Altered placental iron transport and putative ferroptosis pathways in pregnancies with excessive gestational weight...

Excessive gestational weight gain (GWG) is associated with various adverse pregnancy outcomes, including disruption of placental function and fetal development. Iron transport through the placenta is crucial for fetal growth, and transferrin receptor 2 (TfR2) plays a key role in iron homeostasis. However, the effect of excessive GWG on placental TfR2 expression and neonatal iron parameters remains unclear. This study aimed to investigate the effect of excessive GWG on placental TfR2 expression and its association with neonatal iron levels, including cord blood serum iron levels and total iron-binding capacity. A prospective study was conducted with 90 pregnant women divided into 2 groups: 45 with normal weight gain and 45 with excessive GWG. Placental TfR2 expression was assessed via immunohistochemistry, whereas neonatal iron parameters were analyzed in umbilical cord blood using biochemical assays. Additionally, in silico analyses were performed to explore the molecular pathways linking TfR2 expression and iron homeostasis. Placental TfR2 expression was significantly increased in the excessive GWG group compared to controls, with high immunoreactivity observed in the trophoblastic layer, capillaries, and villous connective tissue. Neonates from mothers with excessive GWG had significantly higher cord blood serum iron levels (P = .025) and lower total iron-binding capacity levels (P = .017). Bioinformatics analysis revealed that TfR2 is involved in iron homeostasis regulation, and ferroptosis emerged as a potentially relevant pathway. Excessive GWG may be associated with altered placental iron transport and increased TfR2 expression, which could contribute to iron overload and involvement of ferroptosis-related pathways. However, the lack of direct ferroptosis markers such as GPX4, ACSL4, reactive oxygen species levels, or cell-death assays limits mechanistic confirmation. Further studies are required to validate the role of ferroptosis in this context.