https://orcid.org/0000-0001-5196-297X
The live edition of the ESHRE Journal Club discussion at the 40th ESHRE Annual Meeting focused on the ESHRE good practice recommendations on add-ons in reproductive medicine that formulated 42 recommendations covering diagnosis and diagnostic tests, laboratory tests and interventions, and clinical management (ESHRE Add-Ons Working Group et al., 2023) with the discussion’s central focal points being recommended use of add-ons in laboratory and clinical management, quality of evidence in add-on recommendation and use, suitable markers for assessing add-on efficacy, standardization of treatment and patient perspectives. MAR, medically assisted reproduction; RCTs, randomized controlled trials.
Introduction
Since the invention of IVF, medical advances have contributed to increasing the effectiveness of medically assisted reproduction (MAR). For example, in women aged 18–39 years in the UK, the live birth rate (LBR) per embryo transferred increased from 8% in 1991 to 29% in 2022 (Human Fertilisation and Embryology Authority (HFEA), 2024). However, overall success rates remain low, with LBR per ART cycle ranging from 5% to 29% based on worldwide data obtained between 2004 and 2013 (Kushnir et al., 2004). The low success rates can have profound psychological and emotional impact on MAR patients (Fertility Europe and European Parliamentary Forum for Sexual and Reproductive Rights, 2023), and that in turn may prompt fertility clinics to offer adjunct clinical procedures and tests with the intention to improve patients’ chances of having a live birth (Harper et al., 2017). In recent years, several supplementary laboratory techniques, additional clinical procedures, or adjuncts, commonly known as add-ons, have been introduced in fertility clinics and offered to patients on top of standard IVF/ICSI, and often at an additional cost to patients. These options aim to enhance pregnancy or LBRs, mitigate the risk of miscarriage, or shorten the time to achieving pregnancy (ESHRE Add-Ons Working Group et al., 2023). This emergence of add-ons has spurred intense ethical debates among the professional and public community due to often poor evidence supporting their efficacy and safety, low quality of information available, and their potential mis-selling (Braga et al., 2022; Perrotta et al., 2024). The availability, access, and use of add-ons can be influenced by the legal and regulatory landscape as well as the public funding models surrounding the provision of fertility care, which vary significantly amongst countries (Fertility Europe, 2021; European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE) et al., 2024). In Europe, countries like France, Belgium, and the Netherlands offer some of the most affordable and accessible fertility treatments for most patients (Fertility Europe, 2021). In France and Belgium, ART and IUI are covered by social security funds just like any other medical or surgical procedure (European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE) et al., 2024). In the Netherlands, where infertility treatment is largely publicly funded (European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE) et al., 2024), the use of treatment add-ons is relatively uncommon (The Lancet, 2024). This contrasts with the UK, where the use of add-ons is widespread (Van de Wiel et al., 2020; Perrotta et al., 2024), and 73% of IVF/ICSI cycles were privately funded in 2022 (Human Fertilisation and Embryology Authority (HFEA), 2024).
The lack of clear regulation for the use of add-ons and the limited requirements for introducing treatments into practice (Van de Wiel et al., 2020) have encouraged regulatory and professional bodies such as the Human Fertilisation and Embryology Authority (HFEA), the Competition and Market Authority (CMA), and the European Society for Human Reproduction and Embryology (ESHRE) to develop evidence-based guidance and information to help patients and healthcare providers in making informed decisions about add-ons in fertility treatment. In 2023, the HFEA updated their rating system, which was introduced in 2017, to assess the safety and effectiveness of treatment add-ons and issued a joint statement with national and international professional bodies on the responsible use of add-ons in fertility treatment (Human Fertilisation and Embryology Authority (HFEA), 2023). Similarly, CMA published guidelines that include recommendations to enhance the quality and accessibility of information given to patients and avoid potential mis-selling of add-on treatments (Competition and Markets Authority (CMA), 2021). The first good practice recommendations on add-ons in reproductive medicine summarizing scientific and clinical evidence to guide professional decision-making were published by ESHRE in 2023 (ESHRE Add-Ons Working Group et al., 2023). The ESHRE working group formulated recommendations for 42 add-ons currently offered in fertility clinics, categorizing the recommendations into four main groups based on the quality of available evidence on safety and efficacy for each add-on—‘Recommended’, ‘Can be considered’, ‘Currently not recommended for routine use’, ‘Not recommended’. Following analysis of the evidence, only five of the listed add-ons were suggested by the working group as ‘Recommended’ or ‘Can be considered’, with the authors highlighting the very low quality of evidence and lack of scientific rationale, questionable, or incorrect theoretical foundations as the reasons for this. The live session of the ESHRE Journal Club at the 40th Annual ESHRE Meeting fostered a multi-disciplinary discussion on the published ESHRE good practice recommendations, covering the use of add-ons in diagnostics and therapies, challenges with generating high-quality evidence, and patient perspectives.
Good practice recommendations
The term ‘add-on’ is often used to describe interventions, tests, or treatments that lack robust evidence and are considered supplementary to established treatments. Once substantial evidence is accumulated, an add-on may no longer be categorized as such. For instance, ICSI for male infertility is no longer an add-on but remains categorized as such for non-male infertility cases (Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Electronic address: [email protected], 2020). This evolution in terminology reflects the transition from preliminary to established evidence. The multidisciplinary working group’s 42 recommendations consisted of four diagnosis and diagnostic tests, 17 laboratory tests and interventions, and 21 clinical management add-ons. From the 42 recommendations, only hyaluronic acid (HA) addition to transfer media, artificial oocyte activation (AOA), and artificial sperm activation are ‘recommended’ for application to most patients or to those patient groups for whom it may be of relevance, while microfluidics for sperm selection and screening hysteroscopy ‘can be considered’ (ESHRE Add-Ons Working Group et al., 2023).
Despite optimal conditions for embryo transfer (ET), such as a high-quality embryo and a well-prepared endometrium, implantation often fails due to the complex nature of the implantation process. Studies indicate that high concentrations of HA in transfer media may improve LBR for fresh transfers, although results are mixed and some studies show no benefit, especially with frozen embryos (Heymann et al., 2020, 2022; Yung et al., 2021). Safety data suggest no increased risk of adverse outcomes, but higher multiple pregnancy rates have been observed due to combining an adherence compound and transferring more than one embryo (Heymann et al., 2020). More research is needed to fully understand these effects and refine the use of HA in ET. The AOA technique is used to overcome issues with fertilization when natural activation processes are impaired. Normally, sperm-derived enzyme phospholipase C zeta (PLCz) triggers calcium oscillations essential for oocyte activation (Swann, 2022). In cases where this process is disrupted, AOA can be employed to artificially increase calcium levels. A meta-analysis shows that AOA, particularly with ionophores like ionomycin, can improve LBRs in cases of fertilization failure or low fertilization, while its use is also indicated in cases of globozoospermia (Nikiforaki et al., 2016; Shan et al., 2021). Despite its effectiveness, use of AOA requires careful consideration due to potential variations in outcomes and concerns about safety (Shan et al., 2021; Bolton et al., 2023). Continued research and monitoring are recommended to assess its impact and ensure the health of resulting children. Artificial sperm activation on the other hand is a technique used to enhance sperm motility in cases of severe male infertility where sperm are immotile but viable. This method typically involves using phosphodiesterase (PDE) inhibitors like pentoxifylline and theophylline to increase intracellular cAMP levels, which are crucial for sperm movement. Studies show that these treatments can significantly improve fertilization and pregnancy rates, while their use is recommended in cases of primary or secondary total asthenozoospermia, which are not the result of axonemal structure defects (Ebner et al., 2015). While effective, PDE inhibitors must be used carefully to avoid adverse effects on embryos, as excessive exposure can lead to developmental issues in animal models (Fisher and Gunaga, 1975; Scott and Smith, 1995), with further research and long-term safety monitoring recommended.
Other than the three ‘recommended’ add-ons, an additional two ‘can be considered’ following a thorough discussion of possible benefits and risks with close monitoring, follow-up, and evaluation (ESHRE Add-Ons Working Group et al., 2023). Those are the use of microfluidics for sperm selection and screening hysteroscopy for patients with recurrent implantation failure (RIF). Microfluidics technology, which manipulates tiny fluid volumes in micrometer-sized channels, has been adapted for sperm selection and preparation, aiming to replicate conditions in the female reproductive tract, avoiding centrifugation. It has shown potential benefits, such as improved sperm motility, morphology, and DNA integrity, and a higher LBR compared to conventional methods (Quinn et al., 2018; Gode et al., 2019; Pujol et al., 2022). However, a recent study found no significant advantage over traditional sperm selection techniques in donor egg recipients (Srinivas et al., 2022), while a meta-analysis including 13 studies demonstrated marginal positive outcomes over standard sperm selection techniques for ICSI (Ferreira Aderaldo et al., 2023). While promising, more research is needed to fully establish its efficacy and safety before widespread adoption. Screening hysteroscopy, used to directly visualize the endometrial cavity and endocervical canal before MAR, has shown mixed results. The procedure has been associated with pain and potential complications, but there are no data on its cost-effectiveness. High-quality multicenter randomized controlled trials (RCTs) have shown no significant increase in LBR from screening hysteroscopy before MAR treatment (El-Toukhy and El Tokhy, 2016; Smit et al., 2016;). However, for patients with RIF, hysteroscopy may offer potential benefits, according to a Cochrane review and the ESHRE good practice recommendations on RIF (Kamath et al., 2019; ESHRE Working Group on Recurrent Implantation Failure et al., 2023).
Rethinking clinical practice
The remaining 37 add-ons are either ‘currently not recommended for routine clinical use’ but susceptible to change with accumulation of evidence on efficacy and safety, or ‘not recommended’ based on safety concerns and/or lack of biological rationale, thus advised to only be used in research settings (ESHRE Add-Ons Working Group et al., 2023). In clinical practice, continually reassessing and optimizing procedures is essential for advancing patient care and outcomes. This approach is particularly relevant in the field of reproductive medicine, where various tests and interventions are employed to enhance success rates in MAR. One such example is endometrial receptivity testing, which has gained attention for its potential role in improving implantation rates (Ruiz-Alonso et al., 2013). Endometrial receptivity tests have been developed and commercialized with the intention of assessing the suitability of the endometrium for embryo implantation (Díaz-Gimeno et al., 2013). The Endometrial Receptivity Array (ERA) test marked a significant advancement in understanding how the endometrial environment might impact implantation success (Craciunas et al., 2019). The rationale for the test is based on the premise that while embryo quality is crucial for successful implantation, the endometrium also plays a vital role. Historically, the focus on endometrial quality was driven by the hypothesis that a receptive endometrium could enhance the likelihood of embryo implantation (Lessey and Young, 2019). However, recent insights have revealed that endometrial receptivity is not a binary state but rather a spectrum influenced by multiple factors, including the quality of the embryo where both the ‘soil’ and the ‘seed’ play a central role (Lacconi et al., 2024). High-quality euploid embryos often find their way in a less-than-optimal endometrial environment, whereas the endometrium’s role becomes more pronounced when embryo quality is compromised.
Current guidelines have critically assessed the utility of endometrial receptivity tests and have concluded that these tests are not universally indicated for all patients (ESHRE Working Group on Recurrent Implantation Failure et al., 2023). Despite the relatively low invasiveness and cost of these tests, evidence suggests that their benefits may not outweigh the burdens for most patients. The guidelines highlight the importance of considering the biological rationale and potential benefits of these tests on a case-by-case basis. It is essential to shift our perspective from a blanket application of endometrial receptivity tests to a more nuanced approach. This involves identifying specific patient subgroups if any that might genuinely benefit from these tests. For instance, patients who have experienced multiple failed ETs of high-quality euploid embryos might be more appropriate candidates for such testing (Gill et al., 2024). In these cases, understanding the endometrial environment could provide insights into why implantation has not occurred and guide subsequent management strategies. Moving on from diagnostics to therapies, it becomes apparent that the use of empirical add-ons should be avoided. Unless the individual patients’ endometrial function has been analyzed through a medical history or test results indicating a biological rationale, steroids, heparin, or intralipids should not be used since it is unknown whether their use would be more detrimental than beneficial (ESHRE Add-Ons Working Group et al., 2023; Human Fertilisation and Embryology Authority (HFEA), 2023).
When establishing the best clinical practices for the use of add-on treatments, it is important to consider the most effective outcome measure for each intervention. Preimplantation genetic testing for aneuploidies (PGT-A), timelapse technology (TLT), and other embryo selection tools have been widely adopted with the assumption that they will improve LBR. However, these techniques do not directly enhance embryo quality but rather aim to improve workflow and/or refine the selection process (Illingworth et al., 2024). The literature reveals that PGT-A and TLT do not improve cumulative LBR (Rubio et al., 2017; Verpoest et al., 2018; Armstrong et al., 2019; Cornelisse et al., 2020).
The recommendations suggest that PGT-A is not suitable for routine clinical use, stemming from the understanding that embryo selection tools are designed to mitigate risks associated with aneuploidy rather than enhance the inherent quality of embryos (ESHRE Add-Ons Working Group et al., 2023). Even though high-quality RCTs and observational studies have shown that PGT-A does not increase the overall success rates of MAR treatments, it is important to notice that RCTs are not immune to biases and confounders, which can skew results and lead to misleading conclusions. For instance, non-selection or blinded studies have provided valuable insights into the limitations of PGT-A. These studies have demonstrated that while fully aneuploid embryos are unlikely to result in healthy pregnancies, mosaic embryos, which contain a mix of normal and abnormal cells, can sometimes lead to healthy live births (Treff and Marin, 2021; Capalbo et al., 2022). Advancements in whole genome sequencing have further refined our understanding by distinguishing between meiotic and mitotic aneuploidies (Handyside et al., 2021), thereby guiding more informed transfer decisions.
Quality of evidence
Historically and presently in clinical settings, introduction of new treatments/technologies/adjuvants often takes place prior to conducting RCTs that support their use. Of the 42 recommendations assessed by the ESHRE Add-Ons Working Group, none could be based on high-quality evidence and only four could be based on moderate-quality evidence. This means that 95% of the recommendations are supported only by low-quality RCTs, observational data, professional experience, or consensus of the development group (ESHRE Add-Ons Working Group et al., 2023).
The broader concern with many add-ons in reproductive medicine is that they are often introduced without clear evidence of their efficacy and safety in specific patient populations. Patients frequently request these interventions based on the expectation of improved outcomes, but the lack of discriminative use and specific patient targeting limits their effectiveness. RCTs often test interventions on a broad population rather than focusing on subgroups that may benefit the most. For interventions to be truly beneficial, they should be introduced with a sound biological rationale, clear indications, and evidence supporting their use in specific contexts. Understanding the underlying abnormalities and targeting interventions accordingly could lead to more precise and effective treatments. Without this focused approach, valuable data may be overlooked, and interventions may not achieve their intended outcomes. Additionally, while RCTs are considered the ‘gold standard’ in evidence-based medicine, practical constraints and the nature of clinical research necessitate a broader evaluation of evidence (Macklon et al., 2019). RCTs are highly valued in clinical practice for their rigorous methodology and ability to minimize bias. They provide a robust framework for determining the efficacy of interventions by comparing outcomes between treatment and control groups under controlled conditions. However, the reality of conducting RCTs is fraught with challenges. They are expensive, resource-intensive, and often limited to large research centers with substantial infrastructure (Stocking et al., 2019). As a result, it is impractical to rely solely on RCTs to answer every clinical question, particularly in specialized areas where evidence may be sparse.
In the absence of comprehensive RCT data, clinicians must make decisions based on the available evidence. While RCTs are at the pinnacle of methodological rigor, other study designs, such as high-quality cohort studies and large observational studies, can also provide valuable insights. Although these studies may not offer the same level of evidence as RCTs, they can still justify clinical decisions if their limitations are transparently communicated to patients. Historically, some organizations, such as the HFEA, initially restricted their guidelines to interventions supported solely by RCTs. This stringent criterion limited the inclusion of nuanced evidence from observational studies. However, as understanding has evolved, there has been a shift toward incorporating a broader range of evidence. It is crucial for clinicians to balance the need for evidence with practical considerations and to adopt a pragmatic approach while striving for the highest possible standard of evidence.
Another important aspect when evaluating evidence is differences in clinical guidelines that often arise due to variations in the interpretation of evidence and the subjective judgments of guideline committees. An example of this is the use of HA that is recommended by the ESHRE Add-Ons Working Group, while according to the HFEA evidence-based info given to patients, it is not clear that this add-on is effective at improving the treatment outcome. Discrepancies can manifest in the strength of recommendations, or the level of caution advised before widespread adoption of new interventions. These differences are influenced by the diverse perspectives and communication styles of guideline developers, who may approach evidence with preformed opinions and varying degrees of assertiveness.
Patient perspectives
A key driver of add-on use is demand from assertive patients, even though clinicians often try to discourage it. To understand patients’ perspectives on add-ons, they should be seen within the context of their broader MAR experience. Sarah Franklin (1997) coined the term ‘hope technology’, describing how patients seek closure rather than just pregnancy. The rise of add-ons offers more options to achieve this closure. A study (Perrotta and Hamper, 2021) shows patients are divided: some trust doctors to assess evidence, while others pursue add-ons despite knowing the lack of supporting evidence, driven by hope.
Cost-effectiveness is a key consideration for adopting add-on treatments, especially in healthcare systems where fertility care is funded by authorities. Equitable access to validated techniques is a moral goal, making it crucial for health authorities to fund research that establishes the evidence base for new treatments. Patients should not bear the cost of procedures lacking robust support, and clinicians should communicate transparently about these limitations. Despite this, some patients may still choose to pay for add-ons, even if evidence is weak, making it vital to address potential risks, including compromised outcomes.
Clear communication about the evidence supporting add-ons is vital to help patients make informed decisions and avoid unnecessary costs or risks. Clinics, regulators, and professional bodies should provide accurate, evidence-based information. Studies show that patients often rely on clinic websites for treatment information, but analyses reveal that many websites misrepresent the effectiveness of add-ons like TLT (Perrotta et al., 2024). Proposals from stakeholders, including the Progress Educational Trust, suggest improving transparency through research datasets, monitoring website accuracy via audits, and supporting informed choices by creating cost comparison databases for fertility treatments (Perrotta and Smietana, 2024).
Addressing the issue of add-ons in a commercialized sector requires reframing the debate. Ethical concerns often arise over offering treatments without strong evidence. In the UK, many fertility professionals believe that patients should fund expensive add-ons if public funding is unavailable (Perrotta, 2024). Some questioned extra charges for treatments like TLT when it is the only incubator option, or for both TLT and blastocyst culture, calling it a ‘double whammy’ (Perrotta, 2024). These concerns extend beyond evidence and include high markups. A 2022 Fertility Network UK survey revealed that patients often pay far more than the advertised range of clinic websites (£3000–£7000), averaging £13 750 (Fertility Network UK, 2022).
Conclusion
The good practice recommendations on add-ons in reproductive practice provide a shift from empirical use to evidence-based practice and are available for fertility practitioners to use in their clinical settings. Despite the potential benefits of certain add-ons, it is essential to maintain a critical perspective with their use retained solely for specific patient sub-groups for which benefits are likely and avoiding their empirical use that might be ineffective or even harmful. The cost of add-ons, particularly when passed on to patients, must be carefully considered. It is suggested to implement new interventions with caution, ensuring that they are supported by substantial evidence and provide a clear benefit to patients.
Data availability
No datasets were generated or analyzed in the current manuscript.
Acknowledgements
The authors thank the Editor-in-Chief of Human Reproduction, Prof. Cornelis Lambalk, and all the participants of the ESHRE live journal club at the ESHRE 2024 Annual Meeting.
Authors’ roles
M.S., O.F.A., M.M., C.M., Z.E.A., S.M., J.U., J.J.F.-Z., K.S., and G.L. conceptualized, organized, and moderated the discussion; M.S., O.F.A., M.M., and G.L. led the discussion; I.S., N.M., W.V., and M.P. contributed to the discussion as experts; O.F.A. prepared the graphical abstract; M.S., M.M., and G.L. drafted the manuscript. All authors provided critical revision to the manuscript/graphical abstract/and approved the final version.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest
I.S. is a member of the ESHRE Add-Ons Working Group; has received honoraria for lectures from Vitrolife and Cooper Surgical; and holds stock options in Alife Health. All the other authors have no conflicts of interest to declare.
