NON-ALCOHOLIC FATTY LIVER DISEASE, PREGNANCY LOSS AND PRETERM BIRTH：A MENDELIAN RANDOMIZATION STUDY

Non-alcoholic fatty liver disease (NAFLD) has been positively associated with premature termination of pregnancy, including pregnancy loss and preterm birth. However, the causal relationship of these associations remains to be elucidated and limited research has examined the underlying mechanisms. This study aimed to determine the causality of NAFLD and both pregnancy loss and preterm birth, and to identify potential mediators. The genetic instrument for NAFLD was constructed from a biopsy-confirmed genome-wide association study (GWAS) study (1,483 NAFLD patients and 17,781 controls of European ancestry). The summary statistics for pregnancy loss (N = 243,704) and preterm birth (N = 122,955) were obtained from UK Biobank and FinnGen consortium, respectively. We performed two-sample mendelian randomization (MR) by the inverse variance-weighted (IVW) method, accompanied by pleiotropy-robust MR sensitivity analysis. Two-step MR analysis was used to investigate the mediation effect of five placental diseases. The proportion of mediated effect was calculated by dividing the indirect effect by the total effect. The results from IVW showed that genetic liability to NAFLD was associated with an increased risk for pregnancy loss (odds ratio [95% confidence interval] =1.03[1.003-1.066], p=0.03) and preterm birth (1.08[1.004-1.165], p=0.04). In the first step of the two-step MR analysis, our result showed significant associations between genetically predicted NAFLD and PROM (1.14[1.034-1.254], p=0.009). Genetically driven PROM was found significantly associated with an increased risk of pregnancy loss (1.03 [1.003-1.060], p=0.029), which remained significant even after adjusting for genetically predicted NAFLD (1.05[1.012-1.082], p=0.007). Our findings suggested that PROM partially (17%, 95%CI: 0%-42%) mediates the genetically predicted effect of NAFLD on pregnancy loss. This study suggests a possible higher risk of pregnancy loss and preterm birth in NAFLD and the association for pregnancy loss may be mediated by PROM.