Anxiety during pregnancy speeds up genetic ageing in baby boys

Prenatal maternal anxiety is correlated with markers of epigenetic age acceleration in male infants, irrespective of other genetic, socioeconomic, or obstetric risk factors, according to a recent study

“Our findings point to the foetal origins of biological ageing and further illustrate how the quality of the prenatal environment can influence multiple aspects of child development,” the researchers said. “These findings, paired with a wealth of epidemiological studies, underscore the importance of providing timely and effective mental health support to pregnant individuals, which may have lasting consequences from the cellular to the societal level.”

The present study used prenatal maternal anxiety data from two longitudinal birth cohorts: the Netherlands’ Basal Influences on Baby Development (BIBO; n=165) and Singapore’s Growing Up in Singapore Towards Healthy Outcomes (GUSTO; n=340). In addition, buccal cell DNA samples were used to assess genome-wide methylation at 6 and 10 years of age in BIBO and at 3, 9, and 48 months in GUSTO.

The Pediatric-Buccal-Epigenetic (PedBE) clock was used to measure epigenetic age acceleration (AgeAccPedBE), calculated through linear regression models that compared chronological age with PedBE-derived epigenetic age. The resulting residuals were set as AgeAccPedBE. As a comparator, the Horvath clock was also used to estimate epigenetic age and age acceleration.

Both the PedBE and Horvath clocks produced epigenetic age estimates that correlated significantly with chronological age in the BIBO and GUSTO cohorts. Both clocks were also associated with each other. However, PedBE consistently showed lower median standard errors between the predicted and observed ages, suggesting its greater accuracy over Horvath. [Biol Psychiatry 2022;91:303-312]

In the BIBO cohort, girls at 10 years of age showed significantly greater AceAccPedBE than boys (p=0.003), though no such effect was reported at 6 years (p=0.12). The opposite was true, however, at younger ages. GUSTO showed that boys experienced significantly faster epigenetic ageing at 3 months of age (p=0.044). Such an effect was attenuated by months 9 and 48 (p=0.9 and p=0.17, respectively).

Biological ageing starts in the womb

Using generalized estimating equation models, the researchers then looked for potential foetal predictors of accelerated epigenetic ageing in infants.

They found that in the BIBO cohort, prenatal maternal anxiety led to significantly greater acceleration of epigenetic ageing from ages 6–10 years (estimate, 0.023; p=0.01). GUSTO showed that maternal prenatal anxiety had the same effect on infants between 3 and 48 months of age (estimate, 0.003; p=0.01).

Notably, sex moderated the role between maternal anxiety and epigenetic ageing in the infant. Stratifying the BIBO cohort revealed that a mother’s prenatal anxiety correlated with AgeAccPedBE only in boys (p=1.6×10^–4) but not in girls (P=0.9), an effect confirmed in the much younger GUSTO cohort (p=0.04 and p=0.21, respectively).

As opposed to anxiety, maternal prenatal depression had a much weaker effect on AgeAccPedBE in the BIBO cohort, while it showed no association at all with epigenetic ageing in GUSTO.

“Prenatal maternal anxiety predicted accelerated epigenetic aging across infancy and mid-childhood in two independent cohorts even after controlling for obstetric, socioeconomic, and child genetic risk factors,” the researchers said. “Advanced AgeAccPedBE, in turn, predicted increased externalizing symptoms between 6 and 10 years of age in males from the BIBO cohort only.”

“These findings point to the utility of the PedBE clock as a correlate of the biological embedding of prenatal anxiety and highlight the importance of the prenatal environment for biological aging,” they added. [Cell Rep 2019;29:4276-4284.e3; Trends Mol Med 2021;27:11-19; Sci Rep 2019;27:11-19]