Abstract Body (Do not enter title and authors here): Introduction: Women with a history of gestational diabetes mellitus (GDM) have high cardiovascular disease (CVD) risk, even without subsequent type 2 diabetes (T2D). Metabolic dysregulation precedes CVD and has been associated with T2D in women with GDM history. However, the precise metabolic pathways linking GDM to the persistent CVD risk remain unknown.
Methods: Using elastic net, we identified a postpartum (24-72 hrs after delivery) metabolomic signature of GDM using maternal plasma metabolomics data in the Boston Birth Cohort (BBC; 161 GDM; 1,178 non-GDM; 64% Black). The GDM signature was internally validated in BBC and externally replicated in the Nurses’ Health Study II (NHS2; 392 prior GDM; 2,326 no GDM; 98% White) with available postpartum (median: 17.5 yrs after delivery) plasma metabolomics data. CVD was defined as a composite of coronary artery disease (CAD; coronary artery bypass grafting, myocardial infarction, and coronary death) and stroke. Cox proportional hazards model was used to examine associations between the GDM signature and incident CVD in both NHS2 and Nurses’ Health Study (NHS; no data on GDM history; 95% White). Potential causal relationships were estimated using Mendelian randomization (MR) analyses.
Results: The externally validated GDM signature consists of 44 metabolites (Figure 1A). Women with prior GDM had a higher signature score than those without in both BBC and NHS2 (Figure 1B). In NHS2 (n=2,718), 97 CVD cases (17 cases in 392 women with prior GDM) were documented in 23 years of follow-up. The GDM signature was significantly associated with higher risk of CVD and CAD but not stroke, and the associations did not change after additionally adjusting for GDM history and subsequent T2D (Figure 2A). The GDM signature mediated associations between GDM and CAD (5.7%; p=0.048) and CVD (4.4%; p=0.038). In NHS (n=4,469), 874 CVD cases were documented in 31 years of follow-up. The GDM signature was associated with incident CAD but not CVD and stroke (Figure 2B). In MR analysis, the GDM signature was significantly associated with higher risk of GDM, T2D, CAD, and stroke (Figure 3).
Conclusions: Metabolomic dysregulations related to GDM history could be on the causal pathways to CAD. Women with GDM may have predisposition to metabolic disorders prior to the index pregnancy that was manifested as GDM during pregnancy. Ongoing work is underway to replicate these findings in other racial and ethnic groups.