Maternal Pregnancy-Related Anxiety Is Associated With Sexually Dimorphic Alterations in Amygdala Volume in 4-Year-Old Children

Abstract

Prenatal stress is associated with child behavioral outcomes increasing susceptibility for psychiatric disorders in later life. Altered fetal brain development might partly mediate this association, as some studies suggest. With this study, we investigated the relation between prenatal stress, child's brain structure and behavioral problems. The association between self-reported maternal pregnancy-related anxiety (PRAQ-R2 questionnaire, second and third trimester) and brain gray matter volume was probed in 27 4-year-old children (13 female). Voxel based morphometry was applied with an age-matched template in SPM for the whole-brain analyses, and amygdala volume was assessed with manual segmentation. Possible pre- and postnatal confounders, such as maternal depression and anxiety among others, were controlled for. Child behavioral problems were assessed with the Strength and Difficulties Questionnaire by maternal report. We found a significant interaction effect of pregnancy-related anxiety and child's sex on child's amygdala volume, i.e., higher pregnancy-related anxiety in the second trimester was related to significantly greater left relative amygdala volume in girls compared to boys. Further exploratory analyses yielded that both maternal pregnancy-related anxiety and child's amygdala volume are related to child emotional and behavioral difficulties: While higher pregnancy-related anxiety was associated with more emotional symptoms, peer relationship problems and overall child difficulties, greater left amygdala volume was related to less of these child difficulties and might partly mediate sex-specific associations between pregnancy-related anxiety and child behavioral difficulties. Our data suggest that maternal prenatal distress leads to sexually dimorphic structural changes in the offspring's limbic system and that these changes are also linked to behavioral difficulties. Our results provide further support for the notion that prenatal stress impacts child development.

Keywords: SDQ; VBM; amygdale; behavior; brain; children; development; prenatal stress.

FIGURE 1

Association between pregnancy-related anxiety (PRAQ) and left corrected amygdala volume [residuals of child’s age (CAM): the influence of CAM has been removed from the variable]. Smaller left amygdala volumes in boys compared to girls were significantly associated with higher PRAQ scores of the second trimester [β = –22.5 ± 6.8 (x10⁻⁴), p = 0.003] and with higher PRAQ Sum scores [β = –9.1 ± 3.8 (x10⁻⁴), p = 0.026].

FIGURE 2

Association between SDQ measures, PRAQ gwk24 scores and left corrected amygdala volumes are shown (A) for all SDQ measures in the whole sample, and (B) for emotional symptoms in boys and girls separately. On the left the association of SDQ measures with residuals of PRAQ gwk24 is displayed [residuals: the influence of left relative amygdala volume and child’s age (CAM) has been removed from the variable]. On the right the association of SDQ measures with residuals of left relative amygdala volume is shown [residuals: the influence of PRAQ gwk24 and child’s age (CAM) has been removed from the variable] (F1: emotional symptoms, F2: conduct problems, F3: hyperactivity/inattention, F4: peer relationship problems). Higher PRAQ gwk24 scores were significantly associated with more emotional symptoms (β = 0.13 ± 0.06, p = 0.035) (and with a higher SDQ Sum score, not shown) in the whole sample (A left), and with more emotional symptoms in boys compared to girls (β_boys = 0.26 ± 0.11, p = 0.036) (B left). A larger left amygdala volume was significantly associated with less emotional symptoms (β = –65.0 ± 28.2, p = 0.033) in the whole sample (A right), and with less emotional symptoms in boys compared to girls (significant in some control analyses) (B right).