Presentations

Abstract

Introduction:

Perinatal mental health disorders, maternal stress, and trauma are often associated with poor maternal and fetal outcomes and a child's increased risk for mental illness. The field of fetal programming examines how adversity experienced by the mother affects fetal development and the offspring's mental health risk. This review outlines three related and overlapping mechanisms of fetal programming thought to underpin the impact of maternal stress on maternal/fetal well-being.

Main Body:

Immune activation: Mental illness is linked to chronic inflammation. Moreover, excessive maternal inflammation induces fetal microglial activity which has been shown to enhance indoleamine-2,3 dioxygenase, and thereby decrease serotonin production. Quinolinic acid, a byproduct of this reaction, also causes damage to serotonergic neurons. Both result in decreased serotonin, which has been linked to multiple mental illnesses. Increased levels of maternal Interleukin (IL) 6 is also linked to increased fetal amygdala size and connectivity, which have both been implicated in multiple mental illnesses.

Hypercortisolism: Chronic maternal stress downregulates placental 11β-hydroxysteroid dehydrogenase expression and thus conversion of bioactive cortisol to biologically inactive cortisone. This downregulation permits transfer of maternal cortisol to the fetus earlier than physiologically appropriate and at higher levels, stimulating the fetal hypothalamic-pituitary- adrenal axis (HPA axis), fetal norepinephrine release, and induction of an inflammatory state. HPA activation downregulates brain-derived neurotrophic factor (BDNF), low levels of which are implicated in neurodegeneration of the hippocampus. Interestingly, hippocampal volumes are decreased in fetuses of highly stressed mothers and there is a close association between decreased hippocampal volume and unipolar depression.

Fetal DNA methylation: DNA methylation generally inhibits transcription, is highly plastic and regulated during development, and stabilizes in adulthood. Increased stress generally increases DNA methylation. Glucocorticoid receptor and several serotonin transporter genes have been implicated in both mental illness and maternal stress. The most studied methylation change is the hypermethylation of the Nuclear Receptor Subfamily 3 Group C Member 1 promoter (NR3C1). NR3C1 is involved in inflammatory response and glucocorticoid resistance. NR3C1 hypermethylation has been observed in adult survivors of trauma ranging from childhood abuse, Intimate Partner Violence (IPV), natural disasters, and in suicide victims on postmortem study. Selective NR3C1 knockdown in mice leads to increased progeny HPA axis activity and anxious behavior. NR3C1 placental methylation is inversely associated with infant self-regulation up to 2 weeks. Studies of Tutsi mothers indicated that survivors of the Rwandan genocide and their offspring/children displayed higher rates of NR3C1 methylation and mental illness compared to expatriate controls. This phenomenon has also been observed in mothers who experience IPV and their children. Several other genes are also under investigation but have not demonstrated clear correlation between maternal stress, methylation status, and children's behavior as NR3C1. Fetal biological sex also has an unclear relationship with DNA methylation. Some studies indicate increased methylation and risk of mental illness in female children of stressed mothers compared to males, while others demonstrate the inverse. There remains room for more research including increased characterization of suspected genes and epigenetic mechanisms as well as the role fetal sex. Current studies are limited by high methylation tissue specificity and tissue availability.

Conclusions:

Maternal stress conferred to the fetus during pregnancy may influence the child's future risk of developing mental illness. The three mechanisms outlined, inflammation, hypercortisolism, and DNA methylation appear to overlap and act in tandem to promote a vulnerable phenotype. Maternal stress tends to remain stable from preconception to the post-natal period and is highly correlated with economic insecurity, IPV, and likely other causes. Targeted preventative intervention before pregnancy, liberal screening, and advocacy for greater societal support may help alleviate maternal stress and prevent the deleterious effects of stress on fetal neural development and offspring mental health.