How to diagonose , appraoch and management of NNH

1. Approach to a child with
Neonatal
Hyperbillirubinemia
Dr. Amit Anand
PG 2nd Year
Moderator: Dr. Pallavi Sharma

2. Definition: Hyperbilirubinemia
refers, excessive level of bilirubin in
the blood.
Characterized by jaundice, a
yellowish discoloration of the skin,
sclera, mucous membranes and
nails.

3. Visible form of
bilirubinemia
Newborn skin >5mg
/dl
Adult sclera >2mg / dl

4. Jaundice more common in
newborn
INCIDENCE:
Full term infants: at least 60%.
Preterm infants: over 80%.
6-10% require phototherapy/
other therapeutic options.

5. 1g Hb yields-34mg BR
1g Albumin binds to 8mg BR
Rate of BR production :
Neonate: 6-8mg/kg/day
Adult : 3-4 mg/kg/day
SER
(Glutathione S-transferase)

6. Conjugated bilirubin
(Direct )
•In bile
• Conjugated with
glucuronic acid
• Polar ,Water soluble ,
cannot cross B-B-B
• Excreted in urine and
stool
Unconjugated
bilirubin (Indirect )
• Bind to albumin in plasma
• Non polar ,Fat soluble
• Can cross B-B-B
(KERNICTERUS !)
• High mol wt cannot filter in
kidney
• Toxic in high level to brain

8.  Hemolytic disease is the most common
cause of hyperbilirubinemia . This includes :
• RBC disorders such as isoimmunization (e.g.,
Rh ,ABO and minor blood group
incompatibility),
• Erythrocyte biochemical abnormalities such
as G6PD or pyruvate kinase deficiencies,

9. • Abnormal erythrocyte morphology
such as hereditary spherocytosis (HS).
• Other: sepsis, sequestered blood due
to bruising or cephalohematoma, and
polycythemia

10.  a. Mutations in the gene that encodes
UGT1A1 decrease bilirubin conjugation,
reducing hepatic clearance and increasing
serum TB levels.
 b. Crigler-Najjar syndrome due to either
absent UGT activity (type I) or reduced UGT
activity (type II) results in severe
hyperbilirubinemia.

11.  c. Gilbert syndrome results from a mutation in the
promoter region of the UGT1A1 gene, reducing
production of UGT, and is the most common
inherited disorder of bilirubin glucuronidation.
 d. Polymorphisms of the organic anion transporter
protein OATP-2 may lead to severe
hyperbilirubinemia, especially when combined with
a UGT1A1 mutation.

12. e. Other Causes :
• infants of diabetic mothers
•congenital hypothyroidism,
•galactosemia,
• and other inherited metabolic disorders.

13.  Decreased enteral intake including
breastfeeding failure
 breast milk jaundice;
OR
 Impaired intestinal motility due to intestinal
atresias, meconium ileus, or Hirschsprung
disease.

14. Breast feeding jaundice Breast milk jaundice
Incidence 5-10 % of newborn 2.4 % of newborn
Etiology &
pathogenesis
Decrease intake of breast milk
leads to increased
enterohepatic circulation
Unclear although B-
glucuronidase 
deconjugate intestinal
bilirubin & promotes its
reabsorption and other
factors +nt in breast milk
that interfere BR
conjugation include
Pregnanediol , FFA
Day of appearance 2-3 days in term
3-4 days in preterm
4 to 7 days of age
Duration of jaundice Less than 3 weeks 3 – 10 weeks. Bilirubin
level may reach upto 20-
30 mg/dl
Treatment Adequate breast feeding Usually not harmful
Aggravating factors Dehydration Nil

16. a. Hemolytic disease of new born
a. Rh incompatibility
b. ABO incompatibility
b. Intra uterine infection
a. Toxoplasmosis, CMV, Rubella etc.
c. Deficiency of red cell enzyme
a. G6PD deficiency, pyruvate kinase
deficiency
d. Other: sepsis ,concealed hemorrhage
etc.

17. • PHYSIOLOGICAL JAUNDICE
• CRIGLER- NAJJAR SYNDROME
• EARLY ONSET BREASTFEEDING
JAUNDICE

18. a. Septicemia
b. EHBA
c. Breast milk jaundice
d. Metabolic causes
i. Galactosemia
ii. Tyrosinemia
iii. Hereditary fructosemia
iv. Organic acidemia

19. Increased RBC’s
(Polycythemia)
Shortened RBC lifespan
Immature hepatic
uptake &
conjugation
Increased enterohepatic
Circulation

20. • Can be aggravated & prolonged by
i. Prematurity
ii. Cephalhematoma
iii. Birth asphyxia
iv. Hypothermia
v. Breast feeding
vi. infection

21. Physiological jaundice
• Jaundice due to physiological immaturity of
neonates to handle increased bilirubin
production.
Pathological jaundice
• Jaundice is considered pathological if the
time of appearance, duration or pattern
varies significantly from that of
physiological jaundice

22. PHYSIOLOGICAL PATHOLOGICAL
Onset More than 24 hours Less than 24 hours
Duration Term - <2 wks
Preterm- <3
wks
Term - >2 wks
Preterm- >3
wks
Serum
bilirubin
concentratio
n
Raise < 0.2 mg/dl/hr or
< 5 mg/dl / day
Raise > 0.2 mg/dl/hr or >
5 mg/dl / day
Involvement of
palm and soles
No Yes
Signs of acute
bilirubin
encephalopathy
No Yes
Direct bilirubin Less than 2mg/ dl Can be more than 2 mg/dl

24.  Clinical Features: Jaundice within initial 24hrs of life
• severe anaemia,
• hepatosplenomegaly,
• hypoglycaemia,
• Hydrops fetalis,
• heart failure,
• pulmonary edema or bilateral pleural effusion
 LAB :DCT is Positive
Retic count is Increased
PBF: polychromasia with marked increase in
. . nucleated RBC
WBC count : Normal or Increased
Thromocytopenia in severe cases

25.  If there is concomitant feto-maternal
ABO incompatibility, some protection
is achieved because fetal Rh +ve
cells gets destroyed by maternal
antibodies before they get a chance
to stimulate anti-D antiobody
protection
 Prevention: Unsensitised Rh-ve
mothers should receive anti-D
immunoglobulin within 72hours of
delivery

26.  Mother – O , BABY - A/B
 IgM anti – A , anti – B doesn’t cross placenta but rarely
few mothers have IgG antibodies
 It can cause hemolysis even in 1st born infant
 NOT SEVERE AS Rh Incompatibility because
 Fetal RBC surface A and B antigens are not fully
developed during gestation and so there are a smaller
number of antigenic sites on fetal RBCs
 A , B antigen is seen in other tissues so Few
ANTIBODIES available for RBCs

28. 1. Family history
 a. A family history of jaundice, anemia, splenectomy, or early
gallbladder disease suggests hereditary hemolytic anemia
(e.g., spherocytosis, G6PD deficiency).
 b. A family history of liver disease may suggest galactosemia,
α1-antitrypsin deficiency, tyrosinosis, hypermethioninemia,
Gilbert disease, Crigler-Najjar syndrome types I and II, or
cystic fibrosis.
 c. Ethnic or geographic origin associated with
hyperbilirubinemia (East Asian, Greek, and American Indian)
 d. A sibling with jaundice or anemia may suggest blood group
incompatibility or breast milk jaundice.

29.  2. Antenatal history
 a. Illness during pregnancy may suggest congenital
viral or toxoplasmosis infection.
 b. Infants of diabetic mothers are more likely to
develop hyperbilirubinemia.
 c. Maternal drugs may interfere with bilirubin
binding to albumin, making bilirubin toxic at
relatively low levels (sulfonamides) or may trigger
hemolysis in a G6PD-deficient infant (sulfonamides,
nitrofurantoin, antimalarials).

30.  a. Birth trauma may be associated with extravascular
bleeding and hemolysis.
 b. Oxytocin use may be associated with neonatal
hyperbilirubinemia, although this is controversial.
 c. Infants with hypoxic-ischemic insult may have
elevated bilirubin levels due to intracranial
haemorrhage and inability of liver to process.
 d. Delayed cord clamping may be associated with
neonatal polycythaemia and increased bilirubin load.

31.  4. Infant history
 Delayed or infrequent passage of stool may
be caused by inadequate feeding or
intestinal obstruction and lead to increased
enterohepatic circulation of bilirubin.
 Vomiting can be due to sepsis, pyloric
stenosis, or galactosemia.

32. • Visual inspection of jaundice
1. Examine the baby in bright natural
light or white fluorescent light. No
yellow or off white background
2. Make sure the baby is naked
3. Examine blanched skin and gums
4. Note the extent of jaundice (Kramer’s
rule)
5. Depth of jaundice (degree of
yellowness)

33. 1. Forehead
2. Tip of nose
3. Chest
4. Knee
5. Palms and
soles

35. Zone 1= 5mg/dl
Zone 2 = 5-10 mg/dl
Zone 3 = 10-12
mg/dl Zone 4 =
15mg/dl Zone 5 =
>20mg/dl

36. Jaundiced infants should be examined for the following
contributing factors:
1. Lower gestational age
2. Small for gestational age (SGA) may be associated
with polycythemia and intrauterine infections.
3. Microcephaly may be associated with congenital
infections.
4. Extravascular blood bruising, cephalohematoma,
or other enclosed hemorrhage
5. Pallor associated with hemolytic anemia or
extravascular blood loss

37. 6. Petechiae may suggest congenital infection, sepsis,
or erythroblastosis.
7. Hepatosplenomegaly may be associated with
hemolytic anemia, congenital infection, or liver
disease.
8. Omphalitis or other sign of infection
9. Chorioretinitis associated with congenital infection
10. Evidence of hypothyroidism

38.  should be performed when serum TB is
≥95th percentile for age in hours or at or
near the threshold for initiation of
phototherapy.
 1. The mother's blood type, Rh, and antibody
screen
 2. The infant's blood type, Rh, and direct
Coombs test to assess for isoimmune
hemolytic disease.

39.  3. Peripheral smear for RBC morphology and
reticulocyte count to detect causes of Coombs-
negative hemolytic disease (e.g.,
spherocytosis).
 4. Hematocrit or hemoglobin measurement
will identify polycythemia or suggest blood loss
from occult hemorrhage.

40. Transcutaneus
bilirubinometry (TcB)
• Advantage:
• Reduce invasive blood test
• Disadvantage:
• Costly,
• unreliable- less than 35 weeks,
during initial 24 hr of age & TSB
more than 14mg/dl
• Measured by using multiple
wave length analysis

41. Invasive Methods:
i. Biochemical: High performance
liquid chromatography (HPLC)
ii. Micro method: Based on
spectrophotometry
End tidal CO → it identifies infants with
increased bilirubin production due to hemolytic
conditions who need closer monitoring and
earlier intervention

44. Serious jaundice:
a.Presence of visible jaundice in first
24 hour
b.Yellow palms and soles anytime
c.Signs of acute bilirubin
encephalopathy or kernicterus:
hypertonia, abnormal posturing such as
arching, retrocollis, opisthotonus or
convulsion, fever, high pitched cry)
d.TcB/TSB value more than 95 centile
as per age specific nomogram

46. 1.Infants born at gestation of 35 weeks or
more
AAP provides two age-specific nomograms-
one each for phototherapy and exchange
transfusion. The nomograms have lines for
three different risk categories of neonates :
 lower risk babies (38 wk or more and no risk
factors),
 medium risk babies (38 wk or more with risk
factors, or 35 wk to 37 wk and without any
risk factors) and
 higher risk (35 wk to 37 wk and with risk
factors)

47.  Isoimmune hemolytic disease
 G6PD deficiency
 Asphyxia,
 Lethargy
 Temperature instability
 Sepsis
 Acidosis
 Albumin <3 g/dL (if measured)

50. Gestational
Age(week)
Initiate
Phototheraphy
TSB(mg/gl)
Exchange
Transfusion
TSB(mg/dl)
<28 5-6 11-14
28-29 6-8 12-14
30-31 8-10 13-16
32-33 10-12 15-18
34 12-14 17-19

51. Purposes: reduce level of serum bilirubin and
prevent bilirubin toxicity
Modalities :
1. Phototherapy- Reduction of bilirubin levels
2. Exchange transfusion- Reduction of bilirubin
levels
3. IV IG- prevent- Lysis of RBC’s by blocking
immune mediated antibody
4. Metalloporphyrin tin/ zinc- Prevent breakdown of
Hb by inhibiting heme oxidase

53. Safe and effective method for treatment
of neonatal jaundice
Bilirubin absorbs light maximally in the
blue range (420-470 nm)

54. • Conversion of insoluble Bilirubin into
soluble bilirubin Excretion of
bilirubin
1. Photo- isomerisation
2. Structural isomerisation
3. Photo- oxidation

55. Reversible reaction.
Conversion of insoluble, toxic form Z
isomer non toxic polar (water
soluble) E isomer diffuses into
the blood  excreted easily into bile
without conjugation

56. Main Mechainism
Irreversible reaction
Bilirubin  lumirubin
Rapidly excreted in bile and urine
Mainly responsible for phototherapy
induce decline of TSB
Reduction of bilirubin directly proportional
to dose of phototherapy

57. Minor reaction
Photo-oxidation of Bilirubin to water
soluble polymers
Colourless by product
Riboflavin- catalyze the dermal
photo- oxidation

58. The most effective are characterized by the
following:
1. Light emission in the blue-green spectrum (460 to
490 nm), which includes the region (460 nm) where
bilirubin most strongly absorbs light
2. Irradiance of at least 30 μW/cm2/nm
3. Illumination of maximal body surface area
shown to decrease TB during first 4 to 6 hours of
. exposure

59.  1. Fluorescent blue light : most effectively because
they deliver light in the blue-green spectrum,
providing maximal absorption and good skin
penetration. 1500 hours , cheap but irradiance
changes with time .
 2. Blue light-emitting diodes (LEDs) - optimal high-
intensity light in the absorption spectrum of bilirubin
, 3,000 hours life span ,better than Fluorescent bulbs
. m/c used nowdays
 3. Fiberoptic blankets or pads can be placed directly
under the infant, generate little heat, but provide
lower irradiance → not in intensive PTx
 4. Halogen lights
 Usage of CFL is not recommended

61.  Best is narrow spectral blue lights (460-
490nm)
 Distance from skin – 30 to 45cm
 Intensive PT – 15-20 cm
 Shield eyes & genitalia
 Change position once in every 2-4 hrs
 Level to be checked every 10-12 hrs
 Frequent temperature monitoring &
daily weight check

63. Immediate:
i. Loose stools
ii. Dehydration
iii. Hypo or hyperthermia
iv. Rashes
v. Bronze baby syndrome
Late:
i. Risk of skin malignancies
ii. Damage to intracellular
DNA
iii. Retinal damage
iv. Testicular damage

64. 1)IVIG may act by occupying the Fc receptors on macrophages,
decreasing removal of antibody-coated red cells from the
circulation → reduces hemolysis
 0.5 to 1 g/kg IVIG can be given over 2 hours
2)Heme oxygenase inhibitors : rate limiting step
heme → biliverdin
 TIN-MESOPORPHYRIN (SNMP) for phototherapy resistant
jaundice.
 A single i/m dose on day 1 may reduce need for subsequent
phototheraphy
Phenobarbitone, clofibrate or steroids → NOT
recommended

65. • DVET should be performed if TSB level reaches to age
specific cut off for exchange transfusion or infant shows signs
of ABE irrespective of TSB levels
• The ET should be performed by pull and push technique
using umbilical venous route.
• Umbilical catheter should be inserted just enough to get free
flow of blood
• Indications- infants with Rh isoimmunnisation include:
i. Cord bilirubin 5mg/ dl or more
ii. Cord Hb 10g/ dl or less

66.  The exchange should be carried out over 45-60min
 It involves serial removal of 15-20 ml aliquots of infant
blood (in term infant & 5-10 ml in preterm), alternating
with infusion of equal volume of donor blood
 GOAL: Isovolumic exchange of approx. 2 blood volumes
of infant (2 X 80-90ml/kg) to achieve replacement of
90% fetal RBCs & 50% removal of bilirubin
 At birth, if a baby shows signs of hydrops or cardiac
decompensation in presence of low PCV
(<35%), partial exchange transfusion with 50 mL/kg of
packed cells should be done to quickly
restore oxygen carrying capacity of blood.

67. • Complications
• Hypocalcaemia and Hypomagnesaemia -
Citrate in CPD blood
• Hypoglycaemia
• Metabolic alkalosis or acidosis
• Hyperkelemia
• CVS: overload and arrhythmias
• Infections: HBV HIV
• Haemolysis
• Hypothermia, NEC.

69. • Early and frequent breast feeding
• Adequate hydration
• Administration of Anti‐D injection in
case of Rh Incompatibility

70. 1. ABE is the clinical manifestation of bilirubin
toxicity seen in the neonatal period. The clinical
presentation consists of three phases:
a)Early phase:- Signs are subtle and may include
 lethargy
 hypotonia
 high-pitched cry
 poor suck.
 Loss of moro’s reflex

71. B) Intermediate phase progresses in the
absence of intervention for
hyperbilirubinemia and is characterized by
 hypertonia of extensor muscles (rigidity,
opisthotonus, and retrocollis),
 oculogyric crisis,
 irritability,
 fever, and seizures.
 Some infants die in this phase. All infants
who survive this phase are likely to develop
chronic bilirubin encephalopathy (clinical
diagnosis of kernicterus).

73. c. Advanced phase. Signs include
 pronounced opisthotonus and retrocollis,
 cry that can be weak or shrill,
 apnea,
 Hypertonia
 seizures, and coma.
 Affected infants die from intractable
seizures or respiratory failure

74.  2. Kernicterus refers to the chronic and
permanent sequelae of bilirubin toxicity that
develop during the first year of age. Signs are as
follows:
 a. Choreoathetoid cerebral palsy with
neuromotor impairments
 b. Sensorineural hearing loss (auditory
neuropathy), characterized by abnormal BERA
with normal OAE testing
 c. Limitation of upward gaze
 d. Dental enamel dysplasia

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

76. • Definition :
• Persistence of significant jaundice for
more than 2 weeks in term
or
More than 3 weeks in preterm babies

77. Common:
i. Inadequacy of breast feeding
ii. Breast milk jaundice
iii. Cholestasis
Rare causes:
i. Hypothyroidism
ii. Criggler-Najjar syndrome
iii. GI obstruction due to
malrotation
iv. Gilbert syndrome

78. / CHOLESTASIS• Direct bilirubin level >1 mL/dL or >15% of the TB
level
• Defects in intrahepatic bile production
• Defects in transmembrane transport of bile or
mechanical obstruction to flow to flow
LAB
Abnormal LFT , Raised GGT
USG- Atresia , Choledochal cyst ,
Malformations
HIDA scan , -Hepatobiliary
scintigraphy
Liver biopsy
CLINICAL POINTERS
Pale stools
Dark Urine
Hepatomegaly, Splenomegaly

79. 1. Obstructive bile duct disorders.
 Biliary atresia : frequent cause and must be identified
promptly so that intervention (hepatoportoenterostomy)
can be performed before 2 months of age. This condition
may be associated with situs inversus, polysplenia or
asplenia, and cardiac anomalies
 Alagille syndrome :characterized by unusual facial
appearance, ocular abnormality (posterior
embryotoxon), cardiac abnormalities (pulmonic
stenosis), and vertebral anomalies (butterfly vertebrae).
Choledochal duct cysts are an uncommon but surgically
treatable cause of cholestasis.
2. Infectious causes include sepsis and urinary tract
infections as well as infections caused by numerous
viral, bacterial, and other organisms.

80.  3. Metabolic disorders include α1-antitrypsin
deficiency, cystic fibrosis, galactosemia, tyrosinemia,
galactosemia, storage diseases (Gaucher, Niemann-
Pick), Zellweger
syndrome, mitochondrial disorders, and congenital
disorders of glycosylation.

4. Immunologic disorders include gestational
alloimmune liver disease (formerly neonatal
hemochromatosis) and neonatal lupus erythematosus.

5. Endocrine disorders include hypothyroidism and
panhypopituitarism.

6. Toxic disorders. A frequent cause of cholestasis in
the NICU occurs in infants unable to take enteral
feeding who have prolonged courses of TPN
including lipid. This condition typically resolves with
introduction of enteral feedings.

81. Inherited disorders
Unconjugated
Hyperbilirubinemia
Conjugated Hyperbilirubinemia
Gilbert Syndrome Dubin-JohnsonSyndrome
Crijglar Nijjar Syndrome Rotor Syndrome

82. Dubin-Johnson
Syndrome
Rotor Syndrome
Inheritance AR AR
Defect Impaired Biliary
excretion
Impaired Biliary
excretion
Mutation MRP-2 protein
(multidrug resistene
protein)
SLCO1B1 &SLCO1B3
def of OATP1B1&
OATP1B3
Urine total
Coproporphyrine level
Normal Increased
Clinical Features Asymotomatic Jaundice
Abdominal pain and
fatigue , dark urine
Similar to Dubin-
johnoson syndrome
Oral cholecystogram GB not visualized GB visualized
Liver Biopsy Black Pigment in
hepatocyte
normal

83. • Hyperbilirubinemia is a common and potential
serious issue in neonates
• Important to recognize and diagnose early in
order to initiate prompt treatment when possible