Preimplantation genetic testing for aneuploidy (PGT-A)-finally revealed.

Abstract

Natural fecundity of women decreases gradually and more rapidly after age 37 years. This decrease is accompanied by rising aneuploidy rates of pregnancies and can also be observed in products of conception of spontaneous abortions [1]. These observations lead to the hypothesis that transferring only euploid embryos in association with in vitro fertilization (IVF) might decrease miscarriages and increase live birth rates (LBRs), attesting-procedure now called preimplantation genetic testing (of embryos) for aneuploidy (PGT-A), until recently generally referred to as preimplantation genetic screening (PGS). Verlinsky and Kuliev further proposed that the removal of all aneuploid embryos prior to transfer would improve implantation rates and live birth rates and suggested that the diagnosis be made via biopsy of both polar bodies [2]. Polar body biopsy, however, proved technically too difficult for general IVF practice and would have revealed only meiotic aneuploidies. The procedure was, therefore, initially performed biopsying 1–2 blastomeres of day-3 cleavage-stage embryos, often given the acronym PGS 1.0. This form of embryo testing has, since, been replaced by PGS 2.0, with the embryo biopsy being moved from day-3 cleavage stage to trophectoderm biopsy of blastocyst-stage embryos on days 5–6 after fertilization. In July 2016, another major change in PGT-A was announced, for the first time introducing the concept pf “mosaic” embryos (also called PGS 3.) (Preimplantation Genetic Diagnosis Society (PGDIS) position statement on chromosome mosaicism and preimplantation aneuploidy testing at the blastocyst stage, Chicago, IL; July 19, 2016 http://pgdis.org/docs/newsletter_071816.html). After almost two decades of PGS 1.0 through PGS 3.0, the procedure has, however, still been unable to demonstrate the promised improvements in live births and anticipated declines in miscarriage rates [3–5]. Several studies, even summarized in a meta-analysis [6], have claimed improved clinical IVF outcomes following PGT-A. They, however, reported IVF outcomes with reference point embryo transfer rather than cycle start (intent-to-treat) and, therefore, by excluding poorer prognosis patients, were severely biased [7]. The STAR study This is why the recently published STAR study [8] attracted special attention: It avoided at least some patient selection biases of earlier fresh-cycle studies by being prospectively randomized and reporting on IVF outcomes from transfers of only single frozen-thawed embryos at blastocyst stage. That qualifying patients required having at least two frozen embryos from a prior fresh cycle, however, still demonstrates a favorable patient selection bias. Importantly, however, the study at least analyzed outcomes for study and control groups with reference point initial first cycle start [7]. In doing so, the study convincingly revealed no improvements in live birth rates and no reduction in miscarriage rates when cycle outcomes were compared in singe-embryo transfers at blastocyst stage between women, randomized to either PGT-A or only morphological assessments of a single embryo prior to transfers [8]. For no declared reason, the authors then, however, performed a post hoc sub-group analysis based on age and reported, between ages 35 and 40 years, that PGT-A, still, offered significant increases in ongoing pregnancy rate (OPR). In the discussion of their manuscript, they emphasized this finding as “continuous evidence” for the clinical utility of PGT-A in at least that age group. Again, in contrast to the overall study that had been performed with reference point cycle start (intent-to-treat), their post hoc analysis was performed with reference embryo transfer and, therefore, statistically suspect. Because results of the STAR study are already impacting IVF practice worldwide, we here offer a statistically corrected analysis of the STAR study, reaffirming the study’s overall findings by refuting the results of the post hoc analysis and its interpretation by the authors, claimed benefits for PGT-A utilization for all age groups.