Skip to main content
Log in

Comment on the recent PGDIS Position Statement on the Transfer of Mosaic Embryos 2021

  • Commentary
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

The worldwide demand of preimplantation genetic testing for aneuploidy (PGT-A) is still growing. However, chromosomal mosaic results greatly challenge the clinical practice. The recently published PGDIS Position Statement on the Transfer of Mosaic Embryos is the third PGDIS position statement on how to deal with embryos diagnosed as chromosomal mosaics (CM) and, one of many attempts of different societies and working groups to provide a guideline for clinicians, laboratories, clinics, and genetic counselors. But still, as in previous statements, many issues remained unresolved. Moreover, from our point of view, the question how to deal with embryos diagnosed as CM, consisting of two or more karyological cell lines cannot be separated from all the other aspects of PGT-A including its accuracy. The paucity of clearcut indications for PGT-A and evidence of benefit as well as an overall cost–benefit assessment is given below.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

References

  1. Munne S. Status of preimplantation genetic testing and embryo selection. Reprod Biomed Online. 2018;37:393–6.

    Article  Google Scholar 

  2. Mochizuki L, Gleicher N. The PGS/PGT-A controversy in IVF addressed as a formal conflict resolution analysis. J Assist Reprod Genet. 2020;37:677–87. https://doi.org/10.1007/s10815-020-01688-8.

    Article  Google Scholar 

  3. Cram DS, Leigh D, Handyside A, Rechitsky L, Xu K, Harton G, Grifo J, Rubio C, Fragouli E, Kahraman S, Forman E, Katz-Jaffe M, Tempest H, Thornhill A, Strom C, Escudero T, Qiao J, Munne S, Simpson JL, Kuliev A. PGDIS Position Statement on the Transfer of Mosaic Embryos 2019. Reprod Biomed Online. 2019;39(Suppl 1):e1–4.

    Google Scholar 

  4. Leigh D, Cram DS, Rechitsky S, Handyside A, Wells D, Munne S, Kahraman S, Grifo J, Katz-Jaffe M, Rubio C, Viotti M, Forman E, Xu K, Gordon T, Madjunkova S, Qiao J, Z-Chen J, Harton G, Gianaroli L, Simon C, Scott R, Simpson JL, Kuliev A. PGDIS Position Statement on the Transfer of Mosaic Embryos 2021. Reprod Biomed Online. 2022;45:19–25.

    Article  CAS  Google Scholar 

  5. Scriven PN. Towards a better understanding of preimplantation genetic screening for aneuploidy: insights from a virtual trial for women under the age of 40 when transferring embryos one at a time. Reprod Biol Endocrinol. 2017;15:49. https://doi.org/10.1186/s12958-017-0269-y.

    Article  Google Scholar 

  6. Murugappan G, Ohno MS, Lathi RB. 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.

    Article  Google Scholar 

  7. Robinson RD, Rippentrop S, McLaughlin JE. What are the cost considerations for preimplantation genetic testing for aneuploidy? Fertil Steril. 2019;111:1115–6.

    Article  Google Scholar 

  8. Somigliana E, Busnelli A, Paffoni A, Vigano P, Riccaboni A, Rubio C, Capalbo A. Cost-effectiveness of preimplantation genetic testing for aneuploidies. Fertil Steril. 2019;111:1169–76.

    Article  Google Scholar 

  9. PGDIS. PGDIS Position Statement on Chromosome Mosaicism and Preimplantation Aneuploidy testing at the blastocyst stage. PGDIS Newsletter, July 19, 2016. www.pgdis.org/docs/newsletter_071816.html. Accessed 10 Jul 2022.

  10. CoGEN. A Statement on the use of Preimplantation Genetic Screening (PGS) of chromosomes for IVF patients. https://ivf-worldwide.com/cogen/oep/publications/cogen-statement-on-the-use-of-preimplantation-genetic-screening-pgs-of-chromosomes-for-ivf-patients.html. Accessed 10 Jul 2022.

  11. Practice Committee and Genetic Counseling Professional Group (GCPG) of the American Society for Reproductive Medicine. Clinical management of mosaic results from preimplantation genetic testing for aneuploidy (PGT-A) of blastocysts: a committee opinion. Fertil Steril. 2020;114:246–54.

    Article  Google Scholar 

  12. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, Scott RT Jr. The nature of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil Steril. 2014;101:656-663.e1.

    Article  Google Scholar 

  13. Verlinsky Y, Cieslak J, Freidine M, Ivakhnenko V, Wolf G, Kovalinskaya L, White M, Lifchez A, Kaplan B, Moise J, et al. Pregnancies following pre-conception diagnosis of common aneuploidies by fluorescent in-situ hybridization. Hum Reprod. 1995;10:1923–7.

    Article  CAS  Google Scholar 

  14. Verlinsky Y, Cieslak J, Ivakhnenko V, Evsikov S, Wolf G, White M, Lifchez A, Kaplan B, Moise J, Valle J, Ginsberg N, Strom C, Kuliev A. Preimplantation diagnosis of common aneuploidies by the first- and second-polar body FISH analysis. J Assist Reprod Genet. 1998;15:285–9.

    Article  CAS  Google Scholar 

  15. Soler A, Morales C, Mademont-Soler I, Margarit E, Borrell A, Borobio V, Muñoz M, Sánchez A. Overview of chromosome abnormalities in first trimester miscarriages: a series of 1,011 consecutive chorionic villi sample karyotypes. Cytogenet Genome Res. 2017;152:81–9.

    Article  CAS  Google Scholar 

  16. Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages. Fertil Steril. 2000;73:300–4.

    Article  CAS  Google Scholar 

  17. Scott RT Jr. Galliano D The challenge of embryonic mosaicism in preimplantation genetic screening. Fertil Steril. 2016;105:1150–2.

    Article  Google Scholar 

  18. Yang M, Rito T, Metzger J, Naftaly J, Soman R, Hu J, Albertini DF, Barad DH, Brivanlou AH, Gleicher N. Depletion of aneuploid cells in human embryos and gastruloids. Nat Cell Biol. 2021;23:314–21.

    Article  CAS  Google Scholar 

  19. Kermi C, Aze A, Maiorano D. Preserving genome integrity during the early embryonic DNA replication cycles. Genes (Basel). 2019;10:398. https://doi.org/10.3390/genes10050398.

    Article  CAS  Google Scholar 

  20. Shahbazi MN, Wang T, Tao X, Weatherbee BAT, Sun L, Zhan Y, Keller L, Smith GD, Pellicer A, Scott RT Jr, Seli E, Zernicka-Goetz M. Developmental potential of aneuploid human embryos cultured beyond implantation. Nat Commun. 2020;11:3987. Nat Commun. 2020;11:3987.

    Article  CAS  Google Scholar 

  21. Bolton H, Graham SJ, Van der Aa N, et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential. Nat Commun. 2016;7:11165.

    Article  CAS  Google Scholar 

  22. Marin D, Xu J, Treff NR. Preimplantation genetic testing for aneuploidy: a review of published blastocyst reanalysis concordance data. Prenat Diagn. 2021;41:545–53.

    Article  Google Scholar 

  23. Gleicher N, Metzger J, Croft G, Kushnir VA, Albertini DF, Barad DH. 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.

    Article  Google Scholar 

  24. Gleicher N, Barad DH, Ben-Rafael Z, Glujovsky D, Mochizuki L, Modi D, Murtinger M, Patrizio P, Orvieto R, Takahashi S, Weghofer A, Ziebe S, International Do No Harm Group in IVF (IDNHG-IVF). Commentary on two recently published formal guidelines on management of “mosaic” embryos after preimplantation genetic testing for aneuploidy (PGT-A). Reprod Biol Endocrinol. 2021;19:23. https://doi.org/10.1186/s12958-021-00716-1.

    Article  Google Scholar 

  25. Munné S, Kaplan B, Frattarelli JL, Child T, Nakhuda G, Shamma FN, Silverberg K, Kalista T, Handyside AH, Katz-Jaffe M, Wells D, Gordon T, Stock-Myer S, Willman S, 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;112:1071–9.

    Article  Google Scholar 

  26. McCoy RC, Demko Z, Ryan A, Banjevic M, Hill M, Sigurjonsson S, Rabinowitz M, Fraser HB, Petrov DA. Mosaicism in preimplantation human embryos: when chromosomal abnormalities are the norm. Trends Genet. 2017;33:448–63.

    Article  CAS  Google Scholar 

  27. McCoy RC, Demko Z, Ryan A, Banjevic M, Hill M, Sigurjonsson S, Rabinowitz M, Fraser HB, Petrov DA. Common variants spanning PLK4 are associated with mitotic-origin aneuploidy in human embryos. Science. 2015;348:235–8.

    Article  CAS  Google Scholar 

  28. ESHRE: Guidelines and good practice recommendations under development. Chromosomal Mosaicism in PGT. Available from: https://www.eshre.eu/-/media/sitecore-files/Guidelines/ChromosomalMosaicism/ESHRE-Good-Practice-Recommendation-on-Chromosomal-Mosaicism_Draft-for-review.pdf?la=en&hx0026;hash=BF8024B85D4A06FEC5FFADA26050E3F5ED517C6D. Accessed 28 Jul 2022.

  29. Gleicher N, Patrizio P, Brivanlou A. Preimplantation genetic testing for aneuploidy - a castle built on sand. Trends Mol Med. 2021;27:731–42.

    Article  CAS  Google Scholar 

  30. Chen D, Xu Y, Ding C, Wang Y, Fu Y, Cai B, Wang J, Li R, Guo J, Pan J, Zeng Y, Zhong Y, Shen X, Zhou C. The inconsistency between two major aneuploidy-screening platforms-single-nucleotide polymorphism array and next-generation sequencing-in the detection of embryo mosaicism. BMC Genomics. 2022;23:62.

    Article  Google Scholar 

  31. Capalbo A, Poli M, Rienzi L, Girardi L, Patassini C, Fabiani M, Cimadomo D, Benini F, Farcomeni A, Cuzzi J, Rubio C, Albani E, Sacchi L, Vaiarelli A, Figliuzzi M, Findikli N, Coban O, Boynukalin FK, Vogel I, Hoffmann E, Livi C, Levi-Setti PE, Ubaldi FM, Simón C. Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial. Am J Hum Genet. 2021;108:2238–47.

    Article  CAS  Google Scholar 

  32. Barad DH, Albertini DF, Molinari E, Gleicher N. IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study. Hum Reprod. 2022;30(37):1194–206.

    Article  Google Scholar 

  33. Ata B, Popovich M, Fatemi H. Correct assessment and interpretation of results determines the accuracy of any diagnostic test, and PGT-A is no exception. Hum Reprod. 2022;37:2214–6.

    Article  Google Scholar 

  34. Capalbo A, Cimadomo D, Rienzi L, Garcìa-Velasco JA, Simòn C, Ubaldi FM. Avoid mixing apples and oranges: blastocysts diagnosed with uniform whole chromosome aneuploidies are reproductively incompetent and their transfer is harmful. Hum Reprod. 2022;37:2213–4.

    Article  Google Scholar 

  35. Rubio C, Simón C, Vidal F, Rodrigo L, Pehlivan T, Remohí J, Pellicer A. Chromosomal abnormalities and embryo development in recurrent miscarriage couples. Hum Reprod. 2003;18:182–8.

    Article  CAS  Google Scholar 

  36. Rubio C, Pehlivan T, Rodrigo L, Simón C, Remohí J, Pellicer A. Embryo aneuploidy screening for unexplained recurrent miscarriage: a minireview. Am J Reprod Immunol. 2005;53:159–65.

    Article  Google Scholar 

  37. Munné S, Chen S, Fischer J, Colls P, Zheng X, Stevens J, Escudero T, Oter M, Schoolcraft B, Simpson JL, Cohen J. Preimplantation genetic diagnosis reduces pregnancy loss in women aged 35 years and older with a history of recurrent miscarriages. Fertil Steril. 2005;84:331–5.

    Article  Google Scholar 

  38. Mounts EL, Zhu S, Sanderson R, Coates A, Hesla JS. Mosaic embryo diagnosis correlated with abnormal 15q duplication syndrome in offspring. Fertil Steril. 2019;112:e241–2.

    Article  Google Scholar 

  39. Tiegs AW, Tao X, Zhan Y, Whitehead C, Kim J, Hanson B, Osman E, Kim TJ, Patounakis G, Gutmann J, Castelbaum A, Seli E, Jalas C, Scott RT Jr. A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy. Fertil Steril. 2021;115:627–37.

    Article  CAS  Google Scholar 

  40. Schrurs BM, Winston RM, Handyside AH. Preimplantation diagnosis of aneuploidy using fluorescent in-situ hybridization: evaluation using a chromosome 18-specific probe. Hum Reprod. 1993;8:296–301.

    Article  CAS  Google Scholar 

  41. Twisk M, Mastenbroek S, van Wely M, Heineman MJ, Van der Veen F, Repping S. Preimplantation genetic screening for abnormal number of chromosomes (aneuploidies) in in vitro fertilisation or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2006;1:CD005291.

    Google Scholar 

  42. Theobald R, SenGupta S, Harper J. The status of preimplantation genetic testing in the UK and USA. Hum Reprod. 2020;35:986–98.

    Article  Google Scholar 

  43. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. The use of preimplantation genetic testing for aneuploidy (PGT-A): a committee opinion. Fertil Steril. 2018;109:429–36.

    Article  Google Scholar 

  44. Cornelisse S, Zagers M, Kostova E, Fleischer K, van Wely M, Mastenbroek S. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilization. Cochrane Database Syst Rev. 2020;9(9):CD005291.

    Google Scholar 

  45. Griffin DK. Why PGT-A, most likely, improves IVF success. Reprod Biomed Online. 2022;S1472-6483(22):00217–6. https://doi.org/10.1016/j.rbmo.2022.03.022.

    Article  Google Scholar 

  46. Sanders KD, Silvestri G, Gordon T, Griffin DK. Analysis of IVF live birth outcomes with and without preimplantation genetic testing for aneuploidy (PGT-A): UK Human Fertilisation and Embryology Authority data collection 2016–2018. J Assist Reprod Genet. 2021;38:3277–85.

    Article  Google Scholar 

  47. Verpoest W, Staessen C, Bossuyt PM, Goossens V, Altarescu G, Bonduelle M, Devesa M, Eldar-Geva T, Gianaroli L, Griesinger G, Kakourou G, Kokkali G, Liebenthron J, Magli MC, Parriego M, Schmutzler AG, Tobler M, van der Ven K, Geraedts J, Sermon K. 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.

    Article  CAS  Google Scholar 

  48. Munné S, Kaplan B, Frattarelli JL, Gysler M, Child TJ, Nakhuda G, Shamma FN, Silverberg K, Kalista T, Oliver K, Katz-Jaffe M, Wells D, Gordon T, Willman S. Global multicenter randomized controlled trial comparing single embryo transfer with embryo selected by preimplantation genetic screening using next-generation sequencing versus morphologic assessment. Fertil Steril. 2017;108(3):e19.

    Article  Google Scholar 

  49. Yan J, Qin Y, Zhao H, Sun Y, Gong F, Li R, Sun X, Ling X, Li H, Hao C, Tan J, Yang J, Zhu Y, Liu F, Chen D, Wei D, Lu J, Ni T, Zhou W, Wu K, Gao Y, Shi Y, Lu Y, Zhang T, Wu W, Ma X, Ma H, Fu J, Zhang J, Meng Q, Zhang H, Legro RS, Chen ZJ. Live birth with or without preimplantation genetic testing for aneuploidy. N Engl J Med. 2021;385:2047–58.

    Article  CAS  Google Scholar 

  50. Osman EK, Neal SA, Tiegs AW, Hanson BM, Kim JG, Franasiak JM, Scott RT Jr. Consistency in rates of diagnosis of embryonic mosaicism, segmental abnormalities, and “no call” results among experienced embryologists performing preimplantation genetic testing for aneuploidy. F S Rep. 2020;1:119–24.

    Google Scholar 

  51. Lee H, McCulloh DH, Olivares R, Goldstein-Tufaro A, McCaffrey C, Grifo J. Live births after transfer of rebiopsy and revitrification of blastocyst that had “no diagnosis” following trophectoderm biopsy. Fertil Steril. 2016;106:e164.

    Article  Google Scholar 

  52. Brower M, Hill D, Danzer H, Surrey M, Ghadir S, Chang W, Wambach C, Alexander C, Barritt J. “No diagnosis” embryos after PGS should not be discarded: rebiopsy and reanalysis demonstrate the majority are euploid. Fertil Steril. 2014;102:e31.

    Article  Google Scholar 

  53. Kaing A, Kroener L, Brower M, Hill D, Danzer H, Barritt J. Rebiopsy and preimplanation genetic screening (PGS) reanalysis demonstrate the majority of originally “no diagnosis” embryos are euploid with comparable pregnancy rates. Fertil Steril. 2015;104:e277.

    Article  Google Scholar 

  54. Tsigdinos PM. The big IVF add-on racket. In: New York Times. 2019. https://www.nytimes.com. Accessed 27 Jun 2022.

  55. Cui KH. Human fertilisation & embryology authority in UK put red light on preimplantation genetic testing for aneuploidy. In: HEREDITICS 2021. https://www.hereditics.net/uk-put-red-light-on-pgt-a. Accessed 27 Jun 2022.

  56. Tocci A. The unknown human trophectoderm: implication for biopsy at the blastocyst stage. J Assist Reprod Genet. 2020;37:2699–711.

    Article  Google Scholar 

  57. Aoyama N, Kato K. Trophectoderm biopsy for preimplantation genetic test and technical tips: A review. Reprod Med Biol. 2020;19:222–31.

    Article  Google Scholar 

  58. Lu MM, Wen YX, Liu YL, Ding CH, Zhou CQ, Xu YW. Trophectoderm biopsy reduces the level of serum β-human chorionic gonadotropin in early pregnancy. Fertil Steril. 2020;114:801–8.

    Article  CAS  Google Scholar 

  59. Tocci A. Hypothesis: human trophectoderm biopsy downregulates the expression of the placental growth factor gene. J Assist Reprod Genet. 2021;38:2575–8.

    Article  Google Scholar 

  60. Paulson RJ. Preimplantation genetic screening: what is the clinical efficiency? Fertil Steril. 2017;108:228–30.

    Article  Google Scholar 

  61. Makhijani R, Bartels CB, Godiwala P, Bartolucci A, DiLuigi A, Nulsen J, Grow D, Benadiva C, Engmann L. Impact of trophectoderm biopsy on obstetric and perinatal outcomes following frozen–thawed embryo transfer cycles. Hum Reprod. 2021;36:340–8.

    Article  CAS  Google Scholar 

  62. Zhang WY, von Versen-Höynck F, Kapphahn KI, Fleischmann RR, Zhao Q, Baker VL. Maternal and neonatal outcomes associated with trophectoderm biopsy. Fertil Steril. 2019;112:283-290.e2.

    Article  Google Scholar 

  63. Gleicher N, Albertini DF, Barad DH, Homer H, Modi D, Murtinger M, Patrizio P, Orvieto R, Takahashi S, Weghofer A, Ziebe S, Noyes N, International Do No Harm Group in IVF (IDNHG-IVF). The 2019 PGDIS position statement on transfer of mosaic embryos within a context of new information on PGT-A. Reprod Biol Endocrinol. 2020;18:57. https://doi.org/10.1186/s12958-020-00616-w.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Maximilian Murtinger.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Murtinger, M., Schuff, M., Wirleitner, B. et al. Comment on the recent PGDIS Position Statement on the Transfer of Mosaic Embryos 2021. J Assist Reprod Genet 39, 2563–2570 (2022). https://doi.org/10.1007/s10815-022-02620-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-022-02620-y

Keywords

Navigation