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+/CoombsMom 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