Neonatal Jaundice

Neonatal jaundice or Neonatal hyperbilirubinemia, or Neonatal icterus (from the Greek
word ἴκτερος), attributive adjective: icteric, is a yellowing of the skin and other tissues of a
newborn infant. A bilirubin level of more than 85 μmol/l (5 mg/dL) manifests
clinical jaundice in neonates whereas in adults a level of 34 μmol/l (2 mg/dL) would lookicteric. In
newborns, jaundice is detected by blanching the skin with digital pressure so that it reveals
underlying skin and subcutaneous tissue.
[1]
Jaundiced newborns have an apparent icteric sclera,
and yellowing of the face, extending down onto the chest.
In neonates, the dermal icterus is first noted in the face and as the bilirubin level rises proceeds
caudal to the trunk and then to the extremities.
[2]
This condition is common in newborns affecting
over half (50–60%) of all babies in the first week of life.
[3]

Notoriously inaccurate rules of thumb have been applied to the physical exam of the jaundiced
infant.
[citation needed]
Some include estimation of serum bilirubin based on appearance. One such rule of
thumb includes infants whose jaundice is restricted to the face and part of the trunk above
the umbilicus, have the bilirubin less than 204 μmol/l (12 mg/dL) (less dangerous level). Infants
whose palms and soles are yellow, have serum bilirubin level over 255 μmol/l (15 mg/dL) (more
serious level). Studies have shown that trained examiners assessment of levels of jaundice show
moderate agreement with icterometer bilirubin measurements.
[2]
In infants, jaundice can be
measured using invasive or non-invasive methods.



Classification[edit]
Physiological jaundice[edit]
Most infants develop visible jaundice due to elevation of unconjugated bilirubin concentration during
their first week. This common condition is called physiological jaundice. This pattern
of hyperbilirubinemia has been classified into two functionally distinct periods.
Phase one
1. Term infants - jaundice lasts for about 10 days with a rapid rise of serum bilirubin up to
204 μmol/l (12 mg/dL).
2. Preterm infants - jaundice lasts for about two weeks, with a rapid rise of serum bilirubin up to
255 μmol/l (15 mg/dL).
Phase two - bilirubin levels decline to about 34 μmol/l (2 mg/dL) for two weeks, eventually
mimicking adult values.
1. Preterm infants - phase two can last more than one month.
2. Exclusively breastfed infants - phase two can last more than one month.
Causes[edit]
Mechanism involved in physiological jaundice are mainly:
 Relatively low activity of the enzyme glucuronosyltransferase which normally
converts unconjugated bilirubin to conjugated bilirubin that can be excreted into the
gastrointestinal tract.
[4]
Before birth, this enzyme is actively down-regulated, since bilirubin needs
to remain unconjugated in order to cross the placenta to avoid being accumulated in the
fetus.
[5]
After birth, it takes some time for this enzyme to gain function.
 Shorter life span of fetal red blood cells,
[4]
being approximately 80 to 90 days in a full
term infant,
[6]
compared to 100 to 120 days in adults.
 Relatively low conversion of bilirubin to urobilinogen by the intestinal flora, resulting in relatively
high absorption of bilirubin back into the circulation.
[4]




Pathological Jaundice of Neonates (Unconjugated Pathological
Hyperbilirubinemia)[edit]
Any of the following features characterizes pathological jaundice:
1. Clinical jaundice appearing in the first 24 hours or greater than 14 days of life.
2. Increases in the level of total bilirubin by more than 8.5 μmol/l (0.5 mg/dL) per hour or
(85 μmol/l) 5 mg/dL per 24 hours.
3. Total bilirubin more than 331.5 μmol/l (19.5 mg/dL) (hyperbilirubinemia).
4. Direct bilirubin more than 34 μmol/l (2.0 mg/dL).

Causes of jaundice[edit]
In neonates, jaundice tends to develop because of two factors - the breakdown of fetal
hemoglobin as it is replaced with adult hemoglobin and the relatively immature hepatic metabolic
pathways which are unable to conjugate and so excrete bilirubin as quickly as an adult. This causes
an accumulation of bilirubin in the blood (hyperbilirubinemia), leading to the symptoms of jaundice.
If the neonatal jaundice does not clear up with simple phototherapy, other causes such as biliary
atresia, PFIC, bile duct paucity, Alagille syndrome, alpha 1-antitrypsin deficiency, and other pediatric
liver diseases should be considered. The evaluation for these will include blood work and a variety of
diagnostic tests. Prolonged neonatal jaundice is serious and should be followed up promptly.
Severe neonatal jaundice may indicate the presence of other conditions contributing to the elevated
bilirubin levels, of which there are a large variety of possibilities (see below). These should be
detected or excluded as part of the differential diagnosis to prevent the development of
complications. They can be grouped into the following categories:



Neonatal jaundice








Unconjugated
bilirubin

Conjugated
bilirubin









Pathologic

Physiological
jaundice of
Neonates

Hepatic

Post-
hepatic










Hemolytic

Non-hemolytic












Intrinsic
causes

Extrinsic
causes




Non Conjugated[edit]
Hemolytic[edit]
Intrinsic causes of hemolysis[edit]
 Membrane conditions
 Spherocytosis
 Hereditary elliptocytosis
 Systemic conditions
 Sepsis
 Arteriovenous malformation
 Enzyme conditions
 Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
 Pyruvate kinase deficiency
 Globin synthesis defect
 sickle cell disease
 Alpha-thalassemia, e.g. HbH disease
Extrinsic causes of hemolysis[edit]
 Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the maternal
blood gives a positive indirect Coombs test)
 Hemolytic disease of the newborn (ABO)
[1]

 Rh disease
[1]

 Hemolytic disease of the newborn (anti-Kell)
 Hemolytic disease of the newborn (anti-Rhc)
 Other blood type mismatches causing hemolytic disease of the newborn
Non-hemolytic causes[edit]
 Breast milk jaundice
 Cephalohematoma
 Polycythemia
 Urinary tract infection
 Sepsis
 Hypothyroidism
 Gilbert's syndrome
 Crigler-Najjar syndrome
 High GI obstruction
Conjugated[edit]
Hepatic causes[edit]
 Infections
 Sepsis
 Hepatitis A
 Hepatitis B
 TORCH infections
 Metabolic
 Galactosemia
 Alpha-1-antitrypsin deficiency, which is commonly missed, and must be considered in DDx
 Cystic fibrosis
 Dubin-Johnson Syndrome
 Rotor syndrome
 Drugs
 Total parenteral nutrition
 Idiopathic
Post-hepatic[edit]
 Biliary atresia or bile duct obstruction
 Alagille syndrome
 Choledochal cyst
Non-organic causes[edit]
Breastfeeding failure jaundice[edit]
"Breastfeeding jaundice" or "lack of breastfeeding jaundice," is caused by insufficient breast milk
intake,
[7]
resulting in inadequate quantities of bowel movements to remove bilirubin from the body.
This can usually be ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate
adequate milk production.
Breast Milk jaundice[edit]
Whereas breast feeding jaundice is a mechanical problem, breast milk jaundice is a biochemical
occurrence and the higher bilirubin possibly acts as an antioxidant. Breast milk jaundice occurs later
in the newborn period, with the bilirubin level usually peaking in the sixth to 14th days of life. This
late-onset jaundice may develop in up to one third of healthy breastfed infants.
[8]

 First, at birth, the gut is sterile, and normal gut flora takes time to establish. The bacteria in the
adult gut convert conjugated bilirubin to stercobilinogen which is then oxidized to stercobilin and
excreted in the stool. In the absence of sufficient bacteria, the bilirubin is de-conjugated by brush
border β-glucuronidase and reabsorbed. This process of re-absorption is called enterohepatic
circulation. It has been suggested that bilirubin uptake in the gut (enterohepatic circulation) is
increased in breast fed babies, possibly as the result of increased levels of epidermal growth
factor (EGF) in breast milk.
[9]
Breast milk also contains glucoronidase which will increase
deconjugation and enterohepatic recirculation of bilirubin.
 Second, the breast-milk of some women contains a metabolite of progesterone called 3-alpha-
20-beta pregnanediol. This substance inhibits the action of the enzyme uridine
diphosphoglucuronic acid (UDPGA) glucuronyl transferase responsible for conjugation and
subsequent excretion of bilirubin. In the newborn liver, activity of glucuronyl transferase is only at
0.1-1% of adult levels, so conjugation of bilirubin is already reduced. Further inhibition of bilirubin
conjugation leads to increased levels of bilirubin in the blood.
[10]
However, these results have not
been supported by subsequent studies.
[11]

 Third, an enzyme in breast milk called lipoprotein lipase produces increased concentration of
nonesterified free fatty acids that inhibit hepatic glucuronyl transferase, which again leads to
decreased conjugation and subsequent excretion of bilirubin.
[12]

Despite the advantages of breast feeding, there is a strong association of breast feeding with
neonatal hyperbilirubinemia and thus risk of kernicterus, though this is uncommon. Serum bilirubin
levels may reach as high as 30 mg/dL. Jaundice should be managed either with phototherapy or
with exchange blood transfusion as is needed. Breast feeds however need not be discontinued. The
child should be kept well hydrated and extra feeds given.

Treatment[edit]
The bilirubin levels for initiative of phototherapy varies depends on the age and health status of the
newborn. However, any newborn with a total serum bilirubin greater than 359 μmol/l ( 21 mg/dL)
should receive phototherapy.
[13]

Phototherapy[edit]
The use of phototherapy was first discovered, accidentally, at Rochford Hospital in Essex, England.
The ward sister (Charge Nurse) of the premature baby unit firmly believed that the infants under her
care benefited from fresh air and sunlight in the courtyard. Although this led to the first noticing of
jaundice being improved with sunlight, further studies only progressed when a vial of blood sent for
bilirubin measurement sat on a windowsill in the lab for several hours. The results indicated a much
lower level of bilirubin than expected based on the patient's visible jaundice. Further investigation
lead to the determination that blue light, wavelength of 420-448 nm, oxidized the bilirubin to
biliverdin, a soluble product that does not contribute to kernicterus. Although some pediatricians
began using phototherapy in the United Kingdom following Dr. Cremer's publishing the above facts
in the Lancet in 1958, most hospitals only began to regularly use phototherapy ten years later when
an American group independently made the same discovery.
[14][15]



newborn infant undergoing (white light) phototherapy to treat neonatal jaundice
Infants with neonatal jaundice are treated with colored light called
phototherapy. Physicians randomly assigned 66 infants 35 weeks of gestation to receive
phototherapy. After 15±5 the levels of bilirubin, a yellowish bile pigment that in excessive amounts
causes jaundice, were decreased down to 0.27±0.25 mg/dl/h in the blue light. This suggests that
blue light therapy helps reduce high bilirubin levels that cause neonatal jaundice.
[16]

Exposing infants to high levels of colored light changes trans-bilirubin to the more water soluble cis-
form which is excreted in the bile. Scientists studied 616 capillary blood samples from jaundiced
newborn infants. These samples were randomly divided into three groups. One group contained 133
samples and would receive phototherapy with blue light. Another group contained 202 samples
would receive room light, or white light. The final group contained 215 samples, and were left in a
dark room. The total bilirubin levels were checked at 0, 2, 4, 6, 24, and 48 hours. There was a
significant decrease in bilirubin in the first group exposed to phototherapy after two hours, but no
change occurred in the white light and dark room group. After 6 hours, there was a significant
change in bilirubin level in the white light group but not the dark room group. It took 48 hours to
record a change in the dark room group’s bilirubin level. Phototherapy is the most effective way of
breaking down a neonate’s bilirubin.
[17]

Phototherapy works through a process of isomerization that changes trans-bilirubin into the water-
soluble cis-bilirubin isomer.
[18][19]

In phototherapy, blue light is typically used because it is more effective at breaking down bilirubin
(Amato, Inaebnit, 1991). Two matched groups of newborn infants with jaundice were exposed to
intensive green or blue light phototherapy. The efficiency of the treatment was measured by the rate
of decline of serum bilirubin, which in excessive amounts causes jaundice, concentration after 6, 12
and 24 hours of light exposure. A more rapid response was obtained using the blue lamps than the
green lamps. However, a shorter phototherapy recovery period was noticed in babies exposed to the
green lamps(1). Green light is not commonly used because exposure time must be longer to see
dramatic results(1).
Ultraviolet light therapy may increase the risk of skin moles, in childhood. While an increased
number of moles is related to an increased risk of skin cancer,
[20][21][22]
it is not ultraviolet light that is
used for treating neonatal jaundice. Rather, it is simply a specific frequency of blue light that does
not carry these risks.
Increased feedings help move bilirubin through the neonate’s metabolic system.
[23]

The light can be applied with overhead lamps, which means that the baby's eyes need to be
covered, or with a device called a Biliblanket, which sits under the baby's clothing close to its skin.

Outlook (Prognosis)
Usually newborn jaundice is not harmful. For most babies, jaundice usually gets better without treatment
within 1 to 2 weeks.
Very high levels of bilirubin can damage the brain. This is called kernicterus. However, the condition is
almost always diagnosed before levels become high enough to cause this damage.
For babies who need treatment, the treatment is usually effective.
Possible Complications
Rare, but serious, complications from high bilirubin levels include:
 Cerebral palsy
 Deafness
 Kernicterus -- brain damage from very high bilirubin levels
When to Contact a Medical Professional
All babies should be seen by a health care provider in the first 5 days of life to check for jaundice.
 Those who spend less than 24 hours in a hospital should be seen by age 72 hours.
 Infants sent home between 24 and 48 hours should be seen again by age 96 hours.
 Infants sent home between 48 and 72 hours should be seen again by age 120 hours.
Jaundice is an emergency if the baby has a fever, has become listless, or is not feeding well. Jaundice
may be dangerous in high-risk newborns.
Jaundice is generally NOT dangerous in term, otherwise healthy newborns. Call the infant's health care
provider if:
 Jaundice is severe (the skin is bright yellow)
 Jaundice continues to increase after the newborn visit, lasts longer than 2 weeks, or other
symptoms develop
 The feet, especially the soles, are yellow
Prevention
In newborns, some degree of jaundice is normal and probably not preventable. The risk of significant
jaundice can often be reduced by feeding babies at least 8 to 12 times a day for the first several days and
by carefully identifying infants at highest risk.
All pregnant women should be tested for blood type and unusual antibodies. If the mother is Rh negative,
follow-up testing on the infant's cord is recommended. This may also be done if the mother's blood type is
O+, but it is not needed if careful monitoring takes place.
Careful monitoring of all babies during the first 5 days of life can prevent most complications of jaundice.
Ideally, this includes:
 Considering a baby's risk for jaundice
 Checking bilirubin level in the first day or so
 Scheduling at least one follow-up visit the first week of life for babies sent home from the hospital
in 72 hours
Alternative Names
Jaundice of the newborn; Neonatal hyperbilirubinemia; Bili lights - jaundice

is caused by a yellow substance called bilirubin. Infants with high blood levels of bilirubin, called
hyperbilirubinemia, develop the yellow color when bilirubin accumulates in the skin.
Jaundice is not a disease, but is a symptom of an elevated blood bilirubin level. Jaundice is not painful,
but serious complications can occur if elevated bilirubin levels are not treated in a timely manner.
Jaundice is a marker used to identify those infants who may be at risk for developing severe
hyperbilirubinemia. Severe hyperbilirubinemia can be toxic to the nervous system of infants, potentially
causing brain damage.
JAUNDICE SYMPTOMS
Jaundice initially causes the skin to become yellowed. Later, the whites of the eyes may have a yellowish
tinge. These changes may be hard to recognize in children with a dark skin color or if a baby is unable to
open eyelids. The color change:
●Is noticeable in the face first, and may progress down the chest, abdomen, arms, and then finally
the legs .
●Can be checked by pressing one finger on your baby's forehead or nose. If the skin is jaundiced, it
will appear yellow when you release pressure from the skin.
●Can be tracked in some babies by pressing over the bony prominences of the chest, hips, and
knees to check if the jaundice is progressing.
●Should be checked before your baby leaves the hospital. If your baby goes home sooner than 72
hours after birth, you will need to monitor the baby's skin color at home every day. In addition, your
infant should see a doctor or nurse within one to three days after going home.
Signs of worsening jaundice — Call your child's healthcare provider if you notice any of the following:
●If the yellow coloring is at the knee or lower, or if the yellow color is more intense, lemon yellow to
orange yellow
●If the baby has any difficulty in feeding
●If it is hard to wake up your infant
●If your infant is irritable and is difficult to console
●If your infant arches his/her neck or body backwards
JAUNDICE CAUSES
Jaundice is caused by the accumulation of bilirubin in the blood. Bilirubin is formed when red blood cells
are broken down. Bilirubin (a yellow pigment) is naturally cleared through the liver, and then excreted in
stool and urine. Bilirubin levels become elevated when bilirubin is produced faster than it can be
eliminated.
Jaundice is common in newborns, since two to three times more bilirubin is produced during this period
as compared with during adulthood. "Physiologic jaundice" or benign jaundice, which affects nearly all
newborns, is caused by a mild elevation of bilirubin and is not usually harmful to infants. It develops
between 72 and 96 hours after birth, and usually goes away by one to two weeks after birth. In infants
who are born at 35 to 37 weeks of gestation and those who are severely jaundiced, the jaundice may
require more time to resolve.
Newborns with higher levels of bilirubin in the blood have "severe hyperbilirubinemia", a more serious
condition than physiologic jaundice. Infants may develop severe hyperbilirubinemia within the first 24
hours of life. If this happens, you must consult your doctor urgently.
One reason that bilirubin levels are higher in infants is that more red blood cells are broken down (and as
a result, more bilirubin is produced). This can be related to:
●Bruising and mild injuries from the birth process.
●If the mother and infant's blood types are incompatible; the mother's immune system may attack
the infant's red blood cells.
●Inherited causes of red blood cell breakdown (such as deficiency of an enzyme called glucose-6-
phosphate dehydrogenase [G6PD], which may occur more frequently among African-American,
Mediterranean, and Asian races).
●Asian race or ancestry.
Bilirubin is also more slowly eliminated in the newborn compared with in adults because a newborn’s liver
and intestines are not fully mature.
Breastfeeding — Jaundice is common in infants who are breastfed because of two different reasons:
●Breastfeeding failure occurs in infants with inadequate intake of breast milk because of difficulty in
feeding or if the mother does not have an adequate milk supply. These infants lose a large amount
of weight , thereby increasing bilirubin concentration. Increasing the mother's milk supply, frequent
feeding, and ensuring good sucking (latch) are the best treatments for inadequate intake jaundice.
(See "Patient information: Common breastfeeding problems (Beyond the Basics)".)
●Breast milk jaundice is thought to be due to the infant’s immature liver and intestines. It typically
begins the first week after birth, peaks within two weeks after birth, and declines over the next few
weeks. Breast milk jaundice is not a reason to stop breastfeeding as long as the baby is feeding
well, gaining weight, and otherwise thriving. Infants with breast milk jaundice rarely need treatment
unless severe hyperbilirubinemia develops. All infants with jaundice should be monitored by a doctor
or nurse. (See "Patient information: Common breastfeeding problems (Beyond the Basics)".)
In either setting, the mother should be encouraged to continue breastfeeding because of the overall
benefits of human milk.
JAUNDICE DIAGNOSIS
Newborn jaundice can be diagnosed by examining the infant and testing blood levels of bilirubin. A blood
test involves collecting a small amount (less than one-half teaspoon or 2.5 mL) of blood. Results of blood
testing are available in most hospitals within a few hours.
JAUNDICE COMPLICATIONS
In babies whose bilirubin blood levels reach harmful levels, bilirubin may get into the brain and cause
reversible damage (called acute bilirubin encephalopathy) or permanent damage (called kernicterus).
Frequent monitoring and early treatment of infants at high risk for jaundice can help to prevent severe
hyperbilirubinemia.
JAUNDICE TREATMENT
The goal of jaundice treatment is to quickly and safely reduce the level of bilirubin. Infants with mild
jaundice may need no treatment. Infants with higher bilirubin levels or hyperbilirubinemia will require
treatment, which is described below. (See"Treatment of unconjugated hyperbilirubinemia in term and late
preterm infants".)
Jaundice is common in premature infants (those born before 38 weeks of gestation). Premature infants
are at greater risk for hyperbilirubinemia because brain toxicity occurs at lower levels of bilirubin than in
term infants. As a result, premature infants are treated at lower levels of bilirubin, but with the same
treatments discussed here.
Encourage feeding — Providing adequate breast milk or formula is an important part of preventing and
treating jaundice because it promotes elimination of the yellow pigment in stools and urine. You will know
that your child is getting enough milk or formula if s/he has at least six wet diapers per day, the color of
the bowel movements changes from dark green to yellow, and s/he seems satisfied after feeding.
Phototherapy — Phototherapy (light therapy) is the most common medical treatment for jaundice in
newborns. In most cases, phototherapy is the only treatment required. It consists of exposing an infant's
skin to a special blue light, which breaks bilirubin down into parts that are easier to eliminate in the stool
and urine. Treatment with phototherapy is successful for almost all infants.
Phototherapy is usually done in the hospital, but in select cases, it can be done in the home if the baby
is healthy and at low risk for complications.
Infants undergoing phototherapy should have as much skin exposed to the light as possible. Infants are
usually naked (or wearing only a diaper) in an open bassinet or warmer, but wear eye patches to protect
the eyes (picture 1). It is important to ensure that the lamps do not generate excessive heat, which could
injure an infant's skin. In some institutions, phototherapy blankets are used (picture 2). Phototherapy
should be continuous, with breaks only for feeding.
Exposure to sunlight was previously thought to be helpful, but is not currently recommended due to the
risk of sunburn. Sunburn does not occur with the lights used in phototherapy when used properly.
Phototherapy is stopped when bilirubin levels decline to a safe level. It is not unusual for infants to still
appear jaundiced after phototherapy is completed. Bilirubin levels may rebound 18 to 24 hours after
stopping phototherapy, although this rarely requires further treatment.
●Side effects – Phototherapy is very safe, but it can have temporary side effects, including a skin
rash and loose bowel movements. Overheating and dehydration can occur if the infant does not get
enough breast milk or formula. Therefore, the infant's skin color, body temperature, and number of
wet diapers are closely monitored.
●Rarely, some infants will develop "bronze baby" syndrome, a dark, grayish-brown discoloration of
the skin and urine. Bronze baby syndrome is not harmful and gradually resolves without treatment
after several weeks.
●Hydration – It is important for infants receiving phototherapy to drink adequate fluids (breast milk or
a supplement) since bilirubin is excreted in urine and bowel movements. Breast- or bottle-feeding
should continue during phototherapy. Use of oral glucose water is not necessary. In some babies
with severe dehydration, intravenous fluids may be necessary.
●Breastfeeding – Breastfed infants who are not able to consume enough breast milk, whose weight
loss is excessive, or who are dehydrated may need extra expressed breast milk or other milk
supplements. Mothers who supplement should continue to breastfeed and/or pump to maintain
their milk supply.
There is some controversy about the practice of using cow milk or soy formula to exclusively breastfed
infants. Parents should discuss these issues with the child's doctor. (See "Patient information:
Breastfeeding guide (Beyond the Basics)".)
Exchange transfusion — Exchange transfusion is a procedure that is done urgently to prevent or
minimize bilirubin-related brain damage. The transfusion replaces an infant's blood with donated blood in
an attempt to quickly lower bilirubin levels. Exchange transfusion may be performed in infants who have
not responded to other treatments and who have signs of or are at significant neurologic risk of bilirubin
toxicity.
PREVENTION OF SEVERE HYPERBILIRUBINEMIA
Prevention of severe hyperbilirubinemia is important in avoiding serious complications. Infants who are at
risk for hyperbilirubinemia need close surveillance and follow-up. The following information applies to
infants who are healthy and late preterm or older (greater than or equal to 35 weeks of gestation).
Screen — Leading experts recommend that all infants have bilirubin blood testing before going home.
This is especially true for infants who are jaundiced before 24 hours of age.
Monitor — Parents and healthcare providers should monitor the infant closely if jaundice develops.
Hyperbilirubinemia is usually easy to prevent and treat initially, but the complications can be serious and
irreversible if treatment is delayed. You should contact your child's healthcare provider immediately if you
are concerned about worsening jaundice.
Treat promptly — Infants with elevated bilirubin levels should be treated by a qualified doctor or nurse to
safely reduce bilirubin levels and prevent the risk of brain damage. Parents and healthcare providers
should not delay treatment for any reason.

Fort Belvoir, Virginia
Am Fam Physician. 2002 Feb 15;65(4):599-607.
Patient Information Handout
Hyperbilirubinemia is one of the most common problems encountered in term newborns.
Historically, management guidelines were derived from studies on bilirubin toxicity in infants
with hemolytic disease. More recent recommendations support the use of less intensive
therapy in healthy term newborns with jaundice. Phototherapy should be instituted when
the total serum bilirubin level is at or above 15 mg per dL (257 mol per L) in infants 25 to 48
hours old, 18 mg per dL (308 mol per L) in infants 49 to 72 hours old, and 20 mg per dL (342
mol per L) in infants older than 72 hours. Few term newborns with hyperbilirubinemia have
serious underlying pathology. Jaundice is considered pathologic if it presents within the first
24 hours after birth, the total serum bilirubin level rises by more than 5 mg per dL (86 mol per
L) per day or is higher than 17 mg per dL (290 mol per L), or an infant has signs and
symptoms suggestive of serious illness. The management goals are to exclude pathologic
causes of hyperbilirubinemia and initiate treatment to prevent bilirubin neurotoxicity.
Neonatal hyperbilirubinemia, defined as a total serum bilirubin level above 5 mg per dL (86 μmol per
L), is a frequently encountered problem. Although up to 60 percent of term newborns have clinical
jaundice in the first week of life, few have significant underlying disease.
1,2
However,
hyperbilirubinemia in the newborn period can be associated with severe illnesses such as hemolytic
disease, metabolic and endocrine disorders, anatomic abnormalities of the liver, and infections.
Jaundice typically results from the deposition of unconjugated bilirubin pigment in the skin and
mucus membranes. Depending on the underlying etiology, this condition may present throughout the
neonatal period. Unconjugated hyperbilirubinemia, the primary focus of this article, is the most
common form of jaundice encountered by family physicians. The separate topic of conjugated
hyperbilirubinemia is beyond the scope of this article.
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Risk Factors for Hyperbilirubinemia
Infants without identified risk factors rarely have total serum bilirubin levels above 12 mg per dL (205
μ mol per L). As the number of risk factors increases, the potential to develop markedly elevated
bilirubin levels also increases.
2

Common risk factors for hyperbilirubinemia include fetal-maternal blood group incompatibility,
prematurity, and a previously affected sibling (Table 1).
2–4
Cephalohematomas, bruising, and trauma
from instrumented delivery may increase the risk for serum bilirubin elevation. Delayed meconium
passage also increases the risk. Infants with risk factors should be monitored closely during the first
days to weeks of life.
TABLE 1 Risk Factors for Hyperbilirubinemia in Newborns
View Table
Bilirubin Production and Newborns
Bilirubin is the final product of heme degradation. At physiologic pH, bilirubin is insoluble in plasma
and requires protein binding with albumin. After conjugation in the liver, it is excreted in bile.
3,5–7

Newborns produce bilirubin at a rate of approximately 6 to 8 mg per kg per day. This is more than
twice the production rate in adults, primarily because of relative polycythemia and increased red
blood cell turnover in neonates.
7
Bilirubin production typically declines to the adult level within 10 to
14 days after birth.
2

Bilirubin Toxicity
―Kernicterus‖ refers to the neurologic consequences of the deposition of unconjugated bilirubin in
brain tissue. Subsequent damage and scarring of the basal ganglia and brainstem nuclei may
occur.
5

The precise role of bilirubin in the development of kernicterus is not completely understood. If the
serum unconjugated bilirubin level exceeds the binding capacity of albumin, unbound lipid-soluble
bilirubin crosses the blood-brain barrier. Albumin-bound bilirubin may also cross the blood-brain
barrier if damage has occurred because of asphyxia, acidosis, hypoxia, hypoperfusion,
hyperosmolality, or sepsis in the newborn.
3,8

The exact bilirubin concentration associated with kernicterus in the healthy term infant is
unpredictable.
1
Toxicity levels may vary among ethnic groups, with maturation of an infant, and in the
presence of hemolytic disease. Although the risk of bilirubin toxicity is probably negligible in a
healthy term newborn without hemolysis,
9
the physician should become concerned if the bilirubin
level is above 25 mg per dL (428 μ mol per L).
1,3,10
In the term newborn with hemolysis, a bilirubin
level above 20 mg per dL (342 μ mol per L) is a concern.
1,3

The effects of bilirubin toxicity are often devastating and irreversible (Table 2).
3,9
Early signs of
kernicterus are subtle and nonspecific, typically appearing three to four days after birth. However,
hyperbilirubinemia may lead to kernicterus at any time during the neonatal period.
2
After the first
week of life, the affected newborn begins to demonstrate late effects of bilirubin toxicity. If the infant
survives the initial severe neurologic insult, chronic bilirubin encephalopathy (evident by three years
of age) leads to developmental and motor delays, sensorineural deafness, and mild mental
retardation.
TABLE 2 Effects of Bilirubin Toxicity in Newborns
View Table
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Classification of Neonatal Hyperbilirubinemia
The causes of neonatal hyperbilirubinemia can be classified into three groups based on mechanism
of accumulation: bilirubin overproduction, decreased bilirubin conjugation, and impaired bilirubin
excretion (Table 3).
11

TABLE 3 Classification of Neonatal Hyperbilirubinemia Based on
Mechanism of Accumulation
View Table
PHYSIOLOGIC JAUNDICE
Physiologic jaundice in healthy term newborns follows a typical pattern. The average total serum
bilirubin level usually peaks at 5 to 6 mg per dL (86 to 103 μ mol per L) on the third to fourth day of
life and then declines over the first week after birth.
2
Bilirubin elevations of up to 12 mg per dL, with
less than 2 mg per dL (34 μ mol per L) of the conjugated form, can sometimes occur. Infants with
multiple risk factors may develop an exaggerated form of physiologic jaundice in which the total
serum bilirubin level may rise as high as 17 mg per dL (291 μ mol per L).
3

Factors that contribute to the development of physiologic hyperbilirubinemia in the neonate include
an increased bilirubin load because of relative polycythemia, a shortened erythrocyte life span (80
days compared with the adult 120 days), immature hepatic uptake and conjugation processes, and
increased enterohepatic circulation.
7

JAUNDICE AND BREASTFEEDING
Early-Onset Breastfeeding Jaundice
Breast-fed newborns may be at increased risk for early-onset exaggerated physiologic jaundice
because of relative caloric deprivation in the first few days of life.
12
Decreased volume and frequency
of feedings may result in mild dehydration and the delayed passage of meconium. Compared with
formula-fed newborns, breastfed infants are three to six times more likely to experience moderate
jaundice (total serum bilirubin level above 12 mg per dL) or severe jaundice (total serum bilirubin
level above 15 mg per dL [257 μ mol per L]).
12,13

In a breastfed newborn with early-onset hyperbilirubinemia, the frequency of feedings needs to be
increased to more than 10 per day. If the infant has a decline in weight gain, delayed stooling, and
continued poor caloric intake, formula supplementation may be necessary, but breastfeeding should
be continued to maintain breast milk production. Supplemental water or dextrose-water
administration should be avoided, as it decreases breast milk production and places the newborn at
risk for iatrogenic hyponatremia.
3,5,11

Late-Onset Breast Milk Jaundice
Breast milk jaundice occurs later in the newborn period, with the bilirubin level usually peaking in the
sixth to 14th days of life. This late-onset jaundice may develop in up to one third of healthy
breastfed infants.
1
Total serum bilirubin levels vary from 12 to 20 mg per dL (340 μ mol per L) and
are nonpathologic.
The underlying cause of breast milk jaundice is not entirely understood. Substances in maternal
milk, such as β-glucuronidases, and nonesterified fatty acids, may inhibit normal bilirubin metabolism
.
5,7,14,15
The bilirubin level usually falls continually after the infant is two weeks old, but it may remain
persistently elevated for one to three months.
If the diagnosis of breast milk jaundice is in doubt or the total serum bilirubin level becomes
markedly elevated, breastfeeding may be temporarily interrupted, although the mother should
continue to express breast milk to maintain production. With formula substitution, the total serum
bilirubin level should decline rapidly over 48 hours (at a rate of 3 mg per dL [51 μ mol per L] per
day),
1
confirming the diagnosis. Breastfeeding may then be resumed.
PATHOLOGIC JAUNDICE
All etiologies of jaundice beyond physiologic and breastfeeding or breast milk jaundice are
considered pathologic. Features of pathologic jaundice include the appearance of jaundice within 24
hours after birth, a rapidly rising total serum bilirubin concentration (increase of more than 5 mg per
dL per day), and a total serum bilirubin level higher than 17 mg per dL in a full-term newborn.
3,5
Other
features of concern include prolonged jaundice, evidence of underlying illness, and elevation of the
serum conjugated bilirubin level to greater than 2 mg per dL or more than 20 percent of the total
serum bilirubin concentration. Pathologic causes include disorders such as sepsis, rubella,
toxoplasmosis, occult hemorrhage, and erythroblastosis fetalis.
Diagnosis
PHYSICAL EXAMINATION
The presence of jaundice can be determined by examining the infant in a well-lit room and blanching
the skin with digital pressure to reveal the color of the skin and subcutaneous tissue. Neonatal
dermal icterus is not noticeable at total serum bilirubin levels below 4 mg per dL (68 μmol per L).
16

Increasing total serum bilirubin levels are accompanied by the cephalocaudal progression of dermal
icterus, predictably from the face to the trunk and extremities, and finally to the palms and
soles.
16,17
The total serum bilirubin level can be estimated clinically by the degree of caudal extension:
face, 5 mg per dL; upper chest, 10 mg per dL (171 μmol per L); abdomen, 12 mg per dL; palms and
soles, greater than 15 mg per dL.
The only consistently reliable estimation of total serum bilirubin occurs when dermal icterus is
confined to above the nipple line. In this situation, the bilirubin level is invariably below 12 mg per dL.
As jaundice extends below the middle of the chest, the correlation between physical signs and
measured bilirubin levels becomes increasingly unreliable. Differences in skin color among races,
delays in dermal deposition with rapidly rising bilirubin levels, interobserver variability, and other
factors contribute to the difficulty of accurately predicting the total serum bilirubin concentration
based on caudal progression alone.
18

The physical examination should focus on identifying one of the known causes of pathologic
jaundice. The infant should be assessed for pallor, petechiae, extravasated blood, excessive
bruising, hepatosplenomegaly, weight loss, and evidence of dehydration.
LABORATORY EVALUATION
The initial evaluation of jaundice depends on the age of the newborn (Figure 1).
2
If the serum
conjugated bilirubin level is above 2 mg per dL, the infant should be evaluated for possible
hepatocellular disease or biliary obstruction.
Laboratory Evaluation of Term Newborn with Jaundice

FIGURE 1.
Algorithm for the suggested evaluation of a term newborn with hyperbilirubinemia.
Information from jaundice and hyperbilirubinemia in the newborn. In: Behrman RE, Kliegman RM, Jenson HB,
eds. Nelson Textbook of pediatrics. 16th ed. Philadelphia: Saunders, 2000:511–28.
View Large
Management
Studies on the toxic effects of hyperbilirubinemia historically involved infants with hemolytic disease.
An increased incidence of kernicterus was found to be associated with total serum bilirubin levels
above 20 mg per dL in the presence of hemolysis.
19,20
This observation was the basis for aggressive
guidelines recommending the use of exchange transfusion in all infants with significant
hyperbilirubinemia. More recently, term infants without hemolysis have been found to tolerate higher
total serum bilirubin levels,
21
and management guidelines now focus primarily on phototherapy as
initial treatment.
1

Recommendations for the management of hyperbilirubinemia in healthy term newborns have been
outlined by the American Academy of Pediatrics (Table 4).
1
Jaundice in a term newborn fewer than
24 hours old is always pathologic: it should be investigated thoroughly and treated appropriately.
Depending on the rate at which the bilirubin level rises, a newborn's risk of developing significant
hyperbilirubinemia can be classified as low, intermediate, or high (Figure 2).
22
With the assumption
that the bilirubin level will continue to rise at the same rate, the physician can predict the potential
further progression of the rise and calculate the number of days that the infant may be at risk for
bilirubin toxicity.
TABLE 4
Management of Hyperbilirubinemia in Healthy Term Newborns
The rightsholder did not grant rights to reproduce this item in electronic media. For the missing item,
see the original print version of this publication.
Bilirubin Levels and Risk of Significant Hyperbilirubinemia

FIGURE 2.
Risk for significant hyperbilirubinemia in healthy term and near-term well newborns. Based on age-specific
total serum bilirubin levels, the risk can be classified as high (above 95th percentile), intermediate (40th to
95th percentile), or low (below 40th percentile).
Adapted with permission from Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-
specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns.
Pediatrics 1999;103:6–14.
View Large
Conjugated hyperbilirubinemia is never physiologic, and it may indicate the presence of a potentially
serious underlying disorder. However, elevated conjugated bilirubin levels are not directly toxic to
brain cells in the neonate.
2

If jaundice persists for more than two weeks in a formula-fed infant and more than three weeks in a
breastfed infant, further evaluation is warranted.
1,7
Laboratory studies should include a fractionated
bilirubin level, thyroid studies, evaluations for metabolic disorders or hemolytic disease, and an
assessment for intestinal obstruction.
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Treatment
Before treatment is initiated, the minimum evaluation should include the infant's age and postnatal
course, a maternal and gestational history, physical examination of the infant, and determination of
the total serum bilirubin level and the rate at which it is rising (Figure 2).
22

PHOTOTHERAPY
Phototherapy employs blue wavelengths of light to alter unconjugated bilirubin in the skin. The
bilirubin is converted to less toxic water-soluble photoisomers that are excreted in the bile and urine
without conjugation. The decision to initiate phototherapy is based on the newborn's age and total
serum bilirubin level (Table 4).
1

The efficacy of phototherapy depends on several important factors. The ideal configuration is four
special blue bulbs (F20T12/BB) placed centrally, with two daylight fluorescent tubes on either side.
The power output of the lights (irradiance) is directly related to the distance between the lights and
the newborn.
23
Ideally, all lights should be 15 to 20 cm from the infant.
2
To expose the greatest
surface area, the newborn should be naked except for eye shields. For double phototherapy, a fiber-
optic pad can be placed under the newborn. This method is twice as effective as standard
phototherapy.
5

The only contraindication to the use of phototherapy is conjugated hyperbilirubinemia, as occurs in
patients with cholestasis and hepatic disease. In this setting, phototherapy may cause a dark
grayish-brown discoloration of the skin (bronze baby syndrome).
2
Potential problems that may occur
with phototherapy include burns, retinal damage, thermoregulatory instability, loose stools,
dehydration, skin rash, and tanning of the skin. Because phototherapy is continuous, treatment also
involves significant separation of the infant and parents.
With intensive phototherapy, the total serum bilirubin level should decline by 1 to 2 mg per dL (17 to
34 μ mol per L) within four to six hours.
1,5
The bilirubin level may decline more slowly in breastfed
infants (rate of 2 to 3 mg per dL per day) than in formula-fed infants.
3
Phototherapy usually can be
discontinued when the total serum bilirubin level is below 15 mg per dL.
1
The average rebound
bilirubin level after phototherapy is below 1 mg per dL. Therefore, hospital discharge of most infants
does not have to be delayed to monitor for rebound elevation.
24,25

If the total serum bilirubin level remains elevated after intensive phototherapy or if the initial bilirubin
level is meets defined critical levels based on the infant's age (Table 4),
1
preparations should be
made for exchange transfusion.
EXCHANGE TRANSFUSION
Exchange transfusion is the most rapid method for lowering serum bilirubin concentrations. This
treatment is rarely needed when intensive phototherapy is effective.
1,26,27
The procedure removes
partially hemolyzed and antibody-coated erythrocytes and replaces them with uncoated donor red
blood cells that lack the sensitizing antigen.
In the presence of hemolytic disease, severe anemia, or a rapid rise in the total serum bilirubin level
(greater than 1 mg per dL per hour in less than six hours), exchange transfusion is the
recommended treatment. Exchange transfusion should be considered in a newborn with
nonhemolytic jaundice if intensive phototherapy fails to lower the bilirubin level.
1

Complications of exchange transfusion can include air embolism, vasospasm, infarction, infection,
and even death. Because of the potential seriousness of these complications, intensive
phototherapy efforts should be exhausted before exchange transfusion is initiated.
26

The Authors
MEREDITH L. PORTER, CPT, MC, USA, is a staff family physician at Vicencza Army Health
Clinic, Italy. Dr. Porter received her medical degree from Virginia Commonwealth University School
of Medicine, Richmond, and completed a family practice residency at Dewitt Army Community
Hospital, Fort Belvoir, Va.
BETH L. DENNIS, MAJ, MC, USA, is a staff family physician and clinic director at Dewitt Army
Community Hospital. She also serves as assistant professor of medicine at the Uniformed Services
University of Health Sciences F. Edward Hébert School of Medicine, Bethesda, Md. Dr. Dennis
received her medical degree from the University of Virginia School of Medicine, Charlottesville, and
completed a family practice residency at Tripler Army Medical Center, Honolulu.
Address correspondence to Meredith L. Porter, CMR 427, Box 3389, APO, AE 09630 (e-
mail:[email protected]). Reprints are not available from the authors.
The authors indicate that they do not have any conflicts of interest. Sources of funding: none
reported.
The opinions and assertions contained herein are the private views of the authors and are not to be
construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S.
Army at large.