P-025 Optimising stimulated IUI; a systematic review and network meta-analysis
Authors: Chronopoulou E , Gaetano-Gil A , Shaikh S , Raperport C , H Al Wattar B , Zamora J , Bhide P 
Published: June 2023

Abstract

Study question
What is the effectiveness and safety of various follicular phase ovarian stimulation protocols for intrauterine insemination (IUI) performed for any indication?

Summary answer
Significantly higher LBR/OPR was noted for gonadotrophins versus oral agents. Clomiphene+estrogen and gonadotrophins+letrozole demonstrated significantly higher OPR/LBR compared to no stimulation/stimulation with oral agents alone.

What is known already
Stimulated IUI is one of the most widespread fertility treatments offered for various indications. The rationale of stimulated IUI cycles follows the concept that more available oocytes for fertilisation would lead to increase chances of conception. Although several small pairwise comparisons are reported between different stimulation agents, there is no overall comparison using a network meta-analysis. Optimising the ovarian stimulation is an important step towards evidence-based guidelines. There is a cost- effect balance which should be kept in mind between achieving multi follicular growth to boost success rates and keeping the intervention safe in relation to multiple pregnancies.

Study design, size, duration
This review has been conducted in accordance with PRISMA guidelines and has been registered in PROSPERO (CRD42022300857). A computerized literature search was performed using EMBASE, MEDLINE and CINAHL as well as the Cochrane Central register of trials from database inception to May 2022. Randomized controlled trials (RCTs) were included. A random effects network meta-analysis within a frequentist setting was performed for the primary outcome live birth rate/ongoing pregnancy rate (LBR)/(OPR) and for multiple pregnancy rate.

Participants/materials, setting, methods
Couples/single women undergoing one or more cycles of stimulated IUI for various indications using partner’s or donor sperm were included. The effect sizes of the outcome were estimated as odds ratio (ORs) and presented along with their 95% confidence interval (CIs). We used network plots to illustrate head-to-head comparisons. The superiority of the interventions was assessed; we calculated the probability of being the best, the mean rank, and the surface under cumulative ranking (SUCRA).

Main results and the role of chance
57 RCTs were identified comparing stimulation protocols. These included oral agents (clomiphene, letrozole, anastrozole, tamoxifene, estrogen), injectable hormones (FSH, hMG +/- GnRH agonists and GnRH antagonists), alone or in combination, compared to other stimulation agent (s). The included trials randomized 11341 participants across 14 countries between 1994 and 2020. Fourteen trials were multi-centre and 43 (75%) were single centre. Comparisons were assessed in relation to LBR/OPR and in relation to multiple pregnancy rate in order to identify which combination is superior in achieving maximum success rates without compromising safety.
The comparison between ovarian stimulation with gonadotrophins and clomiphene had the most trials and participants and showed significantly higher OPR/LBR for ovarian stimulation with gonadotrophins compared to clomiphene (OR: 1.58, CI 1.24-2.02). No stimulation or stimulation with clomiphene or aromatase inhibitors demonstrated significantly lower OPR/LBR compared to clomiphene + estrogen (OR no stimulation: 0.29, CI 0.10-0.83; OR clomiphene: 0.27, CI 0.10-0.69; OR letrozole 0.30, CI 0.11-0.83) and gonadotrophins + letrozole (OR no stimulation: 0.22, CI 0.06-0.82; OR clomiphene: 0.21, CI 0.06-0.73; OR letrozole 0.23, CI 0.06-0.85).The safety of each ovarian stimulation strategy was assessed in terms of risk of multiple pregnancy.

Limitations, reasons for caution
Comparing different stimulation protocols for IUI is challenging in view of heterogeneity amongst included trials. Different add-ons could benefit specific patient groups but based on the available data, safe recommendations cannot be proposed according to subfertility diagnosis. Various add-ons, protocol variations and sperm preparation techniques could also affect outcomes.

Wider implications of the findings
Stimulation strategies aiming to increase success rates should be safe in terms of multiple pregnancy. Strict cancellation criteria and monitoring are required. Cost effectiveness, ease of administration, chances of cycle cancellation and couple’s preferences should be taken into consideration. Future trials should take into account subfertility background and patient characteristics.

Trial registration number
not applicable