1. Neonatal Hyperbilirubinemia
CHO NICU Lecture
Prepared by A D’Harlingue MD

2. Objectives Identify risk factors for severe hyperbilirubinemia
Understand the relationship between hyperbilirubinemia and the risk for neurologic or developmental injury
Discuss ways to screen for infants who might develop severe hyperbilirubinemia
Discuss guidelines for treatment
Identify common pitfalls and best practices in bilirubin management

3. Bilirubin production
Heme is released from hemoglobin with RBC breakdown
Heme is converted to bilirubin by the action of heme oxygenase
Hyperbilirubinemia results from excessive production or decreased elimination of bilirubin

4. Epidemiology: increased risk for neonatal jaundice
Race/gender:
Increased risk in males
Increased bilirubin production: East Asian, Native American
G6PD: Greek, East Asian, African
Genetic: history of sibling with jaundice
G6PD deficiency
gene for Gilbert’s syndrome
Spherocytosis, hexokinase, pyruvate kinase

5. Epidemiology: increased risk for neonatal jaundice
Maternal: diabetes mellitus
Increased bilirubin production rate
Correlation with macrosomia and polycythemia
Elevated beta-glucuronidase in breastmilk
Maternal drugs: epidural anesthesia (bupivacaine), oxytocin
Delayed cord clamping (polycythemia)

6. Epidemiology: increased risk for neonatal jaundice: infant factors
Prematurity
Near term infant particularly at risk
Polycythemia
Breast feeding
Caloric deprivation, postnatal weight loss
increased enterohepatic circulation
Delayed passage of meconium

7. Epidemiology: increased risk for neonatal jaundice: infant factors
Isoimmune hemolysis: Rh ,ABO, others
Non-isoimmune hemolysis: infection, drugs, T-antigen exposure, coagulopathy, RBC enzyme deficiencies (G6PD, PK, HK)
Hemorrhage: cephalohematomas, intracranial bleeding, bruising
Infection: sepsis, UTI
Endocrine: hypothyroidism, hypopituitarism, adrenal insufficiency

8. Epidemiology: increased risk for neonatal jaundice
Environmental factors:
Phenolic detergents
Naphthaline (moth balls)
Short hospital stay
Failure to detect significant jaundice
Failure to establish breastfeeding

9. What is a normal physiologic serum bilirubin?
Dennery et al. NEJM 2001: average peak bilirubin in term newborn, 5-6 mg/dL
Breast fed infants are on average about 2 mg/dL higher than bottle fed infants in the first days of life.
Racial differences
Greek, Asian, Navajo at higher risk

10. How should non-physiologic jaundice be defined?
Collaborative Perinatal Project ( ) and Maisels (1986): upper limit of physiologic jaundice (95%) 12.9 mg/dL
Kaiser (1997): 95%-ile 17.5 mg/dL
Multicentered international study (Natus, 1998): 95%-ile 15.5 mg/dL, 2 SD 17 mg/dL at 96 hours
Bhutani. Pediatrics 1999; 103:6
Post discharge: 95th percentile 17.5 mg/dL
predictive curves for severe hyperbilirubinemia

11. Why worry about bilirubin?
Vast majority of patients are asymptomatic except for jaundice
Classic kernicterus is relatively infrequent
Aggressive approach to bilirubin management in the 1970s was followed by a less aggressive approach in the 1980s
Bilirubin 20 mg/dL = Vigintiphobia
Watchko JF, Oski FA. Pediatrics 1983;71:660

12. Why the increase in kernicterus in the late 80s-90s?
Increase in breastfeeding
Trend towards earlier discharge of mothers and newborns
Less aggressive approach to jaundice led to an increase in severe hyperbilirubinemia
Increase in bilirubin encephalopathy and kernicterus

13. Bilirubin injury to the brain
Bilirubin encephalopathy:
Acute reversible changes
Acute irreversible changes
Kernicterus (yellow staining of the brain)
Neurodevelopmental sequelae

14. Clinical features of kernicterus
Acute form:
Phase 1 (first 1-2 days): poor suck, stupor, hypotonia, seizures
Phase 2 (mid 1st week): hypertonia of extensor muscles, opisthotonus, retrocollis, fever
Phase 3 (after 1st week): hypertonia
Chronic form:
First year: hypertonia, active DTRs, obligatory tonic neck reflexes, delayed motor skills
After first year: movement disorders (choreoathetosis, ballismus, tremor), upward gaze, sensorineural hearing loss
Adapted from Dennery, et al. NEJM 2001;344:584

15. Pathology of kernicterus
Orth: described bilirubin pigmentation of the brain of infants with severe jaundice in 1875
Kernicterus: German word meaning jaundice of the nuclei
Term was coined by Christian Schmorl in 1904
Yellow staining of the brain (basal ganglia)
Neuronal swelling
Programmed death of neurons
Gliosis

16. Pathophysiology of bilirubin encephalopathy
Blood brain barrier
Hyperosmolarity opens the barrier
Hypercarbia increases bilirubin deposition in the brain
Bilirubin binding to albumin: 1:1 at the first binding site
Displacement of bilirubin from albumin: sulfa drugs, benzyl alcohol, FFA, ceftriaxone
Free bilirubin hypothesis

17. Cellular mechanisms of bilirubin toxicity
Formation of bilirubin crystals in cells
binding to cellular membranes
Decreased Na-K exchange
Cellular accumulation of water
Axonal swelling
Lowers membrane potentials, decreased action potential
Decreased amplitude and longer intervals in auditory response
Decreased phosphorylation of protein kinase

18. Cellular mechanisms of bilirubin toxicity
Decreased phosphorylation of synapsone 1
Decreased tyrosine uptake and dopamine synthesis in dopaminergic striatal synaptosomes
Bilirubin induced changes in energy metabolism: 31P nuclear magnetic resonance

19. Clinical factors which increase the risk for kernicterus or bilirubin encephalopathy
Displacement of bilirubin from albumin
Duration of severe hyperbilirubinemia
Hemolysis
Prematurity
Hyperosmolarity
Hypoxemia, hyperoxemia
Hypercarbia
Acidosis
Sepsis

20. What is a safe bilirubin level?
1 g/100 ml of albumin binds 8.3 mg /100 ml of bilirubin
Free bilirubin increases when the binding capacity to albumin is exceeded
Safe free bilirubin level (Alfors): 1.3 mcg/dL to a max of 4 mcg/dL.
This test generally not available for clinical use

21. Recent clinical reports of bilirubin encephalopathy
Penn, Stevenson, 1994: TB 50 mg/dL, E. coli sepsis, abnormal neuro exam (acutely and 4 mo), EEG and MRI.
Maisels, 1995: 6 “healthy infants” with bilirubin injury; range peak bilirubin mg/dL
MacDonald, 1995: 4 term infants with G6PD, TB mg/dL, abnormal neuro exam and seizures
Johnson, 1999: kernicterus registry (125 cases reported)
Estimated incidence of kernicterus in USA: 1:27,000-55,000
Unknown incidence of mild injury

22. Recent clinical reports of bilirubin encephalopathy
Ebbesen, 2000: 6 cases of kernicterus in Denmark. Peak TB micromole/L (31-44 mg/dL)
1 spherocytosis, 1 galactosemia, 2 ABO incompatibility
Harris, 2001: 6 term and near term infants, TB mg/dL (5/6 >30). 5/6 presented with abnormal neuro exam. 3/4 had abnormal MRI (increase T1 signal in basal ganglia). 5/6 had normal neurodevelopmental followup. One infant had CP, MR, encephalomalacia.
Ahlfors, 2003: term, TB 31.7 at 4 days, unbound bili 7.7 mcg/dL, seizures, G6PD deficiency, kernicterus at autopsy

23. Outcome of severe hyperbilirubinemia
Newman, 2003: Kaiser, Northern CA
11 newborns (1:10,000 incidence) of TB > 30 mg/dL (mean 34.9, range ). All treated with phototherapy; 5 XTX.
Normal neurologic outcome in all infants.
One infant died of SIDS, no evidence of kernicterus on autopsy.
Newman, 2006:
130 newborns: TB ; 10 newborns TB >= 30 mg/dL
Outcome at >= 2 yr in 132 bili patients compared to 419 controls
17% vs. 29% questionable or abnormal neuro findings in hyperbilirubinemia vs. control, P = 0.04
Lower cognitive scores for hyperbili pts, if direct Coombs +

24. JCAHO Sentinel Alert: April 2001
Risk factors for severe hyperbilirubinemia
Jaundice in the first 24 hours
Inadequate PO intake due to suboptimal breastfeeding
Mild prematurity: weeks
Bruising and cephalohematomas
Unrecognized hemolysis: ABO
G6PD deficiency
Genetic/ethnic factors: siblings with jaundice, East-Asian or Mediterranean descent

25. JCAHO Sentinel Alert: April 2001
Root causes identified:
Unreliability of visual assessment of jaundice
Failure to measure bilirubin before discharge or in an infant with visible jaundice in the first 24 hours
Early discharge: especially in <38 weeks GA infant
Failure to provide early f/u assessment post discharge
Failure to provide lactation support, information to parents about jaundice or poor feeding
Failure to treat appropriately

26. AAP clinical practice guideline
Management of hyperbilirubinemia in the newborn infant 35 or more weeks gestation
Pediatrics 2004;114:297
Committee consensus revision of 1994 CPG
Evidence based recommendations

27. AAP 2004 CPG: Summary recommendations
Promote breastfeeding
Nursery protocols to identify/evaluate jaundice
Jaundice in 1st 24 hr: serum or transcutaneous bilirubin
Recognize inaccuracy of visual bilirubin assessment
Interpret bilirubin based on infant age (hr)

28. AAP 2004 CPG: Summary recommendations
Higher risk: < 38 weeks and breastfed
Assessment of risk for severe hyperbilirubinemia at discharge
Parental education
Appropriate follow up based on age at discharge and risk assessment
Appropriate treatment

29. Strategies to diagnose severe hyperbilirubinemia
Predischarge assessment (bilirubinometer, serum bilirubin) with use of nomogram to predict risk
Identify risk factors: breastfeeding, <38 weeks, h/o jaundice in sib, jaundice prior to discharge home
Standardized hospital policies for screening
Procedures for followup of all newborns hr
Informational materials for parents about jaundice
Lactation support

30. Algorithm for the management of jaundice in the newborn nursery
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

31. Common pitfalls in recognition of at risk infants
Treating the near term infant (35-37 wk) like a full term infant
Poor feeding
Failure to establish breast feeding
Risk for dehydration
More prolonged jaundice with higher peak in the preterm infant

32. Best practices Promotion of breast feeding Lactation support
Weight checks
Parental education re: expected feeding, voiding, stooling patterns

33. Bilirubin measurement and interpretation: common pitfalls
Failure to measure bilirubin in a jaundiced patient, especially in the 1st 24 hr
Cephalad to caudad progression of skin color used alone to assess jaundice
Failure to interpret the bilirubin level with respect to age in hours

34. Transcutaneous bilirubin meter to screen for jaundice

35. Bhutani: hour specific serum bilirubin. Pediatrics 1999;103:6-14

36. Predictive nomograms for severe hyperbilirubinemia: Bhutani 1999
Risk for severe hyperbilirubinemia? (any subsequent bilirubin in the high risk zone, 95%)
Above 95%: 39.5%
75-95%: %
40-75%: %
Below 40%: very low (0)

37. Use of Bhutani curves to determine timing of follow up visit and/or bilirubin test (one approach)
Compare serum bilirubin or transcutaneous photometer to Bhutani curves
Above 95%: bilirubin within 24 hours
75-95%: bilirubin within 48 hours
40-75%: if risk factors present, bilirubin within 48 hours
Below 40%: usually no followup bili needed

38. Risk factors for severe hyperbilirubinemia for consideration with hour specific bilirubin
Exclusive breastfeeding: poor feeding, weight loss
Isoimmune or other hemolytic disease
Previous sibling with jaundice
Cephalohematomas or bruising
East Asian race
Lower gestational age

39. An approach to time follow-up for repeat jaundice and bilirubin evaluation based on pre-discharge bilirubin testing. Bhutani & Johnson. Journal of Perinatology (2009) 29, S61–S67

40. Laboratory evaluation of hyperbilirubinemia
Blood type and Coombs
CBC and smear, reticulocyte count
Direct bilirubin
Albumin level
G6PD
Blood culture
UA and urine culture
Check results of state screen
Thyroid studies

41. Acute management of severe hyperbilirubinemia
Phototherapy with fluorescent blue lights: maximal surface exposure and dose
Correct dehydration: no need to give extra fluids if hydration is normal
Correct acidosis (respiratory and metabolic), and hypotension
Correct hypoalbuminemia (1 g/dL of albumin binds 8.3 mg/dL bilirubin)
Augments removal of bilirubin with exchange transfusion

42. Acute management of severe hyperbilirubinemia
Avoid drugs which displace bilirubin from albumin
Sulfa drugs, ceftriaxone
IVIG for Rh or ABO isoimmunization
Reduces need for exchange transfusion by blocking Fc receptor of the hemolytic antibody
Dose: g/kg, repeat q hr as needed
May increase risk of NEC
Reduce enterohepatic circulation of bilirubin:
limited restriction of breast milk feedings
use formula feedings
Stimulate stooling: frequent feeds, glycerin suppositories
Agar, charcoal use has been reported

43. Phototherapy: pitfalls in its use
Inadequate light source
White vs. blue light
Inadequate output
Non-optimal use of lights
Amount of skin exposure
Distance of the light from the patient
Delays in starting treatment
Referral to ED vs. direct admission

44. Factors that Determine “Dose” of Phototherapy
Spectrum of light
Irradiance of light source
Design of phototherapy device
Surface area exposed to light
Distance of infant from light
Maisels: N Engl J Med 2008;358:920-8

45. Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Effect of light source and distance from the light source to the infant on average spectral irradiance
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

46. Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Relationship between average spectral irradiance and decrease in serum bilirubin concentration
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

47. Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

48. Risk factors for neurotoxicity affecting bilirubin level to start phototherapy
Immune hemolytic disease
G6PD deficiency
Asphyxia
Sepsis
Acidosis
Albumin < 3.0

51. Light emitting diode phototherapy

52. When to stop phototherapy?
Term and near term infants: TB < mg/dL
Lower levels if high risk or early severe jaundice
Premature infants <35 weeks: TB <6-10 mg/dL
Cholestasis: elevated direct bilirubin
Most infants need not remain in hospital for measurement of “rebound” bilirubin
High risk infants may need f/u outpatient testing

53. Complications of phototherapy
Increase in stool water loss
Change in skin water loss is minimal
Thermal burns with inappropriate use of halogen lamps
Abrasive injuries with bili blankets in premature infants
Rare skin eruptions
Bronze baby syndrome

54. Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Guidelines for exchange transfusion in infants 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

55. Prematures: observation studies, bilirubin encephalopathy or kernicterus
Study bilirubin, mg/dL
Crosse, >18
Meyer, >18
Crosse, >22
Crosse, >22
Koch, >20
Hugh-Jones, >30
adapted from Watchko, Pediatrics 1992;90:707

56. Randomized study of exchange transfusion for hyperbilirubinemia, prematures
Patients with indirect bilirubin >18 mg/dL at >36 hours of age were randomized to exchange transfusion or observation.
Study group #kernicterus/total
Exchange, bilirubin >18 mg/dL 0/50
No exchange, bilirubin >18 mg/dL 1*/50
Not randomized, bilirubin <15 mg/dL 0/87
*peak indirect bilirubin 27.6, clinical symptoms noted at 17.7, seizures at 22.8, kernicterus noted at autopsy
Wishingrad, Pediatrics 1965;36:162

57. Exchange transfusion: criteria
Term: >= 25 mg/dL
>= 20 mg/dL, Rh disease
35-36 weeks: > 25 mg/dL
30-34 weeks: > 20 mg/dL
< 30 weeks: mg/dL
Reduce exchange level 3-5 mg/dL for seriously ill infants: sepsis, acidosis, respiratory failure
Acute symptoms of bilirubin encephalopathy

58. Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Fig 4. Guidelines for exchange transfusion in infants 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:
Copyright ©2004 American Academy of Pediatrics

59. Exchange transfusion (XTX): criteria
Immediate XTX for patients with acute bilirubin encephalopathy or TB >= 5 mg/dL above exchange level
Hospitalized patients on intensive phototherapy who cross XTX threshold
Readmitted patients who remain above XTX threshold despite 6 hours of phototherapy

60. Pitfalls with respect to patients near or above exchange level
Failure to provide intensive phototherapy
Exchange transfusion performed by inexperienced personnel
Failure to recognize the risks and complications of exchange transfusion

61. Complications of exchange transfusion
Vascular: thrombi, air embolism
Metabolic: hypocalcemia, hypoglycemia
Hematologic: hemolysis, thrombocytopenia, anemia, coagulopathy
Infectious: blood exposure and vascular device related
Mortality: <= 1%
Other: NEC

62. Patients who might need XTX: Best Practices
Prompt recognition of severe hyperbilirubinemia
Intensive phototherapy
Expanded laboratory evaluation: serum albumin, G6PD, blood gas
Blood bank sets up blood for exchange transfusion
Vascular access
Timely referral to a NICU with experienced staff in XTX

63. Discharge and follow up issues
“Rebound” bilirubin testing
Hearing testing

64. Final take home messages
Screen all newborns prior to discharge
Bilirubin photometer vs. measured bilirubin in lab
Risk assessment
Appropriate outpatient bilirubin assessment of at risk infants
Beware of the mildly premature infant (35-37 wk)
Use effective (intensive) phototherapy (blue light)
Parental education about bilirubin
Lactation support