Novel Mediators of Excessive Fetal Growth in Type 1 Diabetes Pregnancy

Type 1 diabetes (T1D) incidence has risen sharply over the past 30 years, affecting increasing numbers of women of childbearing age. Unfortunately, infants of women with T1D are at high risk for life-threatening complications in the neonatal period. Over 40% of infants of diabetic mothers are admitted to neonatal intensive care units, as compared to 6% in the general population. Excessive fetal growth, or being "large for gestational age" (LGA), is among the most common and serious complications of diabetic pregnancy. LGA infants are at increased risk for birth trauma, asphyxia, jaundice, and hypoglycemia, each of which may cause lasting neurological impairments or death. Also of great concern is the recent discovery that LGA infants are at increased risk of obesity and type 2 diabetes later in life. Maintaining near-normal glucose levels during pregnancy can reduce risk of LGA, but the incidence remains high even in optimally managed pregnancies, with ~50% of infants born LGA. Thus, novel approaches for preventing LGA and its accompanying complications are urgently needed. In this grant, we will leverage the unique patient population of the Joslin Pregnancy Program together with state-of-the-art techniques, including continuous glucose monitoring and metabolomics analysis, to identify novel mechanisms for LGA in pregnancies complicated by T1D. In Aim 1, we will examine associations between maternal glycemic variability, as assessed by continuous glucose monitoring, and fetal glycemic exposure. In Aim 2, we will test whether lipids and other nutrients are associated with LGA risk in T1D pregnancy. We will perform global metabolomic analysis to comprehensively quantify lipids, metabolic intermediates, and other small molecules in (i) maternal plasma, and (ii) cord plasma. Because we are focusing on modifiable factors, including maternal glucose variability and nutrient metabolism, these studies will be readily translatable to the development of new clinical strategies to prevent LGA and its accompanying neonatal complications in the setting of T1D pregnancy.