Skip to main content
Log in

Is the presence of a non-cleaved embryo on day 3 associated with poorer quality of the remaining embryos in the cohort?

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Morphological evaluation is currently considered the single most important predictive measure for assessing embryo quality. The aim of this study was to investigate whether cycles with at least one non-cleaved embryo (i.e., a 1-cell embryo on day 3) have different outcomes compared with cycles in which all embryos had cleaved by day 3.

Methods

All autologous IVF/ICSI cycles with a fresh day 3 transfer and without using a gestational carrier performed at our center between 1/1/2010 and 12/31/2011 were analyzed retrospectively. Those cycles with at least one non-cleaved embryo on day 3 were compared with all other autologous cycles that had l00 % cleaved embryos performed during the study period.

Results

Eight hundred and forty two cycles were included. Of them, 144 cycles comprised the non-cleaved group, and 698 cycles comprised the cleaved group. Cycles in the non-cleaved group had more oocytes retrieved (15.4 ± 7.1 vs. 12.5 ± 7.1, p < 0.001), more zygotes obtained (10.0 ± 5.3 vs. 7.9 ± 5.2, p = <0.001), but the embryos exhibited lower cleavage rates and higher rates of fragmentation and asymmetry compared with controls (p < 0.001). However, spontaneous abortion rates, ectopic pregnancies rates as well as delivery rates were similar between the two groups.

Conclusions

Our results show that the presence of a non-cleaved embryo on day 3 is associated with a more exuberant response to controlled ovarian stimulation as reflected by more oocytes retrieved. Despite the significant decrease in quality of the whole cohort in the non-cleaved group, implantation, delivery rates and number of embryos frozen were not adversely affected by the presence of a non-cleaved embryo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Edwards RG, Steptoe PC, Purdy JM. Establishing full-term human pregnancies using cleaving embryos grown in vitro. Br J Obstet Gynaecol. 1980;87(9):737–56.

    Article  CAS  PubMed  Google Scholar 

  2. Balakier H, Casper RF. A morphologic study of unfertilized oocytes and abnormal embryos in human in vitro fertilization. J In Vitro Fert Embryo Trans : IVF. 1991;8(2):73–9.

    Article  CAS  Google Scholar 

  3. Capmany G, Taylor A, Braude PR, Bolton VN. The timing of pronuclear formation, DNA synthesis and cleavage in the human 1-cell embryo. Mol Hum Reprod. 1996;2(5):299–306.

    Article  CAS  PubMed  Google Scholar 

  4. Trounson AO, Mohr LR, Wood C, Leeton JF. Effect of delayed insemination on in-vitro fertilization, culture and transfer of human embryos. J Reprod Fertil. 1982;64(2):285–94.

    Article  CAS  PubMed  Google Scholar 

  5. Chamayou S, Patrizio P, Storaci G, Tomaselli V, Alecci C, Ragolia C, et al. The use of morphokinetic parameters to select all embryos with full capacity to implant. J Assist Reprod Genet. 2013;30(5):703–10. doi:10.1007/s10815-013-9992-2.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Kaser DJ, Racowsky C. Clinical outcomes following selection of human preimplantation embryos with time-lapse monitoring: a systematic review. Hum Reprod Update. 2014;20(5):617–31. doi:10.1093/humupd/dmu023.

    Article  PubMed  Google Scholar 

  7. Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod. 2011;26(10):2658–71. doi:10.1093/humrep/der256.

    Article  PubMed  Google Scholar 

  8. 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(10):1115–21. doi:10.1038/nbt.1686.

    Article  CAS  PubMed  Google Scholar 

  9. Alpha Scientists in Reproductive M, Embryology ESIGo. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26(6):1270–83. doi:10.1093/humrep/der037.

    Article  Google Scholar 

  10. Herrero J, Meseguer M. Selection of high potential embryos using time-lapse imaging: the era of morphokinetics. Fertil Steril. 2013;99(4):1030–4. doi:10.1016/j.fertnstert.2013.01.089.

    Article  PubMed  Google Scholar 

  11. Boostanfar R, Jain JK, Slater CC, Tourgeman DE, Francis MM, Paulson RJ. The prognostic significance of day 3 embryo cleavage stage on subsequent blastocyst development in a sequential culture system. J Assist Reprod Genet. 2001;18(10):548–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Carrillo AJ, Lane B, Pridman DD, Risch PP, Pool TB, Silverman IH, et al. Improved clinical outcomes for in vitro fertilization with delay of embryo transfer from 48 to 72 hours after oocyte retrieval: use of glucose- and phosphate-free media. Fertil Steril. 1998;69(2):329–34.

    Article  CAS  PubMed  Google Scholar 

  13. Edwards RG, Purdy JM, Steptoe PC, Walters DE. The growth of human preimplantation embryos in vitro. Am J Obstet Gynecol. 1981;141(4):408–16.

    CAS  PubMed  Google Scholar 

  14. Jones GM, Trounson AO, Lolatgis N, Wood C. Factors affecting the success of human blastocyst development and pregnancy following in vitro fertilization and embryo transfer. Fertil Steril. 1998;70(6):1022–9.

    Article  CAS  PubMed  Google Scholar 

  15. Giorgetti C, Terriou P, Auquier P, Hans E, Spach JL, Salzmann J, et al. Embryo score to predict implantation after in-vitro fertilization: based on 957 single embryo transfers. Hum Reprod. 1995;10(9):2427–31.

    Article  CAS  PubMed  Google Scholar 

  16. Machtinger R, Racowsky C. Morphological systems of human embryo assessment and clinical evidence. Reprod Biomed Online. 2013;26(3):210–21. doi:10.1016/j.rbmo.2012.10.021.

    Article  PubMed  Google Scholar 

  17. Puissant F, Van Rysselberge M, Barlow P, Deweze J, Leroy F. Embryo scoring as a prognostic tool in IVF treatment. Hum Reprod. 1987;2(8):705–8.

    CAS  PubMed  Google Scholar 

  18. Racowsky C, Combelles CM, Nureddin A, Pan Y, Finn A, Miles L, et al. Day 3 and day 5 morphological predictors of embryo viability. Reprod Biomed Online. 2003;6(3):323–31.

    Article  PubMed  Google Scholar 

  19. Steer CV, Mills CL, Tan SL, Campbell S, Edwards RG. The cumulative embryo score: a predictive embryo scoring technique to select the optimal number of embryos to transfer in an in-vitro fertilization and embryo transfer programme. Hum Reprod. 1992;7(1):117–9.

    CAS  PubMed  Google Scholar 

  20. Van Royen E, Mangelschots K, De Neubourg D, Valkenburg M, Van de Meerssche M, Ryckaert G, et al. Characterization of a top quality embryo, a step towards single-embryo transfer. Hum Reprod. 1999;14(9):2345–9.

    Article  PubMed  Google Scholar 

  21. Ziebe S, Petersen K, Lindenberg S, Andersen AG, Gabrielsen A, Andersen AN. Embryo morphology or cleavage stage: how to select the best embryos for transfer after in-vitro fertilization. Hum Reprod. 1997;12(7):1545–9.

    Article  CAS  PubMed  Google Scholar 

  22. Magli MC, Gianaroli L, Ferraretti AP, Lappi M, Ruberti A, Farfalli V. Embryo morphology and development are dependent on the chromosomal complement. Fertil Steril. 2007;87(3):534–41. doi:10.1016/j.fertnstert.2006.07.1512.

    Article  PubMed  Google Scholar 

  23. Racowsky C, Ohno-Machado L, Kim J, Biggers JD. Is there an advantage in scoring early embryos on more than one day? Hum Reprod. 2009;24(9):2104–13. doi:10.1093/humrep/dep198.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Skiadas CC, Jackson KV, Racowsky C. Early compaction on day 3 may be associated with increased implantation potential. Fertil Steril. 2006;86(5):1386–91. doi:10.1016/j.fertnstert.2006.03.051.

    Article  PubMed  Google Scholar 

  25. Yanushpolsky E, Hurwitz S, Greenberg L, Racowsky C, Hornstein MD. Comparison of Crinone 8 % intravaginal gel and intramuscular progesterone supplementation for in vitro fertilization/embryo transfer in women under age 40: interim analysis of a prospective randomized trial. Fertil Steril. 2008;89(2):485–7. doi:10.1016/j.fertnstert.2007.03.006.

    Article  CAS  PubMed  Google Scholar 

  26. Machtinger R, Politch JA, Hornstein MD, Ginsburg ES, Racowsky C. A giant oocyte in a cohort of retrieved oocytes: does it have any effect on the in vitro fertilization cycle outcome? Fertil Steril. 2011;95(2):573–6. doi:10.1016/j.fertnstert.2010.06.037.

    Article  PubMed  Google Scholar 

  27. Reichman DE, Jackson KV, Racowsky C. Incidence and development of zygotes exhibiting abnormal pronuclear disposition after identification of two pronuclei at the fertilization check. Fertil Steril. 2010;94(3):965–70. doi:10.1016/j.fertnstert.2009.04.018.

    Article  PubMed  Google Scholar 

  28. Cruz M, Gadea B, Garrido N, Pedersen KS, Martinez M, Perez-Cano I, et al. Embryo quality, blastocyst and ongoing pregnancy rates in oocyte donation patients whose embryos were monitored by time-lapse imaging. J Assist Reprod Genet. 2011;28(7):569–73. doi:10.1007/s10815-011-9549-1.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Kirkegaard K, Agerholm IE, Ingerslev HJ. Time-lapse monitoring as a tool for clinical embryo assessment. Hum Reprod. 2012;27(5):1277–85. doi:10.1093/humrep/des079.

    Article  PubMed  Google Scholar 

  30. Basile N, Vime P, Florensa M, Aparicio Ruiz B, Garcia Velasco JA, Remohi J, et al. The use of morphokinetics as a predictor of implantation: a multicentric study to define and validate an algorithm for embryo selection. Hum Reprod. 2014. doi:10.1093/humrep/deu331.

    PubMed  Google Scholar 

  31. Sela R, Samuelov L, Almog B, Schwartz T, Cohen T, Amit A, et al. An embryo cleavage pattern based on the relative blastomere size as a function of cell number for predicting implantation outcome. Fertil Steril. 2012;98(3):650–6. doi:10.1016/j.fertnstert.2012.05.041.

    Article  PubMed  Google Scholar 

  32. della Ragione T, Verheyen G, Papanikolaou EG, Van Landuyt L, Devroey P, Van Steirteghem A. Developmental stage on day-5 and fragmentation rate on day-3 can influence the implantation potential of top-quality blastocysts in IVF cycles with single embryo transfer. Reprod Biol Endocrinol : RB&E. 2007;5:2. doi:10.1186/1477-7827-5-2.

  33. Scott L, Finn A, O’Leary T, McLellan S, Hill J. Morphologic parameters of early cleavage-stage embryos that correlate with fetal development and delivery: prospective and applied data for increased pregnancy rates. Hum Reprod. 2007;22(1):230–40. doi:10.1093/humrep/del358.

    Article  CAS  PubMed  Google Scholar 

  34. Braude P, Bolton V, Moore S. Human gene expression first occurs between the four- and eight-cell stages of preimplantation development. Nature. 1988;332(6163):459–61. doi:10.1038/332459a0.

    Article  CAS  PubMed  Google Scholar 

  35. Edwards RG, Fishel SB, Cohen J, Fehilly CB, Purdy JM, Slater JM, et al. Factors influencing the success of in vitro fertilization for alleviating human infertility. J In Vitro Fert Embryo Trans : IVF. 1984;1(1):3–23.

    Article  CAS  Google Scholar 

  36. Lechniak D, Pers-Kamczyc E, Pawlak P. Timing of the first zygotic cleavage as a marker of developmental potential of mammalian embryos. Reprod Biol. 2008;8(1):23–42.

    Article  PubMed  Google Scholar 

  37. Sakkas D, Shoukir Y, Chardonnens D, Bianchi PG, Campana A. Early cleavage of human embryos to the two-cell stage after intracytoplasmic sperm injection as an indicator of embryo viability. Hum Reprod. 1998;13(1):182–7.

    Article  CAS  PubMed  Google Scholar 

  38. Giorgetti C, Hans E, Terriou P, Salzmann J, Barry B, Chabert-Orsini V, et al. Early cleavage: an additional predictor of high implantation rate following elective single embryo transfer. Reprod Biomed Online. 2007;14(1):85–91.

    Article  CAS  PubMed  Google Scholar 

  39. Isom SC, Li RF, Whitworth KM, Prather RS. Timing of first embryonic cleavage is a positive indicator of the in vitro developmental potential of porcine embryos derived from in vitro fertilization, somatic cell nuclear transfer and parthenogenesis. Mol Reprod Dev. 2012;79(3):197–207. doi:10.1002/mrd.22013.

    Article  CAS  PubMed  Google Scholar 

  40. Lee MJ, Lee RK, Lin MH, Hwu YM. Cleavage speed and implantation potential of early-cleavage embryos in IVF or ICSI cycles. J Assist Reprod Genet. 2012;29(8):745–50. doi:10.1007/s10815-012-9777-z.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Lian WL, Xin ZM, Jin HX, Song WY, Peng ZF, Sun YP. Effects of early-cleavage embryo transfer on in vitro fertilization-embryo transfer pregnancy outcomes. Clin Exp Obstet Gynecol. 2013;40(3):319–22.

    CAS  PubMed  Google Scholar 

  42. Lundin K, Bergh C, Hardarson T. Early embryo cleavage is a strong indicator of embryo quality in human IVF. Hum Reprod. 2001;16(12):2652–7.

    Article  CAS  PubMed  Google Scholar 

  43. Salumets A, Hyden-Granskog C, Makinen S, Suikkari AM, Tiitinen A, Tuuri T. Early cleavage predicts the viability of human embryos in elective single embryo transfer procedures. Hum Reprod. 2003;18(4):821–5.

    Article  PubMed  Google Scholar 

  44. Terriou P, Giorgetti C, Hans E, Salzmann J, Charles O, Cignetti L, et al. Relationship between even early cleavage and day 2 embryo score and assessment of their predictive value for pregnancy. Reprod Biomed Online. 2007;14(3):294–9.

    Article  CAS  PubMed  Google Scholar 

  45. Rubio I, Kuhlmann R, Agerholm I, Kirk J, Herrero J, Escriba MJ, et al. Limited implantation success of direct-cleaved human zygotes: a time-lapse study. Fertil Steril. 2012;98(6):1458–63. doi:10.1016/j.fertnstert.2012.07.1135.

    Article  PubMed  Google Scholar 

  46. Somfai T, Inaba Y, Aikawa Y, Ohtake M, Kobayashi S, Konishi K, et al. Relationship between the length of cell cycles, cleavage pattern and developmental competence in bovine embryos generated by in vitro fertilization or parthenogenesis. J Reprod Dev. 2010;56(2):200–7.

    Article  PubMed  Google Scholar 

  47. Valbuena D, Martin J, de Pablo JL, Remohi J, Pellicer A, Simon C. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril. 2001;76(5):962–8.

    Article  CAS  PubMed  Google Scholar 

  48. Bianco K, Mahutte NG, Arici A, Sakkas D, Taylor HS. Effect of estradiol on oocyte development. Int J Gynaecol Obstet : Off Organ Int Fed Gynaecol Obstet. 2009;104(3):230–2. doi:10.1016/j.ijgo.2008.10.015.

    Article  CAS  Google Scholar 

  49. Balakier H, Bouman D, Sojecki A, Librach C, Squire JA. Morphological and cytogenetic analysis of human giant oocytes and giant embryos. Hum Reprod. 2002;17(9):2394–401.

    Article  PubMed  Google Scholar 

  50. Cai Q, Wan F, Huang K, Zhang H. Does the number of oocytes retrieved influence pregnancy after fresh embryo transfer? PLoS One. 2013;8(2):e56189. doi:10.1371/journal.pone.0056189.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Meniru GI, Craft IL. Utilization of retrieved oocytes as an index of the efficiency of superovulation strategies for in-vitro fertilization treatment. Hum Reprod. 1997;12(10):2129–32.

    Article  CAS  PubMed  Google Scholar 

  52. Yih MC, Spandorfer SD, Rosenwaks Z. Egg production predicts a doubling of in vitro fertilization pregnancy rates even within defined age and ovarian reserve categories. Fertil Steril. 2005;83(1):24–9. doi:10.1016/j.fertnstert.2004.05.096.

    Article  PubMed  Google Scholar 

  53. Sunkara SK, Rittenberg V, Raine-Fenning N, Bhattacharya S, Zamora J, Coomarasamy A. Association between the number of eggs and live birth in IVF treatment: an analysis of 400 135 treatment cycles. Hum Reprod. 2011;26(7):1768–74. doi:10.1093/humrep/der106.

    Article  PubMed  Google Scholar 

  54. van der Gaast MH, Eijkemans MJ, van der Net JB, de Boer EJ, Burger CW, van Leeuwen FE, et al. Optimum number of oocytes for a successful first IVF treatment cycle. Reprod Biomed Online. 2006;13(4):476–80.

    Article  PubMed  Google Scholar 

Download references

Ethical Statement

For this type of study formal consent is not required.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Catherine Racowsky.

Additional information

Capsule The presence of a non-cleaved embryo on day 3 is associated with a decrease in the cohort quality but does not impact the clinical outcome.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Machtinger, R., Bormann, C.L., Ginsburg, E.S. et al. Is the presence of a non-cleaved embryo on day 3 associated with poorer quality of the remaining embryos in the cohort?. J Assist Reprod Genet 32, 677–683 (2015). https://doi.org/10.1007/s10815-015-0455-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-015-0455-9

Keywords

Navigation