Lecture no.

Neonatal hyperbilirubinemia and jaundice

Case 1
This is a jaundiced, 4 day old, 3.1 kg, appropriate for gestational age (AGA) Asian female
infant born at term to a 25 year old A+ primiparous woman with gestational diabetes. The pregnancy
was otherwise uneventful. Labor was augmented with oxytocin. The baby was discharged home on
day of life 2 at which time her weight was down 4% from birth weight and she had mild facial
jaundice. In the hospital, she was breast fed every 3 hours and had 2 wet diapers and one meconium
stool over a 24 hour period. On day 3, her parents gave her water on two occasions as she appeared
hungry despite regular and frequent breast feeding attempts. In addition, they noted an increase in
the degree of jaundice, but failed to address it after being reassured by family members that
jaundice is common. They also had an appointment to see their pediatrician the following day. In
the office, on day 4, mother reports that she is breastfeeding the baby every three hours and that
there have been 2 wet diapers per day. The urine is described as dark yellow in color and the stools
appear dark green.
Exam: VS T 37.8, P 162, RR 55, BP 63/45. Weight 2.7 kg (25%ile), length 50 cm (75%ile), head
circumference 34 cm (75%ile). The infant is jaundiced and irritable. The anterior fontanel is slightly
sunken, the oral mucosa is tacky, and there is jaundice to the lower extremities. No
cephalohematoma or bruising is present. The sclera of both eyes are icteric. Muscle tone and
activity are normal. The remainder of the physical exam is normal.
The total bilirubin is 20 mg% with a direct fraction of 0.7 mg%. She is admitted to the
hospital for phototherapy, supplementary formula feedings, and lactation consultation. By the
following day, the bilirubin has decreased to 12 mg% and she is discharged home on breast milk
feedings. The baby is scheduled for follow-up with both the pediatrician and the lactation
consultant.
Etiology: breast fed infant

Case 2
A 4 day old, 36 week gestation male presents to his primary care physician with worsening
jaundice. The maternal blood type is 0+. He was discharged home on day 2 of life after successfully
breastfeeding for a 24 hour period. At the time of discharge, his physical exam was remarkable for
mild jaundice and a cephalohematoma. At today's visit there is an 8% weight loss from birth and a
history of "fair" urine output and yellow stools. He is markedly jaundiced and has a resolving
cephalohematoma. Other physical exam findings are remarkable for a normal cry, flat anterior
fontanelle, moist oral mucosa and a normal neurologic examination. The total bilirubin is 27 mg%
with a direct fraction of 1 mg%. He is admitted to the hospital where phototherapy is initiated. His
blood type is A+ with a positive direct Coombs. The hematocrit is 42% with a reticulocyte count of
12% and the pathologist identifies spherocytes on the blood smear. The G6PD is pending. After one
hour of phototherapy, a repeat bilirubin is 25 mg%. The G6PD is normal. The decision is made to
perform a double volume exchange transfusion. The infant remains on phototherapy for an
additional 2 days and is discharged home after being off phototherapy for 1 day. The serum bilirubin
on the day of discharge is 12 mg% and he passes an auditory brainstem response test.
Etiology: ABO incompatibility +/- resorbtion from cephalohematoma

***
 More than 50% of term neonates become jaundiced. The primary reason for the level of
concern over jaundice and hyperbilirubinemia in the newborn is the association of
hyperbilirubinemia with kernicterus, which is a rare, but devastating neurologic complication of
hyperbilirubinemia.
Kernicterus can occur without signs and symptoms, but acute kernicterus in term babies is
usually characterized by:
– changes in muscle tone,
– drowsiness, poor feeding,
– a high pitched cry,
– apnea, possible seizures,
– fever, and
– death.
Although kernicterus is rare, it is potentially preventable by being aware of the risk factors,
mainly indirect hyperbilirubinemia and hemolysis.

Neonatal jaundice refers to yellow coloration of the skin and the sclera (whites of the eyes) of
newborn babies that results from accumulation of bilirubin in the skin and mucous membranes. This
is associated with a raised level of bilirubin in the circulation, a condition known as
hyperbilirubinemia.
Jaundice can be detected clinically with tactile blanching of the skin revealing an underlying
yellow color. The examination should be done in a well-lit, neutral light. Jaundice usually begins on
the face and progresses caudally. The presence of scleral icterus should be assessed. Generally, the
farther the jaundice progresses down the body, the higher the total serum bilirubin. The more
intense the color (which can approach a yellow-orange) also suggests a higher total serum bilirubin.
Jaundice may be clinically detected with a total serum bilirubin of 5 mg/dl. Any time there is
uncertainty, the recommendation is to check a total serum bilirubin. If a patient is under
phototherapy, jaundice is difficult to visually assess because phototherapy preferentially reduces
bilirubin concentrations near the skin. If assessing a patient under phototherapy, jaundice severity is
best determined by examining unexposed sites (e.g., under the eye shield) and phototherapy should
be interrupted during the exam.
If the skin is green or bronze colored, this suggests an elevated direct (conjugated) bilirubin
fraction, so a fractionated bilirubin should be obtained. The patient should also be assessed for
pallor, plethora and hepatosplenomegaly.

It is essential to distinguish whether the jaundice is physiologic or pathologic. Jaundice noted

within the first 24 hours is pathologic and a total serum bilirubin should be drawn . Early jaundice is
usually related to:
– hemolysis,
– infection,
– drug effect,
– neonatal hepatitis or liver enzyme defects.
A total bilirubin greater than 17 mg/dl in a full term neonate is pathologic. Jaundice that
persists beyond 2 weeks should be evaluated beginning with a fractionated bilirubin. Direct
hyperbilirubinemia is also considered pathologic, (i.e., direct bilirubin >1.5-2 mg/dl or > 20% of the
total bilirubin).
The assessment and management of hyperbilirubinemia is different depending on the age
and maturity of the newborn baby. For instance, a bilirubin of 11 mg/dl has a different significance
under different circumstances. It would be considered physiologic (not pathologic) in a 4 day old
term breast fed baby, while the same level would be pathologic on day 1. A serum bilirubin of 11
mg/dl would also be concerning in a sick, two day old, 27 week gestation premature infant.

Hyperbilirubinemia is more common in neonates due to:

– the shortened life span of their red blood cells,
– declining hematocrit,
– immature liver uptake and conjugation of bilirubin, and
– increased intestinal reabsorption of bilirubin.
Hemoglobin breakdown releases iron, carbon monoxide, and biliverdin. The latter is reduced
to bilirubin, which enters the liver. Uridine diphosphate glucuronyltransferase (UDPGT) conjugates
bilirubin into an excretable form. Intestinal bacteria can deconjugate bilirubin allowing for
reabsorption of bilirubin into the circulation. This increased enterohepatic circulation occurs
particularly in preterm neonates with diminished stool passage.
Most unconjugated bilirubin is bound to albumin, but free unconjugated bilirubin (a form
unbound to albumin) can enter the brain (i.e., it can cross the blood brain barrier). Sulfonamides are
contraindicated in the neonatal period because they displace bilirubin from albumin. Conditions that
disrupt the integrity of the blood brain barrier, such as infection (e.g., sepsis, meningitis, and
congenital viral infections), acidosis, prematurity, and hyperosmolarity, place the infant at increased
risk for kernicterus.
Hemolytic causes of hyperbilirubinemia (e.g., Rh incompatibility and G6PD deficiency) have
higher risks of kernicterus compared to other causes of jaundice at comparable bilirubin levels.

Direct (conjugated) hyperbilirubinemia cases are relatively uncommon. The differential

diagnosis includes
– neonatal hepatitis,
– biliary atresia, sepsis,
– metabolic disorders (e.g., galactosemia), and
– hepatotoxicity from hyperalimentation.
A detailed discussion of direct hyperbilirubinemia is beyond the scope of this chapter. One of
the principal diagnoses to exclude is biliary atresia which is associated with dark urine or light colored
stool. Early surgical intervention done prior to 2 months of age reduces mortality and the probability
of future liver transplantation in cases of biliary atresia.

Indirect (unconjugated) hyperbilirubinemia, is more common and presents a risk for

kernicterus. The most common causes of indirect hyperbilirubinemia are:
– physiologic,
– breast milk inhibitors,
– breast feeding with a large postnatal weight loss,
– ABO incompatibility,
– cephalohematoma and bruising (resorbtion).
Rh incompatibility is less common, but represents a high risk of kernicterus.
Breastfeeding jaundice is related to inadequate intake by the newborn (i.e., components of
poor feeding and dehydration are contributory). Breast milk jaundice (i.e., due to breast milk itself)
has its onset later than breastfeeding jaundice. It is related to increased enterohepatic circulation
and is relatively uncommon.
Uncommon causes of indirect hyperbilirubinemia include other RBC membrane defects (e.g.,
hereditary spherocytosis) and hemoglobinopathies.

A rise in bilirubin greater than 0.5 mg/dl per hour and failure to control hyperbilirubinemia
despite phototherapy are suggestive of hemolytic disease (blood type incompatibilities or red blood
cells defects). ABO incompatibility occurs in approximately 20% to 25% of pregnancies of which
significant hemolysis occurs in 10%. G6PD deficiency (X-linked recessive) occurs in African,
Mediterranean, and Southeast Asian ethnic groups.
Prenatal testing includes maternal blood typing and screening for antibodies to major RBC
antigens.
Rh incompatibility occurs with an Rh negative mother (usually not a primigravida) and an Rh
positive baby. The routine use of RhoGAM at 28 weeks gestation and following delivery or pregnancy
termination is generally effective in preventing maternal Rh sensitization (i.e., the production of anti-
Rh antibodies by the mother). An adequate amount of RhoGAM must be given to neutralize the
amount of Rh Ag or the volume of blood from a feto-maternal transfusion. The Rh antigen is
markedly more antigenic than the A or B antigen.
In ABO incompatibility, the mother's blood type is O. More commonly, the babies blood type
is A rather than B. Hemolysis in ABO isoimmunization usually has a positive direct antiglobulin
testing (DAT), also known as a direct Coombs test. Clinically significant hemolysis is associated with
decreasing hemoglobin, hematocrit and an elevated reticulocyte count. Due to phagocytic removal
of antibody and portions of the RBC membrane, the smear in ABO incompatibility may have
spherocytes, mimicking spherocytosis. Therefore, a CBC with differential, reticulocyte count and a
smear should be requested with suspected hemolysis. Nucleated RBCs may also be present with
more severe causes of hemolysis, but is classically associated with Rh incompatibility.

Management

At 25 to 48 hours, phototherapy is recommended at a bilirubin of greater than or equal to 15

mg/dl. At 49 to 72 hours, the threshold increases to 18 mg/dl. From greater than 72 hours, the
threshold is 20 mg/dl. If G6PD deficiency or other kernicterus risk factors are present, it is advisable
to have a lower threshold to begin phototherapy. Table 1 below describes hyperbilirubinemia
treatment guidelines for preterm infants. Table 2 below describes hyperbilirubinemia treatment
guidelines for term infants.

Table 1 - Suggested Maximum Indirect Serum Bilirubin Concentrations (mg%) in Preterm

Infants

Birthweight (g) Uncomplicated Complicated*

<1,000 12-13 10-12
1,000-1,250 12-14 10-12
1,251-1,499 14-16 12-14
1,500-1,999 16-20 15-17
2,000-2,500 20-22 18-20

For table 1 above, phototherapy is usually started at 50% to 70% of the maximum indirect
levels. If values greatly exceed this level, if phototherapy is unsuccessful in reducing the maximum
bilirubin level, or if there are signs of kernicterus, exchange transfusion is indicated.
*Complicated cases include those associated with perinatal asphyxia, acidosis, hypoxia,
hypothermia, hypoalbuminemia, meningitis, intraventricular hemorrhage, hemolysis, hypoglycemia,
or signs of kernicterus.
 Table 2 - Treatment Strategies for Indirect Hyperbilirubinemia in Healthy Term Infants
without Hemolysis
Intensive phototherapy
and preparation for
Age exchange transfusion if Exchange
(hrs) Phototherapy phototherapy fails transfusion

24-48 15-18 25 20
49-72 18-20 30 25
>72 20 30 25

If the initial bilirubin on presentation is high, intense phototherapy should be initiated and
preparation made for exchange transfusion. If the phototherapy fails to reduce the bilirubin level to
the levels noted on the column to the right (table 2), an exchange transfusion should be initiated.
Intensive phototherapy usually reduces serum bilirubin levels 1 to 2 mg/dl in 4 to 6 hours. This is
often done with IV fluid administration at 1 to 1.5 times maintenance and oral alimentation should
continue.

Guidelines for phototerapy

The mainstay of treatment is phototherapy with a wavelength of 450 nm. It induces

photoisomerization of bilirubin, forming lumirubin which is water soluble and excreted in the urine.
Phototherapy is generally delivered by fluorescent lights, spot lights, or fiberoptics, the latter
generating less heat. Unless there is a high risk for an exchange transfusion, phototherapy can
usually be discontinued for an hour to allow for neonatal care. Discontinuation of phototherapy in a
term baby without hemolysis generally is not associated with rebound hyperbilirubinemia, i.e., a
significant increase in bilirubin.
 Phototherapy's major role is to avoid an exchange transfusion. By implementing
phototherapy, the belief is that this will reduce the likelihood that bilirubin levels will reach these
exchange transfusion levels, thus avoiding an exchange transfusion.
In term neonates with hemolytic disease, if the bilirubin approaches 20 mg/dl despite medical
management, informed consent should be obtained for an exchange transfusion. In preterm
neonates less than 37 weeks gestation, most neonatologists will await serum bilirubin levels of 15-20
mg/dl before considering an exchange. Exchange transfusion removes bilirubin and antibodies
causing hemolysis. Twice the patient's blood volume is exchanged (i.e., double volume exchange –
about 160ml/kg) while monitoring cardiovascular stability. Risk factors include those related to
catheters, electrolyte imbalance and blood products superimposed onto preexisting medical
problems. Thrombocytopenia is common. Necrotizing enterocolitis, graft versus host disease, and
death have also been reported as complications of exchange transfusion.

Although extreme bilirubin levels are associated with kernicterus, the adverse effects of
moderate hyperbilirubinemia may be more difficult to identify. For example, subclinical adverse
effects, learning disabilities or behavioral disorders would be more difficult to causally link to
moderate hyperbilirubinemia, since this would only be manifested in later childhood.
Most cases of hyperbilirubinemia resolve without sequelae. However, there may be
impairment of auditory nerve conduction. After significant hyperbilirubinemia, the patient should
undergo auditory brainstem response testing.

Questions

1. Which of the following factors leads to neonatal hyperbilirubinemia?

a. Shortened neonatal red cell life span.
b. Impaired excretion of unconjugated bilirubin.
c. Limited conjugation of bilirubin in the liver.
d. Increased entero-hepatic circulation.
e. All of the above.

2. A total serum bilirubin >17 mg% in a term neonate is:

a. physiologic
b. pathologic

3. In G6PD deficiency, there is hyperbilirubinemia on the basis of:

a. hemolysis
b. decreased conjugation
c. both
d. neither

4. True/False: Systemic sulfonamide medications are avoided in the newborn because they
displace bilirubin from albumin and increase free bilirubin.

5. Discontinuation of phototherapy in a healthy, term neonate is usually associated with

rebound hyperbilirubinemia.

6. Which of the following factors should be strongly considered in determining whether an

exchange transfusion is indicated in a term neonate with an indirect bilirubin of 21 mg%.
a. Age of the neonate (time since birth).
 b. Whether the cause is hemolytic or non-hemolytic.
c. The presence of other clinical factors such as intraventricular hemorrhage or
meningitis.
d. All of the above.
e. None of the above.

7. True/False: Rh incompatibility occurs with an Rh negative mother (usually not a

primigravida) and an Rh positive baby.
Answers to questions
1.e,
2.b,
3.c,
4.True,
5.False,
6.d
7.True