Karen Sermon1, Antonio Capalbo2, Jacques Cohen3, Edith Coonen4, Martine De Rycke5, Anick De Vos6, Joy Delhanty7, Francesco Fiorentino8, Norbert Gleicher9, Georg Griesinger10, Jamie Grifo11, Alan Handyside12, Joyce Harper7, Georgia Kokkali13, Sebastiaan Mastenbroek14, David Meldrum15, Marcos Meseguer16, Markus Montag17, Santiago Munné18, Laura Rienzi19, Carmen Rubio20, Katherine Scott21, Richard Scott22, Carlos Simon23, Jason Swain24, Nathan Treff22, Filippo Ubaldi19, Rita Vassena25, Joris Robert Vermeesch26, Willem Verpoest6, Dagan Wells27, Joep Geraedts4. 1. Research Group Reproduction and Genetics, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium karen.sermon@uzbrussel.be. 2. GENETYX, Molecular Genetics Laboratory, Via Fermi 1, 36063 Marostica (VI), Italy. 3. ART Institute of Washington at Walter Reed National Military Medical Center, Bethesda, MD, USA. 4. Department of Reproductive Medicine, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands Department of Clinical Genetics, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands. 5. Centre for Medical Genetics, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. 6. Centre for Reproductive Medicine, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. 7. University College London Centre for PGD, UCL, 86-96 Chenies Mews, London WC1E 6HX, UK. 8. GENOMA-Molecular Genetics Laboratories, Via di Castel Giubileo, 11 00138, Rome, Italy. 9. The Center for Human Reproduction, New York, NY 10021, USA The Foundation for Reproductive Medicine, New York, NY 1022, USA The Rockefeller University, New York, NY 10065, USA. 10. Department of Reproductive Medicine and Gynecological Endocrinology, University Hospital of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. 11. NYU Fertility Center, NYU Langone Medical Center, 660 1st Ave, New York, NY 10016, USA. 12. The Bridge Centre, London SE1 9RY, UK Illumina Cambridge Ltd, Capital Park CPC4, Fulbourn, Cambridge CB21 5XE, UK. 13. Centre for Human Reproduction, Reproductive Medicine Unit, Genesis Athens Clinic, Papanicoli 14-16, Chalandri, 152-32, Athens, Greece. 14. Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 15. Division of Reproductive Endocrinology and Infertility, University of California San Diego, San Diego, CA, USA. 16. Instituto Valenciano de Infertilidad (IVI) Clinic Valencia, Valencia, Spain. 17. ilabcomm GmbH, Eisenachstr. 34, 53757 Sankt Augustin, Germany. 18. Reprogenetics, Livingston, NJ 07039, USA. 19. GENERA, Centres for Reproductive Medicine, Rome, Italy. 20. Igenomix, and IVI Fundation, Parc Cientific Universitat de Valencia, Catedrático Agustín Escardino 9, 46980 Paterna, Valencia, Spain. 21. Foundation for Embryonic Competence, Basking Ridge, NJ, USA. 22. Reproductive Medicine Associates (RMA) of New Jersey, 140 Allen Road, Basking Ridge, NJ 07920, USA. 23. Fundación Instituto Valenciano de Infertilidad, Department of Obstetrics and Gynecology, University of Valencia, Valencia, Spain INCLIVA Health Research Institute, Valencia, Spain IGenomix, Valencia, Spain. 24. CCRM IVF Laboratory Network, Englewood, CO 80112 USA. 25. Clinica EUGIN, Travessera de Les Corts 322, 08029 Barcelona, Spain. 26. Department of Human Genetics, Katholic University Leuven (KUL), Leuven, Belgium. 27. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK Reprogenetics UK, Institute of Reproductive Sciences, Oxford Business Park, Oxford OX4 2HW, UK.
Abstract
STUDY QUESTION: We wanted to probe the opinions and current practices on preimplantation genetic screening (PGS), and more specifically on PGS in its newest form: PGS 2.0? STUDY FINDING: Consensus is lacking on which patient groups, if any at all, can benefit from PGS 2.0 and, a fortiori, whether all IVF patients should be offered PGS. WHAT IS KNOWN ALREADY: It is clear from all experts that PGS 2.0 can be defined as biopsy at the blastocyst stage followed by comprehensive chromosome screening and possibly combined with vitrification. Most agree that mosaicism is less of an issue at the blastocyst stage than at the cleavage stage but whether mosaicism is no issue at all at the blastocyst stage is currently called into question. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: A questionnaire was developed on the three major aspects of PGS 2.0: the Why, with general questions such as PGS 2.0 indications; the How, specifically on genetic analysis methods; the When, on the ideal method and timing of embryo biopsy. Thirty-five colleagues have been selected to address these questions on the basis of their experience with PGS, and demonstrated by peer-reviewed publications, presentations at meetings and participation in the discussion. The first group of experts who were asked about 'The Why' comprised fertility experts, the second group of molecular biologists were asked about 'The How' and the third group of embryologists were asked about 'The When'. Furthermore, the geographical distribution of the experts has been taken into account. Thirty have filled in the questionnaire as well as actively participated in the redaction of the current paper. MAIN RESULTS AND THE ROLE OF CHANCE: The 30 participants were from Europe (Belgium, Germany, Greece, Italy, Netherlands, Spain, UK) and the USA. Array comparative genome hybridization is the most widely used method amongst the participants, but it is slowly being replaced by massive parallel sequencing. Most participants offering PGS 2.0 to their patients prefer blastocyst biopsy. The high efficiency of vitrification of blastocysts has added a layer of complexity to the discussion, and it is not clear whether PGS in combination with vitrification, PGS alone, or vitrification alone, followed by serial thawing and eSET will be the favoured approach. The opinions range from in favour of the introduction of PGS 2.0 for all IVF patients, over the proposal to use PGS as a tool to rank embryos according to their implantation potential, to scepticism towards PGS pending a positive outcome of robust, reliable and large-scale RCTs in distinct patient groups. LIMITATIONS, REASONS FOR CAUTION: Care was taken to obtain a wide spectrum of views from carefully chosen experts. However, not all invited experts agreed to participate, which explains a lack of geographical coverage in some areas, for example China. This paper is a collation of current practices and opinions, and it was outside the scope of this study to bring a scientific, once-and-for-all solution to the ongoing debate. WIDER IMPLICATIONS OF THE FINDINGS: This paper is unique in that it brings together opinions on PGS 2.0 from all different perspectives and gives an overview of currently applied technologies as well as potential future developments. It will be a useful reference for fertility specialists with an expertise outside reproductive genetics. LARGE SCALE DATA: none. STUDY FUNDING AND COMPETING INTERESTS: No specific funding was obtained to conduct this questionnaire.
STUDY QUESTION: We wanted to probe the opinions and current practices on preimplantation genetic screening (PGS), and more specifically on PGS in its newest form: PGS 2.0? STUDY FINDING: Consensus is lacking on which patient groups, if any at all, can benefit from PGS 2.0 and, a fortiori, whether all IVFpatients should be offered PGS. WHAT IS KNOWN ALREADY: It is clear from all experts that PGS 2.0 can be defined as biopsy at the blastocyst stage followed by comprehensive chromosome screening and possibly combined with vitrification. Most agree that mosaicism is less of an issue at the blastocyst stage than at the cleavage stage but whether mosaicism is no issue at all at the blastocyst stage is currently called into question. STUDY DESIGN, SAMPLES/MATERIALS, METHODS: A questionnaire was developed on the three major aspects of PGS 2.0: the Why, with general questions such as PGS 2.0 indications; the How, specifically on genetic analysis methods; the When, on the ideal method and timing of embryo biopsy. Thirty-five colleagues have been selected to address these questions on the basis of their experience with PGS, and demonstrated by peer-reviewed publications, presentations at meetings and participation in the discussion. The first group of experts who were asked about 'The Why' comprised fertility experts, the second group of molecular biologists were asked about 'The How' and the third group of embryologists were asked about 'The When'. Furthermore, the geographical distribution of the experts has been taken into account. Thirty have filled in the questionnaire as well as actively participated in the redaction of the current paper. MAIN RESULTS AND THE ROLE OF CHANCE: The 30 participants were from Europe (Belgium, Germany, Greece, Italy, Netherlands, Spain, UK) and the USA. Array comparative genome hybridization is the most widely used method amongst the participants, but it is slowly being replaced by massive parallel sequencing. Most participants offering PGS 2.0 to their patients prefer blastocyst biopsy. The high efficiency of vitrification of blastocysts has added a layer of complexity to the discussion, and it is not clear whether PGS in combination with vitrification, PGS alone, or vitrification alone, followed by serial thawing and eSET will be the favoured approach. The opinions range from in favour of the introduction of PGS 2.0 for all IVFpatients, over the proposal to use PGS as a tool to rank embryos according to their implantation potential, to scepticism towards PGS pending a positive outcome of robust, reliable and large-scale RCTs in distinct patient groups. LIMITATIONS, REASONS FOR CAUTION: Care was taken to obtain a wide spectrum of views from carefully chosen experts. However, not all invited experts agreed to participate, which explains a lack of geographical coverage in some areas, for example China. This paper is a collation of current practices and opinions, and it was outside the scope of this study to bring a scientific, once-and-for-all solution to the ongoing debate. WIDER IMPLICATIONS OF THE FINDINGS: This paper is unique in that it brings together opinions on PGS 2.0 from all different perspectives and gives an overview of currently applied technologies as well as potential future developments. It will be a useful reference for fertility specialists with an expertise outside reproductive genetics. LARGE SCALE DATA: none. STUDY FUNDING AND COMPETING INTERESTS: No specific funding was obtained to conduct this questionnaire.
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