Mediating role of body mass index and fetal fraction in the association between advanced maternal age and gestational diabetes mellitus risk: a retrospective non-invasive prenatal testing cohort study

OBJECTIVE: This study aimed to investigate the association between advanced maternal age (AMA) and the risk of gestational diabetes mellitus (GDM) and to evaluate the potential mediating roles of maternal body mass index (BMI) and fetal fraction (FF) measured in non-invasive prenatal testing (NIPT). METHODS: A retrospective cohort study was conducted among 2,163 singleton pregnancies that underwent NIPT at 13-22 weeks' gestation, were diagnosed with GDM at 24-28 weeks' gestation, and delivered at a tertiary care hospital in China. Participants were categorized into the AMA group (≥ 35 years, n = 575) and non-AMA group (< 35 years, n = 1588). Logistic and linear regression models were used to assess the association between AMA and BMI at NIPT, FF, and GDM risk, adjusting for confounders. Mediation analysis was performed to quantify the proportion of the total effect of AMA on GDM mediated by BMI and FF. RESULTS: , 95% CI 1.08-1.15, P < 0.001) were independently associated with increased GDM risk, while lower FF (per 1% decrease) was also significantly associated with a higher GDM risk (adjusted OR = 1.06, 95% CI 1.03-1.09, P < 0.001). AMA was also associated with both higher BMI (adjusted β = 0.57, 95% CI 0.24-0.90, P < 0.001) and lower FF (adjusted β = -0.58, 95% CI -0.99 to -0.16, P = 0.007). Mediation analysis indicated that BMI and FF mediated 7.08% and 4.36% of the total effect of AMA on GDM risk, respectively (both P < 0.001). CONCLUSION: AMA significantly increases GDM risk, partly mediated by elevated BMI and reduced NIPT-derived FF. These findings highlight the role of maternal metabolic and placental factors as key intermediaries in AMA-related GDM, offering insights for targeted prenatal risk stratification and intervention. Given the retrospective design, causal inference cannot be established.