Association Between Metabolic Score for Insulin Resistance (METS-IR) and Risk of Infertility: Evidence from NHANES 2013–2020 and Mendelian Randomization Study

Xin Li,1 Qixi Sun,1 Juanjuan Zhang,1 Xiufeng Ling,1 Yu Liu,2 Chun Zhao1 1Department of Reproductive Medicine, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, Nanjing, People’s Republic of China; 2Department of Obstetrics and Gynecology, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, Nanjing, People’s Republic of ChinaCorrespondence: Yu Liu, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, 123 Tianfeixiang, Mochou Road, Qinhuai District, Nanjing, Jiangsu, 210004, People’s Republic of China, Tel +86-25-52226102, Email [email protected] Chun Zhao, Women’s Hospital of Nanjing Medical University, Nanjing Women and Children’s Healthcare Hospital, 123 Tianfeixiang, Mochou Road, Qinhuai District, Nanjing, Jiangsu, 210004, People’s Republic of China, Tel +86-25-52226102, Email [email protected]: Infertility affects approximately 15% of couples worldwide and represents a significant global health burden with profound psychological, social, and economic consequences. Nearly 15% of couples globally experience infertility while insulin resistance (IR) has been identified as a possible risk factor. Despite growing evidence linking metabolic dysfunction to reproductive impairment, the relationship between comprehensive insulin resistance indices and infertility risk remains poorly characterized. Metabolic Score for Insulin Resistance (METS-IR) demonstrates potential for metabolic disease evaluation yet its connection to infertility has not yet been examined. This study aims to provide the first comprehensive evaluation of the association between METS-IR and infertility risk, utilizing both cross-sectional analysis and genetic causal inference methods to establish robust evidence for clinical translation. The research examines how METS-IR relates to infertility risk through observational studies and genetic analysis.Methods: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 2013– 2020 and performed Mendelian randomization (MR) analysis. The study examined METS-IR’s association with infertility through multivariate regression, restricted cubic spline analysis, and subgroup analyses. MR analysis investigated causal relationships between metabolic traits and infertility, with sensitivity analyses including weighted median, MR-Egger regression, and Steiger directionality testing to ensure robust causal inference.Results: Women with infertility exhibited significantly higher METS-IR values (47.56± 1.33) compared to non-infertile women (41.42± 0.44, P< 0.0001). The highest METS-IR quartile showed increased infertility risk in the fully adjusted model (OR 1.53, 95% CI 1.24– 5.21, P=0.04). Restricted cubic spline analysis revealed a significant non-linear relationship (P< 0.001), with stronger associations in younger women. Subgroup analyses identified significant effect modifications by race and age. MR analysis demonstrated causal relationships between triglycerides (IVW OR: 1.149, 95% CI: 1.042– 1.268, P=0.005), body mass index (IVW OR: 0.967, 95% CI: 0.937– 0.998, P=0.04), and inflammatory markers (Interleukin-18 and CXCL11) with infertility risk, with no evidence of reverse causation.Conclusion: Women with markedly elevated METS-IR (highest quartile) demonstrated increased infertility risk in this cross-sectional analysis, though the association was primarily driven by BMI. MR analysis revealed causal relationships between triglycerides and BMI as risk factors, while IL-18 and CXCL11 showed protective effects against infertility, suggesting that metabolic and inflammatory factors contribute to reproductive dysfunction through multiple pathways. These findings highlight the potential utility of metabolic assessment in fertility evaluation, while underscoring that the METS-IR-infertility relationship may largely reflect the well-established link between obesity and reproductive impairment.Keywords: METS-IR, insulin resistance NHANES, infertility, cross-sectional study, mendelian randomization