Mosaicism: throwing the baby out with the bath water?

Abstract

With the advent of next-generation sequencing (NGS), cytogenetic laboratories now have the ability to detect low-level mosaicism in the trophectoderm of blastocysts [1]. An abstract presented by Dagan Wells, PhD, and his collaborators at the European Society for Human Reproduction and Embryology (ESHRE) Meeting titled: BEvidence that differences between embryology laboratories can influence the rate of mitotic errors, leading to increased chromosomal mosaicism, with significant implications for IVF success rates,^was well-received. In this study, the authors retrospectively analyzed 623 blastocysts from seven fertility clinics and suggested that under different laboratory conditions, the same embryo can have different mosaicism rates ranging from 32 to 60 % [2]. The abstract focuses on mosaicism-introduced post-fertilization (mitotic non-disjunction of the embryo) and therefore during laboratory culture, rather than due to meiotic nondisjunction of the oocyte.The concept that laboratory conditions may cause postfertilization aneuploidy or mosaicism in embryos is provocative. This could explain the large dissimilarities seen in aneuploidy rates among different clinical trials and why some embryology laboratories see a decrease in their live birth rates per cycle start when performing preimplantation genetic screening (PGS) due to no euploid embryo being available for transfer [3][4][5]. Munne et al. first described a possible increase in postfertilization mosaicism when comparing different embryology laboratories [6]. More recently, it has been shown that embryos with better morphological scores have fewer chromosomal errors [7,8]. What specific embryo culture conditions can impact embryo morphology and possibly ploidy status? According to a recent systematic review and meta-analysis of randomized controlled trials (RCTs), culture at 5 % vs. 20 % oxygen concentration increased the number of high/top morphology embryos at the cleavage stage (RR = 1.2, 95 % CI 1.1-1.3) [9]. Different culture media with different recommended pH ranges support blastocyst development in culture, but the optimal pH level has not been established [10,11]; animal models suggest that strict control of pH at different developmental stages improves embryo quality [12]. A recent RCT showed that embryos cultured at 37°C have higher blastulation rates (60.1 vs. 51.6 %, p 0.03) and form more usable blastocysts (48.1 vs. 41.2 %, p 0.03) when compared to embryos cultured at 36°C [13], indicating the need for strictly controlled temperature of incubators and heated surfaces in the laboratory. If we follow this same principle, variations in the biopsy technique such as location of biopsy in the trophectoderm, due to segregation of abnormal cell lines, and/or number of cells removed, may impact the level of mosaicism reported [14]. We know that controlling for these variables by strict adherence to protocols and training of staff lead to comparable and reproducible outcomes with no difference in aneuploidy rates [15].If indeed there is variation amo...

Metabolic imaging via fluorescence lifetime imaging microscopy for egg and embryo assessment

“…Preimplantation genetic testing for aneuploidy has demonstrated some improvement in IVF success (18)(19)(20). However, concerns exist regarding the consistency of these diagnostic methods (21) and around the impact of mosaicism on diagnostic accuracy (22,23). In addition, preimplantation genetic testing for aneuploidy does not provide information about metabolic or other nongenetic viability parameters.…”