Human embryos with segmental aneuploidies display delayed early development: a multicenter morphokinetic analysis

Objective: To assess whether segmental aneuploid embryos display unique morphokinetic patterns.

Design: Retrospective multicenter study including a total of 7,027 embryos cultured between 2016 and 2021 in three European in vitro fertilization centers. Analysis was performed on aggregated multicenter data and separately for data from each center. Embryos with no more than four chromosomal alterations were considered in the analysis, resulting in 3,040 euploids and 2,818 whole-chromosome and 697 segmental aneuploids. Overall, the data set contained 3,742 distinct euploid-segmental sibling pairs.

Setting: In vitro fertilization clinics.

Patient(s): Standard morphokinetic features were annotated using various time-lapse systems. Blastocysts were subjected to comprehensive chromosomal screening via preimplantation genetic testing for aneuploidy.

Intervention(s): Morphokinetic patterns were compared among euploid, whole-chromosome aneuploid, and segmental aneuploid embryos.

Main outcome measure(s): Morphokinetic timings across groups were compared using statistical analysis, and associations with cleavage features were assessed. Multicenter and center-specific multivariate logistic regression models were calibrated, and their predictive performance was evaluated on independent test set data using area under the receiver operating characteristic curve (AUROC) metrics.

Result(s): Segmental aneuploid embryos cleaved significantly slower than their euploid siblings across the first three cell cycles, with a delay reaching the blastocyst-stage of development. Specifically during these early cell cycles, segmental aneuploid embryos were also shown to be significantly slower than their aneuploid siblings. A logistic model on the basis of morphokinetic data from the multicenter data set and regressed against type of aneuploidy displayed modest predictive performance on an independent test set (train-AUROC = 0.58; test-AUROC = 0.57). Predictive performance improved on the basis of data from a single center displaying adequate predictive performance on an independent test set from the same center (train-AUROC = 0.74; test-AUROC = 0.64). However, the predictive value diminished when tested on data from other centers (AUROC = 0.52-0.55). Finally, the presence of multinucleation and blastomere exclusion at the cleavage stage were associated with segmental aneuploidies. The combination of morphokinetic features and these discrete embryo morphological features into the logistic regression model (train-AUROC = 0.71) provided an improved prediction of segmental aneuploidy, supporting future investigations using more comprehensive annotation systems.

Conclusion(s): The developed predictive framework may help improve decision-making in preimplantation genetic testing for aneuploidy cycles, helping in the evaluation of embryos showing segmental aneuploidy and distinguishing which embryos are more likely to not have lethal uniform aneuploidies for transfer.