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Clinical features and management of unconjugated hyperbilirubinemia in term and

near term infants

Ronald J Wong, BA
David K Stevenson, MD

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INTRODUCTION Neonatal jaundice is the yellowish discoloration of the skin and/or


sclerae of newborn infants caused by tissue deposition of bilirubin. Physiologic jaundice is
mild unconjugated (indirect-reacting) bilirubinemia and affects nearly all newborns. The
peak level in physiologic jaundice typically is 5 to 6 mg/dL (86 to 103 mol/L), occurs at 48
to 120 hours of age, and does not exceed 17 to 18 mg/dL (291-308 mol/L). The peak may
not be reached until seven days of age in Asian infants or infants who are born at 35 to 37
weeks gestation. Higher levels of unconjugated hyperbilirubinemia are pathologic and occur
in a variety of conditions.

The clinical features and management of unconjugated hyperbilirubinemia in healthy term


and near term infants, as well as bilirubin toxicity and the prevention of kernicterus, are
reviewed here. The pathogenesis and etiology of this disorder are discussed separately. (See
"Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn").

EPIDEMIOLOGY Nearly all newborn infants have a total serum bilirubin (TSB) value
greater than 1 mg/dL (17 mol/L), the upper limit of normal for an adult. Most newborns
appear clinically jaundiced [1].

Pathologic hyperbilirubinemia occurs when the TSB exceeds the age-in-hours-specific 95th
percentile using the Bhutani nomogram (show figure 1) [2]. The nomogram was developed
for a racially diverse population in Philadelphia in which nearly 60 percent were breastfed;
infants were excluded if they had hemolytic conditions or required phototherapy before 60
hours to control rapidly rising TSB levels.

However, rates of hyperbilirubinemia vary substantially among institutions because of


differences in racial composition, hemolytic conditions, or breastfeeding practices. In a
multinational study, the proportion of infants with TSB 95th percentile at 30 hours of age
ranged from approximately 5 (Hong Kong, China) to 40 percent (Kobe, Japan) [3].

Studies of term or near-term infant from a large Northern California health maintenance
organization report the following incidences of hyperbilirubinemia at different levels of TSB
[4,5]:

TSB > 30 mg/dL (513 mol/L): 0.01 percent [4]

TSB > 25 mg/dL (428 mol/L): 0.14 percent [5]

TSB > 20 mg/dL (340 mol/L): 2.00 percent [5]

In a Danish population-based study over 2 years (2000 to 2001), the incidence of extreme
hyperbilirubinemia (defined as a level greater than 22 mg/dL or 376 mol/L) was 25 per
100,000 (0.03 percent) live births at term or near-term [6].

It is unclear whether or not the incidence of kernicterus is increasing. Data from Denmark
suggest a higher incidence as demonstrated by the increase of reported cases from zero in
the 20 years before 1994 to six cases between 1994 and 1998 [7]. Whether an increased
incidence is present in countries that do not have population-based surveillance for
kernicterus, such as the United States, is not known [8].

Changes in clinical practice that might result in a higher incidence of kernicterus include
increased prevalence of breastfeeding and early discharge of infants from the hospital. Early
hospital discharge has been associated with inadequacies in lactation education at
discharge, support for ongoing lactation, and ambulatory followup [7,8]. (See "Prevention of
severe hyperbilirubinemia" below, and see "Initial routine management of the newborn",
section on Length of hospital stay).

CLINICAL FEATURES

Risk factors Risk factors for the development of severe hyperbilirubinemia in term and
near-term infants are obtained from the clinical history and examination. They include [9]:

Jaundice within the first 24 hours of life [10]

Blood group incompatibility with positive direct antiglobulin test

Gestational age <38 weeks (the risk increases with decreasing gestational age) [11,12]

Known hemolytic disease (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency) or


elevated end tidal carbon monoxide (CO) levels corrected for inhaled CO (ETCOc)

Inherited deficiencies in hepatic conjugating capacity (eg, Crigler-Najjar or Gilbert


Syndrome) [8]. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the
newborn")

Previous sibling who received phototherapy or had jaundice [12,13]

Cephalohematoma or significant bruising [11]

Exclusive breastfeeding, particularly if nursing is not going well and weight loss is
excessive (>12 percent of birth weight) [11,12]

East Asian race

Jaundice before discharge [12]

Macrosomic infant of a diabetic mother [14,15]

Polycythemia

Male gender [11]

Maternal age 25 years [12]

Factors associated with decreased risk of severe hyperbilirubinemia include, gestational age
41 weeks [11], exclusive bottle feeding [11,12], Black race [3], and discharge from the
hospital after 72 hours [12,16].

Examination Visual inspection of skin color can be used to detect jaundice but is not a
reliable method to assess the level of bilirubin or identify infants at risk for rapidly rising
bilirubin, especially in those with dark skin [17,18]. The examination should be performed
with adequate ambient light. Pressing on the skin with a finger reduces local skin perfusion
and may facilitate detection of jaundice.

Jaundice progresses in a cephalocaudal direction. The face and sclera typically appear icteric
at bilirubin levels of 4 to 8 mg/dL (68 to 137 mol/L), whereas the entire body, including
palms and soles, appears jaundiced at values of >15 mg/dL (257 mol/L) [19]. TSB or
transcutaneous bilirubin (TcB) levels should be measured in an infant with jaundice detected
below the umbilicus. (See "Transcutaneous bilirubin (TcB)" below).

Other findings on physical examination may suggest an increased risk for pathologic
jaundice. They include pallor, enclosed hemorrhage such as cephalohematoma, bruising,
and hepatosplenomegaly.

Complications
Bilirubin toxicity Bilirubin is a potential neurotoxin [20-28]. Unconjugated bilirubin
that is not bound to albumin (free bilirubin) can enter the brain and cause cell death by
apoptosis (programmed cell death) and/or necrosis [26-28]. In vitro, animal cell culture
studies suggested that lower levels of unconjugated bilirubin induced apoptosis and higher
levels induced necrotic cell death [26]. Which mechanism predominates in infants with
severe unconjugated hyperbilirubinemia who develop acute bilirubin encephalopathy or
chronic permanent sequelae (ie, kernicterus) remains uncertain [9]. The regions most often
affected include the basal ganglia and the brain stem nuclei for oculomotor and auditory
function, accounting for the clinical features of this condition [29]. The long-term morbidity
and mortality of kernicterus are 70 and 10 percent, respectively [30].

Term infants are at risk for bilirubin toxicity when TSB concentrations exceed 25 to 30
mg/dL (428 to 513 mol/L). However, the relationship between TSB and bilirubin toxicity is
variable and influenced by other factors such as bilirubin affinity, which is reduced in
premature and sick infants. Most bilirubin is normally bound to albumin, resulting in low
levels of free bilirubin. High TSB concentrations may exceed the capacity of albumin to bind
bilirubin and lead to higher levels of free bilirubin that may be neurotoxic. Although
measurement of free bilirubin concentration would be useful to guide therapy, clinical testing
is not universally available; the ratio of bilirubin to albumin can be used as an approximate
surrogate for free bilirubin [31,32].

Drugs such as sulfisoxazole, moxalactam, and ceftriaxone can displace bilirubin from
albumin and increase the risk of bilirubin toxicity. Acidosis increases movement of bilirubin
into tissues and, thus, can contribute to the development of acute bilirubin encephalopathy.

Bilirubin toxicity can occur in healthy term infants. Infants at increased risk are those who
are near term (35 to 37 weeks), breastfed, have hemolytic disease, and are discharged
home before 48 hours. To minimize the risk of acute bilirubin encephalopathy, these infants
require close surveillance because the peak TSB level will be reached after discharge.

Clinical manifestations Acute bilirubin encephalopathy typically progresses through


three phases [29]:

Phase one occurs in the first few days and consists of lethargy, hypotonia, and poor
sucking, with a slightly high-pitched cry.

Phase two evolves later in the first week. The infant becomes irritable with a high-pitched
cry, and develops hypertonia, often with backward arching of the neck (retrocollis) and
trunk (opisthotonus) and fever.

Phase three typically starts after the first week and includes hypertonia with marked
retrocollis and opisthotonus, stupor or coma, and a shrill cry.

Kernicterus (the chronic and permanent sequelae of bilirubin toxicity) develops during the
first year after birth [29]. The three major features are:

Movement disorder (chorea, ballismus, tremor)

Gaze abnormalities, especially limitation of upward gaze

Auditory abnormalities

Cognitive function usually is relatively spared. In addition to neurologic abnormalities, some


children with bilirubin toxicity have dental enamel hypoplasia [33]. (See "Hyperkinetic
movement disorders").

Abnormal BAER Brainstem auditory evoked responses (BAER) are affected by


hyperbilirubinemia [34-36]. In one study, increased TSB correlated with prolonged
brainstem conduction time [35]. These abnormalities may resolve as TSB values decline.
Changes in BAER also have been associated with elevated free bilirubin levels. An abnormal
BAER and normal otoacoustic emission (OAE) suggest an auditory neuropathy.

Mild neurologic dysfunction Moderate hyperbilirubinemia may be associated with an


increased risk of minor neurologic dysfunction, although the level of bilirubin at which injury
occurs remains uncertain [37-39]. As an example, infants with neonatal bilirubin values of
13.6 to 25.9 mg/dL (233 to 244 mol/L) had more abnormalities of muscle tone at one year
of age than controls without jaundice (10/20 versus 2/20) [37]. Because of methodologic
limitations of the available studies, more information is needed on the effect of moderate
hyperbilirubinemia on outcome before recommendations regarding management are
modified [40-42].

LABORATORY EVALUATION

Total serum bilirubin (TSB) Total serum bilirubin (TSB) and the direct-reacting serum
bilirubin concentration should be measured in an infant with jaundice. If the direct-reacting
bilirubin is greater than 1.0 mg/dL (17.1 mol/L) if the TSB is <5 mg/dL (85 mol/L), or
>20 percent of TSB if the TSB is >5 mg/dL (85 mol/L) causes of cholestatic jaundice
should be investigated. (See "Approach to neonatal cholestasis").

The following discussion applies to healthy term and near-term infants with unconjugated
hyperbilirubinemia. Infants who appear ill or are premature require more extensive
evaluation (eg, for infection or metabolic disease such as galactosemia or hypothyroidism)

The TSB concentration is compared to an age-in-hours-specific percentile-based nomogram


[2]. Peak TSB concentration in a low-risk term newborn ( 38 weeks gestation and well) is as
follows [1,2]:

Should not exceed 12 mg/dL (205 mol/L) at 24 hours

Should not exceed 15 mg/dL (257 mol/L) at 48 hours

Should not exceed 18 mg/dL (308 mol/L) at 72 hours

Should not exceed 20 mg/dL (342 mol/L) at 96 hours or 21 mg/dL (359 mol/L) at any
time after five days

The peak may not be reached until seven days of age in Asian infants or infants who are
born at 35 to 37 weeks gestation.

For infants at higher risk, such as term infants with risk factors or premature infants
between 35 and 37 weeks with or without additional risk factors, lower TSB concentrations
may direct further diagnostic workup and, possibly, earlier intervention with phototherapy
(see "Phototherapy" below).

Infants with hour-specific values 95th percentile are at increased risk for the development
of clinically significant hyperbilirubinemia that requires intervention. In a racially diverse
population with a 60 percent rate of breastfeeding, 95th percentile values for TSB were
approximately 8, 10, 12, and 16 mg/dL (137, 171, 205, and 274 mol/L) at 24, 36, 48, and
72 hours, respectively [2].

Transcutaneous bilirubin (TcB) Transcutaneous devices that use multiwavelength


spectral reflectance can be used to estimate TSB and avoid blood sampling. In contrast to
older devices, this method is not affected by skin pigmentation [43,44]. In several reports
of racially and ethnically diverse groups of term and near-term newborns, close correlation
was found between TcB and TSB measurements [44-46]. Because TcB measurements have
been determined to be valid estimates of TSB [30], TcB can replace TSB in many
circumstances, particularly when TSB is less than 15 mg/dL (257 mol/L) [9]. At higher
levels of TSB, TcB measurements in certain ethnic groups, such as Hispanics, may
underestimate the TSB [47-49]. TcB measurements are not reliable in infants undergoing
phototherapy [9].

A confirmatory TSB should be measured when TcB exceeds the age-in-hours-specific 75th
percentile using the Bhutani nomogram (show figure 1) [50]. Alternatively, a TSB should be
measured if the management plan would be altered by considering the TSB to be equal to
TcB + 3 mg/dL (51 mol/L) since TcB underestimates TSB by 3 mg/dL (51 mol/L) only
rarely (0.6 percent of cases [45]) [50].
End-tidal carbon monoxide End-tidal measurement of CO corrected for ambient CO
(ETCOc) provides a noninvasive assessment of bilirubin production because catabolism of
heme results in equimolar quantities of bilirubin and CO [3,51-54]. Elevated ETCOc values
(>2.0 ppm) can identify infants with increased bilirubin production (most often caused by
hemolysis) who require additional evaluation or close monitoring. In one study, the ETCOc
value at 30 hours of age exceeded the mean value (1.48 ppm) in 76 percent of
hyperbilirubinemic infants [3].

Additional evaluation Infants who have TSB values 95th percentile or suspicion of
hemolytic disease require subsequent measurement of TSB and further evaluation to
determine the etiology of jaundice. (See "Pathogenesis and etiology of unconjugated
hyperbilirubinemia in the newborn").

Initial tests that should be obtained are [9]:

Blood type and direct Coombs test

Complete blood count and smear

Reticulocyte count, G6PD screen, or ETCOc (if available)

Direct or conjugated bilirubin

The TSB should be repeated in 4 to 24 hours depending upon the infant's age and TSB level.
Serum albumin may be measured to help determine the need for phototherapy or exchange
transfusion [9]. (See "Phototherapy" below and see "Exchange transfusion" below).

The mother's blood type and antibody status usually are known from the prenatal history. If
the parents are of Mediterranean, Nigerian, or Asian ancestry, or if the TSB concentration is
18 mg/dL (222 mol/L), G6PD is measured. However, G6PD measurements are not
universally available, and the results usually are not timely enough to affect clinical
decisions. (See "Diagnosis and treatment of glucose-6-phosphate dehydrogenase
deficiency").

PREVENTION OF SEVERE HYPERBILIRUBINEMIA Infants with severe


hyperbilirubinemia are at risk for developing bilirubin toxicity, although only a small number
will do so (see "Bilirubin toxicity" above). Identification and treatment of infants with severe
hyperbilirubinemia will prevent most cases of acute bilirubin encephalopathy. Infants at risk
require close surveillance and follow-up.

A root cause analysis of factors contributing to cases of acute bilirubin encephalopathy


identified potentially correctable causes [55]. These include:

Discharge before 48 hours after birth with no follow-up within 48 hours of discharge

Failure to measure the bilirubin concentration in an infant with jaundice within 24 hours
of birth

Failure to recognize risk factors for hyperbilirubinemia

Lack of concern regarding the presence of jaundice

Delayed measurement of TSB in infants with severe jaundice

Delayed initiation of phototherapy in infants with elevated TSB levels

Lack of response to parental concerns regarding jaundice, lethargy, or poor feeding

Term and near term infants should be assessed for jaundice every eight to 12 hours [9].
TSB or TcB should be measured in all infants who are jaundiced before 24 hours of age and
in older infants in whom jaundice appears excessive for age (ie, below the level of the
umbilicus) [9]. The bilirubin concentration should be interpreted according to the infant's
age in hours (show figure 1). TSB concentrations typically peak between 72 and 96 hours of
age [1,2].
Universal predischarge screening The risk of development of severe
hyperbilirubinemia should be assessed in every infant before he or she is discharged from
the nursery, particularly those infants who are discharged before 72 hours of age [9]. The
American Academy of Pediatrics (AAP) recommends two options for risk assessment:
assessment of clinical risk factors (see "Risk factors" above) and/or predischarge
measurement of TSB or TcB (see "Prediction of severe hyperbilirubinemia" below) [9].

Clinical risk factors are most helpful in predicting the risk of severe hyperbilirubinemia when
they are present in combination (the more risk factors the greater the risk) or altogether
absent. The predictability of individual risk factors is poor [11].

Universal screening of infants with TSB levels before discharge has been proposed to
facilitate identification of infants at high risk for the development of severe
hyperbilirubinemia [2,9]. Limitations of this approach are the need for blood sampling and
the cost of TSB measurement [56]. Use of TcB for screening may decrease the need for
phlebotomy and reduce costs (see "Transcutaneous bilirubin (TcB)" above) [43,44]. An
alternative approach is clinical assessment of jaundice before and within one to two days of
discharge and subsequent TSB measurement in jaundiced infants.

Follow-up Appropriate follow-up after discharge is essential; all infants should be seen in
the first few days after discharge to determine the infant's weight and percent change from
birth weight, adequacy of intake, pattern of voiding and stooling, and the presence or
absence of jaundice [9]. TSB or TcB measurements should be made if jaundice is suspected.

The timing and frequency of follow-up depend upon the age of the infant at the time of
discharge and the presence or absence of risk factors for hyperbilirubinemia [9]. The initial
visit should occur by 72, 96, and 120 hours of age for infants discharged before 24 hours,
between 24 and 47.9 hours, and between 48 and 72 hours, respectively [9]. Delayed
discharge (at least 72 to 96 hours of age) from the nursery should be considered if
appropriate follow-up cannot be ensured.

Prediction of severe hyperbilirubinemia A percentile-based nomogram of age-in-


hours-specific TSB values developed in a population of healthy term infants can be used to
predict the subsequent risk of severe hyperbilirubinemia (show figure 1) [2]. In this study,
TSB measured before hospital discharge at 18 to 72 hours of age was plotted in the
appropriate hour-specific zone of low (<40th percentile), low intermediate ( 40th to 75th
percentile), high intermediate (>75th to 95th percentile), and severe (>95th percentile)
risk and compared to TSB measured within 24 to 48 hours after discharge. Positive and
negative predictive values for hour-specific TSB before discharge and the development of
clinically significant hyperbilirubinemia ( 95th percentile) after discharge were 12 and 100
percent (low zone); 22 and 99.5 percent (intermediate zone); and 40 and 98 percent (high
zone), respectively.

In another report, the combined use of an hour-specific TSB measurement and ETCOc did
not improve the predictive ability of an hour-specific TSB alone [3]. However, this dual
approach can identify infants with increased bilirubin production, such as hemolysis, or
decreased elimination, such as conjugation defects, who may need more intensive follow-
up. In this study, in contrast to the report on which the nomogram was based that used TSB
alone, 4 of 620 infants with TSB <40th percentile (low risk zone) at 30 6 hours
subsequently developed TSB 95th percentile. This finding supports the need for early
follow-up of all infants.

Breastfed infants TSB levels are higher in breastfed than in formula-fed infants. In
addition, milk intake may be inadequate until lactation is well established, resulting in
volume depletion and weight loss. Increased surveillance is needed for infants born at 35 to
37 weeks gestation because they are at increased risk for early difficulty with breastfeeding.

One possible mechanism for increased TSB in breastfed compared to formula-fed infants is
the increased concentration of beta-glucuronidase in breast milk. Beta-glucuronidase
deconjugates intestinal bilirubin, increasing its ability to be absorbed (ie, increasing
enterohepatic circulation). Blocking the deconjugation of bilirubin through beta-
glucuronidase inhibition may provide a mechanism to reduce intestinal absorption of
bilirubin in breast-fed infants, but this is as yet unproven [57]. (See "Pathogenesis and
etiology of unconjugated hyperbilirubinemia in the newborn").

Counseling regarding jaundice and breastfeeding should be provided before discharge. The
importance of frequent feedings (at least 8 to 12 times per day for the first several days)
should be emphasized. Lactation consultants and home visits by a nurse may be helpful.
Until lactation is well established, jaundiced infants may benefit from a short period of
supplementation with cow's milk-based or soy formula (but not water) [58-62].

PHOTOTHERAPY Phototherapy consists of exposing the infant's skin to light. It is a safe


and efficient method to reduce the toxicity of bilirubin and increase its elimination. The use
of phototherapy decreases the risk that total serum bilirubin (TSB) concentration will reach
the level at which exchange transfusion is recommended (see "Exchange transfusion"
below). It is estimated that 5 to 10 infants with TSB between 15 and 20 mg/dL (257 to 342
mol/L) must receive phototherapy must receive phototherapy to prevent the TSB in one
infant from reaching 20 mg/dL (342 mol/L) [9].

Mechanisms Phototherapy detoxifies bilirubin by three mechanisms: structural


isomerization to lumirubin, photoisomerization to a less toxic isomer, and photo-oxidation to
polar molecules. These processes are thought to occur in the blood vessels or interstitial
spaces of the skin.

Phototherapy converts bilirubin into lumirubin in a process of structural isomerization that is


not reversible [63]. Lumirubin, a more soluble substance than bilirubin, is excreted without
conjugation into bile and urine. It is the principal mechanism by which phototherapy reduces
the TSB concentration.

Phototherapy also converts the stable 4Z-15Z bilirubin isomer to the 4Z-15E isomer, which
is more polar and less toxic than is the common form. Like lumirubin, it is excreted into bile
without conjugation. Unlike structural isomerization to lumirubin, photoisomerization is
reversible, and some of the 4Z-15E isomer in bile is converted back the stable 4Z-15Z
isomer. Photoisomerization is the most important mechanism to increase bilirubin excretion.
However, this pathway may have little effect on TSB levels because laboratory
measurements do not distinguish among the isomers.

Photo-oxidation reactions convert bilirubin to colorless, polar compounds that are excreted
primarily in the urine. This mechanism accounts for a small proportion of bilirubin
elimination.

Technique The dose of phototherapy, known as irradiance (measured in W/cm(2) per


nm), determines its efficacy. Irradiance depends upon the power of the light, its distance
from the infant, and the surface area exposed. It usually is expressed for a certain
wavelength band (spectral irradiance).

Fluorescent white light typically is used at a dose of approximately 6 to 12 W/cm(2) of


body surface area exposed per nm of wavelength (425 to 475 nm). Blue lights are more
effective at reducing bilirubin but may cause discomfort among clinicians and interfere with
the detection of cyanosis [64,65]. Fluorescent lights are placed 15 to 20 cm above the
infant. We use light banks in which eight white and blue fluorescent bulbs are alternated.
This combination dramatically decreases the irradiance but lessens the eye strain for
clinicians.

Halogen white lamps are hot and can cause thermal injury. They should be placed at the
distance from the patient recommended by the manufacturer.

Fiberoptic blankets generate little heat and can be placed close to the infant, providing
higher irradiance than do fluorescent lights [66]. However, blankets are small and rarely
cover sufficient surface area to be effective when used alone in term infants. They can be
used as an adjunct to overhead fluorescent or halogen lights. Use of devices incorporating
high intensity blue gallium nitride light emitting diodes (LEDs) as the light source are as
effective as conventional phototherapy [67,68] and are now commercially available.
Phototherapy should be continuous, with interruptions only for feeding. If the TSB is at a
near toxic level, blanket exposure can continue during the feedings.

Intensive phototherapy For intensive (aggressive) phototherapy, high levels of


irradiance in the 430 to 490 nm band (usually 30 W/cm(2) per nm) are delivered to as
much of the infant's surface area as possible [9]. The necessary irradiance can be achieved
with a bank of special blue lights placed at a distance of 10 to 12 cm from the infant's body
and a fiberoptic pad or special blue fluorescent tubes below the infant. The area covered by
the diaper should be minimized. The eyes are shielded with a blindfold; care should be
taken so that the blindfold does not cover the nose. The infant should be placed in an open
crib, bassinet, or on a warmer, rather than an incubator (the top of the incubator prevents
the light from being brought sufficiently close to the infant). Lining the sides of the bassinet
or warmer with aluminum foil or white material increases the exposed surface area of the
infant and the efficacy of phototherapy [69,70].

Home phototherapy As an alternative to readmission to the hospital, fiberoptic


phototherapy can be administered to infants at home. Home phototherapy is less disruptive
to the family and can be considered for healthy infants without hemolysis or other risk
factors who have TSB levels 2 to 3 mg/dL (35 to 50 mol/L) below the recommended
treatment levels, are feeding well, and can be closely followed [9].

Sunlight exposure Although exposure to sunlight provides sufficient irradiance in the


425 to 475 nm band and is known to lower the TSB [71], exposure to sunlight is not
recommended to prevent severe hyperbilirubinemia [9]. The difficulties of avoiding sunburn
while exposing a naked infant to sunlight preclude the use of sunlight exposure as a reliable
therapeutic option.

Indications The following indications apply to healthy infants born at 35 weeks


gestation. Infants who appear ill or were born at <35 weeks gestation require more
aggressive intervention. We initiate phototherapy based upon the newly revised
recommendations of the American Academy of Pediatrics (AAP) Clinical Practice Guideline on
the management of hyperbilirubinemia in the newborn infant 35 weeks of gestation [9].

Phototherapy is started if the bilirubin exceeds the 95th percentile for hour-specific TSB
concentrations and risk category, predicting increased risk for developing severe
hyperbilirubinemia after discharge [9]. The risk factors mentioned below are defined as
isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency,
asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin <3.0 g/dL
(if measured):

For infants at lower risk ( 38 weeks gestation and without risk factors), phototherapy is
initiated if the bilirubin is >12, 15, or 18 mg/dL (205, 257, and 308 mol/L) at 24, 48, or
>72 hr, respectively.

Infants in this category who have TSB levels 2 to 3 mg/dL (35 to 51 mol/L) below the
recommended levels may be treated with fiberoptic or conventional phototherapy at home
or in the hospital, respectively.

For infants at medium risk ( 38 weeks gestation with risk factors or 35 to 37 6/7 weeks
gestation without risk factors), phototherapy is initiated if the bilirubin is >10,13, or 15
mg/dL (171, 222, or 257 mol/L) at 24, 48, or >72 hr, respectively; the threshold for
intervention may be lowered for infants closer to 35 weeks and raised for those closer to 37
6/7 weeks

For infants at higher risk (35 to 37 6/7 weeks gestation with risk factors), phototherapy
is initiated if the bilirubin is >8, 11, or 13.5 (137, 188, or 231 mol/L) at 24, 48, or >72 hr,
respectively.

Special circumstances Infants with clinical jaundice within the first 24 hours
frequently have hemolysis. They require immediate evaluation and close surveillance to
assess the need for phototherapy.
In infants with other causes of increased bilirubin production, such as cephalohematoma or
extensive bruising, or in infants suspected of having conjugation disorders, we start
phototherapy when the hour-specific TSB concentration is in the high intermediate risk zone
(>75th percentile) (show figure 1).

Hydration It is important to maintain adequate hydration and urine output during


phototherapy since urinary excretion of lumirubin is the principle mechanism by which
phototherapy reduces the TSB concentration. Thus, during phototherapy, infants should
continue oral feedings by breast or bottle. Intravenous hydration may be necessary to
correct hypovolemia in infants with significant volume depletion whose oral intake is
inadequate; otherwise, routine intravenous fluid or other supplementation of normovolemic
infants is not recommended by the AAP [9].

Breastfed infants whose intake is inadequate, weight loss is excessive (>12 percent of birth
weight), or are hypovolemic may receive supplementation with expressed breast milk or
formula [9]. The temporary interruption of breastfeeding with the substitution of cow's milk-
based or soy formula may enhance the efficacy of phototherapy by inhibiting the
enterohepatic circulation of bilirubin [60-62]. (See "Pathogenesis and etiology of
unconjugated hyperbilirubinemia in the newborn").

Monitoring During phototherapy, the irradiance and the infant's temperature, hydration
status, time of exposure, and TSB are monitored. The frequency of TSB measurements
depends upon the initial value. When TSB values exceed the 95th percentile for age-in-
hours-specific TSB levels (show figure 1), the measurement should be repeated two to three
hours after phototherapy is initiated to assess the response. For lower initial values, TSB
should be measured after 4 to 6 hours and then within 8 to 12 hours, if TSB continues to
fall.

A decrease in TSB level can be measured as soon as two hours after initiation of treatment.
Intensive phototherapy should result in a decline of TSB of at least 2 to 3 mg/dL (34 to 51
mol/L) within four to six hours. In infants 35 weeks gestation, 24 hours of intensive
phototherapy can result in a 30 to 40 percent decrease in the initial TSB [72]. With
conventional phototherapy, a decline of 6 to 20 percent can be expected in the first 18 to 24
hours [66,73,74].

The rate of decline of TSB during phototherapy is affected by a number of factors [9].
Increased irradiance and increased surface area exposed to phototherapy increase the rate
of decline. The higher the initial TSB (>30 mg/dL [513 mol/L]), the more rapid is the rate
of decline (as much as 10 mg/dL [171 mol/L] within a few hours). However, phototherapy
is less effective in infants whose hyperbilirubinemia is due to cholestasis or hemolysis than
in infants with other causes.

If, despite intensive phototherapy, the TSB is at or approaching the exchange level (see
"Exchange transfusion" below), blood should be sent for immediate type and crossmatch. In
addition, if exchange transfusion is being considered, the serum albumin level should be
measured so that the serum bilirubin/albumin ratio can be used in conjunction with the TSB
level and other factors to determine the need for exchange transfusion (see "Exchange
transfusion" below).

Discontinuation We discontinue phototherapy when the age-in-hours-specific TSB level


is <95th percentile (show figure 1) or has decreased to <13 to 14 mg/dL (222 to 239
mol/L), and measure TSB 18 to 24 hours later. Although the value following discontinuation
is known as the rebound bilirubin, typically it is lower than the previous TSB during
treatment. In one study of 161 infants with birth weight more than 1800 g, the rebound
TSB was significantly lower 17 hours after termination of phototherapy (11.5 versus 12.2
mg/dL, 197 versus 209 mol/L) [75].

Adverse effects Phototherapy is considered safe. Side effects include transient


erythematous rashes, loose stools, and hyperthermia. Increased insensible water loss
caused by enhanced peripheral blood flow may lead to dehydration.

The "bronze baby syndrome" is an important, but uncommon complication of phototherapy


that occurs in some infants with cholestatic jaundice and is manifested by a dark, grayish-
brown discoloration of the skin, serum, and urine [76]. The bronze color is thought to result
from cholestasis and impaired biliary excretion of bile pigment photoproducts, including
copper porphyrins, which are brown [76]. The condition gradually resolves without sequelae
within several weeks after discontinuation of therapy [77].

EXCHANGE TRANSFUSION Exchange transfusion is used to remove bilirubin from the


circulation when intensive phototherapy fails. It is especially useful for infants with increased
bilirubin production from immune-mediated hemolysis because the circulating antibodies
and the sensitized red blood cells also are removed. Exchange transfusions should be
performed only by trained personnel in a neonatal intensive care unit with full monitoring
and resuscitation capabilities [9].

Indications Exchange transfusion is performed when severe hyperbilirubinemia does not


respond to intensive phototherapy. In infants with isoimmune hemolytic disease and rising
TSB despite intensive phototherapy, administration of intravenous immunoglobulin (IVIG) is
recommended since it may avoid the need for exchange transfusion (see "Intravenous
immunoglobulin" below).

Exchange transfusion should be immediately performed in infants with high TSB


concentrations (according to the age-in-hours-specific TSB nomogram, show figure 1), TSB
25 mg/dL (428 mol/L), and in infants with early signs of bilirubin neurotoxicity (eg,
lethargy, hypotonia, poor sucking, high-pitched cry, see "Bilirubin toxicity" above). These
criteria constitute a medical emergency and the infant should be directly admitted to the
neonatal intensive care unit.

In infants without signs of bilirubin neurotoxicity, the threshold for exchange transfusion
recommended in the AAP guidelines, and described below, depends upon the age of the
child and the presence or absence of risk factors, which for this purpose are defined as
isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature
instability, sepsis, or acidosis [9]. Immediate exchange transfusion also is recommended if
TSB is 5 mg/dL (85 mol/L) above the threshold values described below.

In infants who have not yet been discharged from the birth hospital,
exchange transfusion is recommended if the TSB reaches the threshold level despite
intensive phototherapy [9]. In infants who are readmitted for management of
hyperbilirubinemia and have a TSB above these thresholds, the TSB should be repeated
every two to three hours and exchange transfusion considered if the TSB remains above the
indicated levels after six hours of intensive phototherapy (see "Intensive phototherapy"
above).

For infants at lower risk ( 38 weeks gestation and well), exchange transfusion is initiated
if the TSB is >19, 22, or 24 mg/dL (325, 376, and 410 mol/L) at 24, 48, or >72 hr,
respectively, or 25 mg/dL (428 mol/L) at any time [9].

For infants at medium risk ( 38 weeks gestation with risk factors or 35 to 37 6/7 weeks
gestation without risk factors), exchange transfusion is initiated if the TSB is >16.5,19, or
21 mg/dL (282, 325, or 359 mol/L) at 24, 48, or >72 hr, respectively; the threshold for
intervention may be lowered for well infants closer to 35 weeks and raised for those closer
to 37 6/7 weeks

For infants at higher risk (35 to 37 6/7 weeks gestation with risk factors), exchange
transfusion is initiated if the TSB is >15, 17, or 18.5 (257, 291, or 316 mol/L) at 24, 48, or
>72 hr, respectively.

TSB/albumin ratio The TSB/albumin ratio can be used as an additional factor in


determining the need for exchange transfusion; it should not be used in isolation [9,31].

For infants 38 weeks gestation, consider exchange transfusion when TSB


(mg/dL)/albumin (g/dL) ratio is >8.0 or TSB (mol/L)/albumin (mol/L) is >0.94

For infants 35 to 37 6/7 weeks and well or 38 weeks with higher risk or isoimmune
hemolytic disease or G6PD deficiency, consider exchange transfusion when TSB
(mg/dL)/albumin (g/dL) ratio is >7.2 or TSB (mol/L)/albumin (mol/L) is >0.84.
For infants 35 to 37 6/7 weeks with higher risk or isoimmune hemolytic disease or G6PD
deficiency, consider exchange transfusion when TSB (mg/dL)/albumin (g/dL) ratio is >6.8 or
TSB (mol/L)/albumin (mol/L) is >0.80.

Special circumstances Exchange transfusion should be considered in infants receiving


phototherapy who develop the bronze infant syndrome if the TSB is in the range for which
intensive phototherapy is indicated and phototherapy does not promptly lower the TSB [9].

Technique A double-volume exchange transfusion removes approximately twice the


infant's circulating blood volume (blood volume is approximately 80 to 90 mL/kg), replacing
it with appropriately cross-matched fresh or reconstituted (from packed red blood cells and
fresh frozen plasma) whole blood.

The procedure involves placement of a central catheter and removing and replacing blood in
aliquots that are approximately 10 percent or less of the infant's blood volume. Most of the
bilirubin is extravascular; as a result, exchange transfusion removes approximately 25
percent of the total body bilirubin [78]. Infusion of albumin (1 g/kg) one to two hours
before the procedure shifts more extravascular bilirubin into the circulation, allowing
removal of more bilirubin.

After the procedure, TSB typically falls to approximately one-half of the pre-exchange value,
then increases to approximately two-thirds of that level as the extravascular and vascular
bilirubin re-equilibrate. A double volume exchange transfusion replaces approximately 85
percent of the infant's red blood cells.

Risks The risks of exchange transfusion result from the use of blood products and from
the procedure itself. Complications include blood-borne infection, thrombocytopenia,
coagulopathy, graft-versus-host disease, necrotizing enterocolitis, portal vein thrombosis,
electrolyte abnormalities, cardiac arrhythmias, and sudden death.

Most complications occur in ill infants and are rare in healthy infants. In a retrospective
review of 15 years of experience at two academic medical centers, one of 81 healthy infants
developed necrotizing enterocolitis after exchange transfusion and none died [79].

PHARMACOLOGIC AGENTS Pharmacologic agents including IVIG, phenobarbital, and


metalloporphyrins can be used to inhibit hemolysis, increase conjugation and excretion of
bilirubin, or inhibit the formation of bilirubin. However, currently only IVIG is used to treat
unconjugated hyperbilirubinemia.

Intravenous immunoglobulin IVIG (500 to 1000 mg/kg per dose IV over two hours)
may reduce the need for exchange transfusion in infants with hemolytic disease caused by
Rh or ABO incompatibility [80-82]. The dose may be repeated in 12 hours if necessary [9].
(See "Diagnosis and management of Rhesus (Rh) alloimmunization"). The mechanism is
uncertain, but IVIG is thought to inhibit hemolysis by blocking antibody receptors on red
blood cells.

Indications IVIG is recommended in infants with isoimmune hemolytic disease if the


TSB is rising despite intensive phototherapy or is within 2 or 3 mg/dL (34 to 51 mol/L) of
the threshold for exchange transfusion (see "Exchange transfusion" above) [9,83].

Phenobarbital Phenobarbital increases the conjugation and excretion of bilirubin and


decreases postnatal TSB levels when given to pregnant women or infants. However, prenatal
administration of phenobarbital may adversely affect cognitive development and
reproduction [84,85]. As a result, phenobarbital is not used to treat indirect
hyperbilirubinemia.

Metalloporphyrins Synthetic metalloporphyrins, such as tin mesoporphyrin (SnMP,


Stanate, Stannsoporfin [WellSpring Pharmaceutical Corp. Neptune, NJ]), reduce bilirubin
production by competitive inhibition of heme oxygenase [86-89]. In one report, for
example, term infants with G6PD deficiency given SnMP at approximately 27 hours of age
had lower and earlier peak TSB values than did control infants with and without G6PD
deficiency [86]. No treated infant required phototherapy, compared to 31 and 15 percent in
the controls with and without G6PD deficiency, respectively.
In a systematic review of three randomized trials including 170 infants, short-term benefits
of metalloporphyrin therapy included lower maximum TSB, lower frequency of severe
hyperbilirubinemia, decreased need for phototherapy, and shorter duration of hospitalization
[87,88,90]. None of the enrolled infants required exchange transfusion. None of the studies
reported on kernicterus, death, or long-term neurodevelopmental outcome.

SnMP is not yet approved, but being evaluated by the Food and Drug Administration for
clinical use in the United States.

RECOMMENDATIONS The following recommendations apply to healthy term and near-


term infants ( 35 weeks gestation). Infants who appear ill, are <35 weeks gestation, or
have evidence of hemolysis require more intensive evaluation and management.

Infants should be assessed for jaundice every 8 to 12 hours and before hospital discharge.
Measurement of TSB or TcB is preferred. Alternatively, the infant can be assessed by visual
inspection and TSB measurement obtained in those who appear jaundiced.

Risk factors for severe hyperbilirubinemia should be assessed in all infants before discharge
(either by clinical history or TSB or TcB measurement), especially in infants discharged
before 72 hours of age.

TSB values should be compared to an hour-specific nomogram [2] to predict the risk of
subsequent development of clinically significant hyperbilirubinemia (show figure 1).
Increased surveillance is necessary for infants at high risk (<38 weeks gestation, isoimmune
hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability,
sepsis, or acidosis).

Infants discharged before 24, 24 to 47.9, and 48 to 72 hours after birth require follow-up
evaluation within 24 to 72, 96, and 120 hours of discharge, respectively. Infants at high risk
for the development of significant hyperbilirubinemia should be evaluated within 24 hours of
discharge.

Infants at risk for severe hyperbilirubinemia should be treated as indicated with


phototherapy, IVIG, and/or exchange transfusion (see above) [9]. Infants who have been
discharged from the nursery and have TSB levels >25 mg/dL (428 mol/L) or approaching
the threshold for exchange transfusion should be directly admitted to a pediatric hospital
service for intensive phototherapy; referral through an emergency department delays the
initiation of treatment [91].

Breastfeeding should be promoted and encouraged for all healthy term and near-term
newborns. Lactation counseling should be provided for breastfeeding mothers. Near-term
(35 to 37 weeks) infants are at greater risk to receive inadequate fluid and nutrition and
require increased surveillance.

Information and written guidelines about jaundice should be provided to the parents of all
newborn infants [9].

RESOURCES A list of frequently asked questions and answers for parents is available in
English and Spanish through the AAP (www.aap.org/family/jaundicefaq.htm).

ACKNOWLEDGMENT The authors and editorial staff at UpToDate, Inc. would like to
acknowledge Ashima Madan, MD, who contributed to an earlier version of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

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