The fate of irregularly divided blastomeres: why does “Direct cleavage” reduce blastocyst development rate but not blastocyst euploid rate? (第38回ヨーロッパ生殖医学会(ESHRE))
Shinichi Watanabe1, Kaori Yoshikai1, Mari Tomida1, Shigenori Suzuki1, Yukino Matsuda1, Shunsuke Miyai2, Eiko Nakano1, Hiroki Kurahashi2, Tomio Sawada1


1 Sawada Women’s Clinic, Nagoya, Japan

2 Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan


Study question:

How do the blastomeres formed by direct cleavage (dynamics of one cell dividing into three or more cells) subsequently develop?


Summary answer:

About half of the blastomeres by direct cleavage did not form blastocysts.


What is known already:

There are many reports that embryos with direct cleavage in the early development have a lower blastocyst development rate because direct cleavage produces chromosomal abnormal cells. However, when such embryos develop into blastocysts, there have been some reports that the transfer pregnancy rate and euploid rate did not decrease, but the reasons for this have not been clarified.


Study design, size, duration:

This is a retrospective study of 89 blastocysts obtained during 2013-18.These embryos were those that patients requested to be discarded and consented to be used in this study. All target embryos were time-lapse monitored by EmbryoScope (Vitrolife, Sweden), and several trophectoderms were biopsied and examined for euploidy.


Participants/materials, setting, methods:

The target embryos were classified into three groups: embryos with normal first and second cleavage (NC group), embryos with irregular division (one cell dividing into three or more cells) called direct cleavage at the first cleavage (DC1 group), and embryos with direct cleavage of one blastomere at the second cleavage (DC2 group). It was recorded whether the blastomeres of the embryos subsequently developed into blastocysts or not. NGS analysis was performed on the embryos.


Main results and the role of chance:

The target embryos were classified as 48 in the NC group, 32 in the DC1 group, and 9 in the DC2 group. Whether the blastomeres in the target embryos subsequently formed blastocysts or not was recorded one by one by time-lapse images, resulting in the blastomeres’ blastocyst formation rate was 95.1% in the NC group and 55.9% in the DC1 group, which was significantly lower in the DC1 group (P<0.01). In the DC2 group, blastomeres formed by normal division and those by direct cleavage at the second cleavage were recorded separately, and the blastocyst formation rate was 90.8% for normal cleavage blastomeres and 46.0% for direct cleavage blastomeres, with significantly lower rates for direct cleavage blastomeres (P<0.01). Therefore, about half of the blastomeres generated by direct cleavage at the first or second cleavage did not form blastocysts. The results of NGS analysis were as follows: NC group: 35.4% euploid, 45.8% aneuploid, and 18.8% mosaic; DC1 group: 37.5%, 53.1%, and 9.4%, respectively; and DC2 group: 55.6%, 33.3%, and 11.1%, respectively. There was no significant difference in any of the items, suggesting that direct cleavage does not affect the euploidy of blastocysts.


Limitations, reasons for caution:

For the purpose of NGS analysis, all the target embryos in this study were blastocysts, but if all the cultured embryos were included, arrested embryos would be included, which would probably result in more blastomeres formed by direct cleavage not developing into blastocysts.


Wider implications of the findings:

The blastomeres generated by direct cleavage were often excluded from blastocyst formation. This may be an exclusion of chromosomally abnormal cells and may be one of the reasons why direct cleavage decreases blastocyst development rate but does not decrease blastocyst euploid rate.

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