Jaundice 2019, salem cme - - Dr Karthik Nagesh

1. Dr.N.Karthik Nagesh MD,FRCPCH ( U.K.),FNNF
Neonatal Intensive Care Fellowship ( U.K.)

2. Bilirubin Encephalopathy – Classic Kernicterus

3. Bilirubin Encephalopathy
It still happens!!
Prevention is the Key!!
Dr. N Karthik Nagesh MD,FRCPCH ( U.K.), FNNF
Chairman of Neonatology & NICUs,
Chairman, Manipal Advanced Children’s Centre,
Manipal Hospitals,
Bangalore
karthik.nagesh@manipalhospitals.com

4. Estimated rates of kernicterus (per 100,000
live births)
Hyperbilirubin
emia
1.Prematurity
- yellow.
2. G6PD
deficiency -
green.
3. Hemolytic
and idiopathic
conditions-
blue
4. Rhesus (Rh)
disease -red.

5. Number of infants with major impairments due to
kernicterus as presented
1. Hearing
loss- white
bar.
2. Athetoid
cerebral
palsy-
black bar.

6. Shah Z, Chawla A, Patkar D, Pungaonkar S. MRI in kernicterus.
Australasian Radiology 2003;47:55–57

7. The syndrome of Bilirubin-induced Neurologic Dysfunction
[BIND] represents
• Spectrum of minor neurologic manifestations among
vulnerable infants who have experienced an exposure to
bilirubin of lesser degree than generally described
• Can occur in the absence of classical kernicterus
• When total serum/plasma bilirubin (TB) levels exceed an
infant's neuroprotective defenses
BIND

8. Neuroanatomical vulnerability
• Globus pallidus- Classic Kernicterus
• Other vulnerable areas- cerebellum,
hippocampus, and subthalamic nuclear bodies,
cranial nerves.
• Increased neuromotor activity level in infants
with BIND at age 18 months may be a reflection
of minor dysfunction in subcortical circuitries,
especially in the networks of the basal ganglia
and cerebellum.

9. Confounding effects include
• Prematurity,
• Hemolysis,
• Perinatal-neonatal complications,
• Altered bilirubin-albumin binding,
• Severity and duration of bilirubin exposure,
• Individual vulnerability - related to genetic factors

10. Features of BIND
1. Neuromotor signs
2. Muscle tone
abnormalities
3. Hyperexcitable
neonatal reflexes
4. Variety of
neurobehavior
manifestations
5. Speech and language
abnormalities
6. Evolving array of
central processing
abnormalities, such as
sensorineural
audiological and visuo-
motor dysfunctions.

11. BIND…Pathogenesis
Complex
interplay of
protective
factors and
factors that
increase
susceptibility.

12. Hypothesized Pathophysiologic Mechanisms in Bilirubin-Induced Neuronal
Injury.

13. Risk factors for Neonatal Jaundice

14. Model for reversible bilirubin neurotoxicity

15. Acute Bilirubin Encephalopathy (ABE)
The signs and symptoms of ABE may be
• Subtle requiring a high index of suspicion,
• Apparent with overt neurologic abnormalities.
……… Spectrum of manifestation-3 phases.

16. • Phase 1 (early ABE) manifests early usually at 3–5 days of life with
decreased alertness, poor feeding, hypotonia and weak Moro.
• Phase 2 (intermediate ABE) has variable onset and duration,
usually presenting in the 1st week but can be later with
stupor, irritability, hypertonia of extensor muscles, which may
alternate with hypotonia, opisthotonos, retrocollis and high-
pitched cry. (SOS)
• Phase 3 (advanced ABE) often presents after the
1st week and is typically characterized by hypotonia. Other
features include coma, pronator spasm of upper extremities, sun
setting eyes, inability to feed and apnea.
**Mortality may be as high as 21%, usually due to
respiratory failure or refractory seizures

17. Neonate With Features Of Advanced
Bilirubin Encephalopathy

18. Prevention of ABE and Kernicterus
Spectrum Disorders(KSD)
• An anticipatory and individualized approach with
the goal of avoiding excessive hyperbilirubinemia
is the key to preventing severe neonatal jaundice,
ABE and its subsequent progression to KSD.
• Using a systematic tiered approach, targeted
preventive strategies are essential at each level
during the assessment of newborn infants to
prevent these complications.

19. How to prevent BIND ?...
Review- Pathophysiology of Neo jaundice
Etiology
Clinical Evaluation
Management
– Phototherapy
– Exchange transfusion
– Newer therapies
Prolonged jaundice…approach

20. Neonatal Jaundice
Visible form of bilirubinemia
– Adult sclera >2mg / dl
– Newborn skin >5 mg / dl
Occurs in 60% of term and 80% of preterm
neonates
Significant jaundice occurs in 6 % of term
babies

21. Clinical assessment of
jaundice…unreliable!
Area of body Bilirubin levels
mg/dl
Face 4-8
Upper trunk 5-12
Lower trunk & thighs 8-16
Arms and lower legs 11-18
Palms & soles > 15

22. Bilirubin metabolism
Hb → globin + heme
1g Hb = 34mg bilirubin
Non – heme source
1 mg / kg
Bilirubin
glucuronidase
Bilirubin
Bilirubin
Ligandin
(Y - acceptor)
Bil glucuronide
Intestine
Bil
glucuronide
Stercobilin
bacteria
β glucuronidase

23. Why does jaundice develop?
Increased production of bilirubin
Defective conjugation
Increased entero-hepatic circulation

25. Physiological jaundice in Neonates
Characteristics
Appears between 24 to 72 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
Note: Baby should, however, be watched for worsening
jaundice

26. Teaching Aids: NNF NJ- 26
Age in Days
Term
Preterm
1 2 3 4 5 6 10 11 12 13 14
15
10
5
Bilirubin
level
mg/dl
Course of physiological jaundice

27. 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

28. Etiology of Jaundice
Increased load (Polycythemia, bleeds)
Hemolysis
– Immune vs. Non Immune
– Rh, ABO, G6PD, Membrane defects, Enzyme
defects
Defective Conjugation
– Criggler Najjar, Gilbert’s, Infections
Increased Enterohepatic Circulation
– Breast feeding, Obstruction,

29. Common causes in India
Exaggerated physiological
Blood group incompatibility – ABO,Rh
G6PD deficiency
Bruising and cephalhematoma
Intrauterine and postnatal infections
Breast milk jaundice

30. Risk factors for jaundice
JAUNDICE
J - jaundice within first 24 hrs of life
A - affected sibling jaundiced when neonate
U - unrecognized hemolysis
N – non-optimal sucking/nursing
D - deficiency of G6PD
I - infection
C – cephalhematoma /bruising
E - East Asian/North West Indian

31. Risk factors
Severe Jaundice
– Cephalhematoma
– Early gestational age
– Exclusive breastfeeding
– Weight loss >8%
BIND
– Early gestational age
– Hemolysis/G6PD
– Sepsis/Acidosis
– LBW/Albumin<3g/dl Asphyxia
SGA

32. Approach to Etiology
Age of appearance
– < 24 hours
– 24 to 72 hours
– > 72 hours

33. Causes of jaundice
Appearing within 24 hours of age
Hemolytic disease of NB : Rh, ABO
Infections: TORCH, malaria, bacterial
Appearing between 24-72 hours of life
Physiological
G6PD deficiency…Family History
Sepsis
Polycythemia
Concealed hemorrhage
Intraventricular hemorrhage
Increased entero-hepatic circulation

34. Causes of jaundice
After 72 hours of age
Sepsis
Cephalhematoma
Neonatal hepatitis
Extra-hepatic biliary atresia
Breast milk jaundice
Metabolic disorders

35. Hemolysis (immune/non-immune)
– Pallor, spleen, liver, peripheral smear, retics
– Blood groups, DCT

36. NPV and sensitivity: 100 %
PPV: 40 %
Pre-discharge TcB/TSB

37. Pre-discharge TcB or TSB
TSB at 24 + 6 hours of age > 6mg/dl
– Risk of jaundice ~ 30%,
– NPV ~ 100%
TSB Zone Newborns (%) % with TSB >95th %
High risk 6 39.5
High intermed 12.5 12.9
Low intermed 19.6 2.26
Low 61.8 0

39. Is it necessary for Pre-discharge screening
of all newborns?
What are the available approaches?

40. Universal Screening versus Targeted
approach
• Universal Screening with TSB or TcB
– Increased phototherapy rates
– Decreased readmission for jaundice
• Risk factor based approach
– As effective as screening with TcB or TSB
• Any approach only for infants with clinical
jaundice

43. TcB- Current stand
For assessment of Hyperbil use TcB as first line
– GA > 35 wks and >24 hrs
If TcB value >15 mg%: Use serum bilirubin
For subsequent measurements: TcB can be used if
photo-occlusive pad is used.
Use for prediction (pre discharge): If >75th centile, take
TSB
Use Serum Bil: GA < 35 wks, < 24hrs NICE guidelines

44. Specifically Targeted Newborns
Rh Negative and O positive mothers
G6PD endemic areas
Late preterm Infants
Babies on Exclusive Breastfeeds

45. Evaluation of the Jaundiced Infant
Severity of jaundice
– Age of appearance
– Weight and gestation
– Staining of palms and soles
– TcB or TSB
Etiology
– Hemolysis Evidence: Pallor, spleen, subgaleal,
cephal, blood groups, DCT
– IUGR, rash, petecheie, hepatosplenomegaly: TORCH
infection
– Rapid rise, affected previous sibling, north west state:
G6PD
Encephalopathy*
– Infections
– BIND
*Lethargy and poor feeding, poor or absent Moro's, opisthotonus/convulsions

46. BIND Scoring System
Condition 1 point 2 points 3 points
Mental
Status
Sleepy,
poor
feeding
Lethargy, irritability, very poor feeding Semicoma, seizures,
apnea
Muscle
Tone
Slight
decrease
Moderate hyper- or hypotonia
depending on arousal state, mild
arching, posturing, bicycling
Severe hyper- or
hypotonia,
opisthotonus, fever
Cry High-
pitched
Shrill and frequent or too infrequent Inconsolable or only
with stimulation
Total score: 1-3
points
Stage IA: minimal signs of encephalopathy
4-6
points
Stage IB: progressive, but reversible with treatment
7-9
points
Stage II: advanced, largely irreversible, but severity decreased
with treatment
Close Window
BIND Scoring

47. Workup
Maternal & Perinatal history
Physical examination
Laboratory tests (must in all)*
– Total & direct bilirubin*
– Blood group and Rh for mother and baby*
– Hematocrit, retic count and peripheral smear*
– G6PD
– Sepsis screen
– Liver and thyroid function
– TORCH titers, liver scan (conjugated)

48. Management
Rationale: reduce level of serum bilirubin
and prevent bilirubin toxicity
Preventing rise of bilirubin
– early feeds, adequate hydration
Reduction of bilirubin levels
– phototherapy, exchange transfusion, drugs

49. If a newborn requires phototherapy
which guidelines to follow
Term and Preterm ?

50. AAP charts - Phototherapy

51. Category of Jaundice and PT
1. Infants at low risk: Gestation >38 weeks and well
2. Infants at medium risk: Gestation >38 weeks and
risk factors* OR 35-37+6 weeks and well
3. Infants at low risk: Gestation 35-37+6 weeks and
risk factors*
*Isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant
lethargy, temperature instability, sepsis, acidosis or albumin <3 g/dL

52. Phototherapy/ET in Preterms
NNF Guidelines

53. J Perinatol 2012;32(9):660–4;

54. Principle of phototherapy
Native bilirubin Photo isomers of bilirubin
Insoluble Soluble
450-460nm
of light

55. Type of phototherapy
Bilirubin peak
absorption spectrum

56. Phototherapy equipment
4 to 6 blue light tubes (Phillips TL
52)/CFL/LED
Cradle or incubator
Eye shades

57. Intensive Phototherapy
Intensity atleast 30 Microwt/cm2/nm at
center of baby
Blue green Spectrum (460 to 490 nm)
As much surface area exposed as
possible

58. Intensive Phototherapy
Intensive Phototherapy
Keep the lights as close, monitor temparature

59. LED Phototherapy

60. Babies under phototherapy
CFL + BiliBlanket Fibre-Optic
phototherapy

61. LED And Super LED
CFL  LED  Super LED  intelligent
super LED
Advantages
– High irradiance
– Long shelf life
– Low power consumption (0.1W/LED)
– Environmental friendly
– Does not produce heat

62. Principles of Good Phototherapy
Irradiance
Spectrum of Light
Surface area of Exposure
Feeding of the baby

63. Side effects of phototherapy
Increased insensible water loss
Loose stools
Skin rash
Bronze baby syndrome
Hyperthermia
Upsets maternal baby interaction
May result in hypocalcemia

64. Care during Phototherapy
Frequent extra breast feeding
Turn baby after each feed
Temperature record 2 to 4 hourly
Weight record- daily
Monitor urine frequency
Monitor bilirubin level periodically

65. American Academy of Pediatrics. Management of
hyperbilirubinemia in the newborn infant 35 or more weeks of
gestation. Pediatrics. 2004;114: 297–316.

66. Bilirubin-Albumin Ratio
Unbound (free) bilirubin is expected to be a more
appropriate measure of the risk for BE than TSB.
However, it is currently not practical to assay UB
in clinical settings.
Bilirubin:albumin (B:A) molar ratio, on the other
hand,is easily assayed and has previously been
proposed as a surrogate for UB and, consequently,
CNS exposure to bilirubin.

67. Hulzebos CV, Diljk PH, van Imhoff DE, et al. The bilirubin
albumin ratio in the management of hyperbilirubinemia in preterm
infants to improve neurodevelopmental outcome: a randomized
controlled trial – BARTrial. PLoS One. 2014;9:e99466.
**

68. Choice of blood for exchange
blood transfusion
Depends on mothers blood group
– If Mother is O, Donor blood be O group
– If mother is Negative, Donor blood should be
Negative
– Other cases its Baby's blood group
Mother Baby Donor group
O +ve A –ve O -ve
B –ve A +ve A –ve
AB –ve B + ve B -ve

69. Any role for Home PT or Day Care PT?

70. At discharge
• Neurological examination
– Hypotonia
– Poor suck
– Persistent ATNR
• BERA at 1 month of age
• Development follow up till 18 months of age

71. Breastfeeding Jaundice
TSB >12 gmd/dl : 3 times higher risk
TSB>15mg/dl: 6 times higher risk

72. Breastfeeding and Jaundice

73. Jaundice in late Preterms
57% of late preterm infants have Jaundice
36% have bilirubin >15mg/dl
Mean age of onset is day 3
Risk factors
– Lower gestation
– LGA
– Birth trauma
– Previous sibling jaundice

74. Newer Therapies
Intravenous Immunoglobulins
– ABO and Rh Isoimmunization
– 1gram/kg/day for 2 days
Sn Mesoporphyrin
– Hem-oxygenase inhibitor
LED phototherapy
– Cost effective
Fiber optic phototherapy (adjunct)

75. Prolonged indirect jaundice (>14 days)
Causes
Breast milk jaundice
Hypothyroidism
Ongoing hemolysis, malaria
Pyloric stenosis
Crigler Najjar syndrome
UTI

76. Conjugated hyperbilirubinemia
Suspect
High colored urine
White or clay colored stool
Caution
Always refer to hospital for investigations so that
biliary atresia or metabolic disorders can be
diagnosed and managed early

77. Conjugated hyperbilirubinemia
Biliary causes
– Extrahepatic biliary atresia
– Choledochal cyst
– Inspissated bile syndrome
– Paucity of bile ducts (syndromic and non syndromic)
Hepatic
– Infections (TORCH, Hepatitis B, Sepsis, Malaria)
– Idiopathic neonatal hepatitis
Metabolic
– Galactosemia/Fructosemia
– Tyrosinemia
– Glycogen storage disease type IV
– Alpha-l antitrypsin deficiency
Hypothyroidism
Total parenteral nutrition

78. FILTERED SUNLIGHT FOR NEONATAL
JAUNDICE
Safe, low-tech treatment
Nigeria Study: Filtered sunlight
was efficacious on 93% of
treatment days, as compared
with 90% for conventional
phototherapy, and had a
higher mean level of irradiance
(40 vs. 17 μW/ cm2/ nm,
P<0.001)
Slusher et al. Safety and efficacy of filtered
sunlight in treatment of jaundice in African
neonates. Pediatrics. 2014; 133(6): e1568-
74.
Slusher et al. A Randomized Trial of
Phototherapy with Filtered Sunlight in African
Neonates. NEJM. 2015; 373(12): 1115-24

79. Filtered sunlight
Option in resource poor setting ?? – needs evaluation

80. Summary
Pre-Discharge TSB/TcB
TSB for preterm
Early Followup if ‘High Risk’, latePreterm,SGA,ABO,BF
AAP guidelines and Preterm guidelines
Intensive PT (LED/CFL)
Day care PT only for select babies
TSH Screening
Jaundice beyond 2 Weeks…Evaluate
Pale Coloured Stools( stools should always be yellow)
Prevent RhDisease
BIND newborns to follow up till 18 to 24 months