Our results suggest that while the overall rate of mosaicism does not differ by BMI category, both low and high BMI may be associated with increased risks of LL mosaicism compared with normal BMI, and overweight may be associated with decreased rates of HL and whole chromosome mosaicism. These findings indicate that body weight may influence the early embryonic mechanisms associated with mosaicism.
There are various mechanisms thought to contribute to oocyte abnormalities in patients with elevated BMI, leading to poorer reproductive outcomes. For example, a study by Robker, et al. [12] found increased follicular concentrations of insulin, triglycerides and inflammatory markers in obese women, which may lead to impaired folliculogenesis and oocyte competence. Abnormalities of oxidative balance and steroidogenesis have also been observed in patients with obesity [13]. However, whether BMI impacts the chromosomal complement of oocytes is an avenue of ongoing investigation.
A study by Goldman, et al. [4], demonstrated similar findings to our results, in which no significant relationship between BMI and the number or percentage of euploid embryos was found. Their study evaluated 279 women who underwent IVF with PGT using aCGH between 2010 and 2013 and was limited by sample size, as there were only 50 patients with overweight and 22 patients with obese BMIs. Additionally, mosaicism was not reported over that study’s timeframe. To date, there are no published studies evaluating whether BMI affects euploid or mosaicism rates using embryos subjected to testing by NGS.
Importantly, our analysis of euploid rate by BMI category used re-classified embryos that were originally designated as “LL mosaic” to “euploid” (2018-2019 data). This assumption was made because prior to mosaicism reporting, those embryos would have been routinely classified as euploid. A sensitivity analysis evaluating the true “euploid” rate in the subset of NGS-tested embryos (i.e., without re-classification of LL mosaic to euploid) demonstrated similar findings.
While whole chromosome mosaicism of embryos arises from mitotic errors, literature suggests that segmental aneuploidies may arise from mechanisms associated with genomic instability [14]. Our results demonstrate differences in rates of whole chromosome mosaicism by BMI category, but did not show any difference in the rate of segmental mosaicism between groups. This supports our hypothesis that BMI may affect factors in the oocyte that have an effect on chromatid separation and alignment more so than those impacting genomic stability.
To our knowledge, this is the first study to report on BMI and embryonic mosaicism. We identified a novel finding that both low and high BMI were associated with increased risks of LL mosaicism. An additional strength of our study is the patient population, with a relatively high proportion of patients with overweight (24%) or obesity (21%). This study used strict inclusion criteria, including only patients’ first fresh autologous cycles wherein all eligible embryos were biopsied for PGT-A testing. PGT-A testing was completed at a single laboratory, minimizing potential confounders from differences in testing technique or interpretation.
Our study is limited due to its retrospective nature with a single patient population. Despite having a larger study population than previous studies, there were still relatively few patients with underweight BMI, obesity class II and obesity class III. While obesity was associated with increased risks of LL mosaicism, individual obesity classes demonstrated non-statistically significant increases in the risks of LL mosaicism, likely due to limited sample size. Additionally, there was a change in technology from aCGH to NGS during our study timeframe, but this change affected all study subjects equally. There are inherent limitations to using BMI as an exposure, as BMI is an indirect and imperfect measurement, and fails to distinguish between body fat and lean body mass. However, BMI is easily calculable from height and weight, which are routinely recorded at patient visits, whereas waist circumference is not; BMI is therefore widely used as a health measurement in both clinic and community settings, as well as in large research studies.
As with any study reporting on mosaicism by PGT-A, it is important to consider the reproducibility of mosaic results by re-biopsy, or inner cell mass (ICM) biopsy. Mosaicism is often due to mitotic non-disjunction events and are not necessarily uniformly distributed throughout the blastocyst. A recent study investigated 32 blastocysts and calculated per chromosome concordances between trophectoderm biopsy and ICM biopsy, and found concordance rates of 99.5% for euploid results, 97.3% for aneuploid results, but only 35.2% for mosaic results [15]. Future research which incorporates re-biopsy data would strengthen our findings. Improvements in PGT-A technology to reduce the occurrence of technical artifacts that may contribute to erroneous mosaicism reporting would also allow for more refined results. Importantly, as embryonic euploidy rates may vary by fertility practice [16], and a prior study using cleavage-stage embryos and fluorescence in situ hybridization suggested that mosaicism rate may similarly vary by infertility center [17], we encourage repeat investigation with a distinct study population to further evaluate the relationship between BMI and mosaicism.
This is the first study to examine the effect of BMI on embryo mosaicism. Our findings support previous research demonstrating a lack of evidence that BMI is associated with the rate of embryonic euploidy. We introduce the possibility that a patient’s BMI may play a role in the rate of embryonic mosaicism following IVF with PGT-A. An increase in the risk of low-level mosaicism for patients with obesity versus normal BMI may help explain unfavorable ART outcomes demonstrated by these patients. Though a large proportion of our patient cohort had elevated BMI, further research is needed to clarify the impact of BMI on embryo mosaicism and to elucidate possible mechanisms.