HIV in pregnancy – An update

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Full length article

HIV in pregnancy – An update

Victor N. Chilaka

^a,b,

*, Justin C. Konje

^b,c,d

aWomen’sWellnessResearchCenter,HamadMedicalCorporation,Doha,Qatar

bWeillCornellMedicine,Doha,Qatar

cSidraMedicine,Doha,Qatar

dUniversityofLeicester,UK

ARTICLE INFO Articlehistory:

Received13September2020

Receivedinrevisedform9November2020 Accepted11November2020

Keywords:

Humanimmunodeﬁciencyvirus(HIV) Combinedanti-retroviraltherapy(cART) Verticaltransmission

Pregnancy

Breast-feedingserodiscordant

ABSTRACT

Humanimmunodeﬁciencyvirus(HIV)isaninfectionwithaglobalprevalenceandcurrentlynocureor vaccine.WomenlivingwithHIVwhobecomepregnantorwhoacquirethevirusduringpregnancyareat riskofbothmaternalandperinatalmorbidityandmortalitymainlyifthevirusispoorlycontrolled.

Furthermore,thereisariskofverticaltransmissiontothefetusduringpregnancylabourandpostpartum throughbreastfeeding.

AppropriatemanagementmustbeinstitutedtoreducetheconsequencesofHIVinpregnancy,ideally startingwithpreconceptioncounsellingandplanningpregnancieswhentheviralloadisminimum.

Duringpregnancy,anappropriatecombinedanti-retroviral(cART)medicationismandatorywithvery closemonitoringoftheviralload,clusterofdifferentiation4(CD4)cellcounts,bloodcounts,liverand kidneyfunctiontests.

PlanningdeliveryshouldnotbedifferentinwomenoncARTandsuppressedviralloads.However, specialcaremustbetakentolimitverticaltransmissioninthosewhopresentlateandinwhomviralload isunknownornotcontrolledatthetimeofdelivery.

Breastfeedingremainsapotentialsourceofinfectionforthebabyandisbeingdiscouragedinhigh- incomecountriesforwomenlivingwithHIV;however,inlow-incomecountries,therecommendationis exclusivebreastfeeding.Ifbreastfeedingmusthappen,itisbestwhenviralloadissuppressed,andcART continueduntilweaning.

Serodiscordant couples presentunique problems, and theirmanagement shouldbeginwith the planningofpregnancy.EmphasisshouldbeontakingstepstopreventHIVtransmissiontothenegative partnerandverticaltransmissiontothenew-born.

Introduction

Human immunodeﬁciencyvirus(HIV) was shown tobethe causeofacquiredimmunodeﬁciencysyndrome(AIDS)in1983[1].

Although AIDSwas ﬁrst reported in theUnited States in 1981, mainly amongst homosexuals, HIV infection has now been reportedineverycountryworld-wide andhasbecomeaglobal epidemic[2].Approximately37.9millionpeopleacrosstheglobe werelivingwithHIV/AIDSin2018,and1.7millionofthesewere children(<15yearsold)[3].Anestimated1.7millionindividuals worldwidebecamenewlyinfectedwithHIVin2018[3].Inrecent times,theexistenceofHIVseemstobeentirelyovershadowedby thecurrentcoronaviruspandemiccausingCOVID19[4].COVID19

likeothercoronavirusinfections(e.g.,SARs,MERs,etc.)arelikelyto ﬂareanddisappearwithsurvivorsreturningtoahealthylife.HIV, ontheotherhand,seemstobeheretostayandonceapersonis infected,willhavetodealwiththeconsequencesoflivingwiththe virusforlifeasthereisstillnoknowncureorvaccinetoprotect fromit.

Sub-SaharanAfricahassomeofthehighestincidencesofHIV, accountingfor more than 60% ofall newinfections [3]. Other regionscurrentlybearinganincreasedburdenofinfectionsinclude Asia,LatinAmerica, theCaribbean,EasternEurope,and Central Asia[3].

The prevalence in the ante-natal population in most high income(HIC)countriesvariesbetween0.1–2/1000[5]whereas,in somelowincome(LIC)countries,itcouldbeashighas29%[6].

However,withtheglobalactiononHIV/AIDS,thesetrendsseemto bedecreasing[3].HIV infectioninpregnancyhasanimpactfor both the mother and child if untreated and therefore requires prudent management antenatally intrapartum and postpartum.

*Correspondingauthorat:Women’sWellnessResearchCenter,HamadMedical Corporation,Doha,Qatar.

E-mailaddress:[email protected](V.N. Chilaka).

https://doi.org/10.1016/j.ejogrb.2020.11.034

ContentslistsavailableatScienceDirect

European Journal of Obstetrics & Gynecology and Reproductive Biology

j o u r n a l h o m e p a g e : w w w . e l s ev i er . c o m / l o c a t e/ e j o g r b

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TheprimaryaimsofmanagingHIVinfectioninpregnancyarethe preventionofmother-to-childtransmission(MTCT)ofthevirus, maintaining maternal health, and offering a safe and healthy environmentfordeliveryformotherandchild.

Diseasedescription–HIV/AIDS

Therearetwoserotypesofthehumanimmunodeﬁciency(HIV) virus–HIV1and2.Thevirusbelongstothefamilyofretroviruses withthreemajorclasses:-M(main),N(new),andO(outlier)[7].The Mgroupofvirusesaccountsformorethan90%ofHIVinfections worldwideandhasninesubtypes,calledclades,designatedbythe lettersA–D,F–H,J,andK,aswellasmanyrecombinantforms[7].The mostprevalentsubtypeinWestAfricaisCladeA,whileCladeBis commonerintheAmericasandWesternEurope[8].Viraldiversities arehighestinsub-SaharanAfrica[9].HIV-2whichisfoundmore commonlyinWestAfricaandisassociatedwithalowerviralload,a slowerrateofbothCD4celldeclineandclinicalprogressionismuch moreprevalentthanHIV-2as acausative agentfor AIDS.When comparedwith HIV-1, HIV-2is lesstransmissible(5 8-fold less efﬁcientthanHIV-1inearly-stagediseaseandanabout20 30-fold lowerrateofverticaltransmission)[10].

HIV infection begins with the binding of the virus particle (virion) tothehostcell,followedbyreplicationand integration intothehostgenome.Thisthencausesprogressivedepletionof CD4cells[11],compromisestheimmunityofthehostandcreates the potential for opportunistic infections and tumours, and if uncheckedcanresultinfull-blownAIDS.

HIVvirionshavebeenisolatedfromanumberofhumanbodily ﬂuids (in both cell-free and cell-associated fractions)including blood, seminalplasma, pre-ejaculate,cerebrospinalﬂuid,saliva, tearsandbreastmilk.TherearefourstagesofHIVdisease(1–4)– Stage 1 beingasymptomaticwhile Stage4 is fully blownAIDS (WHO).[12]

ImpactofHIVonpregnancyandpregnancyoutcomes HIV infection is associated with varying rates of adverse pregnancyoutcomes.Someoftheknownassociatedpooroutcomes includeincreasedspontaneousmiscarriages,stillbirths,increased perinatal mortality, intrauterine growth restriction, low birth weight,andchorioamnionitis[13].Becauseofimmunosuppression, HIVcanadverselyaffectthefrequency andcourseofmanyinfections inpregnancy,includinggenitalherpessimplex,humanpapilloma- virus,vulvovaginalcandidiasis,bacterialvaginosis,syphilis,tricho- monasvaginalis,cytomegalovirus,toxoplasmosis,hepatitisBandC, malaria,urinarytractinfectionsandbacterialpneumonia.Besides, parasiticinfestationsandHIV-relatedopportunisticinfections-such as tuberculosis, pneumocystis jerovecii pneumonia seem to be frequentduringpregnancyandinthepuerperium[8].

PregnancydoesnotseemtoadverselyaffectthecourseofHIV infection,progressionorsurvival.ThedeclineintheCD4cellcount in women withHIV during pregnancyresolves typically in the postpartumperiodandisattributabletohaemodilution[14].HIV RNAlevelsseemtoremainstableduringpregnancy,althoughsome studiessuggestanincreaseinviralloadinthepostpartumperiod.

In HIC countries, HIV infection is a rare cause of maternal mortalitybecauseofavailableandspecialisedhealthcareservices whereas,inLICcountriesespeciallyinsub-SaharanAfrica,itisan important anda leadingcontributor tomaternalmorbidityand mortality[15].

ScreeningforHIVinpregnancy

The effects of HIV on pregnancyand the risk ofMother-to- Child-Transmission (MTCT) make screening for infections an

essential part of antenatal care for all pregnant women. The WorldHealthOrganisationrecommendsthatinhigh-prevalence settings(>5%prevalence),provider-initiatedtestingandcounsel- ling(PITC)forHIVshouldbeconsideredastandardcomponentof thepackageofcareinallantenatalcaresettings.Inlow-prevalence settings(<5%),PITCcanbeconsideredasavitalcomponentofthe efforttoeliminateMCTCandintegrateitwithtestingforsyphilis andotherrelevanttestsdependingonthesettingtostrengthenthe underlyingmaternalandchildhealthsystems[16].

The"opt-out"approach toHIV testingmaybe offeredtoall womenaspartofroutineantenataltestsduringtheﬁrstantenatal visit.Thewomeninthisapproachreservetherighttodeclinethe testwithoutanysanctionsfromtheprovider.Womenwhodecline thetestinitiallyoftenaccepttobetestedlaterinpregnancywith moredetailedcounselling.HIVtestingmayalsobeofferedlatein pregnancy(about36weeks)orinlabourtowomenwhosestatusis unknownor who had tested negative earlier inpregnancy but remain at risk of a newinfection. HIV testing and counselling shouldbevoluntarywiththeprinciplesofconsent,conﬁdentiality, counselling, and ensuring that test results are linked with appropriatecare,treatmentandpreventiveservices.HIVscreening andcounsellinginvolvepre-testinformation,HIVtesting,post-test andfollow-upcounselling[5].

Screeninginpregnancygoesbeyondhavingasimplebloodtest asapositiveresultislikelytohavealife-longimpactonthepatient sincethereisyetnorealcureorvaccinationforHIVinfection.In HICcountries, alargeproportionof womenwould knowabout theirHIVstatusbeforetheonsetofpregnancy,butsomewillhave tolearnfortheﬁrsttimeduringthecourseofpregnancy.IntheUK, forexamplebetween2012and2014,ofthepregnanciesinwomen withHIV,85%ofdeliveriesweretothosewhoknewtheirHIV statusbeforepregnancy,andabout50%ofthemwerehavinga secondorsubsequentbabysincediagnosis[5].

ThepsychosocialimpactofhavingapositiveHIVtestandliving withHIVcanbeoverwhelmingfornewmothers,andBritishHIV Association (BHIVA) strongly recommend psychosocial assess- ment and support for these women [5]. This should be done throughawell-constitutedanddedicatedMulti-DisciplinaryTeam (MDT).Besides,they shouldalsobescreened forothersexually transmitted infections as well as bacterial vaginosis, herpes simplexinfectionsandofferedcervicalcytology[5].

Preconceptioncounselling

AllwomeninthereproductiveagegroupwhoareHIVpositive should seek counselling before starting a pregnancy sothat a detailed discussion on pregnancy and childbearing can be established.Pregnancyshouldbecarefullyplanned,andcontra- ceptionshouldbeanintegralpartofthisplan.

ThemainissueshouldcentreonthepreventionofMTCTof HIV. Thereshouldalso be the needto review medications to initiateappropriatecombinedanti-retroviraltreatment(cART) thatisappropriateforpregnancy[17].Thiswillbetheperiodto emphasise the importance of compliance with medications during pregnancy and the postpartum period and identify potentialbarriersthatmayaffectantenatal,intraandpostpar- tum care[18]. It is also important to stress that successfully achieving maximal viral suppression before conception and throughoutpregnancyisthemostpredictivemeansofensuring the lowest riskof potential MTCT [17].Partof preconception counselling should also be aimedat identifying women who may be victims of domestic violence, depression, and other psychosocialorpsychiatricillnessesthatmayserveasbarriers topreventing MTCT. Itmay be essential totreat and achieve effectivecontrol/managementoftheseco-morbiditiesprior to becomingpregnant [17].

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Ante-natalmanagementofHIV:(Table3) Diagnosis

ThediagnosisofHIVinfectioncanbemadeeitherdirectlyfrom thedetectionoftheviralparticlesorcomponentsorindirectlyby thedetectionofantibodiesagainstthevirus.Screeningisusually done by traditional HIV testing modalities - either an HIV 1/2 Antigen/AntibodytestoraFourthGenerationtestwiththereﬂex ability of multi-type(combi)detectionwhich essentiallyestab- lishesadiagnosisofHIVinfection[19].Newertestingmodalities have also been introduced. An example of this is the reﬂex MultispotrapidHIVtest,whichprovidesforacombinedHIV-1/

HIV-2rapid testtodistinguishbetweenHIV-1and 2 infections [20]. Recentlya more rapidtest hasbecomeavailable that can makethediagnosiswithin1–2handcanbeself-performed.Ifthe Multispottestisnegative,additionalreflextestingshouldbedone toconfirmthenegativetestandthenruleoutHIVinfectionwitha polymerasechainreaction(PCR)test[21](Table1).Therapidtest hasasensitivitycloseto100%,butthepositivepredictivevalueis dependentontheprevalenceofHIVinthepopulation[21].Itis particularlyusefulondeliverysuitesforwomenofunknownHIV status.Ifpositiveinalabouringpatient,interventionsshouldbe instituted immediatelywithout waitingfor a confirmatorytest.

Table1showsthecurrentlyavailabletestsandthetimetoresults.

Monitoring

Women with HIV must be carefully monitored all through pregnancyontheeffectsofinfectionsaswellastheeffectsofcART (Tables2&3).ThosewhoarenewlydiagnosedwithHIVdonot require any additional baseline investigations compared with nonpregnantwomenlivingwithHIVotherthanthose routinely performedinthegeneralantenatalclinic[5].

Itwill,however,beessentialtohavemonthlyassessmentsofviral loads tomonitor theprogressand efﬁcacy ofmanagement.Inwomen who commencecARTinpregnancy,an HIVviralload shouldbe performed2–4weeksafterinitiatingtreatment,andlateratleast onceeverytrimester,andat36weeksandatdelivery[5].

MostcARTdrugsaremetabolisedinthekidneysandtheliver.It isthereforeprudenttomonitortheliverfunctiontestsandserum creatinine with a complete metabolic proﬁle (CMP). This will detect early renal or liver insufﬁciency that might require management. Thiscanbedonemorefrequently attheonset of

treatment and spaced out more as they stabilise on their medications.

Amonthlycomplete bloodcountis alsorecommendedwith particular emphasis on the haemoglobin concentration and platelet counts. This is because some cART drugs cause bone marrowsuppression[22].Aclusterofdifferentiation4(CD4)cell countshouldbemonitoredapproximatelyeverythreemonthsasis recommendedinnonpregnantwomen.AnadditionalCD4countat deliveryshouldbedoneeveniftheCD4countwashigherthan 350cells/mm,attheﬁrsttestinpregnancy^3,[5].

Abaseline HIV genotypeand hepatitis panelisnecessary to assessforanyviralresistanceandhepaticdisease,bothofwhich areimportanttoknowbeforeinitiatingantiretrovirals[22].

ApartfromtheHIV-speciﬁcmonitoring,theantenatalmanage- mentshouldbeasclosetonormalaspossible[5].Fetalultrasound imagingshouldbeperformedaspernationalguidelinesregardless of maternal HIV status. The combined screening test for fetal aneuploidiesand non-invasiveprenataltesting (NIPT)for those who screen as highrisk is recommended as this has the best sensitivityandspeciﬁcityandwillminimisethenumberofwomen whomayneedinvasive testing[5].Invasive prenataldiagnostic testingshouldbedeferreduntilaftertheHIVstatusofthewoman isknown,andeventhen,shouldideallybedeferreduntilHIVviral loadhasbeenadequatelysuppressedto<50HIVRNAcopies/mL.

Thereislimiteddatathatsuggeststhatamniocentesismightbe safe in women on cART [23]. If not on cART and an invasive diagnostictestprocedurecannotbedelayeduntilviralsuppression isachieved,itisrecommendedthatwomenarecommencedon cARTtoincluderaltegravirandbegivenasingledoseofnevirapine 2–4hbeforetheprocedure[5].Therisksneedtobebalancedwith the beneﬁts and advice taken from theHIV physiciansand an informedconsenttakenfromthepatient.Table2summarisesthe monitoringtestsonwomenwithHIVinpregnancy.

Antiretroviraltreatmentinpregnancy

TheonlyARTlicensedforuseinpregnancyiszidovudineinthe thirdtrimester.Thereis,however,aglobalconsensusthatwomen whoconceiveoneffectivecARTshouldcontinuecARTthroughout pregnancyandthenlifelong[5].Thiscan,ofcourse,bemodiﬁedif the regimen is non-standard (e.g. monotherapy with protease inhibitors) or with drugs showing lower pharmacokinetics in pregnancysuchasdarunavir/cobicistatandelvitegravir/cobicistat etc.[5].

Table1

TestsanddiagnosisofHIV.

HIVTest Timetoavailabilityofresult Whatistested WindowPeriod* Sensitivity Speciﬁcity

ELISA 2days–2weeks HIVantibodies 3Months >99 >98

Antigentest(p24) 2days–1week P24viralproteins 11days–1month 90 100

4thgenerationtests 2days–2weeks Antibodiesandp24 11days–1month >99.7 >99.3

PCR/NAATtests 2days–1week GeneticmaterialofHIV 12days >99 99

Rapidtest Within20min Antibodies 3months >99 >98

*Windowperiod–periodfrominfection(exposure)tohavingapositiveresult.

Table2

MonitoringHIVinpregnancy.

Interval Reason

Viralloads Monthlyevery2–4weeksoninitiationoftreatment

andspaceoutlater.

Progressandefﬁcacyofmanagement LiverFunctiontestsandRenalFunctions Weeklyatonsetoftreatmentandspacedoutwhenstable. Detectearlyliverofkidneycompromise

secondarytodrugs.

FullBloodCount Monthly(attentiontoHbandplatelets) MarrowsuppressionbycARTMedications

Clusterofdifferentiation4(CD4)count Every3months Diseaseprogression

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Intreatingpregnantwomen,considerationshouldbegivennot only totheir health but alsothat of their unborn babieswith particularattentiontocongenitalabnormalities.Theaimofdrug therapy here is to induce and maintain maximum viral load suppression; hencetriple-drug therapyisrecommended, which maynotalwaysbeappropriateforuseinstandardadulttreatment outsideofpregnancy.TheWorldHealthOrganisationrecommends thatallpregnantandbreastfeedingwomenwithHIVirrespective ofCD4cellcount,viralload,andclinicalstageshouldhavetriple antiretroviraldrugs,whichshouldbemaintainedthroughoutthe periodofriskofMTCT(latepregnancy,labourandbreastfeeding) andcontinuedforlife[24]asforotherpatientswithlivingHIV.The choiceofdrugsshoulddependonwhetherthewomanistreatment naïve (i.e. those who have never had treatment before), drug- resistance, toxicity of the drugs and co-morbidities including hepatitisBvirus(HBV)andhepatitisCvirus(HCV)infections.Itis ofgreatadvantageifoneofthedrugsisabletocrosstheplacentato providepre-exposureprophylaxisforthefetus.

BHIVA recommends the use of two nucleoside backbone combinations, including tenofovir/emtricitabine and abacavir/

lamivudine, or zidovudine/lamivudine combinations [5,25]

(Table4).Inchoosingthebackbonecombinations,considerations should begiven to theside-effect profile, frequencyof dosing, interactionswiththethirdagent,adverse outcomeprofilesand priorcARTexperience,includingresistanceprofilewhereavailable [5] (Table 5). The combination of tenofovir/emtricitabine and lopinavir/r(especiallyhigh-doselopinavir/r),shouldbeusedwith careinlightofthereportedincreasedriskofneonataldeathand prematurityinarecenttrial[26].

DrugtoxicitiesarenotuncommonwithARTsandcanmanifest as anaemia,mitochondrial toxicity (lactic acidosis, pancreatitis, peripheralneuropathy,myopathy,andcardiomyopathy),hyperlip- idemia,fatredistribution,andinsulinresistance.Bonedisordersas osteopenia, osteoporosisand osteonecrosishave allbeen docu- mented.Nevirapinehasbeenassociatedwithmucusmembrane /skineruptions,including StevenJohnson'ssyndrome[27].It is therefore essential to monitor haematological and clinical chemistryparametersforpatientsonantiretroviral.

StartingcART

Once a diagnosis of HIV has been made in pregnancy, antiretroviraltreatmentshouldbestartedassoonaspossibleto achieve maximal viral load suppression before delivery. While achievingthisshouldbethepriority,someconsiderationshouldbe giventotheissueofnauseaandvomitinginearlypregnancyand thepotentialforteratogenicityhence,iftheimmunestatusisgood, theremaybeacasefordelayingtreatmenttilltheendoftheﬁrst trimester.Thedurationoftherapyaffectsverticaltransmission.Ina Frenchcohort,themediandurationoftherapyof9.5weekswas observed in women where vertical transmission occurred, comparedwith16weekswithnotransmission[28].

GoodadvicewouldbetostartoncART[5]

a)assoonaspossibleinthesecondtrimesterwherethebaseline viralload30,000HIVRNAcopies/mL;

Table3

SummaryofANCare.

Investigations:

AllRoutineANinvestigationasotherclients

ViralLoad:2–4weeklyatonsetandonceeverytrimesterifstable) LiverandRenalFunctions:Weeklyatonsetandspacedoutwhenstable.

FullBloodCount:Monthly

Clusterofdifferentiation4(CD4)count:Every3months.

HIVGenotype:Baselineatonset.

Monitoring:

AllANMonitoringasinnon-HIVpatients USSaspernationalguidelines

Combinedscreeningtestforfetalaneuploidies Non-invasiveprenataltesting(NIPT) Invasivetests:

DeferuntiltheHIVstatusofthewomanisknownandHIVviralloadhasbeen adequatelysuppressedto<50HIV.

IfnotConsidercART(Startonraltegravirandgivesingledoseofnevirapine2–4 hbeforeprocedure)

Table4

Classesofantiretroviraldrugs.

DrugClass Examples

1 Nucleoside/nucleotidereverse-transcriptase inhibitors(NRTIs/NtRTIs)

Azidothymidine(AZT)orZidovudine(ZDV),Lamivudine(3TC), Abacavir(ABC),Emtricitabine(FTC),Stavudine(d4T),Tenofovir(DF)

2 Non-nucleosidereverse-transcriptase

inhibitors(NNRTIs)

Efavirenz(EFV),Nevirapine(NVP)andEtravirine(ETV)

3 Proteaseinhibitors(PIs) Lopinavir(LPV),Ritonavir(RTV),Atazanavir(ATV),Indinavir(IDV),

Saquinavir(SQV),Nelﬁnavir(NFV) 4 Integrasestrandtransferinhibitors(INSTIs) Raltegravir(RAL),Dolutegravir(DTG)

Table5

RecommendedandalternativecARTagentsinpregnancyandbreastfeeding.

BHIVA2019[5]

Recommended Alternative

Nucleosidereversetranscriptase inhibitor(NRTI)backbone

Abacavir/lamivudine TenofovirDF/emtricitabine

Zidovudine/lamivudine

Thirdagent Efavirenz

Atazanavir/r

Rilpivirine,Darunavir/r,RaltegravirorDolutegravir (after8weeks'gestation)

WHO2018[68]

PreferredRegimen AlternativeRegimen

First-lineART Tenofovir+Lamivudine(orEmtricitabine)+Dolutegravir Tenofovir+Lamivudine(orEmtricitabine)+Efavirence Azidothymidine+Lamivudine+Dolutegravir Second-lineART Azidothymidine+Lamivudine(orEmtricitabine)+Lopinavir/r

(orAtazanavir/r)

Tenofovir+Lamivudine(orEmtricitabine)+Dolutegravir Third-lineART Darunavir/r+Dolutegravir(orRaltegravir)+1 2NRTIs

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b)at the start of the second trimester, or as soon as possible thereafterinthosewithabaselineviralloadof30,000–100,000 HIVRNAcopies/mL;

c)intheﬁrsttrimesterifviralload>100,000HIVRNAcopies/mL and/orCD4cellcountislessthan200cells/mm³.

d) All women should have commenced cART by the 24th of pregnancy.

Mostdrugsareconsideredtobereasonablysafeinpregnancy, butrecentsurveillanceofdolutegravirinBotswanalinkedittoa slightlyhigherthanexpectedratesofneuraltubedefects[29].It will,therefore,bebettertoavoidusingitintheﬁrsttrimesterandif possible,switchingtoothermedicationsinwomenwhoaretrying toconceive[5].

Specialcircumstances

Anywomanwhopresentsafter28weeksofpregnancyshould commencecARTwithoutdelay,andifherviralloadisunknownor

>100,000HIVRNAcopies/mLathreeorfour-drugregimenthat includes raltegravir is suggested. This is because integrase inhibitor-basedcARTregimenstendtoinduceamorerapidviral loaddeclinecomparedtootherdrugcombinations[30].Theaim willbetosuppressviralloadmaximallyatthetimeofdelivery.

External cephalicversion (ECV)can beofferedtowomen at termfrom37⁺⁰weeksofpregnancyiftheplasmaviralloadis<50 HIV RNAcopies/mL. This is, however, not supported by robust clinicalevidence,butthereissometheoreticalevidencetosupport ECV.Thereisevidencethatfeto-maternalhaemorrhageoccursin about2.4 %ofpatientsafterECV,but thisrepresents newfetal bloodcellsinthematernalcirculation(notthereverse).Ithasbeen postulatedthat,duetothestructureandfunctionoftheplacenta, theriskofmaternalbloodenteringthefetalcirculationduetoECV isevenmuchlower[31].

Modeofdelivery

Normal deliveryshouldbeofferedtowomenwitha plasma viral load of <50 HIV RNA copies/mL at 36 weeks, and in the absence ofobstetric contraindications.Planned vaginal delivery shouldbesupported,butiftheviralloadis400HIVRNAcopies/

mLat36weeks,aplannedCaesareansectionshouldbeoffered[5].

Forwomenwithaviralloadof50–399HIVRNAcopies/mLat36 weeks,pre-labourCaesareansectionshouldbeconsidered,taking intoaccounttheactualviralload,thetrajectoryoftheviralload, lengthof timeontreatment, adherenceissues, obstetricfactors anddetailedconsultationwiththepatient[5].Thereisverygood evidencethattheverticaltransmissionrateisconsistentlylower than0.5%inwomenwithviralloadsof<50HIVRNAcopies/mL taking cART, irrespective of the modeof delivery [32,33]. It is noteworthy that the risk of vertical transmission for women deliveringvaginallyisabouttwicethatofthosedeliveredbyCS, and this rises to four-fold when in-utero transmissions are excluded[5,34].

Thereisnoevidencetodenywomenwithwellsuppressedviral loadthechanceforavaginalbirthafterCaesareanSection(VBAC), anditshouldbeofferedforobstetricreasonsinwomenwithaviral load <50 HIV RNA copies/mL. Timing of Caesarean section for preventionofverticaltransmissionshouldbebetween38and39 weeks'gestation,butplannedCaesareansectioninwomenwith suppressedviralloadshouldbeperformedat39weeks[5,35].

Managementoflabouranddelivery

Once the decision for vaginal delivery has been made, the management of labour should be as near-normal as possible.

Previously theadvicehadbeentoavoidamniotomy, fetalscalp electrodes and fetal blood sampling, instrumental delivery and episiotomybecauseofatheoreticalriskoftransmission.Mostof theseweredevelopedinthepre-cARTera,andcurrentevidence doesnotsupporttheseconclusions.ThereisnodoubtthatcART hasplayedasignificantroleinreducingMTCTofHIV.ASpanish retrospectivestudypredominantlyinthepre-cARTerashoweda verticaltransmissionof26.3%in infantsexposed tofetalscalp monitoringwithelectrodes orpH samplingor both)compared with13.6%inthosewhohadnoneofthese[36].Inamorerecent Swisscohort,neitherfetalscalpelectrodes(RR2.0;95%CI0.58– 6.91)norpHbloodsampling(RR 1.73;95 %CI0.58–5.15) were confirmedas independentrisk factors[37]. In the Womenand InfantsTransmissionStudy(WITS) cohort(1989–1994)artificial ruptureofmembranes(RR1.06;95%CI0.74–1.53)andexposureto bloodduringlabour(RR0.7;95%CI0.4–1.27)ordelivery(RR1.06;

95%CI0.74–1.52)werenotassociatedwithtransmission[38].Also, fetalskinlesions(RR1.2;95%CI0.7–1.8)andepisiotomy/tear(RR 1.0;95%CI0.7–1.3)havenotbeenassociatedwithtransmission [39,27].

InstrumentaldeliveryisnolongerasriskywithregardstoMTCT aspreviouslythought.Datafromdifferentsourceshavefailedto identifyinstrumentaldeliveryasacauseofverticaltransmission [37,40].Thechoiceofinstrumentshouldbebasedonit,causing minimalfetaltrauma.However,itisunlikelythattherewillbeany signiﬁcant difference in outcome between a low forceps and vacuuminwomenwithwellsuppressedviralloads.

In allcases of termpre-labour spontaneousruptureof fetal membranes (PROM), delivery within 24 h should be the aim.

Currently,thereisnoevidenceofincreasedverticaltransmissionin womenwithundetectableviralloadwithSROM<4handbetween 4and24h[41].Thereis,however,lackofdatafortransmissionrisk beyond24h,hencetheadvicetodeliverwithinthistimelimit.One ofthemajorfactorsassociatedwithverticaltransmissioninthis casesisacute orchronicchorioamnionitis[42,43]hence labour shouldbeexpeditedforallwomenwithPROMattermtoavoidthis.

If the viral load is well suppressed, labour should be induced immediatelywithalowthresholdtotreatforchorioamnionitis.If the viralload is not wellsuppressed, an immediate Caesarean section should beconsidered. However, somebeneﬁt of doubt couldbegiventowomenwitha viralloadof 50–399HIV RNA copies/mL considering the actual viral load and its trajectory, lengthoftime ontreatment,adherence issues,obstetric factors andthewoman'sownviews[5].

Asthereisnogoodevidencetoshowthatrupturedmembranes for more than 4 h is associated witha higher risk of vertical transmission for women on cART and suppressed viral loads [44,45]themanagementofpretermSROMat34weeksshouldbe thesameasthatofnon-HIVwomenwithtermSROM,exceptthat women at 34–37 weeks' gestation should be offered group B streptococcus prophylaxis in line with national guidelines [5].

Under34weeks,steroidsshouldbegiven,andifHIVviralloadis not controlled, it should be optimised, and a multidisciplinary discussionheldonthetimingofdelivery.

Theuseofintrapartumintravenousinfusionofzidovudineisno longerrecommendedforwomenwithaviralload<50HIVRNA copies/mL.However,itshouldbeconsideredinthosewithaviral loadof50–1000HIVRNAcopies/mLanddeﬁnitelyofferedifthe viralloadis>1000HIVRNAcopies/mL.Itisalsorecommendedfor untreatedwomenpresentinginlabourorwithSROMinwhomthe currentviralloadisnotknown[5,46].

Breastfeeding

Breastfeedingisparticularlyimportanttosomemothers,butit is essential for all to understand that HIV can be transmitted

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through breast milk in erstwhile uninfected babies. In HIC countries,mostwomenwithHIVdonotbreastfeed,sothereare hardly any more data comingfromthese countries. In low- to middle- income countries, the overall postnatal risk of HIV transmissionthroughbreastmilkwhenwomenaretreatedwith cARThasbeenreportedas1.08%(95%CI0.32–1.85)atsixmonths and2.93%(95%CI0.68–5.18)at12months[47,48].Forwomennot oncART,theriskofinfectingthebabyisaffectedbydetectableHIV viral load; advanced maternal HIV disease, longer duration of breastfeeding, breast and nipple infection/inﬂammation, infant mouth or gut infection/inﬂammation and mixed feeding, in particular solid food given toinfants less than two months of age[49].

ManyHICcountriesliketheUnitedKingdomactivelydiscour- agebreastfeedinginHIVinfectedwomenbecauseoftheon-going risk.IntheLICcountries,theadviceisdifferentandisrelatedto highermortalityandmorbidityfromdiarrhoea,malnutritionand pneumonia in formula-fed infants. These are the basis for the currentWHOrecommendationofexclusivebreastfeedingforthe ﬁrst sixmonthsof life,introducingappropriatecomplementary foods thereafter, and continuing breastfeeding until the infant reaches12monthsofage.Breastfeedingcanbediscontinuedonce anutritionallyadequateandsafedietwithoutbreast-milkcanbe provided.Thereis,however,nodoubtthatthetransmissionrate willbebetterreducedifthemotherstaysonlifelongantiretroviral treatmentorextendedantiretroviralprophylaxisuntiloneweek aftercessationofallbreastfeeding.

Theneonate

Treating theneonateis beyondthescopeof thisarticle, but babiesborntoHIVpositivemothersrequirespecialattentionthat isworthmentioning.Theirriskofacquiringverticaltransmission shouldbeobjectively categoriseddependingontheduration of cARTinthemother,documentedsuppressionofviralload(<50 HIV RNA copies/mL), and if delivered beyond 34 weeks of gestation.Thosecategorisedasverylowriskwillneedtwoweeks ofzidovudinemonotherapy.Incomparison,thelow-riskoneswill requirefourweeksoftreatment,andthehigh-riskoneswithout goodorunknownviralloadsuppressionwillrequirecombination therapy[5].Ideally,allmedicationsshouldbestartedwithin4hof birth.

Managementofserodiscordantcouples

The term “serodiscordant couple” refers to an intimate partnership inwhich oneperson is HIV-positive,and theother is HIV-negative [50]. Such a relationship may be deﬁned by marital, cohabitating,orco-parentingstatusor bythelengthof relationship (e.g., minimum of 3–6 months), intention to stay together,orreportingacertainminimumnumberofsexualacts withthispartnerwithinagiventimeframe[51].Thefrequencyof such couples tends to reﬂect the prevalence of HIV in the community[52].Forinstance,inKenya,over40%ofHIVinfected individualshaveHIVuninfectedregularpartners.Manyofthese couples are of reproductive age with strong desires to have children[52],whichmayputtheHIVuninfectedpartneratriskof HIV acquisition as they pursue their pregnancy goals through unprotectedsexualintercourse[53].

The managementof suchcouplesshouldprecedepregnancy with safer conception strategies to offer affected couples the opportunity to conceive while reducing the risk of sexual transmission [53]. Some of thesestrategies include the use of antiretroviral therapy (ART) for viral suppression for the HIV uninfectedpartner-Pre-ExposureProphylaxis(PrEP)[53].Other useful methods include restricting condom-less sex to peak

fertility periods [54,55], vaginal self-insemination for couples with HIV infected women [56] male circumcision for HIV uninfected men [57] and medically assisted reproduction by spermwashing[58].Whenusedsinglyorincombination,these interventions will reduce the risk of HIV transmission in serodiscordantcouplesseekingpregnancy[52,59].Thereisgood evidencetoshowthatthelifetimeriskofsexualHIVtransmission forheterosexualserodiscordantcouplesisonly0–5%iftheHIV- positivepartnerachievesfullviralsuppressionanddonothaveany othersexually-transmittedinfection[60,61].

There is a lot of medical evidence on the efﬁcacy of Pre- ExposureProphylaxis(PrEP).InthePARTNERSstudy,1166couples ofdifferingHIVstatuses(bothheterosexualcouplesandmenwho have sex with men) where the infected partner was kept on suppressiveARTwhilehavingsexwithoutusingcondoms,nocases ofHIVtransmissionwerereportedafteramedianfollowupof1.3 yearsandapproximately58,000condom-lesssexacts[62].

Theidealchemoprophylacticdrugshouldhavealonghalf-life and high barrier for genetic resistance, achieve high levels of concentrationsinmonocytes,macrophages,andgenitalsecretions, andbesafeandinexpensive[63].Mostofthesecharacteristicsare reachedbytenofovir(TDF).TheFDAhasapprovedthecombination ofTDFandemtricitabine(FTC)(TruvadaTDF/FTC300/200mg)for PrEPagainstsexualHIVacquisitionbymenwhohavesexwithmen (MSM),aswellasforheterosexuallyactiveserodiscordantwomen andmen[64].TheCDCrecommendsthatanindividualwhodoes nothaveHIVandwhoisplanningapregnancywithapartnerwho hasHIVshouldstartonPrEPaboutonemonthbeforeconceptionis attemptedandcontinueforanotheronemonthafterconception occurs[65].Iftheywillcontinuehavingunprotectedintercourse after conception, and the partner with HIV has not achieved sustained viral suppression, the partner without HIV should continue to take PrEP to decrease the risk of secondary transmission[65].

Therearestillalotofissuesaboutthecost-effectivenessofPrEP which depends on other factors including the prevalence and incidenceofHIVinthepopulationtakingupPrEP(andtherefore theirage and theirlevel of condom use), PrEP drug-cost,PrEP efﬁcacy(sometimesexpressedintermsofadherencetoPrEP),rate of HIV diagnosis in the population and cost of antiretroviral treatmentfortheHIV-positivepopulation[63].Theuseofgeneric formulationsofTDF/FTC(Truvada),ifandwhereavailable,might helptoimprovethecost-effectivenessofPrEP,whichisessential for use asa publichealth approach toreduce community HIV transmission.

Beforeattemptingconception,itis essentialthatthepartner withHIVshouldbeonARTandshouldhaveachievedsustained viralsuppression [59]. If the couple decides totakePrEP, they shouldbeeducatedaboutthepotentialrisksandbeneﬁtsandall availablealternativesforsaferconception[65].Theimplicationsof initiating therapy before conception goes beyond viral load suppressionandentailsthechoiceofproperARTcompatiblewith pregnancy with expert counselling and the need to adhere to treatmentthroughpregnancy,deliveryandbreastfeeding.

Monitoringpregnantwomeninserodiscordantrelationships HIVpositivewomenlivingwithHIVnegativepartnersshould be managedlike other HIV positive woman with emphasis on preventingthepartnersandthebabiesfromacquiringHIV.

Womenwho areHIV negativebutlivingwithnHIVpositive partnersshouldhaveabaselineHIVdiagnostictest,renalfunction test,andpregnancytestdoneatbaseline.HIVandpregnancytest shouldberepeatedeverythreemonths,andrenalfunctionsevery sixmonths[59].TestingforhepatitisBvirus(HBV)infectionshould beperformed,andindividualswithoutHBVinfectionshouldbe V.N.ChilakaandJ.C.Konje EuropeanJournalofObstetrics&GynecologyandReproductiveBiology256(2021)484–491

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vaccinatedifpreviouslynotvaccinatedorlackimmunitytoHBV [59,65].

When booking for ante-natal care, HIV testing should be repeated. Also,theyshouldbecounselledontheimportanceof theirpartners’adherencetoARTandtheneedtoachievesustained virologicsuppressiontoreducetheriskofsexualtransmissionof HIVduringthecourseofpregnancy.HIVtestingshouldbecarried outineverytrimester,andaRapidtestisdonewhentheladyis admittedfordelivery.HIVtestingshouldthenbecarriedonevery threemonthsafterdeliveryatleastthroughoutbreastfeeding.

Itisalsonecessarytodiscussthesymptomsofacuteretroviral syndrome (i.e., fever, pharyngitis, rash, myalgia, arthralgia, diarrhoea,andheadache)andtheimportanceofseekingmedical care and testing if theyexperiencesuch symptoms.Acute HIV infection during pregnancyor lactation isassociated with high viralloadandincreasedriskoftransmittingHIVtotheirinfants [66,67].

Summaryandconclusion

HIVinfectionremainsveryprevalentallovertheworld,with thehighestprevalenceinSub-SaharanAfricaandtheLICcountries.

It affects pregnant women and if not appropriately managed, carries signiﬁcantmorbidityandsomemortalityandtheriskof vertical transmissionto babies.Allpregnant women shouldbe presentedwiththeoptionofanHIVtest,andoptingoutshouldbe managedasinfected.Despitetheimmunestatusasevidencedby viral load and CD4 cell count, all pregnant women with HIV infectionshouldreceivecARTduringpregnancy.Thedurationof cARTandsuppressionoftheviralloadanddurationareessential factorsinpreventingMTCT.Whentheviralloadiswellsuppressed, deliveryshouldnotbedifferentfromthatofotherwomen,and mostinterventionsshouldbeforobstetricindications.However,if theviralloadisnotsuppressedoriftheHIVstatusisunknown, special careshouldbetakeninplanninglabouranddeliveryto preventperinataltransmissionofthevirustothebaby.Serodis- cordantcouplespresentspecialproblems,andidealmanagement should beginwith the planning of pregnancy. Emphasis is on takingstepstopreventHIVtransmissiontothenegativepartner, thuspreventingverticaltransmissiontothenew-born.

DeclarationofCompetingInterest

None.

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