NEONATAL

HYPERBILIRUBINEMIA

Presenter : DR Rakesh Dey

DM resident
Dept of Neonatology
 OVERVIEW
1.Introduction
2.Physiological and pathological hyperbilirubinemia
3.Causes of neonatal hyperbilirubinemia
4.Assessment
5.Methods of measurement of bilirubin
6.Approach to neonatal hyperbilirubinemia
7.Management
8.Complications – bilirubin toxicity
INTRODUCTION
• Hyperbilirubinemia  defined as TB >95th percentile on hour
specific Bhutani Chart. (CLOHERTY AND STARK’S MANUAL)

• In neonates Incidence -70-80-%.

• Premature babies -higher incidence ,requiring therapeutic

intervention.

• Hyperbilirubinemia -benign condition in neonates

• Severe hyperbilirubinemia (TSB >20mg/dl)- ABE , if still not

treated  kernicterus
NNF GUIDELINES -2011
METABOLISM OF BILIRUBIN
CO

Se albumin bound
 FETAL BILIRUBIN METABOLISM
• Conjugated bilirubin – cleared by placenta mostly.

• Its formation is limited – decreased fetal hepatic blood flow, decreased hepatic ligandin and
decreased UGT1A1 activity.

• Small amount excreated in gut- hydrolysed by β-glucoronidase and reabsorbed

• Bil. Normally found in amniotic fluid by 12 wk of gestation , absent by 37 wk.

• Increased amniotic fluid bilirubin- hemolytic disease of newborn and fetal intestinal
obstruction below bile ducts.
Avery’s diseases of the newborn
 WHY SO COMMON IN NEONATES.????

1. Decreased survival of RBC (90 days in term).

2. Increased ineffective erythropoesis.
3. Defective uptake-decreased ligandin.
4. Decreased clearance-decreased UGT1A1 activity
5. Decreased hepatic excretion- increased enterohepatic circulation.
6. Paucity of bacterial flora in gut.
CLOHERTY AND STARK’S MANUAL
 NONPATHOLOGICAL HYPERBILIRUBINEMIA

• Jaundice is termed Physiological when:

• Occurs between 24 to 72 hours of age
• Rises to a maximum level of 6-8 mg/dl in term by 3 to 5 days of
life then falls( till 12 mg/dl is in physiological range)
• in preterm peak may be 10 – 12 mg/dl by day 5 , can rise further
in absence of treatment.
• TSB takes weeks to fall under 2mg/dl in both term and preterm.
CLOHERTY AND STARK’S MANUAL
 PATHOLOGICAL HYPERBILIRUBINEMIA

• Jaundice is termed Pathological when:

1. Occurs on the first day of life
2. Rate of rise of TSB or TCB >0.2 mg /dl/hr.
3. Rise in TB requiring phototherapy.
4. Asso signs of illness such as vomiting, lethargy, poor feeding, excessive
weight loss, apnoea, tachypnoea or temperature instability.
5. Jaundice after 2wk in term infant and >3 wk in preterm infant.

CLOHERTY AND STARK’S MANUAL

 CAUSES OF JAUNDICE

• In first 24 hours

• >24 hours

• Prolonged jaundice
 IN FIRST 24 HOURS
Sr. no. Mechanism Cause Investigations

1. Hemolytic ABO or Rh or minor blood Direct Coombs test

disease of gp incompatibility Maternal/infant blood group Rh
newborn and ABO typing

2. Non immune G6PD Family h/o and G6PD assay

hemolysis PK deficiency PK assay
(enzyme heriditary Spherocytosis , Blood film, full blood count
defficiency) HbPathies Hb electrophoresis.

3. Drug induced Large amounts of Vit K ,

Salycylates, kanamycin ,
gentamycin, oxytocin.
 AFTER 24 HOURS
Sr. No. Mechanism Cause Investigations
1. Physiological jaundice Prematurity, Hypoglycemia, Hypoxia,
Dehydration, breastfeeding

2. Excess bilirubin Cephalohematoma, DIC, Intraventricular Complete blood count

production hemorrhage, polycythemia, ingested for polycythemia
mother’s blood

3. Infection Sepsis, intrauterine infection Sepsis screen, Torch

screen

4. Congenital Non Crigler Najjar syndrome

hemolytic Gilbert Syndrome
hyperbilirubinemia

5. Metabolic Galactosemia Urinary reducing

substances
 PROLONGED JAUNDICE
• Jaundice > 14 days of life
• Causes
• Immaturity
• ABO incompatibility
• Breast milk jaundice
• Hypothyroidism
• Pyloric stenosis , functional or organic intestinal stasis
• Criggler – Najjar syndrome
• Gilbert syndrome
• Concealed hemorrhage
• Malaria
ASSESSMENT OF NEONATAL JAUNDICE
 CLINICAL ASSESSMENT

• HISTORY
• Family H/O
• Maternal H/O
• H/O labor and Delivery
• Infant’s H/O

• INFANT’S PHYSICAL EXAM

• LABORATORY DATA
 D/D FROM FAMILY H/O
Information Significance
1. Parent or Sibling with h/o jaundice or Suggests hereditary hemolytic anemia
anemia/ splenectomy such as HS/ G6PD defficiency

2. Previous Sibling with neonatal Suggests hemolytic disease due to ABO

jaundice or Rh isoimmunization

3. H/O liver ds in siblings or disorders All associated with neonatal jaundice

such as cystic fibrosis, galactosemia,
tyrosinemia, hypermethionemia, C.N.
Syndrome or alpha 1 antitrypsin def.

Avery’s textbook/ Cloherty and Stark’s manual

 D/D FROM MATERNAL H/O

• Unexplained fever or illness during pregnancy • Consider congenital infections such as Rubella, CMV,
TOXO, Herpes, Syphilis or Hepatitis

• Diabetes Mellitus
• Increased incidence of jaundice in neonates
• Drug ingestion during pregnancy
• Some drugs can lead to hemolysis in G 6 PD deficient
infants like sulfonamides, nitrofurantoin and
antimalarials

Avery’s textbook/ Cloherty and Stark’s manual

 D/D FROM H/O LABOR AND DELIVERY
• Vacuum extraction------------------------------------- Cephalohematoma and
jaundice
• Oxytocin induced labor------------------------------- Increased incidence of
hyperbilirubinemia
• Delayed cord clamping-------------------------------- Increased incidence
of hyperbilirubinemia in
Polycythemic infants
• Apgar score---------------------------------------------- Increased incident in
Asphyxiated baby inability of liver to
conjugate , i/c bleed
Avery’s textbook/ Cloherty and Stark’s manual
 D/D FROM INFANT’S H/O

• Delayed Passage of meconium or infrequent • Increased enterohepatic circulation

stools consider: intestinal atresia, annular Pancrease,
Hirschsprung’s disease, meconium plug, drug induced
ileus
• Caloric intake • Inadequate calories intake can lead to delay in
bilirubin conjugation

• Vomiting • Sepsis, galactosemia or Pyloric stenosis

Avery’s textbook/ Cloherty and Stark’s manual

 VISUAL INSPECTION OF JAUNDICE
1. Examine the baby in bright natural light. Alternatively, the baby can be examined in white fluorescent light.
Make sure there is no yellow or off white background.
2. Make sure the baby is naked.
3. Examine blanched skin and gums, and sclerae
4. Note the extent of jaundice (Kramer’s rule)
1. Face 4-8 mg/dL
2. Chest 5-12 mg/dL
3. Lower abdomen/thigh 8-16 mg/dL
4. Forearms and lower legs 17-20mg/dl
5. Soles/Palms >20 mg/dL

5. A deep yellow staining (even in absence of yellow soles or palms) is often associated with severe jaundice
and therefore TSB should be estimated in such circumstances.
Kramer Ll. Advancement of dermal icterus in jaundiced newborn. Am J Dis Child
 CLINICAL ASSESSMENT OF JAUNDICE

Area of body Bilirubin levels/dlmg

• Face 6
• Upper trunk 9
• Lower trunk & thighs 12
• Arms and lower legs 15

• Palms & soles > 15

NNF - 2011
 PHYSICAL EXAM
• Small for gestation age--------------------------------intrauterine infections+
polycythemia
• Head size------------------------------------------------- Microcephaly associated with
intrauterine
infections associated with jaundice
• Cephalhematoma/ bruising-------------------------- entrapped hemorrhage
• Pallor------------------------------------------------------ suspects hemolytic anemia/
extravasated blood
• Petechiae------------------------------------------------ sepsis or infection or severe hemolytic
disease
• Appearance of umbilical stump-------------------- omphalitis and sepsis cause jaundice
• Hepatosplenomegaly--------------------------------- hemolytic anemia/ liver diseases
• Optic fundus------------------------------------------- congenital infection CMV or toxo
CLOHERTY AND STARK’S MANUAL
• Umbilical hernia--------------------------------------- hypothyroidism
 LABORATORY EVALUATION

• Transcutaneous bilirubin(TcB) measurement

• Total serum bilirubin(TSB)

• Other relevant lab tests.
 TRANSCUTANEOUS BILIRUBINOMETRY
• Limitations
• Costly
• Only be used in 35wks or more
• Used after 24 hours
• Becomes unreliable at higher conc. of bilirubin
>15mg/dl
• Varies with pigmentation
• Unreliable after phototherapy
• Advantages
• Have high negative predictive value ie. TcB below 50 th
centile for age would rule out risk of subsequent
hyperbilirubinemia
• Can reduce sampling by 30%
TSB indicated if TcB >95 percentile in TcB chart or >75
percentile in TSB normogram
 TOTAL SERUM BILIRUBIN
• Provides definitive value of bilirubin
• Reliable than TcB levels at higher values
• TSB is indicated:
• Jaundice appears in 24 hours
• In infants receiving phototherapy
• Jaundice persisting for more than 3 weeks
• TcB levels above 95th percentile
• TSB measures albumin bound fraction and not free bilirubin
• Methods:
• Biochemical:
• HPLC (high performance liquid chromatography)
GOLD STANDARD
• Vanden bergh reaction
• Micro method: BILIRUBINOMETER
• Spectrophotometry (more useful in neonates as
bilirubin is predominantly unconjugated
 NEWER MODALITIES

• BILIRUBIN : ALBUMIN RATIO(B:A)

• Free bilirubin
• Bilirubin Binding Capacity(BBC)
• Free bilirubin :TSB (proposed)

B:A and BBC as a proxy for free bilirubin which is not

commercially available
 OTHER LABORATORY TESTS

Maternal blood group and indirect Coombs test ABO and Rh incompatibility

Maternal serology For diagnosing congenital syphilis

Infant hemoglobin Anemia suggests hemolysis

Infants reticulocyte count Elevation suggest hemolysis

Platelet count Thrombocytopenia suggest infection

ESR More than 5 in first 2 days indicate infection or ABO

incompatibility

Urinalysis Presence of reducing substances in urine may suggest

a diagnosis of galactosemia
 NEONATES WHICH SHOULD BE AT
ENHANCED SURVEILLANCE
• Gestational age <38 wk
• Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease
• East asian race
• Jaundice in first 24 hrs
• Cephalhematoma or significant bruising
• Previous sibling received phototherapy
• Pre-discharge TCB or TSB in high risk level.

NNF GUIDELINES -2011

 APPROACH TO AN INFANT WITH JAUNDICE
Age 35-37 6/7 wk + hyperbilirubinemia risk
factors

Predischarge TCB/TSB

Assign bilirubin risk zone

High High intermediate Low intermediate Low

If discharging <72hr
Evaluate for PTX –TSB follow up in 2 days. If discharging <72 hr,
in 4-8 hr Evaluate for PTX – Consider TSB/TCB at f/up within 2 days
TSB/TCB in 4-24 hr follow up
 Age 35-37 6/7 wk and no risk factors or age ≥38wk +risk
factors

Predischarge TCB/TSB

Assign bilirubin risk zone

High High intermediate Low intermediate Low

Evaluate for PTX If discharging <72

Evaluate for PTX TCB/TSB within If discharging <72
in 4-24 hr hr followup in 2 hr f/up in 2-3 days
24 hr days
 Gestational age
≥38wk and no risk
factors

Predischarge
TCB/TSB

Assign bilirubin
risk zone

High High intermediate Low intermediate Low

If discharging If discharging f/up

Evaluate for PTX. f/up within 2 days
<72hrs f/up in 2-3 according to age at
TSB in 4-24 hr TCB at f/up
days discharge
 NOMOGRAMS

• AAP provide 2 age specific Nomograms each for phototherapy and exchange transfusion.
• For baby born at 35wks or more there are 3 risk categories suggested by lines on the nomogram:

Risk Category Gestation age Risk factor

Lower risk 38wk or greater ----------------
Medium risk 38wks or greater Present
35wks to 37wks ----------------
Higher risk 35wks to 37wks Present
Nomogram for Phototherapy
Nomogram for Exchange transfusion
 RISK FACTORS?

• Isoimmune hemolytic disease

• G 6 PD deficiency
• Temperature instability- Hypothermia
• Asphyxia
• Acidosis
• Hypoalbuminemia
• Sepsis
• Lethargy
 INFANTS <35WKS

• The proposed cutoffs of TSB for these infants is arbitrary and clinical assessment should be more
emphasized upon.

NNF Guidelines
2011
 PHOTOTHERAPY
• Principle: bilirubin absorbs light in particular wavelength ie. 460nm to 490nm and gets
converted to harmless substitutes which are easily excreted.
• Mainly 2 Mechanisms:
1. Reversible Photo Isomerism: 4 Z,15 Z ------to------ 4 Z,15 E Excreted in Bile
2. Irreversible Structural Isomerism: Bilirubin to Lumirubin
Excreted in urine
• Phototherapy devices
• Conventional phototherapy
• Fibreoptic phototherapy
Light sources used are
• i) Special blue tube-lights (PHILIPS TL52, 20W)
• ii) Special blue CFT lamps (OSRAM 18 W)
• iii) High intensity gallium nitride blue light emitting diode (LED
• STANDARDS FOR PHOTOTHERAPY DEVICES
• Wavelength – 460-490 nm
• Light irradiance- 30 µW/cm3/nm (AAP)
• Doses >65 µW/cm3/nm- unknown sideeffects
• Usefull life of bulbs not to be excreted
• Optimal BSA- >90%, change of position 2-3hourly , minimise diapers, eyepatches, ( in
incubator- perpendicular)
• Impact – fall in TSB of atleast 2mg/dl.

• MONITORING
• Adequate hydration, nutrition , temperature control
• Progression of jaundice

• CONTRAINDICATION – congenital porphyria , t/t with photosensitising drugs

 CONVENTIONAL PHOTOTHERAPY
• Fluorescent tubes
• Inexpensive
• Light intensity and irradiance decreases with time
• Needs change after 1000-1500 hours

• Quartz halogen bulbs

• Longer duration
• Fragile
• Maintain safe distance from neonate due to excessive heat

• LED
• Uses indium and gallium as semiconducter
• Emits high intensity narrow band lights
• Little heat-placed close to infant
• Less transepidermal fluid loss
• Light weight , non fragile ,low energy consumption, durability
 FIBREOPTIC PHOTOTHERAPY

• Fiberoptic phototherapy,
effective in reducing STB for
neonates with jaundice.
• Infants under fiberoptic
phototherapy can be nursed
close to their parents without
mother infant separation,
• LED VS OTHER PHOTOTHERAPY
In a recent meta-analysis (2012) including six randomized controlled trials with
511term and late preterm neonates, no significant difference in STB rate of
decrease was detected between LED and other types of phototherapy

• PROPHYLACTIC VS THRESHOLD PHOTOTHERAPY:

• Phototherapy initiated soon after birth(within 36 hours) prevents significant
rise in hyperbilirubinemia, need for exchange transfusion and long term
neurodevelopmental effects
• Lower vs high threshold phototherapy:
• National Institute of Child Health and Human Development Neonatal Research
Network randomized trial showed increased neurodevelopmental outcome in 751-
1000kgs infants receiving low threshold PT
• Increased death in neonates of 500-750 kgs receiving LOW threshold PT

• DOUBLE VS TRIPLE PHOTOTHERAPY

• Higher irradiance in double(fibreoptic and conventional or both conventional) and
triple phototherapy comparing single phototherapy
• The difference in the TSB in 0 to 4 hours are very less
• OVERHEAD VS UNDERNEATH PHOTOTHERAPY: Overhead
phototherapy illuminates more than one third of the baby surface

• INTERMITTENT VERSUS CONTINOUS PHOTOTHERAPY:

• On for 1hour then off 1 hour, 12 hours on 12 hours off, 1 hour on
3 hours off
Is as effective as the continous phototherapy
 SIDE EFFECTS OF PHOTOTHERAPY

• Short term :
• Interferance with maternal-infant bonding. • Dehydration
• Hyperthermia • Riboflavin deficiency
• Benign skin rashes ( increased with high
• Lipid peroxidation
intensity PT)
• Purpuric and bullous eruptions
• Bronze baby syndrome in babies
receiving PT where the cause is conjugated
hyperbilirubinemia
 POSSIBLE LONG TERM EFFECTS

• Allergic diseases
• Melanocytic naevi
• Melanoma of skin
• Café au lait spots
• Uveal melanoma
INTENSIVE PHOTOTHERAPY

Spectrum - 400-520 nm
Irradiance - >= 30 microW/ cm3/ nm
Reduces level of TSB by 30-40% in 24 hrs
 EXCHANGE TRANSFUSION
• Exchange transfusion (ET) should be started if :
• The TSB level reach age specific cutoff for exchange transfusion
• There are signs of encephalopathy or kernicterus irrespective of the TSB levels
• Isoimmune hemolytic disease
• Severe sepsis
• DVET should be started at birth in infants in which
• Cord blood bilirubin level is >5 mg/dl or
• Cord Hb <10 mg/dl
• If there is cardiac decompensation or appearance of hydrops at birth:
• Do partial exchange transfusion with 50 ml/kg of packed cells
 WHICH BLOOD TO USE FOR ET?
• Depends upon the cause of hemolysis:
Sr. No. Condition Type of blood
MBG BBG Donor
1. Rh incompatibility -ve + or - Rh -
2. ABO incompatibility O ‘O’/ A/ B/ AB O
A/ B/ AB O/ A/ B/ AB O or BBG

Fresh Rh- Negative Type O , Irradiated PRBC Resuspended in AB plasma and

crossmatched against maternal sample.

Intensive PT should be resumed after the procedure and TSB monitored

 BLOOD FOR ET
• Twice the blood volume of that of baby
2 X 80-90ml/kg ie.160 to 180 ml /Kg
• Procedure : .
Through umbilical venous catheter –PUSH-PULL Technique
patient blood replaced by donor blood in aliquots <10%of infant’s
blood volume(max 20 ml)
albumin transfused 1-2 hrs prior to ET-promotes removal of more bil
 PHARMACOLOGICAL THERAPIES

• Intravenous immunoglobin

• Heme oxygenase inhibitors

• Inhibiting enterohepatic circulation

• Enhancing clearance
 INTRAVENOUS IMMUNOGLOBULINS (IVIG)

• Given in :
• Hemolytic disease – TB continues to rise after intensive PT or TB
is within 2-3mg/dl of threshold for ET
• Dosage:
• 0.5 to 1 gm/Kg
• Mechanism :
• Blockage of Fc receptors in Reticulo-endothelial system
 IV HYDRATION

• Given in dehydrated infant and severe hyperbilirubinemia

• Given as 50ml/Kg of N/3 saline given over 8 hours
• Decreases need for exchange transfusion
 OTHER DRUGS
Drug Mechanism Evidence Remark
metalloporp Inhibits heme oxidase Cochrane – 3 studies, poor Routine use not
hyrins quality non-blinded trials. recommended
Adverse effects -
photosensitivity

Clofibrate Dec. enterohepatic circulation Cochrane – 15 studies , 13 done Questionable external

in Iran validity
Activated Dec. enterohepatic circulation Quasi controlled study- Based on small studies.
charcoal beneficial as adjunct to PT Might be useful adjunct to
PT

Agar Oral agar vs agar+ PT max. No recent large studies

drop in TSB with combination
Probiotics Addition to formula feeds causes Emerging option- not
more stools and lower TcB level recommended right now
in infants wit mod. hyperbil
 BREASTFEEDING JAUNDICE

• We need to understand that the most common cause of neonatal jaundice is

inadequate breast feeding termed as breastfeeding jaundice.
• Major problems include:
• Improper positioning and attachment
• Cracked or sore nipple
• Engorgement
• Perceived inadequacy of milk production

• In addition to providing adequate information, actual helping the mother proper

positioning and attachment is important.
 BILIRUBIN TOXICITY AND KERNICTERUS
• Acute bilirubin encephalopathy may develop in hazardous hyperbilirubinemia and may evolve
into the chronic adverse neurodevelopmental sequelae of KERNICTERUS.

Deposited in neurons
B+H - BH2(bilirubin
1gm albumin---8.5 gm of basal ganglia/
acid)- Has surfactant
bilirubin hippocampus/ auditory
like property
nucleus

Deposited b/w LIPID

Deff. Of albumin or Some free bil. Crosses
BILAYER of
↑unconj. Bil. BBB
membranes

Free bilirubin crosses

Binds with tissue BILIRUBIN
interstitial
protein ENCEPHALOPATHY
compartment
• ABE-
• Early phase-lethargy/ hypotonia/high-pitched cry and poor suck.
• Intermediate phase (progresses in absence of intervention)- hypertonia of
extensors/irritability/ fever/ seizures  develop chronicity.
• Advanced phase – ophistotonus and retrocollis/ apnoea/ seizures/ coma death d/t
intractable seizures or resp failure.
bilateral basal ganglia hyperintensity
 MAJOR CLINICAL FEATURES OF ACUTE BILIRUBIN ENCEPHALOPATHY

• Lethargy
• poor sucking
• poor or absent Moro's,
• Retrocollis-opisthotonos
Convulsions

Retrocollis (backward arching of the neck) Opisthotonus

(backward arching of the back
This infant presented at age 30 days with a serum bilirubin level of 30 mg/dL (513 μmol/L) secondary to the Crigler-
Najjar syndrome type I. He demonstrates retrocollis and opisthotonos, signs of the intermediate to advanced stage of
acute bilirubin encephalopathy.
 MAJOR CLINICAL FEATURES OF CHRONIC BILIRUBIN
ENCEPHALOPATHY

• Athetosis

• Upward gaze

• Sensorineural hearing loss

• Intellectual deficits, mild MR