2. Jaundice and Hyperbilirubinemia in the Newborn
Dr. M.A.Fallahi
Pediatric Board degree
Shiraz Medical University

3. CONTENTS: INTRODUCTION P/E PATHOPHYSIOLOGY RISK FACTORS PREVENTION
CAUSES
DIFFERENTIAL DIAGNOSIS
TREATMENT

4. INTRODUCTION Bilirubin is the end product of heme degradation
Most of the daily production comes from the breakdown of RBCs in the RES
Heme biliverdin bilirubin
Bilirubin is released & bound to serum albumin
Bilirubin is uptake & conjugated with glucuronic acid
Finally conjugated bilirubin is excreted in bile

5. PATHOPHYSIOLOGY UNCONJUGATED B. CONJUGATED B.
Tightly compounded to s. albumin
Normally very small amount is present as albumin free
Insoluble in water can not be excreted in urine
Toxic
Non toxic
Water soluble
Loosely bound to albumin

6. Neonatal jaundice is a condition marked by high levels of bilirubin in the blood, yellowish discoloration of skin and mucous membrane, bilirubin level more than 5 mg/dl (85 µmol/lit)
Normally s. bilirubin level vary b/w 0.3 & 1.2mg/dl.
The rate of systemic bilirubin production is equal to the rate of hepatic uptake, conjugation & biliray excretion .

7. Levels as high as 30 to 40mg/dl can occur with sever disease
Jaundice occurs when the bilirubin production &clearance is disturbed by one or more of the following mechanisms:
Excessive production of bilirubin
Reduced hepatic uptake
Impaired conjugation
Decreased hepatocellular excretion
Impaired bile flow

9. Enterohepatic circulation
Uridine diphosphate glucuronyl transferase (UDPGT)
Enterohepatic circulation

10. Increased rbc’s
Shortened rbc lifespan
Immature hepatic uptake & conjugation
Increased enterohepatic
Circulation

11. Risk Factors Major Risk Factors Minor Risk factors
Decreased Risk factors

12. Major Risk Factors
Total bilirubin or transcutaneous bilirubin in the high-
risk zone.
Jaundice observed in the first 24 hours.
Blood group incompatibility with positive direct
antiglobulin test, other known hemolytic disease
Gestational age weeks.

14. Major Risk Factors Previous sibling received phototherapy
Cephalohematoma or significant bruising
Exclusive breastfeeding, particularly if nursing is
not going well and weight loss is excessive
East Asian race

15. Breast Feeding and Jaundice
Breastfeeding is considered one of the most important risk factors for hyperbilirubinemia. Exclusive breastfeeding is most strongly associated with increased risk of jaundice
Breast fed infants are 3 times more likely to have TSB >12mg/dL than formula fed infant
Bilirubin levels peak later in breastfed infants
1/3 of all breastfed infants are clinically jaundiced beyond weeks of age
Despite the increased risk, exclusive breastfeeding is still the recommended feeding choice of the AAP
Goal is to optimize breastfeeding, hydration and nutrition while observing for signs of excessive hyperbilirubinemia

16. Minor Risk Factors
Predischarge total serum bilirubin or transcutaneous
bilirubin in the high-intermediate risk zone
Gestational age weeks
Jaundice observed before discharge
Previous sibling with jaundice

17. Minor Risk Factors Macrosomic infant of a diabetic mother
Maternal age greater than or equal to 25 years
Male gender

18. Decreased Risk Factors
Total serum bilirubin or transcutaneous bilirubin in
the low-risk zone
Gestational age greater than or equal to 41 weeks
Exclusive bottle feeding

19. Decreased Risk Factors
Black race
Discharge from hospital after 72 hours of age

20. Secondary Prevention
All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screen for unusual isoimmune antibodies.
If the mother was not screened or is Rh-negative, a direct antibody test, blood type, and an Rh type on the infant’s blood is strongly recommended.

21. Secondary Prevention
Newborns should be routinely monitored for jaundice and nurseries should have established protocols for jaundice assessment.
Jaundice assessment protocols should include the conditions under which a nurse can obtain a total serum bilirubin or transcutaneous bilirubin level.

22. The important points in P/E of neonatal jaundice
Yellow skin Yellow sclera Sleepiness Poor feeding in infants Brown urine Fever High-pitch cry Vomiting

24. EXAMINATION color of skin severity of jaundice anemia liver spleen
ascites

25. Grading Extent of Jaundice

26. Grading Extent of Jaundice
Area of body Billirubin levels mg/dl (*17=umol)
Face
Upper trunk
Lower trunk & thighs
Arms and lower legs
Palms & soles > 15

27. PREDOMINANTLY DIRECT HYPERBILIRUBINEMIA
CAUSES OF JAUNDICE
PREDOMINANTLY DIRECT HYPERBILIRUBINEMIA
PREDOMINANTLY INDIRECT HYPERBILIRUBINEMIA

28. Excessive production of bilirubin
PREDOMINANTLY INDIRECT HYPERBILIRUBINEMIA
Excessive production of bilirubin
hemolytic anemia's
resorption of blood from internal hemorrhage.
ineffective erythropoiesis

29. Reduced hepatic uptake:
drugs
some cases of Gilbert syndrome

30. Impaired bilirubin conjugation:
physiologic jaundice
breast milk jaundice
genetic deficiency of glcuronosyl transferase
decreased expression of glcuronosyl transferase
diffuse hepatocellular diseases

31. Decrease excretion of conjugated bilirubin:
PREDOMINATLY DIRECT HYPERBILIRUBINEMIA
Decrease excretion of conjugated bilirubin:
deficiency in canalicular membrane transport
drug induced canalicular membrane dysfunction
hepatocelluler damage or toxicity

32. Decreased intrahepatic bile flow :
inflammatory destruction of intrahepatic bile ducts

33. Extra hepatic biliary obstruction:
gall stone obstruction of biliary tree
extra hepatic biliary atresia
biliary stricture & choledochal cyst
primary sclerosing cholangitis
liver fluke infestation
carcinoma

34. Causes of neonatal jaundice
Best classified by age of onset and duration:
Early: within 24 hrs of life
Intermediate: 2 days to 2 weeks
Late: persists for >2 weeks

35. Causes of neonatal jaundice
Early
Intermediate
Late/prolonged
Haemolytic causes:
Rh isoimmunisation
ABO incompatibility
G6PD deficiency
Congenital infection
Physiological jaundice
Breast milk jaundice (inadequate intake)
Sepsis
Haemolysis
Crigler-Najjar syndrome (glucuronyl transferase absent/reduced)
Polycythaemia, bruising
Conjugated (dark urine, pale stools):
Bile duct obstruction
Biliary atresia
Neonatal hepatitis
Unconjugated:
Physiological
Breast milk jaundice
Infection
Hypothyroidism
Blood group incompatibility:
Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia
Most severe cases - hydrops fetalis
Breast milk jaundice
Early: due to lower calorie intake (so check weight gain) and slower passage of meconium
Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation
Management: usually reassurance - do not stop breast feeding unless very severe!

36. Causes of neonatal jaundice
Early
Intermediate
Late/prolonged
Haemolytic causes:
Rh isoimmunisation
ABO incompatibility
G6PD deficiency
Congenital infection
Physiological jaundice
Breast milk jaundice (inadequate intake)
Sepsis
Haemolysis
Crigler-Najjar syndrome (glucuronyl transferase absent/reduced)
Polycythaemia, bruising
Conjugated (dark urine, pale stools):
Bile duct obstruction
Biliary atresia
Neonatal hepatitis
Unconjugated:
Physiological
Breast milk jaundice
Infection
Hypothyroidism
Blood group incompatibility:
Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia
Most severe cases - hydrops fetalis
Breast milk jaundice
Early: due to lower calorie intake (so check weight gain) and slower passage of meconium
Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation
Management: usually reassurance - do not stop breast feeding unless very severe!

37. Early jaundice Apparent before 24 hours of age Always pathological
The main cause for early jaundice is haemolysis such as:
Rhesus isoimmunisation
ABO incompatibility
G6PD deficiency

38. Investigations for early jaundice
Serum bilirubin level
Blood group
Maternal blood group
Direct coombs test
Consider G6PD level

39. Causes of neonatal jaundice
Early
Intermediate
Late/prolonged
Haemolytic causes:
Rh isoimmunisation
ABO incompatibility
G6PD deficiency
Congenital infection
Physiological jaundice
Breast milk jaundice (inadequate intake)
Sepsis
Haemolysis
Crigler-Najjar syndrome (glucuronyl transferase absent/reduced)
Polycythaemia, bruising
Conjugated (dark urine, pale stools):
Bile duct obstruction
Biliary atresia
Neonatal hepatitis
Unconjugated:
Physiological
Breast milk jaundice
Infection
Hypothyroidism
Blood group incompatibility:
Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia
Most severe cases - hydrops fetalis
Breast milk jaundice
Early: due to lower calorie intake (so check weight gain) and slower passage of meconium
Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation
Management: usually reassurance - do not stop breast feeding unless very severe!

40. Physiological jaundice
Physiological jaundice is jaundice that is present between day 2 and day 10

41. Physiological jaundice
Physiological jaundice is due to:
High bilirubin production (fetal Hb, high Hb)
Reduced bilirubin excretion (UDPGT concentrations at term are 1% of adult concentrations)

42. Physiological jaundice
Characteristics:
Appears after 24 hours
Maximum intensity by 4th-5th day in term & 7th day in preterm
Serum level less than 15 mg / dl
Clinically not detectable after 14 days
Disappears without any treatment

43. Factors that can increase the severity of physiological jaundice
Prematurity
Sepsis
Bruising
Cephalohematoma
Polycythaemia
Delayed passage of meconium
Breast feeding
Certain ethnic groups, esp Chinese

44. Breast Milk Jaundice Elevated unconjugated bilirubin
Prolongation of physiologic jaundice
66% of breastfed babies jaundiced into 3rd week of life
May persist up to 3 months
May have second peak at day 10
Average max TSB = mg/dL

45. Breast feeding Jaundice
Elevated unconjugated bilirubin
Benign or pathologic
Elevated bilirubin in the 1st week of life tends to worsen breast milk jaundice during later weeks
Equivalent to starvation jaundice in adults
No water or dextrose supplementation

46. Pathological jaundice
Appears within 24 hours of age
Increase of bilirubin > 5 mg / dl / day
Serum bilirubin > 15 mg / dl
Jaundice persisting after 14 days
Stool clay / white colored and urine staining clothes yellow
Direct bilirubin> 2 mg / dl

47. Causes of neonatal jaundice
Early
Intermediate
Late/prolonged
Haemolytic causes:
Rh isoimmunisation
ABO incompatibility
G6PD deficiency
Congenital infection
Physiological jaundice
Breast milk jaundice (inadequate intake)
Sepsis
Haemolysis
Crigler-Najjar syndrome (glucuronyl transferase absent/reduced)
Polycythaemia, bruising
Conjugated (dark urine, pale stools):
Bile duct obstruction
Biliary atresia
Neonatal hepatitis
Unconjugated:
Physiological
Breast milk jaundice
Infection
Hypothyroidism
Blood group incompatibility:
Maternal antibodies crosses placenta (IgG), reacts against RBC antigens of infant and causes haemolysis +/- anaemia
Most severe cases - hydrops fetalis
Breast milk jaundice
Early: due to lower calorie intake (so check weight gain) and slower passage of meconium
Late: due to beta-glucoronidase in milk leads to deconjugated of bilirubin in the bowel and increased enterohepatic circulation
Management: usually reassurance - do not stop breast feeding unless very severe!

48. Prolonged Jaundice
Jaundice persisting after 14 days in the term infants Or
Jaundice persisting after 21days in the preterm infant 48

49. Kernicterus The chronic form of bilirubin encephalopathy,
manifested by cerebral
palsy, auditory dysfunction, dental-enamel
dysplasia, paralysis of upward gaze, and less
often intellectual handicaps.

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

51. Mechanism of neurotoxicity in kernicterus
Bilirubin accumulates at nerve terminals
Binds to cell components
Impairs mitochondrial functions
neurotransmitter synthesis
Dysfunction and death of neurons
Bilirubin staining of affected areas
Long term clinical sequelae

52. Kernicterus: signs and symptoms
Acute Form :
Phase 1 (1-2 days):Poor suck, hypotonia, stupor and seizures
Phase 2 (middle of 1st week):hypertonia of extensor muscles, opisthotonos, retrocollis and fever
Phase 3 (after the 1st week):hypertonia

53. Chronic Form:
1st year:
hypotonia,active deep tendon reflexes, obligatory tonic neck reflexes and delayed motor skills
After 1st year:
movement disorders (choreoathetosis, ballismus, tremor), upward gaze and sensorineural hearing loss

54. Risk of Kernicterus TSB level > 25-30 mg/dl Acidosis
Increased free bilirubin
low albumin, drug displacement
Blood-brain barrier disruption
prematurity, sepsis, ischemia

55. Pathologic Jaundice Increase load: Hemolytic Disease
Features: elevated reticulocytes, decreased Hgb
Coomb’s + Rh incompatibility, ABO incompatibility
Coomb’s - G6PD, spherocytosis, pyrovate kinase deficiency

56. Non-hemolytic Disease
normal reticulocytes
Extravascular sources (cephalohematoma)
Polycythemia
Exaggerated enterohepatic circulation (CF, GI obstruction)

57. Decreased Bilirubin Conjugation
Elevated unconjugated bilirubin
Crigler-Najjar
Gilbert Syndrome
Hypothyroidism

58. Impaired Bilirubin Excretion
Elevated unconjugated and conjugated bilirubin (> 2 mg/dL or > 20% of TSB)
Biliary Obstruction
Structural defects (biliary atresia)
Genetic defects – Rotor’s & Dubin-Johnson syndromes
Infection – sepsis, TORCH
Metabolic Disorders – I.e. alpha1 antitrypsin deficiency
Chromosomal Abnormalities
Drugs – I.e. ASA, erythromycin

59. Treatment of Neonatal Jaundice
Depends on the cause and level and type of bilirubin
Unconjugated hyperbilirubinaemia:
Ensure adequate fluid intake
Phototherapy
IV immunoglobulin
Exchange transfusion
Conjugated hyperbilirubinaemia:
Ensure adequate nutrition
Treat underlying problem

60. Treatment of Indirect Hyperbilirubinemia:
Phototherapy:

61. Phototherapy
Mechanism: converts bilirubin to water soluble form that is easily excreted
Forms:
Fluorescent lighting
Fiberoptic blankets
Goal is to decrease TSB by 4-5 mg/dL or < 15 mg/dL total
Breastfed infants are slower to recover

62. Bilirubin absorbance and transmittance
Phototherapy
Phototherapy is NOT:
Ultraviolet light
Infrared light
Ultraviolet light
(10 – 400 nm)
Infrared light
(400 – 700 nm)
Spectrum of light
Blue is most effective ( nm)
Figure 3. Important Factors in the Efficacy of Phototherapy.
The absorbance spectrum of bilirubin bound to human serum albumin (white line) is shown superimposed on the spectrum of visible light. Clearly, blue light is most effective for phototherapy, but because the transmittance of skin increases with increasing wavelength, the best wavelengths to use are probably in the range of 460 to 490 nm. Term and near-term infants should be treated in a bassinet, not an incubator, to allow the light source to be brought to within 10 to 15 cm of the infant (except when halogen or tungsten lights are used), increasing irradiance and efficacy.
For intensive phototherapy, an auxiliary light source (fiber-optic pad, light-emitting diode [LED] mattress, or special blue fluorescent tubes) can be placed below the infant or bassinet. If the infant is in an incubator, the light rays should be perpendicular to the surface of the incubator in order to minimize loss of efficacy due to reflectance.
The efficacy of phototherapy depends on the irradiance (energy output) of the light source. Irradiance is measured with a radiometer or spectroradiometer in units of watts per square centimeter or in microwatts per square centimeter per nanometer over a given wavelength band.
Bilirubin absorbance
Bilirubin absorbance and transmittance
Maisels MJ et al. N Engl J Med 2008;358:920-8

63. Phototherapy Mechanism of action Technique
Skin exposure to lights causing geometric photoisomerization and bilirubin photooxidation allowing diffusion and albumin binding
Not useful in neonates with elevated conjugated bilirubin
Technique
wave length: nm
change bulbs every 2000 hours
Positioned 15-20cm above infant

64. When to start phototherapy?

65. Complications of Phototherapy
Dehydration
increased insensible water loss
loose stools
Irritability or lethargy
Skin rashes
Overheating
Retinal injury
Oxidize essential fatty acids, decreases vitamins and calcium in premature infants
Tanning/Bronze Baby Syndrome

66. 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

67. Exchange Transfusion
Mechanism: removes bilirubin and antibodies from circulation and correct anemia
Most beneficial to infants with hemolysis
Generally never used until after intensive phototherapy attempted

69. Complications: Thrombocytopenia Portal vein thrombosis/perforation
Necrotizing Enterocolitis
Cardiac arrythmias
Hypo- Calcemia, magnesemia, glycemia
HIV, Hepatitis B & C infection

73. Thanks For Your Attention