Fetal growth retardation – the latest molecular mechanisms (Literature review)

Fetal growth restriction (FGR) is a complication of pregnancy in which the fetus does not reach the size typical for the gestation period. This complication is the leading cause of stillbirth, more than half of the cases of neonatal mortality, as well as health disorders of the child both in the newborn period and in adulthood.The article is devoted to a review of current literature on various molecular mechanisms of placental changes that lead to FGR. The pathogenesis of fetal growth retardation is multifactorial, based on impaired vascularization and insufficient supply of oxygen and nutrients to the fetus. Morphologically, a smaller number of extravillous trophoblasts, insufficient destruction of the vascular smooth muscle cell layer, i.e. preservation of the muscular layer and vascular wall, less fibrinoid deposition in the vascular wall of the spiral artery, and narrowing of the lumen are observed in the placenta. In placentas from pregnancies with this complication, increased activity of trophoblast apoptosis is determined, which causes its limited invasion, as well as an aseptic inflammatory reaction in the placenta. The release of trophoblast fragments into the maternal circulation provides an opportunity for maternal immune cells to recognize fetal antigens, which breaks tolerance. This interaction can start a “vicious cycle”, as increased oxidative stress potentially attracts more immune cells, which support inflammation. Obesity in a pregnant woman leads to a decrease in the number and size of decidual cells, as well as to a change in the expression of decidualization markers, treatment of human endometrial stromal cells in vitro with palmitic acid leads to a decrease in the regulation of decidualization markers. The reproductive tract, and especially the endometrium, expresses several isoforms of leptin receptors, the most extensively studied being the leptin receptor b. After binding to this receptor, leptin activates the Janus kinase and transcription activator 3 signaling pathway, which leads to the phosphorylation and translocation of these molecules to the nucleus, where they regulate the transcription of proinflammatory cytokine genes. The increased level of sFLT1 is associated with the development of endothelial dysfunction, therefore it can act as a pathogenetic mechanism of FGR. Studies using a specific culture of sFLT1 overexpressing mice have shown reduced fetal and placental weight associated with reduced trophoblast transport layer and changes in the expression of labyrinthine nutrient transporters. Endothelial nitric oxide synthase 3 (eNOS-3) is involved in placental angiogenesis and vasculogenesis and is highly expressed during embryonic and intrauterine development, and a low level of expression is directly related to lower nitric oxide availability, impaired trophoblast invasion, and, as a result, decrease in utero-placental blood flow and oxygenation, which is observed in FGR. In addition, early endothelial dysfunction in individuals born with growth retardation has been suggested to play an important role in the subsequent development of hypertension, which may be related to defective eNOS function and oxidative stress. Defective progesterone-mediated decidualization is associated with an elevated mature dendritic profile and defective uteroplacental vascular remodeling underlying FGR. The microbiological profile of the placenta tissue against the background of FGR showed a significantly higher relative number of pathogenic bacteria when compared with healthy placentas. Metabolites of pathogenic microflora cause pathological changes in the placenta.