Neonatal Hyperbilirubinemia

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 JAUNDICE
mucous
membranes

Unconjugated
bilirubin ACUTE BILIRUBIN
deposits in ENCEPHALOPATHY
the brain

Permanent
neuronal KERNICTERUS
damage
 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

 Exclusion criteria:
1. Jaundice appearing within the first 24 hours of life
2. TSB level >95th percentile for age in hours based on a nomogram for
hour specific serum bilirubin concentration
3. Bilirubin level increasing at rate >0,2 mg/dL/h or >5mg/dL/d
4. Direct serum bilirubin level > 1,5-2,0 mg/dL or 10-20% of the TSB
5. Jaundice persisting for >2 weeks in full term infant
 Differential Dx of Indirect Hyperbilirubinemia:

Disorders of Production: Increased RBC destruction

 Isoimmunization:
 Rh, ABO, other component incompatibilities
 RBC Biochemical defects:
 G6PD, pyruvate kinase deficiency
 RBC Structural Abnormalities:
 Spherocytosis, elliptocytosis, infantile pyknocytosis
 Infection:
 Bacterial, viral, protozoal
 Sequestration:
 Bruising, cephalohematomas, hemangiomas
 Polycythemia:
 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:

 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
 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 Well-
Baby 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

Bhutani Curve: Phototherapy Indication
next?
 Initiate phototherapy
 Monitor serial bilirubin
levels
 Encourage increased
frequency of feedings (q
2-3h ATC) and consider
supplementation prn
 Request lactation
consult
 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):F317-

22. 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