Accepted Article View metadata,citationandsimilarpapersatcore.ac.uk Kingdom. Kingdom. This by is protectedarticle reserved. Allrights copyright. doi: 10.1111/1471-0528.15409 lead to differences between this version and the throughbeen the copyediting, pagination typesetting, which process, may and proofreading hasThis article been accepted publicationfor andundergone peerfull but review not has Amsterdam, Amsterdam, The Netherlands. 7 6 5 4 3 2 1 J Wilkinson Reproductive medicine: still moreART thanscience? Commentary Type: Article Vail Centre forReproductive Academic Medicine, MedicalCentre, University of Gynecology Cochrane Universityand Fertility Group, New Auckland, Auckland, of Zealand. ReproductiveChristian Medicine Vellore, Unit, MedicalCollege, India. Oxford,Oxford, BalliolCollege, Universityof Kingdom. United PrimarySciences, University Oxford,of Care Health Kingdom.Oxford, United The Applied of Institute Aberdeen,Sciences, Universityof Health Aberdeen,United Centre forBiostatistics, University Manchester,United Kingdom. of Manchester, 1 , M van Wely 1 , S Bhattacharya 7 , CM Farquhar 2 , JMN Duffy 6
3,4 , MS Kamath Version of Record. Please Version as this cite ofRecord. article 5 , J Marjoribanks 6 , S Repping, S provided byAberdeenUniversityResearchArchive 7 , A brought toyouby CORE Accepted Article This by is protectedarticle reserved. Allrights copyright. primarydriver clinical decisionfor making expertopinion,and new lureof the technology have frequently evidenceasthe superseded The history obstetrics of and gynaecology is not a tale of evidence-based practice. Tradition, ARTReproductive science? still medicine: more than title: Running [email protected] Centre for Biostatistics, Manchester,University of Manchester, United Kingdom. J Wilkinson Corresponding author: thalidomide,have and performedroutine episiotomyall inprimigravid women pelvimetry stress andantenatal tests, subjected innumerable women and stilboestrol to demonstrating harm. As a specialty, we have relied on investigations including X-ray and,effectiveness attestingdata somein totheir credibleevidence cases, ample interventionswhichgainedwidespread have popularityabsencedespite an highquality of fertility same while problems, time ensuringthe they that at are notexposedunnecessaryto medicine is now “to provide childless couples with the best possible management of their wasadoptionthe only route inthepast.available The inreproductive gold standard advances in the field such that biological parenthood is a reality for many couples, for whom acome has Reproductive longway medicine andthere then since have been dramatic the least evidence-basedbeingspecialty. surprise in1979,Archiethat, Cochranefamouslyawarded ‘wooden obstetrics the spoon’for 1 . The proof can be. The can proof in alitany dubious found of 1, . It is no . Itis Accepted Article This by is protectedarticle reserved. Allrights copyright. treatments” ineffective or risks reproductive technology. As governmentsfew treatment is infertility fund theprivatesector byhasthe causeda fertilityassisted use globalexplosionin commercial of clinics parton unrealistic media couples the expectations fuelled coupledwith of skilful marketing (https://www.hfea.gov.uk/media/2563/hfea-fertility-trends-and-figures-2017-v2.pdf). Yet, ratesin vitro for fertilisation (IVF) estimatedofthe tobe per 27%region in cycle treatment overtreatment, increasingincreasingavoidableharm, healthcare and costs whoearly-onhave areasonablechanceofpromoting incouples still conception, buoyant.Contrary guidelines,reproductive to assisted technologyinitiatedis frequently months Yet,showdata populationbased thegroup half of that will next12to conceivein thison go One in sevencouples will struggle to conceive within a year, and will be labelled as infertile. Too muchtreatment? predilection overdiagnosis,for overuse, and overtreatment. assisted reproduction,has increasingly become which withpronounced commercialised a therapies isitself interpreted asa quality.ofsign storm perfectIt isthe forexploitation. over proof effectiveness of andsafety. For additional expenseofthe couples, add-on many novelty the policies, andapparentsophistication new of these technologies take precedence race between clinics fertility essentiallyadd-on unproveninterventions offered are couples ina to technological arms have goodevidence, its isuptake universal from far usedguidelines.whichwhere developcan be Unfortunately, even we clinical to practice 5 . Meanwhile, success rates for fertility treatments remain modest, with live birthlive with remain modest, treatments fertility success rates for Meanwhile,. 7 . Since financial considerations often. influencetreatment 3 . In order. In toachieve thisstandard,evidence weneedreliable 1 . This. is particularly truein the field of 4 . A plethoraof. Accepted Article This by is protectedarticle reserved. Allrights copyright. dominant vitro in ofform fertilisation The in Cochrane review inmany countries. vitro of to includecoupleswhere semen the parametersareIndeed, normal. it has now the become cytoplasmic injection(ICSI), sperm originally with very designed for quality,poor semen men exampleAnother whereis practice common defies the evidence intra-expansionthe of new-zealand-2015). (https://npesu.unsw.edu.au/surveillance/assisted-reproductive-technology-australia-and- world in the (4%) pregnancies multiple IVF-related of rate lowest the has two athat embryo single provided strategytransfer result, a As New Zealand wasused. now andtheattendant 2005,New costs. In Zealandincreasedfunding forIVFcycle one to from multiple pregnanciesinorderincreases avoid to in neonatal, andchildhood fetal, morbidity also for maternityand neonatalcare, then would there bea strong incentive toreduce covered bystate the orbyinsurance companies. explanationIVFis that self-funded isoften whilst maternitycare often andneonatal are United Kingdom, Europe, andNorthAmerica continue to transfer embryos.multiple One bypracticepreventable the singleofembryo transfer, providersmany healthcare across the withassociated pregnancy. Althoughmultiple pregnancy multiple completelyalmost is whilst downplaying considerable fetal, neonatal,andmaternal, the childhood risks child. Somecontinue IVF clinics practice support to grounds on this patient autonomy, of chancesmaximise their need whileobviating the for treatmentfurther tohavesecond a embryos ata time. This option appears attractive to many couples, who see itas a means to assisted reproductive technology persistent practiceis the transferring of two or more phenomenon.notable Oneof and the regrettableinmost ignoring of examples evidence evidence disregardblatant an inexcusable whichis available butalltoocommon is for evidence absenceof While the in reproductive ofmany areas remains medicine aproblem, Thebetween gap clinical practice and evidence
If the same If paidnotonly the funder but IVF for Accepted Article clinical benefit incubationarea lack becoming routinedespite practicein of clinics, robustevidence many of demonstrated. Similarly, preimplantation genetic testing and time lapse systems for embryo number cases of total births of improvement butan failure, fertilisation inlive has not been of oocytessuggest thatastrategyrandomised innon-male infertilityICSI of reduce the could (livebirth)whichclinicaloutcome has presumablyclinicaldecision influenced trials making; This by is protectedarticle reserved. Allrights copyright. 12 ratio 1.44,0.95confidenceinterval 95% 2.21) to incomparedvitro51/202 fertilisation intra-cytoplasmic inthe to sperm injection(Odds group randomised trial involving 415 couples which reported 70/213 ongoing pregnancies following versus intra-cytoplasmic fertilisation injectionnon-male sperm infertilitya single for includes inform inform Clinicsfrequentlystatisticswield languageand persuadeto creative emotive rather to than ofadvertisingconsumer assistedreproductive technology choice. patient andinformed parenthood leads through their doors. But there isa clearbetween tension directto orderrate.competitive, In be to convincepath couplesthat fertility must to the clinics The primary criterion used by many people with infertility toselect an IVF clinic is itssuccess Marketing trumps informed patient choice clinics on the basis of incomparable figures. Self-regulation does not appear to furnish outcome reporting, couples may be about misled the likelihood of success and may compare cytoplasmic sperm injection failed to show a statistically significant difference in live birthdifferenceshow to injection a statisticallycytoplasmic sperm inlive failed rate significant which randomised 60 women with unexplained infertility to in vitro fertilisation or intra- favourable light constructedbe large a from statisticsin array order tocast a clinic’sperformance ina of . In this context. In ona is itthis surrogatefocus the (fertilisation outcome rate) rather the than 16, 17 16, . Websites speak ofspeak. and‘miracles’ ‘dreams’ Websites 13, 14 13, 17 . Due .to alack binding of standards onreproductive assisted technology . 11 . Data from a subsequent a . Data study Canadian from 16 , while bespoke success rates can Accepted Article This by is protectedarticle reserved. Allrights copyright. safety and efficacyto prove ongoing evaluateup long-term with and safety, effectiveness to follow shouldundergo preclinical followed andclinical trials, (RCTs) by trials controlled randomised Before being implemented as anyroutine, assisted reproductive technologyintervention Challenges for evidence-based assisted reproductive technology interventions. couples withregardingimpartial information effectiveness of treatment thedifferent precluded. Recent Recent precluded. reviews reportingstandards of suggest inthis that field they not do ifnotwillMoreover, report trialsdo hold. outcomes inaconsistent meta-analysisfashion, is Thepooling ‘test’to trend studies. manyinterventions guaranteedoes not insmalltrials this is butthis on predicated smalltrials, individual sufficient sizes sample cumulative after theIn principle, machinery a meta-analysisof overcome to offers thelimitations means of evaluation. reproductivetechnologyassisted treatment pass to a free offer not anyof drawn.These conclusions are essentially observationalstudies, and large-scale do solutionasabsencethe but a random of doubt allocation introduces accuracyregarding the trials. Routinelyfertilisation and electroniccollected largedatabases data havebeen touted exceedsThis thenumbersfar women of weactually vast vitro inthe of in see majority from 27% 32%to at a 5% significance threshold, a sizetrial 2,610of women is required. the undertaken.trials In power to achieve80%order detectan improvement to in birth rate ofeffectiveness interventions is often not robustly assessed. A pivotal limitation is sizethe of interventions has led to a quantity over quality approach to RCTs. Consequently, the clinical Moreover, many outcomesinmeasure trials suchaway benefits the that of randomisation relevant outcomepatients. forestablishtoneed Thepatient-centred statistically valid, and lost, are report to cumulative birth manyfail whichcouple, perrates probably is themost 7 . However, inassisted reproductive. However, technology,eagerness identify to new attractive
18 . Accepted Article This by is protectedarticle reserved. Allrights copyright. with various whichcommittee, consult advisors backgrounds wouldfrom the general regulation publicfor new of by reproductive technologies a national bioethics acceptability regulatingsuch techniquesof support found broad patients andclinicians, from introduction of new therapies in assisted reproductive technology. A studyon the delivered in defiance of evidence would be stronger regulatory standards governing the interventions[added Harper 2017 here]. One solution to the trend for treatment to be robustevidence effectiveness of safety and is notaprerequisite foradoption novel of the coupleswe tothe treat wellbeing generations. offuture Under thestatusquohowever, With respect newto assisted reproductive technologies, our responsibility beyond extends How to introduce new technologies reproductive in medicineresponsibly? Conclusions: ten research gapsin reproductive medicine. unanswered research questions (www.phc.ox.ac.uk/infertility). Table 1, weIn our top present aiming to bring together professionals, researchers, and people with infertility toprioritise clinicalutility.Amaximum has newpriority partnership established been setting infertility for tocommittedof use the reporting common willhigh standards quality ensure with evidence developed through priority-sharing partnerships and enabled by clinical trial networks (https://www.phc.ox.ac.uk/research/hypertension/pregnancy/commit).RCTs Fewer,larger reproductive technologytrials (COMMIT)bewillestablish core outcomes reported to project, which inall assisted outcomebehind isthe motivation measures the CoreOutcome Measures Infertility for Trials comes when we insist thatgeneration of evidence precedes implementation of new anyone otherthanthe peopleand sale, making the harm.may well cause the timeUntil philosophy, wheresold aretreatments to vulnerable benefitsbasis, speculative peopleona evaluationwouldisthe in a it impede progress all notatclear field, since try’ ‘rightto that sympathetic tothe argumentthata requirement prospective rigorous for treatment 24 . We arenot . We Accepted Article This by is protectedarticle reserved. Allrights copyright. No specific supportedfunding thecommentary. writing this of Funding writingNo ethicalapprovalwas sought in commentary. this Detailsof ethical approval devisedAll andauthors and wrote the gaveapproval manuscript, submission. for Contributions of authors areviewinterest availablesupporting forms to information. onlineas editorthe coordinating of Cochrane GynaecologyFertility. disclosureof Completed and Fertilisation and Embryology Authority, outsidethe submitted work. CMF declares that she is and MVW SR, AVdisclose. hasnothinghave grants received to from the Human Thegrants Royal from NewSociety duringthe Zealand, of of conduct study.the MSK, JM, Chieffrom Scientist theScotland, duringOffice, theperiodof Study.this JMNDreports declaresJW thatpublishinginpeer reviewed journalscareer. benefits his SB grants reports Disclosure of interests reproductive isthereal enemyprogress.of medicine with reversing perverse believe ongoing practice. in need this that We reversal for medical technologies rather than follows it, reproductive medical research will be largely preoccupied Accepted Article This by is protectedarticle reserved. Allrights copyright. clinical the regulating for support Broad EAF. Dancet S, Repping R, Vliegenthart S, Hendriks implementation of future reproductive techniques. Human Reproduction. 2018Jan;33(1):39-46. 24. in sets outcome Core al. et S, Ziebland KS, Khan M, Hirsch C, Gale R, Rolph JMN, Duffy women's and newborn health: asystematic review. Bjog-IntGy. JObstet 2017Sep;124(10):1481-9. 18. Wilkinson Roberts J, Vail A, SA.Direct-to-consumer advertising of success rates for medically assisted reproduction: reviewof national clinic a websites. BMJ open. Jan 2017 12;7(1):e012218. 17. Hawkins J. Selling AnEmpiricalART: Assessment of Advertising on Fertility Clinics' Websites. IndianaLaw Fal;88(4):1147-79. J. 2013 16. Jun 1;12(6). fertilization? Ameta-analysis and systematicof randomized review controlled trials. PloS one. 2017 Chen MH, WeiSY, HuJY, YuanDoes J,Liu FH. time-lapse imaging have favorable results for embryo incubation and selectioncompared withconventional methods inclinical in vitro 14. Preimplantation theNew Use of Reasons the Franco About To BeConcerned Seven JG. Genetic ScreeningBras (PGS). Reprod J Assist. Oct-Dec;19(4):189-91. 2015 13. unexplainedinfertility. Journal of assisted reproduction and genetics. 2006Mar;23(3):137-40. Scot JA, O'Keane JA, Fleetham SC, Foong randomized trialconventional of in vitro fertilization intracytoplasmicversus sperm injection in 12. male-factor infertility: arandomised controlled Lancet. trial. Jun 2001 30;357(9274):2075-9. al. et T, Ghobara M, Seddler Y, Khalaf M, MPR, Shaaban Hamilton S, Bhattacharya Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non- 11. . Mar;32(3):485-91. Harper J, Jackson E, Sermon K,Aitken RJ,Ha laboratory: where evidence is the for 'add-on' interventions? Human Reproduction. 2017 7. to time and fecundity couple in Variation HDF. Habbema R, Eijkemans ER, Velde te pregnancy, an essential concept in human reproduction. Lancet. Jun 2000 3;355(9219):1928-9. 5. ESHRE.Goodclinical treatment in assisted reproduction position An - ESHRE 2008.paper. 3. Grimes DA.Discovering need the for randomized controlled trials in obstetrics:personal a odyssey. Bulletin: JLL Commentaries on th 1. References
e history of evaluation. treatment 2007. of e history t SG, Tough SC, Greene CA. A prospective prospective A CA. Greene SC, Tough t SG, rbottle S, Mocanu E, et al. Adjuncts Mocanu IVF etal. in the rbottle S, E, Accepted Article This by is protectedarticle reserved. Allrights copyright. genetic (morphology, selection method embryo is What the optimal environment culture What optimal the is havingIVF In women transfer cleavage blastocyst What is the stage of effect versus children andtheir having IVF In women havingIVF In women havingIVF In women quality semen reduced In men with maturation finalundergoing oocyte and having IVF In women cycles embryoundergoing frozen are who havingIVF In women failure repeated with In women IVF severe oligospermia and azoospermia In men with subfertility unexplained with In women Interventions Population medicine reproductive in gaps Tenresearch 1: Table testing (PGS), time-lapse algorithm)? What is the long term effect (over > years) 20 qualitymanagement, (expectant IUI, IVF or ICSI) semen the to relation in modality treatment optimal ismost the What What is the Gn effect of RhA triggerversus HcG trigger luteal phase support) What is the optimal regimen (e.g. endometrial preparation, triggering, G-CSF scratch,hysteroscopy, immunoglobulin, adjuncts differenttreatmentWhat is the of effect cancer, for others) screening ultrasound, What is the evidence for available screening tests (e.g. genetic testing, What is the IVFeffect of versus expectant management
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