Serum trace and heavy metal exposure and IVF/ICSI outcomes: modifying effects of maternal diet in a prospective cohort

BACKGROUND: Environmental exposure to trace and heavy metals may influence female fertility, yet their impact on assisted reproductive outcomes remains poorly defined. Maternal diet can potentially modulate metal-related toxicity by influencing metabolic pathways and oxidative stress. OBJECTIVES: To evaluate the associations between ten serum metal concentrations and IVF/ICSI outcomes, and to investigate whether maternal dietary patterns modify these relationships. METHODS: This prospective cohort study included 396 women undergoing their first IVF/ICSI cycle. Serum levels of calcium (Ca), magnesium (Mg), selenium (Se), iron (Fe), strontium (Sr), nickel (Ni), lead (Pb), cadmium (Cd), tin (Sn), and molybdenum (Mo) were quantified on menstrual cycle days 2-4. Dietary patterns were derived via principal component analysis from a food frequency questionnaire. Multivariable models were adjusted for demographic factors and clinical indicators, including anti-Müllerian hormone (AMH), basal FSH, and total gonadotropin (Gn) dose. Multiple testing was controlled using the False Discovery Rate (FDR) procedure, and restricted cubic splines (RCS) evaluated non-linear threshold effects. RESULTS: After FDR adjustment, several robust associations remained. Higher serum Mg (adjusted OR = 1.10, 95% CI: 1.04-1.15) and Ca (OR = 1.14, 95% CI: 1.05-1.22) were significantly associated with an increased good embryo rate (P-fdr < 0.05). Conversely, higher Pb levels were robustly linked to a reduced good embryo rate (OR = 0.88, 95% CI: 0.82-0.95), and Se was inversely associated with the total oocyte yield (RR = 0.91, 95% CI: 0.86-0.96; P-fdr < 0.05). RCS analysis identified a significant non-linear threshold effect for Ca (Pnon-linear = 0.005), with benefits on embryo quality plateauing at 136.05 ng/mL. Maternal dietary patterns significantly modified these associations, though these interactions were primarily nominal (P < 0.05). Notably, high adherence to a caffeinated-beverage pattern exacerbated the adverse associations of certain metals with embryo quality, whereas balanced eating patterns appeared to buffer these risks. Among high caffeine consumers, higher Mg levels were associated with a five-fold increase in the odds of achieving a high good embryo rate (OR = 5.10, P interaction < 0.001). CONCLUSIONS: Circulating metals are independently associated with stage-specific IVF outcomes after accounting for ovarian reserve and treatment intensity. Habitual diet functions as a critical modifier of environmental reproductive risks. Preconceptional dietary optimization may improve individual resilience against metal-related developmental toxicity during assisted reproduction.