Preimplantation Genetic Testing for Polygenetic Conditions: A Legal, Ethical, and Scientific Challenge

Abstract

The recent commercialization of the Embryo Health Score (EHS), determined through preimplantation genetic testing for polygenic conditions, offers the potential to select embryos with lower disease risk, thus potentially enhancing offspring longevity and health. Lately, Orchid Health company increased testing from less than 20 diseases to more than 900+ conditions for birth defects. However, the “geneticization” of phenotype estimates to a health state erases the environmental part, including the in vitro fertilization potential risks, questioning its scientific usefulness. EHS is utilized in countries with minimal regulatory oversight and will likely expand, while it remains illegal in other countries due to ethical and legal dilemmas it raises about reproductive autonomy, discrimination, impacts on family dynamics, and genetic diversity. The shift toward commercialized polygenic embryo screening (PES) redefines healthcare relationships, turning prospective parents into consumers and altering the physician's role. Moreover, PES could increase social inequalities, stigmatize those not born following PES, and encourage “desirable” phenotypic or behavioral traits selection, leading to ethical drift. Addressing these issues is essential before further implementation and requires a collaborative approach involving political, governmental, and public health, alongside geneticists, ethicists, and fertility specialists, focusing on the societal implications and acceptability of testing for polygenic traits for embryo selection.

Keywords

polygenic risk score - Embryo Health Score - embryo selection - ethics - legislation

Publication History

Article published online:
22 March 2024

• References

• 1 Iews M, Tan J, Taskin O. et al. Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review. Reprod Biomed Online 2018; 36 (06) 677-685
• 2 Handyside AH, Lesko JG, Tarín JJ, Winston RML, Hughes MR. Birth of a normal girl after in vitro fertilization and preimplantation diagnostic testing for cystic fibrosis. N Engl J Med 1992; 327 (13) 905-909
• 3 Munné S, Kaplan B, Frattarelli JL. et al; STAR Study Group. Preimplantation genetic testing for aneuploidy versus morphology as selection criteria for single frozen-thawed embryo transfer in good-prognosis patients: a multicenter randomized clinical trial. Fertil Steril 2019; 112 (06) 1071-1079.e7
• 4 Rubio C, Bellver J, Rodrigo L. et al. In vitro fertilization with preimplantation genetic diagnosis for aneuploidies in advanced maternal age: a randomized, controlled study. Fertil Steril 2017; 107 (05) 1122-1129
• 5 Yan J, Qin Y, Zhao H. et al. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med 2021; 385 (22) 2047-2058
• 6 Kucherov A, Fazzari M, Lieman H, Ball GD, Doody K, Jindal S. PGT-A is associated with reduced cumulative live birth rate in first reported IVF stimulation cycles age ≤ 40: an analysis of 133,494 autologous cycles reported to SART CORS. J Assist Reprod Genet 2023; 40 (01) 137-149
• 7 LifeView by Genomic Prediction. Accessed March 7, 2023 at: https://www.lifeview.com/
• 8 Tellier LCAM, Eccles J, Treff NR, Lello L, Fishel S, Hsu S. Embryo screening for polygenic disease risk: recent advances and ethical considerations. Genes (Basel) 2021; 12 (08) 1105
• 9 Pre-Implantation Genetic Testing for Birth Defects. Accessed February 8, 2024 at: https://guides.orchidhealth.com/post/pre-implantation-genetic-testing-for-birth-defects
• 10 Lencz T, Backenroth D, Granot-Hershkovitz E. et al. Utility of polygenic embryo screening for disease depends on the selection strategy. eLife 2021; 10: e64716
• 11 Turley P, Meyer MN, Wang N. et al. Problems with using polygenic scores to select embryos. N Engl J Med 2021; 385 (01) 78-86
• 12 Treff NR, Eccles J, Marin D. et al. Preimplantation genetic testing for polygenic disease relative risk reduction: evaluation of genomic index performance in 11,883 adult sibling pairs. Genes (Basel) 2020; 11 (06) 648
• 13 Lello L, Raben TG, Yong SY, Tellier LCAM, Hsu SDH. Genomic prediction of 16 complex disease risks including heart attack, diabetes, breast and prostate cancer. Sci Rep 2019; 9 (01) 15286
• 14 Konuma T, Okada Y. Statistical genetics and polygenic risk score for precision medicine. Inflamm Regen 2021; 41 (01) 18
• 15 Khera AV, Chaffin M, Aragam KG. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet 2018; 50 (09) 1219-1224
• 16 Tada H, Yeo KK, Li JJ. et al. Polygenic risk scores for atherosclerotic cardiovascular disease in the Asia-Pacific region. JACC Asia 2021; 1 (03) 294-302
• 17 Treff NR, Eccles J, Lello L. et al. Utility and first clinical application of screening embryos for polygenic disease risk reduction. Front Endocrinol (Lausanne) 2019; 10: 845
• 18 Lello L, Avery SG, Tellier L, Vazquez AI, de Los Campos G, Hsu SDH. Accurate genomic prediction of human height. Genetics 2018; 210 (02) 477-497
• 19 Widen E, Lello L, Raben TG, Tellier LCAM, Hsu SDH. Polygenic health index, general health, and pleiotropy: sibling analysis and disease risk reduction. Sci Rep 2022; 12 (01) 18173
• 20 Meisner A, Kundu P, Zhang YD. et al. Combined utility of 25 disease and risk factor polygenic risk scores for stratifying risk of all-cause mortality. Am J Hum Genet 2020; 107 (03) 418-431
• 21 Wald NJ, Old R. The illusion of polygenic disease risk prediction. Genet Med 2019; 21 (08) 1705-1707
• 22 Khoury MJ, Janssens ACJW, Ransohoff DF. How can polygenic inheritance be used in population screening for common diseases?. Genet Med 2013; 15 (06) 437-443
• 23 Duncan L, Shen H, Gelaye B. et al. Analysis of polygenic risk score usage and performance in diverse human populations. Nat Commun 2019; 10 (01) 3328
• 24 Mostafavi H, Harpak A, Agarwal I, Conley D, Pritchard JK, Przeworski M. Variable prediction accuracy of polygenic scores within an ancestry group. eLife 2020; 9: e48376
• 25 Amariuta T, Ishigaki K, Sugishita H. et al. Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements. Nat Genet 2020; 52 (12) 1346-1354
• 26 Koyama S, Ito K, Terao C. et al. Population-specific and trans-ancestry genome-wide analyses identify distinct and shared genetic risk loci for coronary artery disease. Nat Genet 2020; 52 (11) 1169-1177
• 27 Forzano F, Antonova O, Clarke A. et al; Executive Committee of the European Society of Human Genetics, Public and Professional Policy Committee of the European Society of Human Genetics. The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice. Eur J Hum Genet 2022; 30 (05) 493-495
• 28 Polyakov A, Amor DJ, Savulescu J. et al. Polygenic risk score for embryo selection-not ready for prime time. Hum Reprod 2022; 37 (10) 2229-2236
• 29 Orchid | Whole Genome Embryo Report. Accessed February 8, 2024 at: https://www.orchidhealth.com/
• 30 Lencz T, Sabatello M, Docherty A. et al. Concerns about the use of polygenic embryo screening for psychiatric and cognitive traits. Lancet Psychiatry 2022; 9 (10) 838-844
• 31 Ginod P, Dahan MH. Polygenic embryo screening: are there potential maternal and fetal harms?. Reprod Biomed Online 2023; 47 (06) 103327
• 32 Qin J, Liu X, Sheng X, Wang H, Gao S. Assisted reproductive technology and the risk of pregnancy-related complications and adverse pregnancy outcomes in singleton pregnancies: a meta-analysis of cohort studies. Fertil Steril 2016; 105 (01) 73-85.e1 , 6
• 33 Roque M, Valle M, Sampaio M, Geber S. Obstetric outcomes after fresh versus frozen-thawed embryo transfers: a systematic review and meta-analysis. JBRA Assist Reprod 2018; 22 (03) 253-260
• 34 Rodriguez-Wallberg KA, Lundberg FE, Ekberg S. et al. Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden. Fertil Steril 2020; 113 (03) 524-532
• 35 Mani S, Ghosh J, Coutifaris C, Sapienza C, Mainigi M. Epigenetic changes and assisted reproductive technologies. Epigenetics 2020; 15 (1-2): 12-25
• 36 D'Angelo DV, Whitehead N, Helms K, Barfield W, Ahluwalia IB. Birth outcomes of intended pregnancies among women who used assisted reproductive technology, ovulation stimulation, or no treatment. Fertil Steril 2011; 96 (02) 314-320.e2
• 37 Imudia AN, Awonuga AO, Doyle JO. et al. Peak serum estradiol level during controlled ovarian hyperstimulation is associated with increased risk of small for gestational age and preeclampsia in singleton pregnancies after in vitro fertilization. Fertil Steril 2012; 97 (06) 1374-1379
• 38 Treff NR, Zimmerman R, Bechor E. et al. Validation of concurrent preimplantation genetic testing for polygenic and monogenic disorders, structural rearrangements, and whole and segmental chromosome aneuploidy with a single universal platform. Eur J Med Genet 2019; 62 (08) 103647
• 39 Peters BA, Kermani BG, Alferov O. et al. Detection and phasing of single base de novo mutations in biopsies from human in vitro fertilized embryos by advanced whole-genome sequencing. Genome Res 2015; 25 (03) 426-434
• 40 Delaneau O, Zagury JF, Robinson MR, Marchini JL, Dermitzakis ET. Accurate, scalable and integrative haplotype estimation. Nat Commun 2019; 10 (01) 5436
• 41 Kumar A, Ryan A, Kitzman JO. et al. Whole genome prediction for preimplantation genetic diagnosis. Genome Med 2015; 7 (01) 35
• 42 Leaver M, Wells D. Non-invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics?. Hum Reprod Update 2020; 26 (01) 16-42
• 43 Brouillet S, Martinez G, Coutton C, Hamamah S. Is cell-free DNA in spent embryo culture medium an alternative to embryo biopsy for preimplantation genetic testing? A systematic review. Reprod Biomed Online 2020; 40 (06) 779-796
• 44 Munné S, Alikani M, Ribustello L, Colls P, Martínez-Ortiz PA, McCulloh DH. Referring Physician Group. Euploidy rates in donor egg cycles significantly differ between fertility centers. Hum Reprod 2017; 32 (04) 743-749
• 45 PRS. Accessed March 10, 2023 at: https://www.eshre.eu/Europe/Position-statements/PRS
• 46 ACMG Board of Directors. Direct-to-consumer prenatal testing for multigenic or polygenic disorders: a position statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2021; 23 (11) 2027-2028
• 47 Zappala MAP, Ariza L, Lima NS. Conceptualization of genotype–phenotype relationships and the assessment of risk in advertising of direct-to-consumer and preimplantation polygenic tests. Biosocieties (Published online September 30, 2023)
• 48 Harvey A. Genetic risks and healthy choices: creating citizen-consumers of genetic services through empowerment and facilitation. Sociol Health Illn 2010; 32 (03) 365-381
• 49 Irvine R. Fabricating health consumers in health care politics. In: Henderson S, Petersen A. eds. Consuming Health: The Commodification of Health Care. Routledge; 2002: 31-47
• 50 Holster K. Making connections: egg donation, the Internet, and the new reproductive technology marketplace. Adv Med Sociol 2001; 10: 53-73
• 51 23AndMe Will Decode Your DNA for $1,000. Welcome to the Age of Genomics | WIRED. Accessed February 4, 2024 at: https://www.wired.com/2007/11/ff-genomics/
• 52 The Politics of Life Itself | Princeton University Press. Published November 19, 2006. Accessed February 5, 2024 at: https://press.princeton.edu/books/paperback/9780691121918/the-politics-of-life-itself
• 53 Swoboda D. Frames of reference: marketing the practice and ethics of PGD on fertility clinic Websites. Adv Med Sociol 2015; 16: 217-247
• 54 Ethics Statements | ISPG - International Society of Psychiatric Genetics. Accessed March 8, 2023 at: https://ispg.net/ethics-statement/
• 55 Polygenic Risk Score Task Force of the International Common Disease Alliance. Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps. Nat Med 2021; 27 (11) 1876-1884
• 56 Polygenic screening of embryos is here, but is it ethical? | Genetics | The Guardian. Accessed February 5, 2024 at: https://www.theguardian.com/science/2021/oct/17/polygenic-screening-of-embryos-is-here-but-is-it-ethical
• 57 Picking Embryos With Best Health Odds Sparks New DNA Debate. Bloomberg.com. Accessed February 5, 2024 at: https://www.bloomberg.com/news/articles/2021-09-17/picking-embryos-with-best-health-odds-sparks-new-dna-debate Published September 17, 2021
• 58 Rank Ordering Embryos for Transfer, Utilizing PGT-P: Patient and Clinician Perspectives. 2021. Accessed February 5, 2024 at: https://www.youtube.com/watch?v=HE5ADe7BgdM
• 59 Treff NR, Savulescu J, de Melo-Martín I, Shulman LP, Feinberg EC. Should preimplantation genetic testing for polygenic disease be offered to all - or none?. Fertil Steril 2022; 117 (06) 1162-1167
• 60 Eugenics 2.0: We're at the Dawn of Choosing Embryos by Health, Height, and More | MIT Technology Review. Accessed February 5, 2024 at: https://www.technologyreview.com/2017/11/01/105176/eugenics-20-were-at-the-dawn-of-choosing-embryos-by-health-height-and-more/
• 61 Choice Over Chance; 2020. Accessed February 5, 2024 at: https://www.youtube.com/watch?v=vwVyv91BcNU
• 62 The Ethics of Embryo Screening. Q&A with a UPenn Bioethicist. Accessed February 5, 2024 at: https://guides.orchidhealth.com/post/the-ethics-of-embryo-screening-q-a-with-a-upenn-bioethicist
• 63 Siermann M, Tšuiko O, Vermeesch JR, Raivio T, Borry P. A review of normative documents on preimplantation genetic testing: recommendations for PGT-P. Genet Med 2022; 24 (06) 1165-1175
• 64 Farsides B, Scott R. No small matter for some: practitioners' views on the moral status and treatment of human embryos. Med Law Rev 2012; 20 (01) 90-107
• 65 Kalfoglou AL, Scott J, Hudson K. PGD patients' and providers' attitudes to the use and regulation of preimplantation genetic diagnosis. Reprod Biomed Online 2005; 11 (04) 486-496
• 66 Klitzman R. Challenges, dilemmas and factors involved in PGD decision-making: providers' and patients' views, experiences and decisions. J Genet Couns 2018; 27 (04) 909-919
• 67 Patrick Olesen A, Mohd Nor SN. Ethical perceptions with regard to pre-implantation genetic diagnosis (PGD) from the perspective of selected medical professionals in Malaysia. J Clin Med Genom 2016; 4 (01)
• 68 Scott R, Williams C, Ehrich K, Farsides B. The appropriate extent of pre-implantation genetic diagnosis: health professionals' and scientists' views on the requirement for a ‘significant risk of a serious genetic condition’. Med Law Rev 2007; 15 (03) 320-356
• 69 Williams C, Ehrich K, Farsides B, Scott R. Facilitating choice, framing choice: staff views on widening the scope of preimplantation genetic diagnosis in the UK. Soc Sci Med 2007; 65 (06) 1094-1105
• 70 Kumar A, Im K, Rabinowitz M. Use of polygenic scores to select embryos. N Engl J Med 2021; 385 (18) 1726-1727
• 71 Griffin DK, Gordon AT. Preimplantation testing for polygenic disease (PGT-P): brave new world or mad pursuit?. DNA (Basel) 2023; 3 (02) 104-108
• 72 Lázaro-Muñoz G, Pereira S, Carmi S, Lencz T. Screening embryos for polygenic conditions and traits: ethical considerations for an emerging technology. Genet Med 2021; 23 (03) 432-434
• 73 Bu Z, Chen ZJ, Huang G. et al. Live birth sex ratio after in vitro fertilization and embryo transfer in China – an analysis of 121,247 babies from 18 centers. PLoS One 2014; 9 (11) e113522
• 74 Arribas-Ayllon M. After geneticization. Soc Sci Med 2016; 159: 132-139
• 75 Lippman A. Led (astray) by genetic maps: the cartography of the human genome and health care. Soc Sci Med 1992; 35 (12) 1469-1476
• 76 Weiner K, Martin P, Richards M, Tutton R. Have we seen the geneticisation of society? Expectations and evidence. Sociol Health Illn 2017; 39 (07) 989-1004
• 77 Turrini M. A genealogy of “healthism”: Healthy subjectivities between individual autonomy and disciplinary control. Eä - Journal of Medical Humanities & Social Studies of Science and Technology. Healthism & Self-Care: Reconfiguring Body & Life through Science & Technology 2015; 7 (01) 11-27