WHO guidelines: phototherapy
Pocket Book of Hospital Care for Children. WHO

24. 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

25. 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

26. 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