Association between fatty acids and female infertility: dual evidence from a cross-sectional study and Mendelian randomization analysis

Background: Infertility poses a considerable threat to female reproductive health on a global scale. Dietary pattern, as a modifiable lifestyle factor, is frequently recommended as an important intervention for infertility-related diseases. Fatty acids play a crucial role in maintaining the health of the female reproductive system. However, the available evidence on the specific relationship between various types of fatty acids and infertility remains insufficient and controversial. Methods: Initially, a cross-sectional study was conducted utilizing the National Health and Nutrition Examination Survey (NHANES) database to collect data from women aged 18-45 years who met the inclusion criteria across the 2013-2020 cycles. Infertility was defined based on information gleaned from reproductive questionnaires. Fatty acid intake was determined by analyzing two 24 hour dietary recall interviews. Weighted logistic regression and weighted restricted cubic spline (RCS) analyses, incorporating covariate adjustments, were employed to preliminarily delineate the association between various types of fatty acids and proportions of fatty acid intake and female infertility risk. Model performance evaluation was carried out through receiver operating characteristic (ROC) curve analysis, complemented by the utilization of a nomogram diagram to gauge the infertility risk attributed to covariates. Genetic instrumental variables pertinent to diverse fatty acid profiles and female infertility were sourced from genome-wide association studies (GWAS). Mendelian randomization (MR), multivariable MR (MVMR) and reverse MR analyses were subsequently used to ascertain causality and reverse causality between distinct fatty acids and infertility, concurrently assessing for heterogeneity and horizontal pleiotropy. Results: In our NHANES analysis, a total of 3159 women were enrolled in the study, with a self-reported infertility prevalence of 11.49%. Infertile women exhibited significantly elevated intake of total omega-6 and omega-6/total fatty acids (TFA) compared to the controls. Weighted logistic regression models confirmed positive correlations between total omega-6 (continuous) and omega-6/TFA (categorical) and infertility risk, while omega-3 (continuous) intake demonstrated a negative correlation. Model 2, post rigorous multivariate covariate adjustment, showed improved predictive performance according to ROC curve analysis. Subgroup analysis suggested that the positive correlation between omega-6/TFA (continuous) and female infertility risk was not affected by stratification. Total omega-6 (continuous) emerged as a risk factor for infertile women aged 18-34 years. However, total saturated fatty acids (TSFAs, continuous), total omega-3 (continuous) and total polyunsaturated fatty acids (PUFAs, categorical) were protective factors only in the infertile women with a BMI ≥ 25 kg m^-2. The positive associations between total omega-6 (Q4) and omega-6/TFA (continuous and Q3-Q4) and infertility risk were consistent across all BMI subgroups. MR analysis employing inverse variance weighted (IVW) as the primary method and Bonferroni correction revealed that genetically predicted TSFAs, monounsaturated fatty acids (MUFAs), omega-6 and MUFA/TFA were positively associated with female infertility risk, whereas PUFA/TFA showed a negative association. Importantly, the positive associations between MUFAs and omega-6 and infertility risk remained robust even after adjusting for potential confounders using MVMR analyses. Reverse MR analysis did not provide any evidence for reverse causality. The MR-Egger regression intercept and Cochran's Q test did not detect any heterogeneity or horizontal pleiotropy. Conclusions: This study presents compelling evidence to substantiate the link between diverse fatty acids, particularly omega-6 PUFAs, and the risk of female infertility. However, to fully comprehend the potential mechanisms and impact of distinct fatty acids and their compositional ratios on female infertility, extensive future research spanning fundamental and large-scale clinical inquiries is imperative.