Prenatal maternal immune disruption and sex-dependent risk for psychoses

Abstract

Background Previous studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring’s brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex. Method Using a nested case–control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1β, IL-8, IL-6, tumor necrosis factor (TNF)-α and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ=44; affective psychoses (AP)=44] and 100 healthy controls from a pregnancy cohort followed for >40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models. Results There were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-α levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)75=3.33, 95% confidence interval (CI) 1.13–9.82], and greater prevalence of low TNF-α levels (<lowest quartile) among SCZ females compared with their controls (OR25=6.30, 95% CI 1.20–33.04) and SCZ males. Higher levels of IL-6 were only found among SCZ compared with AP cases. Lower TNF-α levels (non-significant) also characterized female AP cases versus controls, although the prevalence of the lowest levels was higher in SCZ than AP females (70% v. 40%), with no effect in SCZ or AP males. Conclusions The results underscore the importance of immunologic processes affecting fetal brain development and differential risk for psychoses depending on psychosis subtype and offspring sex.

Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood

“…Although some studies reported that high levels of proinflammatory cytokines during pregnancy were associated with worse outcomes in offspring [e.g., cerebral palsy (19), schizophrenia (21), and autism (22)], we recently reported that lower levels of maternal cytokines were associated with higher risk of depression and psychosis among female offspring (12,13). These studies are consistent with work by Kaukola and colleagues, who reported lower concentrations of IL-6 in cord blood associated with neurologic abnormalities at age 2 (47), and by Von Ehrenstein and colleagues, who reported that higher concentrations of IFN-γ and TNF-α in cord blood were protective against poor cognitive outcomes at age 7 y (18).…”

“…Chan School of Public Health). We obtained prenatal serum samples acquired from mothers during early third trimester from the NIH repository (12,13). Concentrations of maternal cytokines were assessed by multiplexed immunoassays and analyzed in relation to the level of maternal socioeconomic disadvantage during pregnancy and clinical ratings of neurologic development of offspring during the first year of life.…”

“…We preferentially selected samples drawn as close to the beginning of third trimester as available from the specimen repository, given the importance of this period for neurodevelopment and prior evidence that inflammation during mid to late gestation confers risk for offspring neuropsychiatric outcomes (26)(27)(28). Previous work using samples stored under similar conditions and for a similar length of time (>40 y) demonstrated the long-term stability of these cytokines (12,13). Samples blinded with respect to maternal socioeconomic conditions and offspring neurodevelopment were randomly assessed using assay kits and reagents from a single lot, and all assays were completed within a 2-mo period.…”

“…Whether these responses have implications for offspring neurodevelopment remains unknown, although reports that show elevated risks for fetal brain injury, neuropsychiatric disorders, and cognitive deficits for children exposed to prenatal infection and intrauterine inflammation suggest that they do (12)(13)(14)(15)(16)(17)(18). Because both higher and lower levels of inflammatory markers are shown to be associated with adverse neuropsychiatric outcomes in the offspring (18)(19)(20)(21)(22), dysregulation of gestational immune activity, rather than mere suppression or up-regulation of the maternal immune system, may ultimately have the greatest impact on brain development in the offspring.…”

Risks associated with viral infections during pregnancy

“…the association between prenatal rubella infection and cataract in 1941 (25). There is now a large body of work demonstrating that direct infection of the fetus with CMV, HSV-2, or rubella can cause major neurosensory deficits (26)(27)(28), learning disabilities, and psychiatric disorders (29)(30)(31). Microcephaly has also been associated with fetal CMV and ZIKV infection (ZIKV is further discussed below) (32,33).…”