Neonatal Unconjugated Hyperbilirubinemia
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Transcript Neonatal Unconjugated Hyperbilirubinemia
Clinical Case
JR, 7 do hispanic BB, twin B, presented to UCCH
ER with jaundice on 5/9/06
DOB – 5/3/06, at OSH in Indiana
NVD, GA 38 weeks, APGARs 9/9
BWt 3.18 kg (7#0oz)
Maternal Hx: 31 yo G2P3 now, good PNC,
uncomplicated pregnancy
PNL – B+/RPR NR/R Imm/HepB NR/HIV NR/GBS-
Perinatal course
Initial PE unremarkable; + some facial bruising
noted
Wt 2.9 kg
Feeding BM/E20 – well per GCN records
Voiding and stooling well
Discharged at 48 hrs
D/C Wt – 2.03 kg
Mom told that baby had “borderline” jaundice
To call Pediatrician if she sees baby gets yellow
Baby was OK at home, eating well – 10-15
min each breast
Stooling well – per mother
On DOL 5 mother thought babies look
yellow and called the PMD
She was told to go to the hospital next day
for Bili check
Labs
Baby B+/CoombsMom B+
Work Up
CBC – WBC 13.6, H/H 18.9/54, Plt 301
Diff N26, Bn4
Retic count 0.7%
Bilirubin
5/5/06 - @48 hrs (OSH) – 13.0/0.4
5/9/06 – DOL 7 – (OSH) – 30.9/0.6
5/9/04 – UCCH – 31.5/0.8
Sibling’s Bili was 21 – admitted to Peds
Floor for phothotherapy
ER course
VSS, baby was jaundiced and “sleepy”
Placed under phothotherapy
Given IVF
Admitted to PICU for exchange transfusion
Here comes the NICU
0230 – NICU fellow received a call from
upstairs to help with the exchange transfusion
By 0530 baby was in the PICU
Blood ordered
UVC placed
Double volume exchange transfusion was
done
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 visible manifestation in the skin and sclera
of elevated bilirubin concentrations
Adults are usually jaundiced when bilirubin
levels exceed 2 mg/dL
Neonates appear jaundiced when serum total
bilirubin (STB) levels reach 5-7 mg/dL
Some degree of jaundice develops in 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 hyperbilirubinemia, a STB > 2.0 mg/dL,
is virtually universal
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 Bilirubin Production
Decreased Binding and Transport Capacity
Limited Conjugation and Excretion Capacity
Increased Enterohepatic Circulation of
Bilirubin
Bilirubin is the breakdown product of
hemoglobin
Lysis of red cells releases heme from
hemoglobin
Heme is then converted to bilirubin and
excreted
Bilirubin Synthesis
There is increased production of bilirubin in the
newborn because of:
Increased rate of degradation
A shortened circulating erythrocyte life span (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 bilirubin is quickly bound to
albumin in the serum
Newborns have reduced albumin
concentrations and consequently a lower
plasma binding capacity for bilirubin
There is consequently more free bilirubin in
the serum
It is the free bilirubin that is believed to
cause neurological damage in newborns
Conjugation and Excretion
During fetal life, removal of bilirubin is
accomplished by the placenta
In the newborn, bilirubin excretion requires
conversion of the nonpolar unconjugated
bilirubin into a more polar water-soluble
substance, conjugated bilirubin
Blood flow through the hepatic artery develops
during the first week of life
The ductus venosus allows blood to bypass the
liver completely
Conjugation depends on the maturity of the liver
cell
UDPGT
UDPGT in the newborn liver must be
induced
UDPGT activity is extremely low in infants
born at less than 30 weeks, 0.1% of adult
levels
This activity increases to only 1% at term
The activity reaches adult levels by 6-12
weeks of age
Conjugation
Bilirubin dissociates from circulating albumin
before its entry into the liver cell
Bilirubin enters the liver by a process of carriermediated diffusion
It is carried by hepatic ligandin (Y protein) and Z
protein
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 conjugation, bilirubin is then excreted into
bile in the intestine
Increased Enterohepatic Circulation
Conjugated bilirubin is unstable and can be
easily hydrolyzed back to unconjugated bilirubin
and reabsorbed through the intestinal mucosa
High mucosal beta-glucuronidase activity leads
to increased hydrolysis
An alkaline environment also facilitates
hydrolysis
In the newborn, the relative lack of intestinal
bacterial flora to reduce bilirubin to urobilinogen
further increases the bilirubin pool
Neonatal Hyperbilirubinemia
Physiologic Jaundice
A progressive rise in unconjugated bilirubin to a
peak of 5-6 mg/dL between 60 and 72 hours of
life in white and African-American babies and
10-14 mg/dL between 72-120 hours of life in
Asian babies
A rapid decline in TSBs occurs by the 5th or 710th day respectively
Pathologic Unconjugated
Hyperbilirubinemia
Pathologic hyperbilirubinemia is defined as a
prolonged or exaggerated
hyperbilirubinemia
Occurs because of disorders of:
Production
Hepatic Uptake
Conjugation
Enterohepatic Circulation
Disorders of Production
Isoimmunization
Erythrocyte Enzymatic Defects
Erythrocyte Structural Defects
Infection
Sequestration
Polycythemia
Isoimmunization
Rh Incompatibility
ABO Incompatibility
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 D antigen may produce sensitization
with a fetomaternal hemorrhage as small as
0.1 mL
At one time this was the most common
cause of kernicterus; but with the use of
RhoGAM (anti-D immunoglobulin G) and
careful fetal monitoring, the incidence and
severity have decreased
ABO Incompatibility
This is a hemolytic disease caused by a
reaction of maternal anti-A or anti-B
antibodies with fetal A or B antigens
Usually milder than Rh
Almost exclusively in type O mothers
Jaundice appears at 24-72 hours
Half of infants with a positive Coombs show
hemolysis and some with a negative Coombs
have hemolysis
Minor Blood Groups
Kell, Kidd, Duffy, Lutheran
< 2 % of hemolysis from isoimmunization
Erythrocyte Enzymatic Defects
Glucose-6-Phosphate Dehydrogenase
Deficiency
Pyruvate Kinase Deficiency
These defects may have profound effects on
erythrocyte function and life span
Glucose-6-Phosphate
Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase deficiency
(G6PD) is a common disease, especially in people
of Mediterranean; African; and Asian decent
G6PD deficiency occurs in 11-13% of African
Americans
Estimated 200-400 million people carry the gene
X-linked
Presentation is heterogeneous
Hemolysis occurs, but can be absent
Hyperbilirubinemia occurs between 24 and 72
hours of life
RBCs are unable to activate the pentose
phosphate metabolic pathway
And consequently cannot defend against
oxidative stress
Sepsis and Vitamin K analogues
Severity of disease depends on type and
amount of stress
Pyruvate Kinase Deficiency
This is the second most common cause of
enzymatic-related hemolytic anemia
Autosomal recessive
It is common in people of Northern
European decent
It is an enzyme required for production of
ATP in RBCs
Its deficiency leads to decreased RBC life
span and hemolysis
Erythrocyte Structural Defects
Hereditary Spherocytosis
Hereditary Elliptocytosis
These defects alter RBC structure and cause
sequestration
Hereditary Elliptocytosis
Incidence of 1:4000
Autosomal dominant
Abnormality in spectrin or glycophorin C
Hemolysis and hyperbilirubinemia are
unusual in the newborn period
Hereditary Spherocytosis
Incidence of 1:5000
Autosomal dominant
Heterogeneous presentation
Fifty percent present with hemolytic anemia,
hyperbilirubinemia, reticulocytosis, and
increased erythrocyte osmotic fragility
Infection
Hyperbilirubinemia is believed to be
secondary to hemolysis
Sepsis may impair conjugation also leading
to increased bilirubin levels
Sequestration
Sequestration of blood in body cavities may
lead to hyperbilirubinemia as the body
metabolizes hemoglobin
Cephalohematomas, subdural hematomas,
subgaleal hematomas
Excessive bruising
Polycythemia
The increase in red blood cell mass has the
potential to overload the newborn
hemoglobin metabolism capacities
Disorders of Hepatic Uptake
Gilberts Syndrome
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-Najjar Syndrome
Transient Familial Neonatal
Hyperbilirubinemia (Lucey-Driscoll Syndrome)
Pyloric Stenosis
Hypothyroidism
Crigler-Najjar Syndrome
Type I
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 II
There is various degree of decrease of UDPGT
activity
Typically benign
There is unconjugated hyperbilirubinemia in the
first few days of life that does not exceed 20
mg/dL
Hyperbilirubinemia persists into adulthood
The treatment is phenobarbital
Transient Familial Neonatal
Hyperbilirubinemia
Neonates develop severe nonhemolytic
hyperbilirubinemia
Their serum contains high concentrations of
glucuronyl transferase inhibitors
This inhibitor decreases by about 14 days of
life and consequently hyperbilirubinemia
resolves
Pyloric Stenosis
10-25% of babies with pyloric stenosis have
hyperbilirubinemia at the time of
presentation
Hepatic glucuronyl tranferase activity is
reduced
Surgical correction improves bilirubin levels
Hypothyroidism
UDPGT activity is deficient and remains low
for weeks with hypothyroidism
Disorders of Enterohepatic
Circulation
Breast Feeding Jaundice
Breast Milk Jaundice
Breast Feeding Jaundice
Unconjugated hyperbilirubinemia is secondary to a
suboptimal establishment of breastfeeding
Newborns are under-hydrated and in a state of
starvation.
They also have delayed passage of meconium
Enterohepatic reuptake of bilirubin is consequently
increased, leading to hyperbilirubinemia
Treatment and prevention include frequent
feedings (8-12/day)
Breast Milk Jaundice
Occurs after 3-5 days of life, typically at 2-3
weeks of life
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 need to stop breastfeeding unless
bilirubin levels are dangerously high
WHY DO WE WORRY ABOUT
HYPERBILIRUBINEMIA?
Sequelae
Bilirubin may penetrate the brain cell and
cause neuronal dysfunction or death if not
carefully managed
Bilirubin causes staining and necrosis of
neurons in the basal ganglia, hippocampal
cortex, subthalamic nuclei, and cerebellum
which is followed by gliosis
50%of patients with kernicterus die
Acute Bilirubin Encephalopathy
Phase 1 - poor suck, hypotonia, and
depressed sensorium
Phase 2 - fever and hypertonia or
opisthotonos
Phase 3 - less hypertonia, high pitched cry,
hearing and visual abnormalities, poor
feeding, athetosis
Kernicterus
Long term sequelae:
Chorioathetoid cerebral palsy
Sensorineural hearing loss
Upward gaze palsy
Dental-enamel dysplasia
Mental retardation
SO, WHAT CAN WE DO?
Diagnosis and Management
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 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 newborn should be assessed,
especially if discharged before 72 hours of
life
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 zone
Jaundice in the first 24h
Hemolytic disease
Gestational age 35-36 weeks
Sibling received phototherapy
Cephalohematoma or bruising
Poor breastfeeding
East Asian descent
Carbon Monoxide
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 breakdown of hemoglobin by heme
oxygenase produces free iron and carbon
monoxide in equimolar amounts
The carbon monoxide formed by heme
degradation is excreted unchanged by the lungs.
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 of clinical jaundice requires digital
pressure and the proper lighting, preferably
daylight
If clinical jaundice is detected, a total and
direct serum bilirubin or transcutaneous
bilirubin (TcB) should be measured and
plotted on the nomogram
When should I do more?
If:
Cord bilirubin is greater than 4 mg/dL
A rate of rise greater than or equal to 0.5
mg/dL/hour over a 4-8 hour period
An increase of 5 mg/dL per day
13-15 mg/dL in a term infant
10 mg/dL in a preterm infant
If jaundice persist greater than 10 days
Then what?
Determination of maternal blood group and Rh
type
Screen for antibodies directed against minor
erythrocyte antigens
Determination of newborns blood type and Rh
type
Direct Coombs test
Hemoglobin and Hematocrit
Peripheral blood smear
Reticulocyte count
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
Copyright ©2004 American Academy of Pediatrics
Helpful resources
Bili-Aid
Phototherapy
The main mechanism of action
Geometric photoisomerization of unconjugated
bilirubin that can then be excreted without
conjugation
Technique
Wavelength
Bilirubin absorbs light maximally in the blue
range (420-500 nm), with a peak at 460 nm for
albumin-bound bilirubin and 440 nm for free
bilirubin
Special blue lamps have a spectrum between 420480
Irradiance
The energy output measured in microwatts per
square centimeter per nanometer
Optimal level is 11 microwatts per square
centimeter per nanometer
Intensive phototherapy is 30 microwatts per
square centimeter per nanometer
Positioning
Within 10 cm of the patient for fluorescent tubes
Surface area
The greater the surface area exposed, the more
effective the phototherapy
Hydration
There is no evidence that excessive fluid
administration affects the serum bilirubin
concentration
If admitted with dehydration, babies will
need to be rehydrated and then fed
Feeding inhibits enterohepatic circulation of
bilirubin
Important to watch fluid status for excretion
of bilirubin
The TSB level for discontinuing
phototherapy depends on the age at which
phototherapy was started and the etiology
For infants readmitted after birth admission, you
can discontinue usually at 13-14 mg/dL with a
follow up visit 24 hours after discharge
There is no need for a rebound bilirubin, unless
there is hemolytic disease
Pharmacological Therapy
Phenobarbital
Albumin
Tin-mesoporphyrin
Inhibits heme oxygenase
Intravenous gamma-globulin
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 transfusions are recommended if
TSB is greater than or equal to 25 mg/dL in
a healthy full term infant
If rate of rise is greater than or equal to 0.5
mg/dL/hour
If there is active hemolysis or other risk
factors, then an exchange transfusion may
be warranted at a lower bilirubin level
Exchange Transfusion
With a exchange transfusion, approximately
85% of erythrocytes will be replaced
Serum bilirubin levels should decrease by
50%
American Academy of Pediatrics
In 1994 the AAP established practice
parameters for the management of
hyperbilirubinemia
Revised in 2004
Management of Hyperbilirubinemia in the
Newborn Infant 35 or More Weeks of
Gestation
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
age in hours
Recognize that infants less than 38 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 based on the time of
discharge and the risk assessment
Treat infants, when indicated, with phototherapy or
exchange transfusion
Follow Up
Infant Discharged
< 24 hours
24 to 47.9 hours
48 to 72 hours
Should Be Seen By Age
72 hours
96 hours
120 hours
Fanaroff, Martin. Neonatal-Perinatal
Medicine, 7th Edition.
Management of Hyperbilirubinemia in the
Newborn Infant 35 or More Weeks of
Gestation, Pediatrics 2004;114;297-316
Taeusch, Ballard, Gleason. Avery’s
Diseases of the Newborn, 8th Edition