Maternal high-fat, high-sucrose diet-induced excess adiposity is linked to placental hypoxia and disruption of fetoplacental immune homeostasis in late gestation†.

Maternal excess adiposity during pregnancy is linked to placental malperfusion and inflammatory injury. Obesity-associated placental malperfusion may induce fetoplacental hypoxia, contributing to adverse health outcomes within and beyond the perinatal period. However, direct comparisons of tissue oxygen saturation at the uteroplacental interface in pregnancies complicated by excess adiposity are lacking. Using a mouse model of preconception high-fat, high-sucrose (HFHS) diet-induced excess adiposity, we found that both placental junctional and labyrinth zones at E17.5 were hypoxic compared to chow-fed controls (CON). HFHS placentas had a greater burden of histopathological lesions, including tissue calcification and fibrinoid deposition within the labyrinth zone. Calcified placental tissue coincided with the destruction of vasculosyncytial membranes and macrophage-dense foci, alongside altered expression of immunomodulatory and chemotactic cytokines, which differed in magnitude with fetal sex. While fetal growth was not impaired, fetuses from HFHS pregnancies exhibited higher levels of circulating IL-6, prolactin, CXCL1, and CCL2. Collectively, these data confirm that maternal diet-induced excess adiposity leads to a reduction in placental oxygen saturation, even in the absence of marked growth restriction or fetal demise. While this hypoxic state was not linked to gross morphological abnormalities, it was associated with markers indicative of local malperfusion and inflammation, and an altered fetal inflammatory and endocrine milieu in late gestation. Together, these findings demonstrate that a state of placental hypoxia may contribute to the increased risk of adverse perinatal outcomes and long-term disease programming in pregnancies affected by maternal obesity.