Etiology and Pathogenesis of Neonatal Encephalopathy

12/9/2015
Etiologyandpathogenesisofneonatalencephalopathy
OfficialreprintfromUpToDate
www.uptodate.com2015UpToDate
Authors
SidharthaTan,MD
YvonneWu,MD,MPH
SectionEditors
DouglasRNordli,Jr,MD
LeonardEWeisman,MD
DeputyEditor
JohnFDashe,MD,PhD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2015.|Thistopiclastupdated:Jul10,2014.
INTRODUCTIONNeonatalencephalopathyisaheterogeneoussyndromecharacterizedbysignsofcentral
nervoussystemdysfunctioninnewborninfants.Clinicalsuspicionofneonatalencephalopathyshouldbe
consideredinanyinfantexhibitinganabnormallevelofconsciousness,seizures,toneandreflexabnormalities,
apnea,aspiration,feedingdifficulties[1,2],andanabnormalhearingscreen.
Thistopicwillreviewtheetiologyandpathogenesisofneonatalencephalopathy.Otherclinicalaspectsofthis
syndromearediscussedseparately.(See"Clinicalfeatures,diagnosis,andtreatmentofneonatal
encephalopathy".)
TERMINOLOGY"Neonatalencephalopathy"hasemergedasthepreferredtermtodescribecentralnervous
systemdysfunctioninthenewbornperiod[2,3].TheAmericanCollegeofObstetriciansandGynecologists
(ACOG)describesneonatalencephalopathyasaclinicallydefinedsyndromeofdisturbedneurologicfunctioninthe
earliestdaysoflifeinaninfantbornatorbeyond35weeksofgestation,manifestedbyasubnormallevelof
consciousnessorseizures,andoftenaccompaniedbydifficultywithinitiatingandmaintainingrespirationand
depressionoftoneandreflexes[4].
Theterminologydoesnotimplyaspecificunderlyingpathophysiology,whichisappropriatesincethenatureof
braininjurycausingneurologicimpairmentinanewbornispoorlyunderstood.Whileneonatalencephalopathywas
onceautomaticallyascribedtohypoxiaischemia[5],itisnowknownthathypoxiaischemiaisonlyoneofmany
possiblecontributorstoneonatalencephalopathy.Whetheraparticularnewborn'sencephalopathycanbe
attributedtohypoxicischemicbraininjuryisoftenunclear.
Someinvestigatorsrequirestringentcriteriaforusingthetermneonatalencephalopathy,suchastwoormore
symptomsofencephalopathylastingover24hours[6],whileothersrequirenomorethanalowfiveminuteApgar
score[7].However,theuseofApgarscoresaloneisproblematic,asApgarscoresmaybelowduetomaternal
analgesiaorprematurity,orcanbenormalinthepresenceofacutehypoxiaischemicinjury.
Neonatalencephalopathyusuallyreferstocentralnervoussystemdysfunctionintermandnearterminfants,but
forthepurposesofthisreview,encephalopathyofthepreterminfanthasalsobeenincluded.
Whenneonatalencephalopathyisindisputablyduetohypoxicischemic(anoxic)braininjury(see'Hypoxic
ischemicinjury'below),itisappropriatetousethetermhypoxicischemicencephalopathy(HIE)[8].Sincethe
precisecauseandtemporalonsetofneonatalencephalopathyisunknowninmostcases,someexpertsadvocate
callingtheconditionpresumedHIEorapparentHIEwhentheclinicalfeaturesandneonatalbraininjurypatterns
onMRIsuggestthatHIEisthemostlikelymechanism[9].Othersfavorusingthenonspecifictermneonatal
encephalopathywheneverthereisdoubtastotheunderlyingmechanismofinjury[3].Itremainstobeestablished
whetherneuroimagingorothertestingcanonedaybeusedasagoldstandardfordeterminingwhenprenatal
hypoxia,birthasphyxia,orhypoxicischemicbraininjuryisresponsibleforneonatalencephalopathy.(See"Clinical
features,diagnosis,andtreatmentofneonatalencephalopathy".)
TimingofinsultAcommonbutcrucialproblemistheinabilitytotimetheonset,duration,magnitude,andthe
singleorrepetitivenatureoftheexactinsultthatcausesbraininjuryresultinginneonatalencephalopathy.Thisis
animportantpointtoconsiderinviewofneuroprotectivetherapiessuchashypothermia.Theuncertaintimingand
http://www.uptodate.com/contents/etiologyandpathogenesisofneonatalencephalopathy?topicKey=PEDS%2F6205&elapsedTimeMs=5&source=search_res
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etiologyofbraininjuryinmostcasesofneonatalencephalopathyalsofuelsbirthinjurymalpracticelitigation.
Malpracticecases,andtoooftenclinicians,typicallyfocusoneventsaroundthetimeofdelivery,whichhappens
tobethetime(hours)whenthemajorityofdatafrompregnantwomenareobtained,whereastherestofpregnancy
isrelativelyunmonitored[5].However,itisusuallyunknownwhethertheultimatebraininjuryiscausedbythe
eventsonlyarounddeliveryorbycumulativeinsultsthroughoutpregnancy.
Thedefinitionofasphyxiais"aconditionofimpairedbloodgasexchangeleading,ifitpersists,toprogressive
hypoxemiaandhypercapnia.Diagnosisrequiresabloodgas[10].However,evenwithstateofartmonitoring,
thereispresentlynoreliablemeasureofbrainfunction,brainoxygenation,orcerebralbloodflowduringthe
prenatalperiodorevenintheintrapartumperiod.Therefore,theterms"birthasphyxia"and"fetaldistress"arenot
alwaysusedappropriately[11].
DatafromstudiesofneonatalencephalopathyusingbrainMRI,nearinfraredspectroscopyand
electroencephalogrammonitoringsuggestthattheimmediateperinatalperiodisimportantforevolutionofbrain
injuryinmanycases[12].Onereportevaluated351terminfantswitheitherneonatalencephalopathy(definedas
thepresenceofabnormaltone,feedingdifficulties,alteredalertness,andatleastthreeofseveralcriteria
suggestingpossibleperinatalhypoxicischemia)orseizuresaloneduringthefirstthreedaysoflife[13].BrainMRI
wasperformedinthefirstonetotwoweeksafterbirth.
Inthegroupwithencephalopathy,lesionssuggestiveofacutebraininjurywerefoundin80percentmostof
thelesionswerebilateralabnormalitiesinbasalganglia,thalami,cortex,orwhitematter,althoughfocal
infarctionwasdetectedineightinfants.
Inthegroupwithonlyneonatalseizures,acuteischemicorhemorrhagicstrokeswerefoundin69percent.
Clinicalsignsthatpointtoanearlyantenatalonsetofneonatalencephalopathyincludeintrauterinegrowth
restriction,smallheadsize(ifbothheadandbodysizearesmallthentheinsultcouldbeinthefirsttwotrimesters
ofpregnancy),contractures,andfeaturessuggestiveofarthrogryposis.(See'Riskfactors'below.)
RISKFACTORSFewstudieshaveadequatelyevaluatedriskfactorsforneonatalencephalopathyotherthan
hypoxiaischemia.Thestudiesevaluatingprenatalandobstetricfactorsoftenincludesymptomsbutnot
pathogeniceventsthatcouldprovideinformationregardingthetimingofthehypoxicischemicevent.Epidemiologic
populationstudiesofneonatalencephalopathytypicallylackbrainMRIdatatodeterminethepresenceanddegree
ofbraininjury,andalsolackinformationregardinglongtermoutcomes.Incontrast,studiesofneonatal
encephalopathythatdoincludeneuroimagingdataarerarelypopulationbased,andareunderpoweredtodetermine
theeffectofabroadrangeofmaternalantenatalriskfactors.
InalargepopulationbasedcohortofcasesofneonatalencephalopathyfromWesternAustralia,69percent
hadonlyantepartumriskfactors,25percenthadbothantepartumandintrapartumriskfactors,4percenthad
evidenceofonlyintrapartumhypoxia,and2percenthadnoidentifiedriskfactors[14].Thus,approximately
70percentofneonatalencephalopathycaseswereassociatedwitheventsarisingbeforetheonsetoflabor
[15].
Similarly,inaregistryofover4100infantswithneonatalencephalopathy,46percenthadfetalriskfactors
and27percenthadmaternalriskfactorspredatingtheonsetoflabor,whileonly15percenthadaclinically
recognizedsentineleventcapableofcausingasphyxia(35percentiffetalbradycardiawasincludedasan
indicator)[16].
InacasecontrolstudyfromtheUK,405terminfantswithencephalopathywerecomparedwith239
neurologicallynormalinfants[17].Overall,7percentofcaseshadonlyantepartumfactors,20percenthad
onlyintrapartumfactors,70percenthadbothantepartumandintrapartumfactors,and4percenthadno
identifiableriskfactorsforthedevelopmentofneonatalencephalopathy.Limitationsofthisstudyinclude
potentialbiasrelatedtodifferencesinthepopulations(eg,comparedwithcontrols,caseswerefromdifferent
yearsofcollection,hadagreaterincidenceofintrauterinegrowthrestrictionandtwinning,andweremore
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likelytohavemotherswhowereyounger,primipara,andofnonCaucasianorigin),theexclusionofinfection,
theabsenceofplacentaldata,theabsenceofadiagnosisofchorioamnionitis,andinclusionofsome
questionableintrapartumfactorssuchasinducedlaborandvariabledecelerations.
AcasecontrolstudyfromItalycompared27terminfantswithneonatalencephalopathyand100control
infants,suggestingacombinationofantepartumandintrapartumeventsexplainmoderatetosevereneonatal
encephalopathy[18].Comparedwithcontrols,neonateswithencephalopathyhadmorefrequentantepartum
(74percentversus18percent)andintrapartum(67percentversus19percent)riskfactors,includingacute
intrapartumevents(33percentversus2percent).Onthewhole,26percentofcasesofNEhadonly
antepartumriskfactors,22percenthadonlyintrapartumriskfactors,and,and44percenthadacombination
ofthetwo.
InacasecontrolstudyinIrelandthatcompared237terminfantswithneonatalencephalopathywith489
controlinfants,variablesindependentlyassociatedwithneonatalencephalopathyincludedmeconium,
oligohydramnios,andobstetriccomplications,suggestinginvolvementofacombinationofantepartumand
intrapartumriskfactors[19].
Thedisparateresultsofthesereportsarelikelyduetoseveralreasons,includingdifferentinclusion/exclusion
criteriaamongthestudiesandtheassessmentofvariablesthatdonotnecessarilyleadtocriticalbraininjury(eg,
shoulderdystocia,meconiumaspiration,andabnormalfetalheartraterhythmsareominousonlyifassociatedwith
fetalhypoxia,whichisrare).
AntepartumMostcasesofneonatalencephalopathyhavetheirantecedentsintheprenatalperiod.Itis
unknownwhetherneonatalencephalopathyoccursasaresultofasingleinsult(suchashypoxiaischemia),
multipleinsults(eg,infectionplushypoxiaischemia),orcombinationsofacuteorchronicconditions.Incaseswith
multipleinsults,itispossiblethattheoneclosesttobirthmightbeonlyaminoreventthattipsthebalanceto
irreversibleinjury.
Thehighestqualitypopulationbasedstudythatevaluatedriskfactorsforneonatalencephalopathycompared164
infantswithneonatalencephalopathyand400randomlyselectedcontrolsfromterminfantsborninWestern
Australia[6].Thestudyidentifiedanumberofantepartumriskfactorscanbegroupedundercategoriesbasedon
thematernalplacentalfetalunit(figure1):
Maternal
Preconceptualfactorsincludingmaternalunemployment,familyhistoryofseizuresorneurologic
disorder,andinfertilitytreatment
Maternalthyroiddisease
Placental
Severepreeclampsia
Postdates
Abnormalappearanceoftheplacenta
Fetal
Intrauterinegrowthrestriction
Amongtheseantepartumriskfactors,intrauterinegrowthrestriction(IUGR)wasthestrongest(relativerisk[RR]
38.2,95%CI9.4154.8)[6].AlthoughmostbabieswithneonatalencephalopathydonotmeetthecriteriaofIUGR,
asmallhospitalbasedcasecontrolstudyfoundthatagreaterproportionofinfantswithneonatalencephalopathy
werebelowthe10thpercentileofgrowthpotentialcomparedwithcontrols,andthedifferencewasstatistically
significant[20].Thesestudiessuggestthatthereareantenatalfactorscontributingtothebraininjury.
Unfortunately,IUGRprovidesnocluetotheetiology(figure2)becausebothexternalmaternalandplacental
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factorscanaffectfetalgrowthinadditiontointrinsicfactors.
Placentalthrombosis,infection,anddisturbeduteroplacentalflowhavealsobeenassociatedwithneonatal
encephalopathy.
Inahospitalbasedcasecontrolstudycomparing93casesofneonatalencephalopathyto387controls,
placentalfindingsoffetalthromboticvasculopathy,funisitis,andacceleratedvillousmaturationwere
independentlyassociatedwithneonatalencephalopathy[21].
Anotherstudyfoundthatthefrequencyofsevereplacentallesionswasfivefoldhigheramong83casesof
neonatalencephalopathyfromamedicolegalregistrythanamong250controls(52to10percent).These
lesionsincludedfetalthromboticvasculopathy,chronicvillitiswithobliterativefetalvasculopathy,
chorioamnionitiswithseverefetalvasculitis,andmeconiumassociatedfetalvascularnecrosis[22].
Inaretrospectivestudyof100termnewbornswhoreceivedhypothermiatherapyforneonatal
encephalopathy,placentalabnormalitiesweremorecommonamongnewborns(n=49)whodidnothavea
sentinelevent(ie,aclinicalhistoryofdisruptionofbloodflowtothefetusduringdelivery)suchasplacental
abruption,uterinerupture,tightnuchalcordorcordprolapse[23].Asanexample,aninflammatorypathology
wassignificantlymorefrequentininfantswithoutsentinelevents(43percent,versus14percentforinfants
withsentinelevents).
Mostoftheplacentallesionsresultinsomeformofhypoxicischemicdamage.Itissuspectedthatboththe
placentalvasculopathiesandinflammationcancausesynergisticinjurywhencombinedwithhypoxiaischemia.
Placentallesionsmayunderliethefindingofsomestudiesthat>41weeksgestationisanantepartumriskfactor
[17].
IntrapartumIntrapartumriskfactorsforneonatalencephalopathycanbegroupedasfollows[14,16,17]:
Persistentoccipitoposteriorposition
Shoulderdystocia
Emergencycesareandelivery,whichmayincludefailedvacuum
Operativevaginaldelivery
Acuteintrapartumeventsorsentinelevents(eg,uterinerupture,placentalabruption,cordprolapse,tight
nuchalcord,maternalshock/death)
Inflammatoryevents(eg,maternalfever,chorioamnionitis,prolongedruptureofmembranes)
Anacuteintrapartumevent,suchasaplacentalabruptionoruterinerupture,conferredafourfoldincreasedriskof
neonatalencephalopathy,butwaspresentinonly8percentofinfantswithneonatalencephalopathy[14].Uterine
rupturealoneisassociatedwithonlya2to3percentincidenceofneonataldeathbuta6to23percentneonatal
encephalopathy[24,25].Intheseriesof158medicolegalcerebralpalsycases,sentinelintrapartumeventswere
presentin11percent[26].
Outcomesinanotherstudyofbirthsentineleventswithaminimumof12monthsfollowupincludeddeathin20
percent,cerebralpalsyin41percent,developmentaldelayin15percent,andnormaldevelopmentin24percent
[27].Thelattertwonumberssuggestthatplasticityandrepairresponsesoftendetermineoutcometowelldefined
singleinsults.
Someofthesocalledintrapartumriskfactorsincludeobstetrictreatmentstopreventfurtherfetalhypoxia,suchas
emergencycesareandeliveryandoperativevaginaldelivery.Thesemayormaynotbetrueriskfactorsdepending
uponthedurationoftheunderlyinginsult.Inaddition,increaseddurationofsecondstageoflaborrelatedto
shoulderdystociaorfailedvacuummaynotnecessarilyresultincriticalbraininjuryunlessaccompaniedbyfetal
hypoxia.
Someinflammatoryfactors,suchasprolongedruptureofmembranes,mayexertapathogenicinfluenceeven
beforeterminallabor.Theimportanceofinflammationasariskfactorforneonatalencephalopathyisillustratedby
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thefollowingreports[28]:
Inapopulationbasedreportthatcompared1060newborncasesofneonatalencephalopathywith5330
unaffectedcontrolnewborns,independentriskfactorsforneonatalencephalopathywereisolatedintrapartum
maternalfever(RR3.1,95%CI2.34.2)andchorioamnionitis(RR5.4,95%CI3.67.8)[29].
Inacohortstudythatidentified25casesofmoderatetosevereneonatalencephalopathyfrom8299term
births,maternalfeverhadasixfoldincreasedriskofneonatalencephalopathycomparedtoa12foldincrease
foracidosis[30].Althoughtherewasamultiplicativeincreasedriskwithacidosis(76fold),theeffectof
maternalfeverseemedtohavenostatisticalinteractionwithacidosis,implyingthatmaternalfeverand
acidosisrepresentdifferentcausalpathways.
Inaprospectivestudyofinfantsexposedtomaternalchorioamnionitis,therewasathreefoldincreasein
neonataldepressionandneonatalintensivecareunitadmissionfornewbornswithelevatedtemperature[31].
Otherstudieshavefoundthatmaternalfever,oftenaccompaniedbyadiagnosisofchorioamnionitis,isassociated
withlowApgarscores,neonatalseizures,andadiagnosisof"birthasphyxia"amonginfantswhodevelopcerebral
palsy[32,33].
Aninteractionbetweenbraininjuryduetoinflammationandhypoxiaischemiahasbeensuggestedbythefindingin
acasecontrolstudyofanassociationbetweenmaternalchorioamnionitisandcerebralpalsyinchildrenwith
evidenceofhypoxicischemicbraininjury[34],andbytheobservationofincreasedcytokinesinthecerebrospinal
fluidofpatientswithneonatalencephalopathy[35].
Theneedforresuscitationinthedeliveryroomisitselfapoorprognosticsignasitisassociatedwithanincreased
riskateightyearsofageofhavingalower(<80)IQscore,eveniftheinfantdoesnotexhibitencephalopathyin
thenewbornperiod(oddsratio1.65,95%CI1.132.43)[36].
Hypoxiaischemiacanresultinfetalheartrateabnormalitiesandumbilicalacidemia,whichareoftencitedasrisk
factors,moresointhelegalperspective.Fetalheartratevariablesarenotconsideredasgoodasumbilicalcord
acidemiaforestimationoftimingofbirthinsults[18,37]althoughbothhavedeficiencies.Thecorrelationoffetal
heartrateabnormalitieswithumbilicalacidemiamayhaveastrongerassociationwiththepresenceofintrauterine
vasculardisease(ie,preeclampsia,placentalabruption,birthweight<10thpercentile,orhistologicevidenceof
placentalinfarctionorseverevascularpathology)thanwithacuteintrapartumevents[38].Neurologicmorbidities
anddeatharesignificantlymorecommoninnewbornswithapH<7.0thaninthosewithapH7.0,butthe
majorityofacidemicneonatesdonothaveanymajormorbidity[37].
HYPOXICISCHEMICINJURYAsnotedearlier,itisappropriatetousethetermhypoxicischemic
encephalopathy(HIE)whenneonatalencephalopathyisduetohypoxicischemicbraininjury.(See'Terminology'
above.)
ThesignsandsymptomsofHIE,aswellasoutcome,dependuponseveralfactors:
Theimmediatenervoussysteminjurysustainedduringthehypoxicischemicinsult
Physiologicpropertiesthatleadtoselectivevulnerabilitiesofcertaincellpopulations
Thepresenceofendogenousprotectivemechanisms
Consequencesofhypoxiaischemiathatleadtosecondaryinjuries(eg,reperfusioninjury,edema,increased
intracranialpressure,abnormalitiesofautoregulation,andhemorrhage)
Hypoxiacanresultfromischemia(ie,alackofsufficientbloodflowtoallorpartofanorgan),insufficientinspired
oxygen,orinadequatebloodoxygencarryingcapacity(eg,inadequateoxygenininspiredair,severeanemia,
carbonmonoxidepoisoning).Regardlessofthecause,cardiacandvascularcompromiseultimatelyoccurwhen
hypoxiaisprolonged.Theresultishypotension,ischemia,andanaerobicmetabolismleadingtolacticacidosis.
Thus,ischemiaisbothacauseandaresultofhypoxiaandcompoundsthecomplicationsofhypoxiabyimpairing
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theremovalofmetabolicandrespiratorybyproducts(eg,lacticacid,carbondioxide).
FetalhypoxicischemicbraininjuryandsubsequentHIEcanoccurbyoneormoreofthefollowingmechanisms
(table1):
Maternal,viaimpairedoxygenation(eg,asthma,pulmonaryembolism,pneumonia)orinadequateperfusionof
maternalplacenta(eg,cardiorespiratoryarrest,maternalhypotension,preeclampsia,chronicvascular
disease)
Placental,viaabruptioplacenta,tightnuchalcord,cordprolapsed,trueknot,oruterinerupture(see
"Placentalpathologyincasesofneurologicallyimpairedinfants")
Fetal,viaimpairedfetaloxygenation/perfusion(eg,fetomaternalhemorrhage,fetalthrombosis)
AntecedenteventsandriskfactorsBraininjuryfromHIEmayoccurbeforetheonsetoflabor.Supporting
evidencecomesfromaneuropathologicstudyof70infantswhodiedwithinsevendaysofbirth[39].Usingcriteria
oflowfiveminuteApgarscoreandumbilicalcordorinitialbloodgaspH<7.1forasphyxia,findingsconsistentwith
braindamagebeforetheonsetoflaborwerepresentinallasphyxiatedandencephalopathicinfants.Inaddition,
thesamefindingswerepresentin38percentofterminfants,52percentofpreterminfants,and1of12infants
withoutanyevidenceofbirthasphyxia.
ThisreportrevealsthatsomecasesofHIEdiebeforemanifestingbraininjuryorclinicalsignsofneonatal
encephalopathy[39].Inaddition,braininjuryassociatedwithHIEmaybepresentwithoutclinicalsignsofneonatal
encephalopathy.However,therearelimitationstoextrapolatingfindingsfromautopsystudiesinthatthenatureof
death,failedresuscitation,andterminaldrugsarenotcontrolledforinmostinstances.
AmajorriskfactorforHIEisthatofmultiplegestations,particularlythepresenceofmonochorionictwins.Astudy
ofpreterminfantsofmultiplegestationsfoundthattheincidenceofantenatalwhitematternecrosisoncranial
ultrasoundwassignificantlyhigherinmonochorionicthanindichorionicinfants(30vs3.3percent)[40].
InpreterminfantsmeetingcriteriaforHIE,placentalabruptionismorelikelytobeidentifiedastheantecedent
event[41]thanuterineruptureandcordprolapse,whicharemorecommonsentineleventsamongterminfants
diagnosedwithHIE[27].Inpreterminfants,HIEisassociatedwithinjuryon36weekMRIscaninvolvingthe
basalganglia(mostlysevere),whitematter(mostlymild),brainstem,andcortexin75,89,44and58percent,
respectively[41].
Thesestudiesemphasizetheimportanceofearlybrainimagingindocumenting,andpossiblytiming,brainlesions,
aswellastheimportanceofpostmortemexaminationsincasesofstillbirthandneonataldeaths.(See"Clinical
features,diagnosis,andtreatmentofneonatalencephalopathy".)
AcuteeventsDeterminingwhetheranacutehypoxicischemiceventcontributedtoneonatalencephalopathyis
challenging,sincethereisnogoldstandard.Thevariousclinicalsignsofhypoxicischemicencephalopathy,
includinglowApgarscores,lowcordpH,neonatalseizuresandencephalopathy,arenonspecificandmayoccurin
theabsenceofglobalhypoxicischemicbraininjuryorlongtermneurologicsequelae.Aconsensusstatementfrom
theAmericanCollegeofObstetriciansandGynecologists(ACOG)notesthatneonatalencephalopathyrelatedto
acutehypoxiaischemiaispresumedtobeassociatedwithabnormalneonatalsignsandcontributingevents,in
closetemporalproximitytolaboranddelivery,thatareconsistentwithanacutehypoxicischemicevent[4].
Markersthatarehelpfulfordeterminingthelikelihoodthatanacuteperipartumorintrapartumhypoxicischemic
eventcontributedtothedevelopmentofneonatalencephalopathyareasfollows(table2):
Neonatalsignsconsistentwithanacuteperipartumorintrapartumevent:
Apgarscoreof<5at5minutesand10minutes
FetalumbilicalarterypH<7.0,orbasedeficit12mmol/L,orboth
AcutebraininjuryseenonbrainMRIormagneticresonancespectroscopyconsistentwithhypoxia
ischemia
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Presenceofmultisystemorganfailureconsistentwithhypoxicischemicencephalopathy
Contributingfactorsconsistentwithanacuteperipartumorintrapartumevent:
Asentinelhypoxicorischemiceventoccurringimmediatelybeforeorduringlaboranddelivery
Fetalheartratemonitorpatternsconsistentwithanacuteperipartumorintrapartumevent
Braininjurypatternsbasedonimagingstudiesconsistentwithanetiologyofanacuteperipartumor
intrapartumevent
Noevidenceofotherproximalordistalfactorsthatcouldbecontributing
Developmentaloutcomeisspasticquadriplegiaordyskineticcerebralpalsy
LevelanddurationofhypoxiaischemiaThelevelofhypoxiaischemiathatcausesneonatalencephalopathy
isunknown,butanimalstudiesprovidesomeinformation.Therearetwoexperimentalparadigmsthatpresentwith
differentpathophysiologicalpathways:umbilicalcordocclusionandacuteplacentalinsufficiency.
Occlusionoftheumbilicalcordresultsincardiovascularcompromisebecauseoftheremovalofalow
resistivevascularbed
Insheep,fetusescansurviveupto30minutesofocclusionwithincreasingbraindamageobservedinterm
sheepcomparedtoprematuresheepfetuses[42],while20minuteocclusionmaynotcauseanybraininjury
[43]
Innonhumanprimates,itwaslongbelievedthatpermanentneurologicinjuryoccurredwithocclusionof12to
17minutes[44,45]
Theclinicalcorollaryofumbilicalcordprolapsehasamorevariedresponse,probablybecauseofthepresenceof
somebloodflowintheprolapsedcord.Inhumans,umbilicalcordprolapseisanobstetricemergencyexceptfor
theextremeprematuregestationmother.Inachartreviewof87casesofcordprolapseamong36,500deliveries,
themediantimefromdiscoverytodeliverywas15minutes,withthelongestbeing14hours[46].Therewasno
relationbetweentimeofdiscoverytodeliveryandpostnatalmortalityormorbidity[46].Thelongesttoleratedtime
ofumbilicalcordprolapsewithoutmajorconsequencesthreedayswasobservedinanextremelypremature
infant[47],suggestingthatthedurationbecomescriticalonlynearterm.
Acuteplacentalinsufficiencyresultsinfetalcompromiseduetoimpairedabilitytoexchangegasand
nutrients.
Astudyofacuteplacentalinsufficiency(viauterineischemia)inrabbitsat70percentgestationfoundthat
animalssubjectedto30minutesofglobalhypoxiaischemiawerenodifferentthancontrols[48].However,40
minutesofglobalhypoxiaischemiaincreasedfetalmortalityfrom0to25percent,andincreasedmarked
motordeficitsatbirthinthesurvivorsfrom0to75percent[48].Inapopulationofnormalfetuses,the
susceptibilitytoinjuryisnotdependentsolelyonthedurationofhypoxiaischemia.Rabbitfetusesat79
percentgestationundergoingadditionalreperfusionreoxygenationinjuryjustafterthecessationofhypoxia
ischemiahaveagreaterchanceofmotordeficitsthatinthosewithoutreperfusionreoxygenationinjury[49].
Whenexperimentalglobalhypoxiaischemiaismildandchronic,itresultsinintrauterinegrowthrestrictionbut
mayormaynotresultinbraininjury[50,51].
Unfortunately,theonsetofacuteplacentalinsufficiencystatessuchasplacentalabruptioninhumansisalmost
alwaysunknown.
ThespectrumofhypoxicischemicinjuryandoutcomecanbesummarizedasintheFigure(figure3).Theintensity
oftheinsultcanbemodifiedbyprioreventsthatmayserveasapreconditioningstimulus.Also,thereisa
complexinteractionofinfectionwithhypoxiaischemia.Asanexample,preeclampsiamaybeaprotectivefactor
forinfantsborntomotherswithchorioamnionitisandatriskforcerebralpalsy[52].
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VulnerableregionsofdevelopingbrainHypoxiaischemiamayhavedeleteriouseffectsonvulnerablecell
populationspeculiartothedevelopmentalstage(figure4),causingdiscreteinjuriesthatcouldalsoaffectseizure
thresholdorcognition.
Lateoligodendroglialprogenitorsarevulnerabletoinjuryinearlyprematuritywithresultingpredominantwhite
matterinjuryinprematureinfants[53].
Inthetermneonatewithischemicbraininjury,however,certainneuronsinthedeepgraynucleiand
perirolandiccortexaremostlikelytobeaffected.Acutecellinjurycantriggercontinuinglossofcells.There
areneuralglialcellinteractionsthatcanincreasethebraininjury.Selectivedamagetoneuronsinthe
subcorticalgraymattercandirectlycontributetolongtermapoptosisindistalneuronalstructures.
BothgrayandwhitematterinjuryoccurinpretermandtermneonateswithHIE.Earlydetectionofrecenthypoxic
ischemicinsultsdependsuponapparentdiffusioncoefficient(ADC)measurementsonMRI.Beyondaweekafter
theonsetoftheinsult,evidenceofgraymatterinjurybyneuroimagingisscantunlessthereisasignificant
decreaseinvolumeofgraymatterregionsoranincreaseinventricularsizeorobviousinfarctsandhemorrhage.
Whitematterinjuryissomewhateasiertodetectbydiffusiontensorimaging(DTI),asthefractionalanisotropyof
whitematterbundlesnormallyincreasewithage,leadingtoanabilitytodetectminordecreasesinfractional
anisotropyinWMregions.However,whileDTIisperformedatsometertiarycenters,itisnotyetwidelyavailable
inclinicalpractice.
MechanismsofneuronalinjuryHypoxiaischemiainitiallycausesenergyfailureandlossofmitochondrial
function.Thisisaccompaniedbymembranedepolarization,brainedema,anincreaseofneurotransmitterrelease
andinhibitionofuptake,andanincreaseofintracellularcalciumthatsetsoffadditionalpathologiccascades[54].
Theseincludeoxidativestress,withtheproductionofreactiveoxygenspeciesandinteractionwithnitricoxide
pathwaytoproducereactivenitrogenspecies[55].
Itwasoncebelievedthatreactivespeciescauseddamageonlyifantioxidantdefenseswereoverwhelmed,thus
upsettingthebalancebetweenoxidantsandantioxidants.However,itisnowrealizedthattheinteractionitself
betweenreactivespeciesandantioxidantdefensesultimatelycausescellularinjuryanddeath(ie,theyinyang
theoryofbothbeingnecessary)[56].Reperfusionexacerbatestheoxidativestresswithaburstofreactiveoxygen
species.
Theresponseofthefetustothehypoxicischemicinsultdeterminesthesubsequentinjuriouscascadesandthe
clinicalmanifestationsthatresult.Onestudymonitoredtheresponseofrabbitfetusbrainsinuterotoglobal
hypoxiausingMRIdiffusionweightedsequencesandapparentdiffusioncoefficient(ADC)mappingasamarkerof
ischemicinjury[57].FetusesthatshowedaprecipitousdropinbrainADCattheendof40minutesofglobal
hypoxiamanifestedhypertoniaandposturalchangesafterbirth,whilethosewithoutadropinADCwererelatively
normalatbirth.Thus,afterthehypoxicischemicinsult,theinitialenergyfailureandoxidativestressprobablyplay
acriticalroleinsubsequentcascades(figure5)[49].
ExcitotoxicinjuryExcitotoxiccellularinjuryoccursviaexcessactivationofglutamatereceptors,which
leadstoseveralformsofcelldeath.Therearefourreceptortypesforglutamate[58],whicharetheNmethyld
aspartate(NMDA),alphaamino3hydroxy5methyl4isoxazoleproprionicacid(AMPA),kainate,andmetabotropic
glutamatereceptors.Themetabotropicreceptorsarenotdirectlycoupledtoionchannels.
TheNMDAreceptorsarethemostavidandphysiologicallyactive.ThechannelsactivatedbyNMDA
receptorsarevoltagedependentandcalciumpermeable.Theiractivationcausesneurondepolarization[59].
Repeateddepolarizationofaneuronbyunregulatedglutamatereleaseresultsinaccumulationofintracellular
calcium.Duringhypoxiaischemia,thereisfailuretorapidlypumpsynapticallyreleasedglutamateback
acrossthecellmembrane,resultinginexposureofNMDAreceptorstoaccumulatedglutamate,whichleads
tolethalelevationofintracellularcalciumlevels.Thecascadeofeventsinitiatedbythisprocessalsocan
induceapoptosis[60].
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AMPAandkainatereceptorsarebothcoupledtosodiumandpotassiumionchannels.WhereasNMDA
receptorsarealwayspermeabletoCa(2+),cationpermeabilityofAMPAreceptorsdependsonsubunit
composition.Ca(2+)influxisdifferentiallyregulatedbyAMPAreceptorscomparedtokainatereceptors.
Oligodendrogliaareparticularlyvulnerabletoglutamate[61].PreoligodendrocytesubtypesO4andO1+express
subunitsforboththeAMPA(GluR1,GluR2,GluR3,andGluR4)andkainate(KA1,GluR5/6,andGLuR7)receptors
butnotNMDAreceptors,whereasmatureMBP+oligodendrocyteshavelittletonoexpressionofeitherNMDA
receptorsornonNMDAreceptors.
Matureoligodendrocytesinmixedcoculturesdieafterexposuretokainate,butAMPAreceptorsarethemost
importantmediatorsofcellulardemise,withkainatereceptorsplayingasmallerrole[62].Inthisparadigm,cell
deathoccurspredominantlybynecrosis,notapoptosis[62].However,thereisevidencethatmature
oligodendrocytesexpressingmyelinbasicproteinareresistanttoexcitotoxicinjuryproducedbykainate,whereas
earlierstagesintheoligodendrocytelineagearevulnerabletothisinsult[63].
NitricoxideandoxygenfreeradicalsNitricoxide(NO)andoxygenfreeradicalsappeartoplayimportant
rolesinbraininjuryinducedbyhypoxiaischemia.
Nitricoxidecanbehaveasanoxidantaswellasanantioxidant.UnderpathologicalconditionsthereisexcessNO
productionthatresultsincelltoxicitythroughdirectbiochemicaleffectsorthroughreactivenitrogenspeciesthatis
formedfromthereactionofNOandreactiveoxygenspecies[64].
Nitricoxideissynthesizedbynitricoxidesynthase(NOS)fromLarginineinthepresenceofessentialcofactor,
tetrahydrobiopterin.Nitricoxidesynthaseexistsinthreeisoforms:neuronalNOS(nNOS),endothelialNOS
(eNOS),andinducibleNOS(iNOS).
AvailableevidencesuggeststhateNOShasapredominantprotectiveroleinhypoxiaischemia,whereasnNOS
andiNOShaveafacilitativerole.
HistopathologicstudieshaveshownthatnNOSknockoutneonatalanimalsareprotectedfromfocalhypoxic
ischemicinducedhistopathologicbraindamage[65].
Similarly,iNOSknockoutanimalsshowareductionoffocalischemicbraindamageandlocomotordeficits
[66].
AnimalslackingtheeNOSgenehaveenlargedcerebralinfarctsafterischemicinjury[67].
TheuseofspecificNOSinhibitorsasneuroprotectantsiscurrentlybeingstudied.
PERINATALSTROKEPerinatalstrokeisanincreasinglyrecognizedentityintermnewbornswith
encephalopathyandcerebralpalsy.Perinatalstrokeoccursaboutoncein4000births.(See"Strokeinthe
newborn",sectionon'Epidemiology'.)
Themajorityofinfantswithischemicperinatalstrokedevelopneonatalseizures.Additionalsignsofneonatal
encephalopathymayalsobepresent,suchaslethargy,hypotonia,feedingdifficulties,orapnea[68].
Aspecificcauseforperinatalstrokeisnotidentifiedinmostaffectednewborns.Factorscontributingtotherisk
includematernalconditionssuchasprothromboticdisorderandcocaineabuseplacentalcomplicationssuchas
preeclampsia,chorioamnionitisandplacentalvasculopathyandnewbornconditionssuchasprothrombotic
disorders,congenitalheartdisease,meningitis,andsystemicinfection[69].Duringthedeliveryprocess,aninfant
maydevelopacervicalarterialdissectionthatleadstostroke.
Potentiallongtermsequelaeofperinatalarterialstrokeincludecerebralpalsy,cognitivedeficits,hemiparesis,and
epilepsy.However,developmentisnormalinapproximately19to33percentofinfantswithneonatalischemic
infarction.(See"Strokeinthenewborn",sectionon'Prognosis'.)
PROGRESSIVEENCEPHALOPATHYOnemustalwaysconsiderthepossibilityofprogressivedisordersin
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casesofneonatalencephalopathy.Theseincludemetabolic,neurodegenerative,infectiousortoxicetiologiesthat
arerare,withacombinedincidenceofapproximately6per10,000livebirths[70],butamuchhighermortalityrate
thanthegeneralpopulation[71].Ahistoryofparentalconsanguinityisassociatedwithamarkedincreaseinthe
riskofprogressiveencephalopathy,andthusisanimportantcluesuggestingmetabolicandneurodegenerative
disease[72].
MetabolicabnormalitiesAlargenumberofmetabolicandgeneticabnormalitiesmaycauseneonatal
encephalopathy.Inbornerrorsofmetabolismthatpresentinthenewbornperiodtypicallysharestrikinglysimilar
clinicalfeatures,includingdecreasedlevelofconsciousness,seizures,poorfeeding,hypotonia,andvomiting.
Examplesinclude:
Disordersofaminoacidmetabolism(eg,maplesyrupurinedisease,phenylketonuria,nonketotic
hyperglycinemia)(see"Overviewofmaplesyrupurinedisease"and"Overviewofphenylketonuria")
Hyperammonemia(eg,ureacycledefects)(see"Ureacycledisorders:Clinicalfeaturesanddiagnosis")
Neonatalhypoglycemia(see"Pathogenesis,screening,anddiagnosisofneonatalhypoglycemia")
Organicacidemias(see"Organicacidemias")
Mitochondrialdisorders(see"Mitochondrialmyopathies:Clinicalfeaturesanddiagnosis")
Severeperoxisomaldisorders(eg,Zellwegersyndrome)(see"Peroxisomaldisorders")
Specificdisorderssuchasmultiplesulfiteoxidasedeficiencymayproduceneuroimagingandclinicalfindingsthat
verycloselymimichypoxicischemicbraininjury.GeneticdisorderssuchasPraderWilliandchromosomal
abnormalitiesmayalsopresentwithnewbornencephalopathy.However,metabolicandgeneticdisordersaccount
onlyforaverysmallproportionofcasesofneonatalencephalopathy.
OTHERCAUSESGiventhatneonatalencephalopathyisanumbrellatermthatincludesanytypeofbraininjury
orinsultresultingincentralnervoussystemdysfunction,thelistofbraindisordersthatcancauseneonatal
encephalopathyisquitelong[73].Asexamples,brainanomalies,intracranialhemorrhageandinfectioncanalllead
toseizuresandencephalopathyinthenewbornperiod.
Intraventricularhemorrhageinterminfantsmaycausesymptomsofneonatalencephalopathy,andisoftenrelated
tosinovenousthrombosisasopposedtothemoretypicalintraventricularhemorrhageassociatedwithgerminal
matrixhemorrhageseeninpreterminfants[74].Intracerebralhemorrhageinaterminfantisoftenidiopathic,but
mayberelatedtobirthtrauma,congenitalvascularmalformation,oraclottingdisorder.
Finally,avarietyofmaternaltoxinscancauseencephalopathyinthenewbornperiod.Forinstance,passive
addictiontonarcotics,barbiturates,alcohol,tricyclicantidepressants,andserotoninreuptakeinhibitorscan
produceseizuresandencephalopathyintheneonate[75].
SUMMARY
Neonatalencephalopathyisthepreferredterminologytodescribecentralnervoussystemdysfunctioninthe
newbornperiod.Itcanresultfromawidevarietyofconditionsbutoftenremainsunexplained.Thenatureof
braininjurycausingneurologicimpairmentinanewbornispoorlyunderstood.Hypoxiaischemiaisonlyone
ofmanypossiblecontributorstoneonatalencephalopathy.Whetheraparticularnewborn'sencephalopathy
canbeattributedtohypoxicischemicbraininjuryisoftencontroversial.(See'Terminology'above.)
Approximately70percentofneonatalencephalopathycasesareassociatedwitheventsarisingbeforethe
onsetoflabor(figure1andfigure2).Theseinclude:
Maternalfactors,includingunemployment,familyhistoryofseizuresorneurologicdisorder,infertility
treatment,andthyroiddisease
Placentalconditions,includingseverepreeclampsia,postdates,andabnormalappearanceofthe
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placenta
Fetalproblems,suchasintrauterinegrowthrestriction
Ofthese,intrauterinegrowthrestrictionisthestrongestriskfactor.(See'Riskfactors'aboveand
'Antepartum'above.)
Intrapartumriskfactorsforneonatalencephalopathyincludethefollowing:
Persistentoccipitoposteriorposition
Shoulderdystocia
Emergencycesareandelivery,whichmayincludefailedvacuum
Operativevaginaldelivery
Acuteintrapartumeventsorsentinelevents(eg,uterinerupture,placentalabruption,cordprolapse,tight
nuchalcord,maternalshock/death)
Inflammatoryevents(eg,maternalfever,chorioamnionitis,prolongedruptureofmembranes)
Anacute(ie,sentinel)intrapartumevent,suchasaplacentalabruptionoruterinerupture,confersan
increasedriskofneonatalencephalopathy,butispresentinonlyasmallminorityofinfantswithneonatal
encephalopathy.(See'Intrapartum'above.)
Perinatalstrokeisaseparaterecognizedentityintermnewbornswithencephalopathy.(See'Perinatal
stroke'above.)
Metabolicandneurodegenerativedisorderscanunderlieneonatalencephalopathy.(See'Progressive
encephalopathy'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic6205Version11.0
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GRAPHICS
Timingandanatomyofriskfactorsforbraininjury
resultinginneonatalencephalopathy
SidharthaTan,MD.
Graphic70341Version2.0
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Anatomyandetiologyofriskfactorsforbraininjuryresulting
inneonatalencephalopathy
SidharthaTan,MD.
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Mechanismsofneonatalhypoxicischemicencephalopathy
Anatomicalunit
Examples
Maternal
Impairedoxygenation
Asthma
Pulmonaryembolism
Pneumonia
Inadequateperfusionofmaternalplacenta
Cardiorespiratoryarrest
Maternalhypotension
Preeclampsia
Chronicvasculardisease
Placental
Abruptioplacenta
Tightnuchalcord
Cordprolapsed
Trueknot
Uterinerupture
Fetal
Impairedfetaloxygenation/perfusion
Fetomaternalhemorrhage
Fetalthrombosis
SidharthaTan,MD.
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Markersofanacuteperipartumorintrapartumhypoxicischemic
event
Neonatalsignsconsistentwithanacuteperipartumorintrapartum
event:
Apgarscoreof<5at5minutesand10minutes
Fetalumbilicalarteryacidemia:fetalumbilicalarterypH<7.0,orbasedeficit12mmol/L,or
both
NeuroimagingevidenceofacutebraininjuryseenonbrainMRIorMRSconsistentwith
hypoxiaischemia
Presenceofmultisystemorganfailureconsistentwithhypoxicischemicencephalopathy
Typeandtimingofcontributingfactorsthatareconsistentwithan
acuteperipartumorintrapartumevent:
Asentinelhypoxicorischemiceventoccurringimmediatelybeforeorduringlaborand
delivery:
Ruptureduterus
Severeabruptioplacentae
Umbilicalcordprolapse
Amnioticfluidemboluswithcoincidentsevereandprolongedmaternalhypotensionand
hypoxemia
Maternalcardiovascularcollapse
Fetalexsanguinationfromeithervasapreviaormassivefetomaternalhemorrhage
Fetalheartratemonitorpatternsconsistentwithanacuteperipartumorintrapartumevent,
particularlyacategoryIfetalheartratepatternonpresentationthatconvertstooneofthe
followingpatterns:
CategoryIIIpattern
Tachycardiawithrecurrentdecelerations
Persistentminimalvariabilitywithrecurrentdecelerations
Timingandtypeofbraininjurypatternsbasedonimagingstudiesconsistentwithanetiology
ofanacuteperipartumorintrapartumevent.WelldefinedpatternsonbrainMRItypicalof
hypoxicischemiccerebralinjuryinthenewbornare:
Deepnucleargraymatter(ie,basalgangliaorthalamus)injury
Watershed(borderzone)corticalinjury
Noevidenceofotherproximalordistalfactorsthatcouldbecontributing
Developmentaloutcomeisspasticquadriplegiaordyskineticcerebral
palsy:
Othersubtypesofcerebralpalsyarelesslikelytobeassociatedwithacuteintrapartum
hypoxicischemicevents
Otherdevelopmentalabnormalitiesmayoccur,buttheyarenotspecifictoacuteintrapartum
hypoxicischemicencephalopathyandmayarisefromavarietyofothercauses
MRI:magneticresonanceimagingMRS:magneticresonancespectroscopy
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Source:Neonatalencephalopathyandneurologicoutcome,secondedition.ReportoftheAmerican
CollegeofObstetriciansandGynecologists'TaskForceonNeonatalEncephalopathy.ObstetGynecol
2014123:896.
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Outcomefollowingneonatalhypoxicischemicencephalopathy
SidharthaTan,MD.
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Timelineofneonatalhypoxicischemicinjury
Hypoxiaischemiamayhavedeleteriouseffectsonvulnerablecellpopulations
peculiartothedevelopmentalstage.
WM:whitematter.
SidharthaTan,MD.
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Pathophysiologyofhypoxicischemicencephalopathy
Thedownwardpointingbluelinerepresentsthecascadeofeventsthatoccurswithoxidative
stress,andthedownwardpointingblacklinedepictseventsassociatedwithenergyfailure.
SidharthaTan,MD.
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12/9/2015
Disclosures
Disclosures:SidharthaTan,MDNothingtodisclose.YvonneWu,MD,MPHConsultant/Advisory
Board:GSK[Prematurity(Monitoringofclinicaltrial)].DouglasRNordli,Jr,MDGrant/Research/Clinical
TrialSupport:NIH[febrilestatus,SUDEP].Consultant/AdvisoryBoards:Eisai[AED(zonisamide,
perampanel)].LeonardEWeisman,MDConsultant/AdvisoryBoards:GlaxoSmithKline[Malaria
vaccine]NIAID[Staphylococcusaureus(Mupirocin)].PatentHolder:BaylorCollegeofMedicine
[Ureaplasmadiagnosis/vaccines/antibodies,processforpreparingbiologicalsamples].Equity
Ownership/StockOptions:VaxImmune[Ureaplasmadiagnosis,vaccinesandantibodies].JohnF
Dashe,MD,PhDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmust
conformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy
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