O-200 Epigenetic age and fertility timeline: testing an epigenetic clock to forecast in vitro fertilization success rate

Abstract Study question Can a simplified and validated peripheral epigenetic clock(definition), that test the methylation pattern of CpG sites at five genes, predict in vitro fertilization (IVF) success? Summary answer Epigenetic clocks may serve as reliable predictors of IVF success, particularly in women aged 31–35, and they could enhance the accuracy of multiparametric prediction models. What is known already In IVF, finding reliable success predictors is challenging. In recent years, the concept of fertility as a ‘sixth vital sign’ or as a ‘proxy for overall health’ has gained traction, suggesting that fertility may reflect a broader set of factors, including genetic predisposition, environmental exposures, and lifestyle influences. Within this context, epigenetic mechanisms are emerging as promising biomarkers of biological age, offering more accuracy than chronological age alone. Epigenetic clocks, which measure biological age through DNA methylation, could show potential as IVF success predictors, though their role in reproductive outcomes requires further research. Study design, size, duration The project was a single-center, observational prospective study involving 379 women who underwent IVF between 03-2022 and 06-2023. The primary outcome was to assess the predictive accuracy of the epigenetic clock on live birth (LB) rate through multivariate and subgroup analyses. We investigated whether women with a LB after IVF had a younger epigenetic age or exhibited epigenetic deceleration compared to those without, and whether this difference provided additional predictive value beyond ovarian reserve markers. Participants/materials, setting, methods Women of reproductive age who underwent IVF treatment were recruited without age restrictions. Exclusion criteria included severe male factor infertility and any systemic diseases that could affect pregnancy outcomes. A whole blood sample in EDTA was collected prior to ovarian stimulation protocols. The “Zbiec-Piekarska2” epigenetic clock model was applied, analyzing the methylation status of five key genes associated with biological aging (C1orf132, ELOVL2, KLF14, FHL2, TRIM59) from DNA extracted from peripheral leukocytes. Main results and the role of chance Among 379 women, those with a LB (n = 204) were younger, had better ovarian reserve markers, and retrieved more oocytes, compared to those without a LB (n = 175). Women with LB were epigenetically younger (36 ± 5 vs. 39 ± 5 years, p < 0.001), and epigenetic age showed moderate predictive power (AUC 0.663, 95%CI: 0.599-0.726). After adjusting for ovarian reserve parameters (follicular stimulating hormon-FSH, antral follicular count-AFC) both epigenetic age and epigenetic age acceleration differed significantly: the adjusted odds-ratio (adjOR) for LB per year of age was 0.90 (95%CI: 0.86-0.95, p < 0.001) and 0.92 (95%CI: 0.87-0.98, p = 0.01) respectively, suggesting that IVF success was more likely in epigenetically younger women, beyond their ovarian reserve. This difference was lost in subgroup analysis based on infertility cause. When comparing epigenetic age performance with other parameters across chronological age groups, epigenetic age and epigenetic age acceleration were the most accurate predictors in women aged 31–35, with AUCs of 0.689 (95% CI: 0.564-0.814) and 0.695 (95% CI: 0.575-0.816), respectively. Multiparametric models combining epigenetic age with ovarian reserve markers slightly improved predictive accuracy: AUC was of 0.692 (95% CI: 0.637-0.747) with AFC, and of 0.693 (95% CI: 0.635-0.750) with AMH. Limitations, reasons for caution The subgroup analyses based on infertility diagnosis may have been underpowered due to small sample sizes. Larger studies are needed, particularly for idiopathic infertility, where epigenetic disruption may play a role. Additionally, the use of different epigenetic clocks, especially fertility-specific models, could enhance performance in the reproductive field. Wider implications of the findings Our findings highlight the potential of epigenetic clocks as IVF success predictors, particularly in specific age-groups and within multiparametric models. They contribute to the growing evidence of the key role of epigenetic mechanisms in reproductive aging. Further research could integrate epigenetic clocks into fertility assessments, enabling personalized approaches and tailored counseling. Trial registration number No