Fetal chronic hypoxia and oxidative stress in diabetic pregnancy. Could fetal erythropoietin improve offspring outcomes?

Oxidative stress is responsible for microvascular complications (hypertension, nephropathy, retinopathy, peripheral neuropathy) of diabetes, which during pregnancy increase both maternal and fetal complications. Chronic hypoxia and hyperglycemia result in increased oxidative stress and decreased antioxidant enzyme activity. However, oxidative stress induces also anti-oxidative reactions both in pregnant diabetes patients and in their fetuses. Not all type 1 diabetes patients with long-lasting disease develop microvascular complications, which suggests that some of these patients have protective mechanisms against these complications. Fetal erythropoietin (EPO) is the main regulator of red cell production in the mother and in the fetus, but it has also protective effects in various maternal and fetal tissues. This dual effect of EPO is based on EPO receptor (EPO-R) isoforms, which differ structurally and functionally from the hematopoietic EPO-R isoform. The tissue protective effects of EPO are based on its anti-apoptotic, anti-oxidative, anti-inflammatory, cell proliferative and angiogenic properties. Recent experimental and clinical studies have shown that EPO has also positive metabolic effects on hyperglycemia and diabetes, although these have not yet been fully delineated. Whether the tissue protective and metabolic effects of EPO could have clinical benefits, are important topics for future research in diabetic pregnancies.