Anti-diabetic drug utilization of pregnant diabetic women in us managed care

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Anti-diabetic drug utilization of pregnant diabetic women in us managed care
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BMC Pregnancy and Childbirth
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Caitlin A Knox
Joseph AC Delaney
Almut G Winterstein
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BMC Pregnancy and Childbirth
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Pharmacoepidemiology
Drug utilization
Pregnancy
Managed care

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Background: With the increasing prevalence of type 2 diabetes in young adulthood, treatment of diabetes in pregnancy faces new challenges. Anti-diabetic drug utilization patterns of pregnant women with pre-existing diabetes are poorly described. We aim to describe anti-diabetic (AD) agent utilization among diabetic pregnant women. Methods: We utilized IMS LifeLink, including administrative claims data of patients in US managed care plans, to establish a retrospective cohort of women, age 18–46 years (N = 96,740) with billed procedures for a live birth, and a 12 month eligibility period before and 3 month after delivery. Diabetes mellitus was identified from ≥2 in- or outpatient claims with diagnoses (ICD-9-CM 250.XX) before pregnancy. We estimated the prevalence of AD drugs before, during and after pregnancy, and secular trends across the study period (1999–2009), using linear regression. A sensitivity analysis was conducted to identify the extent of misclassification of trimesters. Results: Almost six percent (n = 5,581) of the live birth cohort had diabetes mellitus. Throughout the study, 48% (1999) and 78% (2009) (p < 0.0001) of diabetic women received AD drugs during pregnancy. The most common AD drugs during pregnancy were insulin, metformin, sulfonylureas, thiazolidinediones (TZD), and combination AD. The annual prevalence of insulin use increased by only 1% from 39% (1999) to 40% (2009) (p = 0.589) during pregnancy, while use of sulfonylureas and metformin increased from 2.5% and 4.2% (1999) to 17.3% and 15.3% (2009) (p < 0.0001), respectively. Insulin and sulfonylurea use steadily increased in prevalence from the 1st to 3rd trimester (16.5% and 3.3% to 33.0% and 7.5%), while metformin and TZD use decreased (11.4% and 1.6% to 3.8% and 0.2%). Conclusions: AD use during pregnancy demonstrates the need for additional investigation regarding safety and efficacy of AD drugs on maternal outcomes.

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University of Florida
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University of Florida
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RESEARCHARTICLEOpenAccessAnti-diabeticdrugutilizationofpregnantdiabetic womeninusmanagedcareCaitlinAKnox1*,JosephACDelaney2andAlmutGWinterstein1,3AbstractBackground: Withtheincreasingprevalenceoftype2diabetesinyoungadulthood,treatmentofdiabetesin pregnancyfacesnewchallenges.Anti-diabeticdrugutilizationpatternsofpregnantwomenwithpre-existing diabetesarepoorlydescribed.Weaimtodescribeanti-diabetic(AD)agentutilizationamongdiabeticpregnant women. Methods: WeutilizedIMSLifeLink,includingadministrativeclaimsdataofpatientsinUSmanagedcareplans,to establisharetrospectivecohortofwomen,age18 – 46years(N=96,740)withbilledproceduresforalivebirth,and a12montheligibilityperiodbeforeand3monthafterdelivery.Diabetesmellituswasidentifiedfrom 2in-or outpatientclaimswithdiagnoses(ICD-9-CM250.XX)beforepregnancy.WeestimatedtheprevalenceofADdrugs before,duringandafterpregnancy,andseculartrendsacrossthestudyperiod(1999 – 2009),usinglinearregression. Asensitivityanalysiswasconductedtoidentifytheextentofmisclassificationoftrimesters. Results: Almostsixpercent(n=5,581)ofthelivebirthcohorthaddiabetesmellitus.Throughoutthestudy,48% (1999)and78%(2009)(p<0.0001)ofdiabeticwomenreceivedADdrugsduringpregnancy.ThemostcommonAD drugsduringpregnancywereinsulin,metformin,sulfonylureas,thiazolidinediones(TZD),andcombinationAD.The annualprevalenceofinsulinuseincreasedbyonly1%from39%(1999)to40%(2009)(p=0.589)duringpregnancy, whileuseofsulfonylureasandmetforminincreasedfrom2.5%and4.2%(1999)to17.3%and15.3%(2009) (p<0.0001),respectively.Insulinandsulfonylureausesteadilyincreasedinprevalencefromthe1stto3rdtrimester (16.5%and3.3%to33.0%and7.5%),whilemetforminandTZDusedecreased(11.4%and1.6%to3.8%and0.2%). Conclusions: ADuseduringpregnancydemonstratestheneedforadditionalinvestigationregardingsafetyand efficacyofADdrugsonmaternaloutcomes. Keywords: Pharmacoepidemiology,Drugutilization,Pregnancy,ManagedcareBackgroundCurrentestimatesprojectthatby2025oneinthree adultsintheUnitedStates(US)willhavediabetesmellitus [1].In2010,approximately11%ofUSwomenaged20 yearsorolderwereeitherdiagnosedorhadundiagnosed diabetes[1].Thisreflectsanincreaseindiabetesprevalenceof2%inthisagegroupoverthelastfiveyears,with acorresponding1.9millionnewcasesofdiabetesdiagnosedin2010[1].Thisgrowthisalmostexclusivelyattributabletotype2diabetesmellitus,whichtraditionallyhas haditsonsetinlaterstagesofadulthood[1,2]. Thegrowingprevalenceoftype2diabetesinyoung adultsisparticularlyimportant,asmoreyoungwomen willbediagnosedduringreproductiveyears[2].Poorly controlleddiabetesbothbe foreandduringthefirst trimesterofpregnancycancausemajorbirthdefects, spontaneousabortions,andstillbirths[2].Despitethis well-establishedfact,morethan60%ofwomenwith pre-existingdiabeteshave difficultymanagingtheir glycemiccontrolduringpregn ancy[3-5].Researchers andprovidersagreethatglycemiccontrolisoneofthe mostimportantmodifiableriskfactorsinminimizing birthdefectsofinfantsborntowomenwithpre-existing diabetes[6-10].However,littleexperienceandevidence regardingthesafetyandeffectivenessoforalagentsduring pregnancyexists. *Correspondence: cknox@ufl.edu1DepartmentofPharmaceuticalOutcomes&Policy,CollegeofPharmacy, Gainesville,FL,USA Fulllistofauthorinformationisavailableattheendofthearticle 2014Knoxetal.;licenseeBioMedCentralLtd.ThisisanopenaccessarticledistributedunderthetermsoftheCreative CommonsAttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,and reproductioninanymedium,providedtheoriginalworkisproperlycited.Knox etal.BMCPregnancyandChildbirth 2014, 14 :28 http://www.biomedcentral.com/1471-2393/14/28

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Whiletype1diabetesmanagementrequiresinsulinand thusleaveslittlechoiceduringpregnancy,type2diabetes maybemanagedwithlife-stylemodifications,oralantidiabeticagents,and/orinsulin.Amongoralagents,several newmolecularentitieshavebeenaddedwithinthelastten yearswithlimiteddataonpregnancyoutcomes.Giventhe limitedresearchthatisavailableonanti-diabeticagentuse duringpregnancy,weaimedtodescribeanti-diabetic agentutilizationbefore,duringandafterpregnancyand determineseculartrendsamongclassesofanti-diabetic drugsacrossthe10-yearstudyperiod(1999 – 2009)in womenwithpre-existingdiabetes.MethodsWeutilizedtheIMSLifeLinkDatabase,whichconsists ofcommercialhealthplaninformationfrommorethan 100managedcareplansthroughouttheUS.Themajority ofthepayertypewithinthedatabaseiscommerciallyinsured.TheIMSLifeLinkdatabasealsoincludesMedicaid, Medicare,self-insuredandunknownpayertypes.The databaserecordsaregenerallyrepresentativeofthecommerciallyinsuredpopulationintermsofgenderandage. TheIMSLifeLinkdatabaseiscomprisedofeligibility anddemographicinformation,aswellas,inpatientand outpatientclaimsdatawithdetailondiagnosisandprocedures,andprescriptiondrugclaims.Thisdatabase containedarandomsampleof6millionwomenaged18 to46yearswithnoprescriptiondrugclaimforcontraceptives.Tobeincludedinourstudycohortwerequiredwomentohaveabilledmedicalprocedurescode forlivebirth(Table1),and12monthscontinuousinsurancecoveragebeforeand3monthsafterdelivery. Womenwererequiredtohaveatleastoneprescription drugclaimbeforepregnancy,toconfirmprescriptiondrug coverage.Atotalof96,740womenmettheinclusion criteriaforthecohort. Toidentifypatientswithpre-existingdiabetes,werequiredtwoin-oroutpatientclaimswithdiagnosisof Table1Delivery-relatedprocedure(CPT-4)codesusedtoidentifylivebirthsCodeDescription 01960Anesthesiaforvaginaldeliveryonly 01961Anesthesiaforcesareandeliveryonly 01962Anesthesiaforurgenthysterectomyfollowingdelivery 01963Anesthesiaforcesareanhysterectomyw/oanylaboranalgesia/anesthesiacare 01967Neuraxiallaboranalgesia/anesthesia,plannedvaginaldelivery 01968Anesthesiaforcesareandeliveryfollowingneuraxiallaboranalgesia/anesthesia 01969Anesthesiaforcesareanhysterectomyfollowingneuraxiallaboranalgesia/anesthesia 59050Fetalmonitoringinlabor,physicianw/writtenreport 59051Fetalmonitoringinlabor,physicianw/writtenreport;interpretationonly 59400Routineobstetriccare,antepartumcare,vaginaldelivery,&postpartumcare 59409Vaginaldeliveryonly(w/woepisiotomy&/orforceps) 59410Vaginaldeliveryonly(w/woepisiotomy&/orforceps);w/postpartumcare 59412Externalcephalicversion,w/wotocolysis 59414Delivery,placenta(separateprocedure) 59430Postpartumcareonly(separateprocedure) 59510Routineobstetriccarew/antepartumcare,cesareandelivery,&postpartumcare 59514Cesareandeliveryonly 59515Cesareandeliveryonly;w/postpartumcare 59525Subtotal/totalhysterectomyaftercesareandelivery 59610Routineobstetriccare,vaginaldelivery,w/antepartum,postpartumcare,previousc-section 59612Vaginaldeliveryonly,previouscesareandelivery 59614Vaginaldeliveryonly,previouscesareandelivery;w/postpartumcare 59618Routineobstetriccare,ante/postpartum,cesareandeliveryafterfailedvaginaldelivery,previouscesareandelivery 59620Cesareandelivery,afterfailedvaginaldelivery,previouscesareandelivery 59622Cesareandelivery,afterfailedvaginaldelivery,previouscesareandelivery;w/postpartumcare 99436Attendanceatdelivery,atrequestofdeliveringphysician,&stabilizationofnewborn 99440Newbornresuscitation Knox etal.BMCPregnancyandChildbirth 2014, 14 :28 Page2of8 http://www.biomedcentral.com/1471-2393/14/28

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diabetesmellitus(InternationalClassificationofDiseases, NinthRevision,ClinicalModification(ICD-9-CM)250. XX)withinthe3monthsprecedingconception[11,12]. ICD-9-CMcodesidentifythespecifictypeofdiabetesmellitusbythefifthdigitofthecode,butpreviousresearch suggeststhatcurrentcodingpracticesdonotprovide sufficientaccuracytoidentifythetypeofdiabetesfrom thefifthdigitoftheICD-9-CMcode[13,14].Therefore, wedidnotseparatewomenaccordingtotheirdiabetes mellitustype,butdecidedtopresentasubgroupanalysisinwomenwithhighpropensitytohavetype2diabetes[15].Fortheanalysis,weassumedthepresenceof type2diabeteswhen100%ofdiabetesmellitusdiagnosesintheclaimsindicatedtype2diabetes(ICD-9-CM 250.0or250.2)[15].The “ otherdiabetes ” subgroup includedallwomenwithtype1diabetesmellitusclaims andthosewithmixedorunspecificclaims(i.e.,missing the5thdigit). Wedefinedthedeliverydateasthedateofthefirst CurrentProceduralTerminology(CPT-4)claimforlive birthforeachwoman.Weincludedwomenwithlive birthsonlybecauseweneededtoobtainanestimatedconceptiondateforeachwoman.Inclusionofterminated pregnancieswouldnothaveallowedthedeterminationof trimestersbecausethedateofterminationrelativetoconceptionwouldbeunknown.Sincewedidnothaveaccess totheLastMenstrualPeriod(LMP)date,itwasnecessary forustocalculatetheconceptiondateofthepregnancy. Thiswasdonebysubtractingninemonths(270days)from thedeliverydate[16,17].Eachtrimesterofpregnancywas assigneda91-dayinterval[16,17].Pre-pregnancyinterval wereidentifiedasthethreemonthsprecedingtheimputed conceptiondatetoclassifythepresenceofpre-existing diabetesandcapturepre-pregnancydrugutilization.We separatelydefinedanafterpregnancyintervalasthethreemonthtimeperiodafterthedeliverydate,resultinginfive distinct3-monthperiods,whichwereusedtodefinedrug useprevalence. Becausewereliedonanimputedconceptiondate,there wasapotentialformisclassificationofthepre-pregnancy periodandthefollowingtrimesters.Theriskofmisclassificationofthepregnancyperiodswasparticularlyhighin womenwithdiabetes,becausetheyareathigherriskfor pre-termbirths(i.e.shortergestationperiods).Inorderto evaluatethiseffectweconductedasensitivityanalysis, whereweutilizedthefirsthealthcareencounterwitha pregnancycode(ICD-9-CM:V22,V23,V72.40,V72.42 andCPT-4:81025)toestimateconceptiondate[18].Using thefirstpregnancyclaimastheconceptiondate,themean lengthofpregnancyforthecohortwas6.55monthswith atstandarddeviationof1.64months.Fivepercentofthe diabetescohorthadanICD-9-CMclaimforearlydelivery (644.2,644.20,and644.21).Therefore,weconductedanothersensitivityanalysiswhereweadjustedthegestation lengthto245daysforwomenwithanearlydeliveryclaim [19].Wesawthatthedrugclassutilizationinthesensitivityanalysisdidnotdiffersignificantlywiththeoriginally imputedpregnancyperiodswecalculatedusing270days subtractedfromthedeliverydate. Amongthetenanti-diabeticdrugclassesidentified withintheIMSpregnancycohort,wefocusedouranalysis onthefivemostcommonlyutilizeddrugclassesbefore, duringandafterpregnancy:insulin,biguanides,sulfonylureas,thiazolidinediones,andoralanti-diabeticcombinations.Theremaininganti-diabeticdrugclassesallshowed prevalenceratesoflessthan1%(alpha-glucosidaseinhibitors,amylinanalogs,dipeptidylpeptidase-4,GLP-1 receptoragonistsandmeglitinideanalogues).Allinsulin productswerecollapsedintoonecategoryreflecting AmericanHospitalFormularyService(AHFS)drugclass 68.20.08.Wecalculatedrespectivedrugclassprevalence astheproportionofdiabeticwomenwithadrugclaimof aparticularclassduringeachofthedesignatedperiods. Weestimatedtheprevalencealongwiththe95%confidenceintervalsofanti-diabeticdrugclassutilizationbefore,during(foreachtrimester)andafterpregnancy.We investigatedtheseculartrendofannualdrugutilization prevalenceusinglinearregression.AllanalyseswereconductedwithSAS9.2,Cary,NC.TheUniversityofFlorida InstitutionalReviewandPrivacyBoardsapprovedthis study.ResultsOverthecourseoftheten-yearstudyperiod(1999 – 2009), weidentified5,581(5.9%)womenwithpre-existingdiabetesamongallwomenwithaprocedurecodeforlive birth.Atotalof4,043womenhadonlyICD-9-CMcodes consistentwithtype2diabetesmellitus.Diabeticwomen wereonaverageslightlyolder,hadmorephysicianvisits andmoreprescriptiondrugclaimsbeforepregnancy (Table2).Asexpected,diabeticwomenhadahigher prevalenceofadditionalco-morbidconditionsthannondiabeticwomenhad,buthadsimilarfrequenciesofsmoking,alcoholanddrugabuse.Diabeticwomenalsohada higherprevalenceofcesareansectiondeliverycompared tonon-diabeticwomen,with44.8%versus27.2%respectively.Therewasahigherprevalenceofdiabeticsinthe EastregionoftheUS,andalowerprevalenceintheSouth andWest.Withinthesub-groupanalysis,type2diabetic womenhadsimilarbaselinecharacteristics,buttheaveragenumberofADprescriptionsbeforepregnancywas lowerinthetype2diabetesonlygroupwhencompared toalldiabeticwomen. Theannualmeanageforthediabeticpregnancycohort hadastatisticallysignificantincreasefrom29.85yearsto 32.90yearsfrom1999to2009(beta=0.34,p<0.0001). Theprevalenceofanti-diabetictreatment(insulinor oralanti-diabeticdrugs)amongdiabeticwomenbeforeKnox etal.BMCPregnancyandChildbirth 2014, 14 :28 Page3of8 http://www.biomedcentral.com/1471-2393/14/28

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pregnancyincreasedfrom25.9%(CI:25.74,26.06)to 36.1%(CI:35.94,36.26)from1999to2009(beta=1.3%, p<0.0001)(Figure1).Duringpregnancy,weobserveda statisticallysignificantriseinanti-diabeticdrugtreatmentfrom48.3%in1999to77.9%in2009(beta=3.4%, p<0.0001).Thegrowthintheprevalenceoftreatmentwas similaracrosstrimesterswiththelargestgrowthinthe thirdtrimester,whichsawa23%increaseintreatmentfrom 36.8%(CI:36.58,37.01)in199 9to59.4%(CI:59.18,59.62) in2009(beta=2.4%,p<0.0001).Theprevalenceofdiabetic womenwhoweretreatedwithananti-diabeticdrugafter pregnancyapproximatelydoubledfrom18.3%(CI:18.11, 18.49)to39.7%(CI:39.51,39.89)from1999to2009ata rateof1.8%(CI:1.14,2.53)peryear(p<0.0001)(Figure1). Table2BaselinecharacteristicsofthestudycohortsVariableCategoryDM*DM*NotDM* N=5,581N=5,581N=91,159 T2DM*OtherDM* N=4,043N=1,538 Age:Years(SD) 32.3(5.1)32.5(5.1)32.1(5.0)30.1(5.3) Eligibility:Months(SD)56.8(25.2)57.4(25.2)55.1(24.9)51.3(24.4) Physicianofficevisits3monthsbeforePregnancy(SD)21.3(24.5)20.8(25.2)22.5(22.5)14.6(17.8) NumberofPrescriptionDrugClaims3monthsbeforePregnancy(SD)Anti-Diabetic3.0(7.5)1.4(4.5)7.2(11.2)0.1(0.9) Other14.6(18.8)13.9(18.5)16.4(19.4)9.7(12.4) DeliveryRouteVaginal55.2%58.8%47.7%72.8% CesareanSection44.8%41.2%52.3%27.2% ComorbidConditionsPCOS12.5%13.1%10.9%5.5% Hypertension18.2%17.0%21.4%4.3% Infertility14.7%15.6%12.2%10.6% IVFClaim0.1%0.1%0.1%0.0% Obesity13.9%13.4%15.2%3.8% Smoking6.0%6.0%5.9%4.6% Alcohol0.8%0.8%1.0%0.9% DrugAbuse0.7%0.7%0.6%0.7% RegionEast32.6%33.6%26.6%20.6% Midwest43.1%43.1%40.6%43.8% South12.1%11.1%19.7%17.9% West12.3%12.2%13.2%17.7% ConceptionYear(SD)2005(2.4)2005(2.3)2005(2.6)2005(2.6)*DM=pre-existingdiabetesmellitus,T2DM=type2diabetesmellitus. Figure1 Annualprevalenceofanti-diabetictreatmentbefore,duringandafterpregnancy. Knox etal.BMCPregnancyandChildbirth 2014, 14 :28 Page4of8 http://www.biomedcentral.com/1471-2393/14/28

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Amongthevarioustherapeuticclasses,metforminand sulfonylureasshowedthegreatestincreaseoverthestudy periodfrom4.2%(CI:4.11,4.29)and2.5%(CI:2.44,2.56) in1999to15.3%(CI:15.21,15.39)and17.3%(CI:17.26, 17.36)in2009,respectively(p<0.0001foreachdrugclass) (Figure2).Thesulfonylureadrugclassincludedglimepride,glipizide,andglyburideat28%,47%and25%respectively.Thiazolidinedionesandcombinationdrugs remainedconstantat1.6%(CI:1.56,1.64)and0.5%(CI: 0.47,0.53)overthecours eofthestudy.Asexpected rosiglitazonesawadecreasefrom50%to23.1%within thethiazolidinesdionedrugclass(beta= 3.4,p=0.12). Insulinuseduringpregnancyincreased1%overthe10-year periodfrom39%(CI:38.81,39.19)in1999to40%(CI: 39.81,40.19)in2009(p-value=0.589(Figure2). Whenpooledacrosstheentirestudyperiod,the prevalenceofmetforminusebeforepregnancyinalldiabeticwomenwas13.7%(CI:13.11,14.28),whichdecreasedto12.3%(CI:12.21,12.39)duringpregnancy andthendecreasedfurtherafterpregnancyto7.7%(CI: 7.62,7.78)(Figure3).Insulinutilizationbehavedasexpected,withaloweraverageprevalencebeforepregnancyof10.7%(CI:10.52,10.88),whichmorethan tripledto35.3%(CI:35.11,35.48)duringpregnancyand thendroppedagainto11.8%(CI:11.67,11.93)after pregnancy.Sulfonylureautilizationfollowedasurprisinglysimilartrend,asthepre-pregnancybaselineprevalenceof3.1%(CI:3.08,3.12)grewduringpregnancyto 10.4%(CI:10.34,10.46)andthendecreasedto2.5%(CI: 2.43,2.57)afterpregnancy. Insub-groupanalysisofthetype2diabeticwomenonly, thepatternofanti-diabeticdrugutilizationwasverysimilartoalldiabeticwomen,exceptanexpectedlowerprevalenceofinsulinusethroughouteach3-monthperiod.We notedanevenlowerreboundinutilizationofmetformin afterpregnancy,withonly5.6%(CI:5.51,5.69)oftype2 diabeticwomenwhousedmetforminpost-delivery,but morethan12.4%(CI:12.30,12.50)beforepregnancy.DiscussionWeconductedadescriptiveanalysisonanti-diabeticdrug utilizationbefore,duringandafterpregnancyindiabetic womeninordertoguidefutureresearchondrugsafety andeffectiveness.Ourstudyhadseveralkeyfindings. First,overallanti-diabeticdrugutilizationduringpregnancydoubledoverourten-yearstudyperiod.Second, despitethisincrease,wefoundasignificantproportion ofdiabeticwomenwithnodrugtreatmentbefore,duringandafterpregnancy.Third,amongtheanti-diabetic drugclasseswefoundinterestingADutilizationpattern indicatingchangesinthet reatmentregimenduring pregnancy.Forexample,theprevalenceofmetformin utilizationdecreasedaspregnancyprogressedfromthe 1sttothe3rdtrimester,butwasre-establishedintothe treatmentregimenafterpregnancy,althoughatlessthan halftheprevalenceofthebeforeperiod.Insulinandsulfonylureademonstratedareversedpattern,astheoverall prevalenceofutilizationinbothdrugclassesincreased overthecourseofpregnancyandthenreturnedtoalow prevalenceafterpregnancysimilartoutilizationbefore. Currentrecommendationsfortheinitialtherapyof diabetes(bothtype1andtype2)emphasizepharmacologicalinterventions[20].AccordingtotheAmerican DiabetesAssociation(ADA)andtheEuropeanAssociationfortheStudyofDiabetes(EASD),theinitialmanagementoftype2diabetesshouldusecombinationtherapy ofmetforminandlifestylechangeswithaugmentationof therapywithadditionaloralanti-diabeticdrugtomaintain glycemiccontrol[20].Orinitiateinsulinatdiagnosisfor individualswhopresentwithseverehyperglycemicsymptoms[20].Therecommendationreflectsachangeintreatmentapproachesadecadeago,whichsuggestedthatearly type2diabetesmightbemanagedwithdietandlifestyle modificationsalone.Thisevolutionintreatmentparadigm mayexplaintheincreaseinoverallanti-diabeticdrug utilizationthatweobservedamongdiabeticwomenbefore,during,andafterpregnancyoverourstudyperiod. Figure2 Annualprevalenceofanti-diabeticdrugutilizationduringpregnancybydrugclass. Knox etal.BMCPregnancyandChildbirth 2014, 14 :28 Page5of8 http://www.biomedcentral.com/1471-2393/14/28

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Interestingly,accordingtotheNationalHealthInterview Survey,forthepasttenyearstheprevalenceofdiabetic adultswhodonotuseinsulinororalanti-diabeticdrugs tocontroltheirdiabeteshasslightlygrownby1%tomore than15%ofUSadultswithdiabetes[2,21].Thefactthat weobservedevenhigherproportionsofnon-treatedpatientsinamanagedcarepopulationwithcomprehensive drugbenefitsandincreasedmedicalattentionduetopregnancyissurprisingandraisesquestionsaboutcurrent treatmentapproaches.Whilethemajorityofpregnant womanmayhavehadonsetoftype2diabetesinrecent yearsandthuslimitedneedforaggressiveglycemiccontrol,westillexpectedthatcurrenttreatmentguidelines andtheemphasisontightglucosecontrolduringpregnancywouldhaveresultedinmorecomprehensivedrug therapy.Unfortunately,becauselaboratoryvaluesarenot availableinclaimsdata,itisunclearwhetherthesewomen wereabletoachieveormaintainnormoglycemiathroughoutpregnancy. Ingeneral,theuseofinsulintotreattype2diabetes mellitusduringpregnancyisacceptedandrecommended assafeandeffectiveinachievingnormalbloodglucose levels[22,23].Thereisalsosufficientevidencetosupport thatmetforminisnon-inferiortoinsulinwithregardsto neonatalsafety,butcomparativedataregardingefficacy duringpregnancyarelacking[24,25].Furthermore,the majorityofthemetforminsafetystudieshavebeencompletedinwomenwithpolycysticovariansyndromeor gestationaldiabetes,notinwomenwithpre-existing diabetes,andhavenotevaluatedpregnancyoutcomes (pre-termlabor,preeclampsia,cesareansectiondelivery) assafetyendpoints[24,26]. Thedistinctincreaseofsulfonylureasuseduringpregnancyobservedinthiscohortwasnoteworthyinthis context,becausethisdrugclassiscurrentlynotrecommendedforthisindication,includinganFDAcontraindicationforuseinthelast4weeksofpregnancy.This notwithstanding,severalstudieshavefoundnoharmful effectsandreportgoodglycemiccontrolwiththe useofsulfonylureasduringpregnancy[27-30].Again, themajorityofstudiesontheuseofthisdrugclass inpregnancyaddresstheuseingestationaldiabetic womenandlackevidenceonvariousaspectsofsafety andefficacy. Weconductedthisstudyusingadministrativeclaims data.TheIMSLifeLinkdatabaseallowedustoinvestigate theprevalenceofdiabetesinpregnancyinarelativelylarge cohortofmorethan96,000pregnantwomen,sampled fromover100commercialhealthplansacrosstheUS, withfullyadjudicatedmedicalandpharmaceuticalclaims. Thestudyperiod,whichspannedtenyears,allowedfor theexaminationoftimetrendsindrugutilizationofthese womenbefore,duringandafterpregnancy.Focusona managedcaresettingallowedgoodobservationofprescribingpractices,becauseaccesstocareisnotamajor limitation. Alladministrativedatahav elimitationsandthisstudy isnoexception.Despiteourlargesamplesize,focuson womeninprivateinsuranceisnotrepresentativeofdiabetestreatmentpatternintheUS.Inaddition,theselectionofhealthplansinIMSmaynotberepresentativeas suggestedbythegeographicdistributionofdiabetes prevalencethatdoesnotfollownationallyreporteddata. However,comparisonsacrosstimeandacrosstrimestersareexpectedtobevalidwithinthestudycohort.By restrictingthepregnancycohorttoonlywomenwitha prescriptiondrugclaimbeforepregnancy,weareomittingwomenwithoutdrugcoverageandtheoretically omittingwomenwhoarenotreceivingdrugtreatment orwhoarenon-adherenttotheirmedicationregimen. Wepotentiallyunderestimateddruguseprevalencein instanceswherepharmacyclaimswerenotsubmitted forreimbursementbecausepatientspaidcashfortheir prescriptions.However,sinceprescriptioncopaysshould haveprovidedcheaperalternativestopatientsduringthe studyperiod,weexpectminimalmisclassification.We limitedthisdescriptiveanalysistopregnantwomenwith livebirths.Therefore,thedrugutilizationpatternsthat wereseenwithinthisdescriptiveanalysismaybedifferent frompre-existingdiabeticwomenwithunsuccessfulpregnancies(i.e.miscarriage,stillbirth,ortermination). Finally,weaimedtofocusourstudyonpatientswith type2diabetes,buthadtoacceptlimitationsinthe granularityofICD9-CMcodesusedforbilling.Studies havebeenlargelyunsuccessfulinvalidatingalgorithms todistinguishbetweendiabetestypes[13-15,31].In ordertoestimatetheextentof potentialmisclassificationweprovideresultsofasensitivityanalysisusinga conservativeapproachthatdidnotallowanycodesfor type1orunspecifieddiabetesinoursub-cohortoftype 2diabeticpatients.Thisapproachwaslikelynotsensitiveandmayhaveexcludedpatientsdifferentially. Figure3 Pooledannualprevalenceofanti-diabeticdrug utilization,bydrugclass:before,during,andafterpregnancy. Knox etal.BMCPregnancyandChildbirth 2014, 14 :28 Page6of8 http://www.biomedcentral.com/1471-2393/14/28

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ConclusionPre-existingdiabetesisanincreasingcomorbidityin pregnantwomanintheUS.Whiletheoveralluseof anti-diabeticmedicationsduringpregnancyincreased,a largerthanexpectedproportionofpregnantwomendid nothaveADdrugclaimsthroughoutthestudyperiod. Contrarytocurrentrecommendations,metforminuse decreasedaspregnancyprogressedwhilesulfonylurea useincreased.Thehighrateoforalanti-diabeticdrug useduringpregnancyemphasizestheneedforconclusive evidenceregardingsafetyandefficacyintermsofglucose controlaswellasmaternaloutcomes.Furtherresearchis neededinordertoevaluatethesafetyoforalanti-diabetic agentuseinpregnantwomenwithpre-existingdiabetesin termsofpregnancyandneonataloutcomes.Withinthis study,itwewereunabletoassesstheimpactofglycemic controlandco-morbidconditionsonthechoiceofantidiabeticagentsthroughoutpregnancy.Therefore,itwill alsobeimportantforfutureresearchtofocusonthedeterminatesofmedicationchoicesduringpregnancyincludingthepresenceoron-setofco-morbidconditions andchangesinglycemiccontrol.Additionally,thelower prevalenceofanti-diabeticdrugutilizationpost-delivery indicatesapossibleneedforfurtherinvestigation.Competinginterests Theauthorsdeclarethattheyhavenocompetinginterests. Authors ’ contributions Conceivedanddesignedtheresearch:CK,JD,AW.Analyzedthedata:CK. Wrotethepaper:CK.Interpretationofdata:CK,JD,AW.Criticallyrevised manuscript:CK,JD,AW.Allauthorshaveapprovedthemanuscriptas submitted. Presentationofwork Thesub-groupanalysisofthetype2diabetesdatafromthispaperwas presentedatthe28thInternationalConferenceonPharmacoepidemiology andTherapeuticRiskManagement,inAugust2012. Acknowledgements Wereceivednofundinginsupportofthisresearchandthispaperisnot underreviewelsewhere.TheAmericanFoundationPharmaceutical EducationFellowshipandtheMaryKOwensFellowshipsupportedCK.None oftheseentitieshadinfluenceonthedesignandconductofthestudy, collection,management,analysis,andinterpretationofthedata,andthe preparationorapprovalofthemanuscript. Authordetails1DepartmentofPharmaceuticalOutcomes&Policy,CollegeofPharmacy, Gainesville,FL,USA.2DepartmentofEpidemiology,UniversityofWashington, Seattle,WA,USA.3CollegesofMedicineandPublicHealthandHealth Professions,UniversityofFlorida,Gainesville,FL,USA. Received:5April2013Accepted:23December2013 Published:17January2014 References1. DiagnosedandundiagnoseddiabetesintheUnitedStates,allages,2010. [http://www.cdc.gov/diabetes/pubs/estimates11.htm#1] 2.CowieCC,RustKF,Byrd-HoltDD,EberhardtMS,FlegalKM,EngelgauMM, SaydahSH,WilliamsDE,GeissLS,GreggEW: Prevalenceofdiabetesand impairedfastingglucoseinadultsintheU.S.population:NationalHealth AndNutritionExaminationSurvey1999 – 2002. DiabetesCare 2006, 29 (6):1263 – 1268. 3.HolingEV,BeyerCS,BrownZA,ConnellFA: Whydon'twomenwith diabetesplantheirpregnancies? DiabetesCare 1998, 21 (6):889 – 895. 4.CoustanDR: Pre-conceptionplanning.Therelationship'sthething. 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