Advertisement

Neonatal and clinical outcomes after transfer of a mosaic embryo identified by preimplantation genetic testing for aneuploidies

Published:January 28, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.01.010

      Abstract

      Research question

      Do clinical and neonatal outcomes differ between mosaic embryo transfers (MET) and euploid embryo transfers (EET)?

      Design

      This retrospective cohort study compared the implantation rate, live birth rate (LBR) and miscarriage rate between 513 euploid embryos and 118 mosaic embryos (72 whole chromosome mosaic [WCM], 40 segmental mosaic and six complex mosaic). Blastocysts were analysed using preimplantation genetic testing for aneuploidies with next-generation sequencing, followed by a single vitrified-warmed embryo transfer. Trophectoderm biopsies were classified as mosaic if they had 20–80% abnormal cells.

      Results

      Overall, EET resulted in a significantly higher implantation rate (47.0%) and LBR (40.7%) than MET (implantation rate 39.0%, P = 0.005; LBR 28.8%, P = 0.008) and WCM embryos (implantation rate 37.5%, P = 0.01; LBR 22.2%, P = 0.007) after covariate adjustment. Segmental mosaic embryos had an implantation rate (47.5%) and LBR (45.0%) comparable to those of euploid embryos. Mosaic embryos with a high percentage of aneuploid cells (≥60%) showed a significantly lower LBR (10.5% versus 40.7%, P = 0.03) than euploid embryos after covariate adjustment, with three of the five implantations of mosaic embryos resulting in miscarriage. Neonatal outcomes did not differ significantly between the mosaic and euploid groups. Of the 34 women with a live birth after MET, 13 had a prenatal or postnatal genetic testing result, and no abnormalities were found.

      Conclusions

      Mosaic embryos were associated with a lower LBR, while segmental mosaic embryos had similar clinical outcomes to euploid embryos. Mosaic embryos with a high aneuploidy percentage (≥60%) should be assigned a low transfer priority. Neonatal outcomes did not differ significantly between the euploid and mosaic groups.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Reproductive BioMedicine Online
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Babariya D.
        • Fragouli E.
        • Alfarawati S.
        • Spath K.
        • Wells D.
        The incidence and origin of segmental aneuploidy in human oocytes and preimplantation embryos.
        Hum. Reprod. 2017; 32: 2549-2560
        • Barbash-Hazan S.
        • Frumkin T.
        • Malcov M.
        • Yaron Y.
        • Cohen T.
        • Azem F.
        • Amit A.
        • Ben-Yosef D.
        Preimplantation aneuploidy embryos undergo self-correction in correlation with their developmental potential.
        Fertil. Steril. 2009; 92: 890-896
        • Besser A.G.
        • Blakemore G.K.
        • Del Buono E.J.
        • McCaffrey C.
        • McCulloh D.H.
        • Grifo J.A.
        Four years of prospective mosaic embryo transfer: a single center's experience.
        Fertil. Steril. 2019; 112 (Supplement): e230
        • Bolton H.
        • Graham S.J.
        • Van der Aa N.
        • Kumar P.
        • Theunis K.
        • Fernandez Gallardo E.
        • Voet T.
        • Zernicka-Goetz M.
        Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential.
        Nat. Commun. 2016; 7: 11165
        • Capalbo A.
        • Wright G.
        • Elliott T.
        • Ubaldi F.M.
        • Rienzi L.
        • Nagy Z.P.
        FISH reanalysis of inner cell mass and trophectoderm samples of previously array-CGH screened blastocysts shows high accuracy of diagnosis and no major diagnostic impact of mosaicism at the blastocyst stage.
        Hum. Reprod. 2013; 28: 2298-2307
        • Cram D.S.
        • 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 J.L.
        • Kuliev A.
        PGDIS Position Statement on the Transfer of Mosaic Embryos.
        Reprod. Biomed. Online. 2019; 3 (9): e1-e4
        • Delhanty J.D.
        • Harper J.C.
        • Ao A.
        • Handyside A.H.
        • Winston R.M.
        Multicolour FISH detects frequent chromosomal mosaicism and chaotic. division in normal preimplantation embryos from fertile patients.
        Hum. Genet. 1997; 99: 755-760
        • Fragouli E.
        • Alfarawati S.
        • Spath K.
        • Babariya D.
        • Tarozzi N.
        • Borini A.
        • Wells D.
        Analysis of implantation and ongoing pregnancy rates following the transfer of mosaic diploid- aneuploid blastocysts.
        Hum. Genet. 2017; 136: 805-819
        • Fragouli E.
        • Munné S
        • Wells D.
        The cytogenetic constitution of human blastocysts: insights from comprehensive chromosome screening strategies.
        Hum. Reprod. Update. 2019; 25: 15-33
        • Gardner D.
        • Schoolcraft W.
        In vitro culture of human blastocysts.
        Toward reproductive certainty: fertility and genetics beyond 1999. Parthenon Publishing, London1999: 79-87
        • Garrisi J.
        • Walmsley R.H.
        • Bauckman K.
        • Mendola R.
        • Colls P.
        • Munné S.
        Discordance among serial biopsies of mosaic embryos.
        Fertil. Steril. 2016; 106: e151
        • Girardi L.
        • Serdarogullari M.
        • Patassini C.
        • Poli M.
        • Fabiani M.
        • Caroselli S.
        • Coban O.
        • Findikli N.
        • Kubra Boynukalin F.
        • Bahceci M.
        • Chopra R.
        • Canipari R.
        • Cimadomo D.
        • Rienzi L.
        • Ubaldi F.
        • Hoffmann E.
        • Rubio C.
        • Simon C.
        • Capalbo A.
        Incidence, origin, and predictive model for the detection and clinical management of segmental aneuploidies in human embryos.
        Am. J. Hum. Genet. 2020; 106: 525-534
        • Gleicher N.
        • Albertini D.F.
        • Barad D.H.
        • 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
        • Gleicher N.
        • Metzger J.
        • Croft G.
        • Kushnir V.A.
        • Albertini D.F.
        • Barad D.H.
        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
        • Grati F.R.
        • Malvestiti F.
        • Branca L.
        • Agrati C.
        • Maggi F.
        • Simoni G.
        Chromosomal mosaicism in the fetoplacental unit.
        Best Pract. Res. Clin. Obstet. Gynaecol. 2017; 42: 39-52
        • Greco E.
        • Minasi M.G.
        • Fiorentino F.
        Healthy babies born after intrauterine transfer of mosaic aneuploid blastocyst.
        NEJM. 2015; 373: 2089-2090
        • Malvestiti F.
        • Agrati C.
        • Grimi B.
        • Pompilii E.
        • Izzi C.
        • Martinoni L.
        • Gaetani E.
        • Liuti M.R.
        • Trotta A.
        • Maggi F.
        • Simoni G.
        • Grati F.R.
        Interpreting mosaicism in chorionic villi: results of a monocentric series of 1001 mosaics in chorionic villi with follow-up amniocentesis.
        Prenat. Diagn. 2015; 35: 1117-1127
        • Mantikou E.
        • Wong K.M.
        • Repping S.
        • Mastenbroek S.
        Molecular origin of mitotic aneuploidies in preimplantation embryos.
        Biochim. Biophys. Acta. 2012; 1822: 1921-1930
        • Munné S.
        • Blazek J.
        • Large M.
        • Martinez-Ortiz P.A.
        • Nisson H.
        • Liu E.
        • Tarozzi N.
        • Borini A.
        • Becker A.
        • Zhang J.
        • Maxwell S.
        • Grifo J.
        • Babariya D.
        • Wells D.
        • Fragouli E.
        Detailed investigation into the cytogenetic constitution and pregnancy outcome of replacing mosaic blastocysts detected with the use of high- resolution next-generation sequencing.
        Fertil. Steril. 2017; 108 (e8): 62-71
        • Munné S.
        • Chen S.
        • Colls P.
        • Garrisi J.
        • Zheng X.
        • Cekleniak N.
        • Lenzi M.
        • Hughes P.
        • Fischer J.
        • Garrisi M.
        • Tomkin G.
        • Cohen J.
        Maternal age, morphology, development and chromosome abnormalities in over 6000 cleavage-stage embryos.
        Reprod. Biomed. Online. 2007; 14: 628-634
        • Munné S.
        • Spinella F.
        • Grifo J.
        • Zhang J.
        • Beltran M.P.
        • Fragouli E.
        • Fiorentino F.
        Clinical outcomes after the transfer of blastocysts characterized as mosaic by high resolution Next Generation Sequencing- further insights.
        Eur. J. Med. Genet. 2020; 63103741
        • Munné S.
        • Weier H.U.
        • Grifo J.
        • Cohen J.
        Chromosome mosaicism in human embryos.
        Biol. Reprod. 1994; 51: 373-379
        • Navratil R.
        • Horak J.
        • Hornak M.
        • Kubicek D.
        • Balcova M.
        • Tauwinklova G.
        • Travnik P.
        • Vesela K.
        Concordance of various chromosomal errors among different parts of the embryo and the value of re-biopsy in embryos with segmental aneuploidies.
        Mol. Hum. Reprod. 2020; 26: 269-276
        • Paulson R.J.
        Preimplantation genetic screening: what is the clinical efficiency?.
        Fertil. Steril. 2017; 108: 228-230
        • Pin-Yao Lin.
        • Maw-Sheng Lee.
        • En-Hui Cheng
        Clinical outcomes of single embryo transfer with mosaic embryo: high-grade mosaic or low-grade mosaic embryo, does it matter?.
        Fertil. Steril. 2019; 112 (Supplement): e235-e236
        • Popovic M.
        • Dhaenens L.
        • Boel A.
        • Menten B.
        • Heindryckx B.
        Chromosomal mosaicism in human blastocysts: the ultimate diagnostic dilemma.
        Hum. Reprod. Update. 2020; 26: 450-451
        • Rito T.
        • Naftaly J.
        • Gleicher N.
        • Brivanlou A.
        Self-correction of aneuploidy in human blastocysts and self-organizing gastruloids.
        Fertil. Steril. 2019; 112 (P49): e127
        • Singla S.
        • Iwamoto-Stohl L.K.
        • Zhu M.
        • Zernicka-Goetz M.
        Autophagy-mediated apoptosis eliminates aneuploid cells in a mouse model of chromosome mosaicism.
        Nat. Commun. 2020; 11: 2958
        • Spinella F.
        • Fiorentino F.
        • Biricik A.
        • Bono S.
        • Ruberti A.
        • Cotroneo E.
        • Baldi M.
        • Cursio E.
        • Minasi M.G.
        • Greco E.
        Extent of chromosomal mosaicism influences the clinical outcome of in vitro fertilization treatments.
        Fertil. Steril. 2018; 109: 77-83
        • Taylor T.H.
        • Gitlin S.A.
        • Patrick J.L.
        • Crain J.L.
        • Wilson J.M.
        • Griffin D.K.
        The origin, mechanisms, incidence and clinical consequences of chromosomal mosaicism in humans.
        Hum. Reprod. Update. 2014; 20: 571-581
        • Treff N.R.
        • Franasiak J.M.
        Detection of segmental aneuploidy and mosaicism in the human preimplantation embryo: technical considerations and limitations.
        Fertil. Steril. 2017; 107: 27-31
        • Victor A.R.
        • Griffin D.K.
        • Brake A.J.
        • Tyndall J.C.
        • Murphy A.E.
        • Lepkowsky L.T.
        • Lal A.
        • Zouves C.G.
        • Barnes F.L.
        • McCoy R.C.
        • Viotti M.
        Assessment of aneuploidy concordance between clinical trophectoderm biopsy and blastocyst.
        Hum. Reprod. 2019; 34: 181-192
        • Victor A.R.
        • Tyndall J.C.
        • Brake A.J.
        • Lepkowsky L.T.
        • Murphy A.E.
        • Griffin D.K.
        • McCoy R.C.
        • Barnes F.L.
        • Zouves C.G.
        • Viotti M.
        One hundred mosaic embryos transferred prospectively in a single clinic: exploring when and why they result in healthy pregnancies.
        Feril. Steril. 2019; 111: 280-293
        • Viotti M.
        Preimplantation genetic testing for chromosomal abnormalities: aneuploidy, mosaicism, and structural rearrangements.
        Genes (Basel). 2020; 11: 602
        • Viotti M.
        • Victor A.R.
        • Barnes F.L.
        • Zouves C.G.
        • Besser A.G.
        • Grifo J.A.
        • Cheng E.H.
        • Lee M.S.
        • Horcajadas J.A.
        • Corti L.
        • Fiorentino F.
        • Spinella F.
        • Minasi M.G.
        • Greco E.
        • Munné S.
        Using outcome data from one thousand mosaic embryo transfers to formulate an embryo ranking system for clinical use.
        Fertil. Steril. 2021; 115: 1212-1224
        • Zhang L.
        • Wei D.
        • Zhu Y.
        • Gao Y.
        • Yan J.
        • Chen Z.J.
        Rates of live birth after mosaic embryo transfer compared with euploid embryo transfer.
        J. Assist. Reprod. Genet. 2019; 36: 165-172

      Biography

      Pavel Yakovlev obtained his MD in obstetrics and gynaecology in 2013. He obtained his PhD at the D.O. Ott Research Institute of Obstetrics, Gynecology, and Reproductive Medicine, Saint Petersburg, Russian Federation in 2018. He further specialized in infertility and reproductive medicine at the ART unit of a private IVF centre.
      Key message
      Mosaic embryo transfers are associated with a lower live birth rate. Segmental mosaic embryos show similar clinical outcomes to euploid embryos. Gestational age, birthweight, rates of preterm birth and low birthweight are similar between the mosaic and euploid groups. After euploid embryos, segmental mosaic embryos with low-level mosaicism should be prioritized for transfer.