Effects of Maternal stress on epigenetic markers on fetal tissues and neurodevelopment at various gestational ages: A Systematic review

The Developmental Origins of Health and Disease (DOHaD) theory hypothesized that environmental exposures during early life (particularly the in-utero period) can permanently influence health and vulnerability to disease in later life. This intriguing concept has been the subject matter of great interest in recent research, as much vital development of fetal neuronal networks and brain cell division happens in fetal life. Fetal programming, suggests that the in-utero environment is now increasingly believed to have a great impact on long term health and pattern of disease development in later life. There is also some evidence to show transgenerational epigenetic programming of genes. Various biological mechanisms are likely to be involved in fetal programming, epigenetic modifications being just one of them. This systematic study aims to review currently available primary research data to assess the significance of maternal stress in epigenetic modification affecting fetal neurodevelopment as assessed from fetal or maternal tissue sampling. RationaleMost studies have focused on impact by a particular type of stress. While some studies have studied long term outcomes, into psychiatric and intellectual follow up in adults, few have actually researched the direct effect of maternal stress or trauma on the fetus, and even fewer have documented direct sampling of genetic markers as a result of the same. There is a significant knowledge gap on how to link or classify the epigenetic impact of various kinds of maternal stress on fetal development. This systematic review hopes to evaluate the available evidence that may help us better understand the significance various types of maternal stress during pregnancy and of its diverse epigenetic influence on the developing fetus. ObjectiveTo assess and review the current available research in evaluating the role of epigenetics of the influence of maternal stress during human pregnancy on the neurodevelopment of the developing fetus as evidenced by tissue analysis. MethodsA systematic review was conducted on available literature from online databases and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 checklist. A comprehensive search strategy was developed. Only Observational and interventional studies, which were primary research studies were included in assessing epigenetic markers derived from fetal or maternal tissue in conditions of maternal stress during pregnancy and were analyzed. We retrieved 492 papers most relevant to the query, mostly from PubMed, Semantic search tools and Journals. Both authors rigorously studied and summarized the abstracts to exclude the studies that did not meet the outlined criteria, even though well planned comprehensive studies were found, which lacked key inclusion criteria. Each study was further analysed for specific type of stress, gestational age (temporal characteristics), tissue sample analysed. Forty studies were shortlisted after screening and selected for the review, based on the inclusion criteria. Only human studies, that use validated psychological or physiological measures to assess maternal stress and analyze epigenetic markers in fetal or maternal tissue were included and also must specify the gestational timing of stress exposure. Only observational, cohort, or case-control primary studies that clearly defines and categorizes the type of stress (psychological, physical, or environmental) were included. Non-human studies, or Duplicate publications and studies that were missing key information related to the question asked were excluded. Studies were screened by the two reviewers independently. Risk of bias was assessed using RoB 2.0 tool. Data was analyzed and tabulated descriptively, using the data extraction tool designed for the study. Data extraction table is attached at the end of the article Missing data were not analysed. ResultsThis systematic review of literature spanning at least 40 independent primary studies, involving around 19,400 mothers indicated that different maternal stress types yield distinct epigenetic signatures in tissues linked to fetal development. Factors such as chronic psychological stress, traumatic exposure and symptoms of anxiety or depression are each associated with specific patterns of DNA methylation. Stress response genes, especially NR3C1, FKBP5 and HSD11B2, consistently show altered methylation. One investigation of maternal smoking documented global DNA methylation changes in fetal brain tissue, whereas most studies examined placenta, cord blood, or buccal cells. In early gestations, it was found that maternal depression, perceived stress, and adverse life events relate to altered methylation of NR3C2, MEST, and other markers enriched for neurodevelopmental functions. In contrast, maternal stress during later trimesters was associated with changes in NR3C1, FKBP5, BDNF, and related genes, sometimes also exhibiting sex-specific effects. Traumatic and especially war-related stress yields robust increases in NR3C1 methylation that may persist into later life. These findings support that the type and timing of maternal stress selectively drives epigenetic modifications in gene networks critical to neuroendocrine function and neural development. ConclusionThe timing and type of maternal stress determines which specific genes undergo methylation changes in feto maternal tissue, with early and late gestational periods showing distinct epigenetic signatures. Although several key similarities were noted, there were some conflicting results, which may be attributable to limited sample size or heterogeneity between studies. Further research with more robust standardization and more large scale randomized studies is needed to validate the exact mechanism and impact on epigenetics due to maternal stress.