1. Hyperbilirubinemia SDPA Annual Conference Laurie Hogden, MD
Assistant Professor of Pediatrics, Division of Neonatology
USD- Sanford School of Medicine

2. Jaundice and the Neonate
60% of normal newborns become clinically jaundiced in the first week.
WHY?
Excessive bilirubin formation in newborns
Neonatal liver cannot clear bilirubin from the blood rapidly enough
What is the significance?
Bilirubin is potentially toxic to the central nervous system.

4. Causes of Pathologic Jaundice
Increased production of bilirubin
Blood group incompatibilities (immune mediated)
RBC enzyme deficiencies
Structural defects of RBCs
Deficiency of hepatic uptake
Impaired conjugation of bilirubin
All NBs are relatively deficient in UDP glucuronosyltransferase
Increased enterohepatic circulation

5. Risk Factors for Developing Severe Jaundice
Decreased risk
Minor risk factors
Major risk factors
TSB or TcB in low-risk zone
Gestational age ≥41 weeks
Exclusive bottle feeding
Black race
Discharge from hospital after 72 hrs
TSB or TcB in the high intermediate zone
GA weeks
Jaundice observed before discharge
Previous sibling with jaundice
Macrosomic infant of diabetic mom
Maternal age ≥ 25 years
Male
TSB or TcB in high-risk zone
Jaundice noted in first 24 hrs
Blood group incompatibility with positive DAT or hemolytic dz
GA weeks
Previous sibling required phototherapy
Cephalohematoma/bruising
Exclusive breastfeeding
East Asian race

6. Kramer, LJ. Advancement of dermal icterus in the jaundiced newborn.
Amer J Dis Child ;118:

7. Evaluating your patient
Evaluate for jaundice every 8-12 hours
Jaundice in the first 24 hours of life?
Measure transcutaneous bilirubin &/or total serum bilirubin & interpret by age in hours & risk level.
Jaundice appears excessive for infant’s age?
TSB >95th %
Evaluate cause.
Treat if criteria met by hour specific phototherapy guidelines.
Repeat bili in hours based on risk assessment.

8. Subcommittee on Hyperbilirubinemia Pediatrics 2004;114:297-316

9. Nomograms for TcB levels according to gestational age.
M. Jeffrey Maisels, and Elizabeth Kring Pediatrics 2006;117:
©2006 by American Academy of Pediatrics

10. Nomogram risk assessment
LOW
MEDIUM
HIGH
> 38 weeks gestation and well
38 weeks with risk factors OR
weeks and well
weeks with risk factors
RISK FACTORS
Isoimmune hemolytic disease
G6PD deficiency
Asphyxia
Lethargy, temp instability, sepsis
Albumin <3 g/dL

11. Guidelines for phototherapy in hospitalized infants ≥35 weeks’ gestation
M. Jeffrey Maisels et al. Pediatrics 2009;124:

12. Guidelines for exchange transfusion in infants 35 or more weeks’ gestation.
Measure transcutaneous bilirubin &/or total serum bilirubin
Subcommittee on Hyperbilirubinemia Pediatrics 2004;114:

13. Treatment Options Phototherapy Intravenous Gamma Globulin (IVIG)
Exchange transfusion

14. Sister Jean Ward, phototherapy, and jaundice: a unique human and photochemical interaction
MJ Maisels
Journal of Perinatology (2015) 35, 671–675;.
First noted that exposure to sunlight caused jaundice to fade.
In the same hospital weeks later, a sample of blood from a jaundiced infant was exposed to sunlight and had become green with a bilirubin content much lower than expected.
Dr. Richard Cremer: “It seems that we had stumbled on something that might have a practical application”!!

15. Maisels MJ, McDonagh AF. N Engl J Med 2008;358:920-928

16. Maisels MJ, McDonagh AF. N Engl J Med 2008;358:920-928.

17. Complications of phototherapy
Separation of Mom and Baby
Retinal injury
“Bronze Baby” effect
Infants with cholestasis can develop dark, grayish-brown discoloration of skin, serum and urine
Purpura/bullous eruptions
Increased melanocytic nevi?
Increased risk of childhood cancer?
Failure of closure of PDA in preterm infants?

18. IV Immune Globulin
IVIG is a plasma derived, concentrated form of IgG antibodies pooled from the donor population
IVIG has biologic activity against IMMUNE-MEDIATED hemolysis
IVIG reduces the need for exchange transfusion in Rh and ABO hemolytic disease.
Presumed to be effective in other types of Rh hemolytic disease such as anti-C and anti-E.
IVIG is recommended if TSB is rising despite intensive phototherapy or if the TSB is within 2-3mg/dL of the exchange level.
Dose: g/kg IV over 2 hours
The infusion can repeated 12 hours later. .

20. Exchange Transfusion Indications
Immediate exchange transfusion for jaundiced infants with signs of intermediate-advanced stages of acute bilirubin encephalopathy even if the TSB is falling.
Hypertonia, arching, retrocollis, opisthotonos, fever, high pitched cry
During birth hospitalization: if TSB rises to exchange level despite intensive phototherapy
For readmitted infants: if TSB is above exchange level, provide phototherapy. Consider exchange if the TSB is still above exchange level after intensive phototherapy for 6 hours.
Elevated Bilirubin/Albumin Ratio (TSB mg/dL / Albumin g/dL)
Infants ≥ 38 wks: 8
wks and well or ≥ 38 wks and high risk: 7.2
wks and high risk or hemolytic disease or G6PD def: 6.8

21. Exchange Transfusion
Double volume exchange uses modified whole blood (RBCs and plasma) cross-matched against mother and compatible with infant.
Term infant blood volume = 80ml/kg
Volume of blood needed = 160ml/kg
One or two central catheters are placed.
Small aliquots of blood are removed and replaced with aliquots of donor blood.
Electrolytes and bilirubin should be checked periodically during the procedure.

22. BIND: Bilirubin-Induced Neurologic Damage
Spectrum of subtle neurologic findings which can manifest as disorders of vision, hearing, gait, speech/language and cognition.
ACUTE Bilirubin Encephalopathy: acute neurotoxicity seen in the first weeks after birth.
3 phases
Early with subtle signs: sleepy, mild-moderate hypotonia, high pitched cry.
Intermediate phase: febrile, poor suck, lethargy or irritable/jittery, shrill cry, backward arching neck and trunk.
Advanced: apnea, poor feeding, fever, seizure, semicomatose/coma.
Kernicterus: chronic and permanent sequelae of BIND.
Choreoathetoid CP, sensorineural hearing loss, paralysis of upward gaze, dental enamel dysplasia.

23. Relationship of Albumin-Bound and Unbound Bilirubin Levels in the Vascular Space to the Entry and Clearance from the Central Nervous System (CNS).
Watchko JF, Tiribelli C. N Engl J Med 2013;369:

24. Cell Types and Metabolic Processes Affected by Bilirubin in the CNS.
Watchko JF, Tiribelli C. N Engl J Med 2013;369:

25. BIND score Scores Clinical sign Mental status 0 Normal
1 Sleepy, poor feeding
2 Lethargic, irritable, jittery
3 Unable to feed, apnea, seizures, coma
Muscle tone
0 Normal flexed tone (awake)
1 Hypertonia alternating with hypotonia
2 Neck stiffness, flexor spasm, beginning of neck and back arching, hypertonia
3 Persistent retrocollis and opisthotonos, bicycling, twitching of hands and feet, fisting, severe hypotonia with limp posture
Cry pattern
1 High pitched cry
2 Shrill cry even if intermittent
3 Weak or absent cry. Inconsolable cry
Total score Sum of highest score in each category
El Houchi SZ et al J Pediatr 2017;183:51

26. Relationship of neurologic and auditory outcomes to BIND scores
3-5 mo Neurologic AABR
follow-up findings follow -up
HIGHEST BIND
SCORES
Normal Subtle CBE Bilateral PASS REFER
BIND (0)
BIND (1-3)
BIND (4-6)
BIND (7-9)
Conclusions: BIND score is a strong predictor of neurologic sequelae. Infants with BIND score of 3-4 or greater, irrespective of TSB, should received immediate intensive phototherapy and preparations made for exchange should phototherapy fail to decrease TSB rapidly.

27. KERNICTERUS Pilot Kernicterus Registry (61 patients)
Underlying etiology:
Idiopathic: 19 patients
G6PD deficiency: 19 patients
Hemolysis (non G6PD): 10 patients
Bruising from birth trauma: 6 patients
Infection: 4 patients
Crigler-Najjar or galactosemia: 3 patients
All but one was breastfed. 16 of the patients lost >10% of birthweight at readmission.
Johnson LH et al. J Pediatr 2002;140(4):396

28. What about REBOUND?
AAP recommends discontinuing phototherapy when TSB <14 for readmitted infants, but gives no specific recommendations for the birth hospitalization.
Chang et al devised a Prediction Rule for Rebound Hyperbilirubinemia following inpatient phototherapy. (Pediatrics, March 2017).
Probability of rebound hyperbilirubinemia by score:
Score = 15 (if gestational age <38 weeks) − 7 × (age in days at phototherapy initiation) − 4 × (AAP phototherapy threshold − TSB at phototherapy termination) + 50.
Probability of rebound <10% with score <30
Probability of rebound <4% with score <20

29. Probability of rebound hyperbilirubinemia by score.
Pearl W. Chang et al. Pediatrics 2017;139:e
©2017 by American Academy of Pediatrics

30. Evolutionary considerations?
What evolutionary advantage is there for the human body to convert biliverdin (water soluble) to bilirubin and then back to a water soluble form for excretion via an energy dependent process?
Low concentrations of bilirubin may have some antioxidant benefits, suggesting it should not be completely eliminated.
Antioxidant defense in the neonate is poorly developed.
SO… should we consider hyperbilirubinemia a transitional mechanism in the neonatal circulation, whereby high bilirubin levels provide “back up” to the neonate with a weak immune system and antioxidant defense?

31. In conclusion… For every infant:
Promote and support successful breastfeeding.
Perform a systematic assessment before discharge for the risk of severe hyperbilirubinemia.
Obtain a pre-discharge screening TSB or transcutaneous bilirubin and provide early, focused follow-up based on the risk assessment.
When indicated, treat newborns with phototherapy or exchange transfusion to prevent the development of severe hyperbilirubinemia and BIND.