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Clinicalfeatures,evaluation,anddiagnosisofsepsisintermandlatepreterminfants
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate

Clinicalfeatures,evaluation,anddiagnosisofsepsisintermandlatepreterminfants
Author
MorvenSEdwards,MD

SectionEditors
LeonardEWeisman,MD
SheldonLKaplan,MD

DeputyEditor
CarrieArmsby,MD,MPH

Contributordisclosures
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2016.|Thistopiclastupdated:Apr11,2016.
INTRODUCTIONSepsisisanimportantcauseofmorbidityandmortalityamongnewborninfants.Althoughthe
incidenceofsepsisintermandlatepreterminfantsislow,thepotentialforseriousadverseoutcomes,includingdeath,
isofsuchgreatconsequencethatcaregiversshouldhavealowthresholdforevaluationandtreatmentforpossible
sepsisinneonates.
Theepidemiology,clinicalfeatures,diagnosis,andevaluationofsepsisintermandlatepreterminfantswillbe
reviewedhere.Themanagementandoutcomeofsepsisintermandlatepreterminfants,neonatalsepsisinpreterm
infants,andevaluationoffebrileandillappearingneonatesafterdischargefromthebirthhospitalizationarediscussed
separately:

(See"Managementandoutcomeofsepsisintermandlatepreterminfants".)
(See"Clinicalfeaturesanddiagnosisofbacterialsepsisinthepreterminfant(<34weeksgestation)".)
(See"Treatmentandpreventionofbacterialsepsisinthepreterminfant(<34weeksgestation)".)
(See"Febrileinfants(youngerthan90daysofage):Outpatientevaluation".)
(See"Approachtothesepticappearinginfant".)

TERMINOLOGYThefollowingtermswillbeusedthroughoutthisdiscussiononneonatalsepsis:
Neonatalsepsisisaclinicalsyndromeinaninfant28daysoflifeoryounger,manifestedbysystemicsignsof
infectionandisolationofabacterialpathogenfromthebloodstream[1].Aconsensusdefinitionforneonatal
sepsisislacking[2].(See'Diagnosis'below.)
Terminfantsarethosebornatagestationalageof37weeksorgreater.
Latepreterminfants(alsocallednearterminfants)arethosebornbetween34and36completedweeksof
gestation[3].(See"Latepreterminfants".)
Preterminfantsarethosebornatlessthan34weeksofgestation[3].
Sepsisisclassifiedaccordingtotheinfant'sageattheonsetofsymptoms.
Earlyonsetsepsisisdefinedastheonsetofsymptomsbefore7daysofage,althoughsomeexpertslimitthe
definitiontoinfectionsoccurringwithinthefirst72hoursoflife[4].
Lateonsetsepsisisgenerallydefinedastheonsetofsymptomsat7daysofage[4].Similartoearlyonset
sepsis,thereisvariabilityinitsdefinition,rangingfromanonsetat>72hoursoflifeto7daysofage[4,5].
Infantswithearlyonsetsepsistypicallypresentwithsymptomsduringtheirbirthhospitalization.Terminfantswithlate
onsetsepsisgenerallypresenttotheoutpatientsettingoremergencydepartmentunlesscomorbidconditionshave
prolongedthebirthhospitalization.Theapproachtoevaluationofneonatesintheoutpatientsettingisdiscussed
separately.(See"Approachtothesepticappearinginfant"and"Febrileyounginfant(youngerthan90daysofage):
Management",sectionon'Neonates(28daysofageandyounger)'.)
PATHOGENESISEarlyonsetinfectionisusuallyduetoverticaltransmissionbyascendingcontaminatedamniotic
fluidorduringvaginaldeliveryfrombacteriainthemother'slowergenitaltract[6].Maternalchorioamnionitisisawell
recognizedriskfactorforearlyonsetneonatalsepsis[7,8].MaternalgroupBstreptococcal(GBS)colonizationis
anotherimportantriskfactor.(See'Maternalriskfactors'belowand"GroupBstreptococcalinfectioninneonatesand
younginfants",sectionon'Riskfactors'.)
Lateonsetinfectionscanbeacquiredbythefollowingmechanisms:
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Verticaltransmission,resultingininitialneonatalcolonizationthatevolvesintolaterinfection
Horizontaltransmissionfromdirectcontactwithcareprovidersorenvironmentalsources
Disruptionoftheintactskinormucosa,whichcanbeduetoinvasiveprocedures(eg,intravascularcatheter),
increasestheriskoflateonsetinfection.
Lateonsetsepsisisuncommonlyassociatedwithmaternalobstetricalcomplications.Useofforcepsduringdelivery
andelectrodesplacedforintrauterinemonitoringhavebeenimplicatedinthepathogenesisofearlyonsetsepsis
becausetheypenetratetheneonataldefensiveepithelialbarriers[9].
Metabolicfactors,includinghypoxia,acidosis,hypothermia,andinheritedmetabolicdisorders(eg,galactosemia),are
likelytocontributetoriskforandseverityofneonatalsepsis.Thesefactorsarethoughttodisrupttheneonate'shost
defenses(ie,immunologicresponse)[9].
EPIDEMIOLOGYTheoverallincidenceofneonatalsepsisrangesfromonetofivecasesper1000livebirths.
Estimatedincidenceratesvarybasedonthecasedefinitionandthepopulationstudied.Infectionratesincreasewith
decreasinggestationalage.TheincidenceofearlyonsetsepsishasdecreasedprimarilyduetoreductioningroupB
streptococcal(GBS)infectionsowingtotheuseofintrapartumantibioticprophylaxis[1014].
Theestimatedincidenceofsepsis(bothearlyandlateonset)intermneonatesisonetotwocasesper1000livebirths
[15,16].Inaprospectivenationalsurveillancestudy(2006to2009),theincidenceofearlyonsetsepsis(definedas
positivebloodorcerebrospinalfluidcultures)was0.98casesper1000livebirthstherateamonginfantswithbirth
weight>2500gramswas0.57per1000[17].
Theincidenceishigherinlatepretermthanterminfants.Inanobservationalcohortstudy(1996to2007),thereported
incidencesofearlyandlateonsetsepsis(definedaspositivebloodculture)inlatepretermneonateswere4.4and6.3
per1000,respectively[18].
EarlyonsetGBSinfectionratesintheUnitedStatesreportedthroughtheCentersforDiseaseControland
Prevention's(CDC)ActiveBacterialCoreSurveillanceReporthavedeclinedfrom0.6per1000livebirthsin2000to
0.25per1000livebirthsin2013[19,20].LateonsetGBSinfectionrateshaveremainedrelativelystableinthesame
interval(0.4per1000livebirthsin2000and0.27per1000livebirthsin2013).
BlackracehasbeenidentifiedasanindependentriskfactorforearlyandlateonsetGBSsepsis.Reasonsforthe
disproportionatelyhighdiseaseburdenamongblackpopulationscannotbefullyexplainedbyprematurity,adequacyof
prenatalcare,orsocioeconomicstatus[10].(See"GroupBstreptococcalinfectioninneonatesandyounginfants",
sectionon'Epidemiology'.)
ETIOLOGICAGENTSGroupBStreptococcus(GBS)andEscherichiacoli(E.coli)arethemostcommoncauses
ofbothearlyandlateonsetsepsis,accountingforapproximatelytwothirdsofearlyonsetinfection[11,21,22].
Otherbacterialagentsassociatedwithneonatalsepsisinclude(table1):
Listeriamonocytogenes,althoughawellrecognizedcauseofearlyonsetsepsis,onlyaccountsforraresporadic
casesofneonatalsepsis,andismorecommonlyseenduringanoutbreakoflisteriosis[23,24].
Staphylococcusaureus(S.aureus),includingcommunityacquiredmethicillinresistantS.aureus,isanemerging
pathogeninneonatalsepsis[25].Bacteremicstaphylococcalinfectionsinterminfantsoftenoccurinassociation
withskin,bone,orjointsitesofinvolvement.
Enterococcus,acommonlyencounteredpathogenamongpreterminfants,isararecauseofsepsisinotherwise
healthytermnewborninfants.
Othergramnegativebacteria(includingKlebsiella,Enterobacter,andCitrobacterspp.)andPseudomonas
aeruginosaareassociatedwithlateonsetinfection,especiallyininfantsadmittedtoneonatalintensivecareunits
(NICUs)[26].
Coagulasenegativestaphylococcioftenareacauseofnosocomialinfectioninillinfants(especiallypremature
infantsand/orinfantswhohaveindwellingintravascularcatheters).Itmaybeconsideredacontaminantin
otherwisehealthyterminfantswhohavenotundergoneinvasiveprocedures.
Thepatternsofpathogensassociatedwithneonatalsepsishavechangedovertimeasreflectedbylongitudinal
databasesfromsingletertiarycenters[11,12].TheincidenceofearlyonsetGBShasdeclinedby80percentwiththe

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useofintrapartumantibioticprophylaxis(IAP).IAPappearstoalsoreducetheriskofearlyonsetE.coliinfection[27].
(See"NeonatalgroupBstreptococcaldisease:Prevention".)
Commonnonbacterialagentsassociatedwithneonatalsepsisinclude(see'Differentialdiagnosis'below):
Herpessimplexvirus(see"Neonatalherpessimplexvirusinfection:Clinicalfeaturesanddiagnosis")
Enterovirusandparechovirus(see"Clinicalmanifestationsanddiagnosisofenterovirusandparechovirus
infections",sectionon'Infectionsinneonates'and"Nosocomialviralinfectionsintheneonatalintensivecare
unit",sectionon'Sepsislikeillnessandmeningitis/encephalitis')
Candida(see"ClinicalmanifestationsanddiagnosisofCandidainfectioninneonates",sectionon'Systemic
infections')
MATERNALRISKFACTORSThefollowingmaternalfactorsareassociatedwithanincreasedriskofsepsis,
particularlyGBSinfection[6,7,28].
ChorioamnionitisChorioamnionitismayreflectintrauterineonsetofinfection[29].Consultationwithobstetric
providerstodeterminesuspicionforchorioamnionitisisanimportantaspectofneonatalmanagement.(See
"Intraamnioticinfection(chorioamnionitis)",sectionon'Diagnosisofclinicalchorioamnionitis'.)
Intrapartummaternaltemperature38C(100.4F).
Deliveryat<37weeksgestation.
MaternalGBScolonizationandotherfindingsthatincreasetheriskofGBSinfectionintheneonate,includingany
ofthefollowing:

PositiveGBSvaginalrectalscreeningcultureinlategestationduringcurrentpregnancy
PreviousinfantwithGBSdisease
DocumentedGBSbacteriuriaduringthecurrentpregnancy
IntrapartumnucleicacidamplificationtestpositiveforGBS

Membranerupture18hoursTheriskofprovensepsisincreases10foldto1percentwhenmembranesare
rupturedbeyond18hours[30].
GBSscreeningandmaternalintrapartumantibioticprophylaxis(IAP)reducestheriskofGBSinfectionbutdoesnot
eliminateit.Inaprospectivenationalsurveillancestudy(2006to2009),theGBSscreeningculturewasnegativein81
percentofmothersofterminfantswithearlyonsetGBS[17].Approximatelyonehalfofinfantswhodevelopedearly
onsetsepsiswereborntomotherswhoreceivedintrapartumantibiotics.(See"NeonatalgroupBstreptococcal
disease:Prevention".)
CLINICALMANIFESTATIONSClinicalmanifestationsrangefromsubtlesymptomstoprofoundsepticshock.
Signsandsymptomsofsepsisarenonspecificandincludetemperatureinstability(primarilyfever),irritability,lethargy,
respiratorysymptoms(eg,tachypnea,grunting,hypoxia),poorfeeding,tachycardia,poorperfusion,andhypotension
(table2)[9].
Becausethesignsandsymptomsofsepsiscanbesubtleandnonspecific,itisimportanttoidentifyneonateswithrisk
factorsforsepsisandtohaveahighindexofsuspicionforsepsiswhenaninfantdeviatesfromhisorherusualpattern
ofactivityorfeeding[9].
Signsandsymptomsofneonatalsepsisinclude:
FetalanddeliveryroomdistressThefollowingsignsoffetalandneonataldistressduringlaboranddelivery
maybeearlyindicatorsofneonatalsepsis:
Intrapartumfetaltachycardia,whichmaybeduetointraamnioticinfection.(See"Overviewofthegeneral
approachtodiagnosisandtreatmentoffetalarrhythmias",sectionon'Tachyarrhythmias'.)
Meconiumstainedamnioticfluid,whichisassociatedwithatwofoldincreasedriskofsepsis[7].(See
"Clinicalfeaturesanddiagnosisofmeconiumaspirationsyndrome",sectionon'Meconiumpassage'.)
Apgarscore6,whichisassociatedwitha36foldincreasedriskofsepsis[31].(See"Neonatal
resuscitationinthedeliveryroom",sectionon'Apgarscores'.)

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TemperatureinstabilityThetemperatureofaninfectedinfantcanbeelevated,depressed,ornormal.Term
infantswithsepsisaremorelikelytobefebrilethanpreterminfantswhoaremorelikelytobehypothermic[9].
Temperatureelevationinfullterminfantsisconcerningand,ifpersistent,ishighlyindicativeofinfection[32,33].
RespiratoryandcardiocirculatorysymptomsRespiratoryandcardiocirculatorysymptomsarecommonin
infectedneonates.Approximately85percentofnewbornswithearlyonsetsepsispresentwithrespiratory
distress(eg,tachypnea,grunting,flaring,useofaccessorymuscles)[17].Apneaislesscommon,occurringin38
percentofcases,andismorelikelyinpretermthanterminfants.Apneaisaclassicpresentingsymptominlate
onsetGBSsepsis.Earlyonsetdiseasecanbeassociatedwithpersistentpulmonaryhypertensionofthe
newborn(PPHN).(See"Persistentpulmonaryhypertensionofthenewborn".)
Tachycardiaisacommonfindinginneonatalsepsisbutisnonspecific.Bradycardiamayalsooccur.Poor
perfusionandhypotensionaremoresensitiveindicatorsofsepsisbutthesetendtobelatefindings.Ina
prospectivenationalsurveillancestudy,40percentofneonateswithsepsisrequiredvolumeexpansionand29
percentrequiredvasopressorsupport[17].
NeurologicsymptomsNeurologicmanifestationsofsepsisintheneonateincludelethargy,poortone,poor
feeding,irritability,andseizures[9].Seizuresareanuncommonpresentationofneonatalsepsisbutare
associatedwithahighlikelihoodofinfection.Inaprospectivestudyinasingleneonatalunit,38percentof
neonateswithseizureswerefoundtohavesepsisastheetiology[34].Seizuresareapresentingfeaturein20to
50percentofinfantswithneonatalmeningitis[35].(See"Bacterialmeningitisintheneonate:Clinicalfeatures
anddiagnosis"and"Etiologyandprognosisofneonatalseizures".)
OtherfindingsOtherfindingsassociatedwithneonatalsepsisandtheirapproximatefrequenciesarelisted
below(table2)[9,17]:

Jaundice:35percent
Hepatomegaly:33percent
Poorfeeding:28percent
Vomiting:25percent
Abdominaldistension:17percent
Diarrhea:11percent

EVALUATIONANDINITIALMANAGEMENTNeonateswithsignsandsymptomsofsepsisrequireprompt
evaluationandinitiationofantibiotictherapy[6,9].Becausethesignsandsymptomsofsepsisaresubtleand
nonspecific,laboratorytestingisperformedinanyinfantwithidentifiableriskfactorsand/orsignsandsymptoms
concerningforsepsis.ThisapproachisconsistentwithguidelinespublishedbytheAmericanAcademyofPediatrics
(AAP)andtheCenterforDiseaseControl(CDC)[6,36].
EarlyonsetsepsisEvaluationforearlyonsetneonatalsepsisshouldincludeallofthefollowing:
Reviewofthepregnancy,labor,anddelivery,includingriskfactorsforsepsisandtheuseanddurationof
maternalintrapartumantibioticprophylaxis(IAP)(see'Maternalriskfactors'above)
Acomprehensivephysicalexamination(see"Assessmentofthenewborninfant")
Laboratorytesting(see'Laboratorytests'below)
Theextentofthediagnosticevaluationforsepsisisdirectedbytheinfant'ssymptomsandmaternalriskfactors.
SymptomaticneonatesInfantswithsignsandsymptomsofsepsisshouldundergoafulldiagnostic
evaluationandshouldreceiveempiricantibiotictreatment(algorithm1).(See'Clinicalmanifestations'aboveand
'Empiricantibiotictherapy'below.)
Afulldiagnosticevaluationincludes(see'Laboratorytests'below):

Bloodculture
Lumbarpuncture(iftheinfantisclinicallystableenoughtotoleratetheprocedure)
Completebloodcountwithdifferentialandplateletcount
Chestradiograph(ifrespiratorysymptomsarepresent)
Culturesfromtrachealaspiratesifintubated

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Creactiveprotein(CRP)levelsarenotroutinelyrequiredbutmaybehelpfulindetermininglengthoftherapyiffollowed
serially.(See'Otherinflammatorymarkers'below.)
WellappearingneonatesWellappearinginfantswithidentifiedriskfactorsforneonatalsepsis,particularly
GBS,shouldbeobservedforaminimumof48hours.Theymayrequirealimiteddiagnosticevaluationbasedonthe
natureoftheriskfactorandtheuseanddurationofmaternalIAP(algorithm1).(See"Managementoftheinfantwhose
motherhasreceivedgroupBstreptococcalchemoprophylaxis".)
LateonsetsepsisInfantspresentingwithsignsandsymptomsat7daysofageshouldundergopromptevaluation
andempiricantibiotictreatment.(See"Managementandoutcomeofsepsisintermandlatepreterminfants",section
on'Lateonsetsepsis'.)
Afulldiagnosticevaluationshouldbeperformed.Inadditiontothetestsdescribedaboveforearlyonsetsepsis,the
followingshouldalsobeobtained:
Urineculture
Culturesfromanyotherpotentialfociofinfection(eg,trachealaspiratesifintubated,purulenteyedrainage,or
pustules)
Infantswithlateonsetsepsisgenerallypresenttotheoutpatientoremergencydepartmentsettingunlesscomorbid
conditionshaveprolongedthebirthhospitalization.(See"Approachtothesepticappearinginfant"and"Febrileyoung
infant(youngerthan90daysofage):Management",sectionon'Neonates(28daysofageandyounger)'.)
EmpiricantibiotictherapyIndicationsforempiricantibiotictherapyinclude:
Illappearance(see"Approachtothesepticappearinginfant")
Concerningsymptoms,includingtemperatureinstability,orrespiratory,cardiocirculatory,orneurologicsymptoms
(see'Clinicalmanifestations'above)
Cerebrospinalfluid(CSF)pleocytosis(whitebloodcell[WBC]countof>20to30cells/microL)(table3)(see
"Bacterialmeningitisintheneonate:Clinicalfeaturesanddiagnosis",sectionon'InterpretationofCSF')
Confirmedorsuspectedmaternalchorioamnionitis(see'Maternalriskfactors'above)
TheempiricantibioticregimenshouldincludeagentsactiveagainstGBSandotherorganismsthatcauseneonatal
sepsis(eg,E.coliandothergramnegativepathogens).Thecombinationofampicillinandgentamicinorampicillinand
cefotaximearepotentialregimensthatprovideempiriccoveragefortheseorganismsuntilcultureresultsareavailable.
Ampicillinandgentamicinisgenerallypreferredhowever,localantibioticresistancepatternsmustbeconsidered.In
theeraofGBSIAP,approximately30percentofearlyonsetsepsisisduetoampicillinresistantgramnegative
organisms[13].Theadditionofathirdgenerationcephalosporintotheempirictreatmentofearlyonsetsepsisis
warrantedamongneonateswithsuspectedmeningitis.(See"Managementandoutcomeofsepsisintermandlate
preterminfants",sectionon'Initialempirictherapy'.)
LABORATORYTESTSThegoalsofthediagnosticevaluationaretoidentifyandtreatallinfantswithbacterial
sepsis,andminimizethetreatmentofpatientswhoarenotinfected.Laboratoryassessmentincludesculturesofbody
fluidsthatconfirmthepresenceorabsenceofabacterialpathogen,andotherstudiesthatareusedtoevaluatethe
likelihoodofinfection.
BloodcultureAdefinitivediagnosisofneonatalsepsisisestablishedbyapositivebloodculture.Thesensitivityof
asinglebloodculturetodetectneonatalbacteremiaisapproximately90percent.
BloodsamplingThefollowingconsiderationsareimportantwhenobtainingabloodculture:
SamplingsiteBloodculturescanbeobtainedbyvenipunctureorarterialpuncture,orbysamplingfroma
newlyinsertedumbilicalarteryorvascularaccesscatheter.Positivecultureresultsofblooddrawnfrom
indwellingumbilicalorcentralvenouscathetersmayindicatecontaminationorcathetercolonizationrather
thanatruesystemicinfection[9].
NumberofculturesWeobtainatleastoneculturepriortoinitiatingempiricantibiotictherapyinneonates
withahighclinicalsuspicionforsepsis,althoughotherinstitutionsmayroutinelyobtaintwobloodcultures.
Anaerobicculturesaregenerallynotnecessary.
VolumeofbloodTheoptimalvolumeofbloodisbasedontheweightoftheinfant.Aminimumblood
volumeof1mLisdesirableforoptimaldetectionofbacteremiawhenasinglebloodculturebottleisused
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[6].Attheauthor'sinstitution,thesuggestedoptimalvolumeis2mLforinfantsweighing3kg,and3mL
forthosewhoweigh>3to5kg.Dividingthisvolumeintotwoaliquotstoinoculateananaerobicaswellas
theaerobicculturebottleisdiscouragedasitislikelytodecreasethesensitivity.Anaerobicculturesare
generallynotnecessaryandinvitrodatasuggestthatsmallsamplevolumesdonotreliablydetectlow
levelsofbacteremia[37].
TimetopositivityAutomatedsystemsforcontinuousmonitoringofbloodculturesareroutinelyusedinthe
UnitedStatesandhaveshortenedthetimetoidentifypositivebloodcultures.Inmostcasesofneonatalsepsis,
bloodculturesbecomepositivewithin24to36hours[38].
DistinguishinginfectionfromcontaminationApositivebloodcultureisdiagnosticofsepsiswhenaknown
bacterialpathogenisisolated(table1).Isolationofskinflora(eg,diphtheroids)suggestscontaminationrather
thaninfection.Contaminationisalsosuggestedwhenmultiplespeciesgrowinculture.Coagulasenegative
staphylococci(CoNS)maybepathogenicinpatientswithindwellingvascularcathetersorotherinvasivedevices,
whereasasinglebloodculturepositiveforCoNSislikelytorepresentacontaminantinfullterminfantswithout
theseriskfactors[9].
LumbarpunctureAlumbarpuncture(LP)shouldbeperformedinneonatesundergoingevaluationforsepsis,
becauseclinicalsignssuggestingmeningitiscanbelackinginyounginfants.Whenaninfantiscriticallyillorlikelyto
havecardiovascularorpulmonarycompromisefromtheprocedure,theLPcanbedeferreduntilthepatient'sstatushas
stabilized.
Cerebrospinalfluid(CSF)shouldbesentforGramstain,routineculture,cellcountwithdifferential,andproteinand
glucoseconcentrations.TheinterpretationofCSFneedstoaccountforvariationsduetogestationalage,chronologic
age,andbirthweight(table3).
Theapproachoutlinedbythe2012AmericanAcademyofPediatrics(AAP)clinicalreportrecommendsthatLPbe
performedinaninfantwithanyofthefollowingclinicalconditions[6]:

Apositivebloodculture
Clinicalfindingsthatarehighlysuggestiveofsepsis(see'Clinicalmanifestations'above)
Laboratorydatastronglysuggestiveofsepsis(see'Completebloodcount'below)
Worseningclinicalstatuswhileonantibiotictherapy

Bloodculturemaybenegativeinasmanyas38percentofinfantswithmeningitis[6,39].Inaretrospectivestudy,8of
the36terminfantswithmeningitishadnosymptomsreferabletothecentralnervoussystem,andhadsterileblood
cultures[40].Inaddition,threeinfantswithbothpositiveCSFandbloodcultureswereasymptomatic.
Theclinicalfeaturesanddiagnosisofneonatalbacterialmeningitisarediscussedseparately.(See"Bacterialmeningitis
intheneonate:Clinicalfeaturesanddiagnosis".)
UrinecultureUrinecultureobtainedbycatheterorbladdertapshouldbeincludedinthesepsisevaluationfor
infantsoneweekofageorolder.Aurinecultureneednotberoutinelyperformedintheevaluationofaninfant6days
ofagebecauseapositiveurinecultureinthissettingisareflectionofhighgradebacteremiaratherthananisolated
urinarytractinfection[6,41].(See"Urinarytractinfectionsinneonates".)
OtherculturesInpatientswithlateonsetinfection,culturesshouldbeobtainedfromanyotherpotentialfociof
infection(eg,purulenteyedrainageorpustules).
Trachealaspiratescanbeofvalueifobtainedimmediatelyafterintubation[6].However,theymayreflectlower
respiratorytractcolonizationratherthanindicatingacausativepathogeninaninfantwhohasbeenintubatedfor
severaldays.
Ininfantswithearlyonsetinfection,Gramstainsofgastricaspiratesareoflimitedvalueasarebacterialculturesof
bodysurfacesites(eg,axilla,groin,andexternalearcanal)[6].
CompletebloodcountAcompletebloodcount(CBC)isusedtoevaluatethelikelihoodofsepsisinaneonate
withriskfactorsorsignsofinfection.AbnormalfindingsonaCBCcannotbeusedtoestablishthediagnosisofsepsis.
EarlyonsetsepsisWeobtainaCBCinanyinfantundergoingdiagnosticevaluation(eitherfullorlimited)for
earlyonsetneonatalsepsis.CBCresultsareusedincombinationwithclinicalsymptomsandriskfactorstodetermine
thelikelihoodofsepsisandneedforantibiotictreatment.

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Abnormalneutrophilindices(includingelevatedordepressedabsoluteneutrophilcount[ANC]andelevatedratioof
immaturetototalneutrophilcounts[I/Tratio])areassociatedwithneonatalsepsis.However,thesetestsaremore
usefulinidentifyingneonateswhoareunlikelytohavesepsisthaninidentifyinginfantswithsepsis[6].
TwolargemulticenterstudieshaveevaluatedthediagnosticvalueofCBCsinearlyonsetneonatalsepsis[42,43].
Thesestudiesfoundthatlowwhitebloodcellcount(WBC)(<5000/microL),absoluteneutropenia(ANC<1000
neutrophils/microL),relativeneutropenia(ANC<5000neutrophils/microL),andelevatedI/Tratiowereassociatedwith
cultureprovensepsis.However,noneofthetestsweresufficientlysensitivetoreliablypredictneonatalsepsis.
CBCsobtained6to12hoursafterdeliveryaremorepredictiveofsepsisthanthoseobtainedimmediatelyafterbirth
becausetheWBCandANCnormallyincreaseduringthefirstsixhoursoflife[6,42,44].
Thefollowingneutrophilindicesareusedtodeterminethelikelihoodofinfection:
I/TratioAnelevatedI/Tratio(0.2)hasthebestsensitivityoftheneutrophilindicesforpredictingneonatal
sepsis,andcanbehelpfulasaninitialscreenwhenusedincombinationwithriskfactorsand/orothertests
[7,45,46].AsingledeterminationoftheI/Tratiohashighspecificityandhenceanormalvaluecanhelpruleout
sepsishowever,anelevatedvalueisnothighlypredictiveofsepsisandmaybeobservedin25to50percentof
uninfectedinfants[6].
Inastudyof3154neonateswhounderwentevaluationforearlyonsetsepsiswithbloodcultureandtwoserial
WBCmeasurements,theI/Tratiowas0.2inall142neonateswithculturepositiveorclinicalsepsisaswellas
in1473neonateswithoutinfection[47].
TheI/Tratioislimitedbythewiderangeofnormalvalues,whichreducesitspositivepredictivevalue,especially
inasymptomaticpatients[48].Interreaderdifferencesinbandneutrophilidentificationwithmanualdifferential
countsisanotherlimitation[6].Inaddition,exhaustionofthebonemarrowreserves,whichmayoccurduring
criticalillness,willresultinlowbandcountsandleadtofalselylowratios.(See"Evaluatingdiagnostictests",
sectionon'Howwelldoesthetestperforminspecificpopulations?'.)
AbsoluteneutrophilcountAlthoughbothelevatedandlowneutrophilcountscanbeassociatedwithneonatal
sepsis,neutropeniahasgreaterspecificity,asfewconditionsotherthansepsisandpreeclampsiadepressthe
neutrophilcountofneonates[6].
Neutrophilcountsvarywithgestationalage(countsdecreasewithdecreasinggestationalage),typeofdelivery
(countsarelowerininfantsbornbycesareandelivery),siteofsampling(countsarelowerinarterialthanin
venoussamples),altitude(countsarehigheratelevatedaltitudes),andtimingafterdelivery(countsincrease
duringthefirstsixhoursoflife).
Thelowerlimitofanormalneutrophilcountforinfants>36weeksofgestationis3500/microLatbirthand
7500/microLsixtoeighthoursafterdelivery(figure1)[49].Forinfantsbornat28through36weeksofgestation,
thelowerlimitsofnormalneutrophilcountsatbirthandatsixtoeighthoursafterbirthare1000/microLand
1500/microL,respectively(figure2).
LateonsetsepsisCBCsarefrequentlyusedtosupportthediagnosisoflateonsetsepsis.Inthissetting,
CBCsarelessvariablethaninthefirstdaysoflife.However,WBCindicesstillperformpoorlyinidentifyingneonates
withlateonsetsepsis.
Inastudyof37,826neonates(mostlyinfantscontinuouslyhospitalizedfrombirth)whounderwentevaluationforlate
onset(definedas4to120days)sepsiswithbloodcultureandCBC,abnormalWBC(<1000or>50,000/microL),high
absoluteneutrophilcount(>17,670/microL),elevatedI/Tratio(0.2),andlowplateletcount(<50,000/microL)were
associatedwithculturepositivity[50].However,sensitivitywasinadequatetoreliablypredictlateonsetsepsis.
Screeningprotocolsusedtoidentifyseriousbacterialinfections(SBI)infebrileinfantstwotothreemonthsofageare
inadequateinneonates,astheyfailtoaccuratelyidentifyneonateswithSBI[40].(See"Febrileinfants(youngerthan
90daysofage):Outpatientevaluation",sectionon'Traditionalapproaches'.)
OtherinflammatorymarkersAnumberofacutephasereactantshavebeenusedtoidentifyinfectednewborns.
Manyofthesetestshaveahighsensitivityhowever,theylackspecificity,resultinginapoorpredictivevalue[51].
Creactiveprotein(CRP)CRPisincreasedininflammatoryconditions,includingsepsis.Avarietyof
noninfectiousinflammatoryconditionscanalsocauseelevatedCRP,includingmaternalfever,fetaldistress,
stressfuldelivery,perinatalasphyxia,meconiumaspiration,andintraventricularhemorrhage[52].
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AsinglemeasurementofCRPsoonafterbirthisnotausefulmarkerinthediagnosisofneonatalsepsis.
However,sequentialassessmentofCRPvaluesmayhelpsupportadiagnosisofsepsis.IftheCRPlevel
remainspersistentlynormal(<1mg/dL[10mg/L]),neonatalbacterialsepsisisunlikely[6].
CRPlevelscanbehelpfulinguidingthedurationofantibiotictherapyinsuspectedneonatalbacterialinfection.
InfantswithelevatedCRPlevelsthatdecreaseto<1mg/dL(10mg/L)24to48hoursafterinitiationofantibiotic
therapytypicallyarenotinfectedandgenerallydonotrequirefurtherantibiotictreatmentifculturesarenegative.
However,routineuseofserialCRPmeasurementscanbeassociatedwithlongerlengthofhospitalstay[53].
AnelevatedCRPlevelalonedoesnotjustifycontinuationofempiricantibioticsformorethan48hoursinwell
appearinginfantswithnegativecultureresults[54].Additionalevaluationmaybewarrantedtoinvestigate
alternativeexplanationsforpersistentlyelevatedCRPvalues.
ProcalcitoninProcalcitoninisthepeptideprecursorofcalcitonin.Itisreleasedbyparenchymalcellsin
responsetobacterialtoxins,leadingtoelevatedserumlevelsinpatientswithbacterialinfections.Several
observationalstudieshavesuggestedthatprocalcitoninmaybeausefulmarkertodetectseriousbacterial
infectionsinyoungfebrileinfants[55].Limiteddatainpreterminfantssuggestthatelevatedprocalcitonin(greater
than0.5ng/mL[0.5mcg/L])isequivalentorbetterthanCRPindetectingbacterialinfection[56].Inameta
analysisof16studies,thepooledsensitivityofprocalcitoninfordetectionofneonatalsepsiswas81percentand
thespecificitywas79percent[57].Thus,althoughprocalcitoninisapromisingmarker,itdoesnotappeartobe
reliableasthesoleormaindiagnosticindicatorforneonatalsepsis.
CytokinesBothproinflammatory(interleukin2[IL2],IL6,IL8,interferongamma,andtumornecrosisfactor
alpha)andantiinflammatorycytokines(IL4andIL10)areincreasedininfectedinfantscomparedwiththose
withoutinfections[56,5860].However,thesecytokinesarenotroutinelymeasuredbecauseofthecostoftesting
andbecausenosinglebiomarkerorpaneloftestsissufficientlysensitivetoreliablydetectneonatalsepsis[56].
Furtherresearchaimedatbetterunderstandingtheneonatalinflammatoryresponsetosepsismayresultinthe
identificationofsensitiveandspecificmarkersofinflammationorthedevelopmentofpathogenspecificrapid
diagnostictestsforearlydetectionofneonatalsepsis[56].Withasensitiveandspecificmarkerforsystemicbacterial
infection,themanagementofneonatalsepsiswouldbesignificantlyalteredsothatantimicrobialtherapycouldbe
safelywithheldininfantsforwhomsepsisisunlikely.
DIAGNOSISThediagnosisofneonatalsepsiscanbeestablishedonlybyapositivebloodculture.Otherthanblood
culture,nospecificfindingortestreliablyidentifiesinfectedinfants[61].
Ongoingresearchisfocusedondevelopingvalidatedriskstratificationstrategiesbasedonmaternalriskfactorsand
neonatalpresentationthatwillimprovethepredictiveabilitytodetectneonatalsepsis[62].
CultureprovensepsisTheisolationofpathogenicbacteriafromabloodcultureisthegoldstandardtoconfirmthe
diagnosisofneonatalsepsis.Apositivebloodcultureisdiagnosticofsepsiswhenabacterialpathogenisisolated
(table1).Isolationofskinflora(eg,diphtheroids,andcoagulasenegativestaphylococci)inculturesuggests
contaminationratherthaninfection,althoughcoagulasenegativestaphylococcicanbepathogenicinpatientswith
indwellingvascularcathetersorotherdevices[9].(See'Bloodculture'aboveand"Managementandoutcomeofsepsis
intermandlatepreterminfants",sectionon'Cultureprovensepsis'.)
ProbablesepsisInsomecases,apathogenmaynotbeisolatedinculture,yettheneonatehasaclinicalcourse
thatisconcerningforsepsis(eg,ongoingtemperatureinstabilityongoingrespiratory,cardiocirculatory,orneurologic
symptomsnotexplainedbyotherconditionsorongoinglaboratoryabnormalitiessuggestiveofsepsis[ie,
cerebrospinalfluidpleocytosis,elevatedratioofimmaturetototalneutrophilcounts,orelevatedCreactiveprotein]).
Acompositeofobservationalassessmentandseriallaboratorytestingistypicallyusedtomakeadiagnosisof
probablesepsis[45].Thecriteriausedareusuallybroad,inanattempttoensurethatallinfectedinfantsareidentified,
butatthecostoftestingandtreatinganumberofuninfectedinfants.Thereisnoconsensusdefinitionforthediagnosis
ofprobablesepsisinneonates[2].
Alternativediagnoses(table4)shouldalsobeentertainedwhenaninfantwithsuspectedsepsishasnegativecultures.
(See"Managementandoutcomeofsepsisintermandlatepreterminfants",sectionon'Probablebutunprovensepsis'
and'Differentialdiagnosis'below.)
InfectionunlikelyInfantswithmildand/ortransientsymptoms(ie,feveraloneorothersymptomsthatquickly
resolve)whoremainwellappearingwithnormallaboratoryvaluesandnegativeculturesat48hoursareunlikelyto
havesepsis.Empiricantibiotictherapyshouldbediscontinuedafter48hoursintheseneonates[6,63].
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Inaretrospectivestudyof2785newbornswhounderwentevaluationforsepsisbasedonclinicalsymptoms(54
percent)orriskfactors(46percent),22infants(0.8percent)werefoundtohavecultureprovensepsisand40(1.4
percent)hadprobablesepsis(ie,culturenegativeclinicalsepsis)[7].
DIFFERENTIALDIAGNOSISThedifferentialdiagnosisofneonatalsepsisincludessystemicviral,fungal,and
parasiticinfectionsandnoninfectiouscausesoftemperatureinstability,andrespiratory,cardiocirculatory,and
neurologicsymptoms(table4).Appropriatemicrobiologictestingdistinguishesneonatalbacterialsepsisfromnon
bacterialsystemicinfections.Theclinicalhistory,diseasecourse,chestradiograph,electrocardiogram(ECG),
hyperoxiatesting,drugscreening,neuroimaging,bloodglucose,serumelectrolytes,andnewbornscreeningmayassist
indistinguishingnoninfectiousdisordersfromneonatalsepsis.
Itisoftendifficulttodifferentiateneonatalsepsisfromotherconditions.However,giventhemorbidityandmortalityof
neonatalsepsis,empiricantibiotictherapyshouldbeprovided(afterculturesareobtained)toinfantswithsuspected
sepsispendingdefinitiveculturebaseddiagnosis.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereading
level,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesare
bestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatient
educationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgrade
readinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopics
toyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"
andthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Sepsisinnewbornbabies(TheBasics)")
SUMMARYANDRECOMMENDATIONS
Althoughtheincidenceofsepsisintermandlatepreterminfantsislow(approximatelyonetosixcasesper1000
births),thepotentialforseriousadverseoutcomes,includingdeath,isofsuchgreatconsequencethatcaregivers
shouldhavealowthresholdforevaluationandtreatmentforpossiblesepsis.(See'Epidemiology'above.)
GroupBStreptococcus(GBS)andEscherichiacoliarethemostcommonbacteriacausingneonatalsepsis(table
1).(See'Etiologicagents'above.)
Maternalriskfactorsforneonatalsepsisintermandlatepreterminfantsincludechorioamnionitis,intrapartum
maternaltemperature38C(100.4F),deliveryat<37weeksgestation,maternalGBScolonization,and
prolongedruptureofmembranes(18hours).(See'Maternalriskfactors'above.)
Clinicalmanifestationsarenonspecificandincludefetaldistresslowapgarscoretemperatureinstability(usually
fever)respiratoryandcardiocirculatorysymptoms(mostcommonlyrespiratorydistressandtachycardia)
neurologicsymptoms(irritability,lethargy,poortone,andseizures)andgastrointestinalabnormalities(poor
feeding,vomiting,andabdominaldistension)(table2).(See'Clinicalmanifestations'above.)
Evaluationandinitialmanagementofneonateswithsuspectedsepsisshouldincludeareviewofthepregnancy,
labor,anddeliverycompletephysicalexaminationlaboratoryevaluationandpromptinitiationofempiric
antibiotics.(See'Evaluationandinitialmanagement'aboveand"Managementandoutcomeofsepsisintermand
latepreterminfants",sectionon'Initialempirictherapy'.)
Neonateswithsignsorsymptomsofearlyonsetsepsis(onsetofsymptomsbeforesevendaysofage)should
undergoafulldiagnosticevaluationincludingbloodculture,completebloodcount(CBC)withdifferential,lumbar
puncture,andchestradiograph(ifrespiratorysymptomsarepresent).Empiricantibioticsshouldbeprovidedto
theseneonatespendingbloodcultureresults.(See'Symptomaticneonates'aboveand"Managementand
outcomeofsepsisintermandlatepreterminfants",sectionon'Earlyonsetsepsis'.)
WellappearingnewbornsborntomotherscolonizedwithGBSrequireobservationforaminimumof48hours.
Theneedforalimiteddiagnosticevaluation(whichconsistsofabloodcultureandCBC)intheseasymptomatic
infantsisdeterminedbythenatureoftheriskfactor(s)andwhetherornotthemotherreceivedadequate
intrapartumantibioticprophylaxis(IAP)(algorithm1).Infantsborntomotherswithprovenorsuspected
chorioamnionitisshouldreceiveempiricantibiotictreatmentwhileawaitingcultureresults.(See'Wellappearing
neonates'aboveand"Managementandoutcomeofsepsisintermandlatepreterminfants",sectionon'Early
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onsetsepsis'and"ManagementoftheinfantwhosemotherhasreceivedgroupBstreptococcal
chemoprophylaxis".)
Neonatespresentingwithsignsandsymptomsoflateonsetsepsis(onsetofsymptomsfrom7to28daysoflife)
shouldundergoafulldiagnosticevaluation(similartothatdescribedaboveforearlyonsetsepsis,butalso
includingaurinecultureandculturesfrompotentialfociofinfection[eg,trachealaspiratesifintubated,purulent
eyedrainage,orpustules]).Empiricantibiotictreatmentshouldbeinitiatedintheseinfantspendingbloodculture
results.(See'Lateonsetsepsis'aboveand"Managementandoutcomeofsepsisintermandlatepreterm
infants",sectionon'Lateonsetsepsis'and"Febrileyounginfant(youngerthan90daysofage):Management",
sectionon'Neonates(28daysofageandyounger)'.)
Isolationofapathogenfromabloodcultureconfirmsthediagnosisofneonatalsepsis.(See'Diagnosis'above
and"Managementandoutcomeofsepsisintermandlatepreterminfants",sectionon'Initialempirictherapy'.)
Thedifferentialdiagnosisofneonatalsepsisincludesothersystemicinfectionsandnoninfectiousconditions
includingrespiratorydiseases(eg,transienttachypneaofthenewbornandrespiratorydistresssyndrome)
cardiacdiseases(eg,congenitalheartdiseaseandsupraventriculartachycardia)neurologicinjury(eg,from
anoxiaorhemorrhage)inbornerrorsofmetabolismandneonatalabstinencesyndrome(table4).(See
'Differentialdiagnosis'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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