Oral Concurrent Session 2 - Diabetes
Oral Concurrent Sessions
Kjersti M. Aagaard, MD, PhD
Professor and Vice Chair of Research Department of Obstetrics and Gynecology, Division of MFM
Texas Children's Hospital, Baylor College of Medicine
Houston, TX, United States
Stephanie Wesolowski, PhD
University of Colorado Health Sciences Center-Anschulz
Denver, CO, United States
Jed Friedman, PhD
University of Oklahoma Health Sciences Center & Hamm Diabetes Center
Oklahoma City, OK, United States
Maxim D. Seferovic, PhD
Assistant Professor
Baylor College of Medicine and Texas Children’s Hospital
Houston, TX, United States
Brandon T. Garcia, BS
Baylor College of Medicine and Texas Children’s Hospital
Houston, TX, United States
Feng Li, MD, PhD
Assitant Professor
University of North Carolina at Chapel Hill
Chapel Hill, NC, United States
Traditional maternal drug toxicity studies focus on fetal malformations, overlooking potential childhood outcomes not recognized at birth. Metformin evades 1st pass liver metabolism & crosses the placenta. Based on its pharmacodynamics & limited clinical studies suggesting risk for childhood obesity & insulin resistance, we hypothesized that metformin initiated periconception would lead to fetal bioaccumulation with aberrant fetal growth. We developed a highly novel primate model and applied triple-quadruple pole LC mass spectrometry (UHPLC-QQQ) for direct quantitation of maternal and fetal metformin levels with detailed fetal biometry & histopathology.
Study Design:
Within 30d of confirmed conception, n=19 Rhesus macaque dams fed a control chow or Western style diet (mWSD) were initiated on twice daily, human dose-equivalent (10mg/kg) metformin or vehicle control (dose weight-adjusted Q trimester). G145 fetuses were delivered via Cesarean, measured, and necropsied by primate center experts. All fetal organs & tissue were processed per pediatric clinical pathology standards. Fluid and tissue metformin levels were assayed using UHPLC-QQQ.
Results:
Of n=19 pregnancies, 3 were late-term stillbirths unrelated to drug exposure. Viable pregnancies demonstrated significant bioaccumulation of metformin within the fetal kidney, urine, amniotic fluid, & placenta (Fig1A-D). These findings were associated with significant (p< .05) and specific restriction of overall growth, and decreased kidney, liver, skeletal muscle & retroperitoneal fat mass (Fig1E), driving significantly lower birthweight. Fetal kidney sagittal sections demonstrated delayed maturation with disorganized glomeruli & increased cortical thickness (Fig1F,G).
Conclusion: We are the first to directly demonstrate fetal bioaccumulation of metformin driving fetal growth restriction & significant renal dysmorphology. These findings are consistent with limited clinical trial data suggesting risk of SGA leading to paradoxical childhood obesity & insulin resistance. Additional investigation of the enduring effects of prenatal metformin use is warranted.