201754 CytomegalovirusinfectioninpregnancyUpToDate

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Cytomegalovirusinfectioninpregnancy

Authors: JeanneSSheffield,MD,SureshBBoppana,MD
SectionEditors: LouiseWilkinsHaug,MD,PhD,MartinSHirsch,MD
DeputyEditor: VanessaABarss,MD,FACOG

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Apr2017.|Thistopiclastupdated:Apr12,2017.

INTRODUCTIONCytomegalovirus(CMV)isaubiquitousDNAherpesvirus.Aswithotherherpesviruses,it
becomeslatentafteraprimaryinfectionbutcanreactivatewithrenewedviralshedding.Sheddingcanoccurfrom
multiplesitesandforprolongedperiodsoftime.Womencanalsobecomeinfectedwithadifferentviralstrain.

CMVisthemostcommoncongenitalviralinfection,withbirthprevalenceof0.48to1.3percentinrecentdecades
[14].Congenitalinfectionmaybeasymptomaticorsymptomaticsymptomaticdiseasecanbesevereandlife
threatening.Bothasymptomaticandsymptomaticnewbornsareatriskofdevelopinglongterm
neurodevelopmentalmorbidity,particularlydeafness.

ThistopicwilldiscussissuesspecifictoCMVinpregnantandbreastfeedingwomen.Generalissuesrelatedto
CMVinfectionandCMVinfectionsinotherpopulationsarereviewedseparately.(See"Epidemiology,clinical
manifestations,andtreatmentofcytomegalovirusinfectioninimmunocompetentadults"and"Acquired
cytomegalovirusinfectioninchildren"and"Congenitalcytomegalovirusinfection:Clinicalfeaturesanddiagnosis".)

MATERNALCMVINFECTION

RoutesoftransmissionMaternalacquisitionofCMVinfectioncanoccurviamultipleroutes,includingclose
nonsexualcontact(includinghouseholdandoccupationalexposure[especiallycontactwithyoungchildren]),
sexualexposure,transfusion,andorgantransplant.CMVhasbeenculturedfrommultiplebodyfluids,including
urine,saliva,blood,nasopharyngealsecretions,tears,cervicalandvaginalsecretions,semen,andbreastmilk.
Transmissionfromrespiratorydropletsoraerosolizeddropletsisunlikely[5].(See"Epidemiology,clinical
manifestations,andtreatmentofcytomegalovirusinfectioninimmunocompetentadults",sectionon
'Transmission'.)

SeroprevalenceCMVinfectioniscommon:AnepidemiologicstudyintheUnitedStatesdemonstrated
seropositivityinapproximately58percentofyoungwomenaged15to44years[3].Seroprevalenceincreases
withage,rangingfrom50to100percent,andvariesbygeographicresidence,ethnicity,andsocioeconomic
factors[13].ThefollowingcharacteristicsarepredictiveofpositiveCMVserology:

Lowersocioeconomicstrata.

Contactwithchildrenunderage3years,especiallyiftheyareindaycare[2,6,7].

NonHispanicblackorMexicanAmericanversusnonHispanicwhiterace[3].

Ageolderthan25to30years[2,8].

Higherparity[9].

Residenceinadevelopingcountry.
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RiskofseroconversionAnnualratesofmaternalseroconversionrangefrom1to7percentworldwide[10].
Thelikelihoodofseroconversiondependsonsocial,behavioral,andenvironmentalfactors.Inasystematicreview
ofstudiesthatmeasuredratesofCMVseroconversion,ratesofseroconversionindifferentpopulationswereas
follows[10]:

Pregnantwomen:summaryannualrate2.3percent(95%CI2.12.4percent)

Healthcareworkers,includingthosecaringforinfantsandchildren:summaryannualrate2.3percent(95%
CI1.92.9percent)

Daycareproviders:summaryannualrate8.5percent(95%CI6.111.6percent)

Parentsofachild:

NotsheddingCMV:summaryannualrate2.1percent(95%CI0.36.8percent)
SheddingCMV:summaryannualrate24percent(95%CI1830percent)

OthergroupswithelevatedriskofseroconversionincludedfamilieswithaCMVsheddingmember,female
minorityadolescents,womenattendingsexuallytransmitteddiseaseclinics,andimmunocompromisedindividuals.

ClinicalfindingsPrimaryCMVinfectionmaycauseamildfebrileillnessandothernonspecificsymptoms
(rhinitis,pharyngitis,myalgia,arthralgia,headache,fatigue)butisnotclinicallyapparentinapproximately90
percentofcases.CMVmononucleosiscanbeaccompaniedbydermatologicmanifestationsinapproximately
onethirdofpatientsincludingmacular,papular,maculopapular,rubelliform,morbilliform,andscarlatiniform
eruptions.ReinfectionwithadifferentstrainofCMVorreactivationofvirusinwomenwithpreexistingantibody
generallydoesnotcausematernalclinicalillness[11].Pregnancydoesnotappeartoaffectclinicalseverity.The
integrityofthehostimmunesystemaffectsthespectrumofdisease:Hostswithimpairedcellularimmunityareat
riskforsevereanddisseminatedinfection.TheclinicalmanifestationsofCMVinfectioninadultsarediscussedin
detailseparately.(See"Epidemiology,clinicalmanifestations,andtreatmentofcytomegalovirusinfectionin
immunocompetentadults".)

Diagnosis

WhomtotestTestingpregnantwomenforCMVisindicated[12]:

Aspartofthediagnosticevaluationofmononucleosislikeillnesses(see"Infectiousmononucleosisinadults
andadolescents",sectionon'Clinicalmanifestations')

WhenafetalanomalysuggestiveofcongenitalCMVinfectionisdetectedonprenatalultrasoundexamination
(see'Ultrasoundmarkersandmonitoring'below)

HowtotestThediagnosisofclinicallysuspectedmaternalprimaryCMVinfectionisbasedonserology
(table1).SeroconversionofCMVspecificimmunoglobulinG(IgG)inpairedacuteandconvalescentsera
collected3to4weeksapartisdiagnosticofanewacuteinfection.ThepresenceofCMVimmunoglobulinM(IgM)
isnothelpfulfortimingtheonsetofinfectionbecause(1)itispresentinonly75to90percentofwomenwith
acuteinfection,(2)itcanremainpositiveforoveroneyearafteranacuteinfection,(3)itcanrevertfromnegative
topositiveinwomenwithCMVreactivationorreinfectionwithadifferentstrain,and(4)itcanbecomepositivein
responsetootherviralinfections,suchasEpsteinBarrvirus.

Intheabsenceofdocumentedrecentseroconversion,itisdifficulttodistinguishbetweenprimaryinfection,
reactivation,reinfection,andquiescentdiseasesinceallareassociatedwithIgGandIgMantibodies,andrising
titersalonearenotdiagnostic.DeterminationofIgGavidityishelpfultobetterdeterminetheacuityoftheinfection
andthustheriskofinuterotransmission[1316].HighantiCMVIgGaviditysuggeststhattheprimaryinfection
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occurredmorethansixmonthsinthepastlowavidityantiCMVIgGsuggestsarecentprimaryinfection(within
twotofourmonths)[17].Itshouldbenotedthatcommercialavidityantibodyassayshavevaryingperformance
characteristics[18],theinterpretationofintermediateavidityandtheoptimalcutoffsforlowandhighavidityare
notwellestablished[19,20],andthecutoffsforlowandhighavidityvaryamonglaboratories.Thediagnosisof
CMVisdiscussedindetailseparately.(See"Overviewofdiagnostictestsforcytomegalovirusinfection".)

SerologicaltestscannotdifferentiateamongthemanystrainsofCMV.

ClassificationCMVinfectionsinpregnantwomenaregenerallyclassifiedasprimaryornonprimary

Primary:PrimarymaternalCMVinfectionisdefinedasinitialacquisitionofvirusduringpregnancy.
Seroconversionfromnegativetopositiveisdiagnostic,ifavailable.Primaryinfectionisstronglysuspectedif
IgMandIgGarepositiveandIgGhaslowavidity.

Itisestimatedthat25percentofcongenitalCMVinfectionsintheUnitedStatesresultfromprimarymaternal
infectionandtheremainingthreequartersofinfantswithcongenitalCMVinfectionareborntowomenwith
preexistingseroimmunitytoCMV(nonprimarymaternalinfection)[21].Thisestimatewasbasedon
summarydataonmaternalfetaltransmissionratesfromacomprehensiveliteraturereviewandpreviously
reportednationallyrepresentativedataonageandracespecificCMVseroprevalenceandseroincidence.

AmongpregnantwomenwithaprimaryCMVinfection,theriskofseverenewbornsequelaebasedon
maternalserologicdiagnosisaloneisapproximately3percentandriskofanyadverseoutcomeis
approximately8percent[22].Theserisksareobviouslyhigherifthefetusisconfirmedtobeinfected.(See
'Frequencyofperinataltransmission'belowand'Clinicalfeaturesandsequelae'below.)

Nonprimary:NonprimarymaternalCMVinfectionoccursinwomenwithinitialacquisitionofvirusbefore
pregnancyandischaracterizedbypresenceofmaternalantiCMVantibodiesbeforeconception.Likeother
herpesviruses,CMVestablisheslatencyafterthehostisinitiallyinfected.Nonprimaryinfection,also
sometimescalledrecurrentorsecondaryinfection,maybeduetoreactivationoflatentvirusorreinfection
withanewstrain.

BecausethediagnosisofnonprimaryCMVinfectionisdifficult,itisnotknownhowmanywomenhave
reactivationorreinfectionduringpregnancy,howmanycongenitalinfectionsresultfromreactivationor
reinfection,andwhatclinicalsequelaeresultinoffspringafterreactivationorreinfection[23].Availabledata
onpregnancyrisksofnonprimaryCMVinfectionarebasedonwomenwithpreconceptionalimmunity.These
datasuggestthatthefrequencyoffetalinfectionislowinwomenwhoseroconvertedpriortoconception,but
infectedfetusesarestillatriskforsymptomaticandasymptomaticnewborndiseaseandlongtermsequelae
[4,2428].Inonestudy,thefrequencyofhearinglossininfantswithcongenitalCMVinfectionwas
approximately10percent,regardlessofwhetherseroconversionoccurredbeforeorafterconception[29].
However,thenumberofchildrenwithseveretoprofoundhearinglosswassignificantlylowerinchildren
whosemothersseroconvertedbeforepregnancy.

TreatmentImmunocompetentpregnantwomenwithCMVinfectionshouldbeofferedsupportivecarefor
symptomaticrelief,asneeded(eg,acetaminophenforfever).UseofantiviraldrugsfortreatmentofCMV
infectionsinimmunocompetentadults,includingpregnantwomen,israrelyindicated.Severalmedications(eg,
ganciclovir,foscarnet,cidofovir)areavailabletotreatsevereendorganCMVdisease,butnonehavebeen
showntodecreaseperinataltransmissionandfetalrisksareunknown.(See"Epidemiology,clinical
manifestations,andtreatmentofcytomegalovirusinfectioninimmunocompetentadults",sectionon'Therapy'.)

CONGENITALINFECTION

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RouteoftransmissionMaternalviremiacanresultintransplacentalinfection(placentalcytotrophoblastsare
permissivetoCMVreplication)congenitalinfectionfromantepartumcervical/vaginalviralsheddingisthoughtto
berare.

Postnatalinfectioncanoccurviaintrapartumexposuretocervical/vaginalviralsheddingorviaconsumptionof
infectedbreastmilkandisunlikelytocauseseverediseaseinhealthyfulltermneonates[30,31].

Frequencyofperinataltransmission

SeroconversionduringpregnancyWomenwhoseroconvertduringpregnancy(primaryinfection)areat
highestriskformaternalfetaltransmissionandtherateoftransmissionappearstoincreasewithadvancing
gestationalage.AreviewthatpooleddatafromninestudiesofmaternalfetalCMVtransmissioninwomenwho
seroconvertedjustbeforeorduringpregnancyreportedthefollowingratesoftransmission[24]:

Preconceptionperiod(twomonthstothreeweeksbeforethedateofconception):5.2percent

Periconceptionalperiod(threeweeksbeforetothreeweeksafterthedateofconception):16.4percent

Firsttrimester:36.5percent

Secondtrimester:40.1percent

Thirdtrimester:65percent

SeroconversionremotefromconceptionAswithotherherpesvirusinfections,periodicreactivationof
latentvirusispossible,especiallyinimmunocompromisedhosts(eg,organtransplantrecipients,individualswith
humanimmunodeficiencyvirus[HIV]infection).Reinfectionwithdifferentviralstrainsisalsopossible.Although
maternalantibodiestoCMVformedasaresultofprimaryinfectionprovideprotection[8],theydonotprevent
reactivationorreinfectionwithadifferentstrainandthusdonoteliminatetheriskofcongenitalinfection[32].
However,theoverallriskoffetalinfectionamongseropositivewomenislow:0.15to2percent[33].

WomenwithHIVappeartobeanexception.AhigherbirthprevalenceofcongenitalCMVinfectionhasbeen
observeddespitematernalantiretroviralprophylaxisandhasbeenassociatedwithadvancedmaternal
immunosuppression[3436].

ClinicalfeaturesandsequelaeThefollowingkeyprinciplesareimportantforunderstandingcongenital
infection:

TheoccurrenceoffetalinfectionincreaseswithadvancinggestationalageinwomenwithprimaryCMV
infection,thoughtheoccurrenceofsymptomaticdiseasedecreaseswithadvancinggestationalageandis
unlikelyifaprimarymaternalinfectionoccursnearterm[24].

Preconceptionseroimmunityprovidessubstantialprotectionagainsttheoccurrenceoffetalinfection
comparedwithseroconversionduringearlypregnancy(approximately0.15to2.0percentversus40percent)
[8,24,33].

Oncefetalinfectionoccurs,thefrequencyofnewborndiseaseandlongtermsequelaeissimilarforinfantsof
motherswithprimaryCMVinfectionduringpregnancyandthosewhowereCMVseropositivepriorto
pregnancy[27,29,3739].

Congenitalinfectionmaybesymptomaticorasymptomaticinnewborns.Mostcongenitalinfectionsare
asymptomaticintheneonatalperiod.

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Bothsymptomaticandasymptomaticinfectednewbornsareatriskfordevelopmentofadversesequelaein
earlychildhood,butsymptomaticnewbornsareathigherrisk(eg,death5versus0percent,deafness50
versus10percent)[19].

SymptomaticnewbornsClinicalfindingsinsymptomaticnewbornsincludesmallforgestationalage,
microcephaly,ventriculomegaly,chorioretinitis,jaundice,hepatosplenomegaly,thrombocytopenia,andpetechiae.
Thesefindingsarethoughttoresultfromthefetalimmuneresponsetoviralreplicationindifferentorgans(eg,
salivarygland,lung,liver,kidney,intestine,adrenalgland,placenta,centralnervoussystem)[25,26].The
mortalityrateamongsymptomaticnewbornsisapproximately5percent[40,41],and50to60percentofsurvivors
developseriouslongtermneurologicmorbidity(eg,progressivehearingand/orvisualimpairment,
motor/cognitiveimpairment)[33,42].(See"Congenitalcytomegalovirusinfection:Clinicalfeaturesand
diagnosis".)

TheriskofsymptomaticnewborndiseasehasbeenwellstudiedinwomenwithprimaryCMVinfectionsin
pregnancy.Symptomaticdiseaseatbirthandseveresequelaeoccuralmostexclusivelyamongoffspringof
womenwhoseroconvertinthefirsthalfofpregnancy,particularlythefirsttrimester[24,43].Inastudyof248
primarymaternalinfections,symptomsoccurredinthenewbornperiodin0/24preconceptioninfections(1to10
weeksbeforeLMP),1/29periconceptionalinfections(1weekbeforeLMPto46/7thsweeksofgestation),7/83first
trimesterinfections(50/7thsto136/7thsweeksofgestation),4/76secondtrimesterinfections,and0/36third
trimesterinfections[43].Inanotherstudyof238primarymaternalinfectionsfrompreconceptionthroughthethird
trimester,onlythreenewbornsweresymptomaticandalloftheirmothershadfirsttrimesterinfection(3/72first
trimestermaternalinfections)[24].

Thefrequencyofsymptomaticnewbornsisnotwellestablishedinnonprimaryinfection.Dataarelimitedtocase
reportsandsmallcaseseriesofsymptomaticnewbornsofmotherswithknownpreconceptionalimmunity,not
provenreactivationorreinfectionduringpregnancy[27,29,3739].

AsymptomaticnewbornsMostcongenitallyinfectednewbornsareinitiallyasymptomatic.Fifteento25
percentoftheseinitiallyasymptomaticnewbornsgoontodevelopneurodevelopmentalabnormalities,most
commonlyhearingloss,withinthefirstthreeyearsoflife[33,44].

PlacentalhistopathologyTheclassichistopathologicalplacentalfindingsincludethefollowing,althoughnot
allmaybepresent:

Lymphoplasmacyticvillitis(diffusechronicvillitiswithplasmacells)
Sclerosisofthevillouscapillaries
Chorionicvesselthromboses
Necrotizingvillitis
Hemosiderindepositioninthevillousstroma
Normoblastemia

Virusreplicationhasbeendemonstratedinsmoothmusclecellsofarteriesandveinsinfloatingvilliandthe
chorion[45].Largefibrinoidswithmanyavascularvilliandedematousvilliandinflammation,changesthatlikely
impairplacentaltransport,havebeenobservedinbirthscomplicatedbyintrauterinegrowthrestrictionand
primaryorrecurrentCMVinfection.Progressivefetalthromboticvasculopathyhasbeenobservedinstillbirths.

Viralinclusions(picture1),whichcanbesubtle,areobservedin10percentofcasesinfetalinfectionbutare
moreoftenvisibleincasesassociatedwithstillbirth.Immunohistochemistrywilldetectmanyinclusionsnot
identifiedwithroutinehematoxylineosinstains[46].

PRENATAL(FETAL)DIAGNOSIS

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OurapproachWesuggestofferingamniocentesisforprenatal(fetal)diagnosiswhenfetalinfectionis
suspectedbecauseofprimarymaternalinfectionorfindingsonultrasound(see'Ultrasoundmarkersand
monitoring'below).Therationaleforofferingprenataldiagnosisistodeterminewhetherthefetusisinfected
(verticaltransmissionisnot100percent).Somecouplesmayusethisinformationindecisionmakingregarding
terminationofpregnancy.Italsohelpspatientsprepareforthebirthforaninfected,andpossiblyaffected,infant.
Lastly,itmaychangetheintensityoffetalmonitoring(eg,frequencyofultrasoundexamination)andisinformative
forthepediatricianscaringforthechild.Maternaldrugtherapyhasnotbeenproventoimproveoutcome.(See
'Prenataldrugtherapy'belowand"Congenitalcytomegalovirusinfection:Clinicalfeaturesanddiagnosis".)

AmniocentesisAmniocentesistoperformpolymerasechainreaction(PCR)forCMVDNAinamnioticfluidis
thepreferreddiagnosticapproachforidentifyinganinfectedfetusviralcultureislessdesirablebecauseof
severallimitations.ReportedsensitivityofPCRrangesfrom70to100percent[4751].(See"Overviewof
diagnostictestsforcytomegalovirusinfection".)

Timingofamniocentesisappearstobeacriticalfactorinfluencingsensitivity:sensitivityappearstobehigherafter
21weeksofgestationandbyallowingaminimumsixweeklagtimebetweenmaternalinfectionand
amniocentesis[4749].Thesixweeklagtimereflectsthetimeittakesforplacentalinfectionandreplication,
transmissiontothefetus,viralreplicationinthefetalkidney,andexcretionintoamnioticfluid.Inoneseries,the
sensitivityforcasesfirstsampledbeforeandafter21weeksofgestationwas30and71percent,respectively
[49].Ifamniocentesisisperformedearlieringestationorsoonafterdiagnosisofmaternalinfection,itisreliable
evidenceoffetalinfectionifpositivebutshouldberepeatedlateringestationifnegativetodetectlate
transmission.Rarely,falsepositiveresultsoccurfromcontaminationoftheamnioticfluidsamplebymaternal
fluids.Thefirst1mLoffluidobtainedshouldbediscardedtoreducetheriskofcontamination.

PresenceofCMVDNAinmaternalbloodatthetimeofamniocentesisdoesnotappeartobeasignificantrisk
factorforiatrogenicantepartumtransmission[52].

UltrasoundmarkersandmonitoringThefollowingultrasonographicmarkersaresuggestive,butnot
diagnostic,offetalCMVinfectioninthepresenceofaknownmaternalinfection[2,4749,5357].

Periventricularcalcifications(image1)
Cerebralventriculomegaly(image2)
Microcephaly
Hyperechogenicfetalbowel(image3)
Fetalgrowthrestriction
Ascitesand/orpleuraleffusion(image4AB)
Hepatosplenomegaly
Hepaticcalcifications
Polymicrogyria
Cerebellarhypoplasia
Pseudocysts,periventricularoradjacenttotheoccipitalortemporalhorn
Periventricularechogenicity
Largecisternamagna
Amnioticfluidabnormalities(oligohydramniosorpolyhydramnios)
Hydrops
Placentalenlargement(image5)

ThetypicalsonographicfindingoffetalCMVinfectionisbilateralperiventricularhyperechogenicities
(calcifications)(image1)[58,59].Thesecalcificationsorhyperechoicfocicanbehighlyreflectiveandmaynot

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castanacousticshadow[60].Branchinglinearechogenicareasinthethalamialsooccurandcorrespondto
arteriesinthebasalgangliaandthalamus[61,62].Thepresenceofintraventricularfilmy,thinadhesionsand
linearedgestraversingtheventricleistypicalinCMVinfectionofthebrain[6372].

Ininfectedfetuses,serialultrasoundexaminationsattwotofourweekintervalscanbeusefultodetect
developmentofsonographicabnormalities.Persistentchanges,suchasventriculomegaly,periventricular
calcifications,growthrestriction,microcephaly,andhydropssuggestthepresenceofseverediseaseandhighrisk
oflongtermneurodevelopmentimpairmentandpotentiallycanguidedeliverytiming.Ifanabnormalityis
suspectedonultrasoundandclarificationisneeded,magneticresonanceimaging(MRI)mayhelpful.(See
'Magneticresonanceimaging'below.)

PredictionofclinicaloutcomeUltrasonographicabnormalitiesassociatedwithinuterofetalinfectionhave
beenreportedinuptoaboutonethirdoffetusesinfectedinthefirsthalfofpregnancytherefore,anormal
ultrasoundexaminationdoesnotcompletelyexcludethepossibilityofasymptomaticneonateordevelopmentof
longtermneurologicmorbidity[49,7376].Likewise,thecombinationofanormalultrasoundandanormalPCR
onamnioticfluiddoesnotcompletelyexcludethepossibilityofcongenitalinfectionbecausesensitivityisnot100
percentandmaternalfetaltransmissionmayoccuraftertheamniocentesishowever,thesenewbornsareless
likelytobesymptomaticthanthosewithpositivefindings(4versus25percentinonestudy[77])andunlikelyto
haveneurologicsequelae(0versus14percentinonestudy[77]).

Ifthefetusisinfectedandtheultrasoundisnormal,determinationofviralloadinamnioticfluidmayhelpto
distinguishthosewhoareinfectedbutasymptomaticatbirthfromthosewhoarelikelytodevelopserious
sequelae[2,7880].Forexample,astudyof456womenatweeks21to23ofpregnancyfoundthathigherviral
loadsinamnioticfluid(eg,greaterthan100,000copies/mL)wereassociatedwithsymptomaticnewborns[2,78].
Inanothersmallstudyof21fetuses,themedianDNAlevelinamnioticfluidwashigherinsymptomaticnewborns,
butthedifferencewasnotstatisticallysignificant[79].Lastly,astudyof82fetusesprimarilyexposedtofirst
trimestermaternalinfectionreportedthenegativepredictivevalueforsymptomsatbirthoratterminationof
pregnancywas93percentforultrasoundaloneversus95percentforultrasoundandviralloadinamnioticfluid
[80].

Othertests

FetalbloodsamplingCordocentesisforthepurposeofevaluatingCMVdiseaseisnotrecommended.
Cordocentesistotestfetalblooddoesnotsignificantlyincreasediagnosticsensitivityorspecificityofamnioticfluid
testsbutincreasesriskoffetalloss.Althoughthepresenceofabnormalliverfunctionandhematologicaltests
(especiallythrombocytopenia)andelevatedbeta2microglobulinlevelaresignsofseveredisease,individual
markerlevelsarenotsufficientlyreliablefordistinguishingbetweenasymptomaticandsymptomaticdiseaseand
predictingthelikelihoodofanunfavorablelongtermoutcome[81,82].

Inastudythatlookedatcombinedmarkers,thenegativepredictivevalueforsymptomsatbirthorattermination
ofpregnancywas100percentwhenthecombinationofultrasoundfindings,viralloadinamnioticfluid,andfetal
bloodparameterswereconsidered[80].Thepositivepredictivevaluewas79percentwhenthecombinationof
ultrasoundfindings,amnioticfluidviralload,fetalbloodparameterswereconsidered.Theauthorsconcludedthat
asmallincreaseinpredictivevaluewithfetalbloodsamplingdidnotclearlywarrantexposuretotheadditional
risksoffetalbloodsampling,butthisdecisionshouldbemadebasedonindividualpatientvalues.

MagneticresonanceimagingMRImayprovideadditionalinformationaboutanomalies,particularly
neurologicabnormalities[74,8385].However,anormalultrasoundandMRIdonotcompletelyexcludethe
possibilityofdevelopmentofpostnatalhearingloss[86].Thecostoftheadditionaltestingandlikelihoodof
gaininginformationthatwillaltermanagementshouldbeconsideredpriortoobtainingMRIinthesettingofknown
orsuspectedfetalCMVinfection.
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PRENATALCAREANDDELIVERYInadditiontoroutineprenatalcare,symptomaticwomenareoffered
supportivetherapy.(See'Treatment'above.).Antiviraltherapyformaternalindicationsisrarelyindicated(see
'Treatment'above),andnotindicatedforfetaltherapy(see'Antiviraldrugtherapy'below).Prenataldiagnosisis
offeredtowomenathighriskofhavinganaffectedfetus(primarymaternalinfectionorsuggestivefindingson
ultrasound)andtheirfetusesaremonitoredwithserialultrasoundexaminations.(See'Prenatal(fetal)diagnosis'
above.)HyperimmunoglobulintherapyofpregnantwomenwithprimaryCMVinfectioninearlypregnancyisa
promisingbutinvestigationalapproachtoreducingsymptomaticinfectioninoffspring.(See
'Hyperimmunoglobulin'below.)

Thetimingandrouteofdeliveryaredeterminedbystandardmaternalandfetalindications.RecoveryofCMV
fromthecervixorurineisnotanindicationforcesareandelivery.

STRATEGIESFORPREVENTIONOFMATERNALAND/ORFETALINFECTION

ScreeningWesuggestnotscreeningallpregnantwomenforprimaryCMVinfection.

Inourpractice,weobtainCMVserologyinHIVinfectedwomenattheirinitialprenatalvisitandrepeatthe
serologyinscreennegativewomenwhodevelopsigns/symptomssuggestiveofCMVinfectionorhave
suggestivefetalultrasoundfindings.ForanywomanwithaknownexposuretoCMV,weobtainbaselineserology
atthetimeoftheexposureand,ifnegative,repeatserologyseveralweekslatertoassessforseroconversion.

SinceCMVinfectionisusuallyasymptomaticandtransmissibletothefetus,someexpertssuggestthatallwomen
ofchildbearingageshouldknowtheirCMVserostatus,althoughthereisnoconsensus[47,48,87,88].Others,
includingtheAmericanCollegeofObstetriciansandGynecologists[89]andSocietyofMaternalFetalMedicine
Specialists[22],recommendagainstroutineserologicalscreeningforCMVforseveralreasons:

Novaccineisavailabletopreventinfectioninseronegativewomen.

Inseropositivepregnantwomen,itisdifficulttodistinguishbetweenprimaryandnonprimaryinfectionor
determinethetimingoftheinfection,whichcouldhaveoccurredmanymonthsbeforeconception.

Seropositivewomenremainatriskoffetalinfectionfromreactivationoflatentvirusand/orreinfectionwitha
newviralstrain.

Thereisnoevidencethatantiviraldrugtreatmentofprimaryinfectioninpregnantwomenpreventsor
mitigatessequelaeofCMVinfectionintheneonate.(See'Antiviraldrugtherapy'below.)

Theonlyrandomizedtrialofuseofhyperimmuneglobulintopreventcongenitalinfectiondidnotestablisha
benefit.(See'Hyperimmunoglobulin'below.)

Althoughfetalinfectioncanbedetected,thereisnowaytoaccuratelypredictwhetherornotthefetuswill
developsignificantsequelae.

Routinescreeningcanleadtounnecessary,andpotentiallyharmful,intervention.

Ontheotherhand,proponentsofuniversalscreeningarguethatknowingthatherserologyisnegativeforCMV
antibodiesandCMVcounselingincreasesomewomen'smotivationtopracticegoodhygieneandthusdecrease
theriskofseroconversionduringpregnancy.KnowledgeofCMVseronegativityandeducationaboutroutesof
transmissioncanchangematernalbehavioranddecreaseseroconversioninpregnantwomenathighrisk[53,90
92].However,thisinformationdoesnotappeartosignificantlyaffectseroconversionratesinnonpregnantwomen,
eveninthosetryingtoconceive[91].

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Repeatedserologicalscreeningduringpregnancytodetectseroconversionisnotcommonlyperformedbecause
ofcost,lackofeffectivetreatment,andgenerallypoorabilityofpositiveserologytopredictthefetus'longterm
outcome.

ScreeningchildrenforCMVorexcludingCMVexcretingchildrenfromschoolsorinstitutionsisunnecessary
becausethevirusisfrequentlyfoundinmanyhealthychildrenandadults.

Behavioralriskreductioninterventions

PregnantwomenAllpregnantwomenshouldbeawareofCMVpreventionmeasureshowever,noactions
caneliminateallrisksofbecominginfectedwithCMV.Thefollowingmeasuresmayreducetheriskof
transmission:

Practicegoodpersonalhygienethroughoutpregnancy,especiallyhandwashingwithsoapandwaterafter
contactwithdiapersororalandnasalsecretions(particularlywithachildwhoisindaycare).Washwellforat
least15to20seconds.

Avoidkissingchildrenunderage6onthemouthorcheekinstead,kissthemontheheadorgivethema
hug.

Donotsharefood,drinks,ororalutensils(eg,fork,spoon,toothbrush,pacifier)withyoungchildren.

Cleantoys,countertops,andothersurfacesthatcomeintocontactwithchildren'surineorsaliva.

Womenwhocareforyoungchildren

FemalechildcareemployeesshouldbeeducatedconcerningCMV,itstransmission,andhygienicpractices,
suchashandwashing,whichminimizetheriskofinfection.

Pregnantemployeesworkingwithinfantsandyoungchildrenshouldbeinformedoftheirincreasedriskof
acquiringCMVinfectionandthepossibleeffectsontheunbornchild.

RoutinelaboratoryscreeningforCMVantibodyinfemalechildcareworkersisnotrecommended.
Susceptiblewomenworkingwithinfantsandyoungchildrendonothavetobetransferredtootherwork
situationsbutmayreducetheirriskofinfectionbypracticinggoodhygiene.

HealthcareworkersTheriskofCMVinfectionamonghealthcareworkersappearstobenogreaterthan
thatamongthegeneralpublic.Thisisprobablydue,atleastinpart,toadherencetostandardprecautionsby
healthcareproviderswhenhandlingbodyfluidsandlesspersonalcontactinthehealthcaresettingthaninthe
familysetting.

WomenwithrecentinfectionBecauseCMVDNAhasbeendetectedinbloodof20percentof
immunocompetentpatientsaslongassixmonthsafterdiagnosisofprimaryinfection,someexpertssuggestthat
awomanwaitatleastsixmonthsafteraprimaryinfectionbeforeattemptingtoconceivehowever,dataare
limitedandotherexpertssuggestwaitingaminimumofthreeorfourmonths[2,93].

BreastfeedingwomenThedemonstratedbenefitsofbreastfeedingoutweightheminimalriskofacquiring
CMVfromaninfectedbreastfeedingmother.However,HIVinfectedmothersshouldnotbreastfeedroutinelyin
theUnitedStates.(See"PrenatalevaluationoftheHIVinfectedwomaninresourcerichsettings",sectionon
'Counselingregardingbreastfeeding'.)

TransfusionofCMVnegativebloodCMVseronegativepregnantwomen,fetuses,andnewbornsshouldbe
transfused,whennecessary,withbloodfromCMVseronegativedonors.(See"Redbloodcelltransfusionin
adults:Storage,specializedmodifications,andinfusionparameters",sectionon'Specializedmodifications'.)
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201754 CytomegalovirusinfectioninpregnancyUpToDate

Prenataldrugtherapy

AntiviraldrugtherapyTherearesparsedataontheeffectsofmaternalantiviraltreatmentonintrauterine
infection[94,95].Amulticenter,openlabel,phaseIIstudyoforalvalacyclovirtreatmentofpregnantwomen
carryingaCMVinfectedfetuswithmeasurableextracerebralormildcerebralultrasoundfindingsfoundthatthis
interventionimprovedneonataloutcomeofinfectedfetuseswithoutseverebrainabnormalities[95].Compared
withahistoricalcohortobtainedbyametaanalysis,theuseofvalacyclovirincreasedtheproportionof
asymptomaticneonatesfrom43percentwithouttreatmentto82percentwithtreatment.Valacyclovir8gdaily
wasinitiatedatamedianof25.9weeksofgestationandcontinueduntildeliveryorterminationofpregnancy.
Adherencetotreatmentwas>90percentdespitetheneedtotake16pills/day,andthehighdosagewaswell
tolerated.However,thefindingsarelimitedbytheopenlabelstudydesignandshouldbeconfirmedina
randomizedtrialtobetterdeterminetheefficacyofuterotreatmentbeforeitcanberecommended.

HyperimmunoglobulinHyperimmunoglobulintherapyofpregnantwomenwithprimaryCMVinfectionin
earlypregnancyisapromisingbutinvestigationalapproachtoreducingsymptomaticinfectioninoffspring.

InthreeprospectiveobservationalstudiesfromtwogroupsofinvestigatorsinItaly,administrationofCMVspecific
hyperimmuneglobulintopregnantwomenwithprimaryCMVinfectionwasassociatedwithasignificantreduction
inmaternaltofetaltransmissionandseverityofcongenitalinfection[9698].However,asubsequentrandomized
trialdidnotdemonstrateasignificantbenefit.IntheCongenitalHumanCMVInfectionPrevention(CHIP)trial,
124pregnantwomenat5to26weeksofgestationwithrecentonsetofprimaryCMVinfectionwererandomly
assignedtoreceivehyperimmuneglobulinorplaceboeveryfourweeksuntil36weeksofgestationordetectionof
CMVinamnioticfluid[99].Theoverallrateofcongenitalinfectionwassimilarforbothgroups(30versus44
percentintheplacebogroup,14percentagepointdifference95%CI3to31percentagepoints).Theproportion
ofinfectedinfantssymptomaticatbirthwasalsosimilarforbothgroups(3/10CMVinfectednewbornsinthe
hyperimmuneglobulingroup[30percent]versus4/17CMVinfectednewbornsintheplacebogroup[24percent]).
Therewerealsonodifferencesintheviralorimmunecharacteristicsofinfectedinfantsbetweenthegroups.In
addition,thenumberofobstetricaladverseeventswashigherinthehyperimmuneglobulingroupthaninthe
placebogroup(13versus2percent).Twolimitationsofthistrialarethatitwasnotpoweredtodetectsmallbut
statisticaldifferencesinoutcomeandinvestigatorsdidnotevaluatehearingloss,whichisanimportantclinical
outcomethatpotentiallycouldbeaffectedbythistherapy.Untilmoredatafromrandomizedtrialsareavailable,
practitionersshouldemphasizethesimplepreventivemeasuresnotedbelow.CMVhyperimmunoglobulintherapy
shouldonlybeusedinaresearchsettinguntilmoredataareavailable.(See'Strategiesforpreventionof
maternaland/orfetalinfection'above.)

VaccinedevelopmentNoCMVvaccineisavailableforuseinhumans,althoughseveralcandidatevaccines
havebeendevelopedandtestedinclinicaltrials.Inaphase2trialthatincluded464CMVseronegativewomenof
childbearingage,anMF59adjuvantedCMVglycoproteinBsubunitvaccinehad50percentefficacyatpreventing
CMVinfection,whichwastheprimaryendpoint[100].CongenitalCMVinfectionwasdiagnosedinoneinfantofa
vaccinatedsubjectversusthreeinfantsofsubjectswhoreceivedplacebo.Theoverallbenefitsweremodestand
thestudywasnotpoweredtoassessefficacyinpreventingmaternalfetaltransmission[101].

ItisunlikelythataCMVvaccinewillbeavailableforseveralyears.Inaddition,thestrategyofpreventingprimary
maternalinfectiondoesnotaddresstheCMVassociatedhearinglossandotherneurologicsequelaein
congenitallyinfectedchildrenborntowomenwithpreexistingCMVimmunity.Ideally,aCMVvaccinethatinduces
hightitersofcrossneutralizingantibodieswillbedevelopedandwillprotectindividualsfrominfectionwith
antigenicallydifferentCMVstrains[102].AlthoughtheexactnatureofprotectiveimmuneresponsesagainstCMV
hasnotbeencharacterized,arecombinantCMVglycoproteinBvaccinewithMF59adjuvantappearedtoboost
bothantibodyandCD4TcellresponsesinpreviouslyCMVseropositivewomen,therebyraisingthepossibility
thattheseboostedresponsesmaypreventmothertochildtransmissionofCMV[103].

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201754 CytomegalovirusinfectioninpregnancyUpToDate

SOCIETYGUIDELINELINKSLinkstosocietyandgovernmentsponsoredguidelinesfromselectedcountries
andregionsaroundtheworldareprovidedseparately.(See"Societyguidelinelinks:Cytomegalovirusinsolid
organtransplantrecipients".)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and
"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgrade
readinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.These
articlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.Beyond
theBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewritten
atthe10thto12thgradereadinglevelandarebestforpatientswhowantindepthinformationandare
comfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthese
topicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon
patientinfoandthekeyword(s)ofinterest.)

Basicstopic(see"Patienteducation:Avoidinginfectionsinpregnancy(TheBasics)"and"Patienteducation:
Cytomegalovirus(TheBasics)")

BeyondtheBasicstopic(see"Patienteducation:Avoidinginfectionsinpregnancy(BeyondtheBasics)")

SUMMARYANDRECOMMENDATIONS

Approximately2percentofseronegativepregnantwomenwilldevelopaCMVinfectionduringpregnancy.
CMVinfectionmaycauseamildmaternalfebrileillnessandothernonspecificsymptomsbutisnotapparent
in90percentofwomen.(See'Riskofseroconversion'aboveand'Clinicalfindings'above.)

CMVinfectionsinpregnantwomenareclassifiedasprimaryiftheinitialacquisitionofvirusoccursduring
pregnancy,andnonprimaryifmaternalantibodytoCMVwaspresentbeforeconception.Nonprimary
infection,alsosometimescalledrecurrentorsecondaryinfection,maybeduetoreactivationoflatentvirusor
reinfectionwithanewstrain.(See'Classification'above.)

Thetimingofprimarymaternalinfectionisthemostimportantdeterminantofperinatalsequelae.The
occurrenceoffetalinfectionincreaseswithadvancinggestationalageatthetimeofmaternal
seroconversion,buttheoccurrenceofsymptomaticnewbornsdecreaseswithadvancinggestationalageand
isunlikelynearterm.(See'Frequencyofperinataltransmission'above.)

Preconceptionseroimmunityprovidessubstantialprotectionagainsttheoccurrenceoffetalinfection
comparedwithseroconversionduringpregnancybutdoesnotcompletelyprotectthefetusfrominfection
(fetalinfection:approximately1percentversus40percent)(algorithm1).(See'Frequencyofperinatal
transmission'above.)

Oncefetalinfectionoccurs,preexistingimmunityprovideslimitedprotectionagainstnewborndiseaseand
adverseoutcome.(See'Clinicalfeaturesandsequelae'above.)

Congenitalinfectionmaybesymptomaticorasymptomaticinnewborns.Mostcongenitalinfectionsare
asymptomaticintheneonatalperiod.(See'Clinicalfeaturesandsequelae'above.)

Bothsymptomaticandasymptomaticinfectednewbornsareatriskfordevelopmentofadversesequelaein
earlychildhood,butsymptomaticnewbornsareathigherrisk(eg,death5versus0percent,deafness50
versus10percent).(See'Symptomaticnewborns'aboveand'Asymptomaticnewborns'above.)

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201754 CytomegalovirusinfectioninpregnancyUpToDate

ThegoldstandardfordiagnosisofclinicallysuspectedmaternalprimaryCMVinfectionisbasedon
seroconversion(table1).Intheabsenceofdocumentedseroconversion,thepresenceofantiCMV
immunoglobulinG(IgG)andantiCMVimmunoglobulinM(IgM)mayrepresentprimaryinfection,
reactivation,reinfection,orlatentdisease.Inthesecases,aviditytestingisuseful:Highantibodyavidity
suggestsinfectionoccurredmorethansixmonthsinthepast,whilelowaviditysuggestsrecentinfection.
(See'Howtotest'above.)

TestingpregnantwomenforCMVisindicatedaspartofthediagnosticevaluationofwomenwith
mononucleosislikeillnessesorwhenafetalanomalyconsistentwithcongenitalCMVinfectionisdetectedon
prenatalultrasoundexamination.(See'Whomtotest'above.)

WesuggestnotscreeningallpregnantwomenforCMVinfection(Grade2C).(See'Screening'above.)

Prenatal(fetal)diagnosismaybeofferedwhenfetalinfectionissuspectedbecauseofprimarymaternal
infectionorfindingsonultrasound,giventheriskofseveralsequelaeinoffspring.Testingincludes(1)
amniocentesisafter21weeksofgestationandatleastsixweeksafterthepresumedtimeofmaternal
infectiontoperformPCRforCMVDNAand(2)ultrasoundassessmentoftheinfectedfetustodetect
stigmatasuggestiveoffetalsequelae.(See'Prenatal(fetal)diagnosis'above.)

Althoughfetalinfectioncanbedetectedbypolymerasechainreaction,fetalprognosisisdifficulttopredict.
Anabnormalultrasoundexaminationsuggestsapoorprognosis,whileanormalultrasoundexamination
doesnotexcludethepossibilityofasymptomaticneonateordevelopmentoflongtermneurologicmorbidity.
(See'Predictionofclinicaloutcome'above.)

Duringpregnancy,thereisnotreatmentproventobeeffectiveforpreventionoffetaldiseaseorreductionin
riskofsequelae.ForpregnantwomenwithprimaryCMVinfection,wediscussavailabledataontheefficacy
ofhyperimmunoglobulinandthelimitationsofthefewpublishedstudiesaswellaspotentialsideeffectsof
thistherapy.(See'Hyperimmunoglobulin'above.)

MeasurestopreventCMVinfectionduringpregnancyarebasedongoodpersonalhygieneandusingCMV
negativebloodproductswhentransfusingseronegativepregnantwomen.(See'Strategiesforpreventionof
maternaland/orfetalinfection'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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77.BilavskyE,YardenBilavskyH,WaismanY,MarcusN.Bilateralprimaryspontaneouspneumothorax:
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mothersofcongenitallyinfectedfetuses.JClinMicrobiol199937:3350.
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infection.BrazJInfectDis200812:38.
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cytomegalovirusbychangingbehaviors:arandomizedcontrolledtrial.PediatrInfectDisJ199615:240.
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201754 CytomegalovirusinfectioninpregnancyUpToDate

GRAPHICS

InterpretationofCMVserologyinearlypregnancy

CMVantibodies IgGavidity Interpretation Implications

IgMandIgG Notapplicable Uninfectedorveryearly Counselaboutbehavioral

infection measurestoreduceriskof
acquiringinfection

IgM+andIgG Notapplicable Maybefalsepositive(90%) Repeatintwoweeks

duetoanothervirus,
autoimmunedisease,
laboratorymethods

IgM+andIgG+ Low Recentinfection Counselaboutlikelihoodof

Seroconversionis fetalinfection,possible
diagnosticofprimary sequelae,andoptionsfor
infection prenataldiagnosisand
management

IgM+andIgG+ High Pastinfectionversus Counselaboutlowriskof

recurrentinfection fetalinfection,butpossible
Asignificantrise(atleast sequelaeiffetusisinfected
double)inserialIgGtiters
suggestsreactivationor
reinfection

IgMandIgG+ High Pastinfection Counselaboutlowriskof

Absenceofasignificantrise fetalinfectionandpossible
inserialIgGtiterssuggests sequelae
absenceofreactivationor Noneedforfurthertesting
reinfection

IgMandIgG+ Low Unclearbecauseall

validationstudiesofavidity
havebeeninthesettingof
truepositiveIgM

CMV:cytomegalovirusIgM:immunoglobulinMIgG:immunoglobulinG.

Graphic110083Version1.0

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201754 CytomegalovirusinfectioninpregnancyUpToDate

Cytomegalovirusinfectionofplacenta

Lightmicrographillustratingplacentalcytomegalovirusinfection.Arrowspointto
cellswithnuclearinclusions.

CourtesyofDrucillaJRoberts,MD.

Graphic70713Version3.0

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Inuterocytomegalovirusinfectionat23postmenstrual
weeks

PanelsAthroughCareserialcoronalsectionsfromanteriortoposteriorshowing
dilationofthelateralventriclesandperiventricularcalcifications.PanelDisan
obliquesectionshowingthedilationofthelateralventricles,thedysmorphic
choroidplexus,andperiventricularcalcifications.

CourtesyofAnaMonteagudo,MD.

Graphic54305Version6.0

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201754 CytomegalovirusinfectioninpregnancyUpToDate

Mildfetalventriculomegaly

Imageoffetalheaddemonstratingmildventriculomegaly.Theventricleis
measuredintheaxialplane,atthelevelofthefrontalhornsandcavumsepti
pellucidi.Thecalipersarepositionedattheleveloftheinternalmarginofthe
medialandlateralwallsoftheatria,attheleveloftheglomusofthechoroid
plexus,onanaxisperpendiculartothelongaxisofthelateralventricle.

CourtesyofMaryENorton,MD.

Graphic68701Version2.0

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201754 CytomegalovirusinfectioninpregnancyUpToDate

Echogenicfetalbowel

Inthislongitudinalimage,thereisaveryechogenicportionoffetalbowelseen
inthemidabdomenthatisasechodenseasfetalbone.

CourtesyofStephenChasen,MD.

Graphic73631Version3.0

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Longitudinalviewoffetalabdomenshowingfetal
ascites

CourtesyofSvenaJulien,MDandCharlesLockwood,MD.

Graphic56150Version3.0

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Longitudinalviewofaunilateralpleuraleffusionina
fetuswithhydrops

CourtesyofSvenaJulien,MDandCharlesLockwood,MD.

Graphic54321Version4.0

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Longitudinalviewoffetuswithascitesandenlarged
placenta

CourtesyofSvenaJulien,MDandCharlesLockwood,MD.

Graphic62303Version3.0

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201754 CytomegalovirusinfectioninpregnancyUpToDate

PotentialoutcomesofmaternalCMVinfectionduring
pregnancy

CMV:cytomegalovirus.
*PrimarymaternalCMVinfectionisdefinedasinitialacquisitionofvirusduring
pregnancy.Seroconversionfromnegativetopositiveisdiagnostic,ifavailable.Primary
infectionisstronglysuspectedifimmunoglobulinM(IgM)andimmunoglobulinG
(IgG)arepositiveandIgGhaslowavidity.
NonprimarymaternalCMVinfectionreferstowomenwhoseinitialacquisitionofCMV
virusoccurredbeforepregnancy.ItischaracterizedbypresenceofmaternalantiCMV
antibodiesbeforeconception.Likeotherherpesviruses,CMVestablisheslatencyafter
thehostisinitiallyinfected.Womenwithnonprimaryinfectionmayhavereactivationof
latentvirusorreinfectionwithanewstrainduringpregnancy.
Symptomaticdiseaseatbirthandseveresequelaeoccuralmostexclusivelyamong
offspringofwomenwhoseroconvertinthefirsthalfofpregnancy,particularlythefirst
trimester.Inonereview,therewerenosymptomaticnewbornsamong92pregnancies
withthirdtrimestermaternalinfection.Inanotherstudy,therewerenosymptomatic
newbornsamongwomenwhoseroconvertedinthepericonceptionperiod.

Graphic110084Version1.0

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ContributorDisclosures
JeanneSSheffield,MD Nothingtodisclose SureshBBoppana,MD Nothingtodisclose LouiseWilkins
Haug,MD,PhD Nothingtodisclose MartinSHirsch,MD Nothingtodisclose VanessaABarss,MD,
FACOG Nothingtodisclose

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseare
addressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobe
providedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofallauthorsandmustconformto
UpToDatestandardsofevidence.

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