DNA methylation as a mediator in the association between prenatal maternal stress and child mental health outcomes: Current state of knowledge

Elsevier, Journal of Affective Disorders, Volume 319, 2022, Pages 142-163
Naomi Azar, Linda Booij

Prenatal maternal stress is increasingly recognized as a risk factor for offspring mental health challenges. DNA methylation may be a mechanism, but few studies directly tested mediation. These few integrative studies are reviewed along with studies from three research areas: prenatal maternal stress and child mental health, prenatal maternal stress and child DNA methylation, and child mental health and DNA methylation.

We conducted a narrative review of articles in each research area and the few published integrative studies to evaluate the state of knowledge.

Prenatal maternal stress was related to greater offspring internalizing and externalizing symptoms and to greater offspring peripheral DNA methylation of the NR3C1 gene. Youth mental health problems were also related to NR3C1 hypermethylation while epigenome-wide studies identified genes involved in nervous system development. Integrative studies focused on infant outcomes and did not detect significant mediation by DNA methylation though methodological considerations may partially explain these null results.

Operationalization of prenatal maternal stress and child mental health varied greatly. The few published integrative studies did not report conclusive evidence of mediation by DNA methylation.

DNA methylation likely mediates the association between prenatal maternal stress and child mental health. This conclusion still needs to be tested in a larger number of integrative studies. Key empirical and statistical considerations for future research are discussed. Understanding the consequences of prenatal maternal stress and its pathways of influence will help prevention and intervention efforts and ultimately promote well-being for both mothers and children.