Prenatal immune programming of the sex-dependent risk for major depression

Abstract

Maternal immune functioning during pregnancy contributes to sex-dependent deficits in neurodevelopment and to behaviors associated with affective traits in preclinical studies, and has been indirectly associated with offspring depression in epidemiologic studies. We therefore investigated the association between immune activity during pregnancy and the risk of depression among male and female offspring. We conducted a case-control study of depression (n=484 cases and n=774 controls) using data from the New England Family Study, a pregnancy cohort enrolled between 1959 and 1966 that assessed psychiatric outcomes in adult offspring (mean age=39.7 years). We assayed concentrations of three pro-inflammatory cytokines, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, and the anti-inflammatory cytokine, IL-10, in maternal serum collected at the end of the second and beginning of the third trimesters. High maternal TNF-α was associated with reduced odds of depression among both male and female offspring (odds ratio (OR)=0.68; confidence interval (CI)=0.48, 0.98). However, when considering the TNF-α to IL-10 ratio, a measure of the ratio of pro- to anti-inflammatory loading, maternal immune effects on offspring depression differed significantly by sex (χ(2)=13.9, degrees of freedom=4, P=0.008). Among females, higher maternal TNF-α:IL-10 was associated with reduced odds of depression (OR=0.51; CI=0.32, 0.81), whereas, among males, high maternal TNF-α:IL-10 was associated with elevated odds of depression (OR=1.86; CI=1.02, 3.39). Thus, the balance between TNF-α and IL-10 in maternal prenatal serum was associated with depression in a sex-dependent manner. These findings are consistent with the role of TNF-α in the maturation of the sexually dimorphic fetal brain circuitry that regulates stress and affective responses, and support a prenatal stress-immune model of depression pathogenesis.

Figure 1

Distributions of IL1-β (a), IL-6 (b), TNF-α (c), and IL-10 (d) concentrations in late-second and early-third trimester maternal serum among depression cases and controls without depression (n=1258). The y axis of each graph extends to the 90th percentile of the distribution of each cytokine. The center lines of each box represent the median, and the diagonal notches in each box represent 95% confidence intervals around the median. IL, interleukin; TNF, tumor necrosis factor.

Figure 2

Distributions of pro- versus anti-inflammatory (IL-10) cytokine concentrations (IL-1β:IL-10 in panel a; IL-6:IL-10 in panel b; TNF-α:IL-10 in panel c) in late-second and early-third trimester gestation maternal serum among depression cases and controls without depression (n=1258). The y axis of each graph extends to the 90th percentile of the distribution of each pro:anti-inflammatory ratio. The center lines of each box represent the median, and the diagonal notches in each box represent 95% confidence intervals around the median. IL, interleukin; TNF, tumor necrosis factor.