Download PDF
CC BY 4.0 · Rev Bras Ginecol Obstet 2022; 44(07): 721-722
DOI: 10.1055/s-0042-1744291
Letter to the Editor

Great Challenges Remain for niPGT-A Reliability

Restam grandes desafios para a confiabilidade do niPGT-A
Bruno Ramalho de Carvalho 
1   Bruno Ramalho Reprodução Humana, Brasília, DF, Brazil
› Author Affiliations
› Further Information
   Permissions and Reprints

In the case report First Baby Born in Brazil after Simultaneous Diagnosis through Non-Invasive and Conventional PGT-A (Rev Bras Ginecol Obstet. 2021;43[11]), Kulmann et al.[1] present noninvasive preimplantation genetic test for aneuploidies (niPGT-A) as an alternative to conventional PGT-A. Those who defend the new technology assume that the biopsy of the trophectoderm could affect embryo health and its implantation potential. Also, the proposed technique assumes that the cell-free DNA found in the spent culture media (SCM) represents the genetic status of the embryo. However, as highlighted in their Introduction, the concordance rates between trophectoderm and SCM samples have been reported to greatly vary among studies, from insufficient ∼ 30% (Vera-Rodriguez et al., 2018)[2] to amazing ∼ 94% (Huang et al., 2019).[3] A critical look at this discrepancy leads the observer to realize that a lot of progress needs to be made before introducing that technique into the routine of the reproductive clinic.

Two studies by Rubio et al. (2019, 2020)[4] [5] seem to be the pillars of this case report. The second study (Rubio et al., 2020)[5] is really interesting, since it included 1,301 human blastocysts, with promising concordance rates demonstrated. But uncertainties on the need to extend embryo culture to days 6 and 7, and the theoretical loss on reproductive potential of such blastocysts compared to day-5 ones are still concerning. Even with low-quality evidence, some studies suggest better clinical pregnancy and live birth rates in favor of day 5 blastocysts.[6] [7] [8] [9] [10] [11]

Considering the expectation of presenting an accurate test, it seems intriguing to find out that total concordance between conventional and niPGT-A occurred only for 3/7 blastocysts in the presented case. In real life, partial concordance is a non-encouraging result, and I would dare to say that it is as inutile as a total discordance. Of note, other recent studies present frustrating concordance rates for autosomes or sex chromosomes between trophectoderm or inner cell mass, and SCM analyses.[12] [13]

Finally, it is important to highlight the optimization of culture conditions, SCM retrieval, DNA isolation, and amplification protocols as great challenges for niPGT-A reliability. To date, we must be concerned about the theoretical high risk of maternal contamination.[14] [15] Fortunately, the authors indicate that niPGT-A is not ready to replace conventional technique in routine and that further studies are needed to lead science in the best direction.



Publication History

Received: 04 January 2022

Accepted: 13 January 2022

Article published online:
07 June 2022

© 2022. Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Revinter Publicações Ltda.
Rua do Matoso 170, Rio de Janeiro, RJ, CEP 20270-135, Brazil

 

  • References

  • 1 Kulmann MIR, Riboldi M, Martello C, Bos-Mikich A, Frantz G, Dutra C, Donatti LM, Oliveira N, Frantz N. First Baby Born in Brazil after Simultaneous Diagnosis through Non-Invasive and Conventional PGT-A. Rev Bras Ginecol Obstet 2021 Nov;43(11):878–882. English. doi: 10.1055/s-0041-1736302. Epub 2021 Dec 6. PMID: 34872147
    PubMedGoogle Scholar
  • 2 Vera-Rodriguez M, Diez-Juan A, Jimenez-Almazan J, Martinez S, Navarro R, Peinado V, Mercader A, Meseguer M, Blesa D, Moreno I, Valbuena D, Rubio C, Simon C. Origin and composition of cell-free DNA in spent medium from human embryo culture during preimplantation development. Hum Reprod 2018 Apr 1;33(4):745–756. doi: 10.1093/humrep/dey028. PMID: 29471395
    PubMedGoogle Scholar
  • 3 Huang L, Bogale B, Tang Y, Lu S, Xie XS, Racowsky C. Noninvasive preimplantation genetic testing for aneuploidy in spent medium may be more reliable than trophectoderm biopsy. Proc Natl Acad Sci U S A 2019 Jul 9;116(28):14105–14112. doi: 10.1073/pnas.1907472116. Epub 2019 Jun 24. PMID: 31235575; PMCID: PMC6628824
    PubMedGoogle Scholar
  • 4 Shapiro BS, Richter KS, Harris DC, Daneshmand ST. A comparison of day 5 and day 6 blastocyst transfers. Fertil Steril 2001 Jun;75(6):1126–30. doi: 10.1016/s0015-0282(01)01771-x. PMID: 11384637
    PubMedGoogle Scholar
  • 5 Barrenetxea G, López de Larruzea A, Ganzabal T, Jiménez R, Carbonero K, Mandiola M. Blastocyst culture after repeated failure of cleavage-stage embryo transfers: a comparison of day 5 and day 6 transfers. Fertil Steril 2005 Jan;83(1):49–53. doi: 10.1016/j.fertnstert.2004.06.049. PMID: 15652886
    PubMedGoogle Scholar
  • 6 Haas J, Meriano J, Laskin C, Bentov Y, Barzilay E, Casper RF, Cadesky K. Clinical pregnancy rate following frozen embryo transfer is higher with blastocysts vitrified on day 5 than on day 6. J Assist Reprod Genet 2016 Dec;33(12):1553–1557. doi: 10.1007/s10815-016-0818-x. Epub 2016 Oct 6. PMID: 27714479; PMCID: PMC5171889
    PubMedGoogle Scholar
  • 7 Kaing A, Kroener LL, Tassin R, Li M, Liu L, Buyalos R, Hubert G, Shamonki M. Earlier day of blastocyst development is predictive of embryonic euploidy across all ages: essential data for physician decision-making and counseling patients. J Assist Reprod Genet 2018 Jan;35(1):119–125. doi: 10.1007/s10815-017-1038-8. Epub 2017 Sep 11. PMID: 28894983; PMCID: PMC5758461
    PubMedGoogle Scholar
  • 8 Tubbing A, Shaw-Jackson C, Ameye L, Colin J, Rozenberg S, Autin C. Increased live births after day 5 versus day 6 transfers of vitrified-warmed blastocysts. J Assist Reprod Genet 2018 Mar;35(3):417–424. doi: 10.1007/s10815-017-1097-x. Epub 2017 Dec 4. PMID: 29204868; PMCID: PMC5904067
    PubMedGoogle Scholar
  • 9 Sciorio R, Thong KJ, Pickering SJ. Increased pregnancy outcome after day 5 versus day 6 transfers of human vitrified-warmed blastocysts. Zygote 2019 Oct;27(5):279–284. doi: 10.1017/S0967199419000273. Epub 2019 Aug 15. PMID: 31412960
    PubMedGoogle Scholar
  • 10 Rubio C, Rienzi L, Navarro-Sánchez L, Cimadomo D, García-Pascual CM, Albricci L, Soscia D, Valbuena D, Capalbo A, Ubaldi F, Simón C. Embryonic cell-free DNA versus trophectoderm biopsy for aneuploidy testing: concordance rate and clinical implications. Fertil Steril 2019 Sep;112(3):510–519. doi: 10.1016/j.fertnstert.2019.04.038. Epub 2019 Jun 11. PMID: 31200971
    PubMedGoogle Scholar
  • 11 Rubio C, Navarro-Sánchez L, García-Pascual CM, Ocali O, Cimadomo D, Venier W, Barroso G, Kopcow L, Bahçeci M, Kulmann MIR, López L, De la Fuente E, Navarro R, Valbuena D, Sakkas D, Rienzi L, Simón C. Multicenter prospective study of concordance between embryonic cell-free DNA and trophectoderm biopsies from 1301 human blastocysts. Am J Obstet Gynecol 2020 Nov;223(5):751.e1–751.e13. doi: 10.1016/j.ajog.2020.04.035. Epub 2020 May 26. PMID: 32470458
    PubMedGoogle Scholar
  • 12 Tšuiko O, Zhigalina DI, Jatsenko T, Skryabin NA, Kanbekova OR, Artyukhova VG, Svetlakov AV, Teearu K, Trošin A, Salumets A, Kurg A, Lebedev IN. Karyotype of the blastocoel fluid demonstrates low concordance with both trophectoderm and inner cell mass. Fertil Steril 2018 Jun;109(6):1127–1134.e1. doi: 10.1016/j.fertnstert.2018.02.008. PMID: 29935648
    PubMedGoogle Scholar
  • 13 Yeung QSY, Zhang YX, Chung JPW, Lui WT, Kwok YKY, Gui B, Kong GWS, Cao Y, Li TC, Choy KW. A prospective study of non-invasive preimplantation genetic testing for aneuploidies (NiPGT-A) using next-generation sequencing (NGS) on spent culture media (SCM). J Assist Reprod Genet 2019 Aug;36(8):1609–1621. doi: 10.1007/s10815-019-01517-7. Epub 2019 Jul 10. PMID: 31292818; PMCID: PMC6707994
    PubMedGoogle Scholar
  • 14 Capalbo A, Romanelli V, Patassini C, Poli M, Girardi L, Giancani A, Stoppa M, Cimadomo D, Ubaldi FM, Rienzi L. Diagnostic efficacy of blastocoel fluid and spent media as sources of DNA for preimplantation genetic testing in standard clinical conditions. Fertil Steril 2018 Oct;110(5):870–879.e5. doi: 10.1016/j.fertnstert.2018.05.031. Erratum in: Fertil Steril. 2019 Jan;111(1):194. PMID: 30316433
    PubMedGoogle Scholar
  • 15 Leaver M, Wells D. Non-invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics?. Hum Reprod Update 2020 Jan 1;26(1):16–42. doi: 10.1093/humupd/dmz033. PMID: 31774124
    PubMedGoogle Scholar