Are cleavage anomalies, multinucleation, or specific cell cycle kinetics observed with time-lapse imaging predictive of embryo developmental capacity or ploidy?
Critical evaluation of embryos for cleavage anomalies, multinucleation, and growth kinetics using time-lapse imaging offers a noninvasive means to enhance selection of euploid blastocysts.
Volume 109, Issue 4, Pages 665–674
Authors:
Nina Desai, Ph.D., H.C.L.D., Jeffrey M. Goldberg, M.D., Cynthia Austin, M.D., Tommaso Falcone, M.D.
Abstract:
Objective
To determine whether cleavage anomalies, multinucleation, and specific cellular kinetic parameters available from time-lapse imaging are predictive of developmental capacity or blastocyst chromosomal status.
Design
Retrospective analysis of prospectively collected data.
Setting
Single academic center.
Patient(s)
A total of 1,478 zygotes from patients with blastocysts biopsied for preimplantation genetic screening were cultured in the EmbryoScope.
Intervention(s)
Trophectoderm biopsy.
Main Outcome Measure(s)
Embryo dysmorphisms, developmental kinetics, and euploidy.
Result(s)
Of the 767 biopsied blastocysts, 41.6% (95% confidence interval [CI], 38%–45%) were diagnosed as euploid. Individual dysmorphisms such as multinucleation, reverse cleavage, irregular chaotic division, or direct uneven cleavage were not associated with aneuploidy. Direct uneven cleavage and irregular chaotic division embryos did, however, exhibit lower developmental potential. The presence of two or more dysmorphisms was associated with an overall lower euploidy rate, 27.6% (95% CI 19%–39%). Early embryo kinetics were predictive of blastocyst development but not ploidy status. In contrast, chromosomal status correlated significantly with start time of blastulation (tSB), expansion (tEB), and the tEB-tSB interval. A lower euploidy rate, 36.6% (95% CI 33%–42%) was observed with tSB ≥ 96.2 hours, compared with 48.2% with tSB < 96.2 (95% CI 42%–54%). A drop in euploidy rate to 30% (95% CI 25%–37%) was observed in blastDesain@ccf.orgocysts with delayed expansion (tEB > 116). The proportion of euploid blastocysts was increased with tEB-tSB intervals of ≤13 hours. A logistic regression model to enhance the probability of selecting a euploid blastocyst was constructed.
Conclusion(s)
Morphokinetics may aid in selection of euploid embryos from a cohort of day 5/6 blastocysts.
4 Comments
Thank you for your interesting article. It certainly challenges some of the beliefs on embryo selection. I have two questions:
1. was the degree of multinucleation associated with aneuplodidy?
2. the data was analyzed with tests that assume that each observation is independent, but it contained 767 embryos from 130 patients. So these embryos are not independent observations. This could be important since we sometimes see abnormalities like multinucleation cluster within a given patient. So the multinucleation of an embryo might be related to the patient and associated with other embryos from that same patient. Mixed models or generalized estimating equations can be built to account for this. Sometimes this changes the outcome of the analysis and sometimes it doesn't. My question is if you analyze your data to account for the non-independence of embryos from the same patient, do the main results remain the same?
Great discussion on this article at F&S Journal Club Global. Thank you to the authors for all your work. Any further thoughts the authors have to add to the discussion we had?
Thank you! As regards your questions:
Surprisingly multinucleation presented alone did not seem to be associated with aneuploidy. However embryos with two or more dysmorphisms, were associated with higher rate of aneuploidy and in 66% of these embryos one of the dysmorphisms was in fact multinucleation. This may in part explain why there are so many reports of lower outcomes with multinucleated embryos.
Yes-we did in fact consider each embryo as an independent observation for the purposes of this study. Your point about the possibility of higher clusters of dysmorphisms possibly being associated with specific patients is very valid. Re-analysis of the data to address this question is planned. We also feel it makes sense to expand the data set to include more patients. This will allow us to better examine the question you have posed .
Great! Thank you for the updates!