Cardiometabolic Disease and Substrate Metabolism

Cardiometabolic disease such as pre-eclampsia (PreE) and gestational diabetes (GDM) affect close to 15% of pregnancies and are a major cause of maternal and neonatal morbidity and mortality. Much of the clinical data surrounding these disorders focuses on management during pregnancy and counseling regarding risks of continued cardiometabolic dysfunction after pregnancy. Data are much more limited regarding assessing and managing cardiometabolic dysfunction leading into or early in pregnancy. Furthermore, there are even less data describing metabolic dysfunction outside of GDM and PreE as relate to future cardiometabolic risk.

The standard of care of assessing metabolic dysfunction during pregnancy, specifically gestational diabetes, is a two-step glucose challenge approach. Outside of pregnant populations, metabolic dysfunction is assessed from a more holistic approach including assessment of insulin, lactate, triglycerides, HDL, LDL, VDRL, cholesterol and free fatty acids.

Data are currently lacking on substrate metabolism other than glucose in pregnancy. There are some data that describe maternal lipid metabolism in pregnancy, but most of these data focus on lipid metabolism as it relates to fetal growth and fat mass, but none describe substrate metabolism as it relates to development of maternal disease such as insulin resistance.

Additionally, the placenta is an extremely metabolically active organ that responds to changes in maternal stress. There is evidence in animal studies that the placenta can alter transportation of carbohydrates, lipids and amnio acids in response to changes in heat, undernutrition, hypoglycemia and glucocorticoid administration.

Traditional hypotheses regarding development of cardiometabolic disease in pregnancy surrounded topics such as abnormal placentation, dysfunctional spiral arteries and hormones such as human placental lactogen. Outside of pregnancy, studies have shown that endothelial dysfunction has been linked to cardiometabolic disease due to its role in regulating vascular tone and glycolysis. Furthermore, there is evidence to support that gestational diabetes is a risk factor for development of endothelial dysfunction; however, in vivo endothelial dysfunction in GDM is not well explored. While there are data that describe endothelial dysfunction in pregnancy as it relates to pre-eclampsia, most studies describe indirect measures of endothelial dysfunction using proteins such as VEGF, PLGF, and SFLT1.

The metabolic profiles in pregnant people at risk for cardiometabolic disease has not been explored heavily. By assessing both maternal substrate metabolism as well as placental function and pathology, we hope to better understand disease from the lens of not just the maternal but also the fetal and placental unit. Therefore, this study seeks to evaluate the relationship between substrate metabolism of pregnant individuals as it relates to their development of cardiometabolic disease in pregnancy with hopes for more translational research to design better targeted therapies.

Inclusion criteria

• Age 18-45
• Any pre-pregnancy BMI
• At least one high risk OR one moderate risk factor for pre-eclampsia based on ACOG and USPSTF guidelines
• Willingness to adhere to aspirin therapy
• Willingness to undergo 2h OGTT for serum collection in addition to survey collection, indirect calorimetry, body composition measures, neonatal measures, etc.
• Gestational age at enrollment <18 weeks
• Ability to speak, read, and communicate via English

Exclusion criteria

• Type 2 Diabetes Mellitus
• Type 1 Diabetes Mellitus
• Current gestational diabetes mellitus
• Current/active platelet disorder or bleeding diathesis (thrombocytopenia of any etiology, idiopathic thrombocytopenic purpura/ITP, thrombotic thrombocytopenic purpura/TTP, von Willebrand disease, etc.)
• Thrombophilia
• Current use of NSAID for other indication (indomethacin, ibuprofen, etc.)
• Current use of other immune-modulating agents and biologics (hydroxychloroquine, azathioprine, 6-mercaptopurine, IL-6 inhibitors, etc.)
• Current or recent use of steroids
• Current use of prophylactic or therapeutic anticoagulation
• Medical contraindication to aspirin therapy
• Molar pregnancy
• Renal disease
• Inability or unwillingness to give informed consent
• Current psychiatric illness/social situation that would limit compliance with study requirements, as determined by the principal investigators