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11.05.2015 Differentcombinedoralcontraceptivesandtheriskofvenousthrombosis:systematicreviewandnetworkmetaanalysis|TheBMJ

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Differentcombinedoralcontraceptivesandtheriskofvenousthrombosis:systematicreviewandnetworkmetaanalysisBMJ2013347doi:http://dx.doi.org/10.1136/bmj.f5298(Published12September2013)Citethisas:BMJ2013347:f5298

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BernardineHStegeman,researchassociate13,MarcosdeBastos,researchfellow2,FritsRRosendaal,professorofclinicalepidemiology3,AvanHylckamaVlieg,researchfellow4,FransMHelmerhorst,professorofclinicalepidemiologyoffertility25,TheoStijnen,professorofmedicalstatistics6,OlafMDekkers,researchfellow7

Authoraffiliations

Correspondenceto:[email protected]

AbstractObjectiveToprovideacomprehensiveoverviewoftheriskofvenousthrombosisinwomenusingdifferentcombinedoralcontraceptives.

DesignSystematicreviewandnetworkmetaanalysis.

DatasourcesPubMed,Embase,WebofScience,Cochrane,CumulativeIndextoNursingandAlliedHealthLiterature,AcademicSearchPremier,andScienceDirectupto22April2013.

ReviewmethodsObservationalstudiesthatassessedtheeffectofcombinedoralcontraceptivesonvenousthrombosisinhealthywomen.Theprimaryoutcomeofinterestwasafatalornonfatalfirsteventofvenousthrombosiswiththemainfocusondeepvenousthrombosisorpulmonaryembolism.Publicationswithatleast10eventsintotalwereeligible.Thenetworkmetaanalysiswasperformedusinganextensionoffrequentistrandomeffectsmodelsformixedmultipletreatmentcomparisons.Unadjustedrelativeriskswith95%confidenceintervalswerereported.Therequirementforcrudenumbersdidnotallowadjustmentforpotentialconfoundingvariables.



Results3110publicationswereretrievedthroughasearchstrategy25publicationsreportingon26studieswereincluded.Incidenceofvenousthrombosisinnonusersfromtwoincludedcohortswas1.9and3.7per10000womanyears,inlinewithpreviouslyreportedincidencesof16per10000womanyears.Useofcombinedoralcontraceptivesincreasedtheriskofvenousthrombosiscomparedwithnonuse(relativerisk3.5,95%confidenceinterval2.9to4.3).Therelativeriskofvenousthrombosisforcombinedoralcontraceptiveswith3035gethinylestradiolandgestodene,desogestrel,cyproteroneacetate,ordrospirenoneweresimilarandabout5080%higherthanforcombinedoralcontraceptiveswithlevonorgestrel.Adoserelatedeffectofethinylestradiolwasobservedforgestodene,desogestrel,andlevonorgestrel,withhigherdosesbeingassociatedwithhigherthrombosisrisk.

ConclusionAllcombinedoralcontraceptivesinvestigatedinthisanalysiswereassociatedwithanincreasedriskofvenousthrombosis.Theeffectsizedependedbothontheprogestogenusedandthedoseofethinylestradiol.

IntroductionShortlyaftertheintroductionofthefirstcombinedoralcontraceptive(containinganoestrogenandaprogestogen),acaseofvenousthrombosisassociatedwithcontraceptiveusewasreported.1Sincethen,manyobservationalstudieshaveshownthatcombinedoralcontraceptivesareassociatedwithatwofoldtosixfoldincreasedriskofvenousthrombosis.2345Despitethelowincidenceofvenousthrombosisaboutthreeper10000womanyearsamongwomenofreproductiveage,6theeffectofcombinedoralcontraceptivesonvenousthrombosisislarge,owingtothefactthatmanywomenuseoralcontraceptives.

Becausetheoestrogencompound(ethinylestradiol)incombinedoralcontraceptiveswasthoughttocausetheincreasedriskinthrombosis,thedoseofethinylestradiolwasloweredfrom150100gintheearliestbrandsto50ginthe1960s,andto3035gand20ginthe1970s.789Thereduceddoseofethinylestradiolincontraceptiveswasindeedassociatedwithareductionintheriskofvenousthrombosis.1011121314Apartfromadjustmentsinthedoseofethinylestradiol,theprogestogencompoundwasalsochangedinanefforttoreducesideeffects.Afterthefirstgenerationprogestogens(thatis,norethisteroneandlynestrol),newprogestogensweredeveloped.Thesenewcompoundswerecalledsecondgeneration(thatis,levonorgestrel)andthirdgenerationprogestogens(thatis,gestodene,desogestrel,norgestimate).15However,usersofcombinedoralcontraceptiveswiththirdgenerationprogestogenshaveahigherriskofvenousthrombosisthanthoseusingsecondgenerationprogestogens.16171819Otherprogestogenshavebeendevelopedaftertheintroductionofthirdgenerationprogestogensthatis,drospirenone(introducedin2001).Thethrombosisriskforcontraceptiveswithdrospirenonewasfoundtobehigherthanforcombinedoralcontraceptiveswithsecondgenerationprogestogens.2021

Thepresentnetworkmetaanalysisaimedtoprovideanoverviewoftheriskofvenousthrombosispercombinedoralcontraceptiveinhealthywomen,andassesstheeffectofthegenerationofprogestogenused.Weperformedanetworkmetaanalysisbecausecombinedoralcontraceptivesaremostlycomparedwithnonuseorwithacontraceptivecontaininglevonorgestrelwith30gethinylestradiol.Thesecomparisonsresultedingapsindirectevidence,becausenoteverycombinedoralcontraceptivewasdirectlycomparedwithotherpossiblecombinedoralcontraceptives.Anetworkmetaanalysisallowsevidencefromdirectandindirectcomparisonstobesummarisedinaweightedaverageforallpossible



comparisons.

MethodsSearchstrategyandselectioncriteriaPublicationsofinterestwereobservationalstudies(cohortor(nested)casecontrolstudies)thatincludedhealthywomenusingcombinedoralcontraceptives.Theprimaryoutcomeofinterestwasafatalornonfatalfirsteventofvenousthrombosiswiththemainfocusondeepvenousthrombosisorpulmonaryembolism.Publicationswithaminimumof10eventsintotalwereeligible.

Thefollowingdatabasesweresearched:PubMed(984articlesretrieved),Embase(1339),WebofScience(306),Cochrane(57),CumulativeIndextoNursingandAlliedHealthLiterature(122),AcademicSearchPremier(197),andScienceDirect(105).OursearchtermsconsistedofMeSHheadingsandsubheadings,textwords,andwordvariationsforcombinedoralcontraceptive,estrogens,progestogens,andvenousthromboembolism.Thissearchstrategywasamendedforeachdatabase.Wesearchedeachdatabasefrominceptionuntil22April2013(dateoffinalsearch).Nolanguagerestrictionwasapplied.Inadditiontodatabasesearches,wecheckedreferencesofpotentialinterestingpublications.

Astandardformwasusedtoselectpublications.Twoinvestigators(BHS,MdB)independentlyassessedpublicationsforeligibility.Titlesandabstractswerescreenedandifdeemedpotentiallyrelevant,fulltextarticleswereretrieved.Anydisagreementsbetweentheinvestigatorswerediscussedandifnecessary,athirdreviewer(OMD)wasaskedtoresolvedisagreements.Incaseofmultiplepublicationsfromthesamestudy,thepublicationwiththemostupdatedorthemostinclusivedatawasincluded.Webappendix1showsdetailsofthesearchstrategy.

DatacollectionTwoinvestigators(BHSandMdB)independentlyextracteddatausingastandardform.Datawereextractedontypeofcombinedoralcontraceptive(doseandtypeofoestrogenandprogestogen),crudenumbersforexposureandoutcome,crudeandadjustedriskestimates,andvariablesadjustedforintheanalysis.Incaseofincompletedatafordoseortypeofoestrogenorprogestogen,authorswereapproachedforextrainformation.Intotal,10authorsweresentanemailon25July2012andifnecessary,areminderon20August2012.Oftheseauthors,80%repliedtoouremails.Ifprovided,datafortheabsolutethrombosisriskinnonuserswereextractedfromthecohortstudies.Forsensitivityanalyses,dataforthefundingsourceandfirsttimeusewereabstracted.

Riskofbiasassessmentwasbasedondesignfeaturesthatcouldpotentiallybiastheassociationbetweenexposureandoutcome.Weassessedadequacyofexposure(oralcontraceptive)andoutcome(venousthrombosis)measurement,losstofollowup(cohortstudies),andadequacyofcontrolselection(casecontrolstudies).Womenaremorelikelytorememberthattheyusedoralcontraceptivesthanwhatspecificpreparationtheyused.2223Therefore,assessmentofthetypeofcombinedoralcontraceptivethroughanintervieworquestionnairewasclassifiedashighriskofbias,andinformationfromaprescriptiondatabaseaslowrisk.Only2533%ofpatientspresentingwithclinicalsymptomssuggestiveofvenousthrombosisareobjectivelydiagnosedwithvenousthrombosis.24Therefore,studieswithobjectiveconfirmationinallpatientswerejudgedaslowriskofbias.Venousthrombosiswasconsideredobjectivelyconfirmedwhenadeepvenousthrombosiswasdiagnosedbyplethysmography,ultrasoundexamination,computed



tomography,orvenographyorwhenpulmonaryembolismwasdiagnosedbyventilationperfusionscanning,spiralcomputedtomography,orpulmonaryangiography.2526Lessthan10%losstofollowupwasconsideredtorepresentalowriskofbias.Forcasecontrolstudies,controlsselectedfromhospitalpopulationswasconsideredtoconferahighriskofbias.27

ClassificationoftypeofcombinedoralcontraceptiveThereisnogenerallyacceptedwaytoclassifycombinedoralcontraceptivesaccordingtogenerationsofprogestogens.Inthisanalysis,themostcommonclassificationsystemwasused,whichisinlinewithbiologicalpropertiespergroupandisreflectedintheireffectsonlevelsofsexhormonebindingglobulin.2829Fortheaimofthepresentnetworkmetaanalysispergenerationofprogestogen,thefollowingprogestogenswereclassifiedasfirstgenerationlynestrenolandnorethisterone.Norgestrelandlevonorgestrelwerecategorisedassecondgenerationprogestogensanddesogestrel,gestodene,andnorgestimatewereclassifiedasthirdgenerationprogestogens.15Thisclassificationwasirrespectiveofethinylestradioldose.Publicationsreportingongenerationsaccordingtoanotherclassificationwereincluded.Toassesstheinfluenceofcombiningdifferentclassifications,weperformedananalysisrestrictedtostudiesusingtheabovedescribedclassification.

Manydifferentcombinedoralcontraceptivesareavailable.Weselected10frequentlyprescribedoralcontraceptivesforthenetworkmetaanalysis:

20gethinylestradiolwithlevonorgestrel(20LNG)



20gethinylestradiolwithgestodene(20GSD)

30gethinylestradiolwithgestodene(30GSD)

20gethinylestradiolwithdesogestrel(20DSG)

30gethinylestradiolwithdesogestrel(30DSG)

35gethinylestradiolwithnorgestimate(35NRG)

35gethinylestradiolwithcyproteroneacetate(35CPA)

30gethinylestradiolwithdrospirenone(30DRSP)

Wecategorised20LNG,30LNG,and50LNGassecondgenerationprogestogens,and20GSD,30GSD,20DSG,30DSG,and35NRGasthirdgenerationprogestogens.35CPAand30DRSPwerenotusedinthisclassificationbygenerations.

StatisticalanalysisAnetworkmetaanalysiswasconductedpergenerationofprogestogeninacombinedoralcontraceptiveandperselectedoralcontraceptivepreparation.Weusedanextensionoffrequentistrandomeffects



modelsformixedmultipletreatmentcomparisons.ThenetworkmetaanalysiswasperformedwiththemvmetacommandforStata,asdescribedbyWhiteandcolleagues.30Weusedcrudedatafroma22tableintheanalysis.Oddsratios,riskratios,orrateratiosandappropriatevarianceswerecomputedandcombinedintheanalysisleadingtoanoverallrelativerisk.Forpublicationswithzeroeventsinonecellofa22table,allcellsofthat22tablewereinflatedbyadding0.5.Ifmorethanonestudyprovideddataforthesamestratum(thatis,dataforgenerationsofprogestogenoronspecificcontraceptivepreparations),wecheckedconsistencyoftheresults.Aninteractiontermwasaddedtothemodeltoestimatethedifferenceinresultsfromdirectandindirectevidence.Allpotentialinteractionsweretestedinanoveralltesttodeterminewhethertherewereanyinconsistenciesinournetworkmetaanalysis.

Thefollowingsensitivityanalyseswereplanned:perstudydesign,perfundingsource(whetherindustrysponsoredornot),withinfirsttimeusers,andaccordingtoriskofbias.AllstatisticalanalyseswereperformedwithStata,version12.0(StatacorpLP).

ResultsCharacteristicsofincludedstudiesOf3110publicationsretrievedthroughelectronicandreferencessearches,2144wereexcludedafterscreeningthetitleandabstractand81wereexcludedafterdetailedassessmentofthefulltext(fig1webtable1providesreasonsforexclusion).Overall,26studiesreportedin25articleswereincluded(onearticle10presentedtwostudies).Twopublicationsprovidedimportantadditionalinformationtostudiesincludedinthemetaanalysis(informationonfirsttimeuse)datafromthesepublicationswereaddedtotherespectivestudiesalreadyincluded.Table1showsdetailsofincludedstudies.Ninecohortstudies,threenestedcasecontrolstudies,and14casecontrolstudieswereincluded.



Fig1Flowdiagramofincludedandexcludedpublications

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Table1Characteristicsofincludedstudies

Twostudiesreportedtheabsoluteriskofvenousthrombosisinnonusers:1.9and3.7per10000womanyears.Basedondatafrom15studiesthatincludedanonusergroup,useofcombinedoralcontraceptiveswasfoundtoincreasetheriskofvenousthrombosisfourfold(relativerisk3.5,95%confidenceinterval2.9to4.3).

RiskofbiasEightstudiesassessedcombinedoralcontraceptiveusethroughanintervieworquestionnaire(webtable2).Onlyfivestudiesobjectivelyconfirmedvenousthrombosisinallpatients,whereas14studiesobjectivelyconfirmedvenousthrombosisinaproportionofthepopulationorsubjectivelyconfirmedvenousthrombosis.Fivecasecontrolstudiesselectedcontrolsfromapopulationinhospitalcare.Ofthenine



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cohortstudies,noneprovidedinformationaboutlosstofollowup.

NetworkmetaanalysiscomparinggenerationsofprogestogensAtotalof23studieswereincludedfortheanalysisstratifiedpergenerationofprogestogen.Threestudiesreportedsolelyontheriskofvenousthrombosisindrospirenone,whichisnotclassifiedasagenerationofprogestogen.Webtable3providesdetailsofthenumberofeventsandtotalnumberofwomenortotalfollowuptimepergeneration,andwebtable4providesthestudyspecificadjustedriskestimates.

Table2showsresultsofthenetworkmetaanalysisaccordingtogenerationsofprogestogen.Comparedwithnonusers,theriskofvenousthrombosisinusersoforalcontraceptiveswithafirstgenerationprogestogenincreased3.2fold(95%confidenceinterval2.0to5.1),2.8fold(2.0to4.1)forsecondgenerationprogestogens,and3.8fold(2.7to5.4)forthirdgenerationprogestogens.Theriskofvenousthrombosisinsecondgenerationprogestogenuserswassimilartotheriskinfirstgenerationusers(relativerisk0.9,0.6to1.4).Thirdgenerationusershadaslightlyhigherriskthansecondgenerationusers(1.3,1.0to1.8).Restrictedtostudieswithanidenticalclassificationofgenerations(seemethodssectionforclassificationused),theresultsofeachgenerationcomparedwithnonuseremainedthesame(firstgenerationrelativerisk3.2,95%confidenceinterval1.6to6.4secondgeneration2.6,1.5to4.7thirdgeneration3.5,2.0to6.1).Aformalinteractiontestdidnotshowinconsistenciesinthenetwork( =2.97,P=0.71).

Table2Networkmetaanalysis,bygenerationofprogestogenusedincombinedoralcontraceptives

NetworkmetaanalysiscomparingdifferentcombinedoralcontraceptivesOf14studiesprovidingdatapertypeoforalcontraceptive(webtables5and6),atleastonepreparationwascomparedwithnonuseortwotypeswerecompareddirectly.Table3showsresultsoftheanalysis.Allpreparationswereassociatedwithamorethantwofoldincreasedriskofvenous

thrombosiscomparedwithnonuse(fig2).Therelativeriskestimatewashighestin50LNGusersandlowestin20LNGand20GSDusers.Adoserelatedeffectwasobservedforgestodene,desogestrel,andlevonorgestrel,withhigherdosesbeingassociatedwithhigherthrombosisrisk.Theriskofvenousthrombosisfor35CPAand30DRSPwassimilartotheriskfor30DSG(relativerisk0.9,95%confidenceinterval0.6to1.3and0.9,0.7to1.3,respectively,comparedwith30DSG).Aformalinteractiontestcouldnotbeperformedbecauseonlytwoof14studiesprovideddataforexactlythesamecontraceptives.

2



Fig2Networkmetaanalysis,percontraceptiveplottedonalogarithmicscale.20LNG=20gethinylestradiolwithlevonorgestrel30LNG=30gethinylestradiolwithlevonorgestrel50LNG=50gethinylestradiolwithlevonorgestrel20GSD=20gethinylestradiolwithgestodene30GSD=30gethinylestradiolwithgestodene20DSG=20gethinylestradiolwithdesogestrel30DSG=30gethinylestradiolwithdesogestrel35NRG=35gethinylestradiolwithnorgestimate35CPA=35gethinylestradiolwithcyproteroneacetate30DRSP=30gethinylestradiolwithdrospirenonedots(lines)=overallrelativerisk(95%confidenceinterval)ofvenousthrombosisnonuse=reference

group

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Table3Networkmetaanalysis,bycombinedoralcontraceptivepill

SensitivityanalysesWeperformedsensitivityanalysesaccordingtofundingsource,studydesign,andmethodofdiagnosisconfirmation(objectivevsubjectiveconfirmationofvenousthrombosis).Table4showssensitivityanalysesperformedaccordingtogenerationofprogestogen.Resultsfromthe

sensitivityanalysisstratifiedbyfundingsourceshowedthattheriskestimateforthirdgenerationusers(comparedwithnonusers)waslowerinindustrysponsoredstudiesthaninnonindustrysponsoredstudies(relativerisk1.9v5.2).Incohortstudies,theriskestimateforthirdgenerationusers(comparedwithnonusers)waslowerthantheriskforthirdgenerationusersincasecontrolstudies(2.0v4.2).Allriskestimateswerehigherinstudieswithobjectivelyconfirmedvenousthrombosis,ofwhichnonewereindustrysponsored.



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Table4Sensitivityanalyses

DiscussionWeperformedanetworkmetaanalysisbasedon26studies.Overall,combinedoralcontraceptiveuseincreasedtheriskofvenousthrombosisfourfold.Thereportedincidenceofvenousthrombosisinnonuserswasinlinewiththeliterature.Weobservedthatallgenerationsofprogestogenswereassociatedwithanincreasedriskofvenousthrombosisandthatthirdgenerationusershadaslightincreasedriskcomparedwithsecondgenerationusers.Allindividualtypesofcombinedoralcontraceptivesincreasedthrombosisriskcomparedwithnonusemorethantwofold.Thehighestriskofvenousthrombosiswasfoundamong50LNGusers,andtheriskwassimilarin30DRSP,35CPA,and30DSGusers.Usersof30LNG,20LNG,and20GSDhadthelowestthrombosisrisk.

StrengthsandlimitationsAnetworkmetaanalysissummarisesdatafromdirectandindirectcomparisonsinaweightedaverage.Inthepresentstudy,thisresultedinacomprehensiveoverviewoftheriskofvenousthrombosisinfrequentlyprescribedcombinedoralcontraceptives.Theinternalvalidityofthenetworkmetaanalysiswasassessedthroughinteractionanalysismodellingpotentialinconsistenciesinthenetwork.30Ourresultsoftheanalysisbasedongenerationsofprogestogensindicatedthatpotentialinconsistenciesarelikelytheresultofchance.

Alimitationofournetworkmetaanalysiswasthatpublicationshadtoprovidethecrudenumberofusersandnumberofeventspertypeofcombinedoralcontraceptive.Atotalof15studiesprovidedinformationoncombinedoralcontraceptiveuseandthrombosisriskwithoutspecificationofwhichcontraceptivepreparationswereused.Thesestudiescouldthereforenotbeincluded.Becauseoftheneedforcrudenumbersinthenetworkmetaanalysis,adjustedriskestimateswerenotusedforpoolingthedata.Confoundingcouldhaveinfluencedourresults.Ageisapotentialconfounderfortheassociationbetweencontraceptiveuseandvenousthrombosis.Womenusingsecondgenerationcontraceptivesaregenerallyolderthanusersofthirdgenerationcontraceptives.Ifananalysisisnotadjustedforage,therelativeriskwillthenunderestimatetheriskofvenousthrombosisinusersofthirdgenerationcontraceptivescomparedwithusersofsecondgenerationcontraceptives.Thisimpliesthattheriskofthirdgenerationusersmaybehigherthanreportedhere.However,agewasoftendealtwithinthedesignofthestudies.Bodymassindexisonlyweaklyassociatedwithcombinedoralcontraceptiveuse,andanalysesunadjustedforbodymassindexareprobablynotconfounded.

Thereisnogenerallyacceptedwaytoclassifyoralcontraceptivesaccordingtogenerationsofprogestogens.Forinstance,norgestimatecanbecategorisedasasecondorathirdgenerationprogestogen.Asaconsequence,theclassificationofthesegenerationswasnotthesameinevery



publication.However,theresultsdidnotmateriallychangewhenrestrictedtostudieswithanidenticalclassificationofgenerationsasdescribedinthemethodsnorwhencontraceptiveswithdesogestrelorgestodenewerecomparedwithlevonorgestrel(thatis,norgestimatewasnottakenintoaccountwhenclassifyingcontraceptivesintogenerations)(datanotshown).

Intheclassificationofprogestogengenerationsusedinthismetaanalysis,thedoseofethinylestradiolwasnottakenintoaccount.Theobservedincreasedriskinthirdgenerationcontraceptives,comparedwithsecondgenerationcontraceptives,cannotbeexplainedbyadifferenceinethinylestradioldosebecauseahigherdoseofethinylestradiol(50g)canbepresentinasecondgenerationcontraceptivebutnotinathirdgenerationcontraceptive.

Inonlyafewincludedstudies,venousthrombosiswasobjectivelyconfirmedinallpatients.Onlyabout30%ofpatientswithclinicalsymptomsofthrombosisarediagnosedwithvenousthrombosis.24Includingpatientswithoutobjectivelyconfirmedvenousthrombosiswouldleadtooverestimatingtheassociationwhenoralcontraceptivesusersweremorelikelytobediagnosedthannonusers(diagnosticsuspicionbias).However,twostudiesshowedthatthisbiaswasindependentoftypeoforalcontraceptive.1852Instudieswithoutobjectiveconfirmation,womenweremisclassifiedirrespectiveoftheircontraceptiveuse,leadingtonondifferentialmisclassification.Therefore,resultsofsuchstudiesmayunderestimatethetrueassociation,whichwasconfirmedbyoursensitivityanalysiswheretheriskestimateswerehigherinstudieswithobjectivelyconfirmedvenousthrombosisthaninthosewithoutanobjectiveconfirmation.

Twoothermetaanalyses1853haveevaluatedtheriskofvenousthrombosiscomparingthirdgenerationcontraceptiveuserswithsecondgenerationusers.Bothstudiesfoundanincreasedriskinthirdgenerationusers(relativerisk1.5,95%confidenceinterval1.2to1.8181.57,1.24to1.9853),whichareinlinewithourresults.Themajorityofincludedstudiesfrombothmetaanalyseswereincludedinouranalysis.

ClinicalimplicationsofthestudyAlthoughweobservedthattheriskofvenousthrombosisincreasedwiththedoseofethinylestradiol,thisseemedtodependontheprogestogenprovided.Therewasnodifferenceinthevenousthrombosisriskbetween20LNGand30LNG,whereasadifferenceintheriskwasobservedbetween20DSGand30DSG,forexample.Itisunclearwhythedoseeffectofethinylestradiolmightdependontheprogestogen.Apossibilityisthatthereisadifferenceininhibitoryeffectsoftheprogestogenontheprocoagulanteffectofethinylestradiol.OralcontraceptiveuseincreasesthelevelsoffactorsII,VII,VIII,proteinC,anddecreasesthelevelsofantithrombin,tissuefactorpathwayinhibitor,andproteinS.Clinicalstudieshaveshowedthatthiseffectoncoagulationfactorswasmorepronouncedindesogestrelusersthaninlevonorgestrelusers,andlimitedtocombinedoralcontraceptives.5455

Combiningdifferentpreparationsoforalcontraceptiveintogenerationsofprogestogensmaynotbeanappropriatewaytopresenttheriskofthrombosis,becausetheriskdependsonthedoseofethinylestradiolaswellasontheprogestogenprovided.Wesuggestabstainingfromanyclassificationofcontraceptives,buttocomparetheriskofvenousthrombosisperoralcontraceptivepreparation.

Itshouldbekeptinmindthatallcombinedoralcontraceptivesincreasetheriskofvenousthrombosis,whichisnotthecaseforthelevonorgestrelintrauterinedevice.56However,ifawomanprefersusingcombinedoralcontraceptives,onlycontraceptiveswiththelowestriskofvenousthrombosisandgood



complianceshouldbeprescribed,suchaslevonorgestrelwith30gethinylestradiol.Currentpracticeistoincreasethedoseofethinylestradiolincaseofdisruptionsinbleedingpatterns.57Ourresultsindicatethatprescribing50LNGincaseofspottingduringtheuseof30LNGmightcarryaseriousriskforvenousthrombosis.

WhatisalreadyknownonthistopicCombinedoralcontraceptiveuseincreasestheriskofvenousthrombosis

Despitethelowincidenceofvenousthrombosis,theriskinwomenusingcombinedoralcontraceptivesisarealconcernbecauseofthewidespreaduseofthesecontraceptives

WhatthispaperaddsRiskofvenousthrombosisforcombinedoralcontraceptiveswith3035gethinylestradiolandgestodene,desogestrel,cyproteroneacetateanddrospirenoneweresimilar,andabout5080%higherthanwithlevonorgestrel

Thecombinedoralcontraceptivewiththelowestpossibledoseofethinylestradiolandgoodcomplianceshouldbeprescribedthatis,30gethinylestradiolwithlevonorgestrel

NotesCitethisas:BMJ2013347:f5298

Footnotes

Contributors:BHS,MdB,FMH,andOMDdevelopedthestudydesign.BHSandMdBindependentlyselectedthepublicationsandextracteddata.BHS,TS,andOMDperformedthestatisticalanalysis.Allauthorsinterpretedthedataandcriticallyrevieweddraftsofthemanuscript.BHSisguarantor.

Funding:Thisstudyreceivednospecificfunding.BHSwassupportedbygrant40008129807045fromtheNetherlandsOrganizationforScientificResearch.MdBwassupportedbygrantfromCapesNuffic,Brazil.Thefundingagencieshadnoroleinthestudydesign,implementation,orpreparationofresults.

Competinginterests:AllauthorshavecompletedtheICMJEuniformdisclosureformatwww.icmje.org/coi_disclosure.pdfanddeclare:nosupportfromanyorganisationforthesubmittedworkBHSwassupportedbytheNetherlandsOrganizationforScientificResearchMdBwassupportedbyagrantfromCapesNuffic,Brazilnootherrelationshipsoractivitiesthatcouldappeartohaveinfluencedthesubmittedwork.

Ethicalapproval:Notrequired.



Datasharing:Noadditionaldataavailable.

ThisisanOpenAccessarticledistributedinaccordancewiththeCreativeCommonsAttributionNonCommercial(CCBYNC3.0)license,whichpermitsotherstodistribute,remix,adapt,builduponthisworknoncommercially,andlicensetheirderivativeworksondifferentterms,providedtheoriginalworkisproperlycitedandtheuseisnoncommercial.See:http://creativecommons.org/licenses/bync/3.0/.

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StegemanBernardineH,deBastosMarcos,RosendaalFritsR,vanHylckamaVliegA,HelmerhorstFransM,StijnenTheoetal.Differentcombinedoralcontraceptivesandtheriskofvenousthrombosis:systematicreviewandnetworkmetaanalysisBMJ2013347:f5298

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