Clinical Manifestations of Unconjugated Hyperbilirubinemia in Term and Late Preterm Infants

1/1/2016
Clinicalmanifestationsofunconjugatedhyperbilirubinemiaintermandlatepreterminfants
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate
Authors
RonaldJWong,BA
VinodKBhutani,MD,FAAP
SectionEditor
StevenAAbrams,MD
DeputyEditor
MelanieSKim,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2015.|Thistopiclastupdated:Dec14,2015.
INTRODUCTIONAlmostallnewborninfantsdevelopatotalserumorplasmabilirubin(TB)valuegreaterthan1
mg/dL(17.1micromol/L),whichistheupperlimitofnormalforadults.AsTBincreases,itcausesneonatal
jaundice,theyellowishdiscolorationoftheskinand/orconjunctivacausedbybilirubindepositioninhalfofall
newborninfants.Neonateswithseverehyperbilirubinemia(definedasaTB>25mg/dL[428micromol/L])areat
riskforbilirubininducedneurologicdysfunction(BIND),whichoccurswhenbilirubincrossesthebloodbrainbarrier
andbindstobraintissue.
Theclinicalmanifestationsofneonatalunconjugatedhyperbilirubinemiaincludingriskfactorsforsevere
hyperbilirubinemiaintermandlatepreterminfantsarereviewedhere.Thepathogenesis,etiology,evaluation,
preventionandtreatmentofthisdisorderarediscussedseparately.(See"Pathogenesisandetiologyof
unconjugatedhyperbilirubinemiainthenewborn"and"Evaluationofunconjugatedhyperbilirubinemiaintermand
latepreterminfants"and"Treatmentofunconjugatedhyperbilirubinemiaintermandlatepreterminfants".)
DEFINITIONS
Neonatalhyperbilirubinemiaininfants35weeksgestationalage(GA)isdefinedastotalserumorplasma
bilirubin(TB)>95thpercentileonthehourspecificBhutaninomogram(figure1)[1].
SevereneonatalhyperbilirubinemiaisdefinedasaTB>25mg/dL(428micromol/L).Itisassociatedwithan
increasedriskforbilirubininducedneurologicdysfunction(BIND),whichoccurswhenbilirubincrossesthe
bloodbrainbarrierandbindstobraintissue.(See'Neurologicmanifestations'below.)
Acutebilirubinencephalopathy(ABE)isusedtodescribetheacutemanifestationsofBIND.(See'Acute
bilirubinencephalopathy'below.)
KernicterusisusedtodescribethechronicandpermanentsequelaeofBIND.(See'Kernicterus'below.)
OVERVIEWTheadministrationofRh(D)immunoglobulintoRhnegativemothersinthelate1960sdramatically
decreasedtheincidenceofneonatalRhisoimmunehemolyticdisease.Thus,theriskofkernicteruswasreduced
fromitspeakinthe1950sthroughthe1970s.Nevertheless,isolatedcasesofkernicterus,apreventablecondition,
continuetobereported[2,3].(See'Epidemiology'below.)
Sincetheassociationbetweenhyperbilirubinemiaandkernicteruswasfirstidentifiedininfantswith
erythroblastosisfetalismorethan50yearsago[46],therehasbeenadebateonwhatdegreeanddurationof
hyperbilirubinemiacausesbilirubininducedneurologicdysfunction(BIND).Additionalfactorssuchastherateof
riseoftotalserumorplasmabilirubin(TB),theproportionofunbound(or"free")bilirubin,andthepermeabilityof
thebloodbrainbarrieraffectthepotentialforneurotoxicity.(See'Neurologicmanifestations'below.)
LimiteddatabaseduponcasereportssuggestthatkernicterusisunlikelytooccurinhealthyterminfantswithTB
20mg/dL(342micromol/L)[2,7].Thisisillustratedinareportof61casesofreadmittedpatients(beforeseven
daysofage)thatwerevoluntarilyreportedtothePilotKernicterusRegistry[2].ThemedianTBonreadmission
was39mg/dL(667micromol/L),range21.5to50mg/dL(368to855micromol/L)[2].Areviewoftheliteraturein
2002of123casesreportedsimilarresultsmorethan90percentofinfantshadTB>25mg/dL(428micromol/L).
Baseduponthesedata,themanagementofunconjugatedhyperbilirubinemiaintermandlatepreterminfantsis
http://www.uptodate.com/contents/clinicalmanifestationsofunconjugatedhyperbilirubinemiaintermandlatepreterminfants?topicKey=PEDS%2F4994&el
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focusedontwokeyelements:
Preventionofhyperbilirubinemia,definedasTB>95thpercentileforhoursofageontheBhutaninomogram
[8],byidentifyingatriskinfantsandbeginningpreventativetherapeuticinterventions(eg,phototherapy)as
needed[3]
ReductionofTBininfantswithseverehyperbilirubinemia
(See"Evaluationofunconjugatedhyperbilirubinemiaintermandlatepreterminfants"and"Treatmentof
unconjugatedhyperbilirubinemiaintermandlatepreterminfants".)
EPIDEMIOLOGY
Totalserum/plasmabilirubin(TB)Intheneonate,TBvaluesvarysubstantiallyamonginstitutionsbecauseof
differencesinracialcomposition,hemolyticconditions,orbreastfeedingpractices.(See"Evaluationof
unconjugatedhyperbilirubinemiaintermandlatepreterminfants",sectionon'Epidemiology'and"Pathogenesis
andetiologyofunconjugatedhyperbilirubinemiainthenewborn",sectionon'Neonataljaundice'.)
Thesefactorsmaycontributetotheobservedglobalvariationsintheincidenceofhyperbilirubinemia(TB>20
mg/dL[342micromol/L]).
InstudiesoftermorlatepreterminfantsfromalargeNorthernCaliforniahealthmaintenanceorganization
(HMO),thefollowingincidencesofseverehyperbilirubinemiaatdifferentTBvalueswerereportedfrombirth
datacollectedbetween1995and1998[9,10]:
TB>20mg/dL(342micromol/L):2percent[10]
TB>25mg/dL(428micromol/L):0.14percent[10]
TB>30mg/dL(513micromol/L):0.01percent[9]
TheriskofTB>20mg/dL(342micromol/L)waslowerininfantsborntomotherswhoselfreportedasAfrican
AmericanthaninthosewhowereCaucasian(0.9versus1.5percent,relativerisk[RR]0.62,95%CI0.56
0.69)[11].However,theriskofseverehyperbilirubinemia,definedasTB>30mg/dL(513micromol/L),was
higherinAfricanAmericaninfants(0.13versus0.03percent,RR4.2,95%CI1.3313.2).
InalatercohortofinfantsfromthesameHMObornbetween1995and2011(n=525,409),47infantswere
identifiedwithseverehyperbilirubinemiaresultinginanincidenceof8.6per100,000births[12].Theetiology
wasnotidentifiedin33patients,and10of25patientstestedforglucose6phosphatedehydrogenase
(G6PD)activitywerefoundtobedeficient.Fourpatientshadacutebilirubinencephalopathy(ABE).This
includedthreeinfantswithG6PDdeficiencywithTBlevels>40mg/dL(684micromol/L),inwhomcerebral
palsy(CP)andsensorineuralhearingloss(SNHL)developedintwopatients,andSNHLonlyinonepatient.
(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthenewborn",sectionon'Increased
production'.)
InaDanishpopulationbasedstudyfrom2000to2007,theincidenceof"extreme"hyperbilirubinemia(defined
asaTB26.3mg/dLor450micromol/L)was0.045percentofinfantsbornatgestationalage(GA)35
weeks[13].Ofthe224identifiedinfantswithextremehyperbilirubinemia,threehadadvancedbilirubin
encephalopathyandapeakTBlevelgreaterthan35mg/dL(599micromol/L),whichwasduetohemolysis
eitherfromABOincompatibilityorG6PDdeficiency.Allthreepatientsdevelopedkernicterus.Twoother
infantshadmoderatebilirubinencephalopathyandtheirneurologicconditionnormalizedoverfourtofive
days.OneofthepatientswithmoderatediseasehadABOincompatibility.
InapopulationbasedstudyfromNovaScotia,theincidenceofseverehyperbilirubinemia(definedasaTB
19mg/dLor325micromol/L)was0.6percentoflivebirths(348of61,238)attermorlatepreterm[14].
Severehyperbilirubinemiawasassociatedwithbreastfeeding,oldermaternalage(>35yearsofage),
nulliparous,nonsmokingmother,GA<37weeks,malegender,andrespiratorydistresssyndrome.
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InaprospectivepopulationbasedstudyintheUnitedKingdomandIrelandbetween2003and2005,the
incidenceof"severe"hyperbilirubinemia(definedasaTB>30mg/dLor513micromol/L)was7per100,000
livebirths[15].ThemeanGAofthe108identifiedinfantswas38.2weeks.Eightypercentofthepatients
werebreastfed,twothirdsweremale,andabouthalfwerefromaminorityethnicbackground.Fourteen
infantsdevelopedABE,includingthreeinfantswhodied.
ThehigherreportedincidenceintheUnitedStatescomparedwithWesternEuropeandNovaScotiamayreflect
thegreaternumberofinfantsbornofmotherswhoareEastAsianorAfricanAmerican.
KernicterusKernicterusisthechronicandpermanentneurologicsequelaeofbilirubininducedneurologic
dysfunction(BIND).Althoughtherehadbeenconcernsthattheincidenceofkernicteruswasrising,theriskof
kernicterusappearstobestablebasedonpopulationstudies.
ThiswasillustratedbyastudythatuseddiagnosiscodesfromdatacollectedbytheCaliforniaDepartmentof
DevelopmentalServicestoidentifypatientswithkernicterusbornbetween1988and1997,anddeathcertificate
datafromtheNationalCenterforHealthStatisticstoexaminekernicterusmortalitytrends[16].Thefollowing
findingswerenoted:
Twentyfivecaseswithastrictdiagnosisofkernicteruswereidentifiedoverthe10yearperiodresultinginan
overallincidenceof0.44per100,000livebirthsaveragedperyearwhenreportedfortheentirestudyperiod.
Theincidenceofkernicteruswashigherinboysthaningirls(0.71versus0.30per100,000livebirthsper
year).
Thedeathrateduetokernicteruswas0.28deathsperonemillionlivebirths,whichremainedstable
throughoutthestudyperiodfrom1979to2006.
Determiningtheincidenceofkernicterusisconfoundedbyabsenceofpopulationbaseddata,reportsofselect
patientswhoareadmittedatvaryingstagesofABE,andvariabletimelinesstointervention.Similarincidencesof
kernicterusper100,000livebirthshavebeenreportedintheUnitedStates(0.44)aswerereportedinpopulation
basedstudiesinGermany(0.63)andDenmark(0.40),butahigherratewasseeninCanada[1618].Inareport
thatusedprospectivedatafromtheCanadianPaediatricSurveillanceProgram(CPSP)from2007to2008,20
casesofkernicterus(eg,chronicbilirubinencephalopathy)wereidentifiedresultinginanincidenceof2.3cases
per100,000livebirths[18].Causesofneonatalhyperbilirubinemiaincludedalloimmunehemolyticdiseasedueto
ABOincompatibilityorotherredbloodcellantibodies(n=7),G6PDdeficiency(n=5),andsepsis(n=2).Fifteen
patientshadanabnormalbrainmagneticresonanceimaging(MRI)studyduringtheneonatalperiod.Ofthe14
patientswithfollowupdata,sixpatientshadsignsofneurologicimpairmentand/ordevelopmentaldelay,five
infantshadchoreoathetoidCP,andthreewerereportedashealthy.
Itappearsthattheincidencesofkernicterusandhyperbilirubinemiaaredecreasing.
InonestudyusingselectreportingofnationallyrepresentativehospitaldischargedataintheUS,the
hospitalizationratefornewbornswhowerecodedtohavekernicterusbycliniciansdeclinedfrom5.1per
100,000termneonates(patients30daysofage)in1988to1.5per100,000neonatesin1994[19].Inthis
report,acaseofkernicterus,whenreported,wasdefinedbyadiagnosiscodeandevidenceoftreatmentwith
phototherapyorexchangetransfusion,anddatafromlatepreterminfantswerenotincluded.Asianinfants
hadahigherrateofhospitalizationthanotherethnicgroups,asdidpretermcomparedwithterminfants.
AreportfromamultihospitalhealthcaresystemintheUnitedStatesshowedadecliningrateofinfantswith
extremehyperbilirubinemia,definedasTBbetween25and29.9mg/dL(428and513micromol/L)from2002
to2010[20](figure2).Nopatientinthiscohortdevelopedkernicterus.
RISKFACTORSInthe2004AmericanAcademyofPediatrics(AAP)PracticeGuideline,thefollowingmajor
riskfactorsforseverehyperbilirubinemia(table1)andbilirubininducedneurologicdysfunction(BIND)were
identified[1]:
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Predischargetotalserumorplasmabilirubin(TB)ortranscutaneousbilirubin(TcB)inahighriskzonedefined
as>95thpercentileforage(figure1).Theriskforseverehyperbilirubinemiaandthethresholdforintervention
baseduponthehourspecificTBvaluemaybedeterminedusingthenewbornhyperbilirubinemiaassessment
calculator(calculator1).(See"Evaluationofunconjugatedhyperbilirubinemiaintermandlatepreterm
infants",sectionon'Totalserumorplasmabilirubin(TB)'and"Evaluationofunconjugatedhyperbilirubinemia
intermandlatepreterminfants",sectionon'Transcutaneousbilirubin'.)
Jaundicewithinthefirst24hoursoflife[21].
Hemolyticdiseaseduetoisoimmunemediatedhemolysisfrombloodgroupincompatibilityorinheritedred
cellenzymaticdeficienciesormembranedefects(eg,glucose6phosphatedehydrogenase[G6PD]
deficiency).Inaddition,evidenceofhemolysisisamajorriskfactorforseverehyperbilirubinemia(eg,
elevatedendtidalcarbonmonoxide[CO],correctedforinhaledCOorendtidalcarbonmonoxide
concentration[ETCOc]levels).(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthe
newborn",sectionon'Increasedproduction'and"Evaluationofunconjugatedhyperbilirubinemiaintermand
latepreterminfants",sectionon'Endtidalcarbonmonoxideconcentration'.)
Gestationalage(GA)35to36weeks[22,23].(See"Latepreterminfants".)
Siblingwhopreviouslyreceivedphototherapy[23,24].
Cephalohematomaorsignificantbruisingfrombirthtrauma[22].
Exclusivebreastfeeding,particularlyifnursingisnotgoingwellandweightlossisexcessive(>12percentof
birthweight[BW])[22,23].
EastAsianrace.(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthenewborn",
sectionon'Ethnicvariationinconjugationability'.)
Minorriskfactorsincluded[1](table1):
TBinahighintermediaterange(>75thand95thpercentileforageinhours)
Jaundiceobservedbeforedischarge[23]
Macrosomicinfantofadiabeticmother[25,26]
Polycythemia
Malegender[22]
Maternalage25years[23]
TheabilityoftheAAPmajorriskfactorstopredicthyperbilirubinemiawasillustratedinaretrospectivenested
casecontrolstudyofalargecohortof285,295newborninfantsbornwithaBW2000gataGA34weeks
between1995and2004[27].Inthisstudy,62infants(0.4percent)wereidentifiedwithaTB25mg/dL(428
micromol/L)fromacohortof17,986infants(6.3percent)withaTBbetween17and22.9mg/dL(291to392
micromol/L)atage48hoursoflife.Fourrandomlyselectedcontrolcaseswithintheidentifiedcohortgroupwere
matchedtothepatientswithTB25mg/dL(428micromol/L).LowerGA,bruising,afamilyhistoryofneonatal
hyperbilirubinemia,arapidriseofTB6mg/dL(103micromol/L)perday,andexclusivebreastfeedingwere
associatedwithaTB25mg/dL(428micromol/L).Inthenestedcontrolsample,inpatientphototherapywithin
eighthoursofaqualifyingTBwasassociatedwithadecreasedriskforaTB25mg/dL(428micromol/L).
ApopulationbasedstudyusingdatafromtheSwedishMedicalBirthRightRegisterofterminfants(37weeks
GA)bornfrom1999to2012identifiedthefollowingasriskfactorsforseverehyperbilirubinemia:GAbetween37
and38weeks,failedorsuccessfulvacuumextraction,macrosomicinfants,obesemother,andbeingsmallfor
gestationalage(SGA)[28].Inthiscohort,plannedcesareandeliverywasassociatedwithareducedriskof
hyperbilirubinemia.Inthisstudy,severehyperbilirubinemiawasdefinedas20mg/dL(342micromol/L)before2008
and20.6mg/dL(352micromol/L)from2008andafter.
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Althoughinheriteddeficienciesinhepaticconjugatingcapacity(eg,CriglerNajjarorGilbertsyndromes)werenot
includedintheAAPguidelineorassessedintheSwedishstudyasriskfactors,geneticpredispositionmayplaya
majorroleinseverehyperbilirubinemia,especiallyinGilbertsyndrome,whichaffects9percentofthegeneral
population[29,30].Thismayinpartexplainwhyfamilyhistoryisapredictiveriskfactorforhyperbilirubinemia.The
underlyingdecreaseinbilirubinclearanceofinfantswithGilbertsyndromeincombinationwithotherfactor(s)that
increasesTBcanresultinseverehyperbilirubinemia[31].Asanexample,breastfedinfantswithGilbertsyndrome
haveathreetofourfoldincreasedriskforTB>20mg/dL(342micromol/L)comparedwithbreastfedinfantswithout
Gilbertsyndrome[32].(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthenewborn",
sectionon'Gilbertsyndrome'.)
Analternativesimplerapproachofusingtheinfant'sdischargeTBlevelandGAhasbeenreportedtoaccurately
assessaninfant'sriskofdevelopingsignificanthyperbilirubinemia[33].
Factorsassociatedwithdecreasedriskofseverehyperbilirubinemiainclude[1](table1):
GA41weeks[22]
Exclusivebottlefeeding[22,23]
Neonataldischargefromthehospitalafter72hours[23,34]
AfricanAmericanethnicity,althoughthereappearstobeasubgroupofAfricanAmericanmaleswithG6PD
deficiencywhoremainatrisk[35]
Theseriskfactorsareusedtoassessthelikelihoodofdevelopingclinicallysignificanthyperbilirubinemia.Therisk
assessmentandtheageoftheinfantatthetimeofdischargefromthehospitalareusedtodeterminethetimingof
appropriatefollowup(table2).(See"Evaluationofunconjugatedhyperbilirubinemiaintermandlatepreterm
infants",sectionon'Riskassessment'and"Evaluationofunconjugatedhyperbilirubinemiaintermandlatepreterm
infants",sectionon'Followup'.)
ReadmissionRiskforreadmissionforhyperbilirubinemiaforterminfantsbasedonalargepopulationbased
Australianstudyincluded[36]:
Earlybirthhospitaldischarge(2daysafterbirth).
GA<39weeks.
MotherfromanAsiancountry.
Vaginalbirth.
Firsttimemother.
Breastfeedingatthetimeofbirthhospitaldischarge.Ofnote,thestudydoesnotdifferentiatebetween
suboptimalorsuccessfulinitiationofbreastfeedingatthetimeofdischarge.
CLINICALMANIFESTATIONSTheclinicalmanifestationsofhyperbilirubinemiaareduetobilirubindeposition
intheskin(jaundice)and/orthebrain(bilirubininducedneurologicdysfunction[BIND]).
JaundiceJaundiceistheyellowcolorproducedbythedepositionofbilirubinintheskinandsubcutaneous
tissues.Althoughanimportant,andtimehonoredclinicalsign,thepresenceofjaundiceisnotareliablemethodto
assesstotalserumorplasmabilirubin(TB)concentrationoridentifyinfantsatriskforrapidlyrisingbilirubin,
especiallyinthosewithdarkskin[2,37,38].Theexaminationforjaundiceshouldbeperformedwithadequate
ambientlightorunderdaylightfluorescentlight.Pressingontheskinwithafingerreduceslocalskinperfusionand
facilitatesdetectionofjaundice(picture1).
Jaundiceusuallyprogressesinacephalocaudaldirection,appearingfirstinthefaceTBlevelsof4to8mg/dL(68
to137micromol/L).Theentirebody,includingpalmsandsoles,canappearjaundicedatTB>15mg/dL(257
micromol/L)[39].Inanobservationalstudyof240termorlatepretermneonates,mostinfantswithconjunctival
icterushadTB15mg/dL(257micromol/L)andallinfantswiththisfindinghadTBlevels>75thpercentile
(primarilygreaterthanthe95thpercentile)onthehourspecificBhutaninomogram(figure1)[40].Sevenofthe76
infantswithconjunctivalicterushadaTBinthe10to14.9mg/dL(171to255micromol/L)range.
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TheseresultssuggestthatTBortranscutaneousbilirubin(TcB)levelsshouldalwaysbemeasuredinaninfant
withjaundicebelowtheumbilicusorwithconjunctivalicterus.Ifthereisuncertaintyregardingthepresenceor
extentofjaundice,aTBorTcBmeasurementshouldbeperformed.(See"Evaluationofunconjugated
hyperbilirubinemiaintermandlatepreterminfants".)
Otherfindingsonphysicalexaminationmaysuggestanincreasedriskforhyperbilirubinemia.Theseincludepallor,
enclosedhemorrhage(eg,cephalohematoma),bruising,andhepatosplenomegaly.
NeurologicmanifestationsBilirubinisapotentialneurotoxin[4149].Termandlatepreterminfantsareatrisk
forBINDwhenTBconcentrations25mg/dL(428micromol/L).Ingeneral,atthisthreshold,unconjugatedbilirubin,
whichisnotboundtoalbumin(alsoreferredtoas"free"orunboundbilirubin),canenterthebrainandcausecell
deathbyapoptosis(programmedcelldeath)and/ornecrosis[4749].Invitro,animalcellculturestudiessuggested
thatlowerlevelsofunconjugatedbilirubininduceapoptosisandhigherlevelsinducenecroticcelldeath[47].Which
mechanismpredominatesininfantswithsevereunconjugatedhyperbilirubinemiawhodevelopBINDremains
uncertain[1].BINDisaspectrumofsubtleneurologicfindingsandsequelae[50],whichcanmanifestasdisorders
invision[51],hearing[52],gait[53],andspeech,cognition,andlanguage[54].
Acutebilirubinencephalopathy(ABE)maybereversibleorresultinpermanentirreversibleneurologicdysfunction
(kernicterus).Thebrainregionsmostoftenaffectedincludethebasalgangliaandthebrainstemnucleifor
oculomotorandauditoryfunction,accountingfortheclinicalfeaturesseenininfantswithBIND[55].
AcutebilirubinencephalopathyABEtypicallyprogressesthroughthreephases[55]:
Intheearlyphase,theclinicalsignsmaybesubtle.Theinfantissleepybutarousable,andwhenaroused
hasmildtomoderatehypotoniaandahighpitchedcry.
Ifthereisnointervention,theintermediatephaseevolveswithprogressionandpersistenceof
hyperbilirubinemia.Theinfantcanbefebrile,lethargicwithapoorsuck,orirritableandjitterywithastrong
suck.Thecrycanbeshrillandtheinfantisdifficulttoconsole.Mildtomoderatehypertoniadevelops,
beginningwithbackwardarchingoftheneck(retrocollis)andtrunk(opisthotonos)withstimulation.An
emergentexchangetransfusionatthisstagemightpreventpermanentBIND.
Theadvancedphaseischaracterizedbyapnea,inabilitytofeed,fever,seizures,andasemicomatosestate
thatprogressestocoma.Hypertonicitypresentsaspersistentretrocollisandopisthotonoswithbicyclingor
twitchingofthehandsandfeet.Thecryisinconsolable,ormaybeweakorabsent.Deathisdueto
respiratoryfailureorintractableseizures.
InareportbasedonprospectivedatafromthevoluntaryCanadianPaediatricSurveillanceProgram(CPSP),32of
258infants(12.4percent)withseverehyperbilirubinemia(definedasaTB>24.8mg/dL[424micromol/L])were
diagnosedwithABE[56].Twentyotherinfantshadnonspecificneurologicfindingsthatwerenotsevereenoughto
confidentlymakethediagnosisofABE.InfantswithABEhadhigherpeakTBlevelsthanthosewithoutABE(29.7
versus27.3mg/dL[508versus467micromol/L]).InfantswithABEwhopresentedinthefirst48hoursoflifehad
lowerTBlevelsthanthosewhopresentedafter48hours.Thisstudywasunabletodeterminewhethertherewasa
relationshipbetweenABEandtheetiologyofhyperbilirubinemia,asanunderlyingcausewasdeterminedinonly
41percentofpatientswithABEand35percentofpatientswithoutanyneurologicabnormality.
Inanobservationalstudy,249Egyptianneonateswereselfreferredtoapublichospitalneonatalintensivecare
unit(NICU)followingunknowndurationofhyperbilirubinemiaafterdeliveryatoutlyingfacilitiesovera12month
period(JanuarytoDecember2008).Characteristicsofthisatriskinfantcohortincluded:gestationalage(GA)>34
weeks,birthweight(BW)>2kg,postnatalage<14days,andadmissionTB25mg/dL(428micromol/L).Of
these,44(18percent)werediagnosedwithmoderateorsevereABE,55(22percent)withmildABE,andthe
remaininginfantswereasymptomatic[57].AlthoughthemedianTBwaslowerinpatientswithnoABEsymptoms
(28.3mg/dL[484micromol/L])androseprogressivelyforthosewithmild/moderateandsevereABE(32to33and
36.5mg/dL,[547to564and624micromol/L]),therangeofTBvalueswassimilarinallthreegroups.Ofthe26
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infantswhodiedwithevidenceofABE,19hadaTBlevel30mg/dL(513micromol/L).Theseveninfantswho
diedwithlowerTBhadevidenceofseverehemolysisandincludedsixwithRhincompatibility.Inthisselect
cohortofpatients,multipleregressionanalysesdemonstratedthatsepsis,Rhincompatibility,andincrementalTB
increasesof5mg/dL(86micromol/L)increasedtheriskofABE.
Brainstemauditoryevokedresponses(BAER)canbeusedtodetectneurologiceffectsofhyperbilirubinemia[58
60].Inonestudy,increasedTBcorrelatedwithprolongedbrainstemconductiontime[59].Theseabnormalities
resolveasTBvaluesdecline.ChangesinBAERalsohavebeenassociatedwithelevatedunboundbilirubinlevels
[61].AnabnormalBAERandnormalotoacousticemission(OAE)testssuggestthatseverehyperbilirubinemia
resultsinanauditoryneuropathy.
InfantswhoareatincreasedriskforABEincludethosewhowereborn<37weeksGA,werebreastfed,have
hemolyticdisease,andaredischargedhomebefore48hours.Closesurveillanceoftheseatriskinfantswith
timelyinterventioncanpreventABE.(See'Riskfactors'aboveand"Treatmentofunconjugatedhyperbilirubinemia
intermandlatepreterminfants".)
KernicterusKernicterus(thechronicandpermanentsequelaeofBIND)developsduringthefirstyearafter
birth[55].Cognitivefunctionusuallyisrelativelyspared.Themajorfeaturesofkernicterusinclude:
Choreoathetoidcerebralpalsy(CP)(chorea,ballismus,tremor,anddystonia).(See"Hyperkineticmovement
disordersinchildren".)
Sensorineuralhearingloss(SNHL)commonlymanifestingasauditoryneuropathy(abnormalBAERwith
normalotoacousticemissions).Inaretrospectivecohortstudyfromalargemulticenterhealthcaresystem,
SNHLbasedonchartreviewwasfoundtobemorefrequentlyobservedinpatientswhohadTB10mg/dL
(171micromol/L)abovetheAmericanAcademyofPediatrics(AAP)recommendationforexchange
transfusionthreshold(ETT)comparedwithcontrolswithTBbelowtheETT[62].Inthisstudy,allofthe
extremelyhyperbilirubinemicinfantsweretreatedwithphototherapyinatimelyandeffectivemanner
consistentwiththeroutineclinicalpracticeofthebirthhospitalsinthishealthcaresystem.(See"Hearing
impairmentinchildren:Etiology",sectionon'Hyperbilirubinemia'and"Treatmentofunconjugated
hyperbilirubinemiaintermandlatepreterminfants",sectionon'Managementapproach'and"Treatmentof
unconjugatedhyperbilirubinemiaintermandlatepreterminfants",sectionon'Exchangetransfusion'.)
Gazeabnormalities,especiallylimitationofupwardgaze.
Dentalenameldysplasia.
MostinfantswhodevelopkernicterushavemanifestedsomeorallofthefindingsassociatedwithABE[2].
However,therearereportedcasesofinfantswhodevelopedkernicteruswithhighTB,butwithoutorwithonlya
fewsignsofABE[63,64].
Inthepreviouslymentionedreportof61patientsfromthePilotKernicterusRegistrywhohadbeenreadmittedfor
hyperbilirubinemia,thefollowingdiagnoseswerethemajorcontributingcausesofhyperbilirubinemiathatresulted
inkernicterus[2]:
Noetiologyidentified20patients
Glucose6phosphatedehydrogenase(G6PD)deficiency20patients
Hemolysis9patients
Bruisingfrombirthtrauma6patients
Infection4patients
CriglerNajjarSyndromeorgalactosemia3patients
Allbutoneoftheinfantswerebreastfed.Sixteeninfantshadlost>10percentoftheirBWatthetimeofhospital
readmission.(See"Pathogenesisandetiologyofunconjugatedhyperbilirubinemiainthenewborn".)
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NeurologicdysfunctionandmoderatehyperbilirubinemiaItremainsuncertainwhethermoderate
hyperbilirubinemiamaybeassociatedwithanincreasedriskoflongtermneurologicdysfunction,asdemonstrated
bythefollowingstudies:
Inthealreadymentionedpopulationbasedstudyof61,238infantsbornbetween1994and2000fromNova
Scotia,therewerenodifferencesinthecompositeoutcomeofCP,developmentaldelay,hearingandvision
losses,autism,andattentiondeficithyperactivitydisorder(ADHD)betweeninfantswithout
hyperbilirubinemia(n=52,240)andthe3431infantswithmildhyperbilirubinemia,definedasTBof13.5to19
mg/dL(231to325micromol/L),(adjustedrelativerisk[RR]1.1,95%CI1.012.0)orthe348infantswith
severehyperbilirubinemia,definedasTB>19mg/dL(>325micromol/L),(adjustedRR1.1,95%CI0.81.4).
Whenthegroupswereanalyzedforeachoutcomemeasure,onlydevelopmentaldelaywasincreasedin
thosewithmoderatehyperbilirubinemia(adjustedRR1.6,95%CI1.32.0)andADHDinthosewithsevere
hyperbilirubinemia(adjustedRR1.9,95%CI1.13.3)comparedwithinfantswithouthyperbilirubinemia.
Althoughnotstatisticallysignificant,thereappearedtobeatrendofincreasedlikelihoodofautismininfants
withhyperbilirubinemiacomparedwiththosewithouthyperbilirubinemia(adjustedRR1.6,95%CI1.02.5).
Anotherprospectivecohortstudyfailedtofindanincreaseinneurologicfindingsin132of140infantswith
TBlevels25mg/dL(428micromol/L)compared(blindly)with372matchedcontrolswhowereeithernot
jaundicedorhadTB<22.8mg/dL(390micromol/L)attwotofiveyearsofage[65].Infantswith
hyperbilirubinemia,whoweretreatedwitheitherphototherapy(136cases)orexchangetransfusionshada
lowerincidenceofquestionableorabnormalfindingsonneurologicalexaminationthancontrolinfants(17
versus29percent)[65].Inasubsetanalysis,ninepatientswithhyperbilirubinemiaandapositivedirect
antiglobulintest(DATorCoombstest)hadlowerscoresoncognitivetestingthanotherpatientswith
hyperbilirubinemiawithanegativeDAT.
Inacasecontrolstudy,neonatalhyperbilirubinemiawasnotariskfactorforautismspectrumdisorderforTB
levelsof15to19.9mg/dL(257to340micromol/L,oddsratio[OR]0.7,95%CI0.51.2)20to24.9mg/dL
(342to426micromol/L,OR0.7,95%CI0.31.6)or25mg/dL(428micromol/L,OR1.1,95%CI0.111.2)
[66].
Incontrast,apopulationbasedstudyof733,826infantsbornaliveinDenmarkbetween1994and2004
reportedthatneonataljaundicewasassociatedwithanincreasedriskofpsychologicaldevelopment
disordersincludinginfantileautism[67].Inthisstudy,theexposuretojaundiceandthediagnosesof
psychologicaldisordersweredeterminedbasedondiagnosticcodingfromdataretrievedfromtheDanish
NationalHospitalRegister.
However,untilthereisconvincingevidencethatdemonstratesmoderatehyperbilirubinemiaisassociatedwith
significantpooroutcomes,recommendationsregardingmanagementshouldnotbemodified.(See"Treatmentof
unconjugatedhyperbilirubinemiaintermandlatepreterminfants".)
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortable
withsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
"patientinfo"andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Jaundiceinbabies(TheBasics)")
8/18
1/1/2016
BeyondtheBasicstopics(see"Patientinformation:Jaundiceinnewborninfants(BeyondtheBasics)")
SUMMARY
Totalserum/plasmabilirubin(TB)levels>1mg/dL(17.1micromol/L)occurinalmostallnewborninfantsand
presentasjaundice.Infantswithseverehyperbilirubinemia(TB>25mg/dL[428micromol/L])areatriskfor
bilirubininducedneurologicdysfunction(BIND),presentingacutelyasacutebilirubinencephalopathy(ABE),
andifinadequatelytreated,longtermneurologicsequelae(kernicterus).
Intheneonate,TBvaluesvarybecauseofdifferencesinracialcomposition,breastfeedingpractices,the
prevalenceofhemolyticconditions,andmethodologyofTBmeasurements.InCalifornia,reportedincidences
ofhyperbilirubinemiaforTBvalues>30mg/dL(513micromol/L),>25mg/dL(428micromol/L),and>20mg/dL
(342micromol/L)were0.01,0.14,and2percent,respectively.(See'Epidemiology'aboveand"Evaluationof
unconjugatedhyperbilirubinemiaintermandlatepreterminfants",sectionon'Methodstomeasurebilirubin'.)
Infantsremainatriskforseverehyperbilirubinemiaanditssequelaeofkernicterus,chronicBIND,becauseof
increasedprevalenceofbreastfeedingandearlydischargeofinfantsfromthehospitalwithfailuretosetup
timelyfollowupandinitiatesuccessfulbreastfeeding.(See'Epidemiology'above.)
ThefollowingmajorriskfactorsidentifyinfantsatriskforseverehyperbilirubinemiaandBIND(table1)(see
'Riskfactors'above):
PredischargeTBortranscutaneousbilirubin(TcB)>95thpercentileforage(figure1)
Jaundicewithinthefirst24hoursoflife
Hemolyticdisease
Gestationalage(GA)<37weeks
Siblingwhopreviouslyreceivedphototherapy
Cephalohematomaorsignificantbruising[22]
Exclusivebreastfeeding,particularlyiffeedingisnotgoingwell
EastAsianrace
Clinicalmanifestationsareduetobilirubindepositionintheskin(jaundice)andthebrain.
Jaundiceistheyellowcolorproducedbythedepositionofbilirubinintheskinandsubcutaneoustissues.
Althoughanimportantandtimehonoredclinicalsign,thepresenceofjaundiceisnotareliablemethodfor
assessingtheactualTBconcentrationorforidentifyinginfantsatriskforarapidlyrisingbilirubin,especially
inthosewithdarkskin.Ifjaundiceextendsbelowtheleveloftheumbilicusorifthereisuncertaintyregarding
thepresenceorextentofjaundice,aTBorTcBmeasurementshouldbeperformed.(See'Jaundice'above
and"Evaluationofunconjugatedhyperbilirubinemiaintermandlatepreterminfants".)
BINDcanoccurinotherwisehealthyterminfantswhenTBconcentrationsexceed25mg/dL(428
micromol/L)andismanifestedasABEthatcanbereversibleorresultinkernicterus,achronicpermanent
condition.(See'Neurologicmanifestations'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic4994Version34.0
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1/1/2016
GRAPHICS
Nomogramofhourspecificserumorplasmatotalbilirubin
(TB)concentrationinhealthytermandnearterm
newborns
Thered,blue,andgreenlinesdenotethe95th,75th,and40thpercentiles,
respectively.Riskzonesaredesignatedaccordingtopercentile:high(TB95th),
highintermediate(95th>TB75th),lowintermediate(75th>TB40th),andlow
(TB<40th).Infantswithvaluesinthehighriskzoneareatincreasedriskforthe
developmentofclinicallysignificanthyperbilirubinemiarequiringintervention.
ReproducedwithpermissionfromPediatrics,Vol.114,Pages297316,Copyright2004
bytheAAP.
Graphic70863Version11.0
13/18
1/1/2016
ChangesintheincidenceofextremehyperbilirubinemiaintheUnitedStates
Comparisonoftheincidenceofextremehyperbilirubinemia(totalserumbilirubin>25mg/dL)for302,399
infantsbornatoneoftheIntermountainHealthcare(IMHC)facilitiesfrom2001to2010,historicaldataf
thesevenyearCollaborativePerinatalProjectof41,324singletonwhiteandblackbirthswithbirthweigh
>2.5kginitiatedin1959(priortoavailabilityofphototherapyandmost[85percent]infantswithtotalbi
>20mg/dLweretreatedwithanexchangetransfusion),andfromNorthernCaliforniapopulation(Newma
al)managedsoonaftertheimplementationof1994AmericanAcademyofPediatrics(AAP)Guidelines.
From:BritesD,BhutaniVK.Pathwaysinvolvingbilirubinandotherbraininjuringagents.In:ClinicsinDevelopment
Medicine:Cerebralpalsy:Scienceandclinicalpractice,DanB,MaystonM,PanehtN,RosenbloomL(Eds),MacKeithP
London2014.Copyright2014MacKeithPress.ReproducedwithpermissionofJohnWiley&SonsInc.Thisimage
beenprovidedbyorisownedbyWiley.FurtherpermissionisneededbeforeitcanbedownloadedtoPowerPoint,print
sharedoremailed.PleasecontactWiley'spermissionsdepartmenteitherviaemail:permissions@wiley.comoruseth
RightsLinkservicebyclickingonthe'RequestPermission'linkaccompanyingthisarticleonWileyOnlineLibrary
(http://onlinelibrary.wiley.com).
14/18
1/1/2016
Riskfactorsfordevelopmentofseverehyperbilirubinemiaininfants
of35ormoreweeksgestation(inapproximateorderofimportance)
Majorriskfactors
PredischargeTBorTcBlevelinthehighriskzone
Jaundiceobservedinthefirst24hours
Bloodgroupincompatibilitywithpositivedirectantiglobulintest,otherknownhemolyticdisease
(eg,G6PDdeficiency),elevatedETCOc
Gestationalage35to36weeks
Previoussiblingreceivedphototherapy
Cephalohematomaorsignificantbruising
Exclusivebreastfeeding,particularlyifnursingisnotgoingwellandweightlossisexcessive
EastAsianrace*
Minorriskfactors
PredischargeTBorTcBlevelinthehighintermediateriskzone
Gestationalage37to38weeks
Jaundiceobservedbeforedischarge
Previoussiblingwithjaundice
Macrosomicinfantofadiabeticmother
Maternalage25years
Malegender
Decreasedrisk(thesefactorsareassociatedwithdecreasedriskof
significantjaundice,listedinorderofdecreasingimportance)
TBorTcBlevelinthelowriskzone
Gestationalage41weeks
Exclusivebottlefeeding
Blackrace*
Dischargefromhospitalafter72hours
TB:totalserumorplasmabilirubinTcB:transcutaneousbilirubinG6PD:glucose6phosphate
dehydrogenaseETCOc:endtidalcarbonmonoxideconcentration.
*Raceasdefinedbymother'sdescription.
ReproducedwithpermissionfromPediatrics,Vol.114,Pages297316,Copyright2004bytheAAP.
15/18
1/1/2016
Recommendedtimingoffollowupvisitsfortermandnearterm
infants(>35weeksgestation)
Ageinfantdischarged
Timingoffollowupvisit*
Lessthan24hoursofage
72hours
Between24and47.9hoursofage
96hours
Between48and72hoursofage
120hours
*Earlierfollowupvisitsandperhapsmorefrequentvisitsarerequiredforinfantswhohaveriskfactors
forhyperbilirubinemia.Ifappropriatefollowupcannotbeensured,especiallyininfantswithanincreased
riskforseverehyperbilirubinemia,thendischargeshouldbedelayeduntilappropriatefollowupcanbe
ensuredortheperiodofgreatestriskhaspassed(72to96hours).
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Jaundicenewborn
A)Physiologicjaundice.B)Pressingthecolorfromtheskinallowsbetter
recognitionoftheyellowofjaundice.Infantwithbilirubinlevelof13mg/dL.C)
Infantwithnoappreciablejaundiceatchestlevel.
A)Reproducedwithpermissionfrom:O'DohertyN.AtlasoftheNewborn,JB
Lippincott,Philadelphia1979.Copyright1979LippincottWilliams&Wilkins.
BandC)Reproducedwithpermissionfrom:FletcherM.PhysicalDiagnosisinNeonatology,
LippincottRavenPublishers,Philadelphia1998.Copyright1998LippincottWilliams&
Wilkins.
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Disclosures
Disclosures:RonaldJWong,BANothingtodisclose.VinodKBhutani,MD,FAAPNothingtodisclose.StevenAAbrams,MD
Grant/Research/ClinicalTrialSupport:MeadJohnson,Nutrition[PediatricNutrition(Infantformulas)].Consultant/AdvisoryBoards:
MilkPrep[dairyproducts(fluidmilk)].MelanieSKim,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthrougha
multilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferenced
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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Clinical Manifestations of Unconjugated Hyperbilirubinemia in Term and Late Preterm Infants

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