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

Abstract

Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1β, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomic disadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [−1.53 log(pg/mL); 95% CI: −1.81, −1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.

Associations between maternal cytokine levels during gestation and measures of child cognitive abilities and executive functioning

“…Two studies have shown that across several cytokines, higher mid-gestational levels are associated with an increased risk of autism and autism with intellectual disability or developmental delay relative to controls (Jones et al, 2017; Abdallah et al, 2013). In another recent study utilizing a historical cohort ascertained between 1959 and 1966, investigators found lower IL- 8 assayed from maternal serum obtained in early in the third trimester of pregnancy to be related to a higher risk of physician assessed neurological abnormalities at 4 months and 1 year of age (Gilman et al, 2017). Generally, it is difficult to compare our findings to these studies since the populations and outcomes being assessed across these studies differ materially.…”

“…In humans, developmental neuropsychiatric conditions, such as schizophrenia in adulthood and autism in childhood, have been linked with elevated gestational levels of cytokines and chemokines (Brown et al, 2004; Jones et al, 2017). Further, lower gestational levels of 1L-8 have been associated with physician assessed neurological abnormalities at 1 year of age (Gilman et al, 2017), and at least one study has shown that umbilical cord blood concentrations of inflammatory cytokines are associated with child cognitive intellectual abilities (i.e., intellectual quotient (IQ)) (von Ehrenstein et al, 2012). These studies highlight the association between gestational immune activity and broad-based cognitive abilities, but less is known regarding the extent to which gestational immune activity relates to other domains of functioning, such as those related to executive functioning.…”

“…Second, we included in our assessment the significance and direction of the effect of seven cytokines IL – 1 β , IL – 4, IL – 6, IL – 12 p 70, IL – 17 A , tumor necrosis factor-α ( TNF α ), and interferon-γ ( IFN γ)] and one chemokine ( IL – 8). This panel was custom built based on existing pre-clinical and clinical literature (i.e., analytes with a putative role in normal neurodevelopment (Bilbo and Schwarz, 2009), previously associated with either neuroprotection or adverse neurodevelopmental outcomes (e.g., IL -1 β , IL - 6) in model organism or human studies (von Ehrenstein et al, 2012; Gilman et al, 2017; Bilbo and Schwarz, 2009; Jones et al, 2017), while balancing feasibility in number of analytes assessed. Finally, we included a number of covariates in our models, including the assessment of maternal cognitive ability and executive function, thereby enabling the assessment of the magnitude of the effect of gestational cytokines and chemokines beyond the potential genetic or environmental contributions of maternal cognitive ability and executive functioning.…”

Concentrations of immune marker in newborn dried blood spots and early childhood development: Results from the Upstate KIDS Study

“…Prospective studies among preterm infants that assessed immune markers (ie, before the emergence of behavioural and cognitive impairments) suggest that low‐grade inflammation adversely impacts child brain development . However, few studies examined this association in term infants . Moreover, we do not yet know which markers of immune activity are most important for brain development, nor whether higher or lower levels of immune markers are associated with better or worse developmental outcomes.…”

A Bayesian regularized mediation analysis with multiple exposures

“…For example, in the Longitudinal Investigation of Fertility and the Environment (LIFE) study, a mixture of endocrine‐disrupting chemicals were assessed in relation to a spectrum of reproductive outcomes, including semen quality and couples' time‐to‐pregnancy. Another example is in assessing parental demographic and socioeconomic factors and neonatal outcomes, both through and around maternal lifestyle and immune activity . Similar examples abound in the social sciences, public health, and clinical medicine.…”