Good Clinical Treatment in Assisted Reproduction ‐ An ESHRE position paper potx

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.