ConFIRM trial - conversion of in vitro fertilization cycles to intrauterine inseminations in patients with a poor ovarian response to stimulation: a protocol for a multicentric, prospective randomized trial

In vitro fertilization (IVF), with or without intracytoplasmic spermatozoid injection (ICSI), followed by embryo transfer, is commonly offered for millions of couples with infertility worldwide. It is usually preceded by controlled ovarian stimulation (COS) with exogenous gonadotropins, which allows to increase the number of follicles and mature oocytes available, thus increasing the number of good-quality embryos available for transfer, and improving the pregnancy and live birth rates (LBRs). However, in about 6% of COS cycles for IVF, less than five mature follicles are obtained despite the use of high doses of exogenous gonadotropins [1, 2]. These cases are referred to as “poor ovarian response to stimulation” (POR), and are associated with lower pregnancy and LBRs. When managing patients with POR during a COS cycle, there are three available options. The first is to proceed with the stimulation despite the poor response, and perform the oocyte retrieval and transfer the available embryos. However, there is a high risk of failure to retrieve oocytes and the absence of embryos to transfer, which should be weighed against the risks of complications associated with the oocyte retrieval and anesthesia. Moreover, such events could be the source of significant disappointment and stress for the couple, and they should be thoroughly counseled before proceeding with the stimulation [3, 4]. The second option is conversion of the IVF cycle to an intrauterine insemination (IUI) in patients having at least one patent tube and adequate semen parameters [5, 6]. Conversion to IUI allows the couple to benefit from the treatments already administered, without the risk of an oocyte retrieval/embryo transfer failure. Finally, the third option is to cancel the IVF cycle. The decision to cancel a cycle is always a challenging one, since it involves not only clinical, but also emotional and financial considerations. Indeed, it is often difficult to announce to a couple the decision to abandon a COS cycle following several weeks of preparation, and after the patient has had several days of high-dose gonadotropin injections. Moreover, several studies have shown that in women with POR, it remains advantageous to proceed with the planned assisted reproductive treatment (ART) [7].

In 2011, the European Society of Human Reproduction and Embryology (ESHRE) published the Bologna criteria in order to “standardize the definition of POR in a simple and reproducible manner” [3, 4]. At least two of the following three criteria are required to establish the definition of POR: (1) advanced maternal age (> 40 years) or any other risk factor for POR; (2) a previous POR (at least three oocytes with a conventional stimulation protocol); (3) an abnormal ovarian reserve test (i.e., antral follicle count (AFC) less than five to seven follicles or anti-Müllerian hormone (AMH) below 0.5–1.1 ng/mL). Moreover, two episodes of POR after maximal stimulation are enough to define a patient as a poor responder according to the Bologna criteria, in the absence of advanced maternal age or abnormal ovarian reserve [3]. However, ever since their publication, these criteria have been the subject of many debates and several revisions have been suggested and requested [5]. Indeed, some aspects have been criticized, such as the supposed homogeneity of the population, the defined thresholds for age, AFC and AMH, the proposed risk factors other than age, and the lack of consideration for oocyte quality compared to quantity [5].

Only five studies compared the outcome of IVF and conversion to IUI in patients with POR [2, 8‐11]. These studies have reported that there is no benefit in proceeding with IVF in the presence of only one mature follicle. However, the results in cases with two, three or four mature follicles were divergent. Indeed, three studies reported the superiority of IVF [2, 8, 9], whereas the two others failed to show a difference between IVF and conversion to IUI [10, 11]. Unfortunately, these studies have low levels of evidence, mostly because of their retrospective observational designs, and the presence of multiple biases [2, 8‐11]. Therefore, the ideal management of patients with two, three or four mature follicles following COS remains unknown [12]. This is why we have decided to perform the first randomized controlled trial (RCT) to compare these two treatment methods. If our study shows that conversion to IUI is non-inferior to IVF in terms of clinical efficiency and LBR, it would confirm IUI as a better alternative for patients, both individually (less invasive and more patient-friendly) and collectively (lower cost).

This is the first RCT to compare the outcomes of IVF and embryo transfer to conversion to IUI in patients with poor ovarian response (POR) to controlled ovarian stimulation (COS). If our study shows that conversion to IUI is non-inferior to IVF in terms of clinical efficiency and LBR, it would confirm IUI as a better alternative for patients, both individually (less invasive and more patient-friendly) and collectively (lower cost).

The trial already began on 10 January 2018, and participant recruitment and follow-up will continue over a 48-month period, with the anticipated final follow-up telephone call(s) occurring in January 2022. Primary analyses will be complete by June 2022.