Heavy metals and diminished ovarian reserve: single-exposure and mixture analyses amongst women consulting in French fertility centres

Background and aim: Diminished ovarian reserve (DOR) is one of the most frequent pathology diagnosed in women consulting for infertility. Animal studies have reported impacts of some heavy metals on the ovarian function but research on the ovarian reserve in humans is limited. Methods: We included 139 cases and 153 controls between 2016-2020. The participants were aged 18-40 and consulted for couple infertility in one of four fertility centres in western France. Cases of DOR were defined as women with an antral follicle count < 7 and/or anti-müllerian hormone (AMH) levels ≤ 1.1 ng/ml. Controls were frequency matched on age and centre and were women with normal ovarian reserve evaluations, no malformations, and regular menstrual cycles. Four heavy metals (lead, mercury, cadmium and chromium) were measured in whole blood at inclusion. Single-exposure associations were examined with multivariable logistic regressions adjusted on potential confounders. Mixture effects were investigated with quantile g-computation and bayesian kernel machine regression (BKMR). Results: All metals were detected in over 85% of control samples. We observed non-significant increased risks of DOR for chromium (OR = 1.24 [0.65 - 2.39] for the second tercile of exposure and OR = 1.77 [0.84 - 3.70] for the tercile) and cadmium (OR = 1.89 [0.98 - 3.67] for the second tercile of exposure and OR = 1.18 [0.55 - 2.52] for the tercile). Quantile g-computation and BKMR both yielded a non-significant increased risk of DOR for the mixture of metals, with no evidence of interaction. Conclusions: We detected weak signals that some heavy metals could be associated with DOR. These findings should be replicated in other studies. Keywords: Reproductive outcomes, Female fertility, Heavy metals, Chemical exposures, Mixtures, Environmental epidemiology.