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Soler N, Bautista-Llàcer R, Escrich L, Oller A, Grau N, Tena R, et al. Rescuing monopronucleated-derived human blastocysts: a model to study chromosomal topography and fingerprinting. Fertil Steril. In press.
) in “Rescuing monopronuclear-derived human blastocysts: a model to study chromosomal topography and fingerprinting” used a cohort of discarded monopronuclear-derived blastocyst (MNBs) to show that:•Blastocysts from 1PN can be euploid with diparental genomes; however, a significant proportion of euploid MNB will have maternal uniparental disomy.
•1PN blasts offer novel alternatives to study mosaicism concordance between trophectoderm (TE) and inner cell mass (ICM) biopsies.
For their prospective cohort study, the investigators included 1084 1PN embryos initially, of which 199 (18.4%) reached the blastocyst stage. Of these 199, 89 MNBs were reported and included for study. These 89 MNBs were divided into 3 sets for analysis, with the aim to determine the ploidy and parental origin of the TE and ICM samples. A total of 28 MNBs were analyzed with florescent in situ hybridization as whole embryos for ploidy status. The next 2 embryos groups then were biopsied into 2 TE and 1 ICM samples. These were analyzed comparatively with florescent in situ hybridization (18,XY), single nucleotide polymorphism fingerprinting for parental origin, and next generation sequencing.
In set 1, the investigators found 64.3% MNBs were diploid vs. 21.4% mosaic and 14.3% haploid. In set 2, 44.1% were euploid vs. 44.1% aneuploid, and 11.8% showed segmental aneuploidy. In set 3, 73.3% were biparental vs. 26.7% uniparental. Of the 26.7% uniparental embryos, all genetic material was of maternal origin.
Addressing mosaicism, the PGT testing of these 1PN embryos adds to the evolving mosaicism debate. With the investigators’ 3-pronged approach for simultaneous ICM and 2 TE biopsies, they gathered a robust cohort of data for next generation sequencing analysis and confirmed what has been shown in 2PN-derived blastocysts. Prior studies demonstrate a modestly high concordance for mosaicism between TE and ICM biopsies, whether they were embryos serially biopsied from cleavage to blastocyst stage or were donated noneuploid blastocysts undergoing >30 intratissue biopsies (3Gleicher 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.). The investigators here confirm what is known or suspected: TE biopsy is a helpful but not necessary tool in identifying a likely reproductively competent embryo and that concordance rates approach 57%–78% between the ICM and TE.Historically, with conventional in vitro fertilization, the 1PN embryo classification was made incidentally at the time of fertilization check (4Nagy Z.P. Janssenswillen C. Janssens R. De Vos A. Staessen C. Van de Velde H. et al.Timing of oocyte activation, pronucleus formation and cleavage in humans after intracytoplasmic sperm injection (ICSI) with testicular spermatozoa and after ICSI or in-vitro fertilization on sibling oocytes with ejaculated spermatozoa.). Continued observation resulting in blastulation could be associated with early syngamy and the embryo graded objectively against other counterparts without further bias. Fresh and frozen embryo transfers presumably were performed using a number of 1PN-derived blastocysts over the course of in vitro fertilization history. Risks, such as parthenogenesis, androgenesis, and gynogenesis, were known but assumed to be minor and likely resulted in failed implantation or miscarriage.With the advent of time-lapse incubation and prevalent use of intracytoplasmic sperm injection, a new wealth of data has emerged regarding embryo development from fertilization to blastulation. Included in these data is better characterization of 1PN-derived blastocysts and their developmental probability and trajectory. Armed with the knowledge that a small portion of blastocysts once thought to be “normal” may be 1PN-derived, further questions arise regarding the safety and reproductive potential of these embryos. Beyond PGT testing for euploidy, biparental diploidy verification becomes the next direction for exploration, as shown by Soler et al. (2Soler N, Bautista-Llàcer R, Escrich L, Oller A, Grau N, Tena R, et al. Rescuing monopronucleated-derived human blastocysts: a model to study chromosomal topography and fingerprinting. Fertil Steril. In press.
).Is this clinically necessary for improvement in clinical outcomes, especially given that we have been potentially transferring untested 1PN-derived blastocysts for years? Or is this need for further testing driven by the litigious nature of today’s practice of medicine? Clinical outcomes redemonstrate what is known—that these blastocysts can result in viable offspring; they also offer data that uniparental disomy and chromosomal arrangements may put patients at risk for gestational trophoblastic disease, which are small but theoretical (5Xie P.Y. Tang Y. Hu L. Ouyang Q. Gu Y.F. Gong F. et al.Identification of biparental and diploid blastocysts from monopronuclear zygotes with the use of a single-nucleotide polymorphism array.).Soler et al. (2Soler N, Bautista-Llàcer R, Escrich L, Oller A, Grau N, Tena R, et al. Rescuing monopronucleated-derived human blastocysts: a model to study chromosomal topography and fingerprinting. Fertil Steril. In press.
) add data to the ongoing mosaic discussion with their concordance between TE and ICM biopsies. Their findings also confirm the continued lack of knowledge regarding unspecified pathways between mono pronuclear-derived embryos and their ability to produce the live birth of a healthy child. Although this occurrence likely represents the minority of outcomes, reproductive potential in these zygotes exists and can be leveraged for patients when no other options are available. Just as in the transfer of mosaic embryos, the transfer of a monopronuclear-derived embryo comes with the risk of an unknown outcome. Within the appropriate clinical scenario with adequate counseling, do we need more testing?ReferencesLensen S. Shreeve N. Barnhart K.T. Gibreel A. Ng E.H.Y. Moffett A.In vitro fertilization add-ons for the endometrium: it doesn’t add-up.
Fertil Steril. 112: 987-993Soler N, Bautista-Llàcer R, Escrich L, Oller A, Grau N, Tena R, et al. Rescuing monopronucleated-derived human blastocysts: a model to study chromosomal topography and fingerprinting. Fertil Steril. In press.
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. 15: 33Nagy Z.P. Janssenswillen C. Janssens R. De Vos A. Staessen C. Van de Velde H. et al.Timing of oocyte activation, pronucleus formation and cleavage in humans after intracytoplasmic sperm injection (ICSI) with testicular spermatozoa and after ICSI or in-vitro fertilization on sibling oocytes with ejaculated spermatozoa.
Hum Reprod. 13: 1606-1612Xie P.Y. Tang Y. Hu L. Ouyang Q. Gu Y.F. Gong F. et al.Identification of biparental and diploid blastocysts from monopronuclear zygotes with the use of a single-nucleotide polymorphism array.
Fertil Steril. 110: 545-554.e5Article InfoPublication HistoryPublished online: July 07, 2021
Publication stageIn Press Corrected ProofFootnotesYou can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/33162
IdentificationDOI: https://doi.org/10.1016/j.fertnstert.2021.06.005
Copyright©2021 American Society for Reproductive Medicine, Published by Elsevier Inc.
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