Introduction:
Previous studies have linked placental weight (PW) to cardiovascular diseases, but the causality and potential mediators underlying this relationship are still unknown.

Material and methods:
We conducted Mendelian randomization (MR) analysis via summary statistics from genome-wide association studies (GWAS), including PW adjusted for sex, 21 candidate mediators and atherosclerotic cardiovascular disease (ASCVD), which includes coronary heart disease (CHD) and ischemic stroke (IS).Two-step MR was employed to identify and assess the mediation proportion of potential mediators in the association between PW and ASCVD. Additionally, we conducted a repeated analysis using PW adjusted for gestational age and sex.

Results:
Univariable MR (UVMR) analysis revealed that for each 1-SD decrease in fetal genotype-determined PW adjusted for sex only, the risk of CHD increased by 24% (95% CI: 1.05–1.46) and the risk of large artery stroke (LAS) increased by 46% (95% CI: 1.13–1.89). Similar results were obtained in repeated analyses. The mediation MR analysis revealed that the causal relationship between fetal genotype-determined PW and CHD risk was primarily mediated by birthweight, type 2 diabetes, and education, each mediating 3.66% to 40.80% of the total effect. The causal relationship between fetal genotype-determined PW and LAS risk was mediated mainly by type 2 diabetes, which accounted for 22.11% of the total effect.

Conclusions:
This study elucidated a unidirectional causal relationship between lower PW and a greater ASCVD risk, with factors such as birthweight, type 2 diabetes, and education mediating the association between PW and ASCVD.