1. Neonatal Hyperbilirubinemia
MELISSA NELSON, MD
NEONATAL-PERINATAL FELLOW
YALE-NEW HAVEN HOSPITAL

2. 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

3. Bilirubin:
Biologically active end product of heme metabolism

4. Bilirubin Metabolism:
* Unconjugated bilirubin is bound to albumin in plasma (hydrophobic)

5. 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

6. 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

7. Hyperbilirubinemia & Clinical Outcomes:
Deposits in skin and mucous membranes
Unconjugated bilirubin deposits in the brain
Permanent neuronal damage
JAUNDICE
ACUTE BILIRUBIN ENCEPHALOPATHY
KERNICTERUS

8. 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

9. Jaundice/Icterus:

10. 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

11. Kernicterus:
* Bilirubin deposits typically in basal ganglia, hippocampus, substantia nigra, etc.

12. 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

13. 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)

14. 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)

15. Neonatal Hyperbilirubinemia:
Physiologic vs. Pathologic
Jaundice < 24 hrs is always pathologic!
Indirect vs. Direct (Unconjugated vs. Conjugated)

16. 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

17. 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

18. Differential Dx of Indirect Hyperbilirubinemia:
Physiologic Jaundice
Disorders of Production
Disorders of Hepatic Uptake
Disorders of Conjugation
Other Causes

19. Differential Dx of Indirect Hyperbilirubinemia:
Physiologic Jaundice:
Progressive rise in total bilirubin between 48 and 120 hours of life (peaks at 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

20. 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

21. Differential Dx of Indirect Hyperbilirubinemia:
Disorders of Hepatic Uptake:
Gilbert Syndrome

22. 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

23. 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

24. 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)

25. Management of Indirect Hyperbilirubinemia:
Indications for Phototherapy (Term/Near-Term Infants):
* Bhutani curves (as seen in AAP recommendations and YNHH NBSCU Guidelines)

26. 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

27. Treatment of Indirect Hyperbilirubinemia:
Phototherapy:
* Important factors: Spectrum, irradiance, distance, surface area

28. Management of Indirect Hyperbilirubinemia:
Indications for Exchange Transfusion (Term/Near-Term Infants):
* Adapted from AAP recommendations and YNHH NBSCU Guidelines

29. Treatment of Indirect Hyperbilirubinemia:
Exchange Transfusion:
Double-volume exchange
2 x blood volume = 2 x 80 cc/kg = 160 cc/kg
Takes about hours
Exchange at rate of ~5cc/kg/3 min
Volume withdrawn/infused based on weight

30. 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

31. 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

32. 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

33. 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

34. 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

35. 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:

36. 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?

37. 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.

38. What is your working diagnosis?
Case #1:
What is your working diagnosis?
BREASTFEEDING JAUNDICE

39. 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

40. 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:

41. 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?

42. 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.

43. What is your working diagnosis?
Case #2:
What is your working diagnosis?
ABO INCOMPATIBILITY

44. Case #2: What would you do next? Exchange transfusion
Bhutani Curve: Phototherapy Indication
Exchange Transfusion Indication

45. 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

46. What else would you want to know?
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?

47. 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.

48. Case #3:
What is your working diagnosis?
TPN-ASSOCIATED CHOLESTASIS

49. 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

50. 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

51. 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 Sep;94(5):F Epub 2009 Mar 22.
Mishra S et al. Transcutaneous bilirubinometry reduces the need for blood sampling in neonates with visible jaundice. Acta Paediatr Dec;98(12): Epub 2009 Oct 7.
All images found on google images