L26/O-097 Preconception GLP-1 receptor agonist exposure in couples and fertility outcomes: a danish nationwide cohort study

Abstract Study question What is the effect of preconception GLP-1 receptor agonist exposure in women and men on fertility treatment outcomes, including pregnancy rates and ovarian response? Summary answer Male GLP-1 RA exposure before IUI was linked to higher pregnancy rates, whereas IVF/ICSI showed a trend toward lower rates with exposure in either partner. What is known already The use of assisted reproductive technology (ART) and pharmacological treatment for obesity and type 2 diabetes, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), is increasing among individuals of reproductive age. Fertility clinics therefore more frequently encounter patients with recent or ongoing GLP-1 RA use. However, evidence to guide fertility treatment following preconception GLP-1 RA exposure is limited. Current recommendations advise discontinuation at least two months before pregnancy, which may result in rapid weight regain and adverse changes in body composition, potentially impairing ART outcomes. Study design, size, duration This Danish nationwide, registry-based cohort study used data from multiple national health and socioeconomic registries, covering the period from the introduction of the GLP1-RA semaglutide in Denmark, in the period October 31, 2018, through December 31, 2024. All Danish residents are assigned a unique personal identification number, enabling individual-level linkage across registries. Reporting of all ART procedures in both public and private clinics is mandatory. Participants/materials, setting, methods All women and, when applicable, their male partners undergoing fertility treatment (intrauterine insemination, IUI, or IVF/ICSI) were included. Exposure was defined as redemption of a prescription of GLP-1 RA, semaglutide, prior to treatment. Outcomes of the first cycle and all cycles included clinical intrauterine pregnancy, biochemical pregnancy, and number of oocytes aspirated. Analyses emulated an intention-to-treat approach per initiated treatment cycle. Inverse probability of treatment weighting (IPTW) was applied to adjust for baseline confounding. Main results and the role of chance A total of 38,399 women and their male partner were included. Among women, 226 were exposed to semaglutide before IUI and 238 before IVF/ICSI; among men, 133 were exposed before IUI, and 183 before IVF/ICSI. Prior to adjustment for confounders, exposed and non-exposed difference were found in BMI and pre-existing diabetes for both sexes, PCOS among women, and age among men. Across all IUI cycles (all IUI treatments), male semaglutide exposure was associated with higher clinical and biochemical pregnancy rates (OR 1.52 95%CI 1.10-2.09 and 1.51 95%CI 1.12-2.05), with a similar trend observed for the first IUI cycle (first IUI treatment). No differences for pregnancy rates with IUI following female exposure. For IVF/ICSI pregnancy rates tended to be lower following male and female exposure for a) first embryo transfer (transfer cycle, 0.82 95%CI0.50–1.33; 0.88 95%CI 0.64–1.21, men and women, respectively), b) first IVF/ICSI cycle, including all embryo transfers following the first embryo aspiration, (0.75 95%CI 0.58–0.96, 0.72 (95%CI 0.49–1.04), men and women, respectively), c) for all transfer cycles and IVF/ICSI cycles during their fertility treatment. The number of oocytes aspirated was also lower following exposure, although estimates did not reach statistical significance. Limitations, reasons for caution Despite comprehensive nationwide registry data with mandatory reporting, information on weight loss during semaglutide treatment and subsequent weight regain after discontinuation was unavailable. The observational study design limits causal inference. Wider implications of the findings These findings warrant caution when guiding GLP-1 RA use prior to fertility treatment, despite potential metabolic benefits for both women and men. Confirmation in other populations and study designs is required before clinical recommendations can be established Trial registration number No