UPDATED PGDIS RECOMMENDATIONS FOR REPLACEMENT OF MOSAIC EMBRYOS

Abstract

Objective To review current data on the developmental potential of mosaic embryos and update previous guidelines and recommendations for transfer of mosaic embryos. Background From PGT studies of blastocyst biopsies using next generation sequencing (NGS), the average frequency of embryonic mosaicism is around 10% (range 5% - 30%). Mosaicism is generated by mitotic nondisjunction errors that can affect any chromosome and manifests as either diploid mosaic, aneuploid mosaic or complex aneuploid mosaic embryos. The level of mosaicism, defined from analysis of a trophectoderm (TE) biopsy, is generally related to the timing of mitotic errors during preimplantation development. Currently, there are disputes about the biological relevance of mosaicism levels measured in a blastocyst TE biopsy by NGS. Thus, in situations where there is no available euploid embryo for transfer, even with current guidelines published by PGDIS, confusion still reigns in many clinics on whether to transfer diploid mosaic embryos. Recent observations A number of studies have now been performed to follow the outcome of transferring diploid mosaic embryos detected with either whole chromosome or segmental abnormalities involving one or more chromosomes. Compared to euploid embryos, diploid mosaics with 20-40% levels of trisomy or monosomy have slightly reduced implantation potential and, those that do successfully implant are capable of developing to live births without signs of chromosome disease syndromes. Re-analysis of mosaic embryos indicates that while the majority of second TE biopsies are concordant for the type of mosaicism originally detected by PGT, there can be differences in levels of mosaicism in the TE compartment, and in some cases, second biopsies appear euploid. In general, the mosaicism found in TE biopsies is not reflected in the ICM lineage. These studies suggest that the level of mosaicism determined by NGS and reported to the clinician from a PGT cycle may not always be indicative of the entire blastocyst. More recently, there is also growing evidence from sequencing data that artificial segmental mosaicism can occur due to biased chromosome representation in the WGA and library construction steps. Thus, biological and technical factors may occasionally falsely contribute to a diagnosis of embryonic mosaicism. Recommendations Clinics that routinely observe high levels of mosaicism should systemically review IVF and PGT protocols. In the absence of euploid embryos for transfer, genetic counseling should be first offered to explore the possibility of transferring a diploid mosaic embryo or initiating another PGT cycle. While outcomes are slightly compromised, diploid mosaic embryos with 20-50% mosaicism can be transferred regardless of the chromosomal abnormality involved. Transfer of embryos with 50-80% mosaicism should be considered with more caution, in particular, mosaic embryos associated with (i) trisomies of chromosome 21, 18 and 13 capable of developing to live births, (ii) trisomies causative of intrauterine growth restriction or (iii) segmentals causative of known chromosome disease syndromes. Following an ongoing pregnancy achieved with a diploid mosaic embryo, prenatal diagnosis by amniocentesis is highly recommended.