Efficacy of Artificial Oocyte Activation in Improving the Reproductive Outcome in Poor Responders: A Single Centre Cohort Study
,
Abstract
Objective: Achieving pregnancy in poor ovarian response patients is a challenge. Failed fertilization after ICSI, despite normal semen parameters is due to defects in oocyte activation. In-vitro activation of oocytes using Ca+2 agents can be useful in increasing the fertilization rates in these patients. This study aimed to evaluate the efficacy of artificial oocyte activation by calcium ionophores in poor responders in improving fertilization, cleavage, implantation and clinical pregnancy rates.
Materials and methods: This is a prospective, cohort study conducted on 120 patients having poor ovarian response, (POSEIDON criteria) undergoing in-vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment at Southend Fertility and IVF, New Delhi from 1st August 2019 to 31st March 2020. Exclusion criterion was patients with partners with abnormal semen parameters. After OPU patients were randomized into two groups, study group (n=50) underwent ICSI-AOA (ICSI followed by artificial oocyte activation) using calcium ionophore- GM508 Cult-Active Solution) while the controls (n=57) were subjected to ICSI only.
Results: Comparison of ICSI-AOA and ICSI groups showed: (i) number of fertilized oocytes - 2.42 vs. 2.16, p = 0.049 (ii) No. of cleavage stage embryos 2.32 vs. 1.96, p = 0.008 (iii) No. of grade A embryos 1.52 vs. 1.04, p = 0.009 (iv) fertilization rate - 89.00% vs. 83.04%, p = 0.093 (v) cleavage rate - 96.33% vs. 92.55%, p = 0.165 (vi) implantation rate - 27.14% vs. 11.74%, p = 0.098 (vii) clinical pregnancy rate - 34.3% vs. 20.5%, p = 0.167.
Conclusion: The number of fertilized oocytes, grade A embryos and cleavage stage embryos formed after ICSI-AOA were statistically significantly more than ICSI. ICSI-AOA has not shown improvement in fertilization, cleavage, implantation and clinical pregnancy rate. From the present study the conclusive evidence cannot be drawn due to small sample size hence further studies are needed on a larger population.
1. Drakopoulos P, Blockeel C, Stoop D, Camus M, Vos M, Tournaye H. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod 2016; 31(2): 370–6.
2. 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.
3. Esteves SC, Roque M, Bedoschi GM, Conforti A, Humaidan P, Alviggi C. Defining Low Prognosis Patients Undergoing Assisted Reproductive Technology: POSEIDON Criteria-The Why. Front Endocrinol (Lausanne). 2018 Aug 17;9:461.
4. Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: An overlooked group. Hum Reprod 2015; 30(9): 2005-8.
5. Malchau SS, Henningsen AA, Loft A, Rasmussen S, Forman J, Nyboe Andersen A, et al. The long-term prognosis for live birth in couples initiating fertility treatments. Hum Reprod 2017; 32 (7): 1439–49.
6. Haahr T, Roque M, Esteves SC, Humaidan P. GnRH agonist trigger and LH activity luteal phase support versus hCG trigger and conventional luteal phase support in fresh embryo transfer IVF/ICSI cycles-a systematic PRISMA review and meta-analysis. Front Endocrinol (Lausanne). 2017; 8:116.
7. Krog M, Prior M, Carlsen E, Loft A, Forman J, Pinborg A, Andersen AN. Fertilization failure after IVF in 304 couples--a case-control study on predictors and long-term prognosis. Eur J Obstet Gynecol Reprod Biol. 2015 Jan;184:32-7.
8. Kocourkova J, Burcin B, Kucera T. Demographic relevancy of increased use of assisted reproduction in European countries. Reprod Health. 2014 May 26;11:37.
9. Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One 2010; 5 (1): e8772.
10. Alviggi C, Conforti A, Caprio F, Gizzo S, Noventa M, Strina I, et al. Is estimated good prognosis patients could unexpected “hyporesponse” to controlled ovarian stimulation be related to genetic polymorphisms of FSH receptors. Reprod Sci 2016; 23(8): 1103–8.
11. La Marca A, Papaleo E, Alviggi C, Ruvolo G, De Placido G, Candiani M. The combination of genetic variants of the FSHB and FSHR genes affects serum FSH in women of reproductive age. Hum Reprod 2013; 28 (5): 1369–74.
12. Van Steirteghem AC, Nagy Z, Joris H, Liu J, Staessen C, Smitz J, et al. High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod 1993; 8(7): 1061–6.
13. Neri QV, Lee B, Rosenwaks Z, Machaca K, Palermo GD. Understanding fertilization through intracytoplasmic sperm injection (ICSI). Cell Calcium 2014; 55: 24–37.
14. Williams CJ. Signalling mechanisms of mammalian oocyte activation. Hum Reprod 2002; 8(4): 313–21
15. Tarin JJ, Perez Albala S, Perez Hoyos S, Cano A. Postovulatory ageing of oocytes decreases reproductive fitness and longevity of offspring. Biol Reprod 2002; (66): 495-9.
16. Ebner T, Koster M, Shebl O, Moser M, Ven VH, Tews G, Montag M. Application of a ready-to-use calcium ionophore increases rates of fertilization and pregnancy in severe male factor infertility. Fertil Steril 2012; 98(6): 1432-7.
17. Vanden Meerschaut F, Nikiforaki D, Heindryckx B, De Sutter P. Assisted oocyte activation following ICSI fertilization failure. Reprod Biomed Online. 2014 May;28(5):560-71.
18. Heindryckx B, De Gheselle S, Gerris J, Dhont M, De Sutter P. Efficiency of assisted oocyte activation as a solution for failed intracytoplasmic sperm injection. Reprod Biomed Online. 2008 Nov;17(5):662-8.
19. Yanagida K, Morozumi K, Katayose H, Hayashi S, Sato A. Successful pregnancy after ICSI with strontium oocyte activation in low rates of fertilization. Reprod Biomed Online. 2006 Dec;13(6):801-6.
20. Caglar Aytac P, Kilicdag EB, Haydardedeoglu B, Simsek E, Cok T, Parlakgumus HA. Can calcium ionophore “use” in patients with diminished ovarian reserve increase fertilization and pregnancy rates? A randomized, controlled study. Fertil Steril 2015; 104(5): 1168–74.
21. Ubaldi F, Vaiarelli A, D'Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? Biomed Res Int. 2014;2014:352098.
22. Conforti A, Esteves SC, Danilo C, Alberto V, Rella Di, Ubladi MF, Zullo F, Placido D G, Alviggi G. Management of women with an unexpected low ovarian response to gonadotropin. Front Endocrinol (Lausanne). 2019 Jun 27;10:387.
23. Craft I, Gorgy A, Hill J, Menon D, Podsiadly B. Will GnRH antagonists provide new hope for patients considered 'difficult responders' to GnRH agonist protocols? Hum Reprod. 1999 Dec;14(12):2959-62.
24. Quigley MM. The use of ovulation-inducing agents in in-vitro fertilization. Clin Obstet Gynecol. 1984 Dec;27(4):983-92. Wang B, Sun HX, Hu YL, Chen H, Zhang NY. Application of GnRH-antagonist to IVF-ET for patients with poor ovarian response. National Journal of Andrology 2008; 14: 423–6
25. Wang B, Sun HX, Hu YL, Chen H, Zhang NY. [Application of GnRH-antagonist to IVF-ET for patients with poor ovarian response]. Zhonghua Nan Ke Xue. 2008 May;14(5):423-6. Chinese.
26. Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis. J Hum Reprod Sci 2016; 9(2): 70-81.
27. Fisch JD, Keskintepe L, Sher G. Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming in low responders with prior in vitro fertilization failure. Fertil Steril. 2008 Feb;89(2):342-7.
28. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril. 2002 Apr;77(4):776-80.
29. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, Chakravarty B.N, Kabir S.N. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004; 19 (9): 2031-5.
30. Khamsi F, Yavas Y, Roberge S, Wong JC, Lacanna IC, Endman M. Intracytoplasmic sperm injection increased fertilization and good-quality embryo formation in patients with non-male factor indications for in vitro fertilization: a prospective randomized study. Fertil Steril. 2001 Feb;75(2):342-7.
31. Yang D, Shahata MA, al-Bader M, al-Natsha SD, al-Flamerzia M, al-Shawaf T. Intracytoplasmic sperm injection improving embryo quality: comparison of the sibling oocytes of non-male-factor couples. J Assist Reprod Genet. 1996 Apr;13(4):351-5.
32. Montag M, Köster M, van der Ven K, Bohlen U, van der Ven H. The benefit of artificial oocyte activation is dependent on the fertilization rate in a previous treatment cycle. Reprod Biomed Online. 2012 May;24(5):521-6.
33. Yoon HJ, Bae IH, Kim HJ, Jang JM, Hur YS, Kim HK, Yoon SH, Lee WD, Lim JH. Analysis of clinical outcomes with respect to spermatozoan origin after artificial oocyte activation with a calcium ionophore.
J Assist Reprod Genet. 2013 Dec;30(12):1569-75.
34. Berridge MJ. Calcium signalling and cell proliferation. Bioessays. 1995 Jun;17(6):491-500.
35. Yu Y, Saunders CM, Lai FA, Swann K. Preimplantation development of mouse oocytes activated by different levels of human phospholipase C zeta. Hum Reprod. 2008 Feb;23(2):365-73.
36. Whitaker M. Calcium at fertilization and in early development. Physiol Rev. 2006 Jan;86(1):25-88. doi: 10.1152/physrev.00023.2005.
37. Ebner T, Oppelt P, Wober M, Staples P, Mayer RB, Sonnleitner U. Treatment with Ca2+ ionophore improves embryo development and outcome in cases with previous developmental problems: a prospective multicenter study. Hum Reprod 2015; 30(1): 97-102.
38. Oatway C, Gunby, Daya S. Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2004; 2: CD004378.
39. Bahceci M, Ulug U, Ciray HN, Akman MA, Erden HF. Efficiency of changing the embryo transfer time from day 3 to day 2 among women with poor ovarian response: a prospective randomized trial. Fertil Steril 2006; 86(1): 81-5.
40. Glujovsky D, Blake D, Farquhar C, Bardach A. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev 2012; 7: CD002118.
41. Berkkanoglu M, Coetzee K, Bulut H, Ozgur K. Optimal embryo transfer strategy in poor response may include freeze-all. J Assist Reprod Genet 2017; 34(1): 79-87.
42. Veiga A, Gianaroli L, Ory S, Horton M, Feinberg E, Penzias A. Assisted reproduction and COVID-19: A joint statement of ASRM, ESHRE and IFFS. Fertil Steril. 2020 Sep;114(3):484-485.
43. Murugesu S, Saso S, Jones BP, Milnes TB, Athanasiou T, Mania A, Serhal P, Nagi JB. Does the use of calcium ionophore during artificial oocyte activation demonstrate an effect on pregnancy rate? A meta-analysis. Fertility and sterility 2017; 108(3): 468-82.
2. 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.
3. Esteves SC, Roque M, Bedoschi GM, Conforti A, Humaidan P, Alviggi C. Defining Low Prognosis Patients Undergoing Assisted Reproductive Technology: POSEIDON Criteria-The Why. Front Endocrinol (Lausanne). 2018 Aug 17;9:461.
4. Polyzos NP, Sunkara SK. Sub-optimal responders following controlled ovarian stimulation: An overlooked group. Hum Reprod 2015; 30(9): 2005-8.
5. Malchau SS, Henningsen AA, Loft A, Rasmussen S, Forman J, Nyboe Andersen A, et al. The long-term prognosis for live birth in couples initiating fertility treatments. Hum Reprod 2017; 32 (7): 1439–49.
6. Haahr T, Roque M, Esteves SC, Humaidan P. GnRH agonist trigger and LH activity luteal phase support versus hCG trigger and conventional luteal phase support in fresh embryo transfer IVF/ICSI cycles-a systematic PRISMA review and meta-analysis. Front Endocrinol (Lausanne). 2017; 8:116.
7. Krog M, Prior M, Carlsen E, Loft A, Forman J, Pinborg A, Andersen AN. Fertilization failure after IVF in 304 couples--a case-control study on predictors and long-term prognosis. Eur J Obstet Gynecol Reprod Biol. 2015 Jan;184:32-7.
8. Kocourkova J, Burcin B, Kucera T. Demographic relevancy of increased use of assisted reproduction in European countries. Reprod Health. 2014 May 26;11:37.
9. Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One 2010; 5 (1): e8772.
10. Alviggi C, Conforti A, Caprio F, Gizzo S, Noventa M, Strina I, et al. Is estimated good prognosis patients could unexpected “hyporesponse” to controlled ovarian stimulation be related to genetic polymorphisms of FSH receptors. Reprod Sci 2016; 23(8): 1103–8.
11. La Marca A, Papaleo E, Alviggi C, Ruvolo G, De Placido G, Candiani M. The combination of genetic variants of the FSHB and FSHR genes affects serum FSH in women of reproductive age. Hum Reprod 2013; 28 (5): 1369–74.
12. Van Steirteghem AC, Nagy Z, Joris H, Liu J, Staessen C, Smitz J, et al. High fertilization and implantation rates after intracytoplasmic sperm injection. Hum Reprod 1993; 8(7): 1061–6.
13. Neri QV, Lee B, Rosenwaks Z, Machaca K, Palermo GD. Understanding fertilization through intracytoplasmic sperm injection (ICSI). Cell Calcium 2014; 55: 24–37.
14. Williams CJ. Signalling mechanisms of mammalian oocyte activation. Hum Reprod 2002; 8(4): 313–21
15. Tarin JJ, Perez Albala S, Perez Hoyos S, Cano A. Postovulatory ageing of oocytes decreases reproductive fitness and longevity of offspring. Biol Reprod 2002; (66): 495-9.
16. Ebner T, Koster M, Shebl O, Moser M, Ven VH, Tews G, Montag M. Application of a ready-to-use calcium ionophore increases rates of fertilization and pregnancy in severe male factor infertility. Fertil Steril 2012; 98(6): 1432-7.
17. Vanden Meerschaut F, Nikiforaki D, Heindryckx B, De Sutter P. Assisted oocyte activation following ICSI fertilization failure. Reprod Biomed Online. 2014 May;28(5):560-71.
18. Heindryckx B, De Gheselle S, Gerris J, Dhont M, De Sutter P. Efficiency of assisted oocyte activation as a solution for failed intracytoplasmic sperm injection. Reprod Biomed Online. 2008 Nov;17(5):662-8.
19. Yanagida K, Morozumi K, Katayose H, Hayashi S, Sato A. Successful pregnancy after ICSI with strontium oocyte activation in low rates of fertilization. Reprod Biomed Online. 2006 Dec;13(6):801-6.
20. Caglar Aytac P, Kilicdag EB, Haydardedeoglu B, Simsek E, Cok T, Parlakgumus HA. Can calcium ionophore “use” in patients with diminished ovarian reserve increase fertilization and pregnancy rates? A randomized, controlled study. Fertil Steril 2015; 104(5): 1168–74.
21. Ubaldi F, Vaiarelli A, D'Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? Biomed Res Int. 2014;2014:352098.
22. Conforti A, Esteves SC, Danilo C, Alberto V, Rella Di, Ubladi MF, Zullo F, Placido D G, Alviggi G. Management of women with an unexpected low ovarian response to gonadotropin. Front Endocrinol (Lausanne). 2019 Jun 27;10:387.
23. Craft I, Gorgy A, Hill J, Menon D, Podsiadly B. Will GnRH antagonists provide new hope for patients considered 'difficult responders' to GnRH agonist protocols? Hum Reprod. 1999 Dec;14(12):2959-62.
24. Quigley MM. The use of ovulation-inducing agents in in-vitro fertilization. Clin Obstet Gynecol. 1984 Dec;27(4):983-92. Wang B, Sun HX, Hu YL, Chen H, Zhang NY. Application of GnRH-antagonist to IVF-ET for patients with poor ovarian response. National Journal of Andrology 2008; 14: 423–6
25. Wang B, Sun HX, Hu YL, Chen H, Zhang NY. [Application of GnRH-antagonist to IVF-ET for patients with poor ovarian response]. Zhonghua Nan Ke Xue. 2008 May;14(5):423-6. Chinese.
26. Jeve YB, Bhandari HM. Effective treatment protocol for poor ovarian response: A systematic review and meta-analysis. J Hum Reprod Sci 2016; 9(2): 70-81.
27. Fisch JD, Keskintepe L, Sher G. Gonadotropin-releasing hormone agonist/antagonist conversion with estrogen priming in low responders with prior in vitro fertilization failure. Fertil Steril. 2008 Feb;89(2):342-7.
28. Mitwally MF, Casper RF. Aromatase inhibition improves ovarian response to follicle-stimulating hormone in poor responders. Fertil Steril. 2002 Apr;77(4):776-80.
29. Goswami SK, Das T, Chattopadhyay R, Sawhney V, Kumar J, Chaudhury K, Chakravarty B.N, Kabir S.N. A randomized single-blind controlled trial of letrozole as a low-cost IVF protocol in women with poor ovarian response: a preliminary report. Hum Reprod 2004; 19 (9): 2031-5.
30. Khamsi F, Yavas Y, Roberge S, Wong JC, Lacanna IC, Endman M. Intracytoplasmic sperm injection increased fertilization and good-quality embryo formation in patients with non-male factor indications for in vitro fertilization: a prospective randomized study. Fertil Steril. 2001 Feb;75(2):342-7.
31. Yang D, Shahata MA, al-Bader M, al-Natsha SD, al-Flamerzia M, al-Shawaf T. Intracytoplasmic sperm injection improving embryo quality: comparison of the sibling oocytes of non-male-factor couples. J Assist Reprod Genet. 1996 Apr;13(4):351-5.
32. Montag M, Köster M, van der Ven K, Bohlen U, van der Ven H. The benefit of artificial oocyte activation is dependent on the fertilization rate in a previous treatment cycle. Reprod Biomed Online. 2012 May;24(5):521-6.
33. Yoon HJ, Bae IH, Kim HJ, Jang JM, Hur YS, Kim HK, Yoon SH, Lee WD, Lim JH. Analysis of clinical outcomes with respect to spermatozoan origin after artificial oocyte activation with a calcium ionophore.
J Assist Reprod Genet. 2013 Dec;30(12):1569-75.
34. Berridge MJ. Calcium signalling and cell proliferation. Bioessays. 1995 Jun;17(6):491-500.
35. Yu Y, Saunders CM, Lai FA, Swann K. Preimplantation development of mouse oocytes activated by different levels of human phospholipase C zeta. Hum Reprod. 2008 Feb;23(2):365-73.
36. Whitaker M. Calcium at fertilization and in early development. Physiol Rev. 2006 Jan;86(1):25-88. doi: 10.1152/physrev.00023.2005.
37. Ebner T, Oppelt P, Wober M, Staples P, Mayer RB, Sonnleitner U. Treatment with Ca2+ ionophore improves embryo development and outcome in cases with previous developmental problems: a prospective multicenter study. Hum Reprod 2015; 30(1): 97-102.
38. Oatway C, Gunby, Daya S. Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev 2004; 2: CD004378.
39. Bahceci M, Ulug U, Ciray HN, Akman MA, Erden HF. Efficiency of changing the embryo transfer time from day 3 to day 2 among women with poor ovarian response: a prospective randomized trial. Fertil Steril 2006; 86(1): 81-5.
40. Glujovsky D, Blake D, Farquhar C, Bardach A. Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. Cochrane Database Syst Rev 2012; 7: CD002118.
41. Berkkanoglu M, Coetzee K, Bulut H, Ozgur K. Optimal embryo transfer strategy in poor response may include freeze-all. J Assist Reprod Genet 2017; 34(1): 79-87.
42. Veiga A, Gianaroli L, Ory S, Horton M, Feinberg E, Penzias A. Assisted reproduction and COVID-19: A joint statement of ASRM, ESHRE and IFFS. Fertil Steril. 2020 Sep;114(3):484-485.
43. Murugesu S, Saso S, Jones BP, Milnes TB, Athanasiou T, Mania A, Serhal P, Nagi JB. Does the use of calcium ionophore during artificial oocyte activation demonstrate an effect on pregnancy rate? A meta-analysis. Fertility and sterility 2017; 108(3): 468-82.
| Files | ||
| Issue | Vol 17, No 1 (March 2023) | |
| Section | Original Articles | |
| DOI | https://doi.org/10.18502/jfrh.v17i1.11977 | |
| Keywords | ||
| Calcium Ionophore Poseidon Criteria Bologna Classification Intra cytoplasmic Sperm Injection (ICSI) | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Kaur B, Malik S, Prakash V, Bhatia V, Gupta D. Efficacy of Artificial Oocyte Activation in Improving the Reproductive Outcome in Poor Responders: A Single Centre Cohort Study. J Family Reprod Health. 2023;17(1):45-53.
