Professional Documents
Culture Documents
Ronald J Wong, BA
David K Stevenson, MD
UpToDate performs a continuous review of over 330 journals and other resources. Updates
are added as important new information is published. The literature review for version 13.3
is current through August 2005; this topic was last changed on August 24, 2005. The next
version of UpToDate (14.1) will be released in February 2006.
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.
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]:
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]:
Gestational age <38 weeks (the risk increases with decreasing gestational age) [11,12]
Exclusive breastfeeding, particularly if nursing is not going well and weight loss is
excessive (>12 percent of birth weight) [11,12]
Polycythemia
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.
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:
Auditory abnormalities
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)
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].
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").
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").
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
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.
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 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.
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.
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).
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).
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.
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.
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].
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.
SnMP is not yet approved, but being evaluated by the Food and Drug Administration for
clinical use in the United States.
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.
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.
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