3/12/2015 Hepatitis B and pregnancy

OfficialreprintfromUpToDate
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HepatitisBandpregnancy

Authors SectionEditors DeputyEditor

HannahLee,MD RafaelEsteban,MD JenniferMitty,MD,MPH
AnnaSFLok,MD LouiseWilkinsHaug,MD,
PhD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Nov2015.|Thistopiclastupdated:Jul24,2015.
INTRODUCTIONHepatitisBduringpregnancypresentswithuniquemanagementissuesforboththe
motherandfetus.TheseincludetheeffectsofHBVonmaternalandfetalhealth,theeffectsofpregnancyon
thecourseofHBVinfection,treatmentofHBVduringpregnancy,andpreventionofperinataltransmission.
Preventionofperinataltransmissionisanimportantcomponentofglobaleffortstoreducetheburdenofchronic
HBVsinceverticaltransmissionisresponsibleforapproximatelyonehalfofchronicinfectionworldwide.(See
"Epidemiology,transmission,andpreventionofhepatitisBvirusinfection".)

TheriskofdevelopingchronicHBVinfectionisinverselyproportionaltotheageattimeofexposure.Therisk
isashighas90percentinthoseexposedatbirth,whiletheriskismuchlower(about20to30percent)in
thoseexposedduringchildhood.Maternalscreeningprogramsanduniversalvaccinationhavesignificantly
reducedtransmissionrates.Identificationofatriskmotherspermitsprophylaxisagainsttransmission,which
canreducetransmissionratesfrom90percenttoaslowas5to10percent.Methodsofprophylaxisandrisk
factorsfortransmissiondespiteprophylaxisaredescribedfurtherbelow.

IMPLICATIONSOFHBVINFECTIONFORTHEMOTHER

Effectonpregnancyoutcomes

AcuteHBVAcuteviralhepatitisisthemostcommoncauseofjaundiceinpregnancy[1].Othercauses
includeacuteliverdiseasesassociatedwithpregnancysuchasacutefattyliverofpregnancy,HELLP,and
intrahepaticcholestasisofpregnancy(seeappropriatetopicreviews).

AcuteHBVinfectionduringpregnancyisusuallynotsevereandisnotassociatedwithincreasedmortalityor
teratogenicity[1,2].Thus,infectionduringgestationshouldnotpromptconsiderationofterminationofthe
pregnancy.However,therehavebeenreportsofanincreasedincidenceoflowbirthweightandprematurityin
infantsborntomotherswithacuteHBVinfection[2,3].Furthermore,acuteHBVoccurringearlyinthe
pregnancyhasbeenassociatedwitha10percentperinataltransmissionrate[3].Transmissionrates
significantlyincreaseifacuteinfectionoccursatornearthetimeofdelivery,withratesreportedashighas60
percent[1].

Treatmentofacuteinfectionduringpregnancyismainlysupportive.Liverbiochemicaltestsandprothrombin
timeshouldbemonitored.Antiviraltherapyisusuallyunnecessary,exceptinwomenwhohaveacuteliver
failureorprotractedseverehepatitis[4](see"ClinicalmanifestationsandnaturalhistoryofhepatitisBvirus
infection",sectionon'Acutehepatitis').Inthissetting,lamivudine(100mgdaily)isareasonableoptionsinceit
hasbeenusedsafelyduringpregnancyandtheanticipateddurationoftreatmentisshort[5].Telbivudineor
tenofovir(bothconsideredpregnancyclassBdrugsbytheUSFoodandDrugAdministration[FDA])are
acceptablealternatives.(See'Antiviraltherapyduringpregnancy'below.)

ChronicHBVPregnancyisgenerallywelltoleratedbywomenwithchronichepatitisBinfectionwhodo
nothaveadvancedliverdisease.However,becauseoccasionalpatientsdevelopahepatitisflare,HBsAg
positivemothersshouldbemonitoredclosely.Weobtainliverbiochemicaltestseverythreemonthsduring
pregnancyandforsixmonthspostpartum.HBVDNAshouldbetestedconcurrentlyorwhenthereisALT
elevation.

TherearenoestablishedassociationsbetweenchronicHBVandthedevelopmentofotherdiseasesduring
pregnancy.PossibleassociationshavebeendescribedbetweenchronicHBVandgestationaldiabetesmellitus

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[6,7].However,dataaremixedandconflicting[8,9],andthestrengthoftheseassociationsisunclear.

Pregnancyisconsideredtobeanimmunetolerantstateandisassociatedwithhighlevelsofadrenal
corticosteroidswithmodulationofcytokinesinvolvingtheimmuneresponse.Thishasthepotentialtoincrease
HBVviremia,althoughmoststudieshavefoundthatHBVDNAlevelsremainstableduringpregnancy[10,11].
ALTlevelstendtoincreaselateinpregnancyandinthepostpartumperiodinwomenwithchronicHBV
infection.(See"Immunologyofthematernalfetalinterface".)

Theimmunologicalchangesduringpregnancyandpostpartumhavebeenassociatedwithhepatitisflares
(includinghepaticdecompensation),althoughflares(particularlythosewithseriousclinicalsequelae)appearto
beuncommon[12].Inthepostpartumperiod,flaresmayberelatedtoimmunereconstitution,asituation
immunologicallyanalogoustoflaresthathavebeendescribedfollowingthewithdrawalofcorticosteroidsin
nonpregnantpatientswithchronicHBV[1315].PredictorsofHBVflaresduringpregnancyhavenotbeen
established.

FlareshavebeenassociatedwithHBeAgseroconversioninapproximately12to17percentofpatients[13],a
ratesimilartowhathasbeendescribedinpatientswhoarenotpregnant.PredictorsofHBeAgseroconversion
inpatientswhodevelopaflareremainuncertain.Limitedevidencesuggeststhatseroconversionisunrelatedto
maternalage,parity,orthepresenceofprecoreorbasalcorepromotormutations[13,16].

EffectofpregnancyonliverdiseaseImmunologic,metabolic,andhemodynamicchangesthatoccur
duringpregnancyhavethepotentialtoworsenorunmaskunderlyingliverdisease.Assessmentoftheseverity
ofliverdiseasecanbedifficultduringpregnancybecauseofnormalphysiologicchangesthatcanmimic
clinicalfeaturesofchronicliverdisease.Inparticular,serumalbuminandhematocritoftendecrease,while
alkalinephosphataseandalphafetoproteinincrease.Similarly,physicalexaminationmayrevealfindings
suggestiveofstigmataofchronicliverdiseasesuchaspalmarerythema,lowerextremityedema,andspider
angioma.

Pregnancyinpatientswithadvancedcirrhosisisunusualsincesuchpatientstypicallyhavedecreasedfertility
duetoanovulatorycycles.Pregnancyismorelikelyinthosewithearlycirrhosis.Itisimportanttoidentifyand
monitorsuchpatientssincetheyareatsignificantriskforperinatalcomplicationsandpoormaternalandfetal
outcomesincludingintrauterinegrowthrestriction,intrauterineinfection,prematuredelivery,andintrauterine
fetaldemise.TheincreasedriskwasdemonstratedinapopulationbasedstudyinCanada,whichcompared
maternalandfetaloutcomesin399patientswithcirrhosistoamatchedcontrolgroupwhodeliveredbetween
1993and2005[17].Maternalcomplicationsincludinggestationalhypertension,placentalabruption,and
peripartumhemorrhagewereincreasedinthegroupwithcirrhosis.Inaddition,15percentofmotherswith
cirrhosisdevelopedhepaticdecompensation.Overallmortalitywassignificantlyhigherthancontrols(1.8
versus0percent).Theinfantsbornofmotherswithcirrhosishadhigherratesofprematurityandgrowth
restriction,whilethereweresignificantlyhigherratesoffetalmortality(5.2versus2.1percent).Otherreports
havedescribedanincreasedriskofvaricealbleeding,particularlyduringthethirdtrimesterandduringlabor
becauseofincreasedintraabdominalpressureandplasmavolumeexpansion.

Themanagementofapregnantwomanwithcirrhosisdoesnotdifferfromthatofnonpregnantpatients.
Varicealscreeningwithendoscopyisstillrecommendedandissafeduringpregnancy.Activevaricealbleeding
shouldbemanagedthesamewaywithbandingorsclerotherapy.However,treatmentwithbetablockadeeither
forprophylacticorpostvaricealbleedingmanagementshouldbeusedwithcautionbecauseofanincreased
riskofintrauterinegrowthrestriction,fetal/neonatalbradycardia,neonatalhypoglycemia,and/orneonatal
respiratorydepression.Octreotideshouldnotbegivenduringmanagementofacutevaricealbleedingbecause
oftheriskofuterineischemia.

AntiviraltherapyduringpregnancyVariousfactorsneedtobeconsideredwhendecidingonantiviral
therapyduringpregnancyincludingtheindications,anticipateddurationoftherapy,potentialadverseeffectsto
thefetus,efficacy,andtheriskofthedevelopmentofdrugresistance.Thehealthofthemotherandfetusmust
beconsideredindependentlywhendecidingontreatment.Thesafetyofmedicationexposureinthefetusneeds
tobeweighedagainsttheriskofstoppingorchangingtherapyforthemother.

Therearegenerallytwoindicationsforantiviraltherapyduringpregnancy:

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Treatmentofchronicdiseaseinthemother

Treatmenttodecreasetheriskofperinataltransmission

AntiviraltherapyinwomenwithchildbearingpotentialIndicationsforantiviraltherapyarethesameas
thoseforpatientswhodonothavechildbearingpotential.TheyaredeterminedbyHBVDNAlevels,HBeAg
status,andtheactivityorstageofliverdisease.(See"OverviewofthemanagementofhepatitisBandcase
examples".)

However,thereareimportantconsiderationsinwomenofchildbearingpotential:

Thosewithmildliverdiseasewhoarecontemplatingstartingafamilyinthenearfuturemaychooseto
defertreatmentandbeobserveduntiltheyhavecompletedtheirfamily.

Thosewhoelecttoundergotreatmentbeforeattemptingpregnancymayoptforpegylatedinterferon
becauseofitsfiniteduration(48weeks),providedthattheyareadvisedtopracticecontraceptionduring
treatment.Ifanucleos(t)ideanalogueispreferred,tenofovirmaybeagoodchoicelimitedexperience
supportsitssafetyinpregnancy,andtheriskofdrugresistanceislow.

Patientswhobecomepregnantwhilereceivingantiviraltherapyshouldinformtheirclinicianimmediately.
Therisksandbenefitsofcontinuingtreatmentshouldbediscussed.Continuingtreatmentmayposea
risktothefetus,whilediscontinuingtreatmentmayposeariskofhepatitisflareforthemother.
Discontinuingtreatmentcanbeconsideredinwomenwithoutcirrhosis.Asanalternative,inwomen
receivingentecaviroradefovir(bothratedpregnancyclassCbytheUSFoodandDrugAdministration),
treatmentcanbecontinuedbyswitchingtoantiviralagentsthathavearelativelylowriskofteratogenicity
(suchastelbivudineortenofovir,whichareratedascategoryBbytheUSFoodandDrugAdministration)
orhavesubstantialsafetyinhumans(lamivudineortenofovir).Thesewomenshouldbemonitoredclosely
duringthetransitionperiodtoensureviralsuppressionand,iflamivudineortelbivudineisused,toensure
aswitchbacktoentecavirortenofovirafterdeliverytominimizetheriskofdrugresistance.

ChoiceofantiviraltherapyTherapeuticoptionsforchronicHBVincludeoralnucleos(t)ideanaloguesand
pegylatedinterferon.NoneoftheHBVagentsisapprovedbytheUSFoodandDrugAdministrationforusein
pregnancy.AllareratedpregnancycategoryC,exceptfortenofovirandtelbivudine,whicharecategoryB.The
designationofcategoryBfortenofovirandtelbivudinewasbasedonanimalexposuredata.Therearenolarge
studiesthathaveaddressedthesafetyofantiviraltherapyinpregnancy.Althoughlamivudineisconsidered
categoryC,thereisalonghistoryofsafetydatainHIVinfectedwomen.

Nucleos(t)ideanaloguesAmongthenucleos(t)ideanalogues,tenofovirandentecavirarethefirstline
drugsbecauseoftheirpotencyforviralsuppressionandhighgeneticbarrierforresistance.Bycontrast,
lamivudineandtelbivudinehavelowbarrier(highrisk)fordrugresistance,andadefovirhasweakantiviral
activity.Baseduponcurrentdata,lamivudineandtenofovirarepreferredifantiviraltherapyiscontemplatedin
pregnantwomen.Telbivudinecanalsobeconsidered.Thechoicedependsinpartupontheintendeddurationof
therapy.Tenofovirisabetterchoiceinwomenwhowillreceivelongtermtreatmentbecauseofalowriskof
resistance.

Whenantiviraltherapyshouldbediscontinuedpostpartumhasnotbeendetermined.Manyexpertswouldstop
treatment4to12weeksafterdeliveryifthesolepurposeofantiviraltherapyistodecreasetheriskof
maternalinfanttransmission.Motherscontemplatingbreastfeedingcanstoptreatmentafterdelivery(see
'Breastfeeding'below).Closemonitoringisnecessaryaftertreatmentisdiscontinuedbecauseofthepossibility
ofadevelopingahepatitisflare.

PegylatedinterferonAsnotedabove,pegylatedinterferoncanalsobeconsideredbeforepregnancy.
Althoughithastobegivenasasubcutaneousinjectiononceperweek,anattractivefeatureisitsfinite
durationofonly48weeks.

SafetyThereareseveralconsiderationsrelatedtothesafetyoftherapyinpregnancy.

RiskofteratogenicityTherearelimiteddataavailableontheriskofteratogenicityofHBVdrugs.
TheAntiretroviralPregnancyRegistry(www.apregistry.com),whichwasestablishedin1989toevaluatethe

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potentialteratogeniceffectsofHIVagents,begancollectingdataonexposuretoHBVagentssince2003.
Informationprovidedtotheregistryoriginatesfromclinicalstudiesandretrospectivereportsofantiviral
exposure.Thusfar,birthdefectratesamonginfantsexposedtoHBVantiviralagentshavebeensimilarto
ratesreportedinthegeneralpopulation[18].AsofJuly2013,theregistryincludeddatafor7072infantswho
hadbeenexposedtolamivudineduringthesecondorthirdtrimester[19].Thebirthdefectsratewas2.9
percent,whichwascomparabletobirthdefectsratesofthegeneralpopulation.Ofthe4360infantswhowere
reportedtobeexposedtolamivudineduringthefirsttrimester,thebirthdefectratewas3.1percent.For
tenofovir,1982infantswereexposedduringthefirsttrimester,withabirthdefectrateof2.3percent,and959
infantswereexposedtotenofovirduringthesecondorthirdtrimester,withabirthdefectrateof2.1percent.
Forentecavir,only55infantshadbeenreportedtobeexposedduringthefirsttrimester,andonlytwoduring
thesecondorthirdtrimester,withonlytwoincidenceofbirthdefectreportedinthefirsttrimestergroup.For
adefovir,only48infantshadbeenreportedtobeexposedinthefirsttrimester,withnoreportsofbirthdefects
andnoreportswithregardstoexposureinthesecondorthirdtrimester.Thereistheleastamountof
informationontelbivudineintheregistry,withatotalof24exposuresandnoreportsofbirthdefects,but
telbivudinehadbeenstudiedinatleasttwoclinicaltrials[20,21].

Thereareimportantlimitationstotheseobservations.Theregistrydependsuponvoluntaryreporting,andthe
informationisnotverified.Longtermfollowupislimited,andtherearenoeffortstoconfirmthediagnosisof
birthdefects.Furthermore,dataareavailableforbirthdefectsamonglivebirths,buttherearenodataon
miscarriagesorsubsequentdevelopmentaldelays.Muchoftheclinicaldatahavebeenonlamivudineand
tenofovirbecausethesedrugsarealsousedfortreatmentofHIVinfection.

OtherpotentialadverseeventsAnumberofadverseeventsofnucleos(t)ideanalogueshavebeen
described,includingmitochondrialdamage,lacticacidosis,acutefattyliver,andpossiblyboneabnormalities.

SymptomaticlacticacidosishasbeenreportedininfantsborntoHIVinfectedmotherswhowereexposed
toantiretroviraltherapy(whichincludednucleos(t)ideanalogues)inutero,butithasnotbeenobservedin
infantsexposedtoHBVantiviralagentsinutero.Monitoringforlacticacidosisintheinfantsisnot
necessaryifthemothersreceivedHBVantiviralagentsonly.

Tenofovirhascausedboneabnormalitiesintheoffspringofrhesusmonkeyswhohadbeenexposedto
thedrug[22],butsuchanassociationhasnotbeenobservedininfantsfollowinginuterotenofovir
exposure[2325].

StudiesmainlyintheHIVpopulationhavenotrevealedaneffectoftenofovironbirthweight,although
thereareconflictingresultsregardingtheeffectonheadcircumferenceandgrowth[2427].Interferonhas
beenclassifiedascategoryCbytheFDA.Ithadabortifacienteffectsinrhesusmonkeys[28],butthere
arenosuchreportsinhumans[29],althoughdataarelimited.Becauseofthelimiteddata,allwomen
receivinginterferontherapymustusebirthcontrol.

BreastmilkBreastfeedinghasgenerallynotbeenrecommendedformotherswhoremainonantiviral
therapypostpartum.Thenucleos(t)ideanaloguesareexcretedintothebreastmilk,andtherearelittledata
regardinghowmuchdrugexposuretheremaybetotheinfantduringbreastfeeding.

However,emergingdataindicatethatonlylowlevelsoftenofovirareinmaternalbreastmilk,andtheselevels
areunlikelytohavebiologicaleffectsinthenursinginfant[3033].Asexamples:

AstudyevaluatingtenofovirandemtricitabineinthebreastmilkoffiveHIVinfectedwomeninAfrica
foundthatthemedianamountoftenofovirandemtricitabineingestedviabreastfeedingwouldbe0.03and
2percent,respectively,oftheproposedoralinfantdoses[32].

Ananimalstudyevaluatingtwonursingrhesusmacaquesfoundthatalthoughtenofovirwasdetectedin
breastmilk,thepeakconcentrationswereapproximately2to4percentofthosedetectedintheserum
[31].Inaddition,thebreastmilkareaunderthecurve(AUC)concentrationswasapproximately20
percentoftheserumAUCconcentrations.

Thus,forwomenwhorequirepostpartumantiviraltherapy,safetyinformationabouttheseagents,thebenefits
ofbreastfeeding,andtheavailabilityofalternativestobreastfeedingshouldbediscussedandindividualized

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decisionsshouldbemade.

IMPLICATIONSOFHBVINFECTIONFORTHEINFANT

HBVinneonatesTheimpactofhepatitisBvirus(HBV)onnewbornshasnotbeenwelldefined(see
"Hepatitisvirusesandthenewborn:Clinicalmanifestationsandtreatment",sectionon'HepatitisB').Onelarge
study,compared824hepatitisBsurfaceantigen(HBsAg)positivewomenwith6281HBsAgnegativecontrols
[34].Nodifferenceswereseeningestationalageatdelivery,inbirthweight,inincidenceofprematurity,in
neonataljaundiceorcongenitalanomalies,orinperinatalmortality.Conversely,possibleassociationshave
beendescribedbetweenchronicHBVandgestationaldiabetesmellitus[6,7,35],anincreasedriskof
prematurity[36],lowerbirthweight[37],andantepartumhemorrhage[35].However,dataaremixedand
conflicting[8,9],andthusthestrengthoftheseassociationsisunclear.

PerinataltransmissionTheriskofperinataltransmissionofHBVtoinfantsborntoHBsAgpositive
mothershasbeenreportedtobeashighas90percentwithouttheuseofactiveandpassiveimmunization
[38].Maternalinfanttransmissioncanoccurinutero,atbirth,orafterbirth.(See'Riskfactorsforperinatal
transmission'belowand'Preventionofperinataltransmission'below.)

However,theriskofHBVtransmissionhasbeensignificantlyreducedwiththeintroductionofuniversal
maternalHBVscreening,vaccinationofallnewborns,andtheuseofprophylactichepatitisBimmuneglobulin
(HBIG)forinfantsofHBsAgpositivemothers.Asanexample,perinatalHBVinfectionoccurredin1.1percent
ofnewbornsinacohortstudythatevaluated9252infantsborntoHBsAgpositivemothersintheUnitedStates
[39].Approximately95percentofinfantsreceivedhepatitisBvaccineandHBIGwithin12hoursofbirth,and
almostallcompleted3dosesofthehepatitisBvaccineseries.Transmissionwassignificantlyassociated
withhavingamotherwhowasHBeAgpositive,hadaHBVviralload>2000IU/mL,orwas<25yearsold
transmissionwasalsoassociatedwithreceiving<3dosesofthehepatitisBvaccineseries.

Thehighprotectiveefficacyofneonatalvaccinationsuggeststhatmostinfectionsoccuratbirthwhenmaternal
secretionsinthebirthcanalcomeintocontactwiththeinfant'smucosalmembranes.Insupportofthis
hypothesis,astudyperformedinChinafoundthatonly3.7percentofbabieswhotestedpositiveforHBsAgat
birthwereinfectedthroughintrauterinetransmission[40].

RiskfactorsforperinataltransmissionThemostimportantriskfactorsfortransmission,despite
properadministrationofprophylaxis(HBIGandfirstdoseofhepatitisBvaccinegivenwithin12hoursofbirth,
andcompletionofhepatitisBvaccineseries)appeartobeapositivehepatitisBeantigen(HBeAg)inthe
motherandahighmaternalHBVviralload.

Transplacentaltransmissionandtransmissionduetoobstetricalproceduresarelessfrequentcauses,while
breastfeedingdoesnotappeartoposeasubstantialrisk.Thebenefitofcesareandeliveryinprotectingagainst
transmissionhasnotbeenclearlyestablished.Thus,theobstetricalapproachshouldnotbeinfluencedbythe
HBVstatusofthemother.

HBVreplicativestatusTheriskoftransmissionisincreasedinwomenwhoareinthereplicative
phase(ie,HBeAgpositive)(see"ClinicalmanifestationsandnaturalhistoryofhepatitisBvirusinfection",
sectionon'Replicativephase:Immunetolerance').Inoneseries,transmissionoccurredintheabsenceof
prophylaxisin85to90percentofinfantsborntoHBeAgpositivemothersand32percentofinfantsbornto
HBeAgnegativemothers[41].ChildrenborntoHBeAgpositivemothersremainatriskforHBVinfection,even
iftheyreceivevaccinationandHBIG(approximately9percentinonelargecohortstudy)[42].

HBVDNAlevelMaternalserumHBVDNAlevelscorrelatewiththeriskoftransmission.Vertical
transmissionofhepatitisBoccursin9to39percentofinfantsofhighlyviremicmothers(108copies/mLand
possibly106copies/mL)despitepostnatalvaccination[4346].TheriskofHBVtransmissionisrarewhen
maternalHBVDNAis<105to106int.units/mL.Asexamples:

Inastudyof773HBsAgpositivemothersinTaiwan,theoddsratioforhavinganinfectedinfant
increasedfrom1to147asthematernalserumHBVDNAlevelsincreasedfrom5pg/mL(approximately
150,000IU/mL)to>1400pg/mL(approximately45,000,000IU/mL)[47].

InanotherstudyconductedinChinainvolving112newbornsofmotherswithchronicHBVinfection,the
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rateofinfectionincreasedfrom0percentinmotherswithserumHBVDNA<5log10copies/mL(<20,000
IU/mL)to50percentinthosewithHBVDNAbetween9and10log10copies/mL(approximately109
IU/mL)[48].

AstudyconductedinAustraliaon138babiesborntoHBVDNApositivemothersshowedasimilartrend
[49].HBVtransmissionwasdetectedinfourbabiesdespitetheuseofHBIGandHBVvaccinationin
threeandthevaccinealoneinone.AllfourbabieswereborntomotherswithhighHBVDNAlevels(>108
copies/mL).

Aprospectiveobservationalstudyfollowed303motherinfantpairsinwhichthemotherhadapositive
hepatitisBsurfaceantigen(HBsAg)[50].ChronicHBVinfectiondevelopedin10infantsborntothe87
HBeAgpositivemotherswhereasnoneoftheinfantsborntothe216HBeAgnegativemothersbecame
infected.AlloftheinfantsborntoHBeAgpositivemothersreceivedadoseofHBVvaccinewithinthe
firstweekandHepatitisBimmuneglobulin(HBIG)within24hoursofbirth.Amultivariablelogistic
regressionmodelfoundasignificantassociationbetweenthattherateofmaternallytransmittedHBV
infectionandmaternalHBVDNA.Specifically,themodelpredictedratesofmaternallytransmittedHBV
infectionatHBVDNAlevelsof5,6,7,8,9log10copies/mLtobe0.9percent(95%CI,0.92.7percent),
2.6percent(95%CI,1.16.2percent),6.6percent(95%CI,0.512.6percent),14.6percent(95%CI,
5.623.6percent),and27.7percent(95%CI,13.142.4percent)respectively.

Anobservationalstudyevaluated4446infantsbornto3253HBVpositivemothersbetween1997and
2010[51].ThemajorityofinfantsreceivedimmunotherapywithhepatitisBimmuneglobulinand3doses
ofthehepatitisBvaccine.Perinataltransmissionoccurredin3.4percentofbirthstoHBeAgpositive
mothersand0.04percentofbirthstoHBeAgnegativemothers.HBVDNAandHBeAgtestingwas
availablein835women.Amongsuchwomen,threeinfantsacquiredHBVinfectiondespitepassiveand
activeimmunization.AllthreechildrenwereborntomotherswhowereHBeAgpositiveandhadaHBV
DNAlevel>6x107IU/mL.NoHBVtransmissionoccurredinmotherswithviralloadslessthan5x107
IU/mL,regardlessofthemothersHBeAgstatus.

TransplacentaltransmissionAsnotedabove,transplacentaltransmissionappearstocauseonlya
minorityofinfections.Itcanoccurduetoleakage,suchasduringathreatenedabortion[52,53].HBVhasbeen
foundinthevillouscapillaryendothelialcellsandthetrophoblastsoftheplacenta[40,54].Thissupportsthe
hypothesisthatbreachoftheplacentalbarrierisapossiblemechanismforintrauterineinfection.Asaresult,
whenpretermlabororspontaneousabortionoccurs,theremaybemixingofmaternalandfetalblood,which
mayresultinHBVtransmission[52].OnestudyshowedthatHBVisabletotranslocatethroughtheplacenta
fromthemothertothefetaltrophoblast[55].Thecausesoftransplacentalinfectionareunclear.Highmaternal
viralloadandpretermlaborhavebeendescribedasriskfactors,butthestrengthoftheseassociationsis
uncertain[40,48].

AmniocentesisandotherproceduresTransmissionfollowingamniocentesishasbeendescribed,
buttheriskappearstobelow[56],particularlyinmotherswhoareHBeAgnegativeandwhentheprocedureis
doneusinga22gaugeneedleundercontinuousguidance[57](see"Diagnosticamniocentesis").Inan
illustrativestudy,womenwithHBVwhounderwentamniocentesishadarateofverticaltransmissionthatdid
notdiffersignificantlyfromwomenwithHBVwhodidnotundergoamniocentesis(9versus11percent)[58].
Theeffectofotherinvasiveproceduresduringpregnancy(eg,chorionicvillussampling,cordocentesis,fetal
surgery)ontheriskoftransmissionisunknown.

PretermprematureruptureofmembranesTherearelimiteddatathathaveexaminedpreterm
prematureruptureofmembranesasariskfactorforHBVtransmission,andtheavailabledataareconflicting
[59,60].Asaresult,managementofsuchpatientsshouldnotdifferfromthatofwomenwithchronicHBV
withoutpretermprematureruptureofmembranes.

BreastfeedingBreastfeedingdoesnotappeartoincreasetheriskoftransmission.AlthoughHBVDNA
hasbeendetectedinthecolostrumofHBsAgpositivemothers,astudyon147infantsborntocarriermothers
revealednoevidenceforarelationshipbetweenbreastfeedingandthesubsequentdevelopmentofchronic
HBVinfectioninthebabies[61].Inanotherstudyinvolving369neonatesborntomotherswithchronicHBV
infection,ofwhomallreceivedandcompletedtheHBVimmunoprophylaxisprogram,noneofthe101breastfed

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infantsandnineformulafedinfantswaspositiveforHBsAg[62].

TheseobservationssuggestthatinfantswhoreceivedHBIGandthefirstdoseofvaccineatbirthcanbe
breastfedaslongastheycompletethecourseofvaccination,butcarriermothersshouldnotparticipatein
donatingbreastmilk[44].Mothersintendingtobreastfeedtheirbabiesshouldnotdelayuntilthebabiesarefully
immunized.MotherswithchronichepatitisBwhoarebreastfeedingshouldalsoexercisecaretoprevent
bleedingfromcrackednipples.Aseparateconsiderationisthesafetyofnucleos(t)ideanaloguestobabieswho
arebeingbreastfed.(See'Breastmilk'above.)

CesareandeliveryWhethercesareandeliverycanpreventmaternalinfanttransmissionhasnotbeen
establishedinwellconductedcontrolledtrials[63,64].Thus,cesareandeliveryshouldnotberoutinely
recommendedforcarriermothers.

PreventionofperinataltransmissionPreventingperinataltransmissioninvolvesscreeningpregnant
women,providingantiviraltherapytowomenwithhighHBVDNAlevels,andadministeringpassiveactive
immunizationtonewbornsofmotherswhoareHBsAgpositive(algorithm1).

MaternalscreeningTestingforHBsAgshouldbeperformedonallwomenatthefirstprenatalvisit.
ThisbloodtestwilldeterminewhetherawomanhascurrentHBVinfectionandisatriskoftransmittingHBVto
herinfant.

WomenwhoareHBsAgpositiveshouldhavefurthertestingtomeasurebaselineHBeAg,hepatitisBe
antibody(antiHBe),HBVDNA,andaminotransferaselevels.WomenwhohaveahighHBVDNA(ie,
106int.units/mL),elevatedaminotransferaselevels,and/orapositiveHBeAgshouldbereferredtoa
hepatologisttoseeifearlyinitiationofantiviralmedicationsisneeded.Inaddition,theHBVstatusofany
olderchildrenshouldbeevaluated.

WomenwhoareHBsAgnegativeandareathighriskforHBVinfection(eg,injectiondruguser,sexual
partnerorhouseholdcontacthaschronicHBV),shouldbetestedforhepatitisBsurfaceantibody(anti
HBs)andhepatitisBcoreantibody(antiHBc).MotherswithoutevidenceofpriorHBV(negativeforanti
HBsandantiHBc)shouldbevaccinated.Inaddition,suchwomenshouldhaveHBsAgrepeatedlatein
pregnancy(approximately28weeks).(See"DiagnosisofhepatitisBvirusinfection",sectionon'Who
shouldbetestedorscreened'.)

MaternalantiviraltherapyWesuggestthatantiviraltherapybeofferedtomotherswithhighHBV
DNAlevels,inadditiontostandardpassiveactiveimmunizationoftheinfant,tofurtherreducetheriskof
perinataltransmission(see'Newbornimmunization'below).WerepeattheHBVDNAlevelat26to28weeks
forthosenotalreadyontreatmentandtypicallyofferprophylaxistowomenwhohaveaviralload106int.
units/mL.TreatmentshouldbestartedsixtoeightweeksbeforedeliverytoallowenoughtimeforHBVDNA
levelstodecline.Adiscussionoftheuseofantiviralagentsinpregnancyisfoundabove.(See'Antiviral
therapyduringpregnancy'above.)

Weprefertenofovirratherthanotherantiviralagentssinceresistancetotenofovirisrarethisisimportantsince
manyoftheseyoungmothersmayrequireantiviraltreatmentfortheirliverdiseaseinthefuture.Otheragents
(eg,lamivudine,telbivudine)alsoreduceperinataltransmission,andappeartobesafewhenadministered
duringpregnancy[20,21,6567]however,theyareassociatedwithincreasedratesofantiviralresistance.

Studiesthatsupporttheuseofantiviraltherapytoreduceperinataltransmissioninclude:

Theefficacyoftenofovirinreducingperinataltransmissionwasdemonstratedinanonrandomizedstudy
of118pregnantwomenwhohadanHBVDNA107.5int.units/mLandwerepositiveforHBsAgand
HBeAg[67].Womenreceivedtenofovir(300mgdaily)orplacebo,whichwasinitiatedatweek30to32of
gestation,andwascontinuedforonemonthpostpartum.Allinfantsreceivedpassiveandactive
immunization.NewbornsborntomotherswhoreceivedtenofovirhadsignificantlylowerratesofHBsAg
positivityatsixmonths(1.5versus10.7percent).

Ametaanalysisof10studiesfoundthatadministeringlamivudinetothemotherinlatepregnancy,in
additiontoprovidinghepatitisBvaccinationandHBIGprophylaxistotheinfant,significantlyreduced
mothertochildtransmission[65].Althoughthepreferredendpointfordemonstratingmaternalinfant
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transmissionofHBV(thepresenceofHBsAgintheinfant9to12monthsafterdelivery)wasreportedin
onlyfiveofthestudies,theoveralleffectfavoredlamivudineprophylaxiswhenthesestudieswere
combined(RR0.31,95%CI0.150.63).

Somewomenstopantiviraltherapyafterdeliverybecausetheydonotmeetcriteriaforcontinuedtreatment
(see"OverviewofthemanagementofhepatitisBandcaseexamples",sectionon'Whoshouldbetreatedand
how').SuchpatientsshouldbemonitoredforaflareoftheirHBVdiseasebymeasuringtheALTlevelevery
onetotwomonthsforsixmonthsaftertherapyhasbeenstopped.Forthosethatcontinueantiviraltherapy
afterdelivery,theprosandconsofbreastfeedingmustbediscussedwiththemother.(See'Breastmilk'
above.)

NewbornimmunizationNewbornsofmotherswhotestpositiveforHBsAgshouldreceivepassive
activeimmunization,withthefirstdoseofthehepatitisBvaccineseriesandonedoseofHBIGadministered
within12hoursofdeliveryatdifferentsites.AmoredetaileddiscussionofHBVimmunizationininfantsis
foundelsewhere.(See"HepatitisBvirusimmunizationininfants,children,andadolescents",sectionon
'Routineinfantimmunization'.)

SUMMARYANDRECOMMENDATIONS

HepatitisBduringpregnancypresentswithuniquemanagementissuesforboththemotherandfetus.
TheseincludetheeffectsofHBVonmaternalandfetalhealth,theeffectsofpregnancyonthecourseof
HBVinfection,treatmentofHBVduringpregnancy,andpreventionofperinataltransmission.(See
'Introduction'above.)

AcuteHBVinfectionduringpregnancyisusuallynotsevereandisnotassociatedwithincreased
mortalityorteratogenicity.(See'AcuteHBV'above.)

PregnancyisgenerallywelltoleratedbywomenwithchronichepatitisBinfectionwhodonothave
advancedliverdisease.However,becauseoccasionalpatientsdevelopahepatitisflare,HBsAgpositive
mothersshouldbemonitoredclosely.Weobtainliverbiochemicaltestseverythreemonthsduring
pregnancyandforsixmonthspostpartum.HBVDNAshouldbetestedconcurrentlyorwhenthereisALT
elevation.(See'ChronicHBV'above.)

Variousfactorsneedtobeconsideredwhendecidingonantiviraltherapyduringpregnancyincludingthe
indications,anticipateddurationoftherapy,potentialadverseeffectstothefetus,efficacy,andtheriskof
thedevelopmentofdrugresistance.Thehealthofthemotherandfetusmustbeconsideredindependently
whendecidingontreatment.Thesafetyofmedicationexposureinthefetusneedstobeweighedagainst
theriskofstoppingorchangingtherapyforthemother.(See'Antiviraltherapyinwomenwithchildbearing
potential'above.)

TheinfectionrateamonginfantsborntoHBeAgpositivemotherswhodonotreceiveanyformof
prophylaxisisashighas90percent.Thehighprotectiveefficacy(95percent)ofneonatalvaccination
suggeststhatmostinfectionsoccuratbirthwhenmaternalsecretionsinthebirthcanalcomeincontact
withtheinfant'smucousmembranes.Themostimportantriskfactorsfortransmission,despite
prophylaxis,appeartobeapositiveHBeAginthemotherandahighmaternalHBVviralload.(See'HBV
replicativestatus'aboveand'Perinataltransmission'above.)

TestingforHBsAgshouldbeperformedonallwomenatthefirstprenatalvisitandrepeatedlatein
pregnancyinthoseathighriskforHBVinfection.NewbornsofHBsAgpositivemothersshouldreceive
passiveactiveimmunization.Inadditiontostandardpassiveactiveimmunization,wesuggestantiviral
therapybeofferedtomotherswithhighHBVDNAlevelssinceitcanfurtherreducetheriskofperinatal
transmission(Grade2B)(algorithm1).(See'Preventionofperinataltransmission'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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GRAPHICS

AlgorithmforhepatitisBvirusduringpregnancy

AntiHBc:hepatitisBcoreantibodyantiHBe:hepatitisBeantibodyantiHBs:hepatitisBsurface
antibodyHBeAg:hepatitisBeantigenHBIG:hepatitisBimmuneglobulinHBsAg:hepatitisB
surfaceantigenHBV:hepatitisBvirus.
*CheckantiHBsandantiHBcifmotherisathighriskforHBVinfection(eg,injectiondruguser,
sexualpartnerorhouseholdcontacthaschronicHBV).MotherswithnoevidenceofpriorHBV
infection(ie,negativeforHBsAg,antiHBs,andantiHBc)shouldbevaccinated.
WomenwhohaveahighHBVDNA(>10 6int.units/mL),elevatedaminotransferaselevels,and/or
apositiveHBeAgshouldbereferredtoahepatologisttoseeifearlyinitiationofantiviralmedications
isneeded.
Startat28to30weeksgestation.Weprefertenofovirratherthanotherantiviralagents.Referto
thetopiconHepatitisBandpregnancyforamoredetaileddiscussionoftreatment.
Forthosewhocontinueantiviraltherapyafterdelivery,theprosandconsofbreastfeedingmust
bediscussedwiththemother.RefertothetopiconHepatitisBandpregnancyformoredetailed
discussionsofbreastfeeding.

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Disclosures
Disclosures:HannahLee,MDNothingtodisclose.AnnaSFLok,MDGrant/Research/ClinicalTrial
Support:BristolMyersSquibb[viralhepatitis(entecavir)]Gilead[viralhepatitis(adefovir,tenofovir)]
Merck[viralhepatitis(peginterferonalfa2b)].Consultant/AdvisoryBoards:Gilead[viralhepatitis
(adefovir,tenofovir)]GlaxoSmithKline[viralhepatitis(lamivudine)].RafaelEsteban,MD
Consultant/AdvisoryBoards:AbbVieBristolMyersSquibbGileadSciencesJanssenPharmaceutica
Merck[Hepatitis(Ombitasvir/paritaprevir/ritonaviranddasabuvir,daclatasvir,sofosbuvir/ledipasvir,
simeprevir,boceprevir)].LouiseWilkinsHaug,MD,PhDNothingtodisclose.JenniferMitty,MD,
MPHNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,these
areaddressedbyvettingthroughamultilevelreviewprocess,andthroughrequirementsfor
referencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
authorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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