Lack of data still makes IVF add-ons guidance challenging

So called 'add-ons' are defined as supplementary options available to patients in addition to standard fertility procedures, with the common aim of stating to enhance pregnancy or live birth rates, mitigate the risk of miscarriage, or expedite the time to achieving pregnancy but at the same time lacking substantial evidence regarding the safety and efficacy. Add-ons, particularly in the field of reproductive medicine, sit on the border between innovation and overtreatment, and are one of the significant challenges in the field.

The Human Fertilisation and Embryology Authority (HFEA), the UK fertility regulator, has had in place its well know traffic light list of add-ons since 2019. It was updated in October 2023 and now includes five categories that indicate whether a treatment add-on is effective at improving treatment outcomes for someone undergoing fertility treatment, according to evidence from published studies (see BioNews 1212). The new ratings also show whether a particular patient group would benefit from a certain add-on. In addition, the HFEA, with the European Society of Human Reproduction and Embryology (ESHRE) as signatory, has launched a consensus statement mentioning that 'Where there is no evidence to support safety and efficacy, treatment add-ons should only be offered to patients in a research setting with sound methodology and approval from a research ethics committee'.

There are a multitude of add-ons available in clinical and laboratory practice, both for diagnostic and for treatment purposes. A recent good practice recommendation paper of ESHRE has examined the evidence for 27 groups of tests and interventions. For each of the tests and interventions, a working group revised published data for biological rationale, efficacy and safety. For efficacy, (cumulative) live birth rate was considered the primary outcome, although the working group needed to resort to pregnancy rates in most cases. In addition to efficacy and safety, other technical and practical aspects of possible relevance for the clinic and the patient were also considered and documented. Legislative aspects were not discussed.

The published data on the different groups of tests and interventions was discussed in length within the working group and resulted in recommendations in four categories with predefined implications; recommended, can be considered, currently not recommended for routine clinical use, and not recommended.

Five tests and interventions could be recommended or considered in clinical practice, including some listed as effective only for selected patient groups. The distinction between the two categories is based on the certainty of the evidence, and for the tests and interventions that can be considered, the working group suggests applying them only after a thorough discussion of possible benefits and risks and with close monitoring, follow-up and evaluation.

The list of tests and interventions that are not recommended is extensive. The non-recommendations are primarily based on a lack of effectiveness in terms of improving live birth rates, evidence of possible or confirmed side-effects and harms, or a lack of data for either efficacy or safety. For some identified interventions, offering them should be limited to specific patient groups for which evidence of efficacy exists. Two scholarly examples are ICSI – which should only be performed on indication –, and elective freeze-all, where randomised controlled trials have shown that in terms of efficacy, freeze-all is not superior to fresh embryo transfer. Still, it can be used upon indication, for example in patients with a higher risk of ovarian hyperstimulation syndrome (OHSS). However, employing ICSI and elective freeze-all, and other similarly evaluated tests and interventions indiscriminately across all patients with the expectation that some might benefit is not a sustainable approach.

Specifically for the interventions listed as 'can be considered' or 'currently not recommended for routine clinical use', the ESHRE working group calls for more research and studies. This brings us to another set of difficulties, namely the feasibility of research related to low numbers of patients or rare conditions or obtaining research funding. To counteract these difficulties, the authors urge clinics to 'monitor and follow up on non-established interventions and share the results with other clinics to gather sufficient data for meaningful conclusions'. If the evidence becomes compelling, tailored and personalised implementation of these interventions may be included in future recommendations.

To summarise, it is important to understand the limitations of many of the tests and interventions currently available and provided to patients undergoing fertility treatments. A clear distinction should be made between tests and interventions that have demonstrated benefits for patients and those that have not, and the latter should only be provided within a research context, and to no cost for the patient. Only evidence-based add-ons should be provided to patients in routine clinical practice. We acknowledge that most additional treatments are provided to help patients achieve their reproductive goals, and that it is difficult to deny them a treatment that they believe would 'work' for them, but we hope that the recommendations from ESHRE and the HFEA can assist healthcare professionals who aim to assist women and men in having children in resisting the – sometimes substantial – pressure to use add-ons.