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Meta-Analysis
. 2024 Dec 20;12(12):CD014040.
doi: 10.1002/14651858.CD014040.pub2.

Oocyte activation for women following intracytoplasmic sperm injection (ICSI)

Mohan S Kamath  1 , Paraskevi Vogiatzi  2 , Sesh Kamal Sunkara  3 , Bryan Woodward  4
Affiliations
Meta-Analysis

Oocyte activation for women following intracytoplasmic sperm injection (ICSI)

Mohan S Kamath et al. Cochrane Database Syst Rev. .

Abstract

Background: Intracytoplasmic sperm injection (ICSI), a type of assisted reproductive technology (ART), is offered as a treatment option for male factor infertility. Over the years, the indications for ICSI have been expanded, despite uncertainty about its benefits and harms compared to the conventional method of achieving fertilisation. Artificial oocyte activation (AOA), which can be performed by chemical, electrical or mechanical intervention, has been employed during ART ICSI treatment where there has been a history of low fertilization rate or total fertilization failure, and it has been reported to improve reproductive outcomes. It is important to evaluate the clinical effectiveness and safety of AOA in women undergoing ART ICSI treatment.

Objectives: To evaluate the benefits and harms of artificial oocyte activation in women affected by infertility undergoing intracytoplasmic sperm injection treatment.

Search methods: We searched the following electronic databases: the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov and WHO international Clinical Trials Registry Platform (8 August 2024). We also searched reference lists of relevant articles and contacted experts in the field.

Selection criteria: Randomized controlled trials comparing artificial oocyte activation (AOA) (chemical, electrical or mechanical interventions) versus no intervention, placebo or another method of AOA in women undergoing ART.

Data collection and analysis: We used methodological procedures as per Cochrane recommendations. We assessed the risk of bias in the included studies using ROB 2. The primary outcomes were live birth and miscarriage rates. We analyzed data using the risk ratio (RR) and a fixed-effect model. We assessed the certainty of the evidence by using GRADE criteria. We restricted the primary analyses to studies at low risk of bias.

Main results: We included a total of 20 studies, four of which were participant-based randomized trials with 743 participants. The remaining 16 were sibling-oocyte-model randomized studies. We based the main clinical findings of the current review on the participant-based RCTs, and we restricted our primary analysis to studies with a low risk of bias. Based on the one trial with 343 participants that we included in our primary analysis, the evidence is very uncertain about the effect of AOA on the live birth rate when compared to conventional ICSI without AOA in women undergoing ART ICSI (RR 1.97, 95% CI 1.29 to 3.01; one trial; 343 participants). For a typical clinic with a live birth rate of 18% following ART, the addition of AOA may result in live birth rates between 24% and 55%, but this evidence is very uncertain. The evidence is very uncertain about the effect of AOA on the miscarriage rate compared to conventional ICSI without AOA in women undergoing ART ICSI (RR 0.99, 95% CI 0.48 to 2.04; one trial; 343 participants). If the miscarriage rate was 9% following ART, addition of oocyte activation may result in miscarriage rates between 4% and 18%, but this evidence is very uncertain. The evidence is very uncertain about the effect of AOA on the clinical pregnancy rate compared to conventional ICSI without AOA in women undergoing ART ICSI (RR 1.67, 95% CI 1.20 to 2.32; one trial; 343 participants). The evidence is very uncertain about the effect of AOA on the multiple pregnancy rate per participant compared to conventional ICSI without AOA in women undergoing ART ICSI (RR 1.91, 95% CI 0.48 to 7.67; one trial; 343 participants). The evidence is very uncertain about the effect of AOA on the total fertilization failure rate compared to conventional ICSI without AOA in women undergoing ART ICSI (RR 0.05, 95% CI 0.01 to 0.40; one trial; 343 participants). When we stratified our analysis according to various infertility factors, we found low-certainty evidence that in couples undergoing ICSI treatment who have had a history of low or no fertilization, AOA may help improve the live birth rate while making little or no difference to the miscarriage rate. Further research is needed to confirm or refute this finding. None of the trials reported congenital anomalies (birth defects) as an outcome. Lack of short- or long-term safety data is an important limitation of the review and of the trials in this field. We did not find any trials that compared two different methods of oocyte activation.

Authors' conclusions: We are uncertain about the effect of AOA on the live birth and miscarriage rates in women undergoing ART ICSI. In the subpopulation of those who have had a previous history of low or no fertilization, AOA may result in an increase in the live birth rate when compared to conventional ICSI without AOA, while making little or no difference to the miscarriage rate. There was considerable variation in the protocols used for chemical AOA, which affects the generalizability of the findings. Due to the very low to low certainty of evidence, the results should be interpreted with caution.

PubMed Disclaimer

Conflict of interest statement

Mohan S Kamath is an editorial board member with Cochrane Gynaecology and Fertility but did not take part in the peer review or editorial process for the review. He does not have any other conflict of interest.

Paraskevi Vogiatzi is an editorial board member with Cochrane Gynaecology and Fertility but did not take part in the peer review or editorial process for the review. She does not have any other conflict of interest to declare.

Sesh Kamal Sunkara has no conflict of interest to declare.

Bryan Woodward has no conflict of interest to declare.

Figures

1
1
PRISMA flowchart of study selection process
1.1
1.1. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 1: Live birth per participant randomized (low risk of bias studies)
1.2
1.2. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 2: Live birth per participant randomized (all studies)
1.3
1.3. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 3: Miscarriage rate per participant (low risk of bias studies)
1.4
1.4. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 4: Miscarriage per participant randomized (all studies)
1.5
1.5. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 5: Clinical pregnancy rate per participant (low risk of bias studies)
1.6
1.6. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 6: Clinical pregnancy per participant randomized (all studies)
1.7
1.7. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 7: Multiple pregnancy per participant randomized (low risk of bias studies)
1.8
1.8. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 8: Total fertilization failure rate per participant randomized (low risk of bias studies)
1.9
1.9. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 9: Total fertilization failure per participant (all studies)
1.10
1.10. Analysis
Comparison 1: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (participant‐based RCTs), Outcome 10: Still birth rate per participant randomized (low risk of bias studies)
2.1
2.1. Analysis
Comparison 2: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (sibling‐oocyte‐model randomized studies), Outcome 1: Fertilization rate
2.2
2.2. Analysis
Comparison 2: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (sibling‐oocyte‐model randomized studies), Outcome 2: Cleavage rate
2.3
2.3. Analysis
Comparison 2: Oocyte activation versus no oocyte activation in women undergoing ART‐ICSI (sibling‐oocyte‐model randomized studies), Outcome 3: Blastocyst development rate
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Al‐Faqheri 2023 {published data only}
    1. Al-Faqheri MAZ, Al-Obaidi MT, Al-Kawaz U. Ca ionophore vs. standard culture media In cryopreserved semen of Iraqi patients undergoing ICSI cycles. Journal of Population Therapeutics & Clinical Pharmacology 2023;30(8):e325-9. [DOI: 10.47750/jptcp.2023.30.08.035] - DOI
    1. Alhoda Zaid Al-Faqheri M (Al-Nahrain University Baghdad, Iraq). [personal communication]. Conversation with: MS Kamath (Cochrane review contact author) 9 August 2024.
Aydinuraz 2016 {published data only}
    1. Aydinuraz B, Dirican EK, Olgan S, Aksunger O, Erturk OK. Artificial oocyte activation after intracytoplasmic morphologically selected sperm injection: a prospective randomized sibling oocyte study. Human Fertility (Cambridge) 2016;19(4):282-88. [DOI: 10.1080/14647273.2016.1240374] - DOI - PubMed
    1. Dirican EK, Aksunger O, Erel LR, Aydinuraz B. Fertilization and embryo quality with and without artificial oocyte activation in teratozoospermia after intracytoplasmic morphologically selected sperm injection: a prospective randomized sibling-oocyte study. In: Reproductive Biomedicine Online. Vol. 28 (Suppl 1). 2014:S13-4.
Caglar Aytac 2015 {published data only}
    1. 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. Fertility and Sterility 2015;104(3):1168-74. [DOI: 10.1016/j.fertnstert.2015.07.1163] - DOI - PubMed
    1. NCT02045914. Calcium ionophore solution can increase fertilization rate in patients during intracytoplasmic sperm injection (ICSI) who have poor ovarian reserve? https://classic.clinicaltrials.gov/ct2/show/NCT02045914 (first posted 27 January 2014).
Darwish 2016 {published data only}
    1. Darwish E, Magdi Y. A prospective randomized controlled trial investigating embryonic development and clinical outcome after using Ca2+ ionophore in cases with previous fertilization arrest. In: Human Reproduction. Vol. 31 (Suppl 1). 2016:i2.
    1. NCT02683031. Effect of Ca2+ ionophore on embryonic development and clinical outcome in cases with previous fertilization arrest. https://classic.clinicaltrials.gov/ct2/show/NCT02683031 (first posted on 17 February 2016).
Ebner 2004 {published data only}
    1. Ebner T, Moser M, Sommergruber M, Jesacher K, Tews G. Complete oocyte activation failure after ICSI can be overcome by a modified injection technique. Human Reproduction 2004;19(8):1837-41. [PMID: ] - PubMed
Fawzy 2018 {published data only}
    1. Fawzy M (IbnSina IVF Centre, IbnSina Hospital, Sohag, Egypt). [personal communication]. Conversation with: MS Kamath (Cochrane review contact author) 1 March 2023.
    1. Fawzy M, Emad M, Mahran A, Sabry M, Fetih AN, Abdelghafar H, et al. Artificial oocyte activation with SrCl2 or calcimycin after ICSI improves clinical and embryological outcomes compared with ICSI alone: results of a randomized clinical trial. Human Reproduction 2018;33(9):1636-44. [DOI: 10.1093/humrep/dey258] - DOI - PubMed
    1. NCT02424214. Artificial oocyte activation comparing tow [sic] different agents. https://classic.clinicaltrials.gov/ct2/show/NCT02424214 (first posted 22 April 2015).
Hao 2016 {published data only}
    1. Hao D, Zhang R, Zhang X, Shen C, Yang Y, Wu W, et al. A control study of artificial oocyte activation in the same period. National Medical Journal of China 2016;96(43):3489-93. [DOI: ] - PubMed
Hebisha 2016 {published data only}
    1. Hebisha SA (Alexandria University - Faculty of Medicine, Alexandria, Egypt). [personal communication]. Conversation with: MS Kamath (Cochrane review contact author) 3 August 2023.
    1. Hebisha SA, Aboelazm BA, Adel HM, Aboali AA, Ahmed AI. Effect of oocyte activation with calcium ionophore on ICSI outcomes in patients with previous fertilization failure. In: Fertility and Sterility. Vol. 106 (Suppl 3). 2016:e186-7.
    1. Hebisha SA, Mahmoud HM. Effect of oocyte activation with calcium ionophore on ICSI outcomes in patients with previous fertilization failure. International Journal of Advanced Research 2017;5(12):1574-80. [DOI: 10.21474/IJAR01/6121] - DOI
Mansour 2009 {published data only}
    1. Mansour R, Fahmy I, Tawab NA, Kamal A, El-Demery Y, Aboulghar M, et al. Electrical activation of oocytes after intracytoplasmic sperm injection: a controlled randomized study. Fertility and Sterility 2009;91(1):133-9. [DOI: 10.1016/j.fertnstert.2007.08.017] - DOI - PubMed
Mateizel 2022 {published data only}
    1. Mateizel I, Santos-Ribeiro S, Segers I, Wouters K, Mackens S, Verheyen G. Effect of A23187 ionophore treatment on human blastocyst development-a sibling oocyte study. Journal of Assisted Reproduction and Genetics 2022;39(6):1225-32. [DOI: ] - PMC - PubMed
    1. Mateizel I (Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis, Brussel). [personal communication]. Conversation with: MS Kamath (Cochrane review contact author) 9 August 2024.
McCormick 2017 {published data only}
    1. Katz-Jaffe M (Colorado Center for Reproductive Medicine, Lone Tree, CO, USA). [personal communication]. Conversation with: MS Kamath (Cochrane review contact author) 1 October 2023.
    1. McCormick S, Smith R, Pospisil C, McCubbin NI, Schoolcraft WB, Katz-Jaffe M. Calcium ionophore treatment after ICSI improves blastocyst development for malefactorindications aswellas patients with only a history of poor blastocyst development. In: Fertility and Sterility. Vol. 108 (Suppl 3). 2017:e164. [DOI: 10.1016/j.fertnstert.2017.07.493] - DOI
Nasr‐Esfahani 2008 {published data only}
    1. Nasr-Esfahani MH, Razavi S, Javdan Z, Tavalaee M. Artificial oocyte activation in severe teratozoospermia undergoing intracytoplasmic sperm injection. Fertility and Sterility 2008;90(6):2231-7. [DOI: 10.1016/j.fertnstert.2007.10.047] - DOI - PubMed
Nazarian 2018 {published data only}
    1. IRCT20160722029027N4. Comparison of the effect of using or not using of artificial oocyte activation on intra-cytoplasmic sperm injection outcomes in infertile patients with phospholipase C ζ deficiency. https://www.irct.ir/trial/23425 (first registered 21 January 2018).
    1. Nazarian H, Azad N, Nazari L, Piryaci A, Heidari MH, Masteri-Farahani R, et al. Effect of artificial oocyte activation on intra-cytoplasmic sperm injection outcomes in patients with lower percentage of sperm containing phospholipase Cζ: a randomized clinical trial. Journal of Reproduction and Infertility 2018;20(1):3-9. [PMID: ] - PMC - PubMed
Okuyama 2019 {published data only}
    1. Okuyama N, Obata R, Oka N, Hashimoto T, Kyono K, Aono N. The clinical results of piezo-ICSI compared to conventional-ICSI: a sibling-oocyte study. In: Fertility and Sterility. Vol. 112 (Suppl 3). 2019:e4-5. [DOI: ]
Razavi 2012 {published data only}
    1. Razavi S, Javdan Z, Nasr Esfahani M H, Sadeghi M. Effect of ionomycin as an artificial oocyte activator on fertilization outcome by ICSI. Iranian Journal of Obstetrics, Gynecology and Infertility 2012;15(18):1-9. [DOI: 10.22038/IJOGI.2012.5664] - DOI
Schuff 2019 {published data only}
    1. DRKS00010456. Benefit of oocyte activation with GM508 CultActive in an IVF/ICSI therapy with different clinical pictures of sub- or infertility. A prospective – randomized pilot study. https://drks.de/search/en/trial/DRKS00010456 (first registered on 27 April 2016).
    1. Schuff M, Stecher A, Wirleitner B, Damko A, Kentros F, Bach M, et al. A prospective RCT sibling study to test the efficacy and safety of the calcium ionophore GM508 in two different indication groups-preliminary results. In: Human Reproduction. Vol. 34 (Suppl 1). 2019:i488.
Stecher 2013 {published data only}
    1. Stecher A, Wirleitner B, Vanderzwalmen P, Zintz M, Neyer A, Bach M, et al. Ooocyte activation increases fertilization rate resulting in a higher final number of blastocysts without compromising implantation potential per transferred embryo: a sibling prospective study. In: Human Reproduction. Vol. 28 (Suppl 1). 2013:i149-i206 P-143.
Takahashi 2015 {published data only}
    1. Mizuta S, Takahashi C, Nishiyama R, Kitaya K, Matsubayashi H, Ishikawa T. Clinical outcomes of artificial oocyte activation with calcium ionophore in intracytoplasmic sperm injection (ICSI) using testicular spermatozoa on sibling oocytes. In: Human Reproduction. Vol. Suppl 30. 2015:i 171.
    1. Takahashi C, Mizuta S, Nishiyama R, Yamaguchi K, Kitaya K, Matsubayashi H, et al. Effect of artificial oocyte activation in intracytoplasmic sperm injection using testicular spermatozoa on sibling oocytes. In: Fertility and Sterility. Vol. 104 (Suppl 3). 2015:e317. [DOI: ]
Thondehal Math 2019 {published data only}
    1. Thondehal Math N, Uttur G, Ganesh D, Weon Young S. Can apply artificial chemical oocyte activation with strontium chloride for couples with severe male factor infertility or previous failed IVF cycles? In: Human Reproduction. Vol. 34 ( Suppl 1). 2019:i 251.
Vanden Meerschaut 2012 {published data only}
    1. Vanden Meerschaut F, Nikiforaki D, De Gheselle S, Dullaerts V, Van den Abbeel E, Gerris J, et al. Assisted oocyte activation is not beneficial for all patients with a suspected oocyte-related activation deficiency. Human Reproduction 2012;27(7):1977-84. [DOI: 10.1093/humrep/des097] - DOI - PubMed

References to studies excluded from this review

Borges 2009a {published data only}
    1. Borges E Jr, De Almeida Ferreira Braga DP, De Sousa Bonetti TC, Iaconelli A Jr, Franco JG Jr. Artificial oocyte activation using calcium ionophore in ICSI cycles with spermatozoa from different sources. Reproductive Biomedicine Online 2009;18(1):45-52. [DOI: 10.1016/s1472-6483(10)60423-3.] - DOI - PubMed
ChiCTR2200055839 {published data only}
    1. ChiCTR2200055839. To compare the effects of ionomycin and strontium chloride on embryo outcome in patients with failed fertilization following intracytoplasmic sperm injection. https://trialsearch.who.int/Trial2.aspx?TrialID=ChiCTR2200055839 (first posted 1 October 2020).
Esbert 2021 {published data only}
    1. Esbert M, Carmody AF, Pangasnan R, Seli E, Scott RT, Ballesteros A. Can calcium ionophore A23187 rescue unfertilized oocytes? In: Fertility and Sterility. Vol. 116 (Suppl 3). 2021:e337.
Fawzy 2015 {published data only}
    1. Fawzy M, Alaboudy A, Kasem H, Gad M, Abdelghaffar H, Sabry M, et al. Novel approach for managing decreased fertilization with sequential artificial oocyte activation: prospective randomized clinical trial. In: Fertility and Sterility. Vol. 104 (Suppl 3). 2015:e186.
Koo 2016 {published data only}
    1. Koo JS, Lee H, Moon HS, Moon SE, Park SH, Min SH. Treatment with ionomycin improves pregnancy rates in poor responders. In: Human Reproduction. Vol. 31 (Suppl 1). 2016.
Liu 2013 {published data only}
    1. Liu Y, Cao YX, Zhang ZG, Xing Q. Artificial oocyte activation and human failed-matured oocyte vitrification followed by in vitro maturation. Zygote 2013;21(1):71-6. [DOI: 10.1017/S0967199411000530] - DOI - PubMed
Liu 2014 {published data only}
    1. Liu Y, Han XJ, Liu MH, Wang SY, Jia CW, Yu L, et al. Three-day-old human unfertilized oocytes after in vitro fertilization/intracytoplasmic sperm injection can be activated by calcium ionophore a23187 or strontium chloride and develop to blastocysts. Cellular Reprogramming 2014;16(4):276-80. [DOI: 10.1089/cell.2013.0081] - DOI - PMC - PubMed
Liu 2023 {published data only}
    1. Liu Z, Guo Y, Chen X, Lin C, Guo X, Jiang M, Liu Q. The effect of ionomycin-induced oocyte activation on multiple morphological abnormalities of the sperm flagella. Systems Biology in Reproductive Medicine 2023;69(3):245-54. [DOI: doi: 10.1080/19396368.2023.2167621] - PubMed
Manipalviratn 2005 {published data only}
    1. Manipalviratn S, Ahnonkitpanit V, Numchaisrika P, Chompurat D, Pansatha J, Suwajanakorn S. Fertilization rate after electrical activation of fail to fertilize oocytes after intracytoplasmic sperm injection (ICSI). In: Human Reproduction. Vol. 20 (Suppl 1). 2005:i 167.
    1. Manipalviratn S, Ahnonkitpanit V, Numchaisrika P, Chompurat D, Pansatha J, Suwajanakorn S. Results of direct current electrical activation of failed-to-fertilize oocytes after intracytoplasmic sperm injection. Journal of Reproductive Medicine 2006;51(6):493-9. [PMID: ] - PubMed
Moaz 2006 {published data only}
    1. Moaz M, Khattab S, Aboulfoutouh I. The effect of chemical activation of oocytes on the fertilization rate in different types of sperm morphological abnormality. In: Middle East Fertility Society Journal. Vol. 10 (Suppl 1). 2005:17-18.
    1. Moaz MN, Khattab S, Foutouh IA, Mohsen EA. Chemical activation of oocytes in different types of sperm abnormalities in cases of low or failed fertilization after ICSI: a prospective pilot study. Reproductive Biomedicine Online 2006;13(6):791-4. [DOI: doi: 10.1016/s1472-6483(10)61025-5] - PubMed
NCT02051075 {published data only}
    1. NCT02051075. Fertilizations with immotile sperm: pentoxyphylline activation alone, or with chemical oocyte activation (PXN). https://classic.clinicaltrials.gov/ct2/show/NCT02051075 (first posted on 31 January 2014).
NCT03678610 {published data only}
    1. NCT03678610. Handling medium for ICSI with ionomycin and latrunculin A. https://classic.clinicaltrials.gov/ct2/show/NCT03678610 (first posted on 19 September 2018).
NCT04523103 {published data only}
    1. NCT04523103. Artificial assisted activation following in fertilization failure. https://clinicaltrials.gov/study/NCT04523103?cond=Fertilization%20Failur... (first posted 21 August 2020).
Norozi 2015 {published data only}
    1. Norozi M, Bahadorani M, Tavalaee M, Nasr Esfahani MH. Artifcial oocyte activation alone intra cytoplasmic sperm injection in men with severe semen parameters. In: International Journal of Fertility and Sterility. Vol. 9 (Suppl 1). 2015:67.
Norozi‐Hafshejani 2018 {published data only}
    1. Norozi-Hafshejani M, Tavalaee M, Azadi L, Bahadorani M, Nasr-Esfahani MH. Effects of assisted oocyte activation with calcium- ionophore and strontium chloride on in vitro ICSI outcomes. Iranian Journal of Basic Medical Sciences 2018;21(11):1109-17. [DOI: 10.22038/IJBMS.2018.30422.7331] - DOI - PMC - PubMed
Paffoni 2007 {published data only}
    1. Paffoni A, Brevini TA, Somigliana E, Restelli L, Gandolfi F, Ragni G. In vitro development of human oocytes after parthenogenetic activation or intracytoplasmic sperm injection. Fertility and Sterility 2007;87(1):77-82. [DOI: 10.1016/j.fertnstert.2006.05.063] - DOI - PubMed
Shebl 2021 {published data only}
    1. Shebl O, Trautner PS, Enengl S, Reiter E, Allerstorfer C, Rechberger T, et al. Ionophore application for artificial oocyte activation and its potential effect on morphokinetics: a sibling oocyte study. Journal of Assisted Reproduction and Genetics 2021;38(12):3125-33. [DOI: 10.1007/s10815-021-02338-3] - DOI - PMC - PubMed
UMIN000032038 {published data only}
    1. UMIN000032038. Artiificial oocyte activation for fertilization failure following ICSI. https://trialsearch.who.int/Trial2.aspx?TrialID=JPRN-UMIN000032038 (first registered 1 April 2018).
Zhang 1999 {published data only}
    1. Zhang J, Wang C W, Blaszcyzk A, Grifo J A, Ozil J, Haberman E, et al. Electrical activation and in vitro development of human oocytes that fail to fertilize after intracytoplasmic sperm injection. Fertility and Sterility 1999;72(3):509-12. [DOI: 10.1016/s0015-0282(99)00264-2] - DOI - PubMed

References to studies awaiting assessment

Baltaci 2010 {published data only}
    1. Baltaci V, Ayvaz OU, Unsal E, Aktaş Y, Baltaci A, Turhan F, et al. The effectiveness of intracytoplasmic sperm injection combined with piezoelectric stimulation in infertile couples with total fertilization failure. Fertility and Sterility 2010;94(3):900-4. [DOI: 10.1016/j.fertnstert.2009.03.107] - DOI - PubMed
Borges 2009 {published data only}
    1. Borges E Jr, De Almeida Ferreira Braga DP, De Sousa Bonetti TC, Iaconelli A Jr, Franco JG Jr. Artificial oocyte activation with calcium ionophore A23187 in intracytoplasmic sperm injection cycles using surgically retrieved spermatozoa. Fertility Sterility 2009;91(1):131-36. [DOI: 10.1016/j.fertnstert.2008.04.046] - DOI - PubMed
DRKS00010456 {published data only}
    1. DRKS00010456. Benefit of oocyte activation with GM508 CultActive in an IVF/ICSI therapy with different clinical pictures of sub- or infertility. A prospective – randomized [sic] pilot study. https://trialsearch.who.int/Trial2.aspx?TrialID=DRKS00010456. (first registered 27 April 2016).
Eftekhar 2013 {published data only}
    1. Eftekhar M, Janati S, Rahsepar M, Aflatoonian A. Effect of calcium lonophore on fertilization and pregnancy rate in infertile patients with teratospermia candidate for intracytoplasmic sperm injection. In: International Journal of Fertility and Sterility. Vol. 8 Suppl 1. 2014:106 P-193.
    1. Eftekhar M, Janati S, Rahsepar M, Aflatoonian A. Effect of oocyte activation with calcium ionophore on ICSI outcomes in teratospermia: a randomized clinical trial. Iranian Journal of Reproductive Medicine 2013;11(11):875-82. [PMID: ] - PMC - PubMed
    1. IRCT2012112610328N1. Effect of calcium ionophore on fertilization and pregnancy rate in infertile patients with teratospermia candidate for Intracytoplasmic sperm injection. https://www.irct.ir/trial/10837 (first registered 26 November 2012).
IRCT201501266420N12 {unpublished data only}
    1. IRCT201501266420N12. Comparison of effect of calcium ionophore on oocyte activation in infertile patient with normal sperm morphology and low fertilization after microinjection. https://www.irct.ir/trial/6869 (first registered 20 October 2015).
NCT02992665 {published data only}
    1. NCT02992665. Can calcium ionophore application enhance the ICSI outcomes in severe male factor infertility? https://classic.clinicaltrials.gov/ct2/show/NCT02992665 (first posted 14 December 2016).
NCT04519918 {published data only}
    1. NCT04519918. Clinical application of Artificial Oocyte Activation technique (AOA) in ART. https://classic.clinicaltrials.gov/ct2/show/NCT04519918. (first posted on 20 August 2020).
NCT04744753 {published data only}
    1. NCT04744753. AOA in recurrent fertilization failure (AOA). https://classic.clinicaltrials.gov/ct2/show/NCT04744753 (first posted on 9 February 2021).
Yin 2021 {published and unpublished data}
    1. Yin ESP. Effect of artificial activation of oocytes (AOA-ICSI) on the ploidy status of the resultant blastocysts. A sibling-oocytes pilot study. In: Human Reproduction. Vol. 36 (Suppl. 1). 2021:i232. [DOI: ]

References to ongoing studies

NCT05402605 {published data only}
    1. NCT05402605. AOA versus non-AOA in low prognosis patients by the POSEIDON criteria. https://clinicaltrials.gov/study/NCT05402605 (first posted on 2 June 2022).
TCTR20230302001 {published data only}
    1. TCTR20230302001. The effect of calcium ionophore on fertilization rate after intracytoplasmic sperm injection in infertile couples with advanced female reproductive age: a randomized controlled trial. https://trialsearch.who.int/Trial2.aspx?TrialID=TCTR20230302001 (first posted on 13 February 2023).

Additional references

Abu‐Musa 1999
    1. Abu-Musa A, Hannoun A, Khabbaz A, Devroey P. Failure of fertilization after intracytoplasmic sperm injection in a patient with Kartagener's syndrome and totally immotile spermatozoa: case report. Human Reproduction 1999;14(10):2517-18. - PubMed
Anifandis 2019
    1. Anifandis G, Michopoulos A, Daponte A, Chatzimeletiou K, Simopoulou M, Messini CI, et al. Artificial oocyte activation: physiological, pathophysiological and ethical aspects. Systems Biology in Reproductive Medicine 2019;65(1):3-11. - PubMed
Anzalone 2016
    1. Anzalone DA, Iuso D, Czernik M, Ptak G, Loi P. Plasma membrane and acrosome loss before ICSI is required for sheep embryonic development. Journal of Assisted Reproduction and Genetics 2016;33(6):757-63. - PMC - PubMed
Armstrong 2019
    1. Armstrong S, Atkinson M, MacKenzie J, Pacey A, Farquhar C. Add-ons in the laboratory: hopeful, but not always helpful. Fertility Sterility 2019;112(6):994-99. - PubMed
ASRM 2020
    1. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Intracytoplasmic sperm injection (ICSI) for non–male factor indications: a committee opinion. Fertility Sterility 2020;114(2):239-45. - PubMed
Baltaci 2010
    1. Baltaci V, Ayvaz OU, Unsal E, Aktaş Y, Baltaci A, Turhan F, et al. The effectiveness of intracytoplasmic sperm injection combined with piezoelectric stimulation in infertile couples with total fertilization failure. Fertility Stertility 2010;94(3):900-4. - PubMed
Bhattacharya 2001
    1. Bhattacharya S, Hamilton MP, Shaaban M, Khalaf Y, Seddler M, Ghobara T, et al. Conventionalin vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial. Lancet 2001;357(9274):2075-79. - PubMed
Bos‐Mikich 1997
    1. Bos-Mikich A, Whittingham DG, Jones KT. Meiotic and mitotic Ca2+ oscillations affect cell composition in resulting blastocysts. Developmental Biology 1997;182(1):172-79. - PubMed
CDC 2018
    1. Center for Disease Control and Prevention. Assisted Reproductive Technology (ART). www.cdc.gov/art/artdata/index.html (accessed on 21 July 2020).
Chen 2010
    1. Chen J, Qian Y, Tan Y, Mima H. Successful pregnancy following oocyte activation by strontium in normozoospermic patients of unexplained infertility with fertilisation failures during previous intracytoplasmic sperm injection treatment. Reproduction Fertility and Development 2010;22(5):852-55. - PubMed
Cooper 2010
    1. Cooper TG, Noonan, E, Eckardstein S, Auger J, Gordon Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Human Reproduction Update 2010;16(3):213-45. - PubMed
De Geyter 2020
    1. De Geyter C, Calhaz-Jorge C, Kupka MS, Wyns C, Mocanu E, Motrenko T, et al. ART in Europe, 2015: results generated from European registries by ESHRE. Human Reproduction Open 2020;2020(1):hoz038. - PMC - PubMed
De Mouzon 2020
    1. De Mouzon J, Chambers GM, Zegers-Hochschild F, Mansour R, Ishihara O, Banker M, et al. International Committee for Monitoring Assisted Reproductive Technologies world report: assisted reproductive technology 2012. Human Reproduction 2020;35(8):1900-13. - PubMed
Duffy 2020
    1. Duffy JMN, Bhattacharya S, Bhattacharya S, Bofill M, Collura B, Curtis C, et al. Standardizing definitions and reporting guidelines for the infertility core outcome set: an international consensus development study. Human Reproduction 2020;35(12):2735-45. - PMC - PubMed
Ebner 2004
    1. Ebner T, Moser M, Sommergruber M, Jesacher K, Tews G. Complete oocyte activation failure after ICSI can be overcome by a modified injection technique. Human Reproduction 2004;19(8):1837-41. - PubMed
Ebner 2016
    1. Ebner T, Montag M. Artificial oocyte activation: evidence for clinical readiness. Reproductive Biomedicine Online 2016;32(3):271-73. - PubMed
Esfandiari 2005
    1. Esfandiari N, Javed MH, Gotlieb L, Casper RF. Complete failed fertilization after intracytoplasmic sperm injection–analysis of 10 years’ data. International Journal of Fertility and Women's Medicine 2005;50:187-92. - PubMed
ESHRE Add‐on working group 2023
    1. ESHRE Add-ons working group, Lundin K, Bentzen JG, Bozdag G, Ebner T, Harper J, et al. Good practice recommendations on add-ons in reproductive medicine. Human Reproduction 2023;38(11):2062-204. [PMID: ] - PMC - PubMed
ESHRE atlas 2016
    1. Rienzi L, Balaban B, Ebner T, Mandelbaum J. The Oocyte. In: Atlas of Human Embryology. European Society of Human Reproduction and Embryology, 2016.
ESHRE Special Interest Group of Embryology 2017
    1. ESHRE special interest group of embryology, Alpha scientists in reproductive medicine. The Vienna consensus: report of an expert meeting on the development of art laboratory performance indicators. Human Reproduction Open 2017;2017(2):hox011. - PMC - PubMed
Flaherty 1998
    1. Flaherty SP, Payne D, Matthews CD. Fertilization failures and abnormal fertilization after intracytoplasmic sperm injection. Human Reproduction 1998;13(S1):155-64. - PubMed
Gasca 2008
    1. Gasca S, Reyftmann L, Pellestor F, Rème T, Assou S, Anahory T, et al. Total fertilization failure and molecular abnormalities in metaphase II oocytes. Reproductive Biomedicine Online 2008;17(6):772-81. - PubMed
GRADEpro GDT  [Computer program]
    1. GRADEpro GDT. Hamilton (ON): McMaster University (developed by Evidence Prime), 2023. Available at gradepro.org.
Higgins 2023
    1. Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 6.4 (updated Auguest 2023). The Cochrane Collaboration 2023. Available from handbook.cochrane.org.
Hogben 1998
    1. Hogben M, Parrington J, Shevchenko V, Swann K, Lai FA. Calcium oscillations, sperm factors and egg activation at fertilisation. Journal of Molecular Medicine 1998;76(8):548-54. - PubMed
Kamath 2019
    1. Kamath MS, Mascarenhas M, Franik S, Liu E, Sunkara SK. Clinical adjuncts in in vitro fertilization: a growing list. Fertility Sterility 2019;112(6):978-86. - PubMed
Kilani 2014
    1. Kilani S, Chapman MG. Meiotic spindle normality predicts live birth in patients with recurrent in vitro fertilization failure. Fertility Sterility 2014;101(2):403-6. - PubMed
Liu 1995
    1. Liu J, Nagy Z, Joris H, Tournaye H, Smitz J, Camus M, et al. Analysis of 76 total fertilization failure cycles out of 2732 intracytoplasmic sperm injection cycles. Human Reproduction 1995;10:2630-36. - PubMed
Manipalviratn 2006
    1. Manipalviratn S, Ahnonkitpanit V, Numchaisrika P, Chompurat D, Pansatha J, Suwajanakorn S. Results of direct current electrical activation of failed-to-fertilize oocytes after intracytoplasmic sperm injection. 2006 Journal of Reproductive Medicine;51(6):493-99. - PubMed
Mansour 2009
    1. Mansour R, Fahmy I, Tawab NA, Kamal A, El-Demery Y, Aboulghar M, et al. Electrical activation of oocytes after intracytoplasmic sperm injection: a controlled randomized study. Fertility Sterility 2009;91(1):133-39. - PubMed
Miyara 2003
    1. Miyara F, Aubriot FX, Glissant A, Nathan C, Douard S, Stanovici A, et al. Multiparameter analysis of human oocytes at metaphase II stage after IVF failure in non-male infertility. Human Reproduction 2003;18(7):1494-503. - PubMed
Mor 2020
    1. Mor A, Seli E. Oocyte activation, oolemma piercing, and real-time viability confirmation in human oocytes using electrophysiological techniques. Current Opinion in Obstetrics and Gynecology 2020;32(3):191-97. - PubMed
Murugesu 2017
    1. Murugesu S, Saso S, Jones BP, Bracewell-Milnes T, Athanasiou T, Mania A, et al. Does the use of calcium ionophore during artificial oocyte activation demonstrate an effect on pregnancy rate? A meta-analysis. Fertility Sterility 2017;108(3):468-82. - PubMed
Nasr‐Esfahani 2010
    1. Nasr-Esfahani MH, Deemeh MR, Tavalaee M. Artificial oocyte activation and intracytoplasmic sperm injection. Fertility Sterility 2010;94(2):520-26. - PubMed
Okabe 2018
    1. Okabe M. Sperm–egg interaction and fertilization: past, present, and future. Biology of Reproduction 2018;99(1):134-46. - PubMed
Palermo 1992
    1. Palermo G, Joris H, Devroey P, Van Steirteghem A. Pregnancies after intracytoplasmic sperm injection of a single spermatozoon into an oocyte. Lancet 1992;340(8810):17-8. - PubMed
Rawe 2000
    1. Rawe VY, Olmedo SB, Nodar FN, Doncel GD, Acosta AA, Vitullo AD. Cytoskeletal organization defects and abortive activation in human oocytes after IVF and ICSI failure. Molecular Human Reproduction 2000;6(6):510-16. - PubMed
Review Manager 2014 [Computer program]
    1. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Rubino 2016
    1. Rubino P, Viganò P, Luddi A, Piomboni P. The ICSI procedure from past to future: a systematic review of the more controversial aspects. Human Reproduction Update 2016;22(2):194-227. - PubMed
Sfontouris 2015
    1. Sfontouris IA, Nastri CO, Lima ML, Tahmasbpourmarzouni E, Raine-Fenning N, Martins WP. Artificial oocyte activation to improve reproductive outcomes in women with previous fertilization failure: a systematic review and meta-analysis of RCTs. Human Reproduction 2015;30(8):1831-41. - PubMed
Sterne 2019
    1. Sterne JA, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898. - PubMed
Swain 2008
    1. Swain JE, Pool TB. ART failure: oocyte contributions to unsuccessful fertilization. Human Reproduction Update 2008;14(5):431-46. - PubMed
Swann 2018
    1. Swann K. The role of Ca2+ in oocyte activation during in vitro fertilization: insights into potential therapies for rescuing failed fertilization. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 2018;1865(11 (part B)):1830-37. - PubMed
Tesarik 2002
    1. Tesarik J, Rienzi L, Ubaldi F, Mendoza C, Greco E. Use of a modified intracytoplasmic sperm injection technique to overcome sperm-borne and oocyte-borne oocyte activation failures. Fertility Sterility 2002;78(3):619-24. - PubMed
Vanden Meerschaut 2012
    1. Vanden Meerschaut F, Nikiforaki D, De Gheselle S, Dullaerts V, Van den Abbeel E, Gerris J, et al. Assisted oocyte activation is not beneficial for all patients with a suspected oocyte-related activation deficiency. Human Reproduction 2012;27(7):1977-84. - PubMed
Yeste 2016
    1. Yeste M, Jones C, Amdani SN, Patel S, Coward K. Oocyte activation deficiency: a role for an oocyte contribution? Human Reproduction Update 2016;22(1):23-47. - PubMed
Yoon 2012
    1. Yoon S-Y, Eum JH, Lee JE, Lee HC, Kim YS, Han JE, et al. Recombinant human phospholipase C zeta 1 induces intracellular calcium oscillations and oocyte activation in mouse and human oocytes. Human Reproduction 2012;27(6):1768-70. - PubMed
Zegers‐Hochschild 2017
    1. Zegers-Hochschild F, Adamson GD, Dyer S, Racowsky C, De Mouzon J, Sokol R, et al. The International Glossary on Infertility and Fertility Care. Fertility and Sterility 2017;108(3):393-406. - PubMed

References to other published versions of this review

Kamath 2021
    1. Kamath MS, Vogiatzi P, Sunkara SK, Woodward B. Oocyte activation for women following intracytoplasmic sperm injection (ICSI). Cochrane Database of Systematic Reviews 2021, Issue 6. Art. No: CD014040. [DOI: 10.1002/14651858.CD014040] - DOI - PMC - PubMed

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