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Differentcombinedoralcontraceptivesandthe
riskofvenousthrombosis:systematicreviewand
networkmetaanalysis
BMJ2013347doi:http://dx.doi.org/10.1136/bmj.f5298(Published12September2013)Citethisas:BMJ
2013347:f5298
Article
Relatedcontent
Metrics
Responses
Peerreview

BernardineHStegeman,researchassociate13,MarcosdeBastos,researchfellow2,FritsR
Rosendaal,professorofclinicalepidemiology3,AvanHylckamaVlieg,researchfellow4,FransM
Helmerhorst,professorofclinicalepidemiologyoffertility25,TheoStijnen,professorofmedical
statistics6,OlafMDekkers,researchfellow7

Authoraffiliations
Correspondenceto:OMDekkerso.m.dekkers@lumc.nl
Accepted12August2013

Abstract
ObjectiveToprovideacomprehensiveoverviewoftheriskofvenousthrombosisinwomenusingdifferent
combinedoralcontraceptives.
DesignSystematicreviewandnetworkmetaanalysis.
DatasourcesPubMed,Embase,WebofScience,Cochrane,CumulativeIndextoNursingandAllied
HealthLiterature,AcademicSearchPremier,andScienceDirectupto22April2013.
ReviewmethodsObservationalstudiesthatassessedtheeffectofcombinedoralcontraceptiveson
venousthrombosisinhealthywomen.Theprimaryoutcomeofinterestwasafatalornonfatalfirsteventof
venousthrombosiswiththemainfocusondeepvenousthrombosisorpulmonaryembolism.Publications
withatleast10eventsintotalwereeligible.Thenetworkmetaanalysiswasperformedusinganextension
offrequentistrandomeffectsmodelsformixedmultipletreatmentcomparisons.Unadjustedrelativerisks
with95%confidenceintervalswerereported.Therequirementforcrudenumbersdidnotallowadjustment
forpotentialconfoundingvariables.
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Results3110publicationswereretrievedthroughasearchstrategy25publicationsreportingon26
studieswereincluded.Incidenceofvenousthrombosisinnonusersfromtwoincludedcohortswas1.9and
3.7per10000womanyears,inlinewithpreviouslyreportedincidencesof16per10000womanyears.
Useofcombinedoralcontraceptivesincreasedtheriskofvenousthrombosiscomparedwithnonuse
(relativerisk3.5,95%confidenceinterval2.9to4.3).Therelativeriskofvenousthrombosisforcombined
oralcontraceptiveswith3035gethinylestradiolandgestodene,desogestrel,cyproteroneacetate,or
drospirenoneweresimilarandabout5080%higherthanforcombinedoralcontraceptiveswith
levonorgestrel.Adoserelatedeffectofethinylestradiolwasobservedforgestodene,desogestrel,and
levonorgestrel,withhigherdosesbeingassociatedwithhigherthrombosisrisk.
ConclusionAllcombinedoralcontraceptivesinvestigatedinthisanalysiswereassociatedwithan
increasedriskofvenousthrombosis.Theeffectsizedependedbothontheprogestogenusedandthe
doseofethinylestradiol.

Introduction
Shortlyaftertheintroductionofthefirstcombinedoralcontraceptive(containinganoestrogenanda
progestogen),acaseofvenousthrombosisassociatedwithcontraceptiveusewasreported.1Sincethen,
manyobservationalstudieshaveshownthatcombinedoralcontraceptivesareassociatedwithatwofoldto
sixfoldincreasedriskofvenousthrombosis.2345Despitethelowincidenceofvenousthrombosisabout
threeper10000womanyearsamongwomenofreproductiveage,6theeffectofcombinedoral
contraceptivesonvenousthrombosisislarge,owingtothefactthatmanywomenuseoralcontraceptives.
Becausetheoestrogencompound(ethinylestradiol)incombinedoralcontraceptiveswasthoughttocause
theincreasedriskinthrombosis,thedoseofethinylestradiolwasloweredfrom150100gintheearliest
brandsto50ginthe1960s,andto3035gand20ginthe1970s.789Thereduceddoseof
ethinylestradiolincontraceptiveswasindeedassociatedwithareductionintheriskofvenous
thrombosis.1011121314Apartfromadjustmentsinthedoseofethinylestradiol,theprogestogen
compoundwasalsochangedinanefforttoreducesideeffects.Afterthefirstgenerationprogestogens
(thatis,norethisteroneandlynestrol),newprogestogensweredeveloped.Thesenewcompoundswere
calledsecondgeneration(thatis,levonorgestrel)andthirdgenerationprogestogens(thatis,gestodene,
desogestrel,norgestimate).15However,usersofcombinedoralcontraceptiveswiththirdgeneration
progestogenshaveahigherriskofvenousthrombosisthanthoseusingsecondgeneration
progestogens.16171819Otherprogestogenshavebeendevelopedaftertheintroductionofthird
generationprogestogensthatis,drospirenone(introducedin2001).Thethrombosisriskfor
contraceptiveswithdrospirenonewasfoundtobehigherthanforcombinedoralcontraceptiveswith
secondgenerationprogestogens.2021
Thepresentnetworkmetaanalysisaimedtoprovideanoverviewoftheriskofvenousthrombosisper
combinedoralcontraceptiveinhealthywomen,andassesstheeffectofthegenerationofprogestogen
used.Weperformedanetworkmetaanalysisbecausecombinedoralcontraceptivesaremostlycompared
withnonuseorwithacontraceptivecontaininglevonorgestrelwith30gethinylestradiol.These
comparisonsresultedingapsindirectevidence,becausenoteverycombinedoralcontraceptivewas
directlycomparedwithotherpossiblecombinedoralcontraceptives.Anetworkmetaanalysisallows
evidencefromdirectandindirectcomparisonstobesummarisedinaweightedaverageforallpossible
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comparisons.

Methods
Searchstrategyandselectioncriteria
Publicationsofinterestwereobservationalstudies(cohortor(nested)casecontrolstudies)thatincluded
healthywomenusingcombinedoralcontraceptives.Theprimaryoutcomeofinterestwasafatalornon
fatalfirsteventofvenousthrombosiswiththemainfocusondeepvenousthrombosisorpulmonary
embolism.Publicationswithaminimumof10eventsintotalwereeligible.
Thefollowingdatabasesweresearched:PubMed(984articlesretrieved),Embase(1339),WebofScience
(306),Cochrane(57),CumulativeIndextoNursingandAlliedHealthLiterature(122),AcademicSearch
Premier(197),andScienceDirect(105).OursearchtermsconsistedofMeSHheadingsandsubheadings,
textwords,andwordvariationsforcombinedoralcontraceptive,estrogens,progestogens,and
venousthromboembolism.Thissearchstrategywasamendedforeachdatabase.Wesearchedeach
databasefrominceptionuntil22April2013(dateoffinalsearch).Nolanguagerestrictionwasapplied.In
additiontodatabasesearches,wecheckedreferencesofpotentialinterestingpublications.
Astandardformwasusedtoselectpublications.Twoinvestigators(BHS,MdB)independentlyassessed
publicationsforeligibility.Titlesandabstractswerescreenedandifdeemedpotentiallyrelevant,fulltext
articleswereretrieved.Anydisagreementsbetweentheinvestigatorswerediscussedandifnecessary,a
thirdreviewer(OMD)wasaskedtoresolvedisagreements.Incaseofmultiplepublicationsfromthesame
study,thepublicationwiththemostupdatedorthemostinclusivedatawasincluded.Webappendix1
showsdetailsofthesearchstrategy.

Datacollection
Twoinvestigators(BHSandMdB)independentlyextracteddatausingastandardform.Datawere
extractedontypeofcombinedoralcontraceptive(doseandtypeofoestrogenandprogestogen),crude
numbersforexposureandoutcome,crudeandadjustedriskestimates,andvariablesadjustedforinthe
analysis.Incaseofincompletedatafordoseortypeofoestrogenorprogestogen,authorswere
approachedforextrainformation.Intotal,10authorsweresentanemailon25July2012andifnecessary,
areminderon20August2012.Oftheseauthors,80%repliedtoouremails.Ifprovided,dataforthe
absolutethrombosisriskinnonuserswereextractedfromthecohortstudies.Forsensitivityanalyses,data
forthefundingsourceandfirsttimeusewereabstracted.
Riskofbiasassessmentwasbasedondesignfeaturesthatcouldpotentiallybiastheassociationbetween
exposureandoutcome.Weassessedadequacyofexposure(oralcontraceptive)andoutcome(venous
thrombosis)measurement,losstofollowup(cohortstudies),andadequacyofcontrolselection(case
controlstudies).Womenaremorelikelytorememberthattheyusedoralcontraceptivesthanwhatspecific
preparationtheyused.2223Therefore,assessmentofthetypeofcombinedoralcontraceptivethroughan
intervieworquestionnairewasclassifiedashighriskofbias,andinformationfromaprescriptiondatabase
aslowrisk.Only2533%ofpatientspresentingwithclinicalsymptomssuggestiveofvenousthrombosis
areobjectivelydiagnosedwithvenousthrombosis.24Therefore,studieswithobjectiveconfirmationinall
patientswerejudgedaslowriskofbias.Venousthrombosiswasconsideredobjectivelyconfirmedwhena
deepvenousthrombosiswasdiagnosedbyplethysmography,ultrasoundexamination,computed
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tomography,orvenographyorwhenpulmonaryembolismwasdiagnosedbyventilationperfusion
scanning,spiralcomputedtomography,orpulmonaryangiography.2526Lessthan10%losstofollowup
wasconsideredtorepresentalowriskofbias.Forcasecontrolstudies,controlsselectedfromhospital
populationswasconsideredtoconferahighriskofbias.27

Classificationoftypeofcombinedoralcontraceptive
Thereisnogenerallyacceptedwaytoclassifycombinedoralcontraceptivesaccordingtogenerationsof
progestogens.Inthisanalysis,themostcommonclassificationsystemwasused,whichisinlinewith
biologicalpropertiespergroupandisreflectedintheireffectsonlevelsofsexhormonebindingglobulin.28
29Fortheaimofthepresentnetworkmetaanalysispergenerationofprogestogen,thefollowing
progestogenswereclassifiedasfirstgenerationlynestrenolandnorethisterone.Norgestreland
levonorgestrelwerecategorisedassecondgenerationprogestogensanddesogestrel,gestodene,and
norgestimatewereclassifiedasthirdgenerationprogestogens.15Thisclassificationwasirrespectiveof
ethinylestradioldose.Publicationsreportingongenerationsaccordingtoanotherclassificationwere
included.Toassesstheinfluenceofcombiningdifferentclassifications,weperformedananalysisrestricted
tostudiesusingtheabovedescribedclassification.
Manydifferentcombinedoralcontraceptivesareavailable.Weselected10frequentlyprescribedoral
contraceptivesforthenetworkmetaanalysis:
20gethinylestradiolwithlevonorgestrel(20LNG)
30gethinylestradiolwithlevonorgestrel(30LNG)
50gethinylestradiolwithlevonorgestrel(50LNG)
20gethinylestradiolwithgestodene(20GSD)
30gethinylestradiolwithgestodene(30GSD)
20gethinylestradiolwithdesogestrel(20DSG)
30gethinylestradiolwithdesogestrel(30DSG)
35gethinylestradiolwithnorgestimate(35NRG)
35gethinylestradiolwithcyproteroneacetate(35CPA)
30gethinylestradiolwithdrospirenone(30DRSP)
Wecategorised20LNG,30LNG,and50LNGassecondgenerationprogestogens,and20GSD,30GSD,
20DSG,30DSG,and35NRGasthirdgenerationprogestogens.35CPAand30DRSPwerenotusedinthis
classificationbygenerations.

Statisticalanalysis
Anetworkmetaanalysiswasconductedpergenerationofprogestogeninacombinedoralcontraceptive
andperselectedoralcontraceptivepreparation.Weusedanextensionoffrequentistrandomeffects
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modelsformixedmultipletreatmentcomparisons.Thenetworkmetaanalysiswasperformedwiththe
mvmetacommandforStata,asdescribedbyWhiteandcolleagues.30Weusedcrudedatafroma22
tableintheanalysis.Oddsratios,riskratios,orrateratiosandappropriatevarianceswerecomputedand
combinedintheanalysisleadingtoanoverallrelativerisk.Forpublicationswithzeroeventsinonecellofa
22table,allcellsofthat22tablewereinflatedbyadding0.5.Ifmorethanonestudyprovideddatafor
thesamestratum(thatis,dataforgenerationsofprogestogenoronspecificcontraceptivepreparations),
wecheckedconsistencyoftheresults.Aninteractiontermwasaddedtothemodeltoestimatethe
differenceinresultsfromdirectandindirectevidence.Allpotentialinteractionsweretestedinanoverall
testtodeterminewhethertherewereanyinconsistenciesinournetworkmetaanalysis.
Thefollowingsensitivityanalyseswereplanned:perstudydesign,perfundingsource(whetherindustry
sponsoredornot),withinfirsttimeusers,andaccordingtoriskofbias.Allstatisticalanalyseswere
performedwithStata,version12.0(StatacorpLP).

Results
Characteristicsofincludedstudies
Of3110publicationsretrievedthroughelectronicandreferencessearches,2144wereexcludedafter
screeningthetitleandabstractand81wereexcludedafterdetailedassessmentofthefulltext(fig1web
table1providesreasonsforexclusion).Overall,26studiesreportedin25articleswereincluded(one
article10presentedtwostudies).Twopublicationsprovidedimportantadditionalinformationtostudies
includedinthemetaanalysis(informationonfirsttimeuse)datafromthesepublicationswereaddedto
therespectivestudiesalreadyincluded.Table1showsdetailsofincludedstudies.Ninecohortstudies,
threenestedcasecontrolstudies,and14casecontrolstudieswereincluded.

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Fig1Flowdiagramofincludedandexcludedpublications

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Table1
Characteristicsofincludedstudies

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Twostudiesreportedtheabsoluteriskofvenousthrombosisinnonusers:
1.9and3.7per10000womanyears.Basedondatafrom15studiesthat
includedanonusergroup,useofcombinedoralcontraceptiveswasfound
toincreasetheriskofvenousthrombosisfourfold(relativerisk3.5,95%
confidenceinterval2.9to4.3).

Riskofbias
Eightstudiesassessedcombinedoralcontraceptiveusethroughanintervieworquestionnaire(webtable
2).Onlyfivestudiesobjectivelyconfirmedvenousthrombosisinallpatients,whereas14studiesobjectively
confirmedvenousthrombosisinaproportionofthepopulationorsubjectivelyconfirmedvenous
thrombosis.Fivecasecontrolstudiesselectedcontrolsfromapopulationinhospitalcare.Ofthenine
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cohortstudies,noneprovidedinformationaboutlosstofollowup.

Networkmetaanalysiscomparinggenerationsofprogestogens
Atotalof23studieswereincludedfortheanalysisstratifiedpergenerationofprogestogen.Threestudies
reportedsolelyontheriskofvenousthrombosisindrospirenone,whichisnotclassifiedasagenerationof
progestogen.Webtable3providesdetailsofthenumberofeventsandtotalnumberofwomenortotal
followuptimepergeneration,andwebtable4providesthestudyspecificadjustedriskestimates.
Table2showsresultsofthenetworkmetaanalysisaccordingtogenerationsofprogestogen.Compared
withnonusers,theriskofvenousthrombosisinusersoforalcontraceptiveswithafirstgeneration
progestogenincreased3.2fold(95%confidenceinterval2.0to5.1),2.8fold(2.0to4.1)forsecond
generationprogestogens,and3.8fold(2.7to5.4)forthirdgenerationprogestogens.Theriskofvenous
thrombosisinsecondgenerationprogestogenuserswassimilartotheriskinfirstgenerationusers
(relativerisk0.9,0.6to1.4).Thirdgenerationusershadaslightlyhigherriskthansecondgenerationusers
(1.3,1.0to1.8).Restrictedtostudieswithanidenticalclassificationofgenerations(seemethodssection
forclassificationused),theresultsofeachgenerationcomparedwithnonuseremainedthesame(first
generationrelativerisk3.2,95%confidenceinterval1.6to6.4secondgeneration2.6,1.5to4.7third
2

generation3.5,2.0to6.1).Aformalinteractiontestdidnotshowinconsistenciesinthenetwork( =2.97,
P=0.71).
Table2
Networkmetaanalysis,bygenerationofprogestogenusedincombinedoral
contraceptives

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Networkmetaanalysiscomparingdifferentcombinedoral
contraceptives
Of14studiesprovidingdatapertypeoforalcontraceptive(webtables5and
6),atleastonepreparationwascomparedwithnonuseortwotypeswere
compareddirectly.Table3showsresultsoftheanalysis.Allpreparations
wereassociatedwithamorethantwofoldincreasedriskofvenous

thrombosiscomparedwithnonuse(fig2).Therelativeriskestimatewashighestin50LNGusersand
lowestin20LNGand20GSDusers.Adoserelatedeffectwasobservedforgestodene,desogestrel,and
levonorgestrel,withhigherdosesbeingassociatedwithhigherthrombosisrisk.Theriskofvenous
thrombosisfor35CPAand30DRSPwassimilartotheriskfor30DSG(relativerisk0.9,95%confidence
interval0.6to1.3and0.9,0.7to1.3,respectively,comparedwith30DSG).Aformalinteractiontestcould
notbeperformedbecauseonlytwoof14studiesprovideddataforexactlythesamecontraceptives.

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Fig2Networkmetaanalysis,percontraceptiveplottedonalogarithmicscale.20LNG=20g
ethinylestradiolwithlevonorgestrel30LNG=30gethinylestradiolwithlevonorgestrel50LNG=50
gethinylestradiolwithlevonorgestrel20GSD=20gethinylestradiolwithgestodene30GSD=30
gethinylestradiolwithgestodene20DSG=20gethinylestradiolwithdesogestrel30DSG=30g
ethinylestradiolwithdesogestrel35NRG=35gethinylestradiolwithnorgestimate35CPA=35g
ethinylestradiolwithcyproteroneacetate30DRSP=30gethinylestradiolwithdrospirenonedots
(lines)=overallrelativerisk(95%confidenceinterval)ofvenousthrombosisnonuse=reference
group

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Table3
Networkmetaanalysis,bycombinedoralcontraceptivepill

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Sensitivityanalyses
Weperformedsensitivityanalysesaccordingtofundingsource,study
design,andmethodofdiagnosisconfirmation(objectivevsubjective
confirmationofvenousthrombosis).Table4showssensitivityanalyses

performedaccordingtogenerationofprogestogen.Resultsfromthe
sensitivityanalysisstratifiedbyfundingsourceshowedthattheriskestimateforthirdgenerationusers
(comparedwithnonusers)waslowerinindustrysponsoredstudiesthaninnonindustrysponsoredstudies
(relativerisk1.9v5.2).Incohortstudies,theriskestimateforthirdgenerationusers(comparedwithnon
users)waslowerthantheriskforthirdgenerationusersincasecontrolstudies(2.0v4.2).Allrisk
estimateswerehigherinstudieswithobjectivelyconfirmedvenousthrombosis,ofwhichnonewere
industrysponsored.

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Table4
Sensitivityanalyses

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Discussion
Weperformedanetworkmetaanalysisbasedon26studies.Overall,combinedoralcontraceptiveuse
increasedtheriskofvenousthrombosisfourfold.Thereportedincidenceofvenousthrombosisinnon
userswasinlinewiththeliterature.Weobservedthatallgenerationsofprogestogenswereassociated
withanincreasedriskofvenousthrombosisandthatthirdgenerationusershadaslightincreasedrisk
comparedwithsecondgenerationusers.Allindividualtypesofcombinedoralcontraceptivesincreased
thrombosisriskcomparedwithnonusemorethantwofold.Thehighestriskofvenousthrombosiswas
foundamong50LNGusers,andtheriskwassimilarin30DRSP,35CPA,and30DSGusers.Usersof
30LNG,20LNG,and20GSDhadthelowestthrombosisrisk.

Strengthsandlimitations
Anetworkmetaanalysissummarisesdatafromdirectandindirectcomparisonsinaweightedaverage.In
thepresentstudy,thisresultedinacomprehensiveoverviewoftheriskofvenousthrombosisinfrequently
prescribedcombinedoralcontraceptives.Theinternalvalidityofthenetworkmetaanalysiswasassessed
throughinteractionanalysismodellingpotentialinconsistenciesinthenetwork.30Ourresultsofthe
analysisbasedongenerationsofprogestogensindicatedthatpotentialinconsistenciesarelikelytheresult
ofchance.
Alimitationofournetworkmetaanalysiswasthatpublicationshadtoprovidethecrudenumberofusers
andnumberofeventspertypeofcombinedoralcontraceptive.Atotalof15studiesprovidedinformation
oncombinedoralcontraceptiveuseandthrombosisriskwithoutspecificationofwhichcontraceptive
preparationswereused.Thesestudiescouldthereforenotbeincluded.Becauseoftheneedforcrude
numbersinthenetworkmetaanalysis,adjustedriskestimateswerenotusedforpoolingthedata.
Confoundingcouldhaveinfluencedourresults.Ageisapotentialconfounderfortheassociationbetween
contraceptiveuseandvenousthrombosis.Womenusingsecondgenerationcontraceptivesaregenerally
olderthanusersofthirdgenerationcontraceptives.Ifananalysisisnotadjustedforage,therelativerisk
willthenunderestimatetheriskofvenousthrombosisinusersofthirdgenerationcontraceptivescompared
withusersofsecondgenerationcontraceptives.Thisimpliesthattheriskofthirdgenerationusersmaybe
higherthanreportedhere.However,agewasoftendealtwithinthedesignofthestudies.Bodymass
indexisonlyweaklyassociatedwithcombinedoralcontraceptiveuse,andanalysesunadjustedforbody
massindexareprobablynotconfounded.
Thereisnogenerallyacceptedwaytoclassifyoralcontraceptivesaccordingtogenerationsof
progestogens.Forinstance,norgestimatecanbecategorisedasasecondorathirdgeneration
progestogen.Asaconsequence,theclassificationofthesegenerationswasnotthesameinevery
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publication.However,theresultsdidnotmateriallychangewhenrestrictedtostudieswithanidentical
classificationofgenerationsasdescribedinthemethodsnorwhencontraceptiveswithdesogestrelor
gestodenewerecomparedwithlevonorgestrel(thatis,norgestimatewasnottakenintoaccountwhen
classifyingcontraceptivesintogenerations)(datanotshown).
Intheclassificationofprogestogengenerationsusedinthismetaanalysis,thedoseofethinylestradiolwas
nottakenintoaccount.Theobservedincreasedriskinthirdgenerationcontraceptives,comparedwith
secondgenerationcontraceptives,cannotbeexplainedbyadifferenceinethinylestradioldosebecausea
higherdoseofethinylestradiol(50g)canbepresentinasecondgenerationcontraceptivebutnotina
thirdgenerationcontraceptive.
Inonlyafewincludedstudies,venousthrombosiswasobjectivelyconfirmedinallpatients.Onlyabout30%
ofpatientswithclinicalsymptomsofthrombosisarediagnosedwithvenousthrombosis.24Including
patientswithoutobjectivelyconfirmedvenousthrombosiswouldleadtooverestimatingtheassociation
whenoralcontraceptivesusersweremorelikelytobediagnosedthannonusers(diagnosticsuspicion
bias).However,twostudiesshowedthatthisbiaswasindependentoftypeoforalcontraceptive.1852In
studieswithoutobjectiveconfirmation,womenweremisclassifiedirrespectiveoftheircontraceptiveuse,
leadingtonondifferentialmisclassification.Therefore,resultsofsuchstudiesmayunderestimatethetrue
association,whichwasconfirmedbyoursensitivityanalysiswheretheriskestimateswerehigherinstudies
withobjectivelyconfirmedvenousthrombosisthaninthosewithoutanobjectiveconfirmation.
Twoothermetaanalyses1853haveevaluatedtheriskofvenousthrombosiscomparingthirdgeneration
contraceptiveuserswithsecondgenerationusers.Bothstudiesfoundanincreasedriskinthirdgeneration
users(relativerisk1.5,95%confidenceinterval1.2to1.8181.57,1.24to1.9853),whichareinlinewith
ourresults.Themajorityofincludedstudiesfrombothmetaanalyseswereincludedinouranalysis.

Clinicalimplicationsofthestudy
Althoughweobservedthattheriskofvenousthrombosisincreasedwiththedoseofethinylestradiol,this
seemedtodependontheprogestogenprovided.Therewasnodifferenceinthevenousthrombosisrisk
between20LNGand30LNG,whereasadifferenceintheriskwasobservedbetween20DSGand30DSG,
forexample.Itisunclearwhythedoseeffectofethinylestradiolmightdependontheprogestogen.A
possibilityisthatthereisadifferenceininhibitoryeffectsoftheprogestogenontheprocoagulanteffectof
ethinylestradiol.OralcontraceptiveuseincreasesthelevelsoffactorsII,VII,VIII,proteinC,anddecreases
thelevelsofantithrombin,tissuefactorpathwayinhibitor,andproteinS.Clinicalstudieshaveshowedthat
thiseffectoncoagulationfactorswasmorepronouncedindesogestrelusersthaninlevonorgestrelusers,
andlimitedtocombinedoralcontraceptives.5455
Combiningdifferentpreparationsoforalcontraceptiveintogenerationsofprogestogensmaynotbean
appropriatewaytopresenttheriskofthrombosis,becausetheriskdependsonthedoseofethinylestradiol
aswellasontheprogestogenprovided.Wesuggestabstainingfromanyclassificationofcontraceptives,
buttocomparetheriskofvenousthrombosisperoralcontraceptivepreparation.
Itshouldbekeptinmindthatallcombinedoralcontraceptivesincreasetheriskofvenousthrombosis,
whichisnotthecaseforthelevonorgestrelintrauterinedevice.56However,ifawomanprefersusing
combinedoralcontraceptives,onlycontraceptiveswiththelowestriskofvenousthrombosisandgood
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complianceshouldbeprescribed,suchaslevonorgestrelwith30gethinylestradiol.Currentpracticeisto
increasethedoseofethinylestradiolincaseofdisruptionsinbleedingpatterns.57Ourresultsindicatethat
prescribing50LNGincaseofspottingduringtheuseof30LNGmightcarryaseriousriskforvenous
thrombosis.

Whatisalreadyknownonthistopic
Combinedoralcontraceptiveuseincreasestheriskofvenousthrombosis
Despitethelowincidenceofvenousthrombosis,theriskinwomenusingcombinedoral
contraceptivesisarealconcernbecauseofthewidespreaduseofthesecontraceptives

Whatthispaperadds
Riskofvenousthrombosisforcombinedoralcontraceptiveswith3035gethinylestradioland
gestodene,desogestrel,cyproteroneacetateanddrospirenoneweresimilar,andabout5080%
higherthanwithlevonorgestrel
Thecombinedoralcontraceptivewiththelowestpossibledoseofethinylestradiolandgood
complianceshouldbeprescribedthatis,30gethinylestradiolwithlevonorgestrel

Notes
Citethisas:BMJ2013347:f5298

Footnotes
Contributors:BHS,MdB,FMH,andOMDdevelopedthestudydesign.BHSandMdBindependently
selectedthepublicationsandextracteddata.BHS,TS,andOMDperformedthestatisticalanalysis.
Allauthorsinterpretedthedataandcriticallyrevieweddraftsofthemanuscript.BHSisguarantor.
Funding:Thisstudyreceivednospecificfunding.BHSwassupportedbygrant40008129807045
fromtheNetherlandsOrganizationforScientificResearch.MdBwassupportedbygrantfromCapes
Nuffic,Brazil.Thefundingagencieshadnoroleinthestudydesign,implementation,orpreparationof
results.
Competinginterests:AllauthorshavecompletedtheICMJEuniformdisclosureformat
www.icmje.org/coi_disclosure.pdfanddeclare:nosupportfromanyorganisationforthesubmitted
workBHSwassupportedbytheNetherlandsOrganizationforScientificResearchMdBwas
supportedbyagrantfromCapesNuffic,Brazilnootherrelationshipsoractivitiesthatcouldappear
tohaveinfluencedthesubmittedwork.
Ethicalapproval:Notrequired.

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