Delays in the final stages of fertilization are strongly associated with trichotomous cytokinesis and cleavage arrest.

OA: closed
Full text 9,106 characters · extracted from oa-doi-fallback · 5 sections · click to expand

Abstract

Purpose Recent evidence showed that the phase between pronuclear fading and the first cleavage is a perilous bridge connecting the zygote and the embryo. Indeed, delay in the short interval between pronuclear breakdown (PNBD) and the first cytokinesis may result in chromosome segregation errors. We tested the hypothesis that delays in this final phase of fertilization are associated with a detrimental impact on embryo development.

Methods

This is a retrospective study of 1315 zygotes cultured using time lapse technologies generated in 205 first ICSI-cycles.

Results

We observed an association between increasing times of the pronuclear fading-first cleavage interval (t2-tPNf) and the rates of trichotomous/direct unequal cleavage at the first (DUC-1) and second (DUC-2) mitotic cycle. Moreover, we observed a reduced blastulation rate. No significant associations were observed between rates of direct unequal cleavage at the third mitotic cycle (DUC-3) and top-quality blastocysts, euploidy, and live births. To evaluate whether the interval t2–tPNf could have a predictive value for the onset of DUC-1 and DUC-2, ROC curve analyses were performed. The area under the curve values obtained for DUC-1 showed a significant prediction accuracy. The best cut-offs to identify zygotes with a high risk of DUC-1 and DUC-2 occurrence were t2–tPNf > 2.78 (hours) and t2–tPNf > 2.50 (hours), respectively.

Conclusion

Delay in the short interval between PNBD and the first cytokinesis result in trichotomous cleavage and early developmental arrest. However, if the embryos reach the blastocyst stage, rates of euploidy and live birth do not appear to be compromised. Similar content being viewed by others

References

Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, et al. Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage. Nat Biotechnol. 2010;28:1115–21. Meseguer M, Herrero J, Tejera A, Hilligsøe KM, Ramsing NB, Remohí J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011;26:2658–71. Coticchio G, Mignini Renzini M, Novara PV, Lain M, De Ponti E, Turchi D, et al. Focused time-lapse analysis reveals novel aspects of human fertilization and suggests new parameters of embryo viability. Hum Reprod. 2018;33:23–31. ESHRE Special Interest Group of Embryology and Alpha Scientists in Reproductive Medicine. The Vienna consensus: report of an expert meeting on the development of ART laboratory performance indicators. Reprod Biomed Online. 2017;35(5):494–510. Aguilar J, Motato Y, Escribá MJ, Ojeda M, Muñoz E, Meseguer M. The human first cell cycle: impact on implantation. Reprod Biomed Online. 2014;28:475–84. Coticchio G, Borini A, Zacà C, Makrakis E, Sfontouris I. Fertilization signatures as biomarkers of embryo quality. Hum Reprod. 2022;37:1704–11. Currie CE, Ford E, Benham Whyte L, Taylor DM, Mihalas BP, Erent M, et al. The first mitotic division of human embryos is highly error prone. Nat Commun. 2022;13:6755. Destouni A, Zamani Esteki M, Catteeuw M, Tšuiko O, Dimitriadou E, Smits K, et al. Zygotes segregate entire parental genomes in distinct blastomere lineages causing cleavage-stage chimerism and mixoploidy. Genome Res. 2016;26:567–78. Zhan Q, Ye Z, Clarke R, Rosenwaks Z, Zaninovic N. Direct Unequal cleavages: embryo developmental competence, genetic constitution and clinical outcome. PLoS ONE. 2016;11(12):e0166398. Rubio I, Kuhlmann R, Agerholm I, Kirk J, Herrero J, Escribá M-J, et al. Limited implantation success of direct-cleaved human zygotes: a time-lapse study. Fertil Steril. 2012;98:1458–63. Desai N, Ploskonka S, Goodman LR, Austin C, Goldberg J, Falcone T. Analysis of embryo morphokinetics, multinucleation and cleavage anomalies using continuous time-lapse monitoring in blastocyst transfer cycles. Reprod Biol Endocrinol. 2014;12:54. Hlinka D, Kaľatová B, Uhrinová I, Dolinská S, Rutarová J, Rezáčová J, et al. Time-lapse cleavage rating predicts human embryo viability. Physiol Res. 2012;61:513–25. Cavazza T, Takeda Y, Politi AZ, Aushev M, Aldag P, Baker C, et al. Parental genome unification is highly error-prone in mammalian embryos. Cell. 2021;184:2860-2877.e22. Ottolini CS, Kitchen J, Xanthopoulou L, Gordon T, Summers MC, Handyside AH. Tripolar mitosis and partitioning of the genome arrests human preimplantation development in vitro. Sci Rep. 2017;7:9744. McCoy RC. Mosaicism in preimplantation human embryos: when chromosomal abnormalities are the norm. Trends Genet. 2017;33:448–63. McCollin A, Swann RL, Summers MC, Handyside AH, Ottolini CS. Abnormal cleavage and developmental arrest of human preimplantation embryos in vitro. Eur J Med Genet. 2020;63:103651. Dal Canto M, Coticchio G, Mignini Renzini M, De Ponti E, Novara PV, Brambillasca F, et al. Cleavage kinetics analysis of human embryos predicts development to blastocyst and implantation. Reprod Biomed Online. 2012;25:474–80. World Health Organization. WHO laboratory manual for the examination and processing of human semen. 6th ed. 2021. https://www.who.int/publications/i/item/9789240030787. Tarozzi N, Nadalini M, Stronati A, Bizzaro D, Dal Prato L, Coticchio G, et al. Anomalies in sperm chromatin packaging: implications for assisted reproduction techniques. Reprod Biomed Online. 2009;18:486–95. Coticchio G, Ezoe K, Lagalla C, Shimazaki K, Ohata K, Ninomiya M, et al. Perturbations of morphogenesis at the compaction stage affect blastocyst implantation and live birth rates. Hum Reprod. 2021;36:918–28. Borini A, Lagalla C, Sciajno R, Distratis V, Bonu MA, Cattoli M, et al. Artificial reproductive technology achievements for optimizing embryo quality. Ann N Y Acad Sci. 2004;1034:252–61. Bartolacci A, Buratini J, Moutier C, Guglielmo MC, Novara PV, Brambillasca F, et al. Maternal body mass index affects embryo morphokinetics: a time-lapse study. J Assist Reprod Genet. 2019;36:1109–16. Alpha Scientists in Reproductive Medicine and ESHRE Special Interest Group of Embryology. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26:1270–83. Bartolacci A, Dal Canto M, Guglielmo MC, Mura L, Brigante C, Mignini Renzini M, et al. Early embryo morphokinetics is a better predictor of post-ICSI live birth than embryo morphology: speed is more important than beauty at the cleavage stage. Zygote. 2021;29:495–502. McCoy RC, Summers MC, McCollin A, Ottolini CS, Ahuja K, Handyside AH. Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos. Genome Med. 2023;2(15):77. Coticchio G, Cimadomo D, Cermisoni GC, Rienzi L, Papaleo E, Ubaldi FM, et al. The first mitotic division: a perilous bridge connecting the zygote and the early embryo. Hum Reprod. 2023;38:1019–27. Wilhelm T, Magdalou I, Barascu A, Técher H, Debatisse M, Lopez BS. Spontaneous slow replication fork progression elicits mitosis alterations in homologous recombination-deficient mammalian cells. Proc Natl Acad Sci USA. 2014;111:763–8. Palmerola KL, Amrane S, De Los AA, Xu S, Wang N, de Pinho J, et al. Replication stress impairs chromosome segregation and preimplantation development in human embryos. Cell. 2022;185:2988-3007.e20. Tarozzi N, Nadalini M, Lagalla C, Coticchio G, Zacà C, Borini A. Male factor infertility impacts the rate of mosaic blastocysts in cycles of preimplantation genetic testing for aneuploidy. J Assist Reprod Genet. 2019;36:2047–55. Shavit M, Gonen D, Atzmon Y, Aslih N, Bilgory A, Shibli Abu-Raya Y, et al. Cleavage patterns of 9600 embryos: the importance of irregular cleavage. JCM. 2023;12:5656. Musacchio A, Salmon ED. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol. 2007;8:379–93. Ajduk A, Strauss B, Pines J, Zernicka-Goetz M. Delayed APC/C activation extends the first mitosis of mouse embryos. Sci Rep. 2017;7:9682. Horakova A, Konecna M, Radonova L, Anger M. Early onset of APC/C activity renders SAC inefficient in mouse embryos. Front Cell Dev Biol. 2024;12:1355979. Author information Authors and Affiliations Corresponding author Ethics declarations Conflict of interest The authors declare no competing interests. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Coticchio, G., Marchio, L., Bartolacci, A. et al. Delays in the final stages of fertilization are strongly associated with trichotomous cytokinesis and cleavage arrest. J Assist Reprod Genet 42, 107–114 (2025). https://doi.org/10.1007/s10815-024-03330-3 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s10815-024-03330-3

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

Ask this paper AI returns verbatim quotes from the full text · source: oa-doi-fallback

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Citation neighborhood (no data yet)

We don't have any in-corpus citations linked to this paper yet. This is a recent paper (2025) — citers typically take a year or two to land, and the OpenAlex reference graph may still be filling in.

Source provenance

europepmc
last seen: 2026-07-02T06:07:54.402228+00:00