Medscape Hiperbilirubin Pochi

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Neonatal Jaundice

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 yearsago. Medical theses, essays, and textbooks from the 18 thand 19thcenturies 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 2

phenomena[1] :

Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. Thisis the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass

in neonates.

Hepatic excretory capacity is low both because of low concentrations of the binding proteinligandin 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.
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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, apparently by passive diffusion, 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 UDPGT1A1coding region are at an increased risk of

significant hyperbilirubinemia. Interactions between the Gilbert genotype and hemolytic

anemias such asglucose-6-phosphatase dehydrogenase (G-6-PD) deficiency, hereditary


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spherocytosis, or ABO hemolytic disease also appear to increase the risk of severe neonatal

jaundice.

Further, the observation of jaundice in some infants withhypertrophic pyloric

stenosismay 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-2gene polymorphism with a

variant UDPGT1A1gene further increases this risk to 22-fold.[2] 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. 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[3] .

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 thebreast milk jaundicedescribed 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
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the UDPGT1A1or OATP2genes. 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

developing countries.

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.

Epidemiology


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Frequency

United States

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.[4]

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).[5] 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.[6] In

some developing countries, the incidence of severe neonatal jaundice may be as much as 100

times higher than in more developed countries.[7]

International

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.

[8]

A study from Turkey reported significant jaundice in 10.5% of term infants and in 25.3% of

near-term infants.[9] 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.[7] In Denmark, 24 in 100.000 infants met exchange

transfusion criteria, while 9 in 100.000 developed acute bilirubin encephalopathy.[10]


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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, 2]

Mortality/Morbidity

The incidence of kernicterus in North America and Europe ranges from 0.4-2.7 cases per

100,000 births.[11] 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.[12]

Race

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 non-African 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 alreported 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).[13]

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 UGT1A1andOATP2genes and who are

breastfed are at particularly high risk for severe hyperbilirubinemia.[1]

Sex

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.

Age

The risk of significant neonatal jaundice is inversely proportional to gestational age.


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History

Presentation and duration of neonatal jaundice

Typically, presentation is 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 andmonitoring.

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

congenitalhypothyroidism,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

Previous sibling with jaundice in the neonatal period, particularly if the jaundice requiredtreatment

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 diseaseHistory of pregnancy and delivery

Maternal illness suggestive of viral or other infection Maternal drug intake Delayed cord clamping Birth traumawith bruising and/or fractures.

Postnatal history

Loss of stool color Breastfeeding Greater than average weight loss Symptoms or signs of hypothyroidism Symptoms or signs of metabolic disease (eg, galactosemia) Exposure to total parental nutrition

Physical
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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.[14, 15] 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.[16, 17]

Hepatosplenomegaly, petechiae, and microcephaly may be associated withhemolytic

anemia,sepsis,and congenital infections and should trigger a diagnostic evaluation directed

towards these diagnoses. Neonatal jaundice may be exacerbated in these situations.

Causes

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).
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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 inAfricans/African Americans.

Geography: Incidence is higher in populations living at high altitudes. Greeks living inGreece 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 significantneonatal 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-6-PD) deficiency

and other hereditary hemolytic anemias. Combinations of such genetic variants appear to

exacerbate neonatal jaundice.[18, 1, 19, 2]

Nutrition: Incidence is higher in infants who are breastfed or who receive inadequatenutrition. 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.[20] 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 somedrugs may increase the incidence, whereas others decrease the incidence.

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

Congenital infection


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Differential Diagnoses

Biliary Atresia Breast Milk Jaundice Cholestasis Cytomegalovirus Infection Dubin-Johnson Syndrome Duodenal Atresia Galactose-1-Phosphate Uridyltransferase Deficiency (Galactosemia) Hemolytic Disease of Newborn Hepatitis B Hypothyroidism

Laboratory Studies

Bilirubin measurement may include the following:

Transcutaneous bilirubinometry can be performed using handheld devices that incorporatesophisticated optical algorithms. Use of such devices has been shown to reduce the need for

blood sampling in infants with jaundice.[21] However, they cannot be used to monitor the

progress of phototherapy.[22]

Transcutaneous bilirubinometry performs better than visual assessment. The latter is not areliable technique for estimating levels of bilirubin,[23]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.[24]

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

In infants with moderate jaundice, transcutaneous bilirubinometry may be useful inselecting patients who require phlebotomy or capillary blood sampling for serum bilirubin

measurement.

In infants with extreme jaundice, transcutaneous bilirubinometry may be a useful tool tofast-track such infants to rapid and aggressive therapy.

Usually, a totalserum bilirubinlevel test is the only one required in an infant with moderatejaundice 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
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(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 physiologichyperbilirubinemia

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 needfor phototherapy:

Blood type and Rh determination in mother and infant Direct antiglobulin test(DAT) in the infant (direct Coombs test) Hemoglobinandhematocritvalues Serumalbuminlevels: 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, eitherbefore 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.[25] A

positive DAT test result did not add any value to the clinical management of these infants
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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 (CoSenseTMETCO 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 diagnosingcholestasisunless repeated measurements

confirm the presence of an elevated conjugated bilirubin.

Liver function tests:Aspartate aminotransferase(ASAT or SGOT) andalanineaminotransferase(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 withhepatosplenomegaly, petechiae, thrombocytopenia, or other evidence of hepatocellular

disease.

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

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

Bilirubin-binding tests: Although they are interesting research tools, these tests have notfound 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
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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.[26] 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, the auditory-evoked

potential returns to normal with the resolution of hyperbilirubinemia. However, in patients

with significant neonatal jaundice or kernicterus, the auditory-evoked potential 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 clinicalpractice.

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,


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this has contributed to confusion and uncertainty regarding therapeutic guidelines and

intervention levels.

SeeKernicterusfor 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.

Phototherapy

Phototherapy is the primary treatment in neonates with unconjugated hyperbilirubinemia.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 ofphototherapy. 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 predominant4Z,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.[27] This proportion is not

significantly influenced by the intensity of light. Data have shown that formation of

photoisomers is significant after as little as 15 minutes of phototherapy.[27] Recent studies

suggest that the initial rate of isomerization is inversely related to the hemoglobin level

(Mreihil K et al, unpublished data).

Structural isomerization consists of intramolecular cyclization, resulting in the formation oflumirubin. This process is enhanced by increasing the intensity of light. During

phototherapy, lumirubin may constitute 2-6% of the total serum bilirubin concentration.


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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.[28] 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.


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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 developing countries 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


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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 some newer phototherapy units. Advantages

include low power consumption, low heat production, and a much longer life span of the

light-emitting 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 iscomparable to that of conventional light sources (fluorescent or halogen lamps).[29, 30]

"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.

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.


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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.[31,

32] 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.[33]

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 bilirubin-

albumin 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


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108 neonatal intensive care units (NICUs) worldwide.[34] 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-dot-dash (-..-..-..-) 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.[35] These guidelines have been plotted on the image above.

The 2004 AAP guidelines represent a significant change from the 1994 guidelines.

[35]

Thus,the emphasis on preventive action and risk evaluation is much stronger. An algorithm aids in
http://refimgshow%281%29/


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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.[36]

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.


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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.[37]

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.[38] 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.[37] Recently these data were reanalyzed using

Bayesian statistics[39] 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.


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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 absolutelynecessary 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 awhite 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'sestimated 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 withextreme 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. Ininfants 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


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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 mustbe 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 nopurpose 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 theirradiance 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 aspreviously 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 conservativephototherapy 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.[39] 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.[36] 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


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levels.[40] 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 aneed for fluid supplementation.

Retinal damage has been observed in some animal models during intense phototherapy. Inan 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-strandbreakage 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 inmodern servocontrolled incubators. However, redistribution of blood flow may occur in

small premature infants. An increased incidence ofpatent ductus arteriosus (PDA)has been

reported in these circumstances. The appropriate treatment of PDA has been reviewed.[41]

Hypocalcemiaappears 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 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. One can speculate that differences

in the origin and characteristics of the IVIG preparation could play a role. If one particular
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IVIG preparation appears not to work, it may be worthwhile to try IVIG from a different

source/manufacturer.

The 2004 AAP guidelinessuggest a dose range for IVIG of 500-1000 mg/kg.[35]

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.[33] The author does not use IVIG in the presence

ofhydrops.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. 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.
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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.[35] 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 consultHemolytic 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.[42]
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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 water-soluble 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.[43]

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.[42] 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.

[42]

In the European study,reversal was also seen in 2 patients who did not receive exchange transfusion.[43] In one of


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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:


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Incidence and duration of jaundice have increased as breastfeeding has become morepopular. 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 difficultyadmitting (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. The author refers to this condition as lack-of-breast-

milk jaundice. These infants may respond dramatically to phototherapy plus oral feedings of

milk ad libitum.

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.


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Intravenous immunoglobulin (IVIG) at 500 mg/kg has been shown to significantly reduce the

need for exchange transfusions in infants with isoimmune hemolytic disease.[33] 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 suggesting that the specific origin and characteristics of the IVIG preparation may

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 itsproduction is contemplated.

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