Neonatal jaundice or neonatal hyperbilirubinemia, or neonatal icterus (from the Greek

word ), attributive adjective: icteric, is a yellowing of the skin and other tissues of a
newborn infant. A bilirubin level of more than 85 mol/l (5 mg/dL) leads to a jaundiced
appearance in neonates whereas in adults a level of 34 mol/l (2 mg/dL) is needed for this to
occur. In newborns, jaundice is detected by blanching the skin with pressure applied by a
finger so that it reveals underlying skin and subcutaneous tissue.[1] Jaundiced newborns have
yellow discoloration of the white part of the eye, and yellowing of the face, extending down
onto the chest.

Neonatal jaundice can make the newborn sleepy and interfere with feeding. Extreme jaundice
can cause permanent brain damage from kernicterus.

In neonates, the yellow discoloration of the skin 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 (5060%) of all babies in the first week of life.[3]

Infants whose palms and soles are yellow, have serum bilirubin level over 255 mol/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.

Causes
In neonates, jaundice tends to develop because of two factorsthe breakdown of fetal
hemoglobin as it is replaced with adult hemoglobin and the relatively immature metabolic
pathways of the liver, 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, Progressive familial intrahepatic cholestasis, 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:

Unconjugated

Hemolytic

Intrinsic causes of hemolysis

Membrane conditions
o Spherocytosis
o Hereditary elliptocytosis
Enzyme conditions
 o Glucose-6-phosphate dehydrogenase deficiency (also called G6PD deficiency)
o Pyruvate kinase deficiency
Globin synthesis defect
o sickle cell disease
o Alpha-thalassemia, e.g. HbH disease

Extrinsic causes of hemolysis

Systemic conditions
o Sepsis
o Arteriovenous malformation
Alloimmunity (The neonatal or cord blood gives a positive direct Coombs test and the
maternal blood gives a positive indirect Coombs test)
o Hemolytic disease of the newborn (ABO)[1]
o Rh disease[1]
o Hemolytic disease of the newborn (anti-Kell)
o Hemolytic disease of the newborn (anti-Rhc)
o Other blood type mismatches causing hemolytic disease of the newborn

Non-hemolytic causes

Breastfeeding jaundice
Breast milk jaundice
Cephalohematoma
Polycythemia
Urinary tract infection
Sepsis
Hypothyroidism
Gilbert's syndrome
Crigler-Najjar syndrome
High GI obstruction (Pyloric stenosis, Bowel obstruction)

Conjugated (Direct)

Liver causes

Infections
o Sepsis
o Hepatitis A
o Hepatitis B
o TORCH infections
Metabolic
o Galactosemia
o Alpha-1-antitrypsin deficiency, which is commonly missed, and must be considered
in DDx
o Cystic fibrosis
o Dubin-Johnson Syndrome
o Rotor syndrome
Drugs
Total parenteral nutrition
Idiopathic
Post-liver

Biliary atresia or bile duct obstruction

o Alagille syndrome
o Choledochal cyst

Non-organic causes

Breastfeeding jaundice

"Breastfeeding jaundice" or "lack of breastfeeding jaundice," is caused by insufficient breast

milk intake, resulting in inadequate quantities of bowel movements to remove bilirubin from
the body. This leads to increased enterohepatic circulation, resulting in increased reabsorption
of bilirubin from the intestines. Usually occurring in the first week of life, most cases can be
ameliorated by frequent breastfeeding sessions of sufficient duration to stimulate adequate
milk production.

Breast milk jaundice

Whereas breastfeeding 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.[6]

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 -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.[7] 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.[8]
However, these results have not been supported by subsequent studies.[9]
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.[10]

Physiological jaundice

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 mol/l (12 mg/dL).
2. Preterm infants - jaundice lasts for about two weeks, with a rapid rise of serum bilirubin up
to 255 mol/l (15 mg/dL).

Phase two - bilirubin levels decline to about 34 mol/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.

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.[11] 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.[12] After
birth, it takes some time for this enzyme to gain function.
Shorter life span of fetal red blood cells,[11] being approximately 80 to 90 days in a full term
infant,[13] 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.[11]

Diagnosis
Clinical Assessment

This method is less accurate and more subjective in estimating jaundice.

Ingram icterometer: In this method a piece of transparent plastic known as Ingram

icterometer is used. Ingram icterometer is painted in five transverse strips of graded yellow
lines. The instrument is pressed against the nose and the yellow colour of the blanched skin is
matched with the graded yellow lines and bilirubin level is assigned.

Transcutaneous bilirubinometer: This is hand held, portable and rechargeable but

expensive and sophisticated. When pressure is applied to the photoprobe, a xenon tube
generates a strobe light, and this light passes through the subcutaneous tissue. The reflected
light returns through the second fiber optic bundle to the spectrophotometric module. The
intensity of the yellow color in this light, after correcting for the hemoglobin, is measured and
instantly displayed in arbitrary units.

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 mol/l (0.5 mg/dL) per hour or
(85 mol/l) 5 mg/dL per 24 hours.
3. Total bilirubin more than 331.5 mol/l (19.5 mg/dL) (hyperbilirubinemia).
4. Direct bilirubin more than 34 mol/l (2.0 mg/dL).
The aim of clinical assessment is to distinguish physiological from pathological jaundice. The
signs which help to differentiate pathological jaundice of neonates from physiological
jaundice of neonates are the presence of intrauterine growth restriction, stigma of intrauterine
infections (e.g. cataracts, small head, and enlargement of the liver and spleen),
cephalohematoma, bruising, signs of bleeding in the brain's ventricles. History of illness is
noteworthy. Family history of jaundice and anemia, family history of neonatal or early infant
death due to liver disease, maternal illness suggestive of viral infection (fever, rash or
lymphadenopathy), maternal drugs (e.g. sulphonamides, anti-malarials causing red blood cell
destruction in G6PD deficiency) are suggestive of pathological jaundice in neonates.[14]

Treatment
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 mol/l (
21 mg/dL) should receive phototherapy.[15]

Phenobarbital

Phenobarbital is used to treat neonatal jaundice by increasing liver metabolism and thus
lowering bilirubin levels. In the 1950s, phototherapy was discovered, and became the
standard treatment, however phenobarbital therapy is still in common use when access to
phototherapy is inconvenient or impractical. One striking benefit of successful phenobarbital
therapy is the rapid onset of recovery.[16]

Phototherapy

The use of phototherapy was first discovered, accidentally, at Rochford Hospital in Essex,
England. The ward sister (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 led to the determination that blue light, wavelength of
420-480 nm (peak 458 nm), caused transformation of the trans bilirubin to cis bilirubin, 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.[17][18]
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 155 the
levels of bilirubin, a yellowish bile pigment that in excessive amounts causes jaundice, were
decreased down to 0.270.25 mg/dl/h in the blue light. This suggests that blue light therapy
helps reduce high bilirubin levels that cause neonatal jaundice.[19]

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
groups bilirubin level. Phototherapy is the most effective way of breaking down a neonates
bilirubin.[20]

Phototherapy works through a process of isomerization that changes trans-bilirubin into the
water-soluble cis-bilirubin isomer.[21][22]

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,[23][24][25] 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 neonates metabolic system.[26]

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.

Exchange transfusions

Much like with phototherapy the level at which exchange transfusion should occur depends
on the health status and age of the newborn. It should however be used for any newborn with
a total serum bilirubin of greater than 428 mol/l ( 25 mg/dL ).[15]
Complications
Prolonged hyperbilirubinemia (severe jaundice) can result in chronic bilirubin
encephalopathy (kernicterus).[27][28] Quick and accurate treatment of neonatal jaundice helps
to reduce the risk of neonates developing kernicterus.[29]

Infants with kernicterus may have a fever[30] or seizures.[31] High pitched crying is an effect of
kernicterus. Scientists used a computer to record and measure cranial nerves 8, 9 and 12 in 50
infants who were divided into two groups equally depending upon bilirubin concentrations.
Of the 50 infants, 43 had tracings of high pitched crying.[32]

Exchange transfusions performed to lower high bilirubin levels are an aggressive

treatment.[33]