Do they work, and are they worth it? Proposing a framework of evidence synthesis for guiding the evidence-based use of add-ons in in vitro fertilisation

Add-ons are non-essential interventions offered in addition to standard infertility treatments, mainly in vitro fertilisation (IVF) and associated procedures, aimed at improving chances of pregnancy and live birth. While existing guidelines provide recommendations on the use of add-ons, they often overlook the trustworthiness of the underlying randomised controlled trials (RCTs), which may lead to misleading conclusions. Furthermore, some add-ons that may offer genuine benefits have been dismissed due to misinterpretation of trial results, or they are reserved for repeated implantation failure based on strategic rather than evidence-based arguments. Here, we propose a framework for an evidence synthesis process to guide the rational use of add-ons. The evaluation should begin with establishing effectiveness through systematic reviews of trustworthy RCTs, ignoring RCTs that do not meet trustworthiness criteria. When assessing effectiveness, the evaluation should consider evidence relating to the biological mechanisms targeted by the add-on, in addition to clinical outcomes such as live birth. For diagnostic add-ons, evaluations should focus on the group of patients whose test result leads to a change in clinical management, rather than analysing all test-exposed patients. Once effectiveness is confirmed, evaluating cost-effectiveness becomes crucial. Its cost per additional live birth should be compared to a benchmark (e.g., $27,000 or £20,000 for a live birth via standard IVF). Finally, once proven cost-effective, add-ons should be offered early, rather than delayed until after repeated treatment failures. It might be that effectiveness and cost-effectiveness increase with progression along the continuum of diagnosis or IVF failure such as recurrent implantation failure. In that case, add-ons may be offered as soon as they are considered cost-effective.