Different Combined Oral Contraceptives and the Risk of Venous Thrombosis_ Systematic Review and...

11.05.2015 Differentcombinedoralcontraceptivesandtheriskofvenousthrombosis:systematicreviewandnetworkmetaanalysis|TheBMJ

http://www.bmj.com/content/347/bmj.f5298 1/18

Thissiteusescookies.MoreinfoCloseBycontinuingtobrowsethesiteyouareagreeingtoouruseofcookies.FindoutmorehereCloseCCBYNCOpenaccessResearch

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

ArticleRelatedcontentMetricsResponsesPeerreview

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

DownloadfigureOpeninnewtab

Downloadpowerpoint

Viewthistable:

ViewpopupViewinline

Table1Characteristicsofincludedstudies

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

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



Viewthistable:

ViewpopupViewinline

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

DownloadfigureOpeninnewtab

Downloadpowerpoint

Viewthistable:

ViewpopupViewinline

Table3Networkmetaanalysis,bycombinedoralcontraceptivepill

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

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



Viewthistable:

ViewpopupViewinline

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/.

References1.JordanW.Pulmonaryembolism.Lancet1961278:11467.

2.Oralcontraceptionandthromboembolicdisease.JRCollGenPract196713:26779. Medline

3.InmanWH,VesseyMP.Investigationofdeathsfrompulmonary,coronary,andcerebralthrombosisandembolisminwomenofchildbearingage.BMJ19682:1939. FREEFullText

4.SartwellPE,MasiAT,ArthesFG,GreeneGR,SmithHE.Thromboembolismandoralcontraceptives:anepidemiologiccasecontrolstudy.AmJEpidemiol196990:36580. Abstract/FREEFullText

5.VesseyMP,DollR.Investigationofrelationbetweenuseoforalcontraceptivesandthromboembolicdisease.Afurtherreport.BMJ19692:6517. Abstract/FREEFullText

6.NaessIA,ChristiansenSC,RomundstadP,CannegieterSC,RosendaalFR,HammerstromJ.Incidenceandmortalityofvenousthrombosis:apopulationbasedstudy.JThrombHaemost20075:6929. CrossRef MedlineWebofScience

7.ThorogoodM,VillardMackintoshL.Combinedoralcontraceptives:risksandbenefits.BrMedBull199349:12439. Abstract/FREEFullText

8.WhartonC,BlackburnR.Lowerdosepills.PopulationRep198816:131.

9.StolleyPD,TonasciaJA,TockmanMS,SartwellPE,RutledgeAH,JacobsMP.Thrombosiswithlowestrogenoralcontraceptives.AmJEpidemiol1975102:197208. Abstract/FREEFullText

10.Venousthromboembolicdiseaseandcombinedoralcontraceptives:resultsofinternationalmulticentrecasecontrolstudy.WorldHealthOrganizationCollaborativeStudyofCardiovascularDiseaseandSteroidHormoneContraception.Lancet1995346:157582. CrossRef Medline WebofScience

11.InmanWH,VesseyMP,WesterholmB,EngelundA.Thromboembolicdiseaseandthesteroidalcontentoforalcontraceptives.AreporttotheCommitteeonSafetyofDrugs.BMJ19702:2039. Abstract/FREEFullText

12.VesseyM,MantD,SmithA,YeatesD.Oralcontraceptivesandvenousthromboembolism:findingsinalargeprospectivestudy.BrMedJ(ClinResEd)1986292:526. FREEFullText

13.LidegaardO,EdstromB,KreinerS.Oralcontraceptivesandvenousthromboembolism:afiveyearnationalcasecontrolstudy.Contraception200265:18796. CrossRef Medline WebofScience

14.MeadeTW,GreenbergG,ThompsonSG.Progestogensandcardiovascularreactionsassociatedwithoralcontraceptivesandacomparisonofthesafetyof50and30microgramoestrogenpreparations.BMJ1980280:115761. Abstract/FREEFullText

15.HenzlMR,EdwardsJA.Pharmacologyofprogestins:17alphahydroxyprogesteronederivativesandprogestinsofthefirstandsecondgeneration.In:SitrukWareRL,MishellDRJr,eds.Progestinsandantiprogestinsinclinicalpractice.MarcelDekker,2000:10132.

16.LidegaardO,LokkegaardE,SvendsenAL,AggerC.Hormonalcontraceptionandriskofvenous



thromboembolism:nationalfollowupstudy.BMJ2009339:b2890. Abstract/FREEFullText

17.vanHylckamaVliegA,HelmerhorstFM,VandenbrouckeJP,DoggenCJ,RosendaalFR.Thevenousthromboticriskoforalcontraceptives,effectsofoestrogendoseandprogestogentype:resultsoftheMEGAcasecontrolstudy.BMJ2009339:b2921. Abstract/FREEFullText

18.KemmerenJM,AlgraA,GrobbeeDE.Thirdgenerationoralcontraceptivesandriskofvenousthrombosis:metaanalysis.BMJ2001323:1314. Abstract/FREEFullText

19.VandenbrouckeJP,RosingJ,BloemenkampKW,MiddeldorpS,HelmerhorstFM,BoumaBN,etal.Oralcontraceptivesandtheriskofvenousthrombosis.NEnglJMed2001344:152735. CrossRef MedlineWebofScience

20.JickSS,HernandezRK.Riskofnonfatalvenousthromboembolisminwomenusingoralcontraceptivescontainingdrospirenonecomparedwithwomenusingoralcontraceptivescontaininglevonorgestrel:casecontrolstudyusingUnitedStatesclaimsdata.BMJ2011342:d2151. Abstract/FREEFullText

21.ParkinL,SharplesK,HernandezRK,JickSS.Riskofvenousthromboembolisminusersoforalcontraceptivescontainingdrospirenoneorlevonorgestrel:nestedcasecontrolstudybasedonUKGeneralPracticeResearchDatabase.BMJ2011342:d2139. Abstract/FREEFullText

22.NischanP,EbelingK,ThomasDB,HirschU.Comparisonofrecalledandvalidatedoralcontraceptivehistories.AmJEpidemiol1993138:697703. Abstract/FREEFullText

23.NorellSE,BoethiusG,PerssonI.Oralcontraceptiveuse:interviewdataversuspharmacyrecords.IntJEpidemiol199827:10337. Abstract/FREEFullText

24.WellsPS,HirshJ,AndersonDR,LensingAW,FosterG,KearonC,etal.Accuracyofclinicalassessmentofdeepveinthrombosis.Lancet1995345:132630. CrossRef Medline WebofScience

25.GoodacreS,SampsonF,StevensonM,WailooA,SuttonA,ThomasS,etal.Measurementoftheclinicalandcosteffectivenessofnoninvasivediagnostictestingstrategiesfordeepveinthrombosis.HealthTechnolAssess200610:1168. Medline WebofScience

26.QaseemA,SnowV,BarryP,HornbakeER,RodnickJE,TobolicT,etal.Currentdiagnosisofvenousthromboembolisminprimarycare:aclinicalpracticeguidelinefromtheAmericanAcademyofFamilyPhysiciansandtheAmericanCollegeofPhysicians.AnnFamMed20075:5762. Abstract/FREEFullText

27.GrimesDA,SchulzKF.Comparedtowhat?Findingcontrolsforcasecontrolstudies.Lancet2005365:142933.CrossRef Medline WebofScience

28.RapsM,HelmerhorstF,FleischerK,ThomassenS,RosendaalF,RosingJ,etal.Sexhormonebindingglobulinasamarkerforthethromboticriskofhormonalcontraceptives.JThrombHaemost201210:9927. CrossRefMedline

29.vanVlietHA,FrolichM,ChristellaM,ThomassenLG,DoggenCJ,RosendaalFR,etal.AssociationbetweensexhormonebindingglobulinlevelsandactivatedproteinCresistanceinexplainingtheriskofthrombosisinusersoforalcontraceptivescontainingdifferentprogestogens.HumReprod200520:5638. Abstract/FREEFullText

30.WhiteIR,BarrettJK,JacksonD,HigginsJPT.Consistencyandinconsistencyinnetworkmetaanalysis:modelestimationusingmultivariatemetaregression.ResearchSynthesisMethods20123:11125. CrossRef

31. BirdST,DelaneyJA,EtminanM,BrophyJM,HartzemaAG.Drospirenoneandnonfatalvenousthromboembolism:isthereariskdifferencebydosageofethinylestradiol?JThrombHaemost201311:105968.CrossRef Medline

32. GronichN,LaviI,RennertG.Higherriskofvenousthrombosisassociatedwithdrospirenonecontainingoral



contraceptives:apopulationbasedcohortstudy.CMAJ2011183:E131925. Abstract/FREEFullText

33. LidegaardO,NielsenLH,SkovlundCW,SkjeldestadFE,LokkegaardE.Riskofvenousthromboembolismfromuseoforalcontraceptivescontainingdifferentprogestogensandoestrogendoses:Danishcohortstudy,20019.BMJ2011343:d6423. Abstract/FREEFullText

34. HeinemannLA,DingerJC,AssmannA,MinhTD.Useoforalcontraceptivescontaininggestodeneandriskofvenousthromboembolism:outlook10yearsafterthethirdgenerationpillscare.Contraception201081:4017.CrossRef Medline WebofScience

35. JickSS,KayeJA,RussmannS,JickH.Riskofnonfatalvenousthromboembolismwithoralcontraceptivescontainingnorgestimateordesogestrelcomparedwithoralcontraceptivescontaininglevonorgestrel.Contraception200673:56670. CrossRef Medline WebofScience

36. SamuelssonE,HaggS.IncidenceofvenousthromboembolisminyoungSwedishwomenandpossiblypreventablecasesamongcombinedoralcontraceptiveusers.ActaObstetGynecolScand200483:67481. CrossRef MedlineWebofScience

37. HedenmalmK,SamuelssonE,SpigsetO.Pulmonaryembolismassociatedwithcombinedoralcontraceptives:reportingincidencesandpotentialriskfactorsforafataloutcome.ActaObstetGynecolScand200483:57685.Medline

38. HeinemannLA,LewisMA,AssmannA,ThielC.Casecontrolstudiesonvenousthromboembolism:biasduetodesign?Amethodologicalstudyonvenousthromboembolismandsteroidhormoneuse.Contraception200265:20714. CrossRef Medline WebofScience

39. LidegaardO,EdstromB,KreinerS.Oralcontraceptivesandvenousthromboembolism:afiveyearnationalcasecontrolstudy.Contraception200265:18796. CrossRef Medline WebofScience

40. ParkinL,SkeggDC,WilsonM,HerbisonGP,PaulC.Oralcontraceptivesandfatalpulmonaryembolism.Lancet2000355:21334. CrossRef Medline WebofScience

41. FarmerRD,LawrensonRA,ToddJC,WilliamsTJ,MacRaeKD,TyrerF,etal.Acomparisonoftherisksofvenousthromboembolicdiseaseinassociationwithdifferentcombinedoralcontraceptives.BrJClinPharmacol200049:58090. CrossRef Medline WebofScience

42. HeringsRM,UrquhartJ,LeufkensHG.Venousthromboembolismamongnewusersofdifferentoralcontraceptives.Lancet1999354:1278. CrossRef Medline WebofScience

43. ToddJ,LawrensonR,FarmerRD,WilliamsTJ,LeydonGM.Venousthromboembolicdiseaseandcombinedoralcontraceptives:areanalysisoftheMediPlusdatabase.HumReprod199914:15005. Abstract/FREEFullText

44. MartinelliI,TaioliE,BucciarelliP,AkhavanS,MannucciPM.InteractionbetweentheG20210Amutationoftheprothrombingeneandoralcontraceptiveuseindeepveinthrombosis.ArteriosclerThrombVascBiol199919:7003. Abstract/FREEFullText

45. BloemenkampKW,RosendaalFR,BullerHR,HelmerhorstFM,CollyLP,VandenbrouckeJP.Riskofvenousthrombosiswithuseofcurrentlowdoseoralcontraceptivesisnotexplainedbydiagnosticsuspicionandreferralbias.ArchInternMed1999159:6570. CrossRef Medline WebofScience

46. FarmerRD,ToddJC,LewisMA,MacRaeKD,WilliamsTJ.TherisksofvenousthromboembolicdiseaseamongGermanwomenusingoralcontraceptives:adatabasestudy.Contraception199857:6770. CrossRef MedlineWebofScience

47. AndersenBS,OlsenJ,NielsenGL,SteffensenFH,SorensenHT,BaechJ,etal.Thirdgenerationoralcontraceptivesandheritablethrombophiliaasriskfactorsofnonfatalvenousthromboembolism.ThrombHaemost199879:2831. Medline WebofScience



48. LewisMA,HeinemannLA,MacRaeKD,BruppacherR,SpitzerWO.Theincreasedriskofvenousthromboembolismandtheuseofthirdgenerationprogestagens:roleofbiasinobservationalresearch.TheTransnationalResearchGrouponOralContraceptivesandtheHealthofYoungWomen.Contraception199654:513. CrossRef Medline WebofScience

49. FarmerR.Safetyofmodernoralcontraceptives.Lancet1996347:259. Medline

50. BloemenkampKW,RosendaalFR,HelmerhorstFM,BullerHR,VandenbrouckeJP.EnhancementbyfactorVLeidenmutationofriskofdeepveinthrombosisassociatedwithoralcontraceptivescontainingathirdgenerationprogestagen.Lancet1995346:15936. CrossRef Medline WebofScience

51. Effectofdifferentprogestagensinlowoestrogenoralcontraceptivesonvenousthromboembolicdisease.WorldHealthOrganizationCollaborativeStudyofCardiovascularDiseaseandSteroidHormoneContraception.Lancet1995346:15828. CrossRef Medline WebofScience

52.VandenbrouckeJP,HelmerhorstFM,BloemenkampKW,RosendaalFR.Thirdgenerationoralcontraceptiveanddeepvenousthrombosis:fromepidemiologiccontroversytonewinsightincoagulation.AmJObstetGynecol1997177:88791. CrossRef Medline WebofScience

53.ManzoliL,DeVitoC,MarzuilloC,BocciaA,VillariP.Oralcontraceptivesandvenousthromboembolism:asystematicreviewandmetaanalysis.DrugSaf201235:191205. Medline WebofScience

54.KemmerenJM,AlgraA,MeijersJC,BoumaBN,GrobbeeDE.EffectsofsecondandthirdgenerationoralcontraceptivesandtheirrespectiveprogestagensonthecoagulationsystemintheabsenceorpresenceofthefactorVLeidenmutation.ThrombHaemost200287:199205. Medline WebofScience

55.KemmerenJM,AlgraA,MeijersJC,TansG,BoumaBN,CurversJ,etal.EffectofsecondandthirdgenerationoralcontraceptivesontheproteinCsystemintheabsenceorpresenceofthefactorVLeidenmutation:arandomizedtrial.Blood2004103:92733. Abstract/FREEFullText

56.vanHylckamaVlieg,A,HelmerhorstFM,RosendaalFR.Theriskofdeepvenousthrombosisassociatedwithinjectabledepotmedroxyprogesteroneacetatecontraceptivesoralevonorgestrelintrauterinedevice.ArteriosclerThrombVascBiol201030:2297300. Abstract/FREEFullText

57.GalloMF,NandaK,GrimesDA,LopezLM,SchulzKF.20microgversus>20microgestrogencombinedoralcontraceptivesforcontraception.CochraneDatabaseSystRev20088:CD003989.

ViewAbstract

Tweet 80

223Like

5

ArticletoolsPDF3responses

Respondtothisarticle

DatasupplementPrintAlerts&updates



DownloadDownloadDownloadDownloadDownloadDownload

Articlealerts

Pleasenote:youremailaddressisprovidedtothejournal,whichmayusethisinformationformarketingpurposes.

Loginorregister:

Username*Password*Login

Registerforalerts

Ifyouhaveregisteredforalerts,youshoulduseyourregisteredemailaddressasyourusernameCitationtools

Downloadthisarticletocitationmanager

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

BibTeX(win&mac)EndNote(tagged)EndNote8(xml)RefWorksTagged(win&mac)RIS(winonly)Medlars

HelpIfyouareunabletoimportcitations,pleasecontacttechnicalsupportforyourproductdirectly(linksgotoexternalsites):

EndNoteProCiteReferenceManagerRefWorksZotero

Requestpermissions

Authorcitation

ArticlesbyBernardineHStegemanArticlesbyMarcosdeBastosArticlesbyFritsRRosendaalArticlesbyAvanHylckamaVliegArticlesbyFransMHelmerhorstArticlesbyTheoStijnenArticlesbyOlafMDekkers

AddarticletoBMJPortfolio

Emailtoafriend

Forwardthispage



Seemoredetails

ThankyouforyourinterestinspreadingthewordaboutTheBMJ.

NOTE:Weonlyrequestyouremailaddresssothatthepersonyouarerecommendingthepagetoknowsthatyouwantedthemtoseeit,andthatitisnotjunkmail.Wedonotcaptureanyemailaddress.

Username*YourEmail*SendTo*

YouaregoingtoemailthefollowingDifferentcombinedoralcontraceptivesandtheriskofvenousthrombosis:systematicreviewandnetworkmetaanalysisYourPersonalMessage

Send

TopicsReproductivemedicineContraceptionDrugs:obstetricsandgynaecologyInternetPulmonaryembolism

Whoistalkingaboutthisarticle?

UKjobsInternationaljobs

NHSForthValley:ConsultantinGeneralAdultPsychiatryHomertonUniversityHospitalNHSFoundationTrust:ConsultantHaematologistwithspecialinterestinAnticoagulationandthrombosisHomertonUniversityHospitalNHSFoundationTrust:ConsultantHaematologistwithspecialinterestin

Tweetedby139On13FacebookpagesReferencedin2WikipediapagesMentionedin1Google+postsHighlightedby1platforms

38readersonMendeley1readersonCiteULike



Haematooncology(10PAs+1additionalPA)Dr.SulaimanAlHabibMedicalGroup:JobopportunitiesinSaudiArabiaNHSEngland:NationalClinicalReferenceGroupCCGMembers&ampSenateAreaMembersViewmoreBacktotop

Date post:	04-Sep-2015
Category:	Documents
Upload:	ana-em
View:	225 times
Download:	4 times

Different Combined Oral Contraceptives and the Risk of Venous Thrombosis_ Systematic Review and...

Documents