Aad Tibben

Alison Hall

Anneke Lucassen

Borut Peterlin

Carla G van El

Carsten Bergmann

Diana W Bianchi

Dragica Radojkovic

Florence Fellmann

Francesca Forzano

Guido de Wert

Heidi C Howard

Kelly Ormond

Lidewij Henneman

Lisbeth Tranebjærg

Lyn S Chitty

Maria Soller

Martina C Cornel

Pascal Borry

Wolf Rogowski

Wybo Dondorp

Yvonne Bombard

null null

Crossref

European Journal of Human Genetics

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Summary and recommendations

Dondorp, Wybo

de Wert, Guido

Bombard, Yvonne

Bianchi, Diana W

Bergmann, Carsten

Borry, Pascal

Chitty, Lyn S

Fellmann, Florence

Forzano, Francesca

Hall, Alison

Henneman, Lidewij

Howard, Heidi C

Lucassen, Anneke

Ormond, Kelly

Peterlin, Borut

Radojkovic, Dragica

Rogowski, Wolf

Soller, Maria

Tibben, Aad

Tranebjærg, Lisbeth

van El, Carla G

Cornel, Martina C

Copenhagen University Research Information System

Non-invasive prenatal testing for aneuploidy and beyond:challenges of responsible innovation in prenatal screening. Summary and recommendations

Dondorp, W.

de Wert, G.

Bombard, Y.

Bianchi, D.W.

Bergmann, C.

Borry, P.

Chitty, L.S.

Fellmann, F.

Forzano, F.

Hall, A.

Henneman, L.

Howard, H.C.

Lucassen, A.

Ormond, K.

Peterlin, B.

Radojkovic, D.

Rogowski, W.

Soller, M.

Tibben, A.

van El, C.G.

Cornel, M.C.

Serveur académique lausannois

POLICYNon-invasive prenatal testing for aneuploidy andbeyond: challenges of responsible innovation inprenatal screening. Summary and recommendationsWybo Dondorp*,1, Guido de Wert1, Yvonne Bombard2, Diana W Bianchi3, Carsten Bergmann4,5, Pascal Borry6,Lyn S Chitty7, Florence Fellmann8, Francesca Forzano9, Alison Hall10, Lidewij Henneman11, Heidi C Howard12,Anneke Lucassen13, Kelly Ormond14, Borut Peterlin15, Dragica Radojkovic16, Wolf Rogowski17, Maria Soller18,Aad Tibben19, Lisbeth Tranebjærg20,21,22, Carla G van El11 and Martina C Cornel11 on behalf of the EuropeanSociety of Human Genetics (ESHG) and the American Society of Human Genetics (ASHG)European Journal of Human Genetics advanced online publication, 1 April 2015; doi:10.1038/ejhg.2015.56INTRODUCTIONThis paper contains a summary and the recommendations of a jointEuropean Society of Human Genetics (ESHG)/American Society ofHuman Genetics (ASHG) position statement on responsible innovationin prenatal screening with non-invasive prenatal testing (NIPT). Thisstatement was drafted by the Public and Professional Policy Committeeof the ESHG and the Social Issues Committee of the ASHG, andendorsed by the boards of both societies in December 2014. Thestatement is also endorsed by the Human Genetics Society ofAustralasia, the Australasian Association of Clinical Geneticists, theBritish Society for Genetic Medicine, the Czech Medical GeneticsSociety, and the PHG Foundation (Cambridge, UK). The fulldocument with extensive references is published separately.1SUMMARY OF THE ESHG/ASHG POSITION STATEMENTThis ESHG/ASHG position statement takes as its starting point theinternationally endorsed normative framework for prenatal screening,stressing that the aim of the practice should be to facilitate informedreproductive choices rather than preventing the birth of children withspeciﬁc abnormalities, and that the beneﬁts for those tested shouldclearly outweigh any harms. Moreover, when screening is offered as apublic health programme, societal and justice aspects need to be takeninto account. This includes possible consequences for otherindividuals and groups (including those living with the relevantconditions), as well as cost-effectiveness of publicly funded services.In the past few years, professional bodies and policy authorities haverecommended offering NIPT for common aneuploidies to womenwho belong to a higher risk group, either based on maternal age or apositive combined ﬁrst trimester screening test (cFTS). With recentpublications suggesting equally good test performance in lower-riskpopulations, and depending on the health care setting, differentscenarios for NIPT-based screening for common autosomal aneuploidiesare possible, including NIPT as an alternative ﬁrst-tier test. The greateraccuracy and lower invasive follow-up testing rate that can thus beachieved, has the potential of helping prenatal screening better achieveits aim, provided that balanced pre-test information and non-directivecounseling are available as part of the screening offer. Concerns havebeen raised that as a result of these same features (greater accuracy andlower invasive follow-up testing rate), prenatal screening may increas-ingly be regarded both by professionals and pregnant women as aroutine procedure that as such would not require much reﬂection.This may have the consequence that women or couples are insufﬁ-ciently prepared for the possible eventual diagnosis of a fetus with aserious disorder. Avoiding such ‘routinisation’ effects may well be thegreatest ethical challenge of NIPT-based prenatal screening.Depending on the use of targeted or non-targeted analysis and onthe level of resolution, NIPT for common autosomal aneuploidies may1Department of Health, Ethics & Society, Research Schools CAPHRI and GROW, Maastricht University, Maastricht, The Netherlands; 2Li Ka Shing Knowledge Institute ofSt. Michael’s Hospital & Institute of Health Policy, Management and Evaluation, Faculty of Medicine, University of Toronto,Toronto, ON, Canada; 3Department of Pediatrics,Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA, USA; 4Center for Human Genetics Bioscientia, Ingelheim, Germany; 5Department of Medicine,University Freiburg Medical Center, Freiburg, Germany; 6Department of Public Health and Primary Care, Centre for Biomedical Ethics and Law, Leuven University, Leuven,Belgium; 7Clinical and Molecular Genetics Unit, UCL Institute of Child Health, Great Ormond Street Hospital and UCLH NHS Foundations Trusts, London, UK; 8Service of MedicalGenetics, University Hospital of Lausanne, Lausanne, Switzerland; 9Medical Genetics Unit, Ospedali Galliera, Genova, Italy; 10PHG Foundation, Cambridge, UK; 11SectionCommunity Genetics, Department of Clinical Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands; 12Centrefor Research Ethics and Bioethics, Uppsala University, Uppsala, Sweden; 13Department of clinical ethics and law (CELS), University of Southampton and Wessex Clinical GeneticService, Southampton, UK; 14Department of Genetics and Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA, USA; 15Clinical Institute ofMedical Genetics, Ljubljana University Medical Centre, Ljubljana, Slovenia; 16Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering (IMGGE),University of Belgrade, Belgrade, Serbia; 17Deutsches Forschungszentrum für Gesundheit und Umwelt, Helmholtz Zentrum, München, Germany; 18Division Clinical Genetics,University and Regional Laboratories Region Skåne, Lund University Hospital, Lund, Sweden; 19Department of Clinical Genetics, Leiden University Medical Center, Leiden, TheNetherlands; 20Department of Audiology, Bispebjerg Hospital/Rigshospitalet, Copenhagen, Denmark; 21Department of Clinical Genetics/The Kennedy Center, University ofCopenhagen, Copenhagen, Denmark; 22Institute of Cellular and Molecular Medicine, ICMM, University of Copenhagen, Copenhagen, Denmark*Correspondence: Dr W Dondorp, Department of Health, Ethics & Society, Research Schools CAPHRI and GROW, Maastricht University, PO Box 616, 6200 MD, Maastricht,The Netherlands. Tel: +31 43 3881712; Fax: +31 43 3670932; E-mail: w.dondorp@maastrichtuniversity.nlReceived 23 December 2014; revised 15 February 2015; accepted 19 February 2015European Journal of Human Genetics (2015), 1–3& 2015 Macmillan Publishers Limited All rights reserved 1018-4813/15www.nature.com/ejhglead to ﬁndings of abnormalities in other chromosomes, includingsubmicroscopic abnormalities. This is not a new problem: suchﬁndings also emerge at follow-up testing after positive cFTS. However,at the NIPT stage, they precede decision making about invasive testing.This may entail putting the pregnancy at risk for conﬁrming ﬁndingsthat not only have a low positive predictive value (because of their lowfrequency), but that, if conﬁrmed, may still have highly uncertainimplications for the expected phenotype. If enabling autonomousdecision making is the aim of prenatal screening, then as much asreasonably possible, women or couples should be informed about thepossibility of additional ﬁndings and their possible implications. Theyshould also be given the opportunity to indicate whether or not theywould want to receive information about clinically relevant ﬁndingsbeyond the scope of the screening offer.A speciﬁc ethical issue related with NIPT is sex selection for non-medical reasons. Depending on how the test is carried out, thescenario with NIPT as a ﬁrst screening test might lead to informationabout fetal sex being available at an early stage in all screenedpregnancies. Commercial companies offering NIPT currently alsoprovide this information on an optional basis. There is a concern thatsome pregnant women and their partners may use this to have anabortion if the sex of the fetus does not match their preference. Thebest way to counteract improper use of information about fetal sex isto avoid it becoming available as part of the test results.It is expected that in the coming years, it will become possible to useNIPT to screen for the same range of conditions that are currently testedfor using karyotyping or microarray technologies at the follow-up stage,including sex-chromosomal and submicroscopic abnormalities. Com-mercial providers have already begun expanding their tests to includethese conditions. However, this should not precede a careful assessmentof the beneﬁts and harms of doing so. Relevant aspects include: testaccuracy, counseling challenges, women’s preferences, the interests of thefuture child (see below) and misuse of information about fetal sex.Given the publication of proof of principle analysis of the entire fetalgenome from maternal plasma, it is expected to eventually becometechnically possible to turn NIPT-based screening into a comprehen-sive fetal genome scan, looking beyond chromosomal abnormalities toMendelian disorders and genetic risk proﬁles for multifactorial diseases.Inevitably, this raises the question of what the scope of prenatalscreening for fetal abnormalities should be. Reasons for not expandingprenatal screening beyond serious childhood disorders are the follow-ing. Firstly, unlimited choice may paradoxically undermine rather thanserve or enhance reproductive autonomy. Secondly, given thatexpanded prenatal screening will reveal later onset disorders as wellas abnormalities that might otherwise have remained undiagnosed, andthat these ﬁndings will not always lead to the woman asking for anabortion, the interests and autonomy rights of the future child need tobe taken into account. Bringing a child into the world with all theinformation from a full genome scan may lead to psychosocial harmand amount to a violation of his or her ‘autonomy rights’.Historically and ethically, prenatal screening for fetal abnormalitiessuch as Down syndrome should be distinguished from prenatalscreening for conditions relevant to a healthy outcome of thepregnancy for the mother and child. New developments includingNIPT may increasingly lead to these types of prenatal screeningrunning together. What should be avoided here, is to confuse womenand couples with regard to what they are offered testing for, and whatthey can accept or decline, and on what basis. A further expecteddevelopment is that more disorders will become treatable in utero. As aconsequence, prenatal screening for those disorders will open up moreoptions than only the choice between completion and termination of apregnancy, including treatments that may beneﬁt the health prospectsof the future child. As a result, new ethical questions may arise forwhich the current ethical framework is inadequate. For instance: towhat extent do these new preventative options create obligations forprospective parents?In many countries, prenatal screening has in the past decades beenoffered to pregnant women in the form of national or regionalpopulation screening programmes. Whereas in the past, new screeningtechnologies have been readily introduced in these programmes, theintroduction of NIPT into clinical practice has until now been largelyleft to commercial laboratories offering their version of the testthrough individual practitioners and practices. Governments andpublic health authorities seem hesitant to be involved in this process.Given the importance of offering NIPT in a setting in which allrelevant aspects (including information and counseling) are qualitycontrolled, it is time that these actors take a more active role.The notion that prenatal screening should be regarded a publichealth responsibility does not necessarily entail that all costs are paidfrom public money without any (co-)payment from those beingtested. It is important to note that these are separate (thoughconnected) issues. In light of the aim of providing options forreproductive choice, it might be argued that asking women to payfor prenatal screening increases the awareness that there is trulya choice to be made. On the other hand, depending on the height ofthe ﬁnancial barrier, this may limit access to prenatal screening tothose who are better off, which raises an issue of justice.Finally, NIPT makes it possible in theory to offer prenatal testing forfetal abnormalities as a direct-to-consumer test. However, in order tomaintain minimum quality standards, prenatal testing for fetalabnormalities should always be offered through health professionalswith the expertise and training to provide the necessary pre-and post-test information and counseling.RECOMMENDATIONS1. NIPT offers improved accuracy when testing for commonautosomal aneuploidies compared with existing tests such ascFTS. However, a positive NIPT result should not be regarded as aﬁnal diagnosis: false positives occur for a variety of reasons(including that the DNA sequenced is maternal and fetal in originand that the fetal fraction derives from the placenta as well as thedeveloping fetus). Thus women should be advised to have apositive result conﬁrmed through diagnostic testing, preferably byamniocentesis, if they are considering a possible termination ofpregnancy.2. The better performance including lower invasive testing rate ofNIPT-based screening should not lead to lowering standards forpre-test information and counseling. This is especially important inthe light of the aim of providing pregnant women with meaningfuloptions for reproductive choice. There should be speciﬁc attentionpaid to the information needs of women from other linguistic andcultural backgrounds or who are less health literate.3. If NIPT is offered for a speciﬁc set of conditions (eg trisomies 21,18 and 13), it may not be reasonably possible to avoid additionalﬁndings, such as other chromosomal anomalies or large scaleinsertions or deletions. As part of pre-test information, womenand couples should be made aware of the possibility of suchadditional ﬁndings and the range of their implications. Thereshould be a clear policy for dealing with such ﬁndings, as much aspossible also taking account of pregnant women’s wishes withregard to receiving or not receiving speciﬁc information.Responsible innovation in prenatal screening. SummaryW Dondorp et al2European Journal of Human Genetics4. Expanding NIPT-based prenatal screening to also report on sex-chromosomal abnormalities and microdeletions not only raisesethical concerns related to information and counseling challengesbut also risks reversing the important reduction in invasive testingachieved with implementation of NIPT for aneuploidy, and istherefore currently not recommended.5. Emerging opportunities for combining prenatal screening for fetalabnormalities with screening aimed at prevention may undermineadequate counseling by sending mixed messages. The objective ofany prenatal screening activity should be made explicit and, as faras possible, forms of prenatal screening with different aims shouldbe presented separately. If not physically possible, this separationshould at least be made conceptually when providing the relevantinformation.6. In countries where prenatal screening for fetal abnormalities isoffered as a public health programme, governments and publichealth authorities should adopt an active role to ensure theresponsible introduction of NIPT as a second or ﬁrst-tier screen-ing test for Down syndrome and other common autosomalaneuploidies. This entails ensuring quality control also extendingto the non-laboratory aspects of NIPT-based prenatal screening(information and counseling), education of professionals, sys-tematic evaluation of all aspects of the screening programme aswell as promoting equity of access for all pregnant women withinthe conﬁnes of the available budget, and setting up a governancestructure for responsible further innovation in prenatal screening.7. Different scenarios for NIPT-based screening for commonautosomal aneuploidies are possible, including NIPT as analternative ﬁrst-tier option. The inevitable trade-offs underlyingthose scenarios should not just be regarded as a matter ofscreening technology and health economics; the question is alsohow these trade-offs enable or impede meaningful reproductivechoices and how they affect both the balance of beneﬁts andburdens for pregnant women and their partners, and the screen-ing goals and values acceptable to society.8. In order to adequately evaluate prenatal screening practices, thereis a need to further develop and validate measures of informedchoice as well as interventions aimed at enabling informedchoices. The transition to NIPT-based prenatal screening presentsan opportunity to ﬁll this gap in knowledge.9. In the light of sequencing technologies becoming better andcheaper, there is an acute need for a proactive professional andsocietal debate about what the future scope of prenatal screeningfor fetal abnormalities should be. As argued in this document,there are strong ethical reasons for not expanding the scope ofprenatal screening beyond serious congenital and childhooddisorders.10. The scenario in which prenatal screening would open uppossibilities for fetal therapy in addition to autonomousreproductive choice raises fundamental questions about therelation between reproductive autonomy and parental respon-sibility that require an in depth proactive ethical analysis.CONFLICT OF INTERESTEmployers of WD, GdW, LH, CvE and MC received research grantsfor implementation and evaluation research on NIPT from TheNetherlands Organisation for Health Research and Development(ZonMw) and The Netherlands Genomics Initiative. DB is a memberof the Reproductive and Genetic Health Advisory Board for Illuminaand receives an honorarium for this position. She also has a sponsoredresearch grant from Illumina that is administered through TuftsMedical Center, Boston, MA, USA. CB is an employee of Bioscientia/Sonic Healthcare, Ingelheim, while holding a part-time facultyappointment at the University of Freiburg, Germany. In addition,several of the authors work in health care settings in which NIPT isbeing offered.1 Dondorp W, De Wert G, Bombard Y et al: on behalf of the European Society of HumanGenetics (ESHG) and the American Society of Human Genetics (ASHG): non-invasiveprenatal testing for aneuploidy and beyond: challenges of responsible innovation inprenatal screening. Eur J Hum Genet; e-pub ahead of print 18 March 2015;doi:10.1038/ejhg.2015.57This work is licensed under a Creative CommonsAttribution-NonCommercial-NoDerivs 4.0 InternationalLicense. The images or other third party material in this article areincluded in the article’s Creative Commons license, unless indicatedotherwise in the credit line; if the material is not included under theCreative Commons license, users will need to obtain permission fromthe license holder to reproduce the material. To view a copy of thislicense, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Responsible innovation in prenatal screening. SummaryW Dondorp et al3European Journal of Human Genetics

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Non-invasive prenatal testing for aneuploidy and beyond: Challenges of responsible innovation in prenatal screening. Summary and recommendations.

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Non-invasive prenatal testing for aneuploidy and beyond : challenges of responsible innovation in prenatal screening. Summary and recommendations

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Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Summary and recommendations

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