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AMERICAN ACADEMY OF PEDIATRICS
CLINICAL PRACTICE GUIDELINE
Subcommittee on Hyperbilirubinemia
Management of Hyperbilirubinemia in the Newborn Infant 35 or
MoreWeeks of Gestation
ABSTRACT. Jaundice occurs in most newborn infants.Most jaundice
is benign, but because of the potentialtoxicity of bilirubin,
newborn infants must be monitoredto identify those who might
develop severe hyperbili-rubinemia and, in rare cases, acute
bilirubin encephalop-athy or kernicterus. The focus of this
guideline is toreduce the incidence of severe hyperbilirubinemia
andbilirubin encephalopathy while minimizing the risks ofunintended
harm such as maternal anxiety, decreasedbreastfeeding, and
unnecessary costs or treatment. Al-though kernicterus should almost
always be prevent-able, cases continue to occur. These guidelines
provide aframework for the prevention and management
ofhyperbilirubinemia in newborn infants of 35 or moreweeks of
gestation. In every infant, we recommend thatclinicians 1) promote
and support successful breastfeed-ing; 2) perform a systematic
assessment before dischargefor the risk of severe
hyperbilirubinemia; 3) provideearly and focused follow-up based on
the risk assess-ment; and 4) when indicated, treat newborns with
pho-totherapy or exchange transfusion to prevent the devel-opment
of severe hyperbilirubinemia and, possibly,bilirubin encephalopathy
(kernicterus). Pediatrics 2004;114:297316; hyperbilirubinemia,
newborn, kernicterus,bilirubin encephalopathy, phototherapy.
ABBREVIATIONS. AAP, American Academy of Pediatrics; TSB,total
serum bilirubin; TcB, transcutaneous bilirubin; G6PD,
glu-cose-6-phosphate dehydrogenase; ETCOc, end-tidal carbon
mon-oxide corrected for ambient carbon monoxide; B/A,
bilirubin/albumin; UB, unbound bilirubin.
BACKGROUND
In October 1994, the Provisional Committee forQuality
Improvement and Subcommittee on Hy-perbilirubinemia of the American
Academy ofPediatrics (AAP) produced a practice parameterdealing
with the management of hyperbilirubinemiain the healthy term
newborn.1 The current guidelinerepresents a consensus of the
committee charged bythe AAP with reviewing and updating the
existingguideline and is based on a careful review of theevidence,
including a comprehensive literature re-view by the New England
Medical Center Evidence-Based Practice Center.2 (See An
Evidence-BasedReview of Important Issues Concerning Neonatal
Hyperbilirubinemia3 for a description of the meth-odology,
questions addressed, and conclusions ofthis report.) This guideline
is intended for use byhospitals and pediatricians, neonatologists,
familyphysicians, physician assistants, and advanced prac-tice
nurses who treat newborn infants in the hospitaland as outpatients.
A list of frequently asked ques-tions and answers for parents is
available in Englishand Spanish at
www.aap.org/family/jaundicefaq.htm.
DEFINITION OF RECOMMENDATIONSThe evidence-based approach to
guideline devel-
opment requires that the evidence in support of apolicy be
identified, appraised, and summarized andthat an explicit link
between evidence and recom-mendations be defined. Evidence-based
recommen-dations are based on the quality of evidence and
thebalance of benefits and harms that is anticipatedwhen the
recommendation is followed. This guide-line uses the definitions
for quality of evidence andbalance of benefits and harms
established by theAAP Steering Committee on Quality
ImprovementManagement.4 See Appendix 1 for these definitions.
The draft practice guideline underwent extensivepeer review by
committees and sections within theAAP, outside organizations, and
other individualsidentified by the subcommittee as experts in
thefield. Liaison representatives to the subcommitteewere invited
to distribute the draft to other represen-tatives and committees
within their specialty organi-zations. The resulting comments were
reviewed bythe subcommittee and, when appropriate, incorpo-rated
into the guideline.
BILIRUBIN ENCEPHALOPATHY ANDKERNICTERUS
Although originally a pathologic diagnosis charac-terized by
bilirubin staining of the brainstem nucleiand cerebellum, the term
kernicterus has come tobe used interchangeably with both the acute
andchronic findings of bilirubin encephalopathy. Biliru-bin
encephalopathy describes the clinical central ner-vous system
findings caused by bilirubin toxicity tothe basal ganglia and
various brainstem nuclei. Toavoid confusion and encourage greater
consistencyin the literature, the committee recommends that
ininfants the term acute bilirubin encephalopathy beused to
describe the acute manifestations of bilirubin
The recommendations in this guideline do not indicate an
exclusive courseof treatment or serve as a standard of medical
care. Variations, taking intoaccount individual circumstances, may
be appropriate.PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the
American Acad-emy of Pediatrics.
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toxicity seen in the first weeks after birth and that theterm
kernicterus be reserved for the chronic andpermanent clinical
sequelae of bilirubin toxicity.
See Appendix 1 for the clinical manifestations ofacute bilirubin
encephalopathy and kernicterus.
FOCUS OF GUIDELINEThe overall aim of this guideline is to
promote an
approach that will reduce the frequency of severeneonatal
hyperbilirubinemia and bilirubin encepha-lopathy and minimize the
risk of unintended harmsuch as increased anxiety, decreased
breastfeeding,or unnecessary treatment for the general
populationand excessive cost and waste. Recent reports of
ker-nicterus indicate that this condition, although rare, isstill
occurring.2,510
Analysis of these reported cases of kernicterussuggests that if
health care personnel follow the rec-ommendations listed in this
guideline, kernicteruswould be largely preventable.
These guidelines emphasize the importance of uni-versal
systematic assessment for the risk of severehyperbilirubinemia,
close follow-up, and prompt in-tervention when indicated. The
recommendationsapply to the care of infants at 35 or more weeks
ofgestation. These recommendations seek to furtherthe aims defined
by the Institute of Medicine asappropriate for health care:11
safety, effectiveness,efficiency, timeliness, patient-centeredness,
and eq-uity. They specifically emphasize the principles ofpatient
safety and the key role of timeliness of inter-ventions to prevent
adverse outcomes resulting fromneonatal hyperbilirubinemia.
The following are the key elements of the recom-mendations
provided by this guideline. Cliniciansshould:
1. Promote and support successful breastfeeding.2. Establish
nursery protocols for the identification
and evaluation of hyperbilirubinemia.3. Measure the total serum
bilirubin (TSB) or trans-
cutaneous bilirubin (TcB) level on infants jaun-diced in the
first 24 hours.
4. Recognize that visual estimation of the degree ofjaundice can
lead to errors, particularly in darklypigmented infants.
5. Interpret all bilirubin levels according to the in-fants age
in hours.
6. Recognize that infants at less than 38 weeksgestation,
particularly those who are breastfed,are at higher risk of
developing hyperbiliru-binemia and require closer surveillance
andmonitoring.
7. Perform a systematic assessment on all infantsbefore
discharge for the risk of severe hyperbil-irubinemia.
8. Provide parents with written and verbal infor-mation about
newborn jaundice.
9. Provide appropriate follow-up based on the timeof discharge
and the risk assessment.
10. Treat newborns, when indicated, with photo-therapy or
exchange transfusion.
PRIMARY PREVENTIONIn numerous policy statements, the AAP
recom-mends breastfeeding for all healthy term and near-term
newborns. This guideline strongly supports thisgeneral
recommendation.RECOMMENDATION 1.0: Clinicians should advisemothers
to nurse their infants at least 8 to 12 times perday for the first
several days12 (evidence quality C: benefitsexceed harms).
Poor caloric intake and/or dehydration associatedwith inadequate
breastfeeding may contribute to thedevelopment of
hyperbilirubinemia.6,13,14 Increasingthe frequency of nursing
decreases the likelihood ofsubsequent significant
hyperbilirubinemia in breast-fed infants.1517 Providing appropriate
support andadvice to breastfeeding mothers increases the
likeli-hood that breastfeeding will be successful.
Additional information on how to assess the ade-quacy of intake
in a breastfed newborn is provided inAppendix 1.RECOMMENDATION 1.1:
The AAP recommendsagainst routine supplementation of nondehydrated
breast-fed infants with water or dextrose water (evidence qualityB
and C: harms exceed benefits).
Supplementation with water or dextrose waterwill not prevent
hyperbilirubinemia or decrease TSBlevels.18,19
SECONDARY PREVENTIONRECOMMENDATION 2.0: Clinicians should
performongoing systematic assessments during the neonatal pe-riod
for the risk of an infant developing severe
hyperbil-irubinemia.
Blood TypingRECOMMENDATION 2.1: All pregnant women shouldbe
tested for ABO and Rh (D) blood types and have aserum screen for
unusual isoimmune antibodies (evidencequality B: benefits exceed
harms).RECOMMENDATION 2.1.1: If a mother has not hadprenatal blood
grouping or is Rh-negative, a direct anti-body test (or Coombs
test), blood type, and an Rh (D) typeon the infants (cord) blood
are strongly recommended(evidence quality B: benefits exceed
harms).RECOMMENDATION 2.1.2: If the maternal blood isgroup O,
Rh-positive, it is an option to test the cord bloodfor the infants
blood type and direct antibody test, but itis not required provided
that there is appropriate surveil-lance, risk assessment before
discharge, and follow-up20(evidence quality C: benefits exceed
harms).
Clinical AssessmentRECOMMENDATION 2.2: Clinicians should
ensurethat all infants are routinely monitored for the develop-ment
of jaundice, and nurseries should have establishedprotocols for the
assessment of jaundice. Jaundice shouldbe assessed whenever the
infants vital signs are measuredbut no less than every 8 to 12
hours (evidence quality D:benefits versus harms exceptional).
In newborn infants, jaundice can be detected byblanching the
skin with digital pressure, revealingthe underlying color of the
skin and subcutaneoustissue. The assessment of jaundice must be
per-
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formed in a well-lit room or, preferably, in daylightat a
window. Jaundice is usually seen first in the faceand progresses
caudally to the trunk and extremi-ties,21 but visual estimation of
bilirubin levels fromthe degree of jaundice can lead to errors.2224
In mostinfants with TSB levels of less than 15 mg/dL (257mol/L),
noninvasive TcB-measurement devices canprovide a valid estimate of
the TSB level.2,2529 SeeAppendix 1 for additional information on
the clinicalevaluation of jaundice and the use of TcB
measure-ments.RECOMMENDATION 2.2.1: Protocols for the assess-ment
of jaundice should include the circumstances inwhich nursing staff
can obtain a TcB level or order a TSBmeasurement (evidence quality
D: benefits versus harmsexceptional).
Laboratory EvaluationRECOMMENDATION 3.0: A TcB and/or TSB
measure-ment should be performed on every infant who is jaun-diced
in the first 24 hours after birth (Fig 1 and Table 1)30(evidence
quality C: benefits exceed harms). The need forand timing of a
repeat TcB or TSB measurement willdepend on the zone in which the
TSB falls (Fig 2),25,31 theage of the infant, and the evolution of
the hyperbiliru-binemia. Recommendations for TSB measurements
afterthe age of 24 hours are provided in Fig 1 and Table 1.
See Appendix 1 for capillary versus venous biliru-bin
levels.RECOMMENDATION 3.1: A TcB and/or TSB measure-ment should be
performed if the jaundice appears excessivefor the infants age
(evidence quality D: benefits versusharms exceptional). If there is
any doubt about the degreeof jaundice, the TSB or TcB should be
measured. Visualestimation of bilirubin levels from the degree of
jaundicecan lead to errors, particularly in darkly pigmented
in-fants (evidence quality C: benefits exceed harms).RECOMMENDATION
3.2: All bilirubin levels should beinterpreted according to the
infants age in hours (Fig 2)(evidence quality C: benefits exceed
harms).
Cause of JaundiceRECOMMENDATION 4.1: The possible cause
ofjaundice should be sought in an infant receivingphototherapy or
whose TSB level is rising rapidly (ie,crossing percentiles [Fig 2])
and is not explained bythe history and physical examination
(evidence qual-ity D: benefits versus harms
exceptional).RECOMMENDATION 4.1.1: Infants who have an ele-vation
of direct-reacting or conjugated bilirubin shouldhave a urinalysis
and urine culture.32 Additional labora-tory evaluation for sepsis
should be performed if indicatedby history and physical examination
(evidence quality C:benefits exceed harms).
See Appendix 1 for definitions of abnormal levelsof
direct-reacting and conjugated bilirubin.RECOMMENDATION 4.1.2: Sick
infants and those whoare jaundiced at or beyond 3 weeks should have
a mea-surement of total and direct or conjugated bilirubin
toidentify cholestasis (Table 1) (evidence quality D: benefitversus
harms exceptional). The results of the newbornthyroid and
galactosemia screen should also be checked inthese infants
(evidence quality D: benefits versus
harmsexceptional).RECOMMENDATION 4.1.3: If the direct-reacting
orconjugated bilirubin level is elevated, additional evalua-tion
for the causes of cholestasis is recommended (evidencequality C:
benefits exceed harms).RECOMMENDATION 4.1.4: Measurement of the
glu-cose-6-phosphate dehydrogenase (G6PD) level is recom-mended for
a jaundiced infant who is receiving photother-apy and whose family
history or ethnic or geographicorigin suggest the likelihood of
G6PD deficiency or for aninfant in whom the response to
phototherapy is poor (Fig3) (evidence quality C: benefits exceed
harms).
G6PD deficiency is widespread and frequently un-recognized, and
although it is more common in thepopulations around the
Mediterranean and in theMiddle East, Arabian peninsula, Southeast
Asia, andAfrica, immigration and intermarriage have trans-formed
G6PD deficiency into a global problem.33,34
TABLE 1. Laboratory Evaluation of the Jaundiced Infant of 35 or
More Weeks Gestation
Indications Assessments
Jaundice in first 24 h Measure TcB and/or TSBJaundice appears
excessive for infants age Measure TcB and/or TSBInfant receiving
phototherapy or TSB rising
rapidly (ie, crossing percentilesBlood type and Coombs test, if
not obtained
with cord blood[Fig 2]) and unexplained by history Complete
blood count and smearand physical examination Measure direct or
conjugated bilirubin
It is an option to perform reticulocyte count,G6PD, and ETCOc,
if available
Repeat TSB in 424 h depending on infantsage and TSB level
TSB concentration approaching exchange levelsor not responding
to phototherapy
Perform reticulocyte count, G6PD, albumin,ETCOc, if
available
Elevated direct (or conjugated) bilirubin level Do urinalysis
and urine culture. Evaluate forsepsis if indicated by history and
physicalexamination
Jaundice present at or beyond age 3 wk, orsick infant
Total and direct (or conjugated) bilirubinlevel
If direct bilirubin elevated, evaluate forcauses of
cholestasis
Check results of newborn thyroid andgalactosemia screen, and
evaluate infantfor signs or symptoms of hypothyroidism
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Furthermore, G6PD deficiency occurs in 11% to 13%of African
Americans, and kernicterus has occurredin some of these
infants.5,33 In a recent report, G6PDdeficiency was considered to
be the cause of hyper-bilirubinemia in 19 of 61 (31.5%) infants who
devel-oped kernicterus.5 (See Appendix 1 for additionalinformation
on G6PD deficiency.)
Risk Assessment Before DischargeRECOMMENDATION 5.1: Before
discharge, every new-born should be assessed for the risk of
developing severehyperbilirubinemia, and all nurseries should
establish pro-tocols for assessing this risk. Such assessment is
particu-larly important in infants who are discharged before theage
of 72 hours (evidence quality C: benefits
exceedharms).RECOMMENDATION 5.1.1: The AAP recommends 2clinical
options used individually or in combination for thesystematic
assessment of risk: predischarge measurementof the bilirubin level
using TSB or TcB and/or assessmentof clinical risk factors. Whether
either or both options areused, appropriate follow-up after
discharge is essential(evidence quality C: benefits exceed
harms).
The best documented method for assessing therisk of subsequent
hyperbilirubinemia is to measurethe TSB or TcB level25,31,3538 and
plot the results ona nomogram (Fig 2). A TSB level can be obtained
atthe time of the routine metabolic screen, thus obvi-ating the
need for an additional blood sample. Someauthors have suggested
that a TSB measurementshould be part of the routine screening of
all new-borns.5,31 An infant whose predischarge TSB is in the
low-risk zone (Fig 2) is at very low risk of developingsevere
hyperbilirubinemia.5,38
Table 2 lists those factors that are clinically signif-
Fig 2. Nomogram for designation of risk in 2840 well newborns at
36 or more weeks gestational age with birth weight of 2000 g or
moreor 35 or more weeks gestational age and birth weight of 2500 g
or more based on the hour-specific serum bilirubin values. The
serumbilirubin level was obtained before discharge, and the zone in
which the value fell predicted the likelihood of a subsequent
bilirubin levelexceeding the 95th percentile (high-risk zone) as
shown in Appendix 1, Table 4. Used with permission from Bhutani et
al.31 See Appendix1 for additional information about this nomogram,
which should not be used to represent the natural history of
neonatal hyperbiliru-binemia.
TABLE 2. Risk Factors for Development of Severe
Hyperbil-irubinemia in Infants of 35 or More Weeks Gestation (in
Approx-imate Order of Importance)
Major risk factorsPredischarge TSB or TcB level in the high-risk
zone (Fig 2)25,31Jaundice observed in the first 24 h30Blood group
incompatibility with positive direct antiglobulin
test, other known hemolytic disease (eg, G6PD
deficiency),elevated ETCOc
Gestational age 3536 wk39,40Previous sibling received
phototherapy40,41Cephalohematoma or significant bruising39Exclusive
breastfeeding, particularly if nursing is not going
well and weight loss is excessive39,40East Asian race39*
Minor risk factorsPredischarge TSB or TcB level in the high
intermediate-risk
zone25,31Gestational age 3738 wk39,40Jaundice observed before
discharge40Previous sibling with jaundice40,41Macrosomic infant of
a diabetic mother42,43Maternal age 25 y39Male gender39,40
Decreased risk (these factors are associated with decreased risk
ofsignificant jaundice, listed in order of decreasing
importance)
TSB or TcB level in the low-risk zone (Fig 2)25,31Gestational
age 41 wk39Exclusive bottle feeding39,40Black race38*Discharge from
hospital after 72 h40,44
* Race as defined by mothers description.
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icant and most frequently associated with an in-crease in the
risk of severe hyperbilirubinemia. But,because these risk factors
are common and the risk ofhyperbilirubinemia is small, individually
the factorsare of limited use as predictors of significant
hyper-bilirubinemia.39 Nevertheless, if no risk factors arepresent,
the risk of severe hyperbilirubinemia is ex-tremely low, and the
more risk factors present, thegreater the risk of severe
hyperbilirubinemia.39 Theimportant risk factors most frequently
associatedwith severe hyperbilirubinemia are
breastfeeding,gestation below 38 weeks, significant jaundice in
aprevious sibling, and jaundice noted before dis-charge.39,40 A
formula-fed infant of 40 or moreweeks gestation is at very low risk
of developingsevere hyperbilirubinemia.39
Hospital Policies and ProceduresRECOMMENDATION 6.1: All
hospitals should providewritten and verbal information for parents
at the time ofdischarge, which should include an explanation of
jaun-dice, the need to monitor infants for jaundice, and adviceon
how monitoring should be done (evidence quality D:benefits versus
harms exceptional).
An example of a parent-information handout isavailable in
English and Spanish at www.aap.org/family/jaundicefaq.htm.
Follow-upRECOMMENDATION 6.1.1: All infants should be ex-amined
by a qualified health care professional in the firstfew days after
discharge to assess infant well-being and thepresence or absence of
jaundice. The timing and location ofthis assessment will be
determined by the length of stay inthe nursery, presence or absence
of risk factors for hyper-bilirubinemia (Table 2 and Fig 2), and
risk of other neo-natal problems (evidence quality C: benefits
exceedharms).
Timing of Follow-upRECOMMENDATION 6.1.2: Follow-up should be
pro-vided as follows:
Infant Discharged Should Be Seen by Age
Before age 24 h 72 hBetween 24 and 47.9 h 96 hBetween 48 and 72
h 120 h
For some newborns discharged before 48 hours, 2 fol-low-up
visits may be required, the first visit between 24and 72 hours and
the second between 72 and 120 hours.Clinical judgment should be
used in determining follow-up. Earlier or more frequent follow-up
should be providedfor those who have risk factors for
hyperbilirubinemia(Table 2), whereas those discharged with few or
no riskfactors can be seen after longer intervals (evidence
qualityC: benefits exceed harms).RECOMMENDATION 6.1.3: If
appropriate follow-upcannot be ensured in the presence of elevated
risk fordeveloping severe hyperbilirubinemia, it may be necessaryto
delay discharge either until appropriate follow-up canbe ensured or
the period of greatest risk has passed (72-96hours) (evidence
quality D: benefits versus harms excep-tional).
Follow-up AssessmentRECOMMENDATION 6.1.4: The follow-up
assessmentshould include the infants weight and percent changefrom
birth weight, adequacy of intake, the pattern of void-ing and
stooling, and the presence or absence of jaundice(evidence quality
C: benefits exceed harms). Clinical judg-ment should be used to
determine the need for a bilirubinmeasurement. If there is any
doubt about the degree ofjaundice, the TSB or TcB level should be
measured. Visualestimation of bilirubin levels can lead to errors,
particu-larly in darkly pigmented infants (evidence quality
C:benefits exceed harms).
See Appendix 1 for assessment of the adequacy ofintake in
breastfeeding infants.
TREATMENT
Phototherapy and Exchange TransfusionRECOMMENDATION 7.1:
Recommendations for treat-ment are given in Table 3 and Figs 3 and
4 (evidencequality C: benefits exceed harms). If the TSB does not
fallor continues to rise despite intensive phototherapy, it isvery
likely that hemolysis is occurring. The committeesrecommendations
for discontinuing phototherapy can befound in Appendix
2.RECOMMENDATION 7.1.1: In using the guidelines forphototherapy and
exchange transfusion (Figs 3 and 4), thedirect-reacting (or
conjugated) bilirubin level should notbe subtracted from the total
(evidence quality D: benefitsversus harms exceptional).
In unusual situations in which the direct bilirubinlevel is 50%
or more of the total bilirubin, there areno good data to provide
guidance for therapy, andconsultation with an expert in the field
is recom-mended.RECOMMENDATION 7.1.2: If the TSB is at a level
atwhich exchange transfusion is recommended (Fig 4) or ifthe TSB
level is 25 mg/dL (428 mol/L) or higher at anytime, it is a medical
emergency and the infant should beadmitted immediately and directly
to a hospital pediatricservice for intensive phototherapy. These
infants shouldnot be referred to the emergency department, because
itdelays the initiation of treatment54 (evidence quality C:benefits
exceed harms).RECOMMENDATION 7.1.3: Exchange transfusionsshould be
performed only by trained personnel in a neo-natal intensive care
unit with full monitoring and resus-citation capabilities (evidence
quality D: benefits versusharms exceptional).RECOMMENDATION 7.1.4:
In isoimmune hemolyticdisease, administration of intravenous
-globulin (0.5-1g/kg over 2 hours) is recommended if the TSB is
risingdespite intensive phototherapy or the TSB level is within 2to
3 mg/dL (34-51 mol/L) of the exchange level (Fig4).55 If necessary,
this dose can be repeated in 12 hours(evidence quality B: benefits
exceed harms).
Intravenous -globulin has been shown to reducethe need for
exchange transfusions in Rh and ABOhemolytic disease.5558 Although
data are limited, itis reasonable to assume that intravenous
-globulinwill also be helpful in the other types of Rh
hemolyticdisease such as anti-C and anti-E.
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Serum Albumin Levels and the
Bilirubin/AlbuminRatioRECOMMENDATION 7.1.5: It is an option to
measurethe serum albumin level and consider an albumin level ofless
than 3.0 g/dL as one risk factor for lowering thethreshold for
phototherapy use (see Fig 3) (evidence qual-ity D: benefits versus
risks exceptional.).RECOMMENDATION 7.1.6: If an exchange
transfusionis being considered, the serum albumin level should
bemeasured and the bilirubin/albumin (B/A) ratio used inconjunction
with the TSB level and other factors in deter-mining the need for
exchange transfusion (see Fig 4)(evidence quality D: benefits
versus harms exceptional).
The recommendations shown above for treatinghyperbilirubinemia
are based primarily on TSB lev-els and other factors that affect
the risk of bilirubinencephalopathy. This risk might be increased
by aprolonged (rather than a brief) exposure to a certainTSB
level.59,60 Because the published data that ad-dress this issue are
limited, however, it is not possi-ble to provide specific
recommendations for inter-vention based on the duration of
hyperbilirubinemia.
See Appendix 1 for the basis for recommendations7.1 through
7.1.6 and for the recommendations pro-vided in Figs 3 and 4.
Appendix 1 also contains adiscussion of the risks of exchange
transfusion andthe use of B/A binding.
Acute Bilirubin EncephalopathyRECOMMENDATION 7.1.7: Immediate
exchangetransfusion is recommended in any infant who is jaun-
diced and manifests the signs of the intermediate to ad-vanced
stages of acute bilirubin encephalopathy61,62 (hy-pertonia,
arching, retrocollis, opisthotonos, fever, high-pitched cry) even
if the TSB is falling (evidence quality D:benefits versus risks
exceptional).
PhototherapyRECOMMENDATION 7.2: All nurseries and
servicestreating infants should have the necessary equipment
toprovide intensive phototherapy (see Appendix 2) (evidencequality
D: benefits exceed risks).
Outpatient Management of the Jaundiced
BreastfedInfantRECOMMENDATION 7.3: In breastfed infants who
re-quire phototherapy (Fig 3), the AAP recommends that,if possible,
breastfeeding should be continued (evidencequality C: benefits
exceed harms). It is also an option tointerrupt temporarily
breastfeeding and substitute for-mula. This can reduce bilirubin
levels and/or enhancethe efficacy of phototherapy6365 (evidence
quality B: ben-efits exceed harms). In breastfed infants receiving
photo-therapy, supplementation with expressed breast milk orformula
is appropriate if the infants intake seems inade-quate, weight loss
is excessive, or the infant seems dehy-drated.
IMPLEMENTATION STRATEGIESThe Institute of Medicine11 recommends
a dra-
matic change in the way the US health care system
TABLE 3. Example of a Clinical Pathway for Management of the
Newborn Infant Readmitted forPhototherapy or Exchange
Transfusion
TreatmentUse intensive phototherapy and/or exchange transfusion
as indicated in Figs 3 and 4 (see
Appendix 2 for details of phototherapy use)Laboratory tests
TSB and direct bilirubin levelsBlood type (ABO, Rh)Direct
antibody test (Coombs)Serum albuminComplete blood cell count with
differential and smear for red cell morphologyReticulocyte
countETCOc (if available)G6PD if suggested by ethnic or geographic
origin or if poor response to phototherapyUrine for reducing
substancesIf history and/or presentation suggest sepsis, perform
blood culture, urine culture, and
cerebrospinal fluid for protein, glucose, cell count, and
cultureInterventions
If TSB 25 mg/dL (428 mol/L) or 20 mg/dL (342 mol/L) in a sick
infant or infant 38 wkgestation, obtain a type and crossmatch, and
request blood in case an exchange transfusion isnecessary
In infants with isoimmune hemolytic disease and TSB level rising
in spite of intensivephototherapy or within 23 mg/dL (3451 mol/L)
of exchange level (Fig 4), administerintravenous immunoglobulin
0.51 g/kg over 2 h and repeat in 12 h if necessary
If infants weight loss from birth is 12% or there is clinical or
biochemical evidence ofdehydration, recommend formula or expressed
breast milk. If oral intake is in question, giveintravenous
fluids.
For infants receiving intensive phototherapyBreastfeed or
bottle-feed (formula or expressed breast milk) every 23 hIf TSB 25
mg/dL (428 mol/L), repeat TSB within 23 hIf TSB 2025 mg/dL (342428
mol/L), repeat within 34 h. If TSB 20 mg/dL (342 mol/L),
repeat in 46 h. If TSB continues to fall, repeat in 812 hIf TSB
is not decreasing or is moving closer to level for exchange
transfusion or the
TSB/albumin ratio exceeds levels shown in Fig 4, consider
exchange transfusion (see Fig 4 forexchange transfusion
recommendations)
When TSB is 1314 mg/dL (239 mol/L), discontinue
phototherapyDepending on the cause of the hyperbilirubinemia, it is
an option to measure TSB 24 h after
discharge to check for rebound
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ensures the safety of patients. The perspective ofsafety as a
purely individual responsibility must bereplaced by the concept of
safety as a property ofsystems. Safe systems are characterized by a
sharedknowledge of the goal, a culture emphasizing safety,the
ability of each person within the system to act ina manner that
promotes safety, minimizing the use ofmemory, and emphasizing the
use of standard pro-cedures (such as checklists), and the
involvement ofpatients/families as partners in the process of
care.
These principles can be applied to the challenge ofpreventing
severe hyperbilirubinemia and ker-nicterus. A systematic approach
to the implementa-tion of these guidelines should result in
greatersafety. Such approaches might include
The establishment of standing protocols for nurs-ing assessment
of jaundice, including testing TcBand TSB levels, without requiring
physician or-ders.
Checklists or reminders associated with risk fac-tors, age at
discharge, and laboratory test resultsthat provide guidance for
appropriate follow-up.
Explicit educational materials for parents (a keycomponent of
all AAP guidelines) concerning theidentification of newborns with
jaundice.
FUTURE RESEARCH
Epidemiology of Bilirubin-Induced Central NervousSystem
Damage
There is a need for appropriate epidemiologic datato document
the incidence of kernicterus in the new-born population, the
incidence of other adverse ef-fects attributable to
hyperbilirubinemia and its man-agement, and the number of infants
whose TSBlevels exceed 25 or 30 mg/dL (428-513 mol/L).Organizations
such as the Centers for Disease Con-trol and Prevention should
implement strategies forappropriate data gathering to identify the
number of
Fig 3. Guidelines for phototherapy in hospitalized infants of 35
or more weeks gestation.Note: These guidelines are based on limited
evidence and the levels shown are approximations. The guidelines
refer to the use of
intensive phototherapy which should be used when the TSB exceeds
the line indicated for each category. Infants are designated as
higherrisk because of the potential negative effects of the
conditions listed on albumin binding of bilirubin,4547 the
blood-brain barrier,48 andthe susceptibility of the brain cells to
damage by bilirubin.48
Intensive phototherapy implies irradiance in the blue-green
spectrum (wavelengths of approximately 430490 nm) of at least
30W/cm2 per nm (measured at the infants skin directly below the
center of the phototherapy unit) and delivered to as much of the
infantssurface area as possible. Note that irradiance measured
below the center of the light source is much greater than that
measured at theperiphery. Measurements should be made with a
radiometer specified by the manufacturer of the phototherapy
system.
See Appendix 2 for additional information on measuring the dose
of phototherapy, a description of intensive phototherapy, and of
lightsources used. If total serum bilirubin levels approach or
exceed the exchange transfusion line (Fig 4), the sides of the
bassinet, incubator,or warmer should be lined with aluminum foil or
white material.50 This will increase the surface area of the infant
exposed and increasethe efficacy of phototherapy.51
If the total serum bilirubin does not decrease or continues to
rise in an infant who is receiving intensive phototherapy, this
stronglysuggests the presence of hemolysis.
Infants who receive phototherapy and have an elevated
direct-reacting or conjugated bilirubin level (cholestatic
jaundice) may developthe bronze-baby syndrome. See Appendix 2 for
the use of phototherapy in these infants.
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infants who develop serum bilirubin levels above 25or 30 mg/dL
(428-513 mol/L) and those who de-velop acute and chronic bilirubin
encephalopathy.This information will help to identify the
magnitudeof the problem; the number of infants who need to
bescreened and treated to prevent 1 case of kernicterus;and the
risks, costs, and benefits of different strate-gies for prevention
and treatment of hyperbiliru-binemia. In the absence of these data,
recommenda-tions for intervention cannot be
considereddefinitive.
Effect of Bilirubin on the Central Nervous System
The serum bilirubin level by itself, except when itis extremely
high and associated with bilirubin en-cephalopathy, is an imprecise
indicator of long-termneurodevelopmental outcome.2 Additional
studiesare needed on the relationship between central ner-vous
system damage and the duration of hyperbil-irubinemia, the binding
of bilirubin to albumin, andchanges seen in the brainstem auditory
evoked re-sponse. These studies could help to better identify
Fig 4. Guidelines for exchange transfusion in infants 35 or more
weeks gestation.Note that these suggested levels represent a
consensus of most of the committee but are based on limited
evidence, and the levels shown
are approximations. See ref. 3 for risks and complications of
exchange transfusion. During birth hospitalization, exchange
transfusion isrecommended if the TSB rises to these levels despite
intensive phototherapy. For readmitted infants, if the TSB level is
above the exchangelevel, repeat TSB measurement every 2 to 3 hours
and consider exchange if the TSB remains above the levels indicated
after intensivephototherapy for 6 hours.
The following B/A ratios can be used together with but in not in
lieu of the TSB level as an additional factor in determining the
needfor exchange transfusion52:
Risk Category B/A Ratio at Which Exchange TransfusionShould be
Considered
TSB mg/dL/Alb, g/dL TSB mol/L/Alb, mol/L
Infants 38 0/7 wk 8.0 0.94Infants 35 0/736 6/7 wk and well or 38
0/7 wk
if higher risk or isoimmune hemolytic diseaseor G6PD
deficiency
7.2 0.84
Infants 35 0/737 6/7 wk if higher risk orisoimmune hemolytic
disease or G6PD deficiency
6.8 0.80
If the TSB is at or approaching the exchange level, send blood
for immediate type and crossmatch. Blood for exchange transfusion
ismodified whole blood (red cells and plasma) crossmatched against
the mother and compatible with the infant.53
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risk, clarify the effect of bilirubin on the central ner-vous
system, and guide intervention.
Identification of HemolysisBecause of their poor specificity and
sensitivity,
the standard laboratory tests for hemolysis (Table 1)are
frequently unhelpful.66,67 However, end-tidalcarbon monoxide,
corrected for ambient carbonmonoxide (ETCOc), levels can confirm
the presenceor absence of hemolysis, and measurement of ETCOcis the
only clinical test that provides a direct mea-surement of the rate
of heme catabolism and the rateof bilirubin production.68,69 Thus,
ETCOc may behelpful in determining the degree of surveillanceneeded
and the timing of intervention. It is not yetknown, however, how
ETCOc measurements willaffect management.
Nomograms and the Measurement of Serum and TcBIt would be useful
to develop an age-specific (by
hour) nomogram for TSB in populations of newbornsthat differ
with regard to risk factors for hyperbiliru-binemia. There is also
an urgent need to improve theprecision and accuracy of the
measurement of TSB inthe clinical laboratory.70,71 Additional
studies arealso needed to develop and validate
noninvasive(transcutaneous) measurements of serum bilirubinand to
understand the factors that affect these mea-surements. These
studies should also assess the cost-effectiveness and
reproducibility of TcB measure-ments in clinical practice.2
Pharmacologic TherapyThere is now evidence that
hyperbilirubinemia can
be effectively prevented or treated with tin-mesopor-phyrin,7275
a drug that inhibits the production ofheme oxygenase.
Tin-mesoporphyrin is not ap-proved by the US Food and Drug
Administration. Ifapproved, tin-mesoporphyrin could find
immediateapplication in preventing the need for exchangetransfusion
in infants who are not responding tophototherapy.75
Dissemination and MonitoringResearch should be directed toward
methods for
disseminating the information contained in thisguideline to
increase awareness on the part of phy-sicians, residents, nurses,
and parents concerning theissues of neonatal hyperbilirubinemia and
strategiesfor its management. In addition, monitoring systemsshould
be established to identify the impact of theseguidelines on the
incidence of acute bilirubin en-cephalopathy and kernicterus and
the use of photo-therapy and exchange transfusions.
CONCLUSIONSKernicterus is still occurring but should be
largely
preventable if health care personnel follow the rec-ommendations
listed in this guideline. These recom-mendations emphasize the
importance of universal,systematic assessment for the risk of
severe hyperbi-
lirubinemia, close follow-up, and prompt interven-tion, when
necessary.
Subcommittee on HyperbilirubinemiaM. Jeffrey Maisels, MB, BCh,
ChairpersonRichard D. Baltz, MDVinod K. Bhutani, MDThomas B.
Newman, MD, MPHHeather Palmer, MB, BChWarren Rosenfeld, MDDavid K.
Stevenson, MDHoward B. Weinblatt, MD
ConsultantCharles J. Homer, MD, MPH, Chairperson
American Academy of Pediatrics SteeringCommittee on Quality
Improvement andManagement
StaffCarla T. Herrerias, MPH
ACKNOWLEDGMENTSM.J.M. received grant support from Natus Medical,
Inc, for
multinational study of ambient carbon monoxide;
WellSpringPharmaceutical Corporation for study of Stannsoporfin
(tin-meso-porphyrin); and Minolta, Inc, for study of the
Minolta/Hill-RomAir-Shields transcutaneous jaundice meter model
JM-103. V.K.B.received grant support from WellSpring Pharmaceutical
Corpora-tion for study of Stannsoporfin (tin-mesoporphyrin) and
NatusMedical, Inc, for multinational study of ambient carbon
monoxideand is a consultant (volunteer) to SpectrX (BiliChek
transcutane-ous bilirubinometer). D.K.S. is a consultant to and
holds stockoptions through Natus Medical, Inc.
The American Academy of Pediatrics Subcommittee on
Hyper-bilirubinemia gratefully acknowledges the help of the
followingorganizations, committees, and individuals who reviewed
draftsof this guideline and provided valuable criticisms and
commen-tary: American Academy of Pediatrics Committee on
Nutrition;American Academy of Pediatrics Committee on Practice and
Am-bulatory Medicine; American Academy of Pediatrics Committeeon
Child Health Financing; American Academy of PediatricsCommittee on
Medical Liability; American Academy of PediatricsCommittee on Fetus
and Newborn; American Academy of Pedi-atrics Section on Perinatal
Pediatrics; Centers for Disease Controland Prevention; Parents of
Infants and Children With Kernicterus(PICK); Charles Ahlfors, MD;
Daniel Batton, MD; Thomas Bojko,MD; Sarah Clune, MD; Sudhakar
Ezhuthachan, MD; LawrenceGartner, MD; Cathy Hammerman, MD; Thor
Hansen, MD; LoisJohnson, MD; Michael Kaplan, MB, ChB; Tony
McDonagh, PhD;Gerald Merenstein, MD; Mary OShea, MD; Max Perlman,
MD;Ronald Poland, MD; Alex Robertson, MD; Firmino Rubaltelli,
MD;Steven Shapiro, MD; Stanford Singer, MD; Ann Stark, MD; Gau-tham
Suresh, MD; Margot VandeBor, MD; Hank Vreman, PhD;Philip Walson,
MD; Jon Watchko, MD; Richard Wennberg, MD;and Chap-Yung Yeung,
MD.
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APPENDIX 1: Additional Notes
Definitions of Quality of Evidence and Balance ofBenefits and
Harms
The Steering Committee on Quality Improvementand Management
categorizes evidence quality in 4levels:1. Well-designed,
randomized, controlled trials or
diagnostic studies on relevant populations2. Randomized,
controlled trials or diagnostic stud-
ies with minor limitations; overwhelming, consis-tent evidence
from observational studies
3. Observational studies (case-control and cohort de-sign)
4. Expert opinion, case reports, reasoning from
firstprinciples
The AAP defines evidence-based recommenda-tions as follows:1
Strong recommendation: the committee believesthat the benefits
of the recommended approachclearly exceed the harms of that
approach and thatthe quality of the supporting evidence is
eitherexcellent or impossible to obtain. Clinicians shouldfollow
these recommendations unless a clear andcompelling rationale for an
alternative approach ispresent.
Recommendation: the committee believes that thebenefits exceed
the harms, but the quality of evi-dence on which this
recommendation is based isnot as strong. Clinicians should also
generally fol-low these recommendations but should be alert tonew
information and sensitive to patient prefer-
ences. In this guideline, the term should impliesa
recommendation by the committee.
Option: either the quality of the evidence that ex-ists is
suspect or well-performed studies haveshown little clear advantage
to one approach overanother. Patient preference should have a
substan-tial role in influencing clinical decision-makingwhen a
policy is described as an option.
No recommendation: there is a lack of pertinentevidence and the
anticipated balance of benefitsand harms is unclear.
Anticipated Balance Between Benefits and HarmsThe presence of
clear benefits or harms supports
stronger statements for or against a course of action.In some
cases, however, recommendations are madewhen analysis of the
balance of benefits and harmsprovides an exceptional dysequilibrium
and it wouldbe unethical or impossible to perform clinical trials
toprove the point. In these cases the balance of ben-efit and harm
is termed exceptional.
Clinical Manifestations of Acute BilirubinEncephalopathy and
Kernicterus
Acute Bilirubin EncephalopathyIn the early phase of acute
bilirubin encephalopa-
thy, severely jaundiced infants become lethargic andhypotonic
and suck poorly.2,3 The intermediatephase is characterized by
moderate stupor, irritabil-ity, and hypertonia. The infant may
develop a feverand high-pitched cry, which may alternate
withdrowsiness and hypotonia. The hypertonia is mani-fested by
backward arching of the neck (retrocollis)and trunk (opisthotonos).
There is anecdotal evi-dence that an emergent exchange transfusion
at thisstage, in some cases, might reverse the central ner-vous
system changes.4 The advanced phase, in whichcentral nervous system
damage is probably irrevers-ible, is characterized by pronounced
retrocollis-opis-thotonos, shrill cry, no feeding, apnea, fever,
deepstupor to coma, sometimes seizures, and death.2,3,5
KernicterusIn the chronic form of bilirubin encephalopathy,
surviving infants may develop a severe form of ath-etoid
cerebral palsy, auditory dysfunction, dental-enamel dysplasia,
paralysis of upward gaze, and,less often, intellectual and other
handicaps. Mostinfants who develop kernicterus have manifestedsome
or all of the signs listed above in the acutephase of bilirubin
encephalopathy. However, occa-sionally there are infants who have
developed veryhigh bilirubin levels and, subsequently, the signs
ofkernicterus but have exhibited few, if any, anteced-ent clinical
signs of acute bilirubin encephalopa-thy.3,5,6
Clinical Evaluation of Jaundice and TcB MeasurementsJaundice is
usually seen in the face first and
progresses caudally to the trunk and extremities,7but because
visual estimation of bilirubin levels fromthe degree of jaundice
can lead to errors,810 a lowthreshold should be used for measuring
the TSB.
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Devices that provide a noninvasive TcB measure-ment have proven
very useful as screening tools,11and newer instruments give
measurements that pro-vide a valid estimate of the TSB level.1217
Studiesusing the new TcB-measurement instruments arelimited, but
the data published thus far suggest thatin most newborn
populations, these instrumentsgenerally provide measurements within
2 to 3mg/dL (3451 mol/L) of the TSB and can replace ameasurement of
serum bilirubin in many circum-stances, particularly for TSB levels
less than 15mg/dL (257 mol/L).1217 Because phototherapybleaches the
skin, both visual assessment of jaun-dice and TcB measurements in
infants undergoingphototherapy are not reliable. In addition, the
abilityof transcutaneous instruments to provide
accuratemeasurements in different racial groups requires
ad-ditional study.18,19 The limitations of the accuracyand
reproducibility of TSB measurements in the clin-ical laboratory2022
must also be recognized and arediscussed in the technical
report.23
Capillary Versus Venous Serum BilirubinMeasurement
Almost all published data regarding the relation-ship of TSB
levels to kernicterus or developmentaloutcome are based on
capillary blood TSB levels.Data regarding the differences between
capillary andvenous TSB levels are conflicting.24,25 In 1 study
thecapillary TSB levels were higher, but in another theywere lower
than venous TSB levels.24,25 Thus, obtain-ing a venous sample to
confirm an elevated capil-lary TSB level is not recommended,
because it willdelay the initiation of treatment.
Direct-Reacting and Conjugated BilirubinAlthough commonly used
interchangeably, direct-
reacting bilirubin is not the same as conjugated bili-rubin.
Direct-reacting bilirubin is the bilirubin thatreacts directly
(without the addition of an accelerat-ing agent) with diazotized
sulfanilic acid. Conju-gated bilirubin is bilirubin made water
soluble bybinding with glucuronic acid in the liver. Dependingon
the technique used, the clinical laboratory willreport total and
direct-reacting or unconjugated andconjugated bilirubin levels. In
this guideline and forclinical purposes, the terms may be used
inter-changeably.
Abnormal Direct and Conjugated Bilirubin LevelsLaboratory
measurement of direct bilirubin is not
precise,26 and values between laboratories can varywidely. If
the TSB is at or below 5 mg/dL (85 mol/L), a direct or conjugated
bilirubin of more than 1.0
mg/dL (17.1 mol/L) is generally considered abnor-mal. For TSB
values higher than 5 mg/dL (85 mol/L), a direct bilirubin of more
than 20% of the TSB isconsidered abnormal. If the hospital
laboratory mea-sures conjugated bilirubin using the Vitros
(formerlyEktachem) system (Ortho-Clinical Diagnostics, Rari-tan,
NJ), any value higher than 1 mg/dL is consid-ered abnormal.
Assessment of Adequacy of Intake in BreastfeedingInfants
The data from a number of studies2734 indicatethat
unsupplemented, breastfed infants experiencetheir maximum weight
loss by day 3 and, on aver-age, lose 6.1% 2.5% (SD) of their birth
weight.Thus, 5% to 10% of fully breastfed infants lose 10%or more
of their birth weight by day 3, suggestingthat adequacy of intake
should be evaluated and theinfant monitored if weight loss is more
than 10%.35Evidence of adequate intake in breastfed infants
alsoincludes 4 to 6 thoroughly wet diapers in 24 hoursand the
passage of 3 to 4 stools per day by the fourthday. By the third to
fourth day, the stools in ade-quately breastfed infants should have
changed frommeconium to a mustard yellow, mushy stool.36 Theabove
assessment will also help to identify breastfedinfants who are at
risk for dehydration because ofinadequate intake.
Nomogram for Designation of RiskNote that this nomogram (Fig 2)
does not describe
the natural history of neonatal hyperbilirubinemia,particularly
after 48 to 72 hours, for which, becauseof sampling bias, the lower
zones are spuriouslyelevated.37 This bias, however, will have much
lesseffect on the high-risk zone (95th percentile in
thestudy).38
G6PD Dehydrogenase DeficiencyIt is important to look for G6PD
deficiency in
infants with significant hyperbilirubinemia, becausesome may
develop a sudden increase in the TSB. Inaddition, G6PD-deficient
infants require interventionat lower TSB levels (Figs 3 and 4). It
should be notedalso that in the presence of hemolysis, G6PD
levelscan be elevated, which may obscure the diagnosis inthe
newborn period so that a normal level in a he-molyzing neonate does
not rule out G6PD deficien-cy.39 If G6PD deficiency is strongly
suspected, a re-peat level should be measured when the infant is
3months old. It is also recognized that immediatelaboratory
determination of G6PD is generally notavailable in most US
hospitals, and thus translatingthe above information into clinical
practice is cur-
TABLE 4. Risk Zone as a Predictor of Hyperbilirubinemia39
TSB Before Discharge Newborns(Total 2840),
n (%)
Newborns Who SubsequentlyDeveloped a TSB Level95th Percentile, n
(%)
High-risk zone (95th percentile) 172 (6.0) 68 (39.5)High
intermediate-risk zone 356 (12.5) 46 (12.9)Low intermediate-risk
zone 556 (19.6) 12 (2.26)Low-risk zone 1756 (61.8) 0
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rently difficult. Nevertheless, practitioners are re-minded to
consider the diagnosis of G6PD deficiencyin infants with severe
hyperbilirubinemia, particu-larly if they belong to the population
groups inwhich this condition is prevalent. This is importantin the
African American population, because theseinfants, as a group, have
much lower TSB levels thanwhite or Asian infants.40,41 Thus, severe
hyperbiliru-binemia in an African American infant should al-ways
raise the possibility of G6PD deficiency.
Basis for the Recommendations 7.1.1 Through 7.1.6 andProvided in
Figs 3 and 4
Ideally, recommendations for when to implementphototherapy and
exchange transfusions should bebased on estimates of when the
benefits of theseinterventions exceed their risks and cost. The
evi-dence for these estimates should come from random-ized trials
or systematic observational studies. Un-fortunately, there is
little such evidence on which tobase these recommendations. As a
result, treatmentguidelines must necessarily rely on more
uncertainestimates and extrapolations. For a detailed discus-sion
of this question, please see An Evidence-BasedReview of Important
Issues Concerning NeonatalHyperbilirubinemia.23
The recommendations for phototherapy and ex-change transfusion
are based on the following prin-ciples:
The main demonstrated value of phototherapy isthat it reduces
the risk that TSB levels will reach alevel at which exchange
transfusion is recom-mended.4244 Approximately 5 to 10 infants
withTSB levels between 15 and 20 mg/dL (257342mol/L) will receive
phototherapy to prevent theTSB in 1 infant from reaching 20 mg/dL
(the num-ber needed to treat).12 Thus, 8 to 9 of every 10infants
with these TSB levels will not reach 20mg/dL (342 mol/L) even if
they are not treated.Phototherapy has proven to be a generally
safeprocedure, although rare complications can occur(see Appendix
2).
Recommended TSB levels for exchange transfu-sion (Fig 4) are
based largely on the goal of keep-ing TSB levels below those at
which kernicterushas been reported.12,4548 In almost all cases,
ex-change transfusion is recommended only afterphototherapy has
failed to keep the TSB level be-low the exchange transfusion level
(Fig 4).
The recommendations to use phototherapy andexchange transfusion
at lower TSB levels for in-fants of lower gestation and those who
are sick arebased on limited observations suggesting that
sickinfants (particularly those with the risk factorslisted in Figs
3 and 4)4951 and those of lowergestation5154 are at greater risk
for developingkernicterus at lower bilirubin levels than are
wellinfants of more than 38 6/7 weeks gestation. Nev-ertheless,
other studies have not confirmed all ofthese associations.52,55,56
There is no doubt, how-ever, that infants at 35 to 37 6/7 weeks
gestationare at a much greater risk of developing very high
TSB levels.57,58 Intervention for these infants isbased on this
risk as well as extrapolations frommore premature, lower
birth-weight infants whodo have a higher risk of bilirubin
toxicity.52,53
For all newborns, treatment is recommended atlower TSB levels at
younger ages because one ofthe primary goals of treatment is to
prevent addi-tional increases in the TSB level.
Subtle Neurologic Abnormalities Associated
WithHyperbilirubinemia
There are several studies demonstrating measur-able transient
changes in brainstem-evoked poten-tials, behavioral patterns, and
the infants cry5963associated with TSB levels of 15 to 25 mg/dL
(257428 mol/L). In these studies, the abnormalitiesidentified were
transient and disappeared when theserum bilirubin levels returned
to normal with orwithout treatment.59,60,62,63
A few cohort studies have found an associationbetween
hyperbilirubinemia and long-term adverseneurodevelopmental effects
that are more subtlethan kernicterus.6467 Current studies, however,
sug-gest that although phototherapy lowers the TSB lev-els, it has
no effect on these long-term neurodevel-opmental outcomes.6870
Risks of Exchange TransfusionBecause exchange transfusions are
now rarely per-
formed, the risks of morbidity and mortality associ-ated with
the procedure are difficult to quantify. Inaddition, the
complication rates listed below may notbe generalizable to the
current era if, like most pro-cedures, frequency of performance is
an importantdeterminant of risk. Death associated with
exchangetransfusion has been reported in approximately 3 in1000
procedures,71,72 although in otherwise well in-fants of 35 or more
weeks gestation, the risk isprobably much lower.7173 Significant
morbidity (ap-nea, bradycardia, cyanosis, vasospasm,
thrombosis,necrotizing enterocolitis) occurs in as many as 5%
ofexchange transfusions,71 and the risks associatedwith the use of
blood products must always be con-sidered.74 Hypoxic-ischemic
encephalopathy and ac-quired immunodeficiency syndrome have
occurredin otherwise healthy infants receiving
exchangetransfusions.73,75
Serum Albumin Levels and the B/A RatioThe legends to Figs 3 and
4 and recommendations
7.1.5 and 7.1.6 contain references to the serum albu-min level
and the B/A ratio as factors that can beconsidered in the decision
to initiate phototherapy(Fig 3) or perform an exchange transfusion
(Fig 4).Bilirubin is transported in the plasma tightly boundto
albumin, and the portion that is unbound orloosely bound can more
readily leave the intravas-cular space and cross the intact
blood-brain barrier.76Elevations of unbound bilirubin (UB) have
been as-sociated with kernicterus in sick preterm new-borns.77,78
In addition, elevated UB concentrationsare more closely associated
than TSB levels withtransient abnormalities in the audiometric
brainstemresponse in term79 and preterm80 infants. Long-term
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studies relating B/A binding in infants to develop-mental
outcome are limited and conflicting.69,81,82 Inaddition, clinical
laboratory measurement of UB isnot currently available in the
United States.
The ratio of bilirubin (mg/dL) to albumin (g/dL)does correlate
with measured UB in newborns83 andcan be used as an approximate
surrogate for themeasurement of UB. It must be recognized,
however,that both albumin levels and the ability of albumin tobind
bilirubin vary significantly between new-borns.83,84 Albumin
binding of bilirubin is impairedin sick infants,8486 and some
studies show an in-crease in binding with increasing
gestational86,87 andpostnatal87,88 age, but others have not found a
sig-nificant effect of gestational age on binding.89 Fur-thermore,
the risk of bilirubin encephalopathy is un-likely to be a simple
function of the TSB level or theconcentration of UB but is more
likely a combinationof both (ie, the total amount of bilirubin
available[the miscible pool of bilirubin] as well as the ten-dency
of bilirubin to enter the tissues [the UB con-centration]).83 An
additional factor is the possiblesusceptibility of the cells of the
central nervous sys-tem to damage by bilirubin.90 It is therefore a
clinicaloption to use the B/A ratio together with, but not inlieu
of, the TSB level as an additional factor in deter-mining the need
for exchange transfusion83 (Fig 4).
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APPENDIX 2: PhototherapyThere is no standardized method for
delivering
phototherapy. Phototherapy units vary widely, as dothe types of
lamps used in the units. The efficacy ofphototherapy depends on the
dose of phototherapyadministered as well as a number of clinical
factors(Table 5).1
Measuring the Dose of PhototherapyTable 5 shows the radiometric
quantities used in
measuring the phototherapy dose. The quantity mostcommonly
reported in the literature is the spectralirradiance. In the
nursery, spectral irradiance can bemeasured by using commercially
available radiome-ters. These instruments take a single
measurementacross a band of wavelengths, typically 425 to 475 or400
to 480 nm. Unfortunately, there is no standard-ized method for
reporting phototherapy dosages inthe clinical literature, so it is
difficult to comparepublished studies on the efficacy of
phototherapyand manufacturers data for the irradiance producedby
different systems.2 Measurements of irradiancefrom the same system,
using different radiometers,
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can also produce significantly different results. Thewidth of
the phototherapy lamps emissions spec-trum (narrow versus broad)
will affect the measuredirradiance. Measurements under lights with
a veryfocused emission spectrum (eg, blue light-emittingdiode) will
vary significantly from one radiometer toanother, because the
response spectra of the radiom-eters vary from manufacturer to
manufacturer.Broader-spectrum lights (fluorescent and halogen)have
fewer variations among radiometers. Manufac-turers of phototherapy
systems generally recom-mend the specific radiometer to be used in
measur-ing the dose of phototherapy when their system isused.
It is important also to recognize that the measuredirradiance
will vary widely depending on where themeasurement is taken.
Irradiance measured belowthe center of the light source can be more
than dou-ble that measured at the periphery, and this dropoffat the
periphery will vary with different photother-apy units. Ideally,
irradiance should be measured atmultiple sites under the area
illuminated by the unitand the measurements averaged. The
InternationalElectrotechnical Commission3 defines the
effectivesurface area as the intended treatment surface thatis
illuminated by the phototherapy light. The