Maternal inflammation during pregnancy can alter the trajectory of fetal brain development
and increase risk for offspring psychiatric disorders. However, the majority of relevant
research to date has been conducted in animal models. Here, in humans, we focus on
the structural connectivity of frontolimbic circuitry as it is both critical for socioemotional
and cognitive development, and commonly altered in a range of psychiatric disorders
associated with intrauterine inflammation. Specifically, we test the hypothesis that
elevated maternal concentration of the proinflammatory cytokine interleukin-6 (IL-6)
during pregnancy will be associated with variation in microstructural properties of
this circuitry in the neonatal period and across the first year of life. Pregnant
mothers were recruited in early pregnancy and maternal blood samples were obtained
for assessment of maternal IL-6 concentrations in early (12.6 ± 2.8 weeks [S.D.]),
mid (20.4 ± 1.5 weeks [S.D.]) and late (30.3 ± 1.3 weeks [S.D.]) gestation. Offspring
brain MRI scans were acquired shortly after birth (N = 86, scan age = 3.7 ± 1.7 weeks
[S.D.]) and again at 12-mo age (N = 32, scan age = 54.0 ± 3.1 weeks [S.D.]). Diffusion
Tensor Imaging (DTI) was used to characterize fractional anisotropy (FA) along the
left and right uncinate fasciculus (UF), representing the main frontolimbic fiber
tract. In N = 30 of the infants with serial MRI data at birth and 12-mo age, cognitive
and socioemotional developmental status was characterized using the Bayley Scales
of Infant Development. All analyses tested for potentially confounding influences
of household income, prepregnancy Body-Mass-Index, obstetric risk, smoking during
pregnancy, and infant sex, and outcomes at 12-mo age were additionally adjusted for
the quality of the postnatal caregiving environment. Maternal IL-6 concentration (averaged
across pregnancy) was prospectively and inversely associated with FA (suggestive of
reduced integrity under high inflammatory conditions) in the newborn offspring (bi-lateral,
p < 0.01) in the central portion of the UF proximal to the amygdala. Furthermore,
maternal IL-6 concentration was positively associated with rate of FA increase across
the first year of life (bi-lateral, p < 0.05), resulting in a null association between
maternal IL-6 and UF FA at 12-mo age. Maternal IL-6 was also inversely associated
with offspring cognition at 12-mo age, and this association was mediated by FA growth
across the first year of postnatal life. Findings from the current study support the
premise that susceptibility for cognitive impairment and potentially psychiatric disorders
may be affected in utero, and that maternal inflammation may constitute an intrauterine
condition of particular importance in this context.