Artificial Oocyte Activation (AOA) Following Intracytoplasmic Sperm Injection (ICSI)

- Recommendation

1. AOA for patients with previous no or low fertilisation

IVF facilities could consider offering AOA for patients with previous no or low fertilisation, defined as lower than 30% (low-grade evidence—conditional recommendation) [10, 11, 18-29].

The recommendation for IVF clinics to contemplate providing AOA to patients who have experienced no or limited fertilisation rates, specifically below 30%, is grounded on a careful evaluation of the potential advantages and disadvantages. Despite the limited quality of evidence, certain studies suggest that the use of AOA may enhance fertilisation rates in patients who have encountered low or no fertilisation after ICSI [10, 11, 21, 24, 28]. This potential advantage could help patients who have experienced previous low fertilisation, as enhancing fertilisation may increase the likelihood of successful clinical outcomes. Nevertheless, the available evidence is constrained by the use of small sample sizes, diverse study designs, and potential biases, all of which collectively diminish the strength and reliability of the evidence [6]. Hence, due to the inadequate quality of evidence, patients with low or no fertilisation should receive comprehensive information regarding the potential advantages and uncertainties linked to AOA, enabling them to make well-informed decisions. Clinicians should apply their professional expertise and take into account the unique circumstances of each patient, including their specific history of fertilisation and overall reproductive well-being, in order to determine whether to provide AOA. Implementing AOA requires allocating extra resources. Thus, IVF facilities should carefully evaluate these resource factors in relation to the potential advantages of enhanced fertilisation rates for this specific group of patients.

2. AOA for globozoospermia cases

AOA could be considered after proper counselling and well-informing the patients of globozoospermia cases (low-grade evidence—conditional recommendation) [30, 31].

The recommendation to consider AOA for patients with globozoospermia, after providing thorough counselling and informing the patients adequately, arises from the unique difficulties presented by this uncommon condition. Globozoospermia is a condition where sperm cells have round heads without acrosomes. This often leads to failure in fertilisation because the sperm are unable to start the process of oocyte activation [32]. This condition poses a significant challenge, especially in the context of ICSI, as successful fertilisation greatly depends on the sperm's ability to activate the oocyte. Although the evidence supporting the use of AOA in cases of globozoospermia is limited and of low quality, certain studies and clinical reports have demonstrated that AOA can enhance fertilisation rates in these individuals [30, 31]. Nevertheless, the recommendation lacks strength due to the low-quality evidence, indicating the necessity for cautious optimism. Given the insufficient reliability of the evidence, it is imperative for patients to be knowledgeable and actively engaged in the decision-making process, guaranteeing that their specific circumstances and preferences are thoroughly considered.

3. AOA for the general ICSI population

IVF facilities should NOT recommend AOA for the general ICSI population (very low-grade evidence—conditional recommendation against) [29, 33-37].

The recommendation against recommending AOA for the general ICSI population is justified by the limited and unreliable evidence currently accessible. Although AOA has demonstrated promising advantages in certain groups of patients, such as those with previous fertilisation failure [10, 11, 21, 24, 28], there is inadequate evidence to justify its regular application in all patients undergoing ICSI [37, 38]. The existing literature on AOA frequently has notable shortcomings, resulting in a dearth of strong and dependable data regarding the overall effectiveness and safety when used extensively in all ICSI patients. Standard protocols for most patients undergoing ICSI generally achieve satisfactory fertilisation rates without requiring additional interventions such as AOA. Implementing AOA universally may result in unnecessary intricacy, heightened expenses, and potential hazards without definitive proof of significant advantage [38]. For the broader ICSI population, the existing evidence base for AOA does not meet the required standard, suggesting avoiding AOA as a standard practice and instead only using it in specific cases where the potential benefits have been clearly proven.

4. AOA for improving embryo quality
IVF facilities should NOT recommend AOA for improving embryo quality (very low-grade evidence—conditional recommendation against) [13, 14, 39-41].

The recommendation against recommending AOA to enhance embryo quality in IVF facilities is grounded on the existing evidence, which is currently of insufficient quality [13, 14, 39-41]. The hypothesis that AOA could improve the quality of embryos has not been adequately validated through rigorous scientific investigations. Embryo quality is a multifaceted result that is affected by various factors, such as the inherent quality of the egg and sperm, as well as the conditions in which the embryos are cultured [42]. The evidence indicating that AOA can directly improve the quality of embryos is limited, inconsistent, and plagued by methodological challenges. The precise biological mechanisms by which AOA may enhance embryo quality are not thoroughly comprehended, and current research does not establish a definitive connection between AOA and improved embryonic quality. The lack of comprehensive data weakens the rationale for utilising it in order to enhance the quality of embryos. When it comes to IVF, where the safety of patients and the effectiveness of treatment are of utmost importance, it is essential to rely on reliable evidence when making clinical decisions. The recommendation for using AOA to enhance embryo quality cannot be justified without sufficient empirical evidence. Instead, the emphasis should be on optimising well-established protocols that are supported by substantial evidence in order to enhance embryo quality. The recommendation to not use AOA for enhancing embryo quality is supported by the extremely poor quality of evidence and the absence of proven effectiveness.

5. AOA for improving embryo development and blastocyst formation

IVF facilities should NOT recommend AOA for improving embryo development and blastocyst formation (very low-grade evidence—conditional recommendation against) [13, 14, 39-41].

The recommendation against recommending AOA in IVF facilities for enhancing embryo development and blastocyst formation is supported by the limited and unreliable evidence currently accessible [13, 14, 39-41]. The processes of embryo development and blastocyst formation are affected by various factors, such as the genetic and epigenetic condition of the gametes, the culture environment, and the overall health of the oocyte [42]. Considering the limited and unreliable evidence, it is justified to discourage the routine use of AOA for enhancing embryo development and blastocyst formation. IVF facilities should avoid endorsing unproven methods for this purpose and instead focus on interventions supported by strong evidence to ensure the best possible outcomes.

6. Rescue AOA

IVF facilities should NOT recommend rescue AOA hours or day 1 after ICSI (very low-grade evidence—conditional recommendation against) [43-46].

Rescue AOA aims to initiate fertilisation later when the initial attempt to activate the oocyte after ICSI has failed to achieve timely fertilisation [47]. Nevertheless, the available evidence to substantiate the effectiveness and safety of this practice is severely restricted and of substandard quality. This could be due to limited sample sizes, the absence of control groups, and substantial methodological variability [43-46]. In addition, the timing of the rescue AOA procedure, which is performed several hours or on the first day after ICSI, introduces additional complexity and uncertainty. The postponed initiation may not sufficiently replicate the inherent physiological mechanisms necessary for optimal fertilisation and embryo growth. IVF facilities should abstain from adopting this rescue AOA practice and adhere to established techniques that guarantee the most favourable results for patients based on credible evidence.

7. AOA and sibling-oocyte-split

IVF facilities could consider sibling-oocyte-split if AOA is offered for patients of previous low or no fertilisation, given the scarce long-term safety data (good practice statment) .

The recommendation for IVF facilities to consider using a sibling-oocyte-split approach in cases where patients have experienced low or no fertilisation in the past is rooted in the principle of good practice. This is especially important considering the limited availability of long-term safety data for AOA [48]. The sibling-oocyte-split method entails the division of the inseminated oocytes into two distinct groups: one group undergoes AOA, while the other group does not [27, 37]. This methodology enables a straightforward evaluation of results within the identical treatment period. This approach enables the investigation of the potential advantages of AOA, especially for individuals who have had low or no fertilisation in previous cycles. At the same time, it reduces the risk of exposing all oocytes to an intervention with limited long-term safety information. This method offers the chance to transfer embryos from the group that underwent fertilisation without AOA if they are available. This can be particularly comforting for patients worried about AOA's implications on the future development of embryos and their children's health. By implementing a sibling-oocyte-split strategy, we can gather data to establish a more robust evidence base and evaluate whether AOA truly improves fertilisation rates while maintaining embryo quality. It is advisable to consider a sibling-oocyte-split if AOA is to be used for patients who have experienced low or no fertilisation in previous attempts. This recommendation is a valid and beneficial practice statment.

8. AOA for male factor infertility

Except for globozoospermia cases, IVF facilities should NOT recommend AOA for the ICSI cycle with male factor infertility and no history of no or low fertilisation (very low-grade evidence—conditional recommendation against) [9, 12, 29, 33, 34, 49-60].

The main reason for this recommendation is the insufficient evidence to support the effectiveness of AOA in enhancing fertilisation or clinical outcomes in this group of patients. AOA has demonstrated potential in particular situations, such as in patients with globozoospermia, where the structural abnormalities of the sperm directly hinder the natural activation of the oocyte [30, 31]. Nevertheless, there is limited evidence regarding the advantages of AOA for the overall male factor infertility population who have not experienced previous fertilisation failures. Male factor infertility encompasses a broad spectrum of problems, including reduced sperm count and motility, as well as abnormal sperm morphology. The underlying aetiology and mechanisms can exhibit significant variation, and there is a lack of conclusive evidence supporting the efficacy of AOA in addressing these multifaceted concerns [29, 33, 57]. The recommendation against AOA in this context takes into account the principle of avoiding interventions that lack robust evidence. The recommendation to avoid the use of AOA in ICSI cycles for male factor infertility, unless there is a history of no or low fertilisation, is supported by limited and unreliable evidence, as well as the lack of proven effectiveness.

9. General recommendation

Except for the above recommendations, AOA should only be considered within a research context without charging the patients and after proper counselling and written consent (good practice statment).

The recommendation that AOA should only be taken into account in a research setting, except for the specified situations, is grounded on sound principles. Although there are certain circumstances, such as globozoospermia or previous instances of low or no fertilisation, in which AOA may be advantageous, its wider utilisation lacks substantial evidence [38]. Therefore, it is advisable to limit the utilisation of AOA to a carefully regulated research context where its effectiveness and safety can be thoroughly assessed. Ensuring appropriate guidance and securing documented agreement are essential elements of this suggestion. Patients should receive comprehensive information regarding the experimental nature of AOA within a wider framework, the absence of definitive evidence endorsing its efficacy, and the potential hazards and advantages involved. This level of transparency upholds the principle of patient autonomy and guarantees that patients are fully informed when making decisions about their involvement. In addition, performing AOA within a research framework allows for the monitoring and documenting long-term results, which helps to address existing gaps in the evidence. This data can enhance future guidelines and potentially result in more reliable recommendations if the effectiveness and safety of AOA are confirmed. This approach guarantees that the intervention is implemented with caution and ethical considerations.