Maternal inflammation during pregnancy and neurodevelopmental disorders

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ABSTRACT Neurodevelopmental disorders (NDD) are a group of disorders in which the development of the central nervous system is disturbed. Approximately one in six children in the United States is affected by NDD, and the lifetime cost of supporting one individual with NDD exceeds $2 million. Commonly known NDD include autism spectrum disorders (ASD), cerebral palsy (CP), and developmental delays (DD). The causes of NDD are largely unknown, and few modifiable risk factors have been identified. A growing body of evidence supports a critical role for both genetic and environmental factors, particularly during gestation and the early postnatal period. Common immune-mediated and metabolic conditions as well as levels of immune and metabolic biomarkers have been shown to be associated with NDD risk. Furthermore, the immune and metabolic systems influence each other, and are in turn genetically-influenced. Our central hypothesis is that maternal inflammation during pregnancy stemming from immune or metabolic dysregulation will adversely impact child neurodevelopment. Previous studies of gestational markers of NDD risk primarily focused on one specific NDD, measured immune biomarkers at only one point in pregnancy, and didn't take into account maternal genetics or environmental exposures. We seek to overcome the limitations of previous studies and extend earlier findings linking maternal immune and metabolic function during pregnancy with increased risk of NDD by leveraging the comprehensive data previously collected for the Kaiser Permanente Research Program on Genes Environment and Health (RPGEH) Pregnancy Cohort, which includes ~15,000 pregnant women with archived first and second trimester blood samples, comprehensive information on demographic characteristics, maternal clinical status before and during pregnancy, and child outcomes from electronic health records. We seek funds to perform immune and metabolic assays on first and second trimester blood samples from mothers who gave birth to children diagnosed with ASD (N=150), CP (N=60), DD (N=1500), or who have no NDD (N=1000) and generate genome-wide maternal SNP data to support analyses addressing the following aims: 1) Characterize the maternal immune and metabolic profiles over pregnancy and evaluate whether there are specific longitudinal patterns that are associated with neurodevelopmental outcomes in the offspring, and 2) Identify maternal factors (demographic and clinical characteristics, genetics) that are associated with altered maternal immune or metabolic function during pregnancy and risk of different neurodevelopmental outcomes. Our study has the potential to identify immune and metabolic profiles during pregnancy that indicate risk for specific NDD. This would support the development of prenatal screening for NDD, leading to earlier intervention and the potential for preventing future morbidity and improving quality of life. Furthermore, the identification of prenatal biomarkers will illuminate the biologic mechanisms underlying aberrant neurodevelopment and provide an opportunity for developing preventive strategies.