Neonatal Unconjugated Hyperbilirubinemia

Clinical Case
JR, JR, 7 do hispanic BB, twin B, presented to UCCH
ER with jaundice on 5/9/06
DOB DOB – 5/3/06, at OSH in Indiana
NVD, NVD, GA 38 weeks, APGARs 9/9
BWt BWt 3.18 kg (7#0oz)
Maternal Maternal Hx: Hx:
31 yo G2P3 now, good PNC,
uncomplicated pregnancy
PNL PNL – B+/RPR NR/R Imm/HepB NR/HIV NR/GBS-
NR/GBS

Perinatal course
Initial Initial PE unremarkable; + some facial bruising
noted
Wt Wt 2.9 kg
Feeding Feeding BM/E20 – well per GCN records
Voiding Voiding and stooling well
Discharged Discharged at 48 hrs
D/C D/C Wt – 2.03 kg
Mom Mom told that baby had “borderline borderline” jaundice
To call Pediatrician if she sees baby gets yellow

Baby Baby was OK at home, eating well – 10-15 10 15
min each breast
Stooling Stooling well – per mother
On On DOL 5 mother thought babies look
yellow and called the PMD
She She was told to go to the hospital next day
for Bili check

Baby Baby B+/Coombs-
B+/Coombs
Mom Mom B+
Labs

Work Up
CBC CBC – WBC 13.6, H/H 18.9/54, Plt 301
Diff Diff N26, Bn4
Retic Retic count 0.7%

Bilirubin
5/5/06 5/5/06 - @48 hrs (OSH) – 13.0/0.4
5/9/06 5/9/06 – DOL 7 – (OSH) – 30.9/0.6
5/9/04 5/9/04 – UCCH – 31.5/0.8
Sibling Sibling’s s Bili was 21 – admitted to Peds
Floor for phothotherapy

ER course
VSS, VSS, baby was jaundiced and “sleepy sleepy”
Placed Placed under phothotherapy
Given Given IVF
Admitted Admitted to PICU for exchange transfusion

Here comes the NICU
0230 0230 – NICU fellow received a call from
upstairs to help with the exchange transfusion
By By 0530 baby was in the PICU
Blood Blood ordered
UVC UVC placed
Double Double volume exchange transfusion was
done
Rpt Rpt Bili – 23.8/0.7 half way through the
exchange

Neonatal Hyperbilirubinemia

WHAT IS HYPERBILIRUBINEMIA AND WHY
DO WE WORRY ABOUT IT?

Jaundice
A A visible manifestation in the skin and sclera
of elevated bilirubin concentrations
Adults Adults are usually jaundiced when bilirubin
levels exceed 2 mg/dL
Neonates Neonates appear jaundiced when serum total
bilirubin (STB) levels reach 5-7 5 7 mg/dL

Some Some degree of jaundice develops in 60-70% 60 70% of
all neonates born on the United States
More than 2.7 million neonates born each year in the
United States will develop jaundice
Chemical Chemical hyperbilirubinemia, a STB > 2.0 mg/dL,
is virtually universal
Although Although most jaundice is benign, there is a
potential for neurological devastation and death
and consequently all newborns must be assessed

WHY DO INFANTS DEVELOP
HYPERBILIRUBINEMIA?

Increased Increased Bilirubin Production
Decreased Decreased Binding and Transport Capacity
Limited Limited Conjugation and Excretion Capacity
Increased Increased Enterohepatic Circulation of
Bilirubin

Bilirubin Bilirubin is the breakdown product of
hemoglobin
Lysis Lysis of red cells releases heme from
hemoglobin
Heme Heme is then converted to bilirubin and
excreted

Bilirubin Synthesis
There There is increased production of bilirubin in the
newborn because of:
Increased rate of degradation
A shortened circulating erythrocyte life span (70-90 (70 90 days
versus 120 days) of an increased mass
A very large pool of hematopoietic tissue that ceases to
function shortly after birth resulting in heme degradation
An increased turnover of cytochromes (nonhemoglobin
heme proteins)
An increase in enterohepatic circulation

Binding and Transport
Unconjugated Unconjugated bilirubin is quickly bound to
albumin in the serum
Newborns Newborns have reduced albumin
concentrations and consequently a lower
plasma binding capacity for bilirubin
There There is consequently more free bilirubin in
the serum
It It is the free bilirubin that is believed to
cause neurological damage in newborns

Conjugation and Excretion
During During fetal life, removal of bilirubin is
accomplished by the placenta
In In the newborn, bilirubin excretion requires
conversion of the nonpolar unconjugated
bilirubin into a more polar water-soluble
water soluble
substance, conjugated bilirubin

Blood Blood flow through the hepatic artery develops
during the first week of life
The The ductus venosus allows blood to bypass the
liver completely
Conjugation Conjugation depends on the maturity of the liver
cell

UDPGT
UDPGT UDPGT in the newborn liver must be
induced
UDPGT UDPGT activity is extremely low in infants
born at less than 30 weeks, 0.1% of adult
levels
This This activity increases to only 1% at term
The The activity reaches adult levels by 6-12 6 12
weeks of age

Conjugation
Bilirubin Bilirubin dissociates from circulating albumin
before its entry into the liver cell
Bilirubin Bilirubin enters the liver by a process of carrier-
mediated diffusion
It It is carried by hepatic ligandin (Y protein) and Z
protein
Bilirubin Bilirubin is presumed to be transported from the
liver cell membrane to the endoplasmic reticulum,
the site of the conjugating enzyme uridine
diphosphate glucuronyl transferase (UDPGT)
After After conjugation, bilirubin is then excreted into
bile in the intestine

Increased Enterohepatic Circulation
Conjugated Conjugated bilirubin is unstable and can be
easily hydrolyzed back to unconjugated bilirubin
and reabsorbed through the intestinal mucosa
High High mucosal beta-glucuronidase beta glucuronidase activity leads
to increased hydrolysis
An An alkaline environment also facilitates
hydrolysis
In In the newborn, the relative lack of intestinal
bacterial flora to reduce bilirubin to urobilinogen
further increases the bilirubin pool

Neonatal Hyperbilirubinemia
Physiologic Physiologic Jaundice
A A progressive rise in unconjugated bilirubin to a
peak of 5-6 5 6 mg/dL between 60 and 72 hours of
life in white and African-American African American babies and
10-14 10 14 mg/dL between 72-120 72 120 hours of life in
Asian babies
A A rapid decline in TSBs occurs by the 5 th or 7- 7
10 th day respectively

Pathologic Unconjugated
Hyperbilirubinemia
Pathologic hyperbilirubinemia is defined as a
prolonged or exaggerated
hyperbilirubinemia
Occurs because of disorders of:
Production Production
Hepatic Hepatic Uptake
Conjugation
Conjugation
Enterohepatic Enterohepatic Circulation

Disorders of Production
Isoimmunization
Isoimmunization
Erythrocyte Erythrocyte Enzymatic Defects
Erythrocyte Erythrocyte Structural Defects
Infection Infection
Sequestration
Sequestration
Polycythemia
Polycythemia

Isoimmunization
Rh Rh Incompatibility
ABO ABO Incompatibility
Other Other Blood Group Incompatibilities

Rh Incompatibility
This is a blood group incompatibility between the mother
and newborn that can cause severe hemolytic anemia in
the fetus and newborn
The Rh antibody is produced by a Rh negative mother after
being exposed to a Rh antigen from fetal blood
The initial response is to make IgM antibodies
Later IgG are produced which cross the placenta and bind
to fetal red blood cells which are consequently destroyed
Infants do not appear jaundiced at birth, but severe anemia
can lead to hydrops and death
After birth, infants may develop hyperbilirubinemia rapidly

The The D antigen may produce sensitization
with a fetomaternal hemorrhage as small as
0.1 mL
At At one time this was the most common
cause of kernicterus; but with the use of
RhoGAM (anti-D (anti D immunoglobulin G) and
careful fetal monitoring, the incidence and
severity have decreased

ABO Incompatibility
This This is a hemolytic disease caused by a
reaction of maternal anti-A anti A or anti-B anti B
antibodies with fetal A or B antigens
Usually Usually milder than Rh
Almost Almost exclusively in type O mothers
Jaundice Jaundice appears at 24-72 24 72 hours
Half Half of infants with a positive Coombs show
hemolysis and some with a negative Coombs
have hemolysis

Minor Blood Groups
Kell, Kell, Kidd, Duffy, Lutheran
< < 2 % of hemolysis from isoimmunization

Erythrocyte Enzymatic Defects
Glucose Glucose-6-Phosphate Phosphate Dehydrogenase
Deficiency
Pyruvate Pyruvate Kinase Deficiency
These These defects may have profound effects on
erythrocyte function and life span

Glucose-6-Phosphate
Glucose Phosphate
Dehydrogenase Deficiency
Glucose Glucose-6-phosphate phosphate dehydrogenase deficiency
(G6PD) is a common disease, especially in people
of Mediterranean; African; and Asian decent
G6PD G6PD deficiency occurs in 11-13% 11 13% of African
Americans
Estimated Estimated 200-400 200 400 million people carry the gene
X-linked linked
Presentation Presentation is heterogeneous
Hemolysis Hemolysis occurs, but can be absent
Hyperbilirubinemia Hyperbilirubinemia occurs between 24 and 72
hours of life

RBCs RBCs are unable to activate the pentose
phosphate metabolic pathway
And And consequently cannot defend against
oxidative stress
Sepsis and Vitamin K analogues
Severity Severity of disease depends on type and
amount of stress

Pyruvate Kinase Deficiency
This This is the second most common cause of
enzymatic-related enzymatic related hemolytic anemia
Autosomal Autosomal recessive
It It is common in people of Northern
European decent
It It is an enzyme required for production of
ATP in RBCs

Its Its deficiency leads to decreased RBC life
span and hemolysis

Erythrocyte Structural Defects
Hereditary Hereditary Spherocytosis
Hereditary Hereditary Elliptocytosis
These These defects alter RBC structure and cause
sequestration

Hereditary Elliptocytosis
Incidence Incidence of 1:4000
Autosomal Autosomal dominant
Abnormality Abnormality in spectrin or glycophorin C
Hemolysis Hemolysis and hyperbilirubinemia are
unusual in the newborn period

Hereditary Spherocytosis
Incidence Incidence of 1:5000
Autosomal Autosomal dominant
Heterogeneous presentation
Fifty Fifty percent present with hemolytic anemia,
hyperbilirubinemia, reticulocytosis, and
increased erythrocyte osmotic fragility

Infection
Hyperbilirubinemia Hyperbilirubinemia is believed to be
secondary to hemolysis
Sepsis Sepsis may impair conjugation also leading
to increased bilirubin levels

Sequestration
Sequestration Sequestration of blood in body cavities may
lead to hyperbilirubinemia as the body
metabolizes hemoglobin
Cephalohematomas, Cephalohematomas, subdural hematomas,
subgaleal hematomas
Excessive Excessive bruising

Polycythemia
The The increase in red blood cell mass has the
potential to overload the newborn
hemoglobin metabolism capacities

Disorders of Hepatic Uptake
Gilberts Gilberts Syndrome
This This is a benign disorder producing persistent
unconjugated hyperbilirubinemia
There is defective hepatic uptake and decreased
UDPGT activity
It usually occurs in the second decade of life, but can
present in neonates

Disorders of Conjugation
Crigler Crigler-Najjar Najjar Syndrome
Transient Transient Familial Neonatal
Hyperbilirubinemia (Lucey-Driscoll (Lucey Driscoll Syndrome)
Pyloric Pyloric Stenosis
Hypothyroidism
Hypothyroidism

Type Type I
Crigler-Najjar Crigler Najjar Syndrome
There is absence of UDPGT activity
Autosomal recessive
1:1,000,000
Severe unconjugated hyperbilirubinemia develops and
persists beyond the first week of life
No hemolysis
Lifelong risk of kernicterus
Lifelong phototherapy is needed

Type Type II
There There is various degree of decrease of UDPGT
activity
Typically Typically benign
There There is unconjugated hyperbilirubinemia in the
first few days of life that does not exceed 20
mg/dL
Hyperbilirubinemia Hyperbilirubinemia persists into adulthood
The The treatment is phenobarbital

Transient Familial Neonatal
Hyperbilirubinemia
Neonates Neonates develop severe nonhemolytic
hyperbilirubinemia
Their Their serum contains high concentrations of
glucuronyl transferase inhibitors
This This inhibitor decreases by about 14 days of
life and consequently hyperbilirubinemia
resolves

Pyloric Stenosis
10 10-25% 25% of babies with pyloric stenosis have
hyperbilirubinemia at the time of
presentation
Hepatic Hepatic glucuronyl tranferase activity is
reduced
Surgical Surgical correction improves bilirubin levels

Hypothyroidism
UDPGT UDPGT activity is deficient and remains low
for weeks with hypothyroidism

Disorders of Enterohepatic
Circulation
Breast Breast Feeding Jaundice
Breast Breast Milk Jaundice

Breast Feeding Jaundice
Unconjugated Unconjugated hyperbilirubinemia is secondary to a
suboptimal establishment of breastfeeding
Newborns Newborns are under-hydrated under hydrated and in a state of
starvation.
They They also have delayed passage of meconium
Enterohepatic Enterohepatic reuptake of bilirubin is consequently
increased, leading to hyperbilirubinemia
Treatment Treatment and prevention include frequent
feedings (8-12/day) (8 12/day)

Breast Milk Jaundice
Occurs Occurs after 3-5 3 5 days of life, typically at 2-3 2 3
weeks of life
The The etiology is unknown, but believed to be
a factor in breast milk or an altered
chemistry in breast milk that enhances
intestinal reabsorption of bilirubin
No No need to stop breastfeeding unless
bilirubin levels are dangerously high

WHY DO WE WORRY ABOUT
HYPERBILIRUBINEMIA?

Sequelae
Bilirubin Bilirubin may penetrate the brain cell and
cause neuronal dysfunction or death if not
carefully managed
Bilirubin Bilirubin causes staining and necrosis of
neurons in the basal ganglia, hippocampal
cortex, subthalamic nuclei, and cerebellum
which is followed by gliosis
50%of 50%of patients with kernicterus die

Acute Bilirubin Encephalopathy
Phase Phase 1 - poor suck, hypotonia, and
depressed sensorium
Phase Phase 2 - fever and hypertonia or
opisthotonos
Phase Phase 3 - less hypertonia, high pitched cry,
hearing and visual abnormalities, poor
feeding, athetosis

Long Long term sequelae:
Kernicterus
Chorioathetoid Chorioathetoid cerebral palsy
Sensorineural Sensorineural hearing loss
Upward Upward gaze palsy
Dental Dental-enamel enamel dysplasia
Mental Mental retardation

SO, WHAT CAN WE DO?

Diagnosis and Management
There There has been evidence that neonatal
jaundice can be treated less aggressively,
but there is not a consensus yet and until
then it should be managed conservatively

Diagnosis
All All neonates are entitled to a thorough
physical examination and evaluation to
determine which neonates are at an
increased risk for becoming abnormally
jaundiced and developing sequelae

Risk Assessment
Every Every newborn should be assessed,
especially if discharged before 72 hours of
life
2 2 options:
TSB or TcB before discharge and plot results on the
nomogram

Nomogram for designation of risk in 2840 well newborns at 36 or more weeks'
gestational age with birth weight of 2000 g or more or 35 or more weeks' gestational
age and birth weight of 2500 g or more based on the hour-specific serum bilirubin
values
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Copyright ©2004 American Academy of Pediatrics

Assessment of risk
– Major
Predischarge TSB or TcB in the high-risk high risk zone
Jaundice in the first 24h
Hemolytic disease
Gestational age 35-36 35 36 weeks
Sibling received phototherapy
Cephalohematoma or bruising
Poor breastfeeding
East Asian descent

Carbon Monoxide
End End Tidal Carbon Monoxide detection
allows rapid noninvasive detection of infants
at risk for hemolytic disease and
consequently at high risk for neurological
sequelae

Carbon Monoxide
The The breakdown of hemoglobin by heme
oxygenase produces free iron and carbon
monoxide in equimolar amounts
The The carbon monoxide formed by heme
degradation is excreted unchanged by the lungs.
Although Although there are other endogenous and
exogenous sources of CO, quantitative estimation
of its excretion or synthesis offers a reasonably
accurate assessment of bilirubin synthesis

Physical Examination
Detection Detection of clinical jaundice requires digital
pressure and the proper lighting, preferably
daylight
If If clinical jaundice is detected, a total and
direct serum bilirubin or transcutaneous
bilirubin (TcB) should be measured and
plotted on the nomogram

If: If:
When should I do more?
Cord Cord bilirubin is greater than 4 mg/dL
A A rate of rise greater than or equal to 0.5
mg/dL/hour over a 4-8 4 8 hour period
An An increase of 5 mg/dL per day
13 13-15 15 mg/dL in a term infant
10 10 mg/dL in a preterm infant
If If jaundice persist greater than 10 days

Then what?
Determination Determination of maternal blood group and Rh
type
Screen Screen for antibodies directed against minor
erythrocyte antigens
Determination Determination of newborns blood type and Rh
type
Direct Direct Coombs test
Hemoglobin Hemoglobin and Hematocrit
Peripheral Peripheral blood smear
Reticulocyte Reticulocyte count
G6PD G6PD level

Algorithm for the management of jaundice in the newborn nursery
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Copyright ©2004 American Academy of Pediatrics

Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
opyright ©2004 American Academy of Pediatrics

Helpful resources
Bili-Aid Bili Aid

Phototherapy
The The main mechanism of action
Geometric Geometric photoisomerization of unconjugated
bilirubin that can then be excreted without
conjugation

Wavelength
Wavelength
Technique
Bilirubin Bilirubin absorbs light maximally in the blue
range (420-500 (420 500 nm), with a peak at 460 nm for
albumin-bound albumin bound bilirubin and 440 nm for free
bilirubin
Special blue lamps have a spectrum between 420- 420
480

Irradiance Irradiance
The The energy output measured in microwatts per
square centimeter per nanometer
Optimal Optimal level is 11 microwatts per square
centimeter per nanometer
Intensive Intensive phototherapy is 30 microwatts per
square centimeter per nanometer

Positioning Positioning
Within Within 10 cm of the patient for fluorescent tubes
Surface Surface area
The The greater the surface area exposed, the more
effective the phototherapy

Hydration
There There is no evidence that excessive fluid
administration affects the serum bilirubin
concentration
If If admitted with dehydration, babies will
need to be rehydrated and then fed
Feeding Feeding inhibits enterohepatic circulation of
bilirubin
Important Important to watch fluid status for excretion
of bilirubin

The The TSB level for discontinuing
phototherapy depends on the age at which
phototherapy was started and the etiology
For For infants readmitted after birth admission, you
can discontinue usually at 13-14 13 14 mg/dL with a
follow up visit 24 hours after discharge
There There is no need for a rebound bilirubin, unless
there is hemolytic disease

Pharmacological Therapy
Phenobarbital
Phenobarbital
Albumin Albumin
Tin Tin-mesoporphyrin
mesoporphyrin
Inhibits Inhibits heme oxygenase
Intravenous Intravenous gamma-globulin
gamma globulin
Shown Shown to reduce the need for exchange
transfusions in isoimmune hemolytic disease

Guidelines for exchange transfusion in infants 35 or more weeks' gestation
Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316
Copyright ©2004 American Academy of Pediatrics

Exchange Exchange transfusions are recommended if
TSB is greater than or equal to 25 mg/dL in
a healthy full term infant
If If rate of rise is greater than or equal to 0.5
mg/dL/hour
If If there is active hemolysis or other risk
factors, then an exchange transfusion may
be warranted at a lower bilirubin level

Exchange Transfusion
With With a exchange transfusion, approximately
85% of erythrocytes will be replaced
Serum Serum bilirubin levels should decrease by
50%

American Academy of Pediatrics
In In 1994 the AAP established practice
parameters for the management of
hyperbilirubinemia
Revised Revised in 2004

Management Management of Hyperbilirubinemia in the
Newborn Infant 35 or More Weeks of
Gestation
Goals: Goals:
Promote and support successful breastfeeding
Establish nursery protocols for the identification and
evaluation of hyperbilirubinemia
Measure the total serum bilirubin or transcutaneous
bilirubin levels on infants jaundiced in the first24
hours

Recognize that visual estimation of the degree of
jaundice can lead to errors, particularly in darkly
pigmented infants
Interpret all bilirubin levels according to the infant’s infant s
age in hours
Recognize that infants less than 38 weeks’ weeks gestation,
particularly those who are breast fed, are at higher risk
of developing hyperbilirubinemai and require closer
surveillance and monitoring
Perform a systematic assessment on all infants before
discharge for the risk of severe hyperbilirubinemia

Provide parents with written and verbal information
about newborn jaundice
Provide appropriate follow-up follow up based on the time of
discharge and the risk assessment
Treat infants, when indicated, with phototherapy or
exchange transfusion

Infant Infant Discharged
< 24 hours
24 to 47.9 hours
48 to 72 hours
Follow Up
Should Be Seen By Age
72 hours
96 hours
120 hours

Fanaroff, Fanaroff, Martin. Neonatal-Perinatal
Neonatal Perinatal
Medicine, 7 th Edition.
Management Management of Hyperbilirubinemia in the
Newborn Infant 35 or More Weeks of
Gestation, Pediatrics 2004;114;297-316
2004;114;297 316
Taeusch, Taeusch, Ballard, Gleason. Avery’s Avery s
Diseases of the Newborn, 8 th Edition