A Multidimensional Approach to Understanding Prenatal Health and Psychosocial Factors in Relation to the Maternal Inflammatory Milieu and Offspring Neurodevelopment

PROJECT SUMMARY Preconceptional and prenatal psychological stress, demographics, trauma, health, and nutrition all have potential to alter offspring neurodevelopmental outcomes. These aspects of the prenatal environment are hypothesized to influence the developing fetal brain via stress-sensitive aspects of maternal-placental-fetal biology (MPF),

such as immune and endocrine functioning. However, previous research has centered around univariate analyses that do not consider the wide array of preconceptional and prenatal factors with potential to influence MPF biology and the developing fetal brain. Given the highly complex and interactive nature of these

relationships, multivariate analyses are well-suited to identify canonical patterns in high-dimensionality analyses that may shed light on potential inflammatory mechanisms by which the preconceptional and prenatal environment may influence offspring brain development. Inflammation may be best characterized by considering

multiple cytokines at once, as they appear to act co-dependently—cytokines that frequently work together to communicate form cytokine networks. The use of cytokine networks has become an increasingly popular method of conceptualizing and analyzing inflammation, given that specific cytokine networks are associated with certain

psychopathologies or heterogenous presentations of mental disorders. Further, specific cytokine networks during pregnancy have been associated with altered offspring neurodevelopmental outcomes. Furthermore, little to none of these studies have been reproduced in independent datasets. Given the increasing awareness

of limited reproducibility in neuroscience research, there has been an urgent push, spearheaded by the NIH, towards rigorously designed experiments and increased reproducibility. The overall goal of the proposed study is to examine how multiple preconceptional and prenatal factors affect maternal systemic

inflammation during pregnancy and associated alterations in offspring neurodevelopment, while meeting the need for greater rigor and reproducibility in an innovative study design which will replicate complex multivariate analyses across three high-dimensionality datasets. The specific aims of this proposal are: 1) Identify maternal psychosocial contributors to the maternal inflammatory milieu during

pregnancy at a multivariate level; 2) Identify potent health indicators of the maternal inflammatory milieu during pregnancy at a multivariate level; 3) Identify subgroups of participants with distinct patterns of maternal systemic inflammation and examine potentially relevant interactions between health and psychosocial factors, as well as

neurodevelopmental outcomes associated with each cluster. This proposal intends to innovatively analyze cytokine network activity as a potential pathway by which aspects of the preconceptional and prenatal environment alter offspring neurodevelopment using multivariate statistical techniques. Additionally, given

frequent challenges with reproducibility in science, results from the analyses will be cross validated across three independent datasets.