title: Artificial oocyte activation to improve reproductive outcomes in women with previous fertilization failure: a systematic review and meta-analysis of RCTs.
abstract: OBJECTIVE
  In couples with previous fertilization failure, are reproductive outcomes improved using ICSI followed by artificial oocyte activation (ICSI-AOA) compared with conventional ICSI?
  
  
  CONCLUSIONS
  There is insufficient evidence available from RCTs to judge the efficacy and safety of ICSI-AOA for couples with previous fertilization failure.
  
  
  BACKGROUND
  In cases with previous low fertilization rates or total fertilization failure using ICSI due to sperm-related, oocyte activation deficiency, several methods of AOA have been described, which employ mechanical, electrical or chemical stimuli. Reported fertilization and pregnancy rates appear to be improved after ICSI-AOA compared with conventional ICSI; however, the small studies performed to date make it difficult to assess the clinical efficacy or safety of AOA.
  
  
  METHODS
  The present systematic review and meta-analysis identified RCTs that compared ICSI-AOA and conventional ICSI. The last electronic search was conducted in August 2014 and there was no limitation regarding language, publication date, or publication status. We included studies that randomized either oocytes or women and included them in two different parts of this review: a women-based review and an oocyte-based review. For the women-based review, the primary outcome of effectiveness was live birth per randomized woman and the primary outcome for safety was congenital anomalies per clinical pregnancy. For the oocyte-based review, the primary outcome was embryo formation per oocyte randomized.
  
  
  METHODS
  Record screening and data extraction were performed independently by two authors and risk of bias was assessed by three authors. The effects of ICSI-AOA compared with conventional ICSI were summarized as risk ratio (RR) and the precision of the estimates was evaluated by the 95% confidence interval (CI).
  
  
  RESULTS
  A total of 14 articles were assessed for eligibility and 9 included in the meta-analysis: 2 studies comprised the woman-based review (n = 168 women) and 7 studies the oocyte-based review (n = 4234 oocytes). Only four studies evaluated AOA due to fertilization failure after conventional ICSI: these were included in the quantitative analysis. In two studies evaluating couples with a history of fertilization failure in a previous cycle, ICSI-AOA was associated with an increase in the proportion of cleavage stage embryos (RR 5.44, 95% CI 2.98-9.91) and top/high quality cleavage stage embryos (RR 10.02, 95% CI 2.45-40.95). There was no evidence of effect on fertilization rate (RR 2.97, 95% CI 0.84-10.48). In the two studies that evaluated ICSI-AOA as a rescue method for unfertilized oocytes after conventional ICSI, ICSI-AOA was associated with an increase in fertilization (RR 8.26, 95% CI 1.28-53.32, P = 0.03) and cleavage rates (RR 8.65, 95% CI 2.28-32.77) although there was no significant effect on the likelihood of blastocyst formation (RR 1.97, 95% CI 0.11-34.99). The remaining five studies evaluated ICSI-AOA for reasons other than fertilization failure and were excluded.
  
  
  CONCLUSIONS
  The majority of the studies were not considered to be similar enough for meta-analysis due to different AOA methods and patient inclusion criteria, thus limiting the possibility of pooling studies and achieving a more robust conclusion. Only two studies examined ICSI-AOA in couples with previous fertilization failure, and only one of these included couples with proven male-related, oocyte activation deficiency, which is the primary indication for AOA. The resulting evidence was considered to be of very low quality and should be interpreted with caution.
  
  
  CONCLUSIONS
  There is insufficient evidence available from the currently available RCTs to judge the efficacy or safety of ICSI-AOA on key reproductive outcomes in couples with previous fertilization failure. Such interventions should be further examined by well-designed RCTs before the introduction of ICSI-AOA as a standard treatment.
  
  
  BACKGROUND
  No funding was obtained. No competing interests to declare.
  
  
  BACKGROUND
  PROSPERO CRD42014007445.
authors.affiliation: Eugonia Assisted Reproduction Unit, Athens, Greece.
authors.forename: Ioannis A
authors.initials: IA
authors.lastname: Sfontouris
authors.affiliation: Ribeirao Preto Medical School, University of Sao Paulo (FMRP-USP), Ribeirao Preto, Brazil.
authors.forename: Carolina O
authors.initials: CO
authors.lastname: Nastri
authors.affiliation: Ribeirao Preto Medical School, University of Sao Paulo (FMRP-USP), Ribeirao Preto, Brazil.
authors.forename: Maria L S
authors.initials: ML
authors.lastname: Lima
authors.affiliation: Chemical Injury Research Center, Baqyatallah Medical Science University, Tehran, Iran.
authors.forename: Eisa
authors.initials: E
authors.lastname: Tahmasbpourmarzouni
authors.affiliation: Nurture Fertility, The East Midlands Fertility Centre, Nottingham, UK Division of Child Health, Obstetrics & Gynaecology, School of Medicine, University of Nottingham, Nottingham, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: Raine-Fenning
authors.affiliation: Ribeirao Preto Medical School, University of Sao Paulo (FMRP-USP), Ribeirao Preto, Brazil wpmartins@gmail.com.
authors.forename: Wellington P
authors.initials: WP
authors.lastname: Martins
mesh_terms: D000328:Adult; D005260:Female; D005306:Fertilization; D006801:Humans; D050498:Live Birth; D009865:Oocytes; D011247:Pregnancy; D018873:Pregnancy Rate; D019233:Retreatment; D020554:Sperm Injections, Intracytoplasmic / Q000379:methods*; D016896:Treatment Outcome
keywords: ICSI; artificial oocyte activation; fertilization failure; ionophore