Skip to main content
SpringerLink
Log in

Should the flexibility enabled by performing a day-4 embryo transfer remain as a valid option in the IVF laboratory? A systematic review and network meta-analysis

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

Abstract

Purpose

The present systematic review and network meta-analysis aims to uniquely bring to literature data supporting the true place of the alternative practice of day-4 embryo transfer (D4 ET) in an IVF laboratory, beyond the one-dimensional option of facilitating a highly demanding program.

Methods

A systematic search was conducted in the databases of PubMed/Medline, Embase, and Cochrane Central Library, resulting to six prospective along with nine retrospective cohort studies meeting eligibility criteria for inclusion. A comparison of D4 ET with day-2 (D2), day-3 (D3), and day-5 (D5) ET, respectively, was performed employing R statistics.

Results

The sourced results indicate no statistically significant difference regarding clinical pregnancy rates, and ongoing pregnancy/live birth rates stemming from the comparison of D4 with D2, D4 with D3, and D4 with D5 ET, respectively. Additionally, no statistically significant difference could be established in respect to cancelation, and miscarriage rates, following the comparison of D4 with D3 and D4 with D5 ET. Interestingly, we report statistically significant lower preterm birth rates associated with D4 ET, in contrast with D5 ET (RR, 0.19; 95% CI, 0.05–0.67; p value = 0.01).

Conclusions

The aforementioned results may serve as advocates buttressing the option of D4 ET as a valid candidate in the ET decision-making process. Possible limitations of the current study are the publication bias stemming from the retrospective nature of certain included studies, along with various deviations among studies’ design, referring to number and quality of transferred embryos, or different culture conditions referring to studies of previous decades.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  1. Simopoulou M, Asimakopoulos B, Bakas P, Boyadjiev N, Tzanakaki D, Creatsas G. Oocyte and embryo vitrification in the IVF laboratory: a comprehensive review. Folia Med (Plovdiv). 2014;56:161–9.

    Article  Google Scholar 

  2. Chronopoulou E, Harper JC. IVF culture media: past, present and future. Hum Reprod Update. 2015;21:39–55.

    Article  CAS  PubMed  Google Scholar 

  3. Lu L, Lv B, Huang K, Xue Z, Zhu X, Fan G. Recent advances in preimplantation genetic diagnosis and screening. J Assist Reprod Genet. 2016;33:1129–34.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Casper R, Haas J, Hsieh T-B, Bassil R, Mehta C. Recent advances in in vitro fertilization. F1000Research. 2017;6:1616.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lee S-H, Lee H-S, Lim CK, Park Y-S, Yang KM, Park DW. Comparison of the clinical outcomes of day 4 and 5 embryo transfer cycles. Clin Exp Reprod Med. 2013;40:122–5.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Kiltz RJ, Woodhouse DJ, Miller DB, Sciera AM, Corona JT. Efficacy of day 4 embryo transfer (ET) in minimizing weekend staffing requirements. Fertil Steril. 2003;80:126.

    Article  Google Scholar 

  7. Penzias A, Bendikson K, Butts S, Coutifaris C, Falcone T, Fossum G, et al. Performing the embryo transfer: a guideline. Fertil Steril. 2017;107:882–96.

    Article  Google Scholar 

  8. Holschbach V, Weigert J, Dietrich JE, Roesner S, Montag M, Strowitzki T, Toth B Pregnancy rates of day 4 and day 5 embryos after culture in an integrated time-lapse incubator. Reprod Biol Endocrinol RBE [Internet] 2017. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5422939/, 15, 37. Accessed 26 Dec 2018

  9. Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000;73:1155–8.

    Article  CAS  PubMed  Google Scholar 

  10. Artley JK, Braude PR, Johnson MH. Gene activity and cleavage arrest in human pre-embryos. Hum Reprod Oxf Engl. 1992;7:1014–21.

    Article  CAS  Google Scholar 

  11. Zamora RB, Sánchez RV, Pérez JG, Díaz RR, Quintana DB, Bethencourt JCA. Human zygote morphological indicators of higher rate of arrest at the first cleavage stage. Zygote Camb Engl. 2011;19:339–44.

    Article  Google Scholar 

  12. Niakan KK, Han J, Pedersen RA, Simon C, Pera RAR. Human pre-implantation embryo development. Dev Camb Engl. 2012;139:829–41.

    CAS  Google Scholar 

  13. Huisman GJ, Fauser BCJ, Eijkemans MJ, Pieters MHE. Implantation rates after in vitro fertilization and transfer of a maximum of two embryos that have undergone three to five days of culture. Fertil Steril. 2000;73:117–22.

    Article  CAS  PubMed  Google Scholar 

  14. Martins WP, Nastri CO, Rienzi L, van der Poel SZ, Gracia C, Racowsky C. Blastocyst vs cleavage-stage embryo transfer: systematic review and meta-analysis of reproductive outcomes. Ultrasound Obstet Gynecol. 2017;49:583–91.

    Article  CAS  PubMed  Google Scholar 

  15. Skorupski JC, Stein DE, Acholonu U, Field H, Keltz M. Successful pregnancy rates achieved with day 4 embryo transfers. Fertil Steril. 2007;87:788–91.

    Article  PubMed  Google Scholar 

  16. Miravet-Valenciano JA, Rincon-Bertolin A, Vilella F, Simon C. Understanding and improving endometrial receptivity. Curr Opin Obstet Gynecol. 2015;27:187–92.

    Article  PubMed  Google Scholar 

  17. Huisman GJ, Alberda AT, Leerentveld RA, Verhoeff A, Zeilmaker GH. A comparison of in vitro fertilization results after embryo transfer after 2, 3, and 4 days of embryo culture. Fertil Steril. 1994;61:970–1.

    Article  CAS  PubMed  Google Scholar 

  18. Feil D, Henshaw RC, Lane M. Day 4 embryo selection is equal to day 5 using a new embryo scoring system validated in single embryo transfers. Hum Reprod. 2008;23:1505–10.

    Article  PubMed  Google Scholar 

  19. Goto Y, Kanzaki H, Nakayama T, Takabatake K, Himeno T, Mori T, et al. Relationship between the day of embryo transfer and the outcome in human in vitro fertilization and embryo transfer. J Assist Reprod Genet. 1994;11:401–4.

    Article  CAS  PubMed  Google Scholar 

  20. Kang SM, Lee SW, Jeong HJ, Yoon SH, Koh MW, Lim JH, et al. Clinical outcomes of elective single morula embryo transfer versus elective single blastocyst embryo transfer in IVF-ET. J Assist Reprod Genet. 2012;29:423–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Li R-S, Hwu Y-M, Lee RK-K, Li S-H, Lin M-H. Day 4 good morula embryo transfer provided compatible live birth rate with day 5 blastocyst embryo in fresh IVF/ET cycles. Taiwan J Obstet Gynecol. 2018;57:52–7.

    Article  PubMed  Google Scholar 

  22. Montag M, van der Ven K, Dorn C, van der Ven H. Extended embryo culture reduces the implantation rate on day 4 and day 5 when only a maximum of three embryos are cultured beyond the pronuclear stage. Eur J Obstet Gynecol Reprod Biol. 2006;124:65–9.

    Article  PubMed  Google Scholar 

  23. Nada AM, Khalil RF, Sawaf A, El-halwagy A. Morula transfer as alternative to blastocyst transfer or day 3 transfer: is there a role? Evid Based Womenʼs Health J. 2015;5:43–6.

    Article  Google Scholar 

  24. Pantos K, Makrakis E, Chronopoulou M, Biba M, Perdikaris A, Dafereras A. Day 4 versus day 3 embryo transfer: a prospective study of clinical outcomes. Fertil Steril. 2008;89:573–7.

    Article  PubMed  Google Scholar 

  25. Prapas Y, Prapas N, Hatziparasidou A, Vanderzwalmen P, Nijs M, Prapa S, et al. Ultrasound-guided embryo transfer maximizes the IVF results on day 3 and day 4 embryo transfer but has no impact on day 5. Hum Reprod Oxf Engl. 2001;16:1904–8.

    Article  CAS  Google Scholar 

  26. Saadat P, Yang H, Center RSPR. Day 3 versus day 4 embryo transfer: does one day make a difference? Fertil Steril. 2004;81:23.

    Article  Google Scholar 

  27. Tao J, Tamis R, Fink K, Williams B, Nelson-White T, Craig R. The neglected morula/compact stage embryo transfer. Hum Reprod Oxf Engl. 2002;17:1513–8.

    Article  Google Scholar 

  28. Neri-Vidaurri P, Rojas-Hernández EM, Vielma-Valdez A, Serviere-Zaragoza C. Resultados de un programa de reproducción asistida con transferencia de embriones en día 4. Ginecol Obstet México. 2018;9.

  29. Pavelková J, Rezábek K, Moosová M, Svetlíková M. Extended embryo culture in IVF does not improve pregnancy rate. Ceska Gynekol. 2011;76:120–3.

    PubMed  Google Scholar 

  30. Gianaroli L, Magli M, Munné S, Fiorentino A, Montanaro N, Ferraretti A. Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy? Hum Reprod Oxf Engl. 1997;12:1762–7.

    Article  CAS  Google Scholar 

  31. Margreiter M, Weghofer A, Kogosowski A, Mahmoud KZ, Feichtinger W. A prospective randomized multicenter study to evaluate the best day for embryo transfer: does the outcome justify prolonged embryo culture? J Assist Reprod Genet. 2003;20:91–4.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Zander-Fox DL, Tremellen K, Lane M. Single blastocyst embryo transfer maintains comparable pregnancy rates to double cleavage-stage embryo transfer but results in healthier pregnancy outcomes. Aust N Z J Obstet Gynaecol. 2011;51:406–10.

    Article  PubMed  Google Scholar 

  33. Bulut H, Coetzee K, Ozgur K, Berkkanoglu M. Reduced early pregnancy loss of day 4 blastocysts transferred in artificial FET on progesterone day 5. J Assist Reprod Genet. 2016;33:1701.

    Google Scholar 

  34. Burks H, Buckbinder J, Francis-Hernandez M, Chung K, Jabara S, Bendikson K, et al. Developmentally delayed cleavage-stage embryos maintain comparable implantation rates in frozen embryo transfers. J Assist Reprod Genet. 2015;32:1477–81.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Mehrafza M. Delayed transfer of embryos from 2 to 3 or 4 days after oocyte retrieval and the pregnancy rate in ICSI. Iran J Reprod Med. 2009;7:135.

    Google Scholar 

  36. Sagiri T, Miyako MF, Hiroaki MU, Terumi MH, El Beltagy Khalid MD, Yoshitaka MN, et al. A comparison of day-3 versus day-2 and day-5 versus day-4 embryo transfers among in-vitro fertilization patients. J Clin Embryol. 2009;12:15–22.

    Google Scholar 

  37. Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016:i4919.

  38. Yin Y, Chen G, Li K, Liao Q, Zhang S, Ma N, et al. Propensity score-matched study and meta-analysis of cumulative outcomes of day 2/3 versus day 5/6 embryo transfers. Front Med. 2017;11:563–9.

    Article  PubMed  Google Scholar 

  39. Braga DPAF, Setti AS, de Cássia S, Figueira R, Machado RB, Iaconelli A, et al. Patient selection criteria for blastocyst transfers in extended embryo culture programs. J Assist Reprod Genet. 2012;29:1357–62.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Inhorn MC, Patrizio P. Infertility around the globe: new thinking on gender, reproductive technologies and global movements in the 21st century. Hum Reprod Update. 2015;21:411–26.

    Article  PubMed  Google Scholar 

  41. Glujovsky D, Farquhar C, Quinteiro Retamar AM, Alvarez Sedo CR, Blake D. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev. 2016:CD002118.

  42. Coticchio G, Lagalla C, Sturmey R, Pennetta F, Borini A. The enigmatic morula: mechanisms of development, cell fate determination, self-correction and implications for ART. Hum Reprod Update [Internet] 2019; Available from: https://academic.oup.com/humupd/advance-article/doi/10.1093/humupd/dmz008/5374477. Accessed 17 Mar 2019

  43. Kermi C, Lo Furno E, Maiorano D. Regulation of DNA replication in early embryonic cleavages. Genes. 2017;8:42.

    Article  CAS  PubMed Central  Google Scholar 

  44. Milewski R, Ajduk A. Time-lapse imaging of cleavage divisions in embryo quality assessment. Reproduction. 2017;154:R37–53.

    Article  CAS  PubMed  Google Scholar 

  45. Brison DR, Sturmey RG, Leese HJ. Metabolic heterogeneity during preimplantation development: the missing link? Hum Reprod Update. 2014;20:632–40.

    Article  PubMed  Google Scholar 

  46. Leese HJ. Metabolism of the preimplantation embryo: 40 years on. Reprod Camb Engl. 2012;143:417–27.

    CAS  Google Scholar 

  47. Alpha Scientists in Reproductive Medicine, ESHRE Special Interest Group Embryology. Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Reprod BioMed Online. 2011;22:632–46.

    Article  Google Scholar 

  48. Fabozzi G, Alteri A, Rega E, Starita MF, Piscitelli C, Giannini P, et al. Morphological assessment on day 4 and its prognostic power in selecting viable embryos for transfer. Zygote Camb Engl. 2016;24:477–84.

    Article  Google Scholar 

  49. Tao J, Tamis R, Fink K. Pregnancies achieved after transferring frozen morula/compact stage embryos. Fertil Steril. 2001;75:629–31.

    Article  CAS  PubMed  Google Scholar 

  50. Tao J, Craig RH, Johnson M, Williams B, Lewis W, White J, et al. Cryopreservation of human embryos at the morula stage and outcomes after transfer. Fertil Steril. 2004;82:108–18.

    Article  PubMed  Google Scholar 

  51. Lopes AS, Frederickx V, Van Kerkhoven G, Campo R, Puttemans P, Gordts S. Survival, re-expansion and cell survival of human blastocysts following vitrification and warming using two vitrification systems. J Assist Reprod Genet. 2015;32:83–90.

    Article  PubMed  Google Scholar 

  52. Vanderzwalmen P, Bertin G, Debauche C, Standaert V, van Roosendaal E, Vandervorst M, et al. Births after vitrification at morula and blastocyst stages: effect of artificial reduction of the blastocoelic cavity before vitrification. Hum Reprod. 2002;17:744–51.

    Article  PubMed  Google Scholar 

  53. Chen M, Wei S, Hu J, Yuan J, Liu F. Does time-lapse imaging have favorable results for embryo incubation and selection compared with conventional methods in clinical in vitro fertilization? A meta-analysis and systematic review of randomized controlled trials. Drevet JR, editor. PLoS One 2017;12:e0178720.

  54. Zhang B, Cui L, Tang R, Ding L, Yan L, Chen Z-J. Reduced ectopic pregnancy rate on day 5 embryo transfer compared with day 3: a meta-analysis. Sun Q-Y PLoS One 2017;12:e0169837.

  55. Rossant J, Tam PPL. New insights into early human development: lessons for stem cell derivation and differentiation. Cell Stem Cell. 2017;20:18–28.

    Article  CAS  PubMed  Google Scholar 

  56. Ishihara O, Araki R, Kuwahara A, Itakura A, Saito H, Adamson GD. Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan. Fertil Steril. 2014;101:128–33.

    Article  PubMed  Google Scholar 

  57. Opdahl S, Henningsen AA, Tiitinen A, Bergh C, Pinborg A, Romundstad PR, et al. Risk of hypertensive disorders in pregnancies following assisted reproductive technology: a cohort study from the CoNARTaS group. Hum Reprod Oxf Engl. 2015;30:1724–31.

    Article  CAS  Google Scholar 

  58. Chen L, Yang T, Zheng Z, Yu H, Wang H, Qin J. Birth prevalence of congenital malformations in singleton pregnancies resulting from in vitro fertilization/intracytoplasmic sperm injection worldwide: a systematic review and meta-analysis. Arch Gynecol Obstet. 2018;297:1115–30.

    Article  PubMed  Google Scholar 

  59. Kalra SK, Ratcliffe SJ, Barnhart KT, Coutifaris C. Extended embryo culture and an increased risk of preterm delivery. Obstet Gynecol. 2012;120:69–75.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Medical School, National and Kapodistrian University of Athens, 75, Mikras Asias, 11527, Athens, Greece

    M Simopoulou, P Tsioulou, A Rapani, E Maziotis, P Giannelou, S Grigoriadis & M Koutsilieris

  2. Assisted Conception Unit, 2nd Department of Obstetrics and Gynecology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 76, Vasilisis Sofias Avenue, 11528, Athens, Greece

    M Simopoulou & N Vlahos

  3. Centre for Human Reproduction, Genesis Athens Clinic, 14-16, Papanikoli, 15232, Athens, Greece

    K Sfakianoudis, A Pantou & K Pantos

  4. Assisted Reproduction Unit of Thrace “Embryokosmogenesis”, Apalos, 68132, Alexandroupoli, Greece

    K Nikolettos

Authors
  1. M Simopoulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Sfakianoudis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Tsioulou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Rapani
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Maziotis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Giannelou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S Grigoriadis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Pantou
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K Nikolettos
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N Vlahos
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K Pantos
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Koutsilieris
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Simopoulou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

K Sfakianoudis is joint first author, and K Pantos and M Koutsilieris are joint last authors

Electronic supplementary material

ESM 1

(DOCX 14 kb)

ESM 2

(PNG 5 kb)

ESM 3

(PNG 5 kb)

ESM 4

(PNG 5 kb)

ESM 5

(PNG 5 kb)

ESM 6

(PNG 5 kb)

ESM 7

(PDF 5 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Simopoulou, M., Sfakianoudis, K., Tsioulou, P. et al. Should the flexibility enabled by performing a day-4 embryo transfer remain as a valid option in the IVF laboratory? A systematic review and network meta-analysis. J Assist Reprod Genet 36, 1049–1061 (2019). https://doi.org/10.1007/s10815-019-01475-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-019-01475-0

Keywords

Search

Navigation