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

Breast Milk Jaundice

Lack of volume
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

28 31 6/7

< 28

* 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:
Cholelithiasis
Cystic fibrosis
Hypothyroidism
Rotors Syndrome
Dubin-Johnson Syndrome
Storage diseases (Niemann-Pick, Guachers)
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

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