Maternal Autoantibody Reactivity, Gestational Inflammation, and Child Neurodevelopment (MARGIN) - ABSTRACT Approximately one in six children in the US is affected by neurodevelopmental disorders (NDD). A wide range of medical and psychiatric conditions commonly co-occur with NDD, impacting quality of life. 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. Understanding the underlying etiology is crucial, as the identification of risk factors and the mechanisms by which they act would allow for earlier identification, treatment, and prevention of NDD and associated morbidity. In our currently funded IMPaCT study (1R01HD095128), we are testing the hypothesis that maternal inflammation during pregnancy stemming from immune or metabolic dysregulation adversely impacts neurodevelopment. We are leveraging the unique resources of the Kaiser Permanente Research Biobank Pregnancy Cohort to conduct a longitudinal prospective investigation of maternal gestational inflammatory conditions, immune and metabolic biomarkers during pregnancy, and maternal genetics in relation to NDD. The goal of this new application is to extend the aims of IMPaCT to interrogate additional gestational biomarkers - maternal autoantibodies (MA) to fetal brain proteins - in the pregnancy blood samples collected from the mothers of 750 ASD, 2000 developmental delay (DD), and 2000 general population (GP) control children. Our overarching hypothesis is that maternal gestational immune/metabolic dysregulation is associated with the presence of MA during pregnancy which predisposes to altered neurodevelopment of the child. In Aim 1, we will examine maternal risk profiles related to the presence of MA during pregnancy that are associated with NDD. In Aim 2, we will explore whether maternal genetics are associated with the presence of MA during pregnancy. In Aim 3, we will examine the joint effects of maternal MA reactivity and maternal clinical characteristics, biomarkers of immune and metabolic function and genetic factors on ASD and DD, on phenotypic subgroups of ASD (ASD+/-Intellectual Disability (ID), ASD+/- developmental regression) and DD (language delay, motor delay, global delay, ID), and on clinical subtypes of the child defined by commonly co-occurring inflammation-mediated immune and metabolic conditions, and determine if associations differ by child sex. We seek funds to assay for MA in the maternal pregnancy biospecimens from the ~2500 mothers in our IMPaCT cohort plus an additional ~2250 mothers and perform statistical analyses to address our specific aims. This large scale, comprehensive study provides a framework to explore relationships between maternal immune dysregulation and metabolic function, maternal autoantibody reactivity in the first and second trimesters, maternal genetics, and risk for a range of neurodevelopmental disorders in children. Findings will contribute to the development of prenatal and newborn screening for adverse neurodevelopment, ultimately enabling earlier intervention and primary prevention.
