Maternal Systemic Interleukin-6 During Pregnancy Is Associated With Newborn Amygdala Phenotypes and Subsequent Behavior at 2 Years of Age

Abstract

Background: Maternal inflammation during pregnancy increases the risk for offspring psychiatric disorders and other adverse long-term health outcomes. The influence of inflammation on the developing fetal brain is hypothesized as one potential mechanism but has not been examined in humans.

Methods: Participants were adult women (N = 86) who were recruited during early pregnancy and whose offspring were born after 34 weeks' gestation. A biological indicator of maternal inflammation (interleukin-6) that has been shown to influence fetal brain development in animal models was quantified serially in early, mid-, and late pregnancy. Structural and functional brain magnetic resonance imaging scans were acquired in neonates shortly after birth. Infants' amygdalae were individually segmented for measures of volume and as seeds for resting state functional connectivity. At 24 months of age, children completed a snack delay task to assess impulse control.

Results: Higher average maternal interleukin-6 concentration during pregnancy was prospectively associated with larger right amygdala volume and stronger bilateral amygdala connectivity to brain regions involved in sensory processing and integration (fusiform, somatosensory cortex, and thalamus), salience detection (anterior insula), and learning and memory (caudate and parahippocampal gyrus). Larger newborn right amygdala volume and stronger left amygdala connectivity were in turn associated with lower impulse control at 24 months of age, and mediated the association between higher maternal interleukin-6 concentrations and lower impulse control.

Conclusions: These findings provide new evidence in humans linking maternal inflammation during pregnancy with newborn brain and emerging behavioral phenotypes relevant for psychiatric disorders. A better understanding of intrauterine conditions that influence offspring disease susceptibility is warranted to inform targeted early intervention and prevention efforts.

Keywords: Amygdala; Inflammation; Neonates; Neuroimaging; Pregnancy; Resting state functional connectivity MRI.

Figure 1

Higher maternal IL-6 concentrations during pregnancy are associated with greater newborn right amygdala volume.

Figure 2

Maternal IL-6 concentrations during pregnancy are associated with newborn amygdala functional connectivity. Note. Mean maternal IL-6 concentrations during pregnancy are prospectively associated with stronger newborn right (Panel A) and left (Panel B) amygdala connectivity to several cortical brain regions including fusiform gyrus. Panel C shows the associations between higher maternal IL-6 concentrations and stronger newborn right amygdala connectivity to anterior insula (aI), thalamus and caudate. Panel D illustrates the association between higher maternal IL-6 concentrations and newborn right amygdala-aI connectivity (identified in the voxel-wise analyses and displayed on the brain in Panels A and C).