The effects of maternal anxiety during pregnancy on IGF2/H19 methylation in cord blood

Abstract

Compelling evidence suggests that maternal mental health in pregnancy can influence fetal development. The imprinted genes, insulin-like growth factor 2 (IGF2) and H19, are involved in fetal growth and each is regulated by DNA methylation. This study aimed to determine the association between maternal mental well-being during pregnancy and differentially methylated regions (DMRs) of IGF2 (DMR0) and the IGF2/H19 imprinting control region (ICR) in newborn offspring. Maternal depression, anxiety and perceived stress were assessed at 28 weeks of pregnancy in the Barwon Infant Study (n=576). DNA methylation was measured in purified cord blood mononuclear cells using the Sequenom MassArray Platform. Maternal anxiety was associated with a decrease in average ICR methylation (Δ=−2.23% 95% CI=−3.68 to −0.77%), and across all six of the individual CpG units in anxious compared with non-anxious groups. Birth weight and sex modified the association between prenatal anxiety and infant methylation. When stratified into lower (⩽3530 g) and higher (>3530 g) birth weight groups using the median birth weight, there was a stronger association between anxiety and ICR methylation in the lower birth weight group (Δ=−3.89% 95% CI=−6.06 to −1.72%), with no association in the higher birth weight group. When stratified by infant sex, there was a stronger association in female infants (Δ=−3.70% 95% CI=−5.90 to −1.51%) and no association in males. All the linear regression models were adjusted for maternal age, smoking and folate intake. These findings show that maternal anxiety in pregnancy is associated with decreased IGF2/H19 ICR DNA methylation in progeny at birth, particularly in female, low birth weight neonates. ICR methylation may help link poor maternal mental health and adverse birth outcomes, but further investigation is needed.

Association of prenatal and early childhood stress with reduced lung function in 7-year-olds

“…For example, recent analyses in the Lifestyle and environmental factors and their Influence on Newborns Allergy risk (LINA) study reported differentially methylated regions in calcium- and Wnt-signaling pathways involved in lung maturation prenatally among children exposed to increased prenatal stress who went on to develop wheeze 54 . Other evidence indicates that stress-induced epigenetic changes that influence development can be sex specific 55,56 .…”

Epigenetic Alterations and Prenatal Maternal Depression

“…Importantly, in a subset of samples ( n = 158) higher cord blood MEG3 methylation was associated with internalizing behaviors of 1‐year‐old infants (Fuemmeler et al, ). Also, a later study showed association between maternal anxiety, depression, perceived stress, and decreased methylation at the IGF2/H19 locus in 576 neonatal cord blood samples (Mansell et al, ). Interestingly, both studies observed stronger effects in female infants.…”

Cord Blood DNA Methylation Biomarkers for Predicting Neurodevelopmental Outcomes

“…For example, maternal depression in the third trimester of pregnancy has also been associated with altered methylation of NR3C1 gene promoter regions in cord blood mononuclear cells, and this corresponded to altered stress responses in the three month old infants [35]. Altered DNA methylation of other gene regions has also been reported with maternal anxiety, including changes in the imprinting control region of IGF2/H19 [38]. Additional analyses of these data showed that when segregated by birth weight, the relationship between DNA methylation and maternal anxiety was stronger in the lower birthweight group (≤3530 g) and when stratified by sex, the relationship was only seen in females [38].…”

“…Altered DNA methylation of other gene regions has also been reported with maternal anxiety, including changes in the imprinting control region of IGF2/H19 [38]. Additional analyses of these data showed that when segregated by birth weight, the relationship between DNA methylation and maternal anxiety was stronger in the lower birthweight group (≤3530 g) and when stratified by sex, the relationship was only seen in females [38]. Together, studies in humans and rats demonstrate that maternal mental health and behavior towards her offspring in very early life can result in epigenetic modifications, which appear to increase vulnerability to poor long term neurodevelopmental outcomes.…”