PGDIS Position Statement on the Transfer of Mosaic Embryos 2019

Cram, David S.; Leigh, D. A.; Handyside, Alan H.; Rechitsky, L.; Xu, Kangpu; Harton, G.; Grifo, James A.; Rubio, Carmen; Fragouli, Elpida; Kahraman, Semra; Forman, Eric J.; Katz‐Jaffe, Mandy G.; Tempest, Helen G.; Thornhill, Alan R.; Strom, Charles M.; Escudero, T.; Qiao, Jie; Munné, Santiago; Jl, Simpson; Kuliev, Anver

doi:10.1016/j.rbmo.2019.06.012

Cited by 94 publications

(106 citation statements)

References 16 publications

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“…The few rates of mosaicism reported in the included studies are in line with previous studies, showing that mosaic embryos constitute a small but potentially significant part of the embryo cohort, with potential to produce liveborn offspring . In general, if aneuploidy screening is performed, and there are no euploid embryos available, mosaic embryos could be prioritized based on the chromosome(s) affected by aneuploidy, the type of aneuploidy and the degree of mosaicism detected, preferably according to guidelines provided by the Preimplantation Genetic Diagnosis International Society (PGDIS) and Controversies in Preconception, Preimplantation and Prenatal Diagnosis (COGEN) . In general, each center utilizing PGT‐A should develop evidence‐based guidelines for embryo prioritization to ensure standardization of the treatment and transparency to both patients and piers.…”

Section: Discussionsupporting

confidence: 76%

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

Toft

Ingerslev

Kesmodel

et al. 2020

Acta Obstet Gynecol Scand

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Introduction:In assisted reproductive technology, aneuploidy is considered a primary cause of failed embryo implantation. This has led to the implementation of preimplantation genetic testing for aneuploidy in some clinics. The prevalence of aneuploidy and the use of aneuploidy screening during preimplantation genetic testing for inherited disorders has not previously been reviewed. Here, we systematically review the literature to investigate the prevalence of aneuploidy in blastocysts derived from patients carrying or affected by an inherited disorder, and whether screening for aneuploidy improves clinical outcomes. Material and methods:PubMed and Embase were searched for articles describing preimplantation genetic testing for monogenic disorders and/or structural rearrangements in combination with preimplantation genetic testing for aneuploidy. Original articles reporting aneuploidy rates at the blastocyst stage and/or clinical outcomes (positive human chorionic gonadotropin, gestational sacs/implantation rate, fetal heartbeat/clinical pregnancy, ongoing pregnancy, miscarriage, or live birth/delivery rate on a per transfer basis) were included. Case studies were excluded. Results:Of the 26 identified studies, none were randomized controlled trials, three were historical cohort studies with a reference group not receiving aneuploidy screening, and the remaining were case series. In weighted analysis, 34.1% of 7749 blastocysts were aneuploid. Screening for aneuploidy reduced the proportion of embryos suitable for transfer, thereby increasing the risk of experiencing a cycle without transferable embryos. In pooled analysis the percentage of embryos suitable for transfer was reduced from 57.5% to 37.2% following screening for aneuploidy. Among historical cohort studies, one reported significantly improved pregnancy and birth rates but did | 697 TOFT eT al. K E Y W O R D Saneuploidy screening, clinical outcomes, comprehensive chromosome screening, preimplantation genetic diagnosis-preimplantation screening, preimplantation genetic testing, systematic review Key messageOne-third of embryos derived from patients carrying or affected by an inherited disorder are aneuploid. Hence, prioritizing embryos by ploidy status should in theory improve clinical success rates per transfer. The design and quality of the current available data do not allow a conclusion to be drawn with respect to a clinical effect.

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Section: Discussionsupporting

confidence: 76%

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

Toft

Ingerslev

Kesmodel

et al. 2020

Acta Obstet Gynecol Scand

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show abstract

“…One key limitation of most previous studies of aneuploidy in human preimplantation embryos has been their reliance on biopsies of one or few cells. Many studies have adopted an operational definition of mosaicism based on PGT-A results that are intermediate between those expected of uniform euploid and uniform aneuploid biopsies (Cram et al 2019) . This narrow definition of mosaicism ignores the possibility of aneuploidy among the non-biopsied cells that compose the rest of the embryo.…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Starostik

Sosina

McCoy

2020

Preprint

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Less than half of human zygotes survive to live birth, primarily due to aneuploidies of meiotic or mitotic origin. Mitotic errors lead to chromosomal mosaicism, defined by multiple cell lineages with distinct chromosome complements. The incidence and fitness consequences of chromosomal mosaicism in human embryos remain controversial, with most previous studies based on bulk DNA assays or comparisons of multiple biopsies of a few embryonic cells. Single-cell genomic data provide an opportunity to quantify mosaicism on an embryo-wide scale. To this end, we extended an approach to infer aneuploidies based on chromosome dosage-associated changes in gene expression by integrating signatures of allelic imbalance. We applied this method to published single-cell RNA sequencing data from 74 disaggregated human embryos, spanning the morula to blastocyst stages. Our analysis revealed widespread mosaic aneuploidies across preimplantation development, with 59 of 74 (80%) embryos harboring at least one aneuploid cell (1% FDR). By clustering copy number calls, we reconstructed histories of chromosome mis-segregation, distinguishing meiotic and early mitotic errors from those occurring after lineage differentiation. We observed no significant enrichment of aneuploid cells in the trophectoderm compared to the inner cell mass, though we do detect such an enrichment in published data from later post-implantation stages. Finally, we observed that aneuploid cells exhibit upregulation of immune response genes, as well as downregulation of genes involved in proliferation, metabolism, and protein processing, consistent with stress responses previously documented in other stages and systems. Together, our work provides a high-resolution view of aneuploidy in preimplantation embryos and supports the conclusion that low-level mosaicism is a common feature of early human development.

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“…[6][7][8] That is, embryos classified as mosaic aneuploid may actually be uniform aneuploid in a large percentage of cases, leading the observed reduction in clinical success rates. 11,15 Conversely, many observations of successful outcomes following transfer of embryos classified as mosaic have also been made. 17,18 While some have argued that this is evidence of 'selfcorrection', 19 others have suggested that these embryos may have been misclassified as mosaic and were actually uniformly euploid.…”

Section: Introductionmentioning

confidence: 99%

Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data

Marín

Treff

2020

Prenatal Diagnosis

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Preimplantation genetic testing for aneuploidy (PGT-A) reduces miscarriage risk, increases the success of IVF, shortens time to pregnancy, and reduces multiple gestation rates without compromising outcomes. The progression of PGT-A has included common application of next-generation sequencing (NGS) from single nucleotide polymorphism microarray, quantitative real-time PCR, and array comparative hybridization platforms of analysis. Additional putative advances in PGT-A capability include classifying embryos as mosaic and predicting the presence of segmental imbalance. A critical component in the process of technical validation of these advancements involves evaluation of concordance between reanalysis results and initial testing results. While many independent studies have investigated the concordance of results obtained from the remaining embryo with the original PGT-A diagnosis, compilation and systematic analysis of published data has not been performed. Here, we review results from 26 primary research articles describing concordance in 1271 human blastocysts from 2260 pairwise comparisons. Results illustrate significantly higher discordance from PGT-A methods which utilize NGS and include prediction of mosaicism or segmental imbalance. These results suggest caution when considering new iterations PGT-A.

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PGDIS Position Statement on the Transfer of Mosaic Embryos 2019

Cited by 94 publications

References 16 publications

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

A systematic review on concurrent aneuploidy screening and preimplantation genetic testing for hereditary disorders: What is the prevalence of aneuploidy and is there a clinical effect from aneuploidy screening?

Single-cell analysis of human embryos reveals diverse patterns of aneuploidy and mosaicism

Preimplantation genetic testing for aneuploidy: A review of published blastocyst reanalysis concordance data

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