Causal Relationship Between Circulating Immune Cells and Recurrent Spontaneous Abortion: A Bidirectional Mendelian Randomization Study

ABSTRACT Background Recurrent spontaneous abortion (RSA) is a serious and common complication of pregnancy caused by multiple factors. The etiology remains incompletely understood, but immunologic factors play important roles. Here, we aimed to evaluate whether circulating immune cells causally impacted RSA. Methods In this study, we conducted a comprehensive two‐sample Mendelian randomization (MR) study to determine the causal association between the 731 immunophenotypes of human peripheral blood lymphocytes and the number of spontaneous abortions as well as recurrent miscarriage. Sensitivity analyses were performed to assess and minimize heterogeneity and horizontal pleiotropy. Reverse MR analysis was used to assess reverse causality. Results After Bonferroni‐correction, eight immunophenotypes were significantly associated with the number of spontaneous abortions: FSC‐A on CD4 + T cell (beta = −0.051, 95% CI = [−0.085, −0.017], P ‐value = 0.004), CD8 on HLA DR + CD8 + T cell (beta = −0.040, 95% CI = [−0.067, −0.014], P ‐value = 0.003), HLA DR on CD33 dim HLA DR + CD11b − (beta = −0.021, 95% CI = [−0.036, −0.005], P ‐value = 0.010), HLA DR + T cell Absolute Count (beta = 0.022, 95% CI = [0.006, 0.037], P ‐value = 0.008), HLA DR + T cell % lymphocyte (beta = 0.026, 95% CI = [0.010, 0.041], P ‐value = 0.001), HLA DR + T cell % T cell (beta = 0.023, 95% CI = [0.007, 0.039], P ‐value = 0.004), HLA DR + CD4 + T cell % lymphocyte (beta = 0.034, 95% CI = [0.007, 0.060], P ‐value = 0.012), and HLA DR on B cell (beta = 0.012, 95% CI = [0.003, 0.021], P ‐value = 0.010). In addition, we identified two immunophenotypes associated with recurrent miscarriage: HLA DR on B cell (OR = 0.854, 95% CI = [0.757, 0.964], P ‐value = 0.011), and CD19 on naive‐mature B cell (OR = 4.595, 95% CI = [1.674, 12.617], P ‐value = 0.003). There was no evidence of heterogeneity, horizontal pleiotropy and reverse causality. Conclusions Our study demonstrated a tight link between adaptive immune cells and RSA through genetic means, thus providing potential therapeutic targets or novel diagnostic biomarkers.