Neonatal Hyperbilirubinemia
MELISSA NELSON, MD
NEONATAL-PERINATAL FELLOW
YALE-NEW HAVEN HOSPITAL
Lecture Objectives:
 Describe bilirubin metabolism
 Understand clinical significance of hyperbilirubinemia
 Learn diagnostic approach and further work-up
 Distinguish indirect vs. direct hyperbilirubinemia
 Develop differential diagnoses for each type
 Understand management options for each type
 Apply this knowledge to several clinical cases
Bilirubin:
 Biologically active end product of heme metabolism
Bilirubin Metabolism:
* Unconjugated bilirubin is bound to albumin in plasma (hydrophobic)
Hyperbilirubinemia:
 Imbalance of bilirubin production and elimination
 In order to clear from body must be:
 Conjugated in liver
 Excreted in bile
 Eliminated via urine and stool
Clinical Significance of Hyperbilirubinemia:
 Most common reason that
neonates need medical
attention
 “Physiologic jaundice” is a
normal phenomenon during
transition
 Becomes concerning when
levels continue to rise

Unconjugated bilirubin is
neurotoxic
Hyperbilirubinemia & Clinical Outcomes:
Deposits in
skin and
mucous
membranes
Unconjugated
bilirubin
deposits in
the brain
Permanent
neuronal
damage
JAUNDICE
ACUTE BILIRUBIN
ENCEPHALOPATHY
KERNICTERUS
Clinical Symptoms:
 Jaundice/Icterus:
 Newborn icterus notable once total bilirubin > 5-6 mg/dL
(versus older children/adults once > 2 mg/dL)
 Progresses cranially to caudally
 CAUTION: Visual assessment is subjective, inaccurate, and
dependent on observer experience!



Keren et al Visual assessment of jaundice in term and late-preterm infants (2009)
Nurses at HUP used 5 point-scale to rate cephalocaudal extent of jaundice
Showed weak correlation between predicted and actual levels
Jaundice/Icterus:
Clinical Symptoms:
 Acute Bilirubin Encephalopathy/Kernicterus:
 Irritability, jitteriness, increased high-pitched crying
 Lethargy and poor feeding
 Back arching
 Apnea
 Seizures
 Long-term: Choreoathetoid CP, upward gaze palsy, SN
hearing loss, dental dysplasia
Kernicterus:
* Bilirubin deposits typically in basal ganglia, hippocampus, substantia nigra, etc.
Diagnosis of Hyperbilirubinemia:
 Careful clinical assessment and monitoring
 Thorough history:
 Pregnancy and delivery history
 General health status and infectious risk
 Feeding method and feeding progress
 Vital signs and ins/outs (hydration status)
 Risk factors for isoimmunization
 Family history and ethnicity (ie. G6PD, spherocytosis, etc.)
 Physical exam:
 Activity level, feeding ability, bruising/hematoma, plethora
Diagnosis of Hyperbilirubinemia:
 Transcutaneous measurement:
 Use can reduce need for blood level
monitoring (Mishra et al, 2009)
 Methods exist but not at every institution

Yale: Well-baby nursery uses TcB measures at
24:00 daily
 Blood level measurement:
 Blood level monitoring per hospital
protocol



Yale: NBSCU all babies checked at 24h of life
Yale: Well-baby nursery checks once within
certain range by TcB
Measure Total and Direct Bilirubin levels

Decisions for treatment based on total serum
bilirubin (TSB)
Diagnosis of Hyperbilirubinemia:
 Frequent additional studies to obtain:
 Blood type and Rh screening of mother and infant
 DAT/Coombs testing in infant
 CBC (consider reticulocyte count, blood smear)
 Occasional additional studies to obtain:
 Albumin levels
 LFTs
 TFTs
 Imaging: Liver/GB ultrasound, HIDA scan (r/o biliary atresia)
Neonatal Hyperbilirubinemia:
 Physiologic vs. Pathologic
 Jaundice
< 24 hrs is always pathologic!
 Indirect vs. Direct (Unconjugated vs. Conjugated)
Pre-term vs. Full-term Hyperbilirubinemia:
 Pre-term infants at higher risk due to further
reduced activity of liver conjugating enzymes
 Pre-term infants can develop encephalopathy or
kernicterus at lower total bilirubin levels
Indirect Hyperbilirubinemia:
 Elevated levels of bilirubin due to imbalance in
production, transport, uptake, conjugation,
excretion, and reabsorption
 Most concerning due to risk for
encephalopathy/kernicterus if not treated rapidly
Differential Dx of Indirect Hyperbilirubinemia:
 Physiologic Jaundice
 Disorders of Production
 Disorders of Hepatic Uptake
 Disorders of Conjugation
 Other Causes
Differential Dx of Indirect Hyperbilirubinemia:
 Physiologic Jaundice:
Progressive rise in total bilirubin between 48 and 120
hours of life (peaks at 72-96 hours)
 Due to higher postnatal load of bilirubin and lower
amount of liver conjugating enzyme (UGT) activity
 Occurs in virtually every newborn to some degree

Differential Dx of Indirect Hyperbilirubinemia:
 Disorders of Production: Increased RBC destruction
 Isoimmunization:


RBC Biochemical defects:


Bruising, cephalohematomas, hemangiomas
Polycythemia:


Bacterial, viral, protozoal
Sequestration:


Spherocytosis, elliptocytosis, infantile pyknocytosis
Infection:


G6PD, pyruvate kinase deficiency
RBC Structural Abnormalities:


Rh, ABO, other component incompatibilities
IDM, delayed cord clamping
Hemoglobinopathy
Differential Dx of Indirect Hyperbilirubinemia:
 Disorders of Hepatic Uptake:
 Gilbert Syndrome
Differential Dx of Indirect Hyperbilirubinemia:
 Disorders of Conjugation:
 Crigler-Najjar Syndrome Type I
 Crigler-Najjar Syndrome Type II
 Lucey-Driscoll Syndrome (transient familial neonatal
hyperbilirubinemia)
 Hypothyroidism
Differential Dx of Indirect Hyperbilirubinemia:
 Other Causes:
 Breastfeeding Jaundice


Lack of volume
Breast Milk Jaundice
Unknown mechanism
 Possibly unidentified component in breast milk that causes
increased enterohepatic recirculation?


Infant of Diabetic Mother
Management of Indirect Hyperbilirubinemia:
 Careful assessment and monitoring



Visual assessment
Blood level monitoring per hospital
protocol at 24 hr of life or sooner as
indicated
Interpretation of risk levels and need
for treatment
Phototherapy
 IVIg (reduces need for exchange when isoimmunization)
 Exchange Transfusions
 Phenobarbital (increases hepatic glucuronosyltransferase

activity; used in severe and prolonged cases only)
Management of Indirect Hyperbilirubinemia:
Indications for Phototherapy (Term/Near-Term Infants):
* Bhutani curves (as seen in AAP recommendations and YNHH NBSCU Guidelines)
Management of Indirect Hyperbilirubinemia:
Indications for Phototherapy (Pre-Term Infants):
Gestational Age (weeks)
Total bilirubin level (mg/dL)
32 – 34 6/7
9
28 – 31 6/7
6
< 28
5
* Based on data from YNHH NBSCU Guidelines
Treatment of Indirect Hyperbilirubinemia:
 Phototherapy:
* Important factors: Spectrum, irradiance, distance, surface area
Management of Indirect Hyperbilirubinemia:
Indications for Exchange Transfusion (Term/Near-Term Infants):
* Adapted from AAP recommendations and YNHH NBSCU Guidelines
Treatment of Indirect Hyperbilirubinemia:
 Exchange Transfusion:

Double-volume exchange




2 x blood volume = 2 x 80 cc/kg =
160 cc/kg
Takes about 1-1.5 hours
Exchange at rate of ~5cc/kg/3 min
Volume withdrawn/infused based
on weight
Direct Hyperbilirubinemia:
 Considered elevated when:
 Level > 2.0 mg/dL (severe > 5.0 mg/dL)
 Level > 15% of total serum bilirubin
 Risk factors:
 Low gestational age
 Early and/or prolonged exposure to TPN
 Lack of enteral feeding
 Sepsis
 Clinical hallmarks: icterus, acholic stools, dark urine
Differential Dx of Direct Hyperbilirubinemia:
 More common causes:
 TPN-associated
 Hepatitis: Idiopathic, Infectious, Toxic
 Infection: Sepsis, TORCH, UTI
 Biliary atresia
 Inspissated bile plug
 Choledochal cyst
 Alpha-1-antitrypsin deficiency
 Galactosemia
Differential Dx of Direct Hyperbilirubinemia:
 Less common causes:



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







Cholelithiasis
Cystic fibrosis
Hypothyroidism
Rotor’s Syndrome
Dubin-Johnson Syndrome
Storage diseases (Niemann-Pick, Guacher’s)
Metabolic disorders (tyrosinemia, fructosemia)
Trisomy 21 or 18
Drug-induced
Shock
Alagille Syndrome
Zellweger Syndrome
Management of Direct Hyperbilirubinemia:
 Diagnose underlying cause:
Basic work-up: LFTs, coags, CBC, cultures
 Infectious work-up for TORCH or hepatitis
 Imaging studies (RUQ U/S, HIDA scan)
 Serum alpha-1-antitrypsin levels
 Urine-reducing substances (galactosemia)
 TFTs
 Sweat test

Treatment of Direct Hyperbilirubinemia:
 Treat underlying cause:
 TPN-associated cholestasis:
Stop TPN or at least reduce (especially lipid) and advance feeds
 “TPN-Cholestasis protocol” (remove trace elements certain days)
 Ursodiol (Actigall) and ADEKs
 Phenobarbital use controversial




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Biliary atresia with Kasai procedure +/- liver transplant
Alpha-1-antitrypsin with liver transplant
Choledochal cyst with surgical removal
Galactosemia with dietary elimination
 Supportive care if no treatment possible
Case #1:
 FT baby girl born at 40 weeks




to G1P0 mother
BW 3200 g; Apgars 9,9
Pregnancy and delivery without
complications
Currently DOL #2 (48h of life)
Nurses noted that she looks like
this and call you to the WellBaby Nursery to evaluate her:
Case #1:
 What else would you want to know?
 How is she feeding? How is it going?
 Is she stooling and voiding? How often?
 What is her current weight?
 How is she doing otherwise?
 Does she have any risk factors?
 Has she had her TcB checked?
 Has she had blood bilirubin levels checked?
Case #1:
 Her mother is breastfeeding her. She thinks it is





going well but this is her first baby and she is not
sure if her milk is in yet. She is feeding for 20
minutes every 4 hours.
Voided once and stooled several times since birth.
Current weight is 2850 g (about 11% less than BW).
She seems less active and is sleeping more today.
No known risk factors. Mother and baby are both B
positive.
Total/direct bilirubin is 18/1 mg/dL.
Case #1:
 What is your working diagnosis?
 BREASTFEEDING
JAUNDICE
Case #1:
 What would you do
next?




Initiate phototherapy
Monitor serial
bilirubin levels
Encourage increased
frequency of feedings
(q 2-3h ATC) and
consider
supplementation prn
Request lactation
consult
Bhutani Curve: Phototherapy Indication
Case #2:
 Late pre-term baby boy born at




35 weeks
BW 2500g; Apgars 8,9
Pregnancy and delivery
without complications
Currently DOL #1 (12 h of life)
Nurses noted that he looks like
this and called you into Room 1
to evaluate him:
Case #2:
 What else would you want to know?
 How is he feeding? How is it going?
 Is he stooling and voiding? How often?
 What is his current weight?
 How is he doing otherwise?
 Does he have any risk factors?
 Has he had his TcB checked?
 Has he had blood bilirubin levels checked?
Case #2:
 He is taking Neosure formula 2 ounces q 2-3 hours.
 Voided twice and stooled several times since birth.
 Current weight is 2500 g (same as BW).
 He is less active and sleeping more today.
 Mother is O positive and baby is A positive.
 Total/direct bilirubin is 18/1 mg/dL.
 Coombs positive.
Case #2:
 What is your working diagnosis?
 ABO
INCOMPATIBILITY
Case #2:
 What would you do next?

Exchange transfusion
Bhutani Curve: Phototherapy Indication
Exchange Transfusion Indication
Case #3:
 Pre-term baby boy born at 28 weeks
 Currently DOL 21
 BW 900 g; Apgars 5,8
 Noted to have scleral icterus
 Bilirubin levels 7.2/3.4 mg/dL
Case #3:
 What else would you want to know?
 Does he have any risk factors?
 How has he been acting clinically?
 Has he been receiving TPN? Any enteral feeds?
 Has he had any signs of infection?
 Does he have any syndromic features?
 What were his newborn screen results?
Case #3:
 No known risk factors.
 He has been acting well without infectious
symptoms.
 He had NEC on DOL #4 and has an ostomy and
mucous fistula. He has been on TPN since then.
 No features concerning for syndromes.
 Newborn screening results were normal.
Case #3:
 What is your working diagnosis?

TPN-ASSOCIATED CHOLESTASIS
Case #3:
 What would you do next?
 Try to advance enteral feeds and reduce TPN as soon as
clinically possible
 Start “cholestasis protocol”
 Monitor bilirubin levels with LFTs every 2 weeks
 Consider further work-up if bilirubin levels do not improve
over time once off TPN
Summary:
 Hyperbilirubinemia is a common and potential
serious issue in neonates
 Important to recognize and diagnose early in order
to initiate prompt treatment when possible
References/Further Reading:
 Yale-NHH NBSCU Guidelines: “Indications for phototherapy and
exchange transfusion”
 Lange: “Neonatology: Management, Procedures, On-Call Problems,
Diseases and Drugs”
 Fanaroff and Martin chapters on hyperbilirubinemia
 Keren R et al. Visual assessment of jaundice in term and late preterm
infants. Arch Dis Child Fetal Neonatal Ed. 2009 Sep;94(5):F31722. Epub 2009 Mar 22.
 Mishra S et al. Transcutaneous bilirubinometry reduces the need for
blood sampling in neonates with visible jaundice. Acta Paediatr.
2009 Dec;98(12):1916-9. Epub 2009 Oct 7.
 All images found on google images