Unexplained Total Fertilization Failure after Intracytoplasmic Sperm Injection Cycles: A Case-Control Study on Predictive Factors and Retreatment Prognosis

Document Type : Original Article


1 Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

2 Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran


Background: The aim of our study was to detect the rate of unexplained total fertilization failure (TFF) after intracytoplasmic sperm injection (ICSI) and identify its risk factors and retreatment prognosis.
Materials and Methods: In this retrospective case-control study, we searched the computerized database of
the Royan Institute (Tehran, Iran) from March 2015 to March 2019 and retrieved all cases diagnosed with
TFF after ICSI. TFF cases that did not have any recognized risk factors were classified as unexplained (subgroup
A). Cases with recognized risk factors were classified as subgroup B. The control group was randomly
selected from infertile couples who underwent ICSI cycles with fertilization of at least one oocyte during the
same time interval. Characteristics and treatment outcomes of the cases with unexplained TFF (subgroup A)
were compared to the control group, and to the other TFF cases (subgroup B).
Results: Out of 18,750 couples who underwent ICSI cycles, 296 (1.58%) experienced TFF for the first time.
Of these, 49 (16.5%) couples were diagnosed as unexplained TFF (subgroup A) and 247 (83.5%) were placed
in subgroup B, TFF with expected risk factors. Multivariable logistic regression analysis showed that the total
number of mature oocytes (P<0.001), duration of infertility (P=0.043), and women’s body mass index (BMI,
P<0.001) were significant predictive factors for unexplained TFF. In the ICSI cycle after TFF, clinical pregnancy
and live birth rates in subgroup A were higher than subgroup B. Although differences between these
groups were not statistically significant (P=0.14 and P=0.07, respectively), this finding could be clinically
Conclusion: Unexplained TFF following ICSI is a rare event significantly related to a lower number of mature
oocytes, longer duration of infertility and higher female BMI. It has a good prognosis in retreatment cycles in
comparison with expected TFF cases. Clinicians should take this into consideration for patient counseling and


  1. Kahyaoglu I, Demir B, Turkkanı A, Cınar O, Dilbaz S, Dilbaz B, et al. Total fertilization failure: is it the end of the story? J Assist Reprod Genet. 2014; 31(9): 1155-1160.
  2. Mahutte NG, Arici A. Failed fertilization: is it predictable? Curr Opin Obstet Gynecol. 2003; 15(3): 211-218.
  3. Flaherty SP, Payne D, Matthews CD. Fertilization failures and abnormal fertilization after intracytoplasmic sperm injection. Hum Reprod. 1998; 13 Suppl 1: 155-164.
  4. Bhattacharya S, Hamilton MP, Shaaban M, Khalaf Y, Seddler M, Ghobara T, et al. Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial. Lancet. 2001; 357(9274): 2075-2079.
  5. Sarikaya E, Eryilmaz OG, Deveer R, Dogan M, Mollamahmutoglu L. Analysis of 232 total fertilization failure cycles during intracytoplasmic sperm injection. Iran J Reprod Med. 2011; 9(2): 105-112.
  6. Nasr-Esfahani MH, Razavi S, Tavalaee M. Failed fertilization after ICSI and spermiogenic defects. Fertil Steril. 2008; 89(4): 892-898.
  7. Sang Q, Li B, Kuang Y, Wang X, Zhang Z, Chen B, et al. Homozygous mutations in WEE2 cause fertilization failure and female infertility. Am J Hum Genet. 2018; 102(4): 649-657.
  8. Yeste M, Jones C, Amdani SN, Patel S, Coward K. Oocyte activation deficiency: a role for an oocyte contribution? Hum Reprod Update. 2016; 22(1): 23-47.
  9. Flaherty SP, Dianna P, Swann NJ, Matthews CD. Aetiology of failed and abnormal fertilization after intracytoplasmic sperm injection. Hum Reprod. 1995; 10(10): 2623-2629.
  10. Madani T, Ashrafi M, Mohammadi Yeganeh L. Comparison of different stimulation protocols efficacy in poor responders undergoing IVF: a retrospective study. Gynecol Endocrinol. 2012; 28(2): 102-105.
  11. Cooper TG, Noonan E, Von Eckardstein S, Auger J, Baker HWG, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010; 16(3): 231-245.
  12. Ashrafi M, Karimian L, Eftekhari-Yazdi P, Hasani F, Arabipoor A, Bahmanabadi A, et al. Effect of oocyte dysmorphisms on intracytoplasmic sperm injection cycle outcomes in normal ovarian responders. J Obstet Gynaecol Res. 2015; 41(12): 1912-1920.
  13. Goksan Pabuccu E, Sinem Caglar G, Dogus Demirkiran O, Pabuçcu R. Uncommon but devastating event: total fertilisation failure following intracytoplasmic sperm injection. Andrologia. 2016; 48(2): 164-170.
  14. Esfandiari N, Javed MH, Gotlieb L, Casper RF. Complete failed fertilization after intracytoplasmic sperm injection-analysis of 10 years' data. Int J Fertil Womens Med. 2005; 50(4): 187-192.
  15. Shinar S, Almog B, Levin I, Shwartz T, Amit A, Hasson J. Total fertilization failure in intra-cytoplasmic sperm injection cycles–classification and management. Gynecol Endocrinol. 2014; 30(8): 593-596.
  16. Zhang D, Zhu Y, Gao H, Zhou B, Zhang R, Wang T, et al. Overweight and obesity negatively affect the outcomes of ovarian stimulation and in vitro fertilisation: a cohort study of 2628 Chinese women. Gynecol Endocrinol. 2010; 26(5): 325-332.
  17. Metwally M, Cutting R, Tipton A, Skull J, Ledger WL, Li TC. Effect of increased body mass index on oocyte and embryo quality in IVF patients. Reprod Biomed Online. 2007; 15(5): 532-538.
  18. Yang C, Zhou ZH, Zheng DN, Xu XF, Huang J, Lian Y, et al. Sperm origins and concentration do not impact the clinical outcomes in intracytoplasmic sperm injection cycles. Asian J Androl. 2018; 20(5): 454-458.
  19. Krog M, Prior M, Carlsen E, Loft A, Forman J, Pinborg A, et al. Fertilization failure after IVF in 304 couples—a case-control study on predictors and long-term prognosis. Eur J Obstet Gynecol Reprod Biol. 2015; 184: 32-37.
  20. Khatun A, Rahman MS, Pang MG. Clinical assessment of the male fertility. Obstet Gynecol Sci. 2018; 61(2): 179-191.
  21. Melie NA, Adeniyi OA, Igbineweka OM, Ajayi RA. Predictive value of the number of oocytes retrieved at ultrasound-directed follicular aspiration with regard to fertilization rates and pregnancy outcome in intracytoplasmic sperm injection treatment cycles. Fertil Steril. 2003; 80(6): 1376-1379.
  22. Fleming SD, King RS. Micromanipulation in assisted conception. Cambridge: Cambridge University Press; 2003.
  23. Zhang Y, Ma Y, Fang Z, Hu S, Li Z, Zhu L, et al. Performing ICSI within 4 hours after denudation optimizes clinical outcomes in ICSI cycles. Reprod Biol Endocrinol. 2020; 18(1): 27.
  24. Cardona Barberán A, Boel A, Vanden Meerschaut F, Stoop D, Heindryckx B. Diagnosis and treatment of male infertility-related fertilization failure. J Clin Med. 2020; 9(12): 3899.