Sustained Maternal Cortisol Elevation Links Metabolic Stress to Fetal Growth Restriction in a Guinea Pig Model of Undernutrition

Abstract

Fetal growth restriction (FGR) resulting from maternal undernutrition is commonly attributed to insufficient nutrient substrate delivery to the fetus. However, the contribution of maternal physiological stress responses to this outcome remains poorly characterized. Using the well-established guinea pig maternal nutrient restriction (MNR) model, we conducted a comprehensive retrospective analysis to interrogate the hypothesis that maternal stress physiology actively mediates fetal growth outcomes beyond simple substrate limitation. Maternal salivary and serum cortisol were significantly elevated in MNR dams throughout pregnancy despite no baseline differences at conception, indicating that hypothalamic-pituitary-adrenal (HPA) axis activation was specifically triggered by the combined physiological demands of pregnancy and nutritional constraint. The sustained cortisol elevation was accompanied by acute metabolic perturbations at mid-pregnancy, including hypoglycemia and depleted circulating lipids. While most acute metabolic disturbances resolved by near-term, cortisol remained elevated, and MNR fetuses exhibited parallel cortisol elevation alongside sustained growth restriction. Maternal weight divergence emerged only in late gestation and was driven primarily by reduced conceptus weight. Maternal organ analysis revealed selective hepatic enlargement with apparent lipid accumulation in MNR dams near-term. Overall, these findings help to reframe nutrition-related FGR as a condition in which maternal adaptive stress responses, reduced nutritional components and placental insufficiency are mechanistically intertwined, with important implications for the design of effective interventions beyond simply nutrient supplementation.