Mosaic human preimplantation embryos and their developmental potential in a prospective, non-selection clinical trial

Abstract

Summary Chromosome imbalance (aneuploidy) is the major cause of pregnancy loss and congenital disorders in humans. Analyses of small biopsies from human embryos suggest that aneuploidy commonly originates during early divisions, resulting in mosaicism. However, the developmental potential of mosaic embryos remains unclear. We followed the distribution of aneuploid chromosomes across 73 unselected preimplantation embryos and 365 biopsies, sampled from four multifocal trophectoderm (TE) samples and the inner cell mass (ICM). When mosaicism impacted fewer than 50% of cells in one TE biopsy (low-medium mosaicism), only 1% of aneuploidies affected other portions of the embryo. A double-blinded prospective non-selection trial (NCT03673592) showed equivalent live-birth rates and miscarriage rates across 484 euploid, 282 low-grade mosaic, and 131 medium-grade mosaic embryos. No instances of mosaicism or uniparental disomy were detected in the ensuing pregnancies or newborns, and obstetrical and neonatal outcomes were similar between the study groups. Thus, low-medium mosaicism in the trophectoderm mostly arises after TE and ICM differentiation, and such embryos have equivalent developmental potential as fully euploid ones.

PGT‐A: The biology and hidden failures of randomized control trials

“…Embryo chromosome status is a key variable, but in situations when euploid embryos are not available, any available mosaic embryos can be transferred with good outcomes. 29,30 The decision to test or not test or to transfer or not transfer any embryo, however, is ultimately a clinical decision linked to patient-specific situations and should be left in the hands of the informed clinician, following discussion(s) with their patient. 36 PGT-A can improve initial transfer outcomes when performed well, simply because euploid embryos are more successful than other embryos.…”

“…The area is divided into four quadrants based around the group mean routine IVF IR outcomes for 2018 and the mean for just the euploid embryo transfers from this study (black dots, grouped by colored clouds). Results for seven other cited studies [6][7][8]10,12,27,28 (red stars) with IR data for Preimplantation Genetic Testing -Aneuploidy (PGT-A) and IVF groups and three other cited studies 15,29,30 (blue stars) with PGT-A IR data only are shown for comparison. Circled dots represent clinically significant differences to the means.…”

Prenatal Diagnosis of Chromosomal Mosaicism in Over 18,000 Pregnancies: A Five-Year Single-Tertiary-Center Retrospective Analysis

“…All CMs related to autosomal chromosomes were classified into the group of autosomal abnormalities, whereas CMs related to sex chromosomes were classified into the group of sex chromosomal abnormalities. With respect to the CM fraction, we defined a fraction greater than or equal to 50% as high and others as low ( Bellil et al, 2020 ; Capalbo et al, 2021 ). As the results of karyotyping which were counted manually may introduce human error, the classification of the CM fraction was performed based on the results of CMA.…”

Stem Cell-Based Trophoblast Models to Unravel the Genetic Causes of Human Miscarriages

“…One of the most intriguing questions currently being addressed by research is the selective elimination of aneuploid cells, suggested by normal live births after the intrauterine transfer of mosaic aneuploid embryos [ 16 , 20 ]. Experiments on extended blastocyst cultures showed that a high proportion (71%) of embryos originally diagnosed as mosaic were found to be euploid [ 165 ].…”

“…Data from preimplantation genetic testing (PGT) show that embryos with mosaic karyotypes can develop and produce chromosomally normal fetuses [ 16 , 17 , 18 , 19 , 20 , 21 ]. In some studies, it has been found that, in mosaic embryos, aneuploid cells are located predominantly in the trophectoderm/trophoblast lineage [ 22 , 23 ].…”