Preimplantation genetic screening (PGS) still in search of a clinical application: a systematic review

Abstract

Only a few years ago the American Society of Assisted Reproductive Medicine (ASRM), the European Society for Human Reproduction and Embryology (ESHRE) and the British Fertility Society declared preimplantation genetic screening (PGS#1) ineffective in improving in vitro fertilization (IVF) pregnancy rates and in reducing miscarriage rates. A presumably upgraded form of the procedure (PGS#2) has recently been reintroduced, and is here assessed in a systematic review. PGS#2 in comparison to PGS#1 is characterized by: (i) trophectoderm biopsy on day 5/6 embryos in place of day-3 embryo biopsy; and (ii) fluorescence in-situ hybridization (FISH) of limited chromosome numbers is replaced by techniques, allowing aneuploidy assessments of all 24 chromosome pairs. Reviewing the literature, we were unable to identify properly conducted prospective clinical trials in which IVF outcomes were assessed based on “intent to treat”. Whether PGS#2 improves IVF outcomes can, therefore, not be determined. Reassessments of data, alleged to support the efficacy of PGS#2, indeed, suggest the opposite. Like with PGS#1, the introduction of PGS#2 into unrestricted IVF practice again appears premature, and threatens to repeat the PGS#1 experience, when thousands of women experienced reductions in IVF pregnancy chances, while expecting improvements. PGS#2 is an unproven and still experimental procedure, which, until evidence suggests otherwise, should only be offered under study conditions, and with appropriate informed consents.

Genetic Considerations in Recurrent Pregnancy Loss

“…Unfortunately, there is still an absence of adequate data to support the concept that utilization of new PGS techniques improves outcomes in recurrent miscarriage (Gleicher et al 2014). Although the newest PGS methodologies improve the accuracy of aneuploidy diagnosis when compared with older methods, investigations that examine how these new variables affect the target population of patients who would most benefit from PGS are lacking (Gleicher and Barad 2012).…”

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

“…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.…”

“…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).…”

“…

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 mosaicism

Though 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].

…”

“…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.…”