GoodClinicalTreatmentinAssisted Reproduction‐AnESHREpositionpaper  EXECUTIVESUMMARY     June2008 Theprevalenceofinfertilityisincreasinginthedevelopedworld.Thepostponementofpregnancy,greater prevalenceofobesityandsexuallytransmittedinfectionsallcontributetotheproblem.Thistrendhasbeen acknowledgedbytheEuropeanParliament,whichinFebruary2008calledonMemberStates"toensurethe rightofcouplestouniversalaccesstoinfertilitytreatment”.Asaresult,thereexistsaprogressiveneedfor medicalhelpinresolvingreproductivedisorders. ESHRE,astheEuropeanbodyforprofessionalsinreproductivemedicineandbiology,hasthroughits membershipalwaysaimedtoprovidechildlesscoup leswiththebestpossiblemanagementoftheirfertility problems,whileatthesametimeensuringthattheyarenotexposedtounnecessaryrisksorineffective treatments.ItisESHRE'sviewthatthetreatmentofinfertilityshouldbebasedonabalancedchoicefromthe bestavailableevidence,withrespectbothtoefficacyandsafety.ESHREpromotesimprovementsinmedicaland laboratorypracticeandencourages,throughits educationalactivitiesandtraining,highqualitymedicalcareand laboratoryprocedures.ItistheobjectiveofESHREtodescribeinthispositionpapertheprinciplesofgood clinicaltreatmentinassistedreproductionfromanev idence‐basedprofessionalperspective. Accessibilityisakeyfeatureofgoodclinicalcare.Treatmentsofprovenbenefitshouldbemadeeasilyavailable throughoutEurope,irrespectiveofthepatient'sincomeorplaceofresidence.Reimbursementpolicieshavean impactontheuseofreproductivehealthcare;alackofreimbursementconstitutesabarrierforthoseseeking treatment.IndividualEUcountriesshouldprovideaccesstopubliclyfundedhealthcare,inclusiveof,butnot limitedto,assistedreproductivetechnologiessuchasintrauterineinsemination(IUI),invitrofertilis ation(IVF), andintracytoplasmicsperminjection(ICSI). Ithasbeenshownthat84%ofcouplesnotusingcontraceptionandhavingregularsexualintercoursewill conceivewithinoneyear;another8%willconceiveintheirsecondyearoftrying.So,thefirstobjectiveofa dedicatedfertilityinvestigationshouldbetoidentifythosecoupleswhomostlikelywillnotneedmedical assistance.Asinvolunt arychildlessnesscanbeapsychologicalburden,prope rcounsellingshouldbeoffered aboutallrelatedmedical,psychologicalandsocialquestions.Providingthemwitheasilyunderstoodevidence‐ basedinformationshouldoffercouplestheopportunitytomakeinformeddecisionswithregardtotheir reproductivefutureandthecaretheywishtoreceive. Incouplesinwhomscreeningrevealsaproblem,furtherdelayisnotjustifiedandtreatmentshouldbeoffered. Thismayincludeadviceonlifestylechanges,eatinghabits,smokingandstressfulemployment.Itmayalso includemedicaltreatmentwithdrugs,theinductionofovulation,surgery,insemination,IVF,ICSI,andoocyteor spermdonation(sometimesaftercryopreservation). Moderntechniquesofassistedreproductionhavebeenaccompaniedbyhighrisksinthepast:ovarian hyperstimulationsyndrome,thromboembolism,(highorder)multiplepregnancies,surgicalcomplications. WithinESHRE,responsibilityforhighqualitypatientcarehasstimulatedthedevelopmentofmildappr oachesin IVF,theencouragementofelectivesingleembryotransfer,thedevelopmentofimprovedfreezingprogrammes, andtheabandonmentofaggressivesurgicalproceduresinfavourofminimallyinvasivesurgery. Inordertoensurepropermonitoringofbothqualityandquantityinassistedreproduction,itisimportantthat annualreportsaccordingtotheprinciplesoutlinedbyESHREwithrespecttotypes,efficacy,safetyandrisksare madepubliclyavailable. Dedicated,responsiblecareforchildlesscouplestogetherwithuniversalaccesstoinfertilitytreatmentshouldbe acommongoalofESHRE,patientorganisations and EU politicians alike. INTRODUCTION Despiteinternationalcallsforpreventativemeasuresandreadyaccesstoappropriatetreatment,infertilityisstill amajorprobleminthedevelopedworld(UnitedNations1994).Theincreasedprevalenceofinfertilityinrecent yearscanatleastbepartlyattributedtosu chlifestylefactorsasobesityandsmokingandtothehighincidence ofsexuallytransmittedinfectionssuchasChlamydia.Inaddition,postponement ofafirstpregnancyis increasinglycommoninthedevelopedworld(CommissionoftheEuropeanCommunities2005,Commissionof theEuropeanCommunities2006);thistoocan lead to ovarian ageing and associated infertility. Thedifficultysomefaceinaccessingappropriateadviceandtreatmenthasalsobeenrecentlyacknowledgedby theEuropeanParliamentwhich,inaresolutionadoptedon21February2008,saidthatit"callsontheMember States,therefore,toensuretherightofcouplestouniversalaccesstoinfertilitytreatment"(European Parliament2008). Takentogether,theyimplyandreflectaprogressiveincreaseintheneedforassistedreproductivetechnology (ART)treatment(ESHREEIMdata). AstheEuropeanbodyforprofessionalsinrep r oductive medicineandbiology,ESHREaimstoensurethat patientsthroughoutEuropereceivethebestpossibletreatmentandarenotexposedtounnecessaryrisks.This meansthattreatmentsofferedshould bebasedonthebestavailableevidencewithrespecttoefficacyand safety.TheroleofESHREisalsotosupportimprovementsinthefieldofmedicalpracticeandtopromotethe safetyandqualityofclinical,surgic alandlaboratoryprocedures. ESHREconsidersitafundamentalprinciplethatprofessionalsinreproductivemedicineandbiologyareallowed toutilisethefullbiologicalpotentialofgametesandembr yos.Againstthisbackground,ESHREfindsitimportant thatthereiscoherencebetweenacountry’sdecisiontosupportassistedreproductionandthefinancialand regulatorystrategiesaffectingthequalityoftheserviceprovided. Theobjectiveofthispaperisto describetheprinciplesofgoodclinicaltreatmentwithinselectedareasof assistedreproductionfromanevidence‐basedprofessionalperspective.Veryimportantareasoffertility treatmentincludingsurgery,problemsduringimplantationandearlypregnancyareintentionallyomittedfrom thisdocument. ACCESSIBILITY Afundamentalbasisforprovidingassistedreproductionisthat thedifferenttreatmentsareeasilyavailable. Further,currentevidenceshowsthatreimbursementpoliciescanhavesignificantimpactontheaccessibilityand useofARTtreatments,andthatlackofmedicalreimbursement willactasabarriertotheuseofART. InordertoprovidegoodfertilitytreatmentindividualcountriesshouldprovideaccesstopubliclyfundedARTin arealistic,timelyanddedicatedmanner.Allcountriesshouldbeinapositiontodocumentthattheyprovidea publicprogrammeonascalewhichisconsistentwiththerealneedforARTandwithoutawaiting‐timethathas anegativeimpactonsuccessrates. INVESTIGATIONOFFERTILITYPROBLEMS Peoplewhoareconcernedabouttheirfertilityshouldbeinformedthatsome84%ofcouplesinthegeneral populationwillconceivewithinoneyeariftheydonotusecontraceptionandhaveregularsexualintercourse. Additionally,theyshouldbeinformedthatfemalefertilitydeclineswithage.Womenandme nshould alsobe informedaboutthepossiblenegativeeffectsofalcohol,smokingandbodyweight(overweightand underweight)onfertility,andpreconceptionalcareshouldfocusonassessingtherisksoftreatmentand pregnancyineachindividualcase.Coupleswhohavenotconceivedafteroneyearofregularunprotectedsexual intercourseshouldbeofferedfurtherclinicalinvestigation,includingsemenanalysisandassessmentof ovulation.  Anappropriatehormonalinvestigationshouldbeofferedwhentherearesignsofovulationdisorders.Semen analysisshouldbeperformedbasedontherecommendationsofWHOandESHRE.Furthertests,including clinicalandrologicalinvestigation,areadvisedincaseswhereabnormalitiesaredetected. Theresultsofsemenanalysisandovulationassessmentshouldbeknownbeforeatestoftubalpatencyis performed.Womenthoughttohaveco‐morbiditiesshouldbeofferedlaparoscopy,sothatanytubalandother pelvicpathologycanbeinvestigatedandtreatedatthesametime.Theovariescanbeassessedbyvaginal ultrasound.Insomecaseshysteroscopymaybeindicated. Basedontheoutcomeoftheinvestigation,eachcoupleshouldreceiveinformationwhichincludesanestimate oftheirchanceofspontaneouspregnancyandtheirchanceofpregnancyafterdifferenttreatmentoptions.This informationshouldbeprovidedinaformthatitisaccessibletopeoplewithadditionalneeds,suchasthosewith physical,cognitiveandsensorydisabilities,and those who do not speak the native language. INFORMATIONANDCOUNSELLING Patientsshouldhavetheopportunitytomakeinformeddecisionsabouttheircareandtreatmentbasedon evidence‐basedinformation.Thesedecisionsshouldberecognisedasanintegralpartofthedecision‐making process.Verbalinformationshouldbesupplementedbywrittenand/oraudio‐visualmaterial,including informationaboutotheroptionssuchasadoption. Contacts to fertility support groups should beidentified. Asinvoluntarychildlessnesscanbeapsychologicalburden,counsellingshouldbeofferedwhichraisesallrelated medical,psychologicalandsocialquestions.Counsellingshouldbeanintegralpartofeachcentre'sprogramme andshouldbeperformedbyphysicians,nursesand/orprofessionalcounsellors. Counsellingshouldbeofferedbefore,duringandafterinvestigationandtreatment,irrespectiveoftheoutcome oftheseprocedures,andpatientsshouldbeinformedthatstressinthemaleand/orfemalepartnercanaffect relationshipsandhaveanegativeinfluen ceonsexuality.  OVULATIONINDUCTION Ovulationinductionaimstorestorefertilityinanovulatorywomen.Itshouldbeofferedtakingintoaccount otherfactors,suchasmaleorpelvicfactors,weightoreatingdisorders,stressorover‐exercise.Thus,atleast onesemenanalysisfromthemalepartnershouldbeperformedbeforeovulationinductionisoffered,andtubal patencycheckedasappropriate accordingtoclinical history. Iftherearenoconcernsaboutpelvicortubalhealth,itmaybeappropriatetoperformthreecyclesofovulation inductionpriortocheckingtubalpatency. Whenanovulationdisorderispresent,treatmentisofferedaccordingtoaetiology: 1.WomenwithaloworhighBMIshouldfirstbeofferedcounsellingwithrespecttoeatinghabitsorstress. Thisisalsoimportantforthosesufferingfrompolycysticovarysyndrome,whomayresumeovulationwith weightloss. 2.Clomiphenecitrateremainsthefirst‐linemedicaltreatmentandcanbegivenforupto12months.Patients shouldbeinformedofthesmallriskofmultiplepregnancy.Anovulatorywomenwithpolycysticovary syndromeandBMI>25,whohavenotrespondedtoclomiphenealone,maybeofferedmetforminin addition. 3.Gonadotrophintherapyisappropriateforwomenwhofailtoovulateorconceivewithanti‐estrogen therapy(clomiphenecitrate),orhavehypothalamicfailureordysfunction.Forthelattergroup,pulsatile LHRHtreatmentisalsoappropriateandgenerallypresentsalowerriskofmultiplepregnancy.Nevertheless, anycentrecarryingoutovulationinductionwithgonadotrophinsshouldhavefacilitiesforregular monitoringwithultrasound,andexpertiseinmonitoringsuchcycles. 4.Womenwithhyperprolactinaemiashouldbeofferedtreatmentwithdopamineagonistssuchas bromocriptineorcarbegolineafterchecking for thyroid function and correcting any anomalies. INTRAUTERINEINSEMINATION(IUI) AlthoughIUIrepresentsa“mild”ARTprocedure,itmustbeperformedwithcare,accordingtostrictcriteria. TubalpatencyaswellassemenqualitymustbecheckedpriortoperformingIUI. Thereisgeneralagreementintheliteraturethatchancesofsuccessarebetteraftermildovarianstimulationand thematurationofamaximumoftwoorthreefollicles.However,thecyclemustbemonitoredbyultrasoundand hormonalanalysis;iftherearemorethanthreematurefollicles,theattemptshouldbecancelled.Whilethe concurrentuseofovarianstimulationmayincreasepregnancyrates,itmaybeattheexpenseofahighchance ofmultiplepregnancy. Themajorityofpregnanciesoccurduringthefirstsixcycles.Inanycase,thenumberofattemptsshouldnot exceedninecycles.WhenassessingthedurationofanIUIprogramme,theageofthewomanmustbetakeninto account,toensuretimelytransfertomorecomplextreatmentsifindicated. INVITROFERTILISATION(IVF) BilaterallackoftubalpermeabilityrepresentsanabsoluteindicationforperformingIVF.Otherindications includedoubtfultubalpatency,endometriosis,moderatealterationsofsemencharacteristics,unexplained infertilityorfailureofseveralpreviouscyclesofovulationinductionorIUI.IVFmustbeofferedasafirst‐line treatmentinwomenofadvancedmaternalage,irrespectiveofthecauseofinfertility.ConventionalIVFshould notbeproposedinthepresenceofseverespermabnormalities,orafterseveralfertilisationfailuresinprevious attempts. INTRACYTOPLASMICSPERMINJECTIONS(ICSI) ICSIshouldbeconsideredinthepresenceofseverespermabnormalitiesorahistoryoffertilisationfailurein conventionalIVFattempts.ItmustbeemphasisedthatICSIdoesnotrepresentthemostsuitabletreatmentfor femalepathologiessuchaspoorovarianresponse or previous implantation failures. CRYOPRESERVATION GiventhatexcessembryosareusuallyobtainedduringIVF/ICSItreatments,thecryopreservationofembryos shouldberoutinelyavailableasanintegralpartofinfertilityservices.Theestablishmentofasuccessful cryopreservationprogrammewillincreasecumulativelivebirthratesandalsomakesingleembryotransferan increasinglyefficientoption.Withahighernumberofelectivesingleembryotransfercycles,moregoodquality embryosareavailableforcryopreservation.Cryopreservationnotonlymakestheseembryosavailableforfuture usebythecouple,butmayalsobeusefulinavoidingtherisksofovarianhyperstimulation. MULTIPLEPREGNANCIES ThemostcommoncomplicationofARTismultiplepregnancy.Maternalmorbidityandmortalityinmultiple pregnanciesaresignificantlyincreasedwhencomparedtosingletonpregnancies.Twinsareassociatedwith higherratesofperinatalcomplications.Theriskofneurologicalproblemsinnewborns,cerebralpalsyincluded,is higherthaninsingletons.TwinpregnanciesareincreasinglyacceptedasaseriouscomplicationofARTforthe couple,thenewbornandsociety. Thedeclineinthenumberofmultiplebirthscanberegulatedonlywithareductionofthenumberofembryos transferred.Thisrestrictiveembryotransferpolicycouldbeacceptedastheonlymeansofeliminatinghigh ordermultiplegestations.Althoughthetransferoftwoembryoshaspreventedtripletpregnancy,twin pregnanciesstillaccountformorethan~25%ofdeliveriesaftertwoearlystageembryosaretransferredormore than~35%whentwoblastocystsaretransferred.  SINGLEEMBRYOTRANSFERPOLICY Singleembryotransfer(SET)inselectedgroupsofpatientsisadvocatedastheonlyeffectivemeansoflowering therateoftwinpregnancies.Thetransferofonegoodqualityembryofromatleasttwoavailablecanreducethe twinpregnancyratesignificantly.TheimplementationofelectiveSETispossibleonlyincombinationwithhigh qualitylaboratoriesandgoodcryopreservationprogrammes. Guidelinesforwhichpatientsareeli g ibleforelectiveSETshouldincludethewo man'sage,numberofprevious IVF/ICSIcyclesandembryoquality. Recentobservationalstudiesareindicativeofrelativelypooroutcomesincaseswhereonlyoneembryowas available,andofgoodresultswhenanelectivesingleembryowasselectedfortransfer. AsystematicCochranereviewofrandomisedstudiesdemonstratesadecreaseinthechanceoflivebirthinfresh IVF/ICSIcyclesafterelectiveSETincomparisonwithdoubleembryotransfer(DET).However,thecombinationof SETwithagoodqualityfreezingprogrammeandsubsequentreplacementofasinglefrozen‐thawedembryo achievesalivebirthratecomparablewithDET. Transferofthreeandfourembryosshouldbediscouraged. AtwoembryotransferpolicyisnowcommoninmostEuropeancountries. ElectiveSETistodaypartofthe embryotransferpolicy(bylegislationand/orguidelines/voluntaryagreement)infiveEUcountries. MONITORING InordertoensurethefullmonitoringofbothqualityandquantityinARTitisimportantthatannualreports, compiledaccordingtotheprincipleoutlinedbyESHREcoveringtypes,efficacy,safetyandrisks,aremade publiclyavailable.DatamonitoringofARTshouldbeperformedbothatthelevelofindividualclinicsandasan independent,authority‐basednationalregistry.  References: ThedocumentisbasedonESHREandNICEguidelines, ESHRE monographs and EIM reports.