Analysis of implantation and ongoing pregnancy rates following the transfer of mosaic diploid–aneuploid blastocysts

Abstract

Preimplantation genetic testing for aneuploidy (PGT-A) is widely used in IVF and aims to improve outcomes by avoiding aneuploid embryo transfers. Chromosomal mosaicism is extremely common in early development and could affect the efficacy of PGT-A by causing incorrect embryo classification. Recent innovations have allowed accurate mosaicism detection in trophectoderm samples taken from blastocysts. However, there is little data concerning the impact of mosaicism on viability, and the optimal clinical pathway for such embryos is unclear. This study provides new information concerning the extent to which mosaic preimplantation embryos are capable of producing pregnancies and births. Archived trophectoderm biopsy specimens from transferred blastocysts were analyzed using next generation sequencing (NGS). Unlike other PGT-A methods, NGS accurately detects mosaicism in embryo biopsies. 44 mosaic blastocysts were identified. Their clinical outcomes were compared to 51 euploid blastocysts, derived from a well-matched, contemporary control group. Mosaic embryos were associated with outcomes that were significantly poorer than those of the control group: implantation 30.1 versus 55.8% (P = 0.038); miscarriage rate 55.6 versus 17.2% (P = 0.036); and ongoing pregnancy 15.4 versus 46.2% (P = 0.003). 61% of the mosaic errors affected whole chromosomes and 39% were segmental aneuploidies. Embryo viability is compromised by the presence of aneuploid cells. However, a minority of affected embryos can produce successful pregnancies. Hence, such embryos should not necessarily be excluded, but given a lower priority for transfer than those that are fully euploid. It is recommended that pregnancies established after mosaic embryo transfers be subjected to prenatal testing, with appropriate patient counselling.

Preimplantation Genetic Screening

“…It therefore seems to make clinical sense not to transfer these embryos. A larger problem however seems to be caused by the approximately 20% euploid/aneuploid embryos, of which about 40% may be able to implant and lead to live births [59,62,63]. Not transferring these embryos may reduce the chances for a patient of a healthy pregnancy.…”

“…These trial characteristics lead to a distortion of the real a priori benefit for patients, as they do not represent those patients that for instance do not obtain blastocysts for analysis, or only have abnormal embryos and therefore do not even reach embryo transfer. Although these three RCTs were on specific patient categories, they are often cited as demonstrating PGS efficacy for all IVF patients [62,66,71,72].…”

In vitro fertilisation/intracytoplasmic sperm injection beyond 2020

“…The currently utilised day 5 multi‐cell trophectoderm biopsy is thought to have a much improved embryo implantation rate and thereby has replaced the old day 3 blastomere biopsy; additionally, with the implementation of next generation sequencing (NGS), a higher level of accuracy and lower cost can be achieved . After 10 years of rapidly increasing utilisation of pre‐genetic testing for aneuploidy (PGT‐A), its use has come under the spotlight recently due to the complexity in defining and determining the fate of a mosaic embryo, potentially resulting in the discarding of potentially viable embryos . Mosaicism is thought to arise from mitotic cell divisions after fertilisation, and mosaic cells may reside within the inner cell mass, destined to become the fetus; within the trophectoderm, destined to become the placenta; or in both.…”

“…Mosaicism is thought to arise from mitotic cell divisions after fertilisation, and mosaic cells may reside within the inner cell mass, destined to become the fetus; within the trophectoderm, destined to become the placenta; or in both. Recent studies using NGS have demonstrated that mosaic embryos can implant and become healthy babies and, conversely, embryos previously diagnosed as euploid have been shown to be mosaic . This recent controversy has cast doubt onto the value of PGT‐A, rendering it unsuitable as a routine screening diagnostic tool, and subsequently its utilisation is likely to decline in IVF/ICSI beyond 2020, with some calling for a ban on its use outside of clinical studies.…”

The impact of contemporary preimplantation genetic screening and diagnosis on the detection of aneuploidy and inherited genetic diseases

“…Currently, whether or not to transfer a mosaic embryo remains a topic of debate. Mosaic embryos implant less frequent and miscarry more often than euploid embryos (Fragouli et al, 2017); however, some mosaic embryos result in healthy live born infants (Fragouli et al, 2017;Greco, Minasi, & Fiorentino, 2015). Very few data exist regarding the follow up of babies born after transfer of mosaic embryos, but no abnormal karyotypes have been reported, suggesting that the abnormal cell line was eliminated or grew so slowly that it could no longer be detected (Munn e & Wells, 2017).…”