Global Spatiotemporal Trends and Modifiable Risk Factors for Female Infertility: An Age-Period-Cohort Using Global Burden of Disease Study 2021 and Mendelian Randomization Analysis

Abstract

Background: This study aims to describe the global burden of female infertility, analyze its spatial and temporal trends, and offer targeted epidemiological insights to support the prevention and management of female infertility. Methods: Drawing on insights from the GBD 2021 study, we analyzed age-standardized prevalence rates (ASPR) of female infertility (1990–2021) across global regions and Socio-Demographic Index (SDI) categories. We quantified temporal trends using estimated annual percentage change (EAPC) and Age-Period-Cohort analyses across age groups and geographic regions. Furthermore, the causal relationships between 16 modifiable risk factors, 10 serum biomarkers, and female infertility were assessed by two-sample Mendelian randomization (MR) and mediation analysis. Results: Globally, the ASPR of female infertility exhibited an increasing trend over the study period. Across all SDI regions, infertility prevalence peaked at ages 35–40. MR analysis identified poor general health (IVW OR, 1.94; 95% CI, 1.49–2.52; PFDR = 1.24×10−5), elevated waist-to-hip ratio (WHR) (IVW OR, 1.12; 95% CI, 1.04–1.20; PFDR = 3.26×10−3), and neuroticism (IVW OR, 1.10; 95% CI, 1.04–1.15; PFDR = 1.25×10−3) as significant risk factors, whereas higher educational attainment (IVW OR, 0.95; 95% CI, 0.93–0.97; PFDR = 3.26×10−4), greater body fat percentage (IVW OR, 0.67; 95% CI, 0.52–0.85; PFDR = 4.10×10−3) and napping (IVW OR, 0.63; 95% CI, 0.45–0.89; PFDR = 1.94×10−2) had protective effects. Mediation analysis demonstrated that HbA1c and triglycerides (TG) partially mediated the relationship between WHR and infertility, while TG mediated the effect of educational attainment on female infertility. Conclusion: Age-Period-Cohort modeling suggests that shifts in reproductive age patterns, environmental exposures, and cohort-specific risk profiles are key contributors to observed disparities. Targeted public health interventions, including educational promotion, lifestyle modifications, and routine metabolic screening, are essential to mitigate the rising infertility burden in the coming decades.