Abstract
Central adiposity, measured by waist-to-hip ratio (WHR), is a modifiable risk factor for female infertility, yet its causal role remain underexplored. Combining observational data from National Health and Nutrition Examination Survey (N = 1530 women) and Mendelian randomization (MR) using genome-wide association study summary statistics (GIANT, FinnGen, and IEU), we assessed WHR-infertility associations. Analyses included weighted logistic regression, threshold detection via generalized additive models, subgroup analyses, 2-sample MR and multivariable Mendelian randomization. Sensitivity analyses (MR-Egger, leave-one-out, MR-presso) were used to confirm robustness. Each 0.1 unit increase in WHR increased infertility risk by 46%, and WHR adj body mass index (BMI) was associated with a 23% higher risk after covariate adjustment. Women with a WHR > 0.85 had higher infertility susceptibility. MR and multivariable Mendelian randomization confirmed causality for anovulatory infertility (odds ratio = 2.10, 95% confidence interval: 1.37-3.22), independent of BMI. A nonsignificant threshold at WHR = 1.002 suggested continuous risk. Subgroups aged 30 to 34 years (odds ratio = 4.48) and those with some college education faced amplified risks. This could potentially be a reflection of lifestyle elements such as sedentary habits and dietary patterns. WHR is an independent predictor of female infertility. Our study highlights the need to incorporate WHR measurement into fertility assessments, as it can identify high-risk individuals who may be overlooked by BMI alone. Targeted lifestyle modifications to address central obesity offer a cost-effective approach to reduce the global burden of infertility and improve women's reproductive outcomes.