Maternal Prenatal Stress, Oxidative Stress and Fetal Programming: Integrating Placental, Endocrine, Mitochondrial and Epigenetic Mechanisms and Emerging Therapeutic Strategies

Abstract

Background: Maternal stress during pregnancy is increasingly recognized as an important environmental determinant of fetal development and lifelong disease susceptibility. Although prenatal stress has been associated with adverse neurodevelopmental, cardiovascular, metabolic and behavioural outcomes, the biological pathways linking maternal stress to persistent offspring phenotypes remain incompletely integrated. Objective: This systematic review aimed to synthesize evidence concerning the molecular and physiological mechanisms linking maternal prenatal stress with fetal programming, with particular emphasis on hypothalamic–pituitary–adrenal-axis activation, placental glucocorticoid metabolism, oxidative stress, mitochondrial dysfunction, inflammation and epigenetic regulation. A secondary objective was to examine emerging nutritional, antioxidant, hormonal and phytochemical strategies that may attenuate stress-induced developmental programming. Methods: The review was designed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 framework [1,2]. PubMed/MEDLINE, Embase, Scopus, Web of Science, Google Scholar and the Cochrane Library should constitute the principal information sources. Eligible evidence comprises human observational/interventional studies and experimental animal studies investigating maternal stress during pregnancy and biological or clinical outcomes in offspring. Study characteristics, exposure characteristics, mechanistic pathways, offspring outcomes and interventions will be extracted. Risk of bias will be evaluated using design-appropriate validated instruments. Because substantial heterogeneity is anticipated across populations, species, stress models, developmental windows and outcome measures, the principal synthesis will be narrative and mechanistic. Results: Available evidence indicates that maternal prenatal stress can influence offspring development through interacting endocrine, placental, oxidative, inflammatory, mitochondrial and epigenetic mechanisms. Maternal stress activates the hypothalamic–pituitary–adrenal axis and alters glucocorticoid signalling, while the placenta regulates fetal exposure to maternal glucocorticoids through mechanisms including 11β-hydroxysteroid dehydrogenase type 2. Human and experimental studies implicate altered placental function, oxidative stress and epigenetic modification in offspring programming [3–8]. Prenatal stress has been associated with altered cardiovascular, metabolic, neuroendocrine and behavioural phenotypes [3,4]. Experimental evidence further indicates that placental oxidative stress may mediate effects of maternal stress on offspring brain and behaviour and that antioxidant treatment can attenuate selected phenotypes [9]. Emerging evidence also implicates mitochondrial mechanisms in prenatal stress-induced offspring abnormalities [10]. Conclusion: Maternal prenatal stress should be considered a multisystem developmental exposure involving the maternal–placental–fetal axis rather than an isolated psychological event. Oxidative stress may represent an important mechanistic bridge between maternal endocrine activation, placental dysfunction, mitochondrial disturbance, inflammation and epigenetic programming. Antioxidant, mitochondria-targeted, melatonin-based and selected phytochemical strategies represent promising research directions, but their efficacy and safety during pregnancy require rigorous experimental and clinical investigation.