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TheHospitalforSickChildrenSafetyofantiviralmedicationforthetreatmentofherpesduringpregnancy

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Safetyofantiviralmedicationforthetreatmentofherpesduringpregnancy
SoHeeKang,RPh,AngelaChuaGocheco,MD,PinaBozzoandAdrienneEinarson,RN
April2011
ABSTRACT

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QUESTION
Oneofmypatientsisapregnantwomaninherfirsttrimesterwithahistoryofrecurrentgenitalherpes.Sheisconcerned
aboutwhetheruseofherantiviralmedicationwilladverselyaffectherbaby.WhatshouldItellher?

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ANSWER
Studieshaveshownthattheuseofacyclovirorvalacyclovirisnotassociatedwithanincreaseinbirthdefects.Limited
dataexistforfamciclovirandthereforeitwouldnotbeconsideredafirstlinechoicefortreatmentofherpesduring
pregnancy.

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QUESTION

ConditionsinPregnancy

L'unedemespatientesenceintesenestsonpremiertrimestredegrossesseetelleadesantcdentsd'herpsgnital
rcurrent.Ellesedemandesil'utilisationdesesmdicamentsantivirauxpourraitnuiresonbb.Quedevraisjelui
rpondre?

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RPONSE

MotherNature

Destudesontdmontrquel'utilisationdel'acyclovirouduvalacyclovirn'estpasassocieuneaugmentationdes
anomaliescongnitales.Lesdonnesconcernantlefamciclovirsontlimitesetcemdicamentnedevraitdoncpastre
considrcommechoixdetraitementdepremireintentionpourl'herpsdurantlagrossesse.

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News

CurrentStudies

Herpessimplexvirus(HSV)infectionsarecommonviralinfections,withalmost40%ofinfectedpatientsencounteringfrequent
recurrencewithinthefirstyearofdiseaseonset.1 InOntariotheseroprevalenceforHSVtype1(HSV1)andtype2was51.1%

Apr

and9.1%,respectively.2 ACanadianstudyrevealedHSVtype2seropositivityinpregnantwomentobe17.3%,whichraises

17

theconcernofpotentialviraltransmissionfrommothertoinfant.3 ItisalsoimportanttonotethatgenitalherpesduetoHSV1

2015

infectionshasincreasedinfrequencyandisresponsibleforupto30%to50%ofnewgenitalHSVinfections.3,4 Recent
findingsindicatethatpregnantwomenwhoacquireHSVasaprimaryinfectioninthelatterhalfoftheirpregnanciesareat

Jan

greatestriskoftransmissiontoneonates.5

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NeonatalHSVinfectionsareconsideredmoreseriouscomparedwithadultinfections,havingconsequencesthatincludethe
following:skin,eye,andmouthinfectionscentralnervoussystemdiseasesdisseminatedinfectionsanddeath.The
CanadianneonatalHSVsurveillancedataindicatethatthereare5.9casesper100000livebirths,stressingtheimportance
ofantiviraltreatmentduringpregnancytoreducesuchcomplications.6 Treatmentwithantiviralsinadultshasestablishedtheir
efficacyandsafety,butevidenceofthesafetyofacyclovir,famciclovir,andvalacyclovirduringpregnancyisrelativelylacking.
Itisimportanttodiscusstheuseoftopicalantiviralpreparationsowingtotheneedtopreventpotentialorolabialtogenital
transmissionofHSV1.

2015

Oct

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2014

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Morphinefollowing
commonchildhoodsurgery
maybelifethreatening
Probioticsmaysignificantly
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Generalpropertiesandmechanismofaction
Valacycloviriswellabsorbedafteroraladministrationabsorptionofasingledoseof1000mgis54%higherthanthat
achievedaftersingle200or800mgdosesoforalacyclovir.7 Valacyclovirisrapidlymetabolizedtoacyclovir,the
triphosphorylatedformofwhichselectivelyinhibitshumanHSVDNApolymerase,reducingviralDNAreplication.Similarly,
famcicloviristheoralprodrugofitsactiveformpencicloviritismorestablethanacyclovirtriphosphate,asevidencedby
longerhalflivesintracellularly,whichmightaccountfortheprolongedinvitroantiviralactivity.8 Acyclovir5%andpenciclovir
1%creamsareusedtotreatorolabialherpes(HSV1).Penciclovirwasnotdetectedintheplasmaorurineofhealthy
volunteersaftersingleorrepeatedapplicationofthe1%cream.9 Systemicabsorptionofacyclovirfollowingtopicalapplication
isminimalorundetectableinadults.10
Safetyofantiviralsduringpregnancy
AlthoughcontrolledstudiesevaluatingtheeffectivenessoforalantiviralsforrecurrentHSVoutbreaksinthemotherand
neonatalHSVinfectionsatdeliverydoexist,theyarelimitedbysmallsamplesizes,thelackoffetalsafetyoutcomes,and
variationintimingofexposure.11 However,dataonthesafetyofantiviraldrugsduringpregnancyhavebeencollectedin
pregnancyregistries,usuallyestablishedbythemanufacturers.Theoldestregistry(ie,AcyclovirPregnancyRegistry)was
openfrom1984to1998,evaluatingtheuseoforalorintravenousacyclovirinpregnantwomen.Intotal,1234pregnancies
werenotedwith1246outcomesfrom24countries756exposedpregnancieswerestudiedinthefirsttrimester.Theriskof
birthdefectswas3.2%(95%confidenceinterval2.0%to5.0%),whichissimilartothebaselineriskofbirthdefectsinthe

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TheHospitalforSickChildrenSafetyofantiviralmedicationforthetreatmentofherpesduringpregnancy

generalpopulation.Nounusualdefectsorpatternsofdefectswereseen,butthelimitationoftheresultswasthehighlossto
followup(27%ofregistrants).12 Duringtheyears1995to1999,themanufacturerofvalacyclovirmaintaineditspregnancy
registry,and110exposureswerereportedwith111knownoutcomes.Withinthefirsttrimester,1birthdefectwasreportedout
of28exposures2of31and1of51exposuresresultedindefectsinthesecondandthirdtrimesters,respectively.Prenatal
exposuresweretoolimitedtoprovidepregnancyoutcomes.Accordingtopersonalwrittencorrespondencefrom
GlaxoSmithKlinetoMotherisk(January2010),thisregistrywaslimitedbythenumberofregistrantsandthelengthof
monitoring.
ArecentDanishpopulationbasedretrospectivecohortstudyuseddatafromitsnationwideregistrytoexamineliveborn
infantsbornbetween1996and2008whowereexposedtoantiviralsduringpregnancyandtherateofmajorbirthdefects
withinthefirstyearoflife.Ofthe837795enrolledinfants,1804pregnancieswereexposedtoacyclovir,valacyclovir,or
famciclovirinthefirsttrimesterprevalenceoddsratioswereconsiderednodifferentbetweenexposedandunexposed
cohorts.Similarresultswerefoundwhenevaluatingsecondandthirdtrimesterdata.Therewasalsonosignificantdifference
intheprevalenceofmalformationsbetweenexposedandunexposedgroupswhenexaminingexposureduringthefirst
trimestertoindividualantivirals.Therateofmalformationswas2.0%foracyclovir(32of1561infants)and3.1%for
valacyclovir(7of229infants).Forfamciclovir,exposurewasuncommonwith1infantof26exposedhavingabirthdefect.Asa
supplementaryanalysis,theassociationbetweentheuseofdermatologicacyclovirandpenciclovircreamsandmajorbirth
defectswasevaluated.Therateofmalformationsinthoseexposedtoacyclovircreamandpenciclovircreaminthefirst
trimester(2.3%,65of2850infants,and4.2%,5of118infants,respectively)wasnotdifferentfromtheunexposedcohort
similarresultswerefoundinthesecondandthirdtrimestersofpregnancy.13
Conclusion
Theaccumulatedevidenceforthesafetyoforalacyclovirandvalacyclovir,establishedfromthemanufacturer'spregnancy
registriesandasaresultoftheDanishcohortstudy,doesnotdemonstrateanincreaseintherateofmajorbirthdefectswhen
comparedwiththegeneralpopulationoranunexposedgroup.Dataonthesafetyoffamciclovir'suseduringpregnancyis
quitelimited,andalthoughitmightnotbeexpectedtoincreasetheriskofmajormalformations,itshouldnotbethefirstchoice
ofmedicationfortreatmentofHSVduringpregnancy.Inaddition,topicalantiviralpreparationsofacyclovirandpenciclovir
resultedinnoincreasedrateofmajorbirthdefectsduringpregnancy.Limitationsofthesafetydataonantiviralsincludeahigh
losttofollowuprateintheregistriesandthelackofprospectivecontrolledstudies.However,thesedataarereassuring,
allowingphysicianstoofferpregnantpatientseitheracyclovirorvalacyclovirfortreatmentofprimaryorrecurrentHSV
infection,whichnotonlytreatsthemother'scondition,butalsoreducesthelikelihoodoftransmissiontotheneonate,without
undulycompromisingfetalsafety.
Motherisk
MotheriskquestionsarepreparedbytheMotheriskTeamattheHospitalforSickChildreninToronto,Ont.Ms.Kangisa
doctoralcandidateintheFacultyofPharmacyattheUniversityofToronto.Dr.ChuaGochecoisamemberoftheMotherisk
Program.Atthetimethispaperwaswritten,Ms.BozzowasamemberandMs.EinarsonwasAssistantDirectorofthe
MotheriskProgram.Ms.BozzoisnowAssistantDirectorandMs.Einarsonhasretiredbutcontinuestobeamemberofthe
MotheriskProgram.
Doyouhavequestionsabouttheeffectsofdrugs,chemicals,radiation,orinfectionsinwomenwhoarepregnantor
breastfeeding?WeinviteyoutosubmitthemtotheMotheriskProgrambyfaxat4168137562theywillbeaddressedin
futureMotheriskUpdates.
PublishedMotheriskUpdatesareavailableontheCanadianFamilyPhysicianwebsite(www.cfp.ca)andalsoonthe
Motheriskwebsite(www.motherisk.org).
Viewabstract??
Competinginterests
Nonedeclared
CanadianFamilyPhysician
April2011vol.57no.4427428
Copyright?theCollegeofFamilyPhysiciansofCanada
References
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Med1994121(11):84754.Abstract/FREEFullText
2. HowardM,SellorsJW,JangD,RobinsonNJ,FearonM,KaczorowskiJ,etal.Regionaldistributionofantibodiestoherpes
simplexvirustype1(HSV1)andHSV2inmenandwomeninOntario,Canada.JClinMicrobiol200341(1):849.
Abstract/FREEFullText
3. PatrickDM,DawarM,CookDA,KrajdenM,NgHC,RekartML.Antenatalseroprevalenceofherpessimplexvirustype2
(HSV2)inCanadianwomen:HSV2prevalenceincreasesthroughoutthereproductiveyears.SexTransmDis
200128(7):4248.Medline
4. XuF,SternbergMR,KottiriBJ,McQuillanGM,LeeFK,NahmiasAJ,etal.Trendsinherpessimplexvirustype1andtype2
seroprevalenceintheUnitedStates.JAMA2006296(8):96473.Abstract/FREEFullText
5. AnzivinoE,FioritiD,MischitelliM,BellizziA,BaruccaV,ChiariniF,etal.Herpessimplexvirusinfectioninpregnancyand
inneonate:statusofartofepidemiology,diagnosis,therapyandprevention<.VirolJ20096:40.CrossRef|Medline
6. KroppRY,WongT,CormierL,RingroseA,BurtonS,EmbreeJE,etal.Neonatalherpessimplexvirusinfectionsin
Canada:resultsofa3yearnationalprospectivestudy.Pediatrics2006117(6):195562.Abstract/FREEFullText
7. OrmrodD,ScottLJ,PerryCM.Valaciclovir:areviewofitslongtermutilityinthemanagementofgenitalherpessimplex
virusandcytomegalovirusinfections.Drugs200059(4):83963.CrossRef|Medline
8. SimpsonD,LysengWilliamsonKA.Famciclovir:areviewofitsuseinherpeszosterandgenitalandorolabialherpes.
Drugs200666(18):2397416.CrossRef|Medline
9. Denavircream1%[packageinsert].Parsippany,NJ:NovartisConsumerHealth,Inc2002.

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10. Zoviraxcream5%[packageinsert].ResearchTrianglePark,NC:GlaxoSmithKline2002.
11. HollierLM,WendelGD.Thirdtrimesterantiviralprophylaxisforpreventingmaternalgenitalherpessimplexvirus(HSV)
recurrencesandneonatalinfection.CochraneDatabaseSystRev2008(1):CD004946.
12. GlaxoSmithKline.Acyclovirpregnancyregistryandvalacyclovirpregnancyregistry[interimreport].ResearchTriangle
Park,NC:GlaxoWellcome1997.
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defects.JAMA2010304(8):85966.Abstract/FREEFullText

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