Neonatal Hyperbilirubinemia: Julniar M Tasli Herman Bermawi Afifa Ramadanti

NEONATAL
HYPERBILIRUBINEMIA
Julniar M Tasli
Herman Bermawi
Afifa Ramadanti
Module: Neonatal 1
Hyperbilirubinemia - Session 1
Module Overview: Purpose
• To introduce to the student participants
the knowledge, competencies and skills
required to identify the etiology,
diagnose and manage both
unconjugated and conjugated
hyperbilirubinemia in full term and
preterm infants.
Module: Neonatal 2
Module Overview: Story
• Neonatal hyperbilirubinemia is an elevated serum
bilirubin level in the neonate.
• The most common type is unconjugated
hyperbilirubinemia, which is visible as jaundice in the
first week of life.
• Although 60% of babies will develop jaundice, and
most jaundice is benign, severe hyperbilirubinemia
can cause serious permanent brain damage.
• The goal of this module is to teach student to identify,
assess and manage neonatal hyperbilirubinemia.
Module: Neonatal 3
Module Overview: Learning
Objectives
Broad Outline
Student must:
• Understand the physiology of bilirubin metabolism in
the neonate, and the difference between
unconjugated and conjugated hyperbilirubinemia
• Identify neonatal hyperbilirubinemia and decide
whether it is physiological or pathological.
• Obtain an accurate history and perform a physical
examination in order to diagnose the etiology of
hyperbilirubinemia.
• Identify laboratory tests needed for investigation.
• Manage unconjugated hyperbilirubinemia
• Diagnose conjugated hyperbilirubinemia.
Module: Neonatal 4
CLINICAL JAUNDICE
• 60% of newborn
• Visible jaundice: serum bilirubin > 5 mg/ dl
Module: Neonatal 5
Neonatal Jaundice:
WHY WE WORRY
 bilirubin  bilirubin encephalopathy
Kernicterus
Stage 1: lethargy, hypotonia, poor suck
Stage 2: fever, hypertonia, opisthotonus
Stage 3: apparent improvement
Sequelae: Sensorineural hearing loss
Choreoathetoid cerebral palsy
Gaze abnormalities
Module: Neonatal 6
Kernicterus Neuropathology
yellow staining and neuronal necrosis

• basal ganglia:
globus pallidus
subthalamic nucleus
• cranial nerve nuclei:
vestibulocochlear
oculomotor
facial
• cerebellar nuclei
Module: Neonatal 7
• 1970s - KERNICTERUS ELIMINATED
• 1990s - 125 CASES OF KERNICTERUS

in the United States
• 2000s - ? Cases of kernicterus

in Indonesia
A preventable tragedy
Module: Neonatal 8
NEONATAL JAUNDICE
• Mechanism
•  Physiologic vs  Pathologic
• Non- physiologic jaundice:
differential diagnosis
• Management
Module: Neonatal 9
BILIRUBIN METABOLISM
cabolism of effete rbc Inefective erythropoiesis in bone marrow
tissue haeme & haem protein
haem oxygenase
Biliverdin
biliverdin reductase
bilirubin ( indirect )
+
serum albumin
acceptor protein
Entero
hepatic glucuronyl tr.ase
circulation
bil. Glucuronid ( direct )
( bill. glucuronide )
( )
( gluk.dase )
( )
( bil. Indirect )
( )
( )
( Module: ) Neonatal 10
( )
fecal bilirubin ( stercobilin )
Bilirubin metabolism
HEME + Globin CO
BILIVERDIN
LIVER
UCB
BILIRUBIN
Alb
Free unconjugated
Conjugated bilirubin Module: Neonatal bilirubin 11
BILIRUBIN
UNCONJUGATED CONJUGATED
• Indirect bilirubin • Direct bilirubin
• Water- insoluble • Water soluble
• Bound to albumin
for transport
• Free component • Not fat soluble
fat - soluble
• Free component • Not toxic to brain
TOXIC to brain Module: Neonatal 12
BILIRUBIN TOXICITY
Unconjugated bilirubin level

> 20 mg/ dL? >25 mg/ dl? > 30 mg/ dL?
• Gestational age
• Hemolysis
• Other illness: asphyxia, hypoglycemia,
acidosis, sepsis
• Drugs displacing bilirubin from albumin
binding sites
Module: Neonatal 13
CLINICAL JAUNDICE
• 60% of newborn
• Visible jaundice: serum bilirubin > 5 mg/ dl
Module: Neonatal 14
Why do babies have jaundice in the
first week of life?
• Increased bilirubin production
– Higher turnover of red blood cells
– Decreased life span of red blood cells
• Decreased excretion of bilirubin
– Decreased uptake in the liver
– Decreased conjugation by the liver
– Increased enterohepatic circulation of bilirubin
Bilirubin excretion improves after 1 week
Module: Neonatal 15
PHYSIOLOGICAL JAUNDICE
14
12
10
8
S.Bili mg/dl
6
4
2
0
DAY 1 DAY 3 DAY 5 DAY 7
Module: Neonatal 16
Physiological Jaundice
• Note the natural history of physiologic jaundice in the

full term newborn-
– onset after 24 hours
– peaks at 3 to 5 days
– decreases by 7 days.
• Average full term newborn has peak serum bilirubin
level of 5 to 6 mg/ dl.
• Exaggerated physiologic jaundice- when peak serum
bilirubin is 7 to 15 mg/ dl in full term neonates.
• Always consider age of the baby and bilirubin level
Module: Neonatal 17
Hour- specific bilirubin level
• Bilirubin level of 10 mg/ dl at 72 hours of age in a
term newborn is probably physiological.
• Bilirubin level of 10 mg/ dl at 10 hours of age is NOT
physiological, and needs immediate attention.
(see natural history of physiological jaundice)
Module: Neonatal 18
Serum Bilirubin levels
in term and preterm infants
16
14
12
10
Normal term
8
Preterm
6
4
2
0
day 1 day 2 day 3 day 4 day 5 day 6 day 7
Module: Neonatal 19
Jaundice in preterm neonates
• Onset earlier
• Peaks later
• Higher peak
• Takes longer to resolve- up to 2 weeks
• What level is physiologic?
Module: Neonatal 20
Physiologic vs Non- physiologic
hyperbilirubinemia
20
18
16
14
12
physiologic
10
non- physiologic
8
6
4
2
0
day 1 day 2 day 3 day 4 day 5 day 6 day 7
Module: Neonatal 21
NON- PHYSIOLOGIC JAUNDICE
• Onset before 24 hours of age

• Rate of rise > 0.5 mg/ dl/ hour
• Cutoff levels
> 15 mg/ dl in term infant?
> ? mg/ dl in preterm infant?
• Jaundice persisting
> 8 days in term infant
> 14 days in preterm infant
• Other signs of Module:
illness Neonatal 22
HYPERBILIRUBINEMIA - CAUSES
OVERPRODUCTION ( HEMOLYSIS)
• Extravascular blood- hematomas, bruises

• Feto- maternal blood group incompatibility
Rh- mom / baby Rh+
O group mom / baby A or B
• Intrinsic red cell defects
G-6-PD deficiency
hereditary spherocytosis
• Polycythemia
Module: Neonatal 23
NEONATAL JAUNDICE - case
( ref. MacDonald MG. Pediatrics 1995)
African- American male infant, birth weight 3.47kg

Normal delivery 39 w gestation
Discharged home at 24 hrs of age
Jaundice and lethargy noted at 5 days of age
LABS: Total serum bilirubin 37mg/ dL
Peripheral blood smear normal, retic count 3.6%
Mom O+, Baby O +, Coomb’s test negative
Seizures, apnea, opisthotonus during Exchange Tx
13 months of age: profound hearing loss and
hypotonia
G6PD DEFICIENCY
• X- Linked disorder (2- 6% carrier rate in Indonesia)

• enzyme protects red cell from oxidative damage
• >150 mutations
• Onset of jaundice usually day 2- 3, peaks day 4 - 5
• Hyperbilirubinemia may be out of proportion to
anemia
• microspherocytes/ bite cells/ normal blood picture
• Diagnosis- enzyme assay baby and mother
• False negative test with reticulocytosis
• DNA analysis
HYPERBILIRUBINEMIA CAUSES
UNDERSECRETION
• Prematurity
• Hypothyroidism
• Infants of diabetic mothers
• Inherited deficiency of conjugating enzyme
uridine diphosphate glucuronyl transferase
• Other metabolic disorders
Module: Neonatal 26
Secreted but reabsorbed from gut
 ENTEROHEPATIC CIRCULATION
• Decreased enteral intake
• Pyloric stenosis
• Intestinal atresia/ stenosis
• Meconium ileus
• Meconium plug
• Hirschsprung’s disease
Module: Neonatal 27
OBSTRUCTIVE DISORDERS -
direct hyperbilirubinemia
• Cholestasis
• Biliary atresia
• Choledochal cyst
# Direct bilirubin > 2 mg/ dL

# Time of appearance
# Color of stools
# Color of urine
Module: Neonatal 28
MIXED
• Bacterial sepsis
• Intrauterine infections: TORCH
• Asphyxia
Module: Neonatal 29
Hyperbilirubinemia- diagnosis
• History
• Physical exam:
– gestational age
– activity/ feeding
– level of icterus
– pallor
– hepatosplenomegaly
– bruising, cephalhematoma
Module: Neonatal 30
Rapidly developing jaundice on Day 1
Likely
– Rhesus, ABO, or other hemolytic disease
– Spherocytosis
Less likely
– Congenital infection
– G-6-P-D deficiency
Module: Neonatal 31
RHESUS INCOMPATIBILITY
MOTHER Rh (-) + FATHER Rh (+)
ANTI d ( IgG )
RBC 1st CHILD Rh (+) ……ANTI D +

2nd CHILD Rh (+) ……ANTI D ++
3rd CHILD Rh (+) ….. ANTI D +++
4th CHILD Rh (+) ….. ANTI D ++++
HAEMOLYSIS
Module: Neonatal 32
ABO INCOMPATIBILITY
Substan A
MOTHER blood group O + FATHER blood group A
Agglutinin A
( IgG )
CHILD blood group A
IgG A + Atg A HAEMOLYSIS

Module: Neonatal 33
Rapid Onset jaundice after 48 hours of age
• Likely
– Infection
– G-6-P-D deficiency
• Unlikely
– Rh, ABO, spherocytosis
Module: Neonatal 34
Hyperbilirubinemia- diagnosis
• Laboratory tests
– Bilirubin levels: total and direct
– Mother’s blood group and Rh type
– Baby’s blood group and Rh type
– Direct Coomb’s test on baby
– Hemoglobin
– Blood smear
– Reticulocyte count
Module: Neonatal 35
NEONATAL HYPERBILIRUBINEMIA
MANAGEMENT
• HYDRATION - FEEDING
• PHOTOTHERAPY
• EXCHANGE TRANSFUSION
• Phenobarbital
• Tin protoporphyrin
Module: Neonatal 36
American Academy of Pediatrics
Subcommittee on Hyperbilirubinemia
Clinical Practice Guideline

Management of Hyperbilirubinemia
in the Newborn Infant
35 or more weeks of gestation
Pediatrics July 2004
Module: Neonatal 37
Management of Hyperbilirubinemia
in the Newborn Infant
35 or more weeks of gestation
• Promote and support successful breast-feeding

• Perform a systematic assessment before discharge
for the risk of severe hyperbilirubinemia
• Provide early and focussed follow-up based on risk
assessment
• When indicated, treat newborns with phototherapy or
exchange transfusion to prevent the development of
severe jaundice and possibly, kernicterus.
Module: Neonatal 38
Feeding to Prevent and Treat
Neonatal Jaundice
Mothers should breast feed their babies

at least 8 to 12 times per day
for the first several days
•  caloric intake / dehydration  

Jaundice
• Supplementation with water or dextrose water

will not prevent prevent or treat
hyperbilirubinemia
Module: Neonatal 39
Systematic Assessment for Neonatal Jaundice
• Pregnant women - Blood group and Rh type

• If mom is Rh negative or O group: Baby’s cord blood
group/ Rh type/ DAT
• Monitor infant for jaundice at least every 8 to 12
hours
• If level of jaundice appears excessive for age,
perform transcutaneous bilirubin or total serum
bilirubin measurement
Module: Neonatal 40
Clinical assessment
of severity of
jaundice
• Cephalocaudal progression
– face 5 mg/ dl (approximately)
– upper chest 10 mg/ dl (approx)
– abdomen and upper thighs 15 mg/ dl ( approx)
– soles of feet 20 mg/ dl ( approx)
• Visual inspection may be misleading
Module: Neonatal 41
Transcutaneous Bilirubinometers
•Useful as screening device
•TcB measurement fairly accurate
in most infants with TSB< 15mg/ dL.
•Independent of age, race and weight of newborn
•Not accurate after phototherapy
Module: Neonatal 42
Assess risk factors for significant jaundice
• Blood group incompatibility with positive DAT

• Gestational age 35- 36 weeks
• Exclusive breast feeding - first time mom
• Cephalhematoma or significant bruising
• Asian race
• Previous sibling had significant jaundice
• Jaundice in the first 24 hours of life
• Predischarge bilirubin in the high risk zone
Module: Neonatal 43
Hour Specific Serum Bilirubin
Bhutani et al, Pediatrics 1999
Predictive Ability of a Predischarge Hour Specific Serum Bilirubin for

Subsequent Significant Hyperbilirubinemia in Healthy Term and Near -
term Newborns.
Serum Bilirubin levels predischarge in 13,003 babies
Serum Bilirubin levels post- discharge in 2840 babies
Racially diverse - 5% Asian
Nomogram- 95th percentile for serum bilirubin level
24 hours:  8 mg/ dl (137 M/ L)
48 hours:  14 mg/ dl (239 M/ L)
72 hours:  16 mg/ dl ( M/ L)
84 hours:  17 mg/ dl (290 M/ L)
Module: Neonatal 44
Nomogram for designation of risk based on
hour specific serum bilirubin levels at discharge
Bhutani et al., Pediatrics 1999
Module: Neonatal 45
Guidelines for phototherapy in infants 35 or more weeks gestation
American Academy of Pediatrics, July 2004
Module: Neonatal 46
PHOTOTHERAPY
NOT UV LIGHT @#$%*!
• Light wavelength 450 to 460 nm

• Blue lamps: 425 to 475 nm
• Cool white lamps: 380 to 700 nm
• Spectral irradiance: 30 W / cm2 / nm
Module: Neonatal 47
PHOTOTHERAPY
Natural unconjugated bilirubin isomer: ZZ

ZZ ZE( toxic, no conjugation need)
Photo
isomerization
ZZ lumibilirubin
Structural isomerization
ZZ photooxidation products
photooxidation
Module: Neonatal 48
Module: Neonatal 49
Measuring Adequacy of
Phototherapy
Module: Neonatal 50
Intensive Phototherapy
• Light source: daylight, cool white, blue, special
blue fluorescent tubes,tungten halogen lamps,
fiberoptic blanket, gallium nitride light emitting diode.
• Distance from light: florescent lights should be as
close as possible ( up to 10 cms from baby), halogen
lights can cause overheating
• Surface area: maximal, remove all clothes except
diaper, may remove diaper too
• Intermittent versus Continuous
• Hydration
Module: Neonatal 51
Complications of phototherapy
• Significant complications very rare
– separation of mother and baby
– increased insensible water loss and
dehydration in premature baby
– Bronze- baby syndrome (in babies with
cholestatic jaundice)
Module: Neonatal 52
What decline in serum bilirubin can
you expect with phototherapy ?
• Rate of decline depends on effectiveness of
phototherapy and underlying cause of
jaundice.
• With intensive phototherapy, the initial decline
can be 0.5 to 1.0 mg/ dl/ hour in the first 4 to
8 hours, then slower.
• With standard phototherapy, expect decrease
of 6% to 20% of the initial bilirubin level in the
first 24 hours.
Module: Neonatal 53
When should phototherapy be stopped?
• Depends on the age of the baby

• Cause of the hyperbilirubinemia
Module: Neonatal 54
EXCHANGE TRANSFUSION -
COMPLICATIONS
• cardiac failure
• metabolic- hypoglycemia, hyperkalemia,
hypocalcemia, citrate toxicity,
• air embolism
• thrombocytopenia
• bacterial sepsis
• transfusion transmitted viral disease
• necrotizing enterocolitis
• portal vein thrombosis
Mortality / permanent sequelae 1-12%
Guideline of phototherapy and exchange transfusion in low birth weight
infant
base on body weight
Total bilirubin [ mg/L ( umol/L)]
Birth weight ( gr ) Phototherapy Exchange transfusion
< 1500 5 – 8 ( 85 – 140 ) 13 – 16 ( 220 – 275 )

1500 - 1.999 8 – 12 ( 140 – 200 ) 16 – 18 ( 275 – 300 )
2000 – 2499 11 – 14 ( 190 – 240 ) 18 – 20 ( 300 – 340 )
Guideline of phototherapy and exchange transfusion in low birth weigt infant

base on gestational age
Total bilirubin [ mg/L ( umol/L)]
Gestational age Phototherapy Exchange transfusi health baby Exchane transfusion sick baby
36 14,6 ( 250 ) 17,5 ( 300 ) 20,5 ( 350 )

32 8,6 ( 150 ) 14,6 ( 250 ) 17,5 ( 300 )
28 5,8 ( 100 ) 11,7 ( 200 ) 14,6 ( 250 )
24 4,7 ( 80 ) 8,8 ( 150 ) 11,7 ( 200 )
Module: Neonatal 56
BREAST MILK JAUNDICE
25
20
15 normal
B.M. jaundice
10 BMJ- stop BM
0
day 4 day 8 day 12 day 16 day 20 day 24
Module: Neonatal 57

Neonatal Hyperbilirubinemia: Julniar M Tasli Herman Bermawi Afifa Ramadanti

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NEONATAL

yellow staining and neuronal necrosis

• 1990s - 125 CASES OF KERNICTERUS

• 2000s - ? Cases of kernicterus

Unconjugated bilirubin level

• Note the natural history of physiologic jaundice in the

• Onset before 24 hours of age

• Extravascular blood- hematomas, bruises

African- American male infant, birth weight 3.47kg

• X- Linked disorder (2- 6% carrier rate in Indonesia)

# Direct bilirubin > 2 mg/ dL

RBC 1st CHILD Rh (+) ……ANTI D +

CHILD blood group A

IgG A + Atg A HAEMOLYSIS

Clinical Practice Guideline

Pediatrics July 2004

• Promote and support successful breast-feeding

Mothers should breast feed their babies

•  caloric intake / dehydration  

• Supplementation with water or dextrose water

• Pregnant women - Blood group and Rh type

•Not accurate after phototherapy

• Blood group incompatibility with positive DAT

Predictive Ability of a Predischarge Hour Specific Serum Bilirubin for

NOT UV LIGHT @#$%*!

• Light wavelength 450 to 460 nm

• Spectral irradiance: 30 W / cm2 / nm

Natural unconjugated bilirubin isomer: ZZ

• Depends on the age of the baby

Birth weight ( gr ) Phototherapy Exchange transfusion

< 1500 5 – 8 ( 85 – 140 ) 13 – 16 ( 220 – 275 )

Guideline of phototherapy and exchange transfusion in low birth weigt infant

Total bilirubin [ mg/L ( umol/L)]

36 14,6 ( 250 ) 17,5 ( 300 ) 20,5 ( 350 )

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