Reactive oxygen species in fetal growth restriction mechanisms and therapeutic directions (Review)

Fetal growth restriction (FGR) is strongly associated with adverse perinatal outcomes, and placental oxidative stress has been identified as a central pathological mechanism. In maternal plasma, cord blood and placental tissues from FGR pregnancies, the levels of malondialdehyde, 4‑hydroxynonenal, reactive oxygen metabolites and 8‑hydroxy‑2'‑deoxyguanosine are consistently elevated. In parallel, superoxide dismutase and glutathione peroxidase show compensatory upregulation, while catalase activity declines, reflecting increased oxidative burden coupled with impaired antioxidant defense. Major sources of reactive oxygen species include NADPH oxidase and xanthine oxidase, mitochondrial electron transport and ischemia‑reperfusion events. Mechanistic evidence further indicates that oxidative stress interacts with endoplasmic reticulum stress, metabolic reprogramming and epigenetic alterations, thereby aggravating trophoblast dysfunction and placental vascular injury. Aberrant DNA hypomethylation, histone modifications and dysregulation of noncoding RNAs, such as microRNA (miR)‑199a, miR‑210‑3p and miR‑21, contribute to persistent remodeling of trophoblast behavior and vascular networks. Early clinical studies have suggested that melatonin and pentoxifylline may alleviate placental oxidative injury and improve selected perinatal outcomes, whereas vitamin C and E supplementation shows no clear benefit. Preclinical investigations have highlighted the potential of mitochondria‑targeted and classical antioxidants, including mitoquinone mesylate, N‑acetylcysteine, tempol and resveratrol; however, their efficacy and safety appear to be dependent on gestational timing and dosage. Further well-designed clinical trials are warranted to establish effective antioxidant‑based strategies for FGR.