Preimplantation Genetic Testing for Aneuploidy – a Castle Built on Sand

Abstract

Based on claims of better live birth and reduced miscarriage rates, utilization of PGT-A in association with IVF has rapidly increased in the USA in recent years.Underlying this practice change were representations that PGT-A in a single trophectoderm biopsy at blastocyst stage reliably determines whether an embryo is euploid or chromosomal abnormal, thereby permitting exclusion from transfer of chromosomal abnormal embryos, and improving implantation rates of remaining embryos, while also reducing miscarriages.We here demonstrate that both assumptions are false, PGT-A, therefore, does neither improve IVF outcomes nor, likely, significantly reduces miscarriages and, in women with small embryo numbers, actually reduces pregnancy and live birth chances.Responsible for the previously noted false assumptions have been several fundamental errors in understanding of basic human biology and embryology, including lack of appreciation for the effects of chromosomal instability in preimplantation-stage embryos on embryo mosaicism and the embryo’s innate ability to self-correct aneuploidy especially in the embryonic cell lineage.A single trophectoderm biopsy at blastocyst stage, therefore, for simply biological reasons, can never determine an embryo’s ultimate chromosomal fate with adequate clinical accuracy to warrant its nonuse or even disposal. Frequently false-positive PGT-A diagnoses, therefore, lead to nonuse or disposal of large numbers of human embryos with normal pregnancy and delivery potential, representing a significant ethical as well as regulatory conundrum, demanding authoritative regulatory intervention. Preimplantation genetic testing for aneuploidy (PGT-A) has become a routine add-on for in vitro fertilization (IVF) to determine whether human embryos are to be clinically utilized or disposed of. Studies claiming IVF outcome improvements following PGT-A, however, used highly selected patient populations or inappropriate statistical methodologies. PGT-A was never clinically validated in its ability to define a human embryo as chromosomal normal, mosaic, or aneuploid, nor certified by a regulatory body, or an authoritative professional organization. Because of a high false-positive rate, PGT-A, actually reduces live IVF birth chances for many patients. Furthermore, in recent studies the PGT-A hypothesis was demonstrated to be mistaken for biological, mathematical and technical reasons. PGT-A, therefore, should clinically only be offered within experimental study frameworks. Preimplantation genetic testing for aneuploidy (PGT-A) has become a routine add-on for in vitro fertilization (IVF) to determine whether human embryos are to be clinically utilized or disposed of. Studies claiming IVF outcome improvements following PGT-A, however, used highly selected patient populations or inappropriate statistical methodologies. PGT-A was never clinically validated in its ability to define a human embryo as chromosomal normal, mosaic, or aneuploid, nor certified by a regulatory body, or an authoritative professional organization. Because of a high false-positive rate, PGT-A, actually reduces live IVF birth chances for many patients. Furthermore, in recent studies the PGT-A hypothesis was demonstrated to be mistaken for biological, mathematical and technical reasons. PGT-A, therefore, should clinically only be offered within experimental study frameworks.

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