http://emedicine.medscape.

com/article/974786overview#showall
Author
Thor WR Hansen, MD, PhD, MHA, FAAP Professor, Department of Neonatology, Women
and Children's Division, Director of Clinical Ethics, Oslo University Hospital HC,
Rikshospitalet,; Director of Pediatric Education, Faculty of Medicine, University of Oslo,
Norway

March 04 2016

Background
Jaundice is the most common condition that requires medical attention in newborns. The yellow
coloration of the skin and sclera in newborns with jaundice is the result of accumulation of
unconjugated bilirubin. In most infants, unconjugated hyperbilirubinemia reflects a normal
transitional phenomenon. However, in some infants, serum bilirubin levels may rise excessively,
which can be cause for concern because unconjugated bilirubin is neurotoxic and can cause death
in newborns and lifelong neurologic sequelae in infants who survive (kernicterus). For these
reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation.
Neonatal jaundice may have first been described in a Chinese textbook 1000 years ago. Medical
theses, essays, and textbooks from the 18th and 19th centuries contain discussions about the
causes and treatment of neonatal jaundice. Several of these texts also describe a lethal course in
infants who probably had Rh isoimmunization. In 1875, Orth first described yellow staining of
the brain, in a pattern later referred to by Schmorl as kernicterus.

Pathophysiology
Neonatal physiologic jaundice results from simultaneous occurrence of the following two
phenomena[1] :

Bilirubin production is elevated because of increased breakdown of fetal erythrocytes.

This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte
mass in neonates. [2, 3]

Hepatic excretory capacity is low both because of low concentrations of the binding
protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase,

the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin
water soluble (conjugation).
Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism
and is formed through oxidation-reduction reactions. Approximately 75% of bilirubin is derived
from hemoglobin, but degradation of myoglobin, cytochromes, and catalase also contributes. In
the first oxidation step, biliverdin is formed from heme through the action of heme oxygenase,
the rate-limiting step in the process, releasing iron and carbon monoxide. The iron is conserved
for reuse, whereas carbon monoxide is excreted through the lungs and can be measured in the
patient's breath to quantify bilirubin production.
Next, water-soluble biliverdin is reduced to bilirubin, which, because of the intramolecular
hydrogen bonds, is almost insoluble in water in its most common isomeric form (bilirubin IX
Z,Z). Because of its hydrophobic nature, unconjugated bilirubin is transported in the plasma
tightly bound to albumin. Binding to other proteins and erythrocytes also occurs, but the
physiologic role is probably limited. Binding of bilirubin to albumin increases postnatally with
age and is reduced in infants who are ill.
The presence of endogenous and exogenous binding competitors, such as certain drugs, also
decreases the binding affinity of albumin for bilirubin. A minute fraction of unconjugated
bilirubin in serum is not bound to albumin. This free bilirubin is able to cross lipid-containing
membranes, including the blood-brain barrier, leading to neurotoxicity. In fetal life, free bilirubin
crosses the placenta, possibly by a carrier-mediated process,[4] and excretion of bilirubin from the
fetus occurs primarily through the maternal organism.
When it reaches the liver, bilirubin is transported into liver cells, where it binds to ligandin.
Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. Ligandin
concentrations are low at birth but rapidly increase over the first few weeks of life. Ligandin
concentrations may be increased by the administration of pharmacologic agents such as
phenobarbital.
Bilirubin is bound to glucuronic acid (conjugated) in the hepatocyte endoplasmic reticulum in a
reaction catalyzed by uridine diphosphoglucuronyltransferase (UDPGT). Monoconjugates are
formed first and predominate in the newborn. Diconjugates appear to be formed at the cell
membrane and may require the presence of the UDPGT tetramer.
Bilirubin conjugation is biologically critical because it transforms a water-insoluble bilirubin
molecule into a water-soluble molecule. Water-solubility allows conjugated bilirubin to be
excreted into bile. UDPGT activity is low at birth but increases to adult values by age 4-8 weeks.
In addition, certain drugs (phenobarbital, dexamethasone, clofibrate) can be administered to
increase UDPGT activity.
Infants who have Gilbert syndrome or who are compound heterozygotes for the Gilbert promoter
and structural mutations of the UDPGT1A1 coding region are at an increased risk of significant
hyperbilirubinemia. Interactions between the Gilbert genotype and hemolytic anemias such as

glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency, hereditary spherocytosis, or ABO

hemolytic disease also appear to increase the risk of severe neonatal jaundice.
Further, the observation of jaundice in some infants with hypertrophic pyloric stenosis may also
be related to a Gilbert-type variant. Genetic polymorphism for the organic anion transporter
protein OATP-2 correlates with a 3-fold increased risk for developing marked neonatal jaundice.
Combination of the OATP-2 gene polymorphism with a variant UDPGT1A1 gene further
increases this risk to 22-fold.[5] Studies also suggest that polymorphisms in the gene for
glutathione-S-transferase (ligandin) may contribute to higher levels of total serum bilirubin.
Thus, some interindividual variations in the course and severity of neonatal jaundice may be
explained genetically.[6] As the impact of these genetic variants is more fully understood,
development of a genetic test panel for risk of severe and/or prolonged neonatal jaundice may
become feasible.[7]
Once excreted into bile and transferred to the intestines, bilirubin is eventually reduced to
colorless tetrapyrroles by microbes in the colon. However, some deconjugation occurs in the
proximal small intestine through the action of B-glucuronidases located in the brush border. This
unconjugated bilirubin can be reabsorbed into the circulation, increasing the total plasma
bilirubin pool. This cycle of uptake, conjugation, excretion, deconjugation, and reabsorption is
termed 'enterohepatic circulation'. The process may be extensive in the neonate, partly because
nutrient intake is limited in the first days of life, prolonging the intestinal transit time.
In mother-infant dyads who are experiencing difficulties with the establishment of breast
feeding, inadequate fluid and nutrient intake often leads to significant postnatal weight loss in the
infant. Such infants have an increased risk of developing jaundice through increased
enterohepatic circulation, as described above. This phenomenon is often referred to as
breastfeeding jaundice and is different from the breast milk jaundice described below.
Certain factors present in the breast milk of some mothers may also contribute to increased
enterohepatic circulation of bilirubin (breast milk jaundice). -glucuronidase may play a role by
uncoupling bilirubin from its binding to glucuronic acid, thus making it available for
reabsorption. Data suggest that the risk of breast milk jaundice is significantly increased in
infants who have genetic polymorphisms in the coding sequences of the UDPGT1A1[8] or OATP2
genes. Although the mechanism that causes this phenomenon is not yet agreed on, evidence
suggests that supplementation with certain breast milk substitutes may reduce the degree of
breast milk jaundice (see Other therapies).
Neonatal jaundice, although a normal transitional phenomenon in most infants, can occasionally
become more pronounced. Blood group incompatibilities (eg, Rh, ABO) may increase bilirubin
production through increased hemolysis. Historically, Rh isoimmunization was an important
cause of severe jaundice, often resulting in the development of kernicterus. Although this
condition has become relatively rare in industrialized countries following the use of Rh
prophylaxis in Rh-negative women, Rh isoimmunization remains common in low- and middleincome countries (LMICs).

Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased
jaundice, and increased hemolysis appears to have been present in some of the infants reported to
have developed kernicterus in the United States in the past 15-20 years. The possible interaction
between such conditions and genetic variants of the Gilbert and UDPGT1A1 genes, as well as
genetic variants of several other proteins and enzymes involved in bilirubin metabolism, is
discussed above.
These discoveries also highlight the challenges involved in the common use of the terms
physiologic jaundice and pathologic jaundice. Although physiologic jaundice is a helpful concept
from a didactic perspective, applying it to an actual neonate with jaundice is more difficult.
Consider the following metaphor: Think of total serum bilirubin in neonatal jaundice as a
mountain covered by a glacier. If a measurement of the height of the mountain is taken when
standing on the summit, the amount of rock and the amount of ice that comprise this
measurement is unclear. The same is true for many total serum bilirubin values obtained in
neonatal jaundice. An underpinning of physiologic processes and pathological process (eg,
Rhesus incompatibility) may clearly contribute to the measurement. However, how much of the
measured total value comes from each of these components is unclear. Also, because genetic
variants in bilirubin metabolism are only exceptionally pursued in the diagnostic work-up of
infants with jaundice, their possible contribution to the measured total serum bilirubin is usually
unknown.

Etiology
Physiologic jaundice is caused by a combination of increased bilirubin production secondary to
accelerated destruction of erythrocytes, decreased excretory capacity secondary to low levels of
ligandin in hepatocytes, and low activity of the bilirubin-conjugating enzyme uridine
diphosphoglucuronyltransferase (UDPGT).
Pathologic neonatal jaundice occurs when additional factors accompany the basic mechanisms
described above. Examples include immune or nonimmune hemolytic anemia, polycythemia,
and the presence of bruising or other extravasation of blood.
Decreased clearance of bilirubin may play a role in breast feeding jaundice, breast milk jaundice,
and in several metabolic and endocrine disorders.
Risk factors include the following:

Race: Incidence is higher in East Asians and American Indians and is lower in
Africans/African Americans.

Geography: Incidence is higher in populations living at high altitudes. Greeks living in

Greece appear to have a higher incidence than those living outside of Greece.

Genetics and familial risk: Incidence is higher in infants with siblings who had significant
neonatal jaundice and particularly in infants whose older siblings were treated for
neonatal jaundice. Incidence is also higher in infants with mutations/polymorphisms in
the genes that code for enzymes and proteins involved in bilirubin metabolism, and in
infants with homozygous or heterozygous glucose-6-phosphatase dehydrogenase (G-6PD) deficiency and other hereditary hemolytic anemias. Combinations of such genetic
variants appear to exacerbate neonatal jaundice. [1, 5, 9, 10, 6]

Nutrition: Incidence is higher in infants who are breastfed or who receive inadequate
nutrition. The mechanism for this phenomenon may not be fully understood. However,
when inadequate feeding volume is involved, increased enterohepatic circulation of
bilirubin probably contributes to prolonged jaundice. Recent data have shown that breast
milk jaundice correlates with higher levels of epidermal growth factor, both in breast
milk and in infants' serum. [11] Data suggest that the difference between breastfed and
formula-fed infants may be less pronounced with some modern formulas. However,
formulas containing protein hydrolysates have been shown to promote bilirubin
excretion.

Maternal factors: Infants of mothers with diabetes have higher incidence. Use of some
drugs may increase the incidence, whereas others decrease the incidence. Some herbal
remedies taken by the lactating mother may apparently exacerbate jaundice in the infant.

Birthweight and gestational age: Incidence is higher in premature infants and in infants
with low birthweight.

Congenital infection

Epidemiology
United States data
An estimated 50% of term and 80% of preterm infants develop jaundice, typically 2-4 days afer
birth.[3] Neonatal hyperbilirubinemia is extremely common because almost every newborn
develops an unconjugated serum bilirubin level of more than 30 mol/L (1.8 mg/dL) during the
first week of life. Incidence figures are difficult to compare because authors of different studies
do not use the same definitions for significant neonatal hyperbilirubinemia or jaundice. In
addition, identification of infants to be tested depends on visual recognition of jaundice by health
care providers, which varies widely and depends both on observer attention and on infant
characteristics such as race and gestational age.[12]
With the above caveats, epidemiologic studies provide a frame of reference for estimated
incidence. In 1986, Maisels and Gifford reported 6.1% of infants with serum bilirubin levels of
more than 220 mol/L (12.9 mg/dL).[13] In a 2003 study in the United States, 4.3% of 47,801
infants had total serum bilirubin levels in a range in which phototherapy was recommended by
the 1994 American Academy of Pediatrics (AAP) guidelines, and 2.9% had values in a range in

which the 1994 AAP guidelines suggest considering phototherapy.[14] In some LMICs, the
incidence of severe neonatal jaundice may be as much as 100 times higher than in higher-income
countries.[15]

International data
Incidence varies with ethnicity and geography. Incidence is higher in East Asians and American
Indians and lower in Africans. Greeks living in Greece have a higher incidence than those of
Greek descent living outside of Greece.
Incidence is higher in populations living at high altitudes. In 1984, Moore et al reported 32.7% of
infants with serum bilirubin levels of more than 205 mol/L (12 mg/dL) at 3100 m of altitude.[16]
A study from Turkey reported significant jaundice in 10.5% of term infants and in 25.3% of nearterm infants.[17] Significant jaundice was defined according to gestational and postnatal age and
leveled off at 14 mg/dL (240 mol/L) at 4 days in preterm infants and 17 mg/dL (290 mol/L) in
the term infants. Severe neonatal jaundice is 100-fold more frequent in Nigeria than in
industrialized countries.[15] In Denmark, 24 in 100.000 infants met exchange transfusion criteria,
while 9 in 100.000 developed acute bilirubin encephalopathy.[18]
Studies seem to suggest that some of the ethnic variability in the incidence and severity of
neonatal jaundice may be related to differences in the distribution of the genetic variants in
bilirubin metabolism discussed above.[1, 5]

Race-related demographics
The incidence of neonatal jaundice is increased in infants of East Asian, American Indian, and
Greek descent, although the latter appears to apply only to infants born in Greece and thus may
be environmental rather than ethnic in origin. African infants are affected less often than nonAfrican infants. For this reason, significant jaundice in an African infant merits a closer
evaluation of possible causes, including G-6-PD deficiency. In 1985, Linn et al reported on a
series in which 49% of East Asian, 20% of white, and 12% of black infants had serum bilirubin
levels of more than 170 mol/L (10 mg/dL).[19]
The possible impact of genetic polymorphisms on ethnic variation in incidence and severity
should be recognized. Thus, in a study of Taiwanese infants, Huang et al reported that neonates
who carry the 211 and 388 variants in the UGT1A1 and OATP2 genes and who are breastfed are
at particularly high risk for severe hyperbilirubinemia.[1]

Sex- and age-related demographics

Risk of developing significant neonatal jaundice is higher in male infants. This does not appear
to be related to bilirubin production rates, which are similar to those in female infants.
The risk of significant neonatal jaundice is inversely proportional to gestational age.

Prognosis
Prognosis is excellent if the patient receives treatment according to accepted guidelines.
Brain damage due to kernicterus remains a true risk, and the apparent increased incidence of
kernicterus in recent years may be due to the misconception that jaundice in the healthy full-term
infant is not dangerous and can be disregarded.

Mortality/morbidity
Kernicterus is a complication of neonatal jaundice.
The incidence of kernicterus in North America and Europe ranges from 0.4-2.7 cases per
100,000 births.[20] Death from physiologic neonatal jaundice per se should not occur. Death from
kernicterus may occur, particularly in countries with less developed medical care systems. In one
small study from rural Nigeria, 31% of infants with clinical jaundice tested had G-6-PD
deficiency, and 36% of the infants with G-6-PD deficiency died with presumed kernicterus
compared with only 3% of the infants with a normal G-6-PD screening test result.[21]
Please see the Medscape Drugs & Diseases article Kernicterus for more information.

Patient Education
Parents should be educated about neonatal jaundice and receive written information prior to
discharge from the birth hospital. The parent information leaflet should preferably be available in
several languages.

History
Presentation and duration of neonatal jaundice
Note the following:

Typically, neonatal jaundice presents on the second or third day of life.

Jaundice that is visible during the first 24 hours of life is likely to be nonphysiologic;
further evaluation is suggested.

Infants who present with jaundice after 3-4 days of life may also require closer scrutiny
and monitoring.

In infants with severe jaundice or jaundice that continues beyond the first 1-2 weeks of
life, the results of the newborn metabolic screen should be checked for galactosemia and
congenital hypothyroidism, further family history should be explored (see below), the

infant's weight curve should be evaluated, the mother's impressions as far as adequacy of
breastfeeding should be elicited, and the stool color should be assessed.

Family history
Obtain the following information:

Previous sibling with jaundice in the neonatal period, particularly if the jaundice required
treatment

Other family members with jaundice or known family history of Gilbert syndrome

Anemia, splenectomy, or bile stones in family members or known heredity for hemolytic
disorders

Liver disease in family members

History of pregnancy and delivery

Ascertain the following information:

Maternal illness suggestive of viral or other infection

Maternal drug intake, including the use of herbal remedies

Delayed cord clamping

Birth trauma with bruising and/or fractures.

Postnatal history
Obtain details of the following:

Loss of stool color

Breastfeeding

Use of drugs and herbal remedies in the lactating mother

Greater than average weight loss

Symptoms or signs of hypothyroidism

Symptoms or signs of metabolic disease (eg, galactosemia)

Exposure to total parental nutrition

Physical Examination
Neonatal jaundice first becomes visible in the face and forehead. Identification is aided by
pressure on the skin, since blanching reveals the underlying color. Jaundice then gradually
becomes visible on the trunk and extremities. This cephalocaudal progression is well described,
even in 19th-century medical texts. Jaundice disappears in the opposite direction. The
explanation for this phenomenon is not well understood, but both changes in bilirubin-albumin
binding related to pH and differences in skin temperature and blood flow have been proposed.[22,
23]
This phenomenon is claimed to be clinically useful because, independent of other factors,
visible jaundice in the lower extremities strongly suggests the need to check the bilirubin level,
either in the serum or noninvasively via transcutaneous bilirubinometry.
Recent work in the authors group (Tllfsrud et al, unpublished data) was not able to confirm
this so-called cephalocaudal progression of jaundice. Thus, when dermal jaundice was measured
noninvasively on the forehead, sternum, and symphysis, no cephalocaudal trend was evident.
In most infants, yellow color is the only finding on physical examination. More intense jaundice
may be associated with drowsiness. Brainstem auditory-evoked potentials performed at this time
may reveal prolongation of latencies, decreased amplitudes, or both.
Overt neurologic findings, such as changes in muscle tone, seizures, or altered cry
characteristics, in a significantly jaundiced infant are danger signs and require immediate
attention to prevent kernicterus. In the presence of such symptoms or signs, effective
phototherapy should commence immediately without waiting for the laboratory test results (see
Laboratory Studies). The potential need for exchange transfusion should not preclude the
immediate initiation of phototherapy.[24, 25]
Hepatosplenomegaly, petechiae, and microcephaly may be associated with hemolytic
anemia, sepsis, and congenital infections and should trigger a diagnostic evaluation directed
towards these diagnoses. Neonatal jaundice may be exacerbated in these situations.

Diagnostic ConsiderationsImportant considerationsOther

conditions to be considered
Clinicians should recognize the potential of significant jaundice to cause brain damage, even in
the healthy full-term neonate.
Assess whether a "healthy full-term neonate" is both healthy and was really delivered at term.
Clinician should personally examine an infant reported by parents or other caregivers to be
significantly jaundiced.

Consider risk factors for significant jaundice when an infant is prepared for early discharge from
the birth hospital, and factor such risks, if present, into the plan for follow-up of the baby.
Certain conditions may cause nonphysiologic jaundice. In these infants, a baseline physiologic
jaundice most likely occurs, which is then exaggerated, for example, by increased enterohepatic
circulation in bowel atresia, bile stasis in choledochal cyst, or increased bilirubin production in
hemolytic anemias. Such conditions include the following:

Bowel atresia

Hypertrophic pyloric stenosis

Choledochal cyst

Conjugated hyperbilirubinemia

Crigler-Najjar syndrome

Arias syndrome

Gilbert syndrome

Immune hemolytic anemia

Nonimmune hemolytic anemia

Congenital infections with cytomegalovirus or toxoplasmosis

Differential Diagnoses

Breast Milk Jaundice

Cholestasis

Dubin-Johnson Syndrome

Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia)

Hemolytic Disease of Newborn

Hepatitis B

Pediatric Biliary Atresia

Pediatric Cytomegalovirus Infection

Pediatric Duodenal Atresia

Pediatric Hypothyroidism

Laboratory Studies
Bilirubin measurement may include the following:

Transcutaneous bilirubinometry can be performed using handheld devices that

incorporate sophisticated optical algorithms. Use of such devices has been shown to
reduce the need for blood sampling in infants with jaundice. [26] However, they cannot be
used to monitor the progress of phototherapy. [27]

Transcutaneous bilirubinometry performs better than visual assessment. The latter is not a
reliable technique for estimating levels of bilirubin, [28] but the complete absence of
jaundice as judged by the eye in good lighting conditions has quite high accuracy as far
as predicting which infants are unlikely to develop high total serum bilirubin levels. [29]

In infants with mild jaundice, transcutaneous bilirubinometry may be all that is needed to
assure that total bilirubin levels are safely below those requiring intervention.

In infants with moderate jaundice, transcutaneous bilirubinometry may be useful in

selecting patients who require phlebotomy or capillary blood sampling for serum
bilirubin measurement.

In infants with extreme jaundice, transcutaneous bilirubinometry may be a useful tool to

fast-track such infants to rapid and aggressive therapy.

Usually, a total serum bilirubin level test is the only one required in an infant with
moderate jaundice who presents on the typical second or third day of life without a
history and physical findings suggestive of a pathologic process. Measurement of
bilirubin fractions (conjugated vs unconjugated) in serum is not usually required in
infants who present as described above. However, in infants who have
hepatosplenomegaly, petechiae, thrombocytopenia, or other findings suggestive of
hepatobiliary disease, metabolic disorder, or congenital infection, early measurement of
bilirubin fractions is suggested. The same may apply to infants who remain jaundiced
beyond the first 7-10 days of life, and to infants whose total serum bilirubin levels
repeatedly rebound following treatment.

Additional studies may be indicated in the following situations:

Infants who present with jaundice on the first or after the third day of life

Infants who are anemic at birth

Infants who otherwise appear ill

Infants in whom serum bilirubin levels are elevated enough to trigger treatment

Infants in whom significant jaundice persists beyond the first 2 weeks of life

Infants in whom family, maternal, pregnancy, or case histories suggest the possibility of a
pathologic process

Infants in whom physical examination reveals findings not explained by simple

physiologic hyperbilirubinemia

In addition to total serum bilirubin levels, other suggested studies may include the following,
particularly if the rate of rise or the absolute bilirubin concentration is approaching the need for
phototherapy:

Blood type and Rh determination in mother and infant

Direct antiglobulin test (DAT) in the infant (direct Coombs test)

Hemoglobin and hematocrit values

Serum albumin levels: This appears to be a useful adjunct in evaluating risk of toxicity
levels because albumin binds bilirubin in a ratio of 1:1 at the primary high-affinity
binding site.

Nomogram for hour-specific bilirubin values: This is a useful tool for predicting, either
before or at the time of hospital discharge, which infants are likely to develop high serum
bilirubin values. Infants identified in this manner require close follow-up monitoring and
repeated bilirubin measurements. The predictive ability has been shown both for bilirubin
values measured in serum and for values measured transcutaneously. The nomogram has
also been shown to work well for DAT-positive infants with AB0 incompatibility. [30] A
positive DAT test result did not add any value to the clinical management of these infants
beyond that already obtained by an hour-specific bilirubin value plotted onto the
nomogram.

Measurement of end-tidal carbon monoxide in breath: End-tidal carbon monoxide in

breath (ETCO) may be used as an index of bilirubin production. Measurement of ETCO
may assist in identifying individuals with increased bilirubin production and, thus, at
increased risk of developing high bilirubin levels. An apparatus has been developed that
makes measuring ETCO simple (CoSense TM ETCO Monitor, Capnia, Palo Alto, CA,
USA).

Peripheral blood film for erythrocyte morphology

Reticulocyte count

Conjugated bilirubin levels: Measuring bilirubin fractions may be indicated in the

circumstances described above. Note that direct bilirubin measurements are often
inaccurate, are subject to significant interlaboratory and intralaboratory variation, and are
generally not a sensitive tool for diagnosing cholestasis unless repeated measurements
confirm the presence of an elevated conjugated bilirubin.

Liver function tests: Aspartate aminotransferase (ASAT or SGOT) and alanine

aminotransferase (ALAT or SGPT) levels are elevated in hepatocellular disease. Alkaline
phosphatase and -glutamyltransferase (GGT) levels are often elevated in cholestatic
disease. A -GT/ALAT ratio of more than 1 is strongly suggestive of biliary obstruction.
However, it does not distinguish between intrahepatic and extrahepatic cholestasis.

Tests for viral and/or parasitic infection: These may be indicated in infants with
hepatosplenomegaly, petechiae, thrombocytopenia, or other evidence of hepatocellular
disease.

Reducing substance in urine: This is a useful screening test for galactosemia, provided
the infant has received sufficient quantities of milk.

Blood gas measurements: The risk of bilirubin CNS toxicity is increased in acidosis,
particularly respiratory acidosis.

Bilirubin-binding tests: Although they are interesting research tools, these tests have not
found widespread use in clinical practice. Although elevated levels of unbound ("free")
bilirubin are associated with an increased risk of bilirubin encephalopathy, unbound
bilirubin is but one of several factors that mediate/modulate bilirubin toxicity.

Thyroid function tests

Imaging Studies
Ultrasonography: Ultrasonography of the liver and bile ducts is warranted in infants with
laboratory or clinical signs of cholestatic disease.
Radionuclide scanning: A radionuclide liver scan for uptake of hepatoiminodiacetic acid (HIDA)
is indicated if extrahepatic biliary atresia is suspected. At the author's institution, patients are
pretreated with phenobarbital 5 mg/kg/d for 3-4 days before performing the scan.

Other Tests

Auditory and visually evoked potentials are affected during ongoing significant jaundice;
however, no criteria have been established that allow extrapolation from evoked potential
findings to the risk of kernicterus. Data suggest that the probability of a bilateral "refer" on an
automated auditory brainstem response (AABR) study increases with unbound bilirubin
concentrations.[31] Because unbound bilirubin concentrations may be more closely correlated with
bilirubin neurotoxicity, a "refer" finding may indicate an increased risk of bilirubin neurotoxicity.
A "refer" AABR result obtained shortly after admission of an infant with significant jaundice
seems to argue for immediate and aggressive treatment.
Brainstem auditory-evoked potentials should be obtained in the aftermath of severe neonatal
jaundice to exclude sensorineural hearing loss. In physiologic jaundice, auditory-evoked
potentials return to normal with the resolution of hyperbilirubinemia. However, in patients with
significant neonatal jaundice or kernicterus, auditory-evoked potentials and functional hearing
may remain abnormal.
The phonetic characteristics of the infant's cry are changed in significant neonatal jaundice;
however, computerized analyses of these phonetic characteristics are not used in clinical practice.

Histologic Findings
Organs, including the brain, are yellow in any individual with significant jaundice; however, the
yellow color does not always indicate CNS toxicity. This distinction was not always clearly
understood in older descriptions of so-called "low-bilirubin kernicterus." At present, this has
contributed to confusion and uncertainty regarding therapeutic guidelines and intervention levels.
See Kernicterus for a more detailed description.

Medical Care
Phototherapy, intravenous immune globulin (IVIG), and exchange transfusion are the most
widely used therapeutic modalities in infants with neonatal jaundice. Although medications that
impact bilirubin metabolism have been used in studies, drugs are not ordinarily used in
unconjugated neonatal hyperbilirubinemia.

Phototherapy
Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia.[3] This
therapeutic principle was discovered rather serendipitously in England in the 1950s and is now
arguably the most widespread therapy of any kind (excluding prophylactic treatments) used in
newborns.
Phototherapy is effective because 3 reactions can occur when bilirubin is exposed to light, as
follows:

Initially, photooxidation was believed to be responsible for the beneficial effect of

phototherapy. However, although bilirubin is bleached through the action of light, the
process is slow and is now believed to contribute only minimally to the therapeutic effect
of phototherapy.

Configurational isomerization is a very rapid process that changes some of the

predominant 4Z,15Z bilirubin isomers to water-soluble isomers in which one or both of
the intramolecular bonds are opened (E,Z; Z,E; or E,E). In human infants, the 4Z,15E
isomer predominates, and, at equilibrium conditions, the isomer constitutes about 20-25%
of circulating bilirubin after a few hours of phototherapy. [32] This proportion is not
significantly influenced by the intensity of light, nor by the character of the light source
or use of "double phototherapy." [32] Data have shown that formation of photoisomers is
significant after as little as 15 minutes of phototherapy. [32] More recent studies suggest
that the initial rate of isomerization is inversely related to the hemoglobin level. [32]

Structural isomerization consists of intramolecular cyclization, resulting in the formation

of lumirubin. This process is enhanced by increasing the intensity of light. During
phototherapy, lumirubin may constitute 2-6% of the total serum bilirubin concentration.

The photoisomers of bilirubin are excreted in bile and, to some extent, in urine. The half-life of
lumirubin in serum is much shorter than that in E isomers, and lumirubin is the primary pigment
found in bile during phototherapy.
Bear in mind when initiating phototherapy that lowering of the total serum bilirubin
concentration may be only part of the therapeutic benefit. Because photoisomers, by virtue of
their water-soluble nature, should not be able to cross the blood-brain barrier, phototherapy may
reduce the risk of bilirubin-induced neurotoxicity as soon as the lights are turned on. At any
given total serum bilirubin concentration, the presence of 20-25% of photoisomers means that
only 75-80% of the total bilirubin may be present in a form that can enter the brain. Please note
that although theoretically coherent, no experimental data support this speculation.
Phototherapy can be administered in a number of ways. To understand the benefits and
limitations of the various approaches, some basic principles regarding wavelength and types of
light are discussed below with comments and suggestions regarding each system.
First, wavelength must be considered. Bilirubin absorbs light primarily around 450-460 nm.
However, the ability of light to penetrate skin is also important; longer wavelengths penetrate
better. Thus, lamps with output predominantly in the blue region of the spectrum (460-490 nm)
are probably most effective. In practice, light is used in the white, blue, turquoise, and green
wavelengths.
Second, previously a dose-response relationship was thought to exist between the amount of
irradiation and reduction in serum bilirubin up to an irradiation level of 30-40 W/cm2/nm. Many
older phototherapy units deliver much less energy, some at or near the minimally effective level,
which appears to be approximately 6 W/cm2/nm. On the other hand, newer phototherapy units,
when properly configured and with the use of reflecting blankets and curtains may deliver light

energy above 40 W/cm2/nm. Recent data do not confirm that there really is a saturation level.[33]
Thus, the relationship between irradiance and the 24-hour decrement in total serum bilirubin was
linear up to 55 W/cm2, and with no evidence of a saturation point.
Third, the energy delivered to the infant's skin decreases with increasing distance between the
infant and the light source. This distance should not be greater than 50 cm (20 in) and can be less
(down to 10 cm) provided the infant's temperature is monitored.
Fourth, the efficiency of phototherapy depends on the amount of bilirubin that is irradiated.
Irradiating a large skin surface area is more efficient than irradiating a small area, and the
efficiency of phototherapy increases with serum bilirubin concentration.
Fifth, the nature and character of the light source may affect energy delivery. Irradiation levels
using quartz halide spotlights are maximal at the center of the circle of light and decrease sharply
towards the perimeter of the circle. Large infants and infants who can move away from the
circle's center may receive less efficient phototherapy.
Although green light theoretically penetrates the skin better, it has not been shown unequivocally
to be more efficient in clinical use than blue or white light. Because green light makes babies
look sick and is unpleasant to work in, green light has not gained widespread acceptance.
Blue fluorescent tubes are widely used for phototherapy. Narrow-spectrum blue lamps (special
blue) appear to work best, while ordinary blue fluorescent lamps are probably equivalent to
standard white daylight lamps. Blue lights may cause discomfort in hospital staff members,
which can be ameliorated by mixing blue and white tubes in the phototherapy unit.
White (daylight) fluorescent tubes are less efficient than special blue lamps; however, decreasing
the distance between infants and lamps can compensate for the lower efficiency. Use of
reflecting materials also helps. Thus, in LMICs where the cost of special blue lamps may be
prohibitive, efficient phototherapy is accomplished with white lamps.
White quartz lamps are an integral part of some radiant warmers and incubators. They have a
significant blue component in the light spectrum. When used as spotlights, the energy field is
strongly focused towards the center, with significantly less energy delivered at the perimeter, as
discussed above.
Quartz lamps are also used in single or double banks of 3-4 bulbs attached to the overhead heat
source of some radiant warmers. The energy field delivered by these is much more homogeneous
than that of spotlights, and the energy output is reasonably high. However, because the lamps are
fixed to the overhead heater unit, the ability to increase energy delivery by moving lights closer
to infants is limited.
Fiberoptic lights are also used in phototherapy units. These units deliver high energy levels, but
because spectral power (ie, irradiance multiplied by the size of the irradiated area) is related to
the size of the lighted field, the smaller "pads" are less efficient than larger wrap-around
blankets. Drawbacks of fiberoptic phototherapy units may include noise from the fan in the light

source and a decrease of delivered energy with aging and/or breakage of the optic fibers. Some
new fiberoptic units now incorporate photodiodes as a light source. Advantages of fiberoptic
phototherapy include the following:

Low risk of overheating the infant

No need for eye shields

Ability to deliver phototherapy with the infant in a bassinet next to the mother's bed

Simple deployment for home phototherapy

The possibility of irradiating a large surface area when combined with conventional
overhead phototherapy units (double/triple phototherapy)

Light-emitting diode (LED) lights are found in most newer phototherapy units. Advantages
include low power consumption, low heat production, and a much longer life span of the lightemitting units (20,000 hours) compared with older light sources. Blue LED lights have a narrow
spectral band of high-intensity light that overlaps the absorption spectrum of bilirubin. Trials
comparing LED phototherapy to other light sources were recently reviewed by the Cochrane
Collaboration and by Tridente and DeLuca. The authors of these reviews conclude that the
efficacy of LED lights in reducing total serum bilirubin levels is comparable to that of
conventional light sources (fluorescent or halogen lamps).[34, 35] Formation of bilirubin
photoisomers also appears comparable between LEDs and blue fluorescent lamps.[32]
"Double" and "triple" phototherapy, which implies the concurrent use of 2 or 3 phototherapy
units to treat the same patient, has often been used in the treatment of infants with very high
levels of serum bilirubin. The studies that appeared to show a benefit with this approach were
performed with old, relatively low-yield phototherapy units. Newer phototherapy units provide
much higher levels of irradiance. Whether double or triple phototherapy also confers a benefit
with the newer units, has not been tested in systematic trials. However, because recent studies
appear to rule out the existence of a saturation point (see discussion above), the utility of double
or triple phototherapy in extreme jaundice should not be discounted.[32]
The purpose of treating neonatal jaundice is to avoid neurotoxicity. Thus, indications for
treatment have been based on clinical studies of infants who developed kernicterus. Historical
data, much of which was derived from infants with hemolytic jaundice, appeared to suggest that
total serum bilirubin levels greater than 350 mol/L (20 mg/dL) were associated with increased
risk of neurotoxicity, at least in full-term infants.
As treatment of premature infants became more widespread and increasingly successful during
the last half of the 20th century, autopsy findings and follow-up data suggested that immature
infants were at risk of bilirubin encephalopathy at lower total serum bilirubin levels than mature
infants. Treatment was initiated at lower levels for these infants.

Until the 1940s, a truly effective treatment was not available. At that time, exchange transfusion
was shown to be feasible and was subsequently used in the treatment of Rh-immunized infants
with severe anemia, hyperbilirubinemia, or hydrops. However, exchange transfusion is not
without risk for the infant, and only with the discovery of phototherapy did neonatal jaundice
start to become an indication for treatment on a wider scale. Once phototherapy was shown to be
an apparently innocuous treatment, lights were turned on at lower serum bilirubin values than
those that had triggered exchange transfusion.
Exchange transfusion became the second-line treatment when phototherapy failed to control
serum bilirubin levels. However, data have shown that treatment with IVIG in infants with Rh or
ABO isoimmunization can significantly reduce the need for exchange transfusions.[36, 37] At the
author's institution, a tertiary center where exchange transfusions used to be frequent, currently
only 0-2 such procedures per year are performed, and IVIG has replaced exchange transfusion as
the second-line treatment in infants with isoimmune jaundice.[38] In a recent 1-year prospective
national survey of NICU phototherapy practices in Norway, Mreihil and collaborators found that
only 6 exchange transfusions had been performed in a birth population of 60.000 infants (Mreihil
K et al, preliminary data).
Clearly, the scientific data on which current therapeutic guidelines are based have very
significant shortcomings. Unfortunately, because the endpoint of bilirubin neurotoxicity is
permanent brain damage, a randomized study to reassess the guidelines is ethically unthinkable.
In most neonatal wards, total serum bilirubin levels are used as the primary measure of risk for
bilirubin encephalopathy. Numerous people would prefer to add a test for serum albumin at
higher bilirubin levels because bilirubin entry into the brain, a sine qua non for bilirubin
encephalopathy, increases when the bilirubin-albumin ratio exceeds unity. Tests for bilirubinalbumin binding or unbound bilirubin levels are used by some but have failed to gain widespread
acceptance. New analytical tools for measurement of unbound bilirubin have greatly simplified
the process, but the effect on clinical practice remains to be seen.
Numerous guidelines for the management of neonatal jaundice have been published, and even
more appear to be in local use without submission for critical review. In a survey published in
1996, the author analyzed clinical practices in this field based on responses from 108 neonatal
intensive care units (NICUs) worldwide.[39] The survey revealed a significant disparity in
guidelines.
The image below shows a box-and-whisker plot of the range of serum bilirubin values that
trigger phototherapy and exchange transfusion, respectively, in these NICUs. Evidently, an infant
might receive an exchange transfusion in one NICU for a serum bilirubin level that would not
trigger phototherapy in many other NICUs. This disparity illustrates how difficult it has been to
translate clinical data into sensible treatment guidelines.

The graph represents indications for

phototherapy and exchange transfusion in infants (with a birthweight of 3500 g) in 108 neonatal
ICUs. The left panel shows the range of indications for phototherapy, whereas the right panel
shows the indications for exchange transfusion. Numbers on the vertical axes are serum bilirubin
concentrations in mg/dL (lateral) and mmol/L (middle). In the left panel, the solid line refers to
the current recommendation of the American Academy of Pediatrics (AAP) for low-risk infants,
the line consisting of long dashes (- - - - -) represents the level at which the AAP recommends
phototherapy for infants at intermediate risk, and the line with short dashes (-----) represents the
suggested intervention level for infants at high risk. In the right panel, the dotted line (......)
represents the AAP suggested intervention level for exchange transfusion in infants considered at
low risk, the line consisting of dash-dot-dash (-.-.-.-.) represents the suggested intervention level
for exchange transfusion in infants at intermediate risk, and the line consisting of dash-dot-dotdash (-..-..-..-) represents the suggested intervention level for infants at high risk. Intensive
phototherapy is always recommended while preparations for exchange transfusion are in
progress. The box-and-whisker plots show the following values: lower error bar = 10th
percentile; lower box margin = 25th percentile; line transecting box = median; upper box margin
= 75th percentile; upper error bar = 90th percentile; and lower and upper diamonds = 5th and
95th percentiles, respectively.
In 2004, the AAP published new guidelines for the management of hyperbilirubinemia in healthy
full-term newborns.[40] These guidelines have been plotted on the image above.
The 2004 AAP guidelines represent a significant change from the 1994 guidelines.[40] Thus, the
emphasis on preventive action and risk evaluation is much stronger. An algorithm aids in the
assessment of risk and the decision about further management and follow-up (see the image
below). The committee that wrote the guidelines has carefully assessed the strength of the
scientific evidence on which the guidelines are based.

Algorithm for the management of

jaundice in the newborn nursery.
Practitioners in North America are advised to follow the 2004 AAP guidelines. Although the
2004 AAP guidelines do not provide guidance for treatment of jaundice in the smaller and more
premature/immature infants, a group of US experts recently published their suggestions for
management of jaundice in preterm infants younger than 35 weeks' gestation.[41]
Clinicians in different ethnic or geographic regions should consider tailoring these guidelines as
pertinent to their own populations and must consider factors that are unique to their medical
practice settings. Such factors may include racial characteristics, prevalence of congenital
hemolytic disorders, prevalence of genetic variants, and environmental concerns. Such
adaptation of guidelines should also take into consideration how healthcare delivery systems are
organized, as this is likely affect both in-hospital delivery of care as well as follow-up. At
present, the wisest course of action may be to apply local guidelines, assuming that these have
been successful in the prevention of kernicterus..
With this background and the clear understanding that this is meant only as an example, the
image below shows the chart currently in use in all pediatric departments in Norway. These
guidelines are the result of a 2006 consensus in the Neonatal Subgroup of the Norwegian
Pediatric Society. The similarities between the Norwegian chart and the 2004 AAP guidelines are
apparent.

Guidelines for management of neonatal

jaundice currently in use in all pediatric departments in Norway. The guidelines were based on
previously used charts and were created through a consensus process in the Neonatal Subgroup
of the Norwegian Pediatric Society. These guidelines were adopted as national at the fall meeting
of the Norwegian Pediatric Society. The reverse side of the chart contains explanatory notes to
help the user implement the guidelines. A separate information leaflet for parents was also
created.
The Norwegian chart suggests intervention limits for premature/immature infants. For infants of
less than 1000 gram birthweight, these guidelines propose starting phototherapy at 100 mol/L
(6 mg/dL) at age 24 hours, increasing gradually to 150 mol/L (8.8 mg/dL) at age 4 days, and
remaining steady thereafter at that level. This compares with a range of 85 mol/L (5 mg/dL) to
171 mol/L (10 mg/dL) used in a Neonatal Research Network (NRN) phototherapy trial in
infants of less than 1000 gram birthweight. The intervention level depended on postnatal age and
whether the infant was allocated to conservative or aggressive phototherapy.[42]
In a post hoc analysis of the NRN data, which compared infants who had not received any
phototherapy with those who had received such treatment, the subgroup of infants with
birthweights of 501-750 grams who had not received any phototherapy had a significantly higher
rate of mental developmental index of less than 50.[43] However, it should be noted that in the
original trial analysis, mortality in the aggressive phototherapy group at 501- to 750-g
birthweight was 5 percentage points higher than in the conservative group, which, although not
significant with the statistical approach chosen for analysis, appeared to offset the possible
developmental gain in survivors.[42] Recently these data were reanalyzed using Bayesian
statistics[44] and showed that aggressive phototherapy significantly increased the risk of death in
the sickest (being on mechanical ventilation at 24 h) and smallest infants (750 g birthweight),
while at the same time reducing impairment/severe impairment.

Key points in the practical execution of phototherapy include maximizing energy delivery and
the available surface area. Also consider the following:

The infant should be naked except for diapers (use these only if deemed absolutely
necessary and cut them to minimum workable size), and the eyes should be covered to
reduce risk of retinal damage.

Check the distance between the infant's skin and the light source. With fluorescent lamps,
the distance should be no greater than 50 cm (20 in). This distance may be reduced down
to 10-20 cm (4-8 in) if temperature homeostasis is monitored to reduce the risk of
overheating. Note that this does not apply to quartz lamps.

Cover the inside of the bassinet with reflecting material; white linen works well. Hang a
white curtain around the phototherapy unit and bassinet. These simple expedients can
multiply energy delivery by several fold.

When using spotlights, ensure that the infant is placed at the center of the circle of light,
since photoenergy drops off towards the circle's perimeter. Observe the infant closely to
ensure that the infant doesn't move away from the high-energy area. Spotlights are
probably more appropriate for small premature infants than for larger near-term infants.

Older data suggested that phototherapy was associated with increased insensible water
loss; therefore, many clinicians have routinely added a certain percentage to the infant's
estimated basic fluid requirements. Newer data suggest that if temperature homeostasis is
maintained, fluid loss is not significantly increased by phototherapy. At the author's
institution, routine fluid supplementation for infants under phototherapy has not been
used for more than a decade and is not recommended in national guidelines. Rather, the
infant is monitored for weight loss, urine output, and urine specific gravity. Fluid intake
is adjusted accordingly. In infants who are orally fed, the preferred fluid is milk because
it serves as a vehicle to transport bilirubin out of the gut.

Timing of follow-up serum bilirubin testing must be individualized. In infants admitted

with extreme serum bilirubin values (>500 mol/L or 30 mg/dL), monitoring should
occur every hour or every other hour. Reductions in serum bilirubin values of 85
mol/L/h (5 mg/dL/h) have been documented under such circumstances. In infants with
more moderate elevations of serum bilirubin, monitoring every 6-12 hours is probably
adequate.

Expectations regarding efficacy of phototherapy must be tailored to the circumstances. In

infants in whom serum bilirubin concentrations are still rising, a significant reduction of
the rate of increase may be satisfactory. In infants in whom serum bilirubin
concentrations are close to their peak, phototherapy should result in measurable
reductions in serum bilirubin levels within a few hours. In general, the higher the starting
serum bilirubin concentration, the more dramatic the initial rate of decline.

Discontinuation of phototherapy is a matter of judgment, and individual circumstances

must be taken into consideration. In practice, phototherapy is discontinued when serum
bilirubin levels fall 25-50 mol/L (1.5-3 mg/dL) below the level that triggered the
initiation of phototherapy. Serum bilirubin levels may rebound after treatment has been
discontinued, and follow-up tests should be obtained within 6-12 hours after
discontinuation.

Indications for prophylactic phototherapy are debatable. Phototherapy probably serves no

purpose in an infant who is not clinically jaundiced. In general, the lower the serum
bilirubin level, the less efficient the phototherapy. It seems more rational to apply truly
effective phototherapy once serum (and skin) bilirubin has reached levels at which
photons may do some good.

Wherever phototherapy is offered as a therapeutic modality, a device for measuring the

irradiance delivered by the equipment used should be readily at hand. This assists in
configuring the phototherapy set-up to deliver optimal efficiency. Some recommend this
routinely, every time phototherapy is initiated, and use this as a tool to focus staff
attention on maximizing energy delivery.

Generally, phototherapy is very safe and may have no serious long-term effects in neonates;
however, the following adverse effects and complications have been noted:

Insensible water loss may occur, but data suggest that this issue is not as important as
previously believed. Rather than instituting blanket increases of fluid supplements to all
infants receiving phototherapy, the author recommends fluid supplementation tailored to
the infant's individual needs, as measured through evaluation of weight curves, urine
output, urine specific gravity, and fecal water loss.

As noted above, a reanalysis of the NRN trial of aggressive versus conservative

phototherapy in premature infants of less than 1000 g birthweight showed that mortality
was increased in the subgroup of sick 501- to 750-g birthweight infants receiving
aggressive' phototherapy. [44] In a recent recommendation for treatment of
hyperbilirubinemia in premature infants younger than 35 weeks gestation, the authors
propose that initial irradiance should be reduced in the most vulnerable infants. [41]
However, as pointed out in an editorial to this paper, extant data seem to be more
compatible with the interpretation that duration of phototherapy is more dangerous than
irradiance levels. [45] Thus, it may be argued that phototherapy should be short and
efficient rather than less efficient and of longer duration. This question is still open to
interpretation and discussion.

Phototherapy may be associated with loose stools. Increased fecal water loss may create a
need for fluid supplementation.

Retinal damage has been observed in some animal models during intense phototherapy.
In an NICU environment, infants exposed to higher levels of ambient light were found to

have an increased risk of retinopathy. Therefore, covering the eyes of infants undergoing
phototherapy with eye patches is routine. Care must be taken lest the patches slip and
leave the eyes uncovered or occlude one or both nares.

The combination of hyperbilirubinemia and phototherapy can produce DNA-strand

breakage and other effects on cellular genetic material. In vitro and animal data have not
demonstrated any implication for treatment of human neonates. However, because most
hospitals use (cut-down) diapers during phototherapy, the issue of gonad shielding may
be moot.

Skin blood flow is increased during phototherapy, but this effect is less pronounced in
modern servocontrolled incubators. However, redistribution of blood flow may occur in
small premature infants. An increased incidence of patent ductus arteriosus (PDA) has
been reported in these circumstances. The appropriate treatment of PDA has been
reviewed. [46]

Hypocalcemia appears to be more common in premature infants under phototherapy

lights. This has been suggested to be mediated by altered melatonin metabolism.
Concentrations of certain amino acids in total parenteral nutrition solutions subjected to
phototherapy may deteriorate. Shield total parenteral nutrition solutions from light as
much as possible.

Regular maintenance of the equipment is required because accidents have been reported,
including burns resulting from a failure to replace UV filters.

Intravenous immune globulin

In relatively recent years, IVIG has been used for numerous immunologically mediated
conditions. In the presence of Rh, ABO, or other blood group incompatibilities that cause
significant neonatal jaundice, IVIG has been shown to significantly reduce the need for exchange
transfusions. However, it must be recognized that some studies have failed to show efficacy. The
reasons for this discrepancy have not been explained, but it should be noted that in the studies
that failed to show significant effects, IVIG was used more or less prophylactically for all
apparently immunized infants, whereas in the studies that reported benefits IVIG was used
exclusively as a rescue therapy in infants headed for exchange transfusion. Also, one can
speculate whether differences in the origin and characteristics of the IVIG preparation might play
a role. If one particular IVIG preparation appears not to work, it may be worthwhile to try IVIG
from a different source/manufacturer.
The 2004 AAP guidelines suggest a dose range for IVIG of 500-1000 mg/kg.[40]
The author routinely uses 500 mg/kg infused intravenously over a period of 2 hours for Rh or
ABO incompatibility when the total serum bilirubin levels approach or surpass the exchange
transfusions limits. The author has, on occasion, repeated the dose 2-3 times. In most cases,
when this is combined with intensive phototherapy, avoiding exchange transfusion is possible. In
the authors' institution, with about 750 NICU admissions per year, the use of exchange

transfusions has decreased to 0-2 per year following the implementation of IVIG therapy for Rh
and ABO isoimmunization.[38] The author does not use IVIG in the presence of hydrops.
Anecdotally, IVIG appears less likely to be successful when the infant is anemic (Hb < 10 g/dL).

Exchange transfusion
Exchange transfusion is indicated for avoiding bilirubin neurotoxicity when other therapeutic
modalities have failed or are not sufficient. In addition, the procedure may be indicated in infants
with erythroblastosis who present with severe anemia, hydrops, or both, even in the absence of
high serum bilirubin levels.
Exchange transfusion was once a common procedure. A significant proportion was performed in
infants with Rh isoimmunization. Immunotherapy in Rh-negative women at risk for sensitization
has significantly reduced the incidence of severe Rh erythroblastosis. Therefore, the number of
infants requiring exchange transfusion is now much smaller, and even large NICUs may perform
only a few procedures per year. As mentioned previously, the incidence of infants requiring
exchange transfusion in Norway was in a prospective survey shown to be only 0.01% (Mrehil K
et al, preliminary data). ABO incompatibility has become the most frequent cause of hemolytic
disease in industrialized countries.
Early exchange transfusion has usually been performed because of anemia (cord hemoglobin <
11 g/dL), elevated cord bilirubin level (>70 mol/L or 4.5 mg/dL), or both. A rapid rate of
increase in the serum bilirubin level (>15-20 mol/L /h or 1 mg/dL/h) was an indication for
exchange transfusion, as was a more moderate rate of increase (>8-10 mol/L/h or 0.5 mg/dL/h)
in the presence of moderate anemia (11-13 g/dL).
The serum bilirubin level that triggered an exchange transfusion in infants with hemolytic
jaundice was 350 mol/L (20 mg/dL) or a rate of increase that predicted this level or higher.
Strict adherence to the level of 20 mg/dL has been jocularly referred to as vigintiphobia (fear of
20).
Currently, most experts encourage an individualized approach, recognizing that exchange
transfusion is not a risk-free procedure, that effective phototherapy converts 15-25% of bilirubin
to nontoxic isomers, and that transfusion of a small volume of packed red cells may correct
anemia. Administration of IVIG (500 mg/kg) has been shown to reduce red cell destruction and
to limit the rate of increase of serum bilirubin levels in infants with Rh and ABO
isoimmunization (see above).
Current AAP guidelines distinguish between 3 risk categories: low, intermediate, and high.[40]
These correspond to 3 levels of suggested intervention, which increase from birth and plateau at
age 4 days. Naturally, intervention levels associated with exchange transfusion are higher than
those for phototherapy. Intensive phototherapy is strongly recommended in preparation for an
exchange transfusion. In fact, intensive phototherapy should be performed on an emergency
basis in any infant admitted for pronounced jaundice; do not await laboratory test results in these
cases. Phototherapy has minimal side effects in this scenario, whereas the waiting period for
laboratory test results and blood for exchange can take hours and could constitute the difference

between intact survival and survival with kernicterus. If phototherapy does not significantly
lower serum bilirubin levels, exchange transfusion should be performed.
Many believe that hemolytic jaundice represents a greater risk for neurotoxicity than
nonhemolytic jaundice, although the reasons for this belief are not intuitively obvious, assuming
that total serum bilirubin levels are equal. In animal studies, bilirubin entry into or clearance
from the brain was not affected by the presence of hemolytic anemia.
The technique of exchange transfusion, including adverse effects and complications, is discussed
extensively elsewhere. For more information, please consult Hemolytic Disease of Newborn.

Management of infants with extreme jaundice

Numerous cases have been reported in which infants have been readmitted to hospitals with
extreme jaundice. In some cases, significant delays have occurred between the time the infant
was first seen by medical personnel and the actual commencement of effective therapy.[47]
Any infant who returns to the hospital with significant jaundice within the first 1-2 weeks of
birth should be immediately triaged with measurement of transcutaneous bilirubin. High values
should result in immediate initiation of treatment. If such a measuring device is not available, or
if the infant presents with any kind of neurological symptoms, the infant should be put in
maximally efficient phototherapy as an emergency procedure, preferably by fast-tracking the
infant to a NICU. Waiting for laboratory results is not necessary before instituting such therapy
because no valid contraindications to phototherapy are possible in this scenario. Plans for an
exchange transfusion do not constitute an argument for delaying or not performing phototherapy.
Immediate benefit may be obtained within minutes, as soon as conversion of bilirubin into watersoluble photoisomers is measurable (see discussion above).
The need for intravenous hydration in such infants has been discussed. In the absence of clinical
signs of dehydration, no evidence suggests that overhydration is helpful. If the infant is
dehydrated, hydration should be given as clinically indicated. However, if the infant is able to
tolerate oral feeding, oral hydration with a breast milk substitute is likely to be superior to
intravenous hydration because it reduces enterohepatic circulation of bilirubin and helps "wash"
bilirubin out of the bowel.
Every hospital in which babies are delivered, or which has an emergency department in which
infants may be seen, should develop a protocol and triage algorithm for rapid evaluation and
management of jaundiced infants. The objective of such a protocol should be rapid recognition of
risk severity and reduction in the time to initiate appropriate treatment.
Infants admitted with signs of intermediate to advanced acute bilirubin encephalopathy (ABE)
are in urgent need of treatment because reversibility may be possible, even in such cases. The
term "crash-cart approach" has been used as a recommendation in such cases. The author,
together with other European colleagues, has published a series that included 6 patients with
signs of ABE who were urgently managed and appear to have escaped neurologic sequelae.[48]

In a review of the Kernicterus Registry, full recovery was noted in 8 of 11 cases treated with a
crash-cart approach, which included effective phototherapy plus exchange transfusion; full
recovery was not noted in cases in which delays had occurred.[47] In the Kernicterus Registry,
reversal was not observed in cases treated with only phototherapy; the authors strongly
recommend that exchange transfusion be performed in such cases.[47] In the European study,
reversal was also seen in 2 patients who did not receive exchange transfusion.[48] In one of these
cases, IVIG was used in lieu of exchange transfusion; in the other case, intensive phototherapy
and intravenous albumin were used.

Other therapies
In infants with breast milk jaundice, interruption of breastfeeding for 24-48 hours and feeding
with breast milk substitutes often helps to reduce the bilirubin level. Evidence suggests that the
simple expedient of supplementing feeds of breast milk with 5 mL of a breast milk substitute
reduces the level and duration of jaundice in breast milkfed infants. Because this latter
intervention causes less interference with the establishment of the breastfeeding dyad, the author
prefers to use this approach rather than complete interruption of breast feeding in most cases.
Oral bilirubin oxidase can reduce serum bilirubin levels, presumably by reducing enterohepatic
circulation; however, its use has not gained wide popularity. The same may be said for agar or
charcoal feeds, which act by binding bilirubin in the gut. Bilirubin oxidase is not available as a
drug, and for this reason, its use outside an approved research protocol probably is proscribed in
many countries.
Prophylactic treatment of Rh-negative women with Rh immunoglobulin has significantly
decreased the incidence and severity of Rh-hemolytic disease.

Surgical Care
Surgical care is not indicated in infants with physiologic neonatal jaundice. Surgical therapy is
indicated in infants in whom jaundice is caused by bowel or external bile duct atresia.

Consultations
For infants with physiologic neonatal jaundice, no consultation is required. Gastroenterologists
and surgeons may be consulted regarding infants with jaundice resulting from hepatobiliary or
bowel disease.

Diet
Breastfeeding concerns associated with neonatal jaundice are as follows:

Incidence and duration of jaundice have increased as breastfeeding has become more
popular. The factors in breast milk that contribute to this phenomenon are unclear. In
selected infants, interruption of breastfeeding and its replacement for 24-48 hours by a

breast milk substitute may be indicated. This decision should always be discussed in
person with the mother before implementation. The author's practice is now to first
perform a trial of 5 mL of a hydrolyzed formula given after each breast meal. The author
typically tries this for at least 1-2 days, with follow-up of bilirubin values. Only if this is
unsuccessful does the author occasionally attempt interruption of breast feeding.

With increasing emphasis on breastfeeding, some new mothers may have difficulty
admitting (even to themselves) to a lack of success in establishing lactation. Occasionally,
infants of breastfeeding mothers are admitted to hospitals with severe jaundice. They
typically weigh significantly less than their birthweight at a time when they should have
regained and surpassed that weight. Presumably, the process is one of increased
enterohepatic circulation, as bilirubin is left longer in the proximal gut for lack of milk to
bind it and carry it onward and out. This condition is sometimes referred to as
"breastfeeding jaundice." These infants may respond dramatically to phototherapy plus
oral feedings of milk ad libitum.

Long-Term Monitoring
In the era of early discharge, newborns released within the first 48 hours of life need to be
reassessed for jaundice within 1-2 days. The use of the hour-specific bilirubin nomogram may
assist in selecting infants with a high likelihood of developing significant hyperbilirubinemia.
The 2004 AAP guidelines emphasize the importance of universal systematic assessment for the
risk of severe hyperbilirubinemia.[40] Guidelines from the European Society for Pediatric
Research reiterate the same principles.[24]
Neonatal jaundice is one of the most common reasons why neonates are brought to an emergency
department after discharge from the birth hospital.[49]
Near-term infants are at higher risk than term infants of developing significant jaundice and
merit closer surveillance.[50]
The question of universal bilirubin screening has received attention and is the subject of debate.
Some data suggest that predischarge bilirubin screening reduces the number of infants with
severe jaundice, as well as the rate of hospital readmissions.[51, 52] Others have found that home
nurse visiting was cost-effective and prevented readmissions for jaundice and dehydration.[53]
However, the cost-effectiveness of preventing kernicterus by universal screening has been
questioned.[54]
Nevertheless, in an update to the 2004 AAP jaundice guidelines Maisels et al give a clear
recommendation in favor of predischarge bilirubin screening, either by transcutaneous
measurement or by serum analysis.[55]
These authors also recommend a more structured approach to management and follow-up
according to the predischarge total serum bilirubin and transcutaneous bilirubin (TcB) levels,
gestational age (see the Gestational Age from Estimated Date of Delivery calculator), and other
risk factors for hyperbilirubinemia. These risk factors include the following:[55]

Predischarge total serum bilirubin or transcutaneous bilirubin level measurement in the

high-risk or high-intermediaterisk zone

Lower gestational age

Exclusive breastfeeding, particularly if nursing is not going well and weight loss is
excessive

Jaundice observed in the first 24 hours

Isoimmune or other hemolytic disease (eg, G-6-PD deficiency)

Previous sibling with jaundice

Cephalohematoma or significant bruising

East Asian race

Telephone consultations are not recommended because parental reports cannot be appropriately
gauged. Recently, numerous infants have developed kernicterus, resulting, at least in part, from
inadequate communication between practitioners or their representatives and parents.
The availability of new devices for transcutaneous measurement of bilirubin levels should
facilitate follow-up evaluations of infants discharged before 48 hours of life.
Home phototherapy is used in an effort to limit the high cost of applying such therapy in
hospitals. Note the following:

Home treatment can avoid or limit parent-child separation. Home treatment should be
used with caution, since prevention of neurotoxicity is the goal. Some argue that an infant
at risk for neurologic damage should not be at home.

With effective treatment strategies, the average duration of phototherapy in the regular
neonatal nursery at the author's institution is less than 17 hours. Whether the effort and
cost to set up home therapy is worthwhile is debatable. This assessment may be different
in different socioeconomic and health financing circumstances.

Infants who have been treated for hemolytic jaundice require follow-up observation for several
weeks because hemoglobin levels may fall lower than seen in physiologic anemia. Erythrocyte
transfusions may be required if infants develop symptomatic anemia.

Prevention

Prevention of severe neonatal jaundice is best achieved through attention to the risk status of the
infant prior to discharge from the birth hospital, through parent education, and through careful
planning of postdischarge follow-up.[24, 40]
A predischarge bilirubin measurement, obtained by transcutaneous or serum measurement and
plotted into an hour-specific nomogram, has been shown to be a useful tool in distinguishing
infants with a low risk of subsequently developing high bilirubin values.
Clinical risk factors include gestational age of less than 38 weeks, the use of oxytocin or vacuum
during delivery, exclusive breast feeding, an older sibling with neonatal jaundice that required
phototherapy, a rise of 6 mg/dL/d ( 100 mol/L/d) in total serum bilirubin levels, and
hematomas or extensive bruising. Birth weight is also associated with risk of developing
significant jaundice; the higher the birthweight in term infants, the higher the risk.
Medication Summary

Medications are not usually administered in infants with physiologic neonatal jaundice.
However, in certain instances, phenobarbital, an inducer of hepatic bilirubin metabolism, has
been used to enhance bilirubin metabolism. Several studies have shown that phenobarbital is
effective in reducing mean serum bilirubin values during the first week of life. Phenobarbital
may be administered prenatally in the mother or postnatally in the infant.
In populations in which the incidence of neonatal jaundice or kernicterus is high, this type of
pharmacologic treatment may warrant consideration. However, concerns surround the long-term
effects of phenobarbital on these children. Therefore, this treatment is probably not justified in
populations with a low incidence of severe neonatal jaundice. Other drugs can induce bilirubin
metabolism, but lack of adequate safety data prevents their use outside research protocols.
Intravenous immunoglobulin (IVIG) at 500 mg/kg has been shown to significantly reduce the
need for exchange transfusions in infants with isoimmune hemolytic disease.[38] The mechanism
is unknown but may be related to the way the immune system handles red cells that have been
coated by antibodies. Published experience is still somewhat limited, but administration of
immunoglobulin does not appear to be likely associated with greater risks for the infant than an
exchange transfusion. Published data regarding efficacy are varied, perhaps having to do with
different study sets-up, as studies that show effects of IVIG as far as reducing exchange
transfusion have used this drug in a rescue modailty only. One may also speculate that the
specific origin and characteristics of the IVIG preparation could play a role. Although
speculative, lack of efficacy of a specific IVIG product may warrant trial of one from a different
manufacturer or batch.
A new therapy currently under development consists of inhibition of bilirubin production through
blockage of heme oxygenase. This can be achieved through the use of metal mesoporphyrins and
protoporphyrins. Apparently, heme can be directly excreted through the bile; thus, inhibition of

heme oxygenase does not result in accumulation of unprocessed heme. This approach may
virtually eliminate neonatal jaundice as a clinical problem. However, before the treatment can be
applied on a wide scale, important questions regarding the long-term safety of the drugs must be
answered. Also, in light of data suggesting that bilirubin may play an important role as a free
radical quencher, a more complete understanding of this putative role for bilirubin is required
before wholesale inhibition of its production is contemplated.

Further Inpatient Care

Infants who have been treated for neonatal jaundice can be discharged when they are feeding
adequately and have had 2 successive serum bilirubin levels demonstrating a trend towards lower
values.
If the hospital does not routinely screen newborns for auditory function, ordering such tests prior
to discharge is advisable in infants who have had severe jaundice.
The 2004 AAP guideline recommends a systematic risk assessment for hyperbilirubinemia risk
in all infants before discharge.[40] Parents should be provided with verbal and written information
about jaundice.

Transfer
Infants in need of exchange transfusion born at or admitted to facilities not capable of
performing this procedure should be transferred to the nearest facility with such capability. In
addition to complete records, the infant should be accompanied by a sample of maternal blood
because this is needed by the blood bank to match blood.
However, in determining the best use of time before transfer, as well as the timing of the transfer,
the following factors should be considered:

If the infant is in imminent danger of kernicterus, or is already exhibiting signs of

neurological compromise, the most efficient phototherapy possible under the
circumstances should be immediately initiated and should be continued until transfer
commences. If fiberoptic or any other kind of phototherapy is technically feasible during
transport, it should be continued throughout the duration of the transport.

If the hyperbilirubinemia is due to blood group isoimmunization, an infusion of

intravenous immunoglobulin (IVIG) at 500 mg/kg should be immediately started and
continued before and during transfer until completed (2 h).

Even if the receiving hospital determines that an exchange transfusion should be performed,
continuing optimal phototherapy until the actual exchange procedure can commence is
important. If fiberoptic phototherapy is available, the infant may be left on a fiberoptic mattress
while the exchange is carried out. Oral hydration with a breast milk substitute may aid the

clearance of bilirubin from the gut, thus inhibiting enterohepatic circulation of bilirubin, and
should be given unless clearly contraindicated by the clinical state of the infant. Although none
of these suggestions have been tested in randomized controlled trials, case reports, bilirubin
photobiology, and expert opinion suggest that they may be beneficial and, at the very least, are
unlikely to be harmful.