Should preimplantation genetic screening (PGS) be implemented to routine IVF practice?

Abstract

As compared to day 3 blastomere (spp) biopsy followed by fluorescence in situ hybridization (FISH), PGS 1.0 [1], the utilization of trophectoderm biopsy (days 5-6 embryos) combined with comprehensive chromosome screening (CCS) tests for embryonic aneuploidy, PGS 2.0, has been suggested to improve in vitro fertilization (IVF) outcome [2], though not without criticisms [3,4]. Here, we draw attention to several underlying factors that will influence decisions to employ PGS 2.0 in routine clinical practice. PGS and mosaicismThough excessive mosaicism in cleavage stage in comparison to blastocyst stage embryos was given as a principal reason for the potential superiority of PGS 2.0 over PGS 1.0 [5], mosaicism has been reported in cleavage-and blastocyst-stage embryos derived from IVF [6], with mitotic rather than meiotic errors as main causes [7]. Liu et al. [8] reported that 69 % of blastocyst-stage embryos from women of advanced age are mosaic for inner cell mass as well as trophectoderm, while Johnson et al. [9] reported that in younger women only 20 % of blastocyst stage embryos are aneuploid, with a majority in addition presenting with only one or two structural chromosome abnormalities. Their observation would suggest at younger ages a lower, but still, clinically critical level of mosaicism at the blastocyst stage [6]. These data were to a degree confirmed by Munné's group who at the 2015 ASRM meeting reported clearly increasing aneuploidy rates with advancing female age but surprisingly similar mosaicism rates at all ages at an average of 30.2 %, with actually the youngest women below age 35, quite surprisingly, demonstrating highest rates among all age groups at 33.2 % [10].In assessing the potential clinical value of PGS 2.0 in improving IVF outcomes, before discussing costs, complexities, and the obvious lack of properly conducted prospective clinical trials based on Bintent to treat^ [3], one really has to assess whether the basic biology of the early human embryos allows for the accurate diagnosis of euploidy versus aneuploidy based on as single trophectoderm biopsy at blastocyst stage.In this issue of JARG, Tortoriello et al. report highly divergent outcomes when trophectoderm biopsies from the same embryos were referred for PGS 2.0, at different laboratories, using varying assay platforms [11]. Chromosomal analyses after two sequential trophectoderm biopsies from the same embryos revealed only 11 % (3/27) ploidy detection concordance between microarray-based comparative genomic hybridization (aCGH) and next-generation sequencing (NGS). Moreover, 9/27 (33 %) of originally reported aneuploid embryos, upon repeat assessment, were found to be euploid. The predicted mosaicism rate was 51 % (19/37).Such findings can have only three possible explanations: either laboratory techniques applied in one or more of the utilized PGS laboratories are disappointingly inaccurate; an inherent lack of concordance between platforms; or individual trophectoderm biopsies submitted for analyses differed in Capsule Concerns r...

Human embryo mosaicism: did we drop the ball on chromosomal testing?

“…In well-informed patients with lethal aneuploidy/mosaic embryos and no euploid options, transfer of aneuploid or mosaic embryos may be warranted. This view is based upon the present literature, suggesting that a diagnosis of an aneuploid/ mosaic Babnormal^embryo is not always correct, or if it is correct, mosaicism detected at the blastocyst stage may not manifest as such in a live born [29][30][31]. While testing methodology is able to identify definitely normal and grossly abnormal chromosome complements in most cases, there is a significant, not well-delineated, gray zone into which many chromosome-screening results fall, mostly attributable to the problem of mosaicism.…”

Embryo wastage rates remain high in assisted reproductive technology (ART): a look at the trends from 2004–2013 in the USA

“…In the group of women older than 40 years studies with PGS on trophoblast cells have shown that a large number of embryos produced are chromosomally abnormal, thus explaining at least in part why there is such high BEmbryo Wastage^in this age group [16,34]. However, it remains to be seen whether this technique will ultimately lead to a significant improvement in live birth rate since it is still error-prone with the risk of discarding embryos wrongly diagnosed as aneuploidy because of mosaicism [21][22][23]. Other barriers such as the cost, including the possible need to cryopreserve embryos and defer transfer, and invasiveness of the biopsy and any potential long term effects also need to be addressed.…”

“…Recent improvements in pre-implantation genetic screening (PGS) techniques for identifying normal euploid embryos have been associated with higher pregnancy and delivery rates when analyzed per transfer [15][16][17]; however, several barriers to its widespread use still exist, including cost and particularly the lack of unequivocal evidence that its use improves pregnancy and live birth rates, particularly for patients with few embryos available for testing, due to the presence of high rates of mosaicism in the trophoblast cells [18][19][20][21][22][23]. Other studies have reported on the use of proteomics and metabolomics to identify factors in embryo culture media that may be predictive of embryo competence or assessing gene expression in cumulus cells; however, even these methods are still inefficient and not ready yet for clinical application [24][25][26][27].…”

Improving IVF: is there a limit to our ability to manipulate human biology?

“…All are invasive, not completely reliable, costly, and likely result in the non-transfer/discard of some viable embryos. If one proposes pre-implantation genetic screening (PGS) for all blastocysts, there is now sufficient data to demonstrate that PGS is neither sensitive nor specific enough to select all euploid embryos, and there is accumulating data to demonstrate that this could ironically even lower live birth rates [10][11][12][13][14][15][16]. Indeed offering sophisticated embryo PGS testing (via array CGH or SNP or qPCR or next-generation sequencing (NGS)) has been shown to be impacted by high rates of trophectoderm embryo mosaicism [11,13,14], making the diagnostic accuracy very challenging with the risk of discarding some normal embryos that were incorrectly diagnosed as abnormal.…”

“…Indeed offering sophisticated embryo PGS testing (via array CGH or SNP or qPCR or next-generation sequencing (NGS)) has been shown to be impacted by high rates of trophectoderm embryo mosaicism [11,13,14], making the diagnostic accuracy very challenging with the risk of discarding some normal embryos that were incorrectly diagnosed as abnormal. Therefore, the overall pregnancy rate might be decreased rather than increased [10,14,16]. But, all these methods are only selection, and not improvement of oocytes or embryos.…”