PGT-A: Houston, we have a problem

Abstract

Preimplantation genetic testing for aneuploidy (PGT-A) is a common add-on to IVF cycles. As it is presently performed, PGT-A relies on whole genome amplification of small amounts of DNA from cells removed from the trophectoderm (TE) of a blastocyst for determination of gain or loss of chromosomal material by next-generation sequencing. Whole genome amplification may introduce artifacts such as allele dropout and loss of heterozygosity in up to 25% of cases. In addition, the high prevalence of mosaicism in human embryos is a complicating factor in interpreting the results of PGT-A screening. In the presence of mosaicism, biopsy of TE cells cannot provide accurate results regarding the chromosomal make-up of the inner cell mass. The available clinical data suggest that PGT-A is probably harmful when IVF outcomes are analyzed by intention to treat or by live birth rate per cycle started rather than per embryo transfer, especially in women with three or fewer blastocysts. In addition, hypothesized advantages of reduced spontaneous abortion rate and reduced time to conception may be modest at best.

Keywords: Clonal depletion; Clonal expansion; False positive; IVF; In vitro fertilization; Mosaicism; PGT-A; Preimplantation genetic testing for aneuploidy; Self-correction; Trophectoderm biopsy.

Fig. 1

Illustration of effect of biopsying 2 blastomeres from an eight-cell mosaic embryo containing 5 euploid cells (grey) and three aneuploid cells (black). In example A, the diagnosis from the biopsy is euploid and the embryo is transferred but the biopsy has converted the embryo to a high-level mosaic. In example B, the diagnosis from the biopsy is aneuploid and the embryo would be discarded when in fact, the biopsy has converted the embryo to predominantly euploid cells

Fig. 2

Potential outcomes at the blastocyst stage if mitotic errors occur in one cell of a 4-cell embryo (A) or 2 cells of a 4-cell embryo (B) keeping in mind the concept of clonal proliferation

Fig. 3

Live birth rate (LBR) and spontaneous abortion rate (SAB) in 130 subjects with 3 or fewer blastocysts who underwent trophectoderm biopsy for PGT-A compared to 130 matched controls with 3 or fewer blastocysts who did not do PGT-A. ns, non-significant (adapted from ref 21)

Fig. 4

Comparison of live birth rate (LBR) and spontaneous abortion rate (SAB) in 1126 women with one good quality blastocyst who had TE biopsy for PGT-A and 938 control women with one good quality blastocyst who transferred their embryos without PGT-A. ns, non-significant (adapted from ref 22)