Implications of altered maternal cytokine concentrations on infant outcomes in children with prenatal alcohol exposure

Abstract

Excessive alcohol consumption has been shown to increase serum plasma levels of numerous immune cytokines. Maternal immune activation and elevated cytokines have been implicated in certain neurological disorders (e.g., autism and schizophrenia) in the offspring. We investigated the hypothesis that elevated cytokines during pregnancy are a risk factor in women who gave birth to a child with Fetal Alcohol Spectrum Disorder (FASD) or a child with neurobehavioral impairment, regardless of prenatal alcohol exposure. Moderate to heavy alcohol-exposed (AE) (N = 149) and low or no alcohol-exposed (LNA) (N = 92) women were recruited into the study during mid pregnancy (mean of 19.8 ± 5.8 weeks' gestation) in two regions of Ukraine: Khmelnytsky and Rivne. Maternal blood samples were obtained at enrollment into the study at early to mid-pregnancy and during a third-trimester follow-up visit and analyzed for plasma cytokines. Children were examined at 6 and/or 12 months of age and were classified as having FASD if their mothers reported alcohol use and if they had at least one standardized score (Bayley Scales of Infant Development II Mental Development Index [MDI], or Psychomotor Development Index [PDI]) below 85 with the presence or absence of physical features of FASD. In multivariate analyses of maternal cytokine levels in relation to infant MDI and PDI scores in the entire sample, increases in the ratio of TNF-α/IL-10 and IL-6/IL-10 were negatively associated with PDI scores at 6 months (p = 0.020 and p = 0.036, respectively) and 12 months (p = 0.043 and p = 0.029, respectively), and with MDI scores at 12 months (p = 0.013 and p = 0.050, respectively). A reduction in the odds ratio of having an FASD child was observed with increasing levels of IL-1β, IL-2, IL-4, IL-6, and IL-10 in early to mid-pregnancy and IL-1β and IL-10 during late pregnancy. However, women that failed to increase IL-10 levels in the third trimester in order to maintain the balance of pro- and anti-inflammatory cytokines had an elevated risk of having an FASD child, specifically a significant increase in the odds ratio of FASD with every one-unit log increase in late pregnancy TNF-α/IL-10 levels (aOR: 1.654, CI: 1.096-2.495, p = 0.017). These data support the concept that disruptions in the balance between pro- and anti-inflammatory cytokines may contribute to neurobehavioral impairment and alter the risk of FASD.

Keywords: Cytokines; FASD; Fetal alcohol spectrum disorder; IL-10; Maternal immune activation; TNF-α.

Figure 1

Study Design

Figure 2

Adjusted odds ratios for FASD diagnosis in alcohol-exposed children with increasing maternal cytokine levels in (A) early/mid pregnancy and (B) late pregnancy. Increasing maternal levels of IL-1β (p=0.001), IL-2 (p=0.016), IL-4 (p=0.042), IL-6 (p=0.001), and IL-10 (p=0.042) in early/mid pregnancy, and late pregnancy IL-1β (p=0.009) and IL-10 (p=0.002) decreased the risk of FASD in children. Ratios of IL-1β:IL-10 (p=0.080) and IL-6:IL-10 (p=0.080) in late pregnancy failed to reach significance, however, there was an increased risk of FASD as TNF- α:IL-10 (p=0.013) increased. Logistic Regression model are adjusted for site and SES. ^§Detectable / Non-detectable (Ref group) cytokine classification was used for INF-γ levels *p-value < 0.05 ** p-value < 0.01