Advertisement

Current Stem Cell Reports

, Volume 5, Issue 4, pp 125–132 | Cite as

The Impact of Mosaic Embryos on Procreative Liberty and Procreative Responsibility: Time to Put Innovative Technology on “Pause”

  • Shizuko TakahashiEmail author
  • Pasquale Patrizio
Ethics in Stem/Progenitor Cell Therapeutics (S Latham, Section Editor)
  • 43 Downloads
Part of the following topical collections:
  1. Topical Collection on Ethics in Stem/Progenitor Cell Therapeutics

Abstract

Purpose of Review

Preimplantation genetic testing for aneuploidy (PGT-A) is a controversial and an unvalidated procedure used for embryo screening and yet is being offered to patients undergoing in vitro fertilization (IVF). Recent media coverage of hundreds of normal euploid births from the transfers of “abnormal” mosaic embryos has brought increased social attention to this subject. Given the definition of normalcy is ambiguous, we must ask, is procreative responsibility enough to justify the disposal of mosaic embryos and to ask patients to start anew?

Recent Findings

A gradual change is seen in medical professionals giving patients the choice to transfer mosaic embryos, while patients are simultaneously becoming more aware of the false positives and reluctant to dispose potentially good embryos, hoping for self-repair.

Summary

The decision to intentionally transfer abnormal embryos may be an act of procreative liberty as well as a challenge to reproductive responsibility, but such burden placed on patients from a test prematurely commercialized to increase success rate is unethical. Innovative technologies must be properly validated to prevent further harm by false assumptions of the norm.

Keywords

Mosaic embryo Procreative liberty Procreative responsibility PGT-A PGS Preimplantation genetic testing Ethics Reproductive medicine 

Notes

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    CDC reports Archived ART Reports and Spreadsheets | subsection title | section title | site title. 2019 In: Cdc.gov. https://www.cdc.gov/art/reports/archive.html. Accessed 16 Jul 2019.
  2. 2.
    Ghazal S, Patrizio P. Embryo wastage rates remain high in assisted reproductive technology (ART): a look at the trends from 2004–2013 in the USA. J Assist Reprod Genet. 2016;34:159–66.PubMedPubMedCentralGoogle Scholar
  3. 3.
    • Harper J, Jackson E, Sermon K, et al. Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions? Human Reproduction. 2017;32:485–91. This study listed commonly used add-on technologies without evidence. PubMedGoogle Scholar
  4. 4.
    • Patrizio P, Shoham G, Shoham Z, Leong M, Barad D, Gleicher N. Worldwide live births following the transfer of chromosomally “abnormal” embryos after PGT/A: results of a worldwide web-based survey. J Assist Reprod Genet. 2019.  https://doi.org/10.1007/s10815-019-01510-0This study reported the largest sum of births from abnormal, “mosaic” embryos. PubMedGoogle Scholar
  5. 5.
    •• Orvieto R. Preimplantation genetic screening- the required RCT that has not yet been carried out. Reprod Biol Endocrinol. 2016.  https://doi.org/10.1186/s12958-016-0171-zThis is the first hypothetical RCT of PGT-A.
  6. 6.
    •• Greco E, Minasi M, Fiorentino F. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. N Engl J Med. 2015;373:2089–90. This is the first documentation of live births from mosaic embryos. PubMedGoogle Scholar
  7. 7.
    Taylor T, Gitlin S, Patrick J, Crain J, Wilson J, Griffin D. The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans. Hum Reprod Update. 2014;20:571–81.PubMedGoogle Scholar
  8. 8.
    • McCoy R. Mosaicism in preimplantation human embryos: when chromosomal abnormalities are the norm. Trends Genet. 2017;33:448–63 This is the first to put mosaicism as a “norm” in the title. PubMedPubMedCentralGoogle Scholar
  9. 9.
    •• Paulson R. Preimplantation genetic screening: what is the clinical efficiency? Fertil Steril. 2017;108:228–30. This is the first to mathematically estimate the false positive rate of PGT-A. PubMedGoogle Scholar
  10. 10.
    Reddy S. IVF testing spurs a debate over ‘mosaic’ embryos. 2019. In: WSJ. https://www.wsj.com/articles/ivf-testing-spurs-a-debate-over-mosaic-embryos-1521644178. Accessed 15 Jul 2019.
  11. 11.
    •• Hall S. There is now hope for thousands of women who were told they hit an IVF dead end. 2019. In: The Cut. https://www.thecut.com/2017/09/ivf-abnormal-embryos-new-last-chance.html. Accessed 15 Jul 2019. The article alarmed the general public and fertility patients at large. Google Scholar
  12. 12.
    Cram D, Leigh D, Handyside a (2019) PGDIS newsletter, may 27, 2019 PGDIS position statement on the transfer of mosaic embryos in preimplantation ganetic testing for aneuploidy (PGT-A) * BASED ON MATERIALS OF 18TH INTERNATIONAL CONFERENCE ON PREIMPLANTATION GENETICS, Geneva, Switzerland, April 15–18, 2019. In: Pgdis.org. http://www.pgdis.org/docs/newsletter_052719.pdf. Accessed 9 Jul 2019.
  13. 13.
    • Rechisky S. PGDIS Newsletter, July 19, 2016 PGDIS position statement on chromosome mosaicism and preimplantation aneuploidy testing at the blastocyst stage. 2016. In: Pgdis.org. http://pgdis.org/docs/newsletter_071816.html. Accessed 15 Jul 2019. This is the first to classify the order of mosaic embryo transfer.
  14. 14.
    • Gleicher N, Kushnir V, Barad D. How PGS/PGT-A laboratories succeeded in losing all credibility. Reprod BioMed Online. 2018;37:242–5. This is a thorough review of the rapid uptake of PGT-A without validation. PubMedGoogle Scholar
  15. 15.
    Gleicher N, Vidali A, Braverman J, Kushnir V, Albertini D, Barad D. Further evidence against use of PGS in poor prognosis patients: report of normal births after transfer of embryos reported as aneuploid. Fertil Steril. 2015;104:e59.Google Scholar
  16. 16.
    • Steinbock B. Questions about using “mosaic” embryos in IVF - The Hastings Center. 2019. In: The Hastings Center. https://www.thehastingscenter.org/questions-about-using-mosaic-embryos-in-ivf/. Accessed 17 June 2017. This is the first article written on MET by an ethicist, emphasizing the importance of procreative responsibility in these cases.
  17. 17.
    Murugappan G, Ohno M, Lathi R. Cost-effectiveness analysis of preimplantation genetic screening and in vitro fertilization versus expectant management in patients with unexplained recurrent pregnancy loss. Fertil Steril. 2015;103:1215–20.PubMedGoogle Scholar
  18. 18.
    Takahashi S, Johnston J, Patrizio P. Lessons from the premature adoption of preimplantation embryo testing. Genetics in Medicine. 2018;21:1038–40.PubMedGoogle Scholar
  19. 19.
    Handyside A, Kontogianni E, Hardy K, Winston R. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature. 1990;344:768–70.PubMedGoogle Scholar
  20. 20.
    Verlinsky Y, Kuliev A. Preimplantation diagnosis of common aneuploidies in infertile couples of advanced maternal age. Hum Reprod. 1996;11:2076–7.PubMedGoogle Scholar
  21. 21.
    Verlinsky Y, Cieslak J, Freidine M, Ivakhnenko V, Wolf G, Kovalinskaya L, et al. Polar body diagnosis of common aneuploidies by FISH. J Assist Reprod Genet. 1996;13:157–62.PubMedGoogle Scholar
  22. 22.
    Handyside A, Ogilvie C. Screening oocytes and preimplantation embryos for aneuploidy. Current Opinion in Obstetrics and Gynaecology. 1999;11:301–5.Google Scholar
  23. 23.
    Munné S, Cohen J. The status of preimplantation genetic diagnosis in Japan: a criticism. Reprod BioMed Online. 2004;9:258–9.PubMedGoogle Scholar
  24. 24.
    •• Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitro fertilization with preimplantation genetic screening. New Engl J Med. 2007;357:9–17 This the first RCT to prove that PGT version 1 was not only ineffective but harmful. PubMedGoogle Scholar
  25. 25.
    Mastenbroek S, Twisk M, van der Veen F, Repping S. Preimplantation genetic screening: a systematic review and meta-analysis of RCTs. Hum Reprod Update. 2011;17:454–66.PubMedGoogle Scholar
  26. 26.
    • Yang Z, Liu J, Collins G, Salem S, Liu X, Lyle S, et al. Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study. Mol Cytogenet. 2012;5:24. This the first to show the second version of PGT-A is effective. PubMedPubMedCentralGoogle Scholar
  27. 27.
    Dahdouh E, Balayla J, García-Velasco J. Impact of blastocyst biopsy and comprehensive chromosome screening technology on preimplantation genetic screening: a systematic review of randomized controlled trials. Reprod BioMed Online. 2015;30:281–9.PubMedGoogle Scholar
  28. 28.
    • Gleicher N, Orvieto R. Is the hypothesis of preimplantation genetic screening (PGS) still supportable? A review. J Ovarian Res. 2017.  https://doi.org/10.1186/s13048-017-0318-3. This is a historical review of PGT-A adoption without validation.
  29. 29.
    Chicago IVF. Genetic testing: PGD & PGS. In: Visit Chicago IVF™ in Illinois & Indiana. 2019. https://www.chicagoivf.com/fertility-treatment/genetic-testing-pgs-pgd. Accessed 15 Jul 2019.Google Scholar
  30. 30.
    Zahang J. PGS/NGS increases your IVF pregnancy success rate by 30 percent | Dr. Zhang’s Blog. In: Drjohnzhang.com. https://drjohnzhang.com/pgs-ngs-increases-your-ivf-pregnancy-success-rate-by-30-percent/. Accessed 15 Jul 2018.
  31. 31.
    Chicago A. PGS - preimplantation genetic screening of IVF embryos for success. In: Advancedfertility.com. https://www.advancedfertility.com/pgs-ivf-genetic-testing.htm. Accessed 15 Jul 2018.
  32. 32.
    • Munné S, Grifo J, Wells D. Mosaicism: “survival of the fittest” versus “no embryo left behind”. Fertil Steril. 2016;105:1146–9. This is the first to use NGS as a platform for PGT-A, recognizing mosaicism. PubMedGoogle Scholar
  33. 33.
    • Penzias A, Bendikson K, Butts S, et al. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril. 2018;109:429–36. This is the first time for the American Society of Reproductive Medicine to officially acknowledge PGT-A as an unvalidated test. Google Scholar
  34. 34.
    Verpoest W, Staessen C, Bossuyt P, et al. Preimplantation genetic testing for aneuploidy by microarray analysis of polar bodies in advanced maternal age: a randomized clinical trial. Hum Reprod. 2018;33:1767–76.PubMedGoogle Scholar
  35. 35.
    Rubio C, Rienzi L, Navarro-Sánchez L, Cimadomo D, García-Pascual CM, Albricci L, et al. Embryonic cell-free DNA versus trophectoderm biopsy for aneuploidy testing: concordance rate and clinical implications. Fertil Steril. 2019;112:510–9.  https://doi.org/10.1016/j.fertnstert.2019.04.038.CrossRefPubMedGoogle Scholar
  36. 36.
    Fragouli E, Wells D. Current status and future prospects of noninvasive preimplantation genetic testing for aneuploidy. Fertil Steril. 2018;110:408–9.PubMedGoogle Scholar
  37. 37.
    Huang L, Bogale B, Tang Y, Lu S, Xie X, Racowsky C. Noninvasive preimplantation genetic testing for aneuploidy in spent medium may be more reliable than trophectoderm biopsy. Proc Natl Acad Sci. 2019;116:14105–12.PubMedGoogle Scholar
  38. 38.
    Fiorentino F. The transfer an ‘abnormal’ embryo can still result in pregnancy in IVF. Presented at the ESHRE 33rd Annual Meeting in Geneva. July, 4, 2017. In: Eshre.eu. 2017. https://www.eshre.eu/Annual-Meeting/Geneva-2017/ESHRE-2017-Press-releases/Fiorentino. Accessed 20 Jul 2017.Google Scholar
  39. 39.
    Spinella F, Fiorentino F, Biricik A, Bono S, Ruberti A, Cotroneo E, et al. Extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments. Fertil Steril. 2018;109:77–83.PubMedGoogle Scholar
  40. 40.
    Kim T, Neblett M, Shandley L, Omurtag K, Hipp H, Kawwass J. Mosaic embryo transfer: a survey of current U.S. ART clinic practices. Fertil Steril. 2018;110:e407.Google Scholar
  41. 41.
    • Weissman A, Shoham G, Shoham Z, Fishel S, Leong M, Yaron Y. Chromosomal mosaicism detected during preimplantation genetic screening: results of a worldwide web-based survey. Fertil Steril. 2017;107:1092–7 This is the first survey of physicians towards mosaicism and MET. PubMedGoogle Scholar
  42. 42.
    van Echten-Arends J, Mastenbroek S, Sikkema-Raddatz B, Korevaar J, Heineman M, van der Veen F, et al. Chromosomal mosaicism in human preimplantation embryos: a systematic review. Hum Reprod Update. 2011;17:620–7.PubMedGoogle Scholar
  43. 43.
    Capalbo A, Ubaldi F, Rienzi L, Scott R, Treff N. Detecting mosaicism in trophectoderm biopsies: current challenges and future possibilities. Hum Reprod. 2016.  https://doi.org/10.1093/humrep/dew250.
  44. 44.
    Munné S, Blazek J, Large M, et al. Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high-resolution next-generation sequencing. Fertility and Sterility. 2017;108:62-71.e8.PubMedGoogle Scholar
  45. 45.
    Munné S, Wells D. Detection of mosaicism at blastocyst stage with the use of high-resolution next-generation sequencing. Fertil Steril. 2017;107:1085–91.PubMedGoogle Scholar
  46. 46.
    Igenomix. Prof. Simon joins the debate about mosaicism in The Wall Street Journal. In: Igenomix.com. https://www.igenomix.com/news/prof.simon-joins-the-debate-about-mosaicism-in-the-wall-street-journal. Accessed 9 Jul 2019
  47. 47.
    Gleicher N, Metzger J, Croft G, Kushnir V, Albertini D, Barad D. A single trophectoderm biopsy at blastocyst stage is mathematically unable to determine embryo ploidy accurately enough for clinical use. Reprod Biol Endocrinol. 2017;15:33.  https://doi.org/10.1186/s12958-017-0251-8.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Haddad G, He W, Gill J, Witz C, Wang C, Kaskar K, et al. Mosaic pregnancy after transfer of a “euploid” blastocyst screened by DNA microarray. Journal of Ovarian Research. 2013;6:70.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kalousek D, Vekemans M. Confined placental mosaicism. J Med Genet. 1996;33:529–33.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Sharara F, Goodwin M, Abdo G. Discrepancy in PGT-A results among different genetic reference laboratories: how accurate are the results and are we discarding euploid embryos? Fertil Steril. 2018;110:e407–8.Google Scholar
  51. 51.
    Grati F, Gallazzi G, Branca L, Maggi F, Simoni G, Yaron Y. An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening. Reprod BioMed Online. 2018;36:442–9.PubMedGoogle Scholar
  52. 52.
    Rubino P, Li X, Ruiz De Assin Alonso R, et al. Embryos classified as low-grade mosaic (<50%) after preimplantation genetic screening (PGS) by means of high resolution next-generation screening (hr-NGS), can have the same competence of producing healthy newborns as euploid embryos. Fertil Steril. 2018;109:e46–7.Google Scholar
  53. 53.
    •• Besser A, Mounts E. Counselling considerations for chromosomal mosaicism detected by preimplantation genetic screening. Reprod BioMed Online. 2017;34:369–74 This is the first guide for genetic counselors. PubMedGoogle Scholar
  54. 54.
    Bernhardt B, Kellom K, Barbarese A, Faucett W, Wapner R. An exploration of genetic counselors’ needs and experiences with prenatal chromosomal microarray testing. J Genet Couns. 2014;23:938–47.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Embryology and IVF support. “Can someone shed some light on this? I read and spoke to the embryologist and she said the mosaic has a 20–40% of an issue” Christiane Torello posts a photo of her PGT-A results [Facebook]. 2019 June 18 [cited 2019 June 8]. Available from: https://www.facebook.com/groups/840753359659051/Google Scholar
  56. 56.
    Embryology and IVF support. “Question- is grading out the window when you do pGS testing? For example, if there’s a 3CC that comes back euploid, is that just as good as a 4AA that people don’t test and put in?” Christiane Torello [Facebook]. 2019 July 5 [cited 2019 July 9]. Available from: https://www.facebook.com/groups/840753359659051/
  57. 57.
    Peikoff K (2016) In IVF, questions about ‘mosaic’ embryos. In: Nytimes.com. https://www.nytimes.com/2016/04/19/health/ivf-in-vitro-fertilization-pregnancy-abnormal-embryos-mosaic.html. Accessed 10 Jul 2019.
  58. 58.
    Savulescu J. Procreative beneficence: why we should select the best children. Bioethics. 2001;15:413–26.PubMedGoogle Scholar
  59. 59.
    Gebhart M, Hines R, Penman A, Holland A. How do patient perceived determinants influence the decision-making process to accept or decline preimplantation genetic screening? Fertil Steril. 2016;105:188–93.PubMedGoogle Scholar
  60. 60.
    Besser A, McCulloh D, Grifo J. What are patients doing with their mosaic embryos? Decision making after genetic counseling. Fertil Steril. 2019;111:132-137.e1.PubMedGoogle Scholar
  61. 61.
    de Lacey S. Parent identity and ‘virtual’ children: why patients discard rather than donate unused embryos. Hum Reprod. 2005;20:1661–9.PubMedGoogle Scholar
  62. 62.
    Takahashi S, Fujita M, Fujimoto A, Fujiwara T, Yano T, Tsutsumi O, et al. The decision-making process for the fate of frozen embryos by Japanese infertile women: a qualitative study. BMC Medical Ethics. 2012;13.  https://doi.org/10.1186/1472-6939-13-9.
  63. 63.
    Heneghan C, Spencer E, Bobrovitz N, et al. Lack of evidence for interventions offered in UK fertility centres. BMJ. 2016:i6295.Google Scholar
  64. 64.
    Harper J, Wells D, Simpson J. Current controversies in prenatal diagnosis 4: preimplantation genetic screening should be routinely offered to all preimplantation genetic diagnosis cases. Prenat Diagn. 2016;36:25–8.PubMedGoogle Scholar
  65. 65.
    Cimadomo D, Soscia D, Vaiarelli A, Maggiulli R, Capalbo A, Ubaldi F, et al. Looking past the appearance: a comprehensive description of the clinical contribution of poor-quality blastocysts to increase live birth rates during cycles with aneuploidy testing. Hum Reprod. 2019;34:1206–14.PubMedGoogle Scholar
  66. 66.
    Unknown A(2017) Chakushouzenshindan 180ninbun touroue 6 shisetsu de rinshoukenkyu nihonsankafujinka gatkai (Pilot studies of preimplantation genetic testing done in 6 institutions for 180 people by the Japanese Society of Obstetrics and Gynecology)[in Japanese]. In: Sankei News. http://www.sankei.com/life/news/170214/lif1702140044-n1.html. Accessed 10 Jul 2019.
  67. 67.
    Unknown A. Japan doctor conducts questionable inseminated egg tests. 2012. In: Deccan News. https://www.deccanherald.com/content/263466/japan-doctor-conducts-questionable-inseminated.html. Accessed 18 Aug 2019.
  68. 68.
    • Chiba N. Group’s plan to start preimplantation genetic screening trials criticized as too early - The Mainichi. 2017. In: The Mainichi. http://mainichi.jp/english/articles/20170214/p2a/00m/0na/013000c. Accessed 14 Feb 2017. This is an example of how PGT-A has been pushed and adopted without validation.
  69. 69.
    Author N. Japan to expand study on egg test during fertility treatment aimed at detecting chromosomal abnormalities | The Japan Times. 2019. In: The Japan Times. https://www.japantimes.co.jp/news/2019/06/24/national/science-health/japanese-study-detecting-chromosomal-abnormalities-fertilized-eggs-expanded/#.XS1oL_ZuJpw. Accessed 16 Jul 2019.
  70. 70.
    Irahara M. Towards a proper development of reproductive medicine in Japan [seishokuiryouno teiseina hatten wo mezashite]. In: Presented for the 71st annual congress of the Japanese Obstetrics and Gynecology, on April13, 2019 at Nagoya Congress Center, Nagoya, Japan; 2019.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Biomedical Ethics, Graduate School of MedicineThe University of TokyoTokyoJapan
  2. 2.Department of Obstetrics and Gynecology, Graduate School of MedicineThe University of TokyoTokyoJapan
  3. 3.Yale Fertility CenterNew HavenUSA

Personalised recommendations