Maternal Interleukin-6 concentration during pregnancy is associated with variation in frontolimbic white matter and cognitive development in early life

Abstract

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.

Keywords: Fractional anisotropy; Inflammation; Interleukin-6; Longitudinal DTI; Newborn; Uncinate fasciculus.

Figure 1.. Intratract Principal Components Analysis (PCA).

Intratract PCA reveals two, spatially distinct, principal components. A) Distribution (individual profiles in gray) of Fractional Anisotropy (FA) values along the right Uncinate Fasciculus (UF) spanning from the frontal to the temporal lobe. B) Heat map demonstrating high FA intratract correlation structure, separated by medial and lateral (frontal and temporal) portions of the UF. C) Scree plot showing PC selection criteria. D) PC1 loads uniformly across the tract relative to PC2, which loads primarily in the medial portion of the UF. Left UF statistics and mappings were consistent with those shown here for the right UF. Markers of spatial correspondence between figures 1A/D (vertical gray lines), and 1B (horizontal/vertical gray lines) are overlaid.

Figure 2.. Tract-based Associations Between Early Life Fractional Anisotropy and Average Maternal IL-6 Concentration Across Pregnancy.

Full sample Fractional Anisotropy (top row), tract-based significance for maternal gestational IL-6 associations (middle row) and effect size for maternal gestational IL-6 associations (bottom row) are shown bi-laterally for the uncinate fasciculus. Clusters used in post-hoc analyses are denoted by red circle indicators and a label: (LUF=Left Uncinate Fasciculus, RUF=Right Uncinate Fasciculus).

Figure 3.. Negative Association Between Newborn Fractional Anisotropy and Average Maternal IL-6 Concentration Across Pregnancy.

A) Tract-based significance as projected onto the uncinate fasciculus in template space demonstrates a bilateral pattern of significance along the middle portion of the UF and proximal to the amygdala. B) Linear regression-derived scatter plots of gestational and postnatal age-corrected FA versus mean maternal IL-6 concentration across pregnancy are shown. Clusters used in post-hoc analyses are denoted by an asterisk and a label: (LUF=Left Uncinate Fasciculus, RUF=Right Uncinate Fasciculus).

Figure 4.. Positive Association Between Change in Uncinate Fasciculus (UF) FA from Birth Until 12-mo Age and Average Maternal IL-6 Concentration Across Pregnancy.

Linear regression-derived scatter plots of gestational and postnatal age- corrected change in FA versus mean maternal IL-6 concentration across pregnancy are shown. Scatter points reflect ROI-based extracted FA values from central UF.

Figure 5.. Mediation Model.

Maternal gestational IL-6 concentration is positively associated with longitudinal change in left UF FA during the first 12 mos of life and negatively associated with cognitive developmental status at 12-mo. Longitudinal change in left UF FA is negatively associated with cognitive developmental status at 12-mo. Longitudinal change during the first year of life in the left UF FA mediates the association between maternal gestational IL-6 concentration and cognitive developmental status at 12-mo age (p<0.05).