Hyperglycemia in pregnancy has numerous well-established complications including fetal overgrowth and its attendant risks of cesarean delivery, birth trauma, shoulder dystocia, neonatal hypoglycemia, and childhood obesity, among others. Available evidence suggests that the development of these sequelae begins in early pregnancy, months prior to conventional diagnosis of gestational diabetes mellitus. Despite this, there are no widely accepted diagnostic criteria for hyperglycemia in early pregnancy. This is due, in part, to major limitations of the tools employed for glycemic measurements in pregnancy; pregnant women have not yet fully benefitted from advances accrued over the past four decades in glycemic assessment using continuous glucose monitoring (CGM) and glycated markers (such as hemoglobin A1c). Accurate assessments of glycemia using these tools would allow not only for the investigation of the relationship between early pregnancy glycemia and adverse outcomes, but also for the identification of extra-glycemic factors that modulate the risk of these outcomes in women with early pregnancy hyperglycemia. We propose to use our established infrastructure for recruitment of ethnically-diverse pregnant women in the first trimester to conduct a longitudinal observational cohort study of glycemia in pregnancy at two sites in Boston, Massachusetts (5000 deliveries/year combined) as part of a multi- center Consortium in collaboration with the NIDDK. Our team of investigators, expert in gestational glucose metabolism, glycated protein assays, CGM, and perinatal genomics, brings decades of experience collaborating in multicenter studies with highly successful recruitment and long-term retention. Among pregnant participants without pre-existing diabetes enrolled in the first trimester, we will perform serial glycemic assessment using oral glucose tolerance tests, CGM, and glycated markers across gestation. We will follow participants through delivery to ascertain maternal and neonatal outcomes. In Aim 1 we will use CGM to define hyperglycemia in early pregnancy based on association with large for gestational age birth weight and other hyperglycemia- associated adverse outcomes. In Aim 2 we will identify an optimal glycated marker, measurable on a non-fasting blood sample, to assess glycemia in early pregnancy and across gestation. In Aim 3 we will test key extra- glycemic factors (maternal insulin resistance and common fetal genetic variation) as effect modifiers of the relationship between maternal glycemia and adverse outcomes. These investigations will establish a new standard of care for diagnosis of early pregnancy hyperglycemia, simplify clinical measurement of glycemia in pregnancy, and bring advances in precision diabetes care to the obstetric population.

High blood sugar in pregnancy leads to numerous complications in mothers and their infants but is usually not discovered until the late second or third trimester. We will use the latest advances in blood sugar measurement (continuous glucose monitoring and glycated markers) to study the relationship between pregnancy complications and blood sugar levels in the first trimester and across gestation. This work will lead to improved clinical approaches for gestational diabetes screening, diagnosis, and treatment that are simplified, personalized, and evidenced-based.