Relationship Between Maternal Serum Level of Bilirubin with Sporadic and Recurrent Miscarriage: A Bidirectional 2-Sample Mendelian Randomization Study

Background: The association between maternal serum bilirubin levels and miscarriage risk remains unclear. This study investigates the causal link between maternal bilirubin levels and both sporadic and recurrent miscarriage using Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC). Methods: A bidirectional two-sample MR analysis examined genetic associations between maternal serum bilirubin (direct and total) and miscarriage. Genetic instruments were derived from genome-wide association studies (GWAS). LDSC was used to assess shared genetic architecture. Odds ratios (OR) and p values were employed to determine statistical significance. Results: Elevated maternal direct bilirubin levels were significantly associated with sporadic miscarriage (OR = 1.028, p = 0.019) and recurrent miscarriage (OR = 1.016, p = 0.005). Similarly, maternal total bilirubin was linked to sporadic miscarriage (OR = 1.022, p = 0.030) and recurrent miscarriage (OR = 1.013, p = 0.007). In contrast, reverse MR showed no significant association between maternal bilirubin level and miscarriage. Furthermore, LDSC confirmed no shared genetic architecture. Conclusion: Elevated maternal serum bilirubin may increase miscarriage risk, warranting further investigation.