Project Summary Children of women exposed to childhood abuse exhibit increased risk for a wide array of neurodevelopmental deficits, including elevated risk of anxiety, depression, and social problems. Our studies have found that these children had a more than three-fold higher risk of autism and 70% higher risk of attention-deficit hyperactivity disorder (ADHD). Animal studies similarly find that maternal exposure to stressors is associated with offspring anxiety, depressive symptoms, and attention problems and decreased social behavior. Neurodevelopmental disorders are common and carry lifelong, costly burdens. Yet, extant research has failed to identify pathways by which children of women abused are at risk of harm. Identification of such pathways is a critical step in preventing neurodevelopmental deficits in these children. The present research focuses on three likely pathways that have largely been unexamined. We will identify biological dysregulation during pregnancy in women exposed versus unexposed to abuse in two systems: hormonal function and immune function. Dysregulation in these biological systems is known to harm offspring neurodevelopment and is present in adults who have experienced childhood abuse, yet it is largely unknown whether dysregulation in these systems occurs during the pregnancies of women exposure to abuse. We will collect biological samples to measure the functioning of these systems in a large, prospective cohort of pregnant women. Second, we will examine whether women who experienced abuse carry higher genetic loading for neuropsychiatric disorders by calculating genetic risk scores for 5 disorders including autism and ADHD in more than 8000 women. Genetically informed studies indicate that genetic variation plays a role in increased risk of negative neurodevelopmental outcomes in children of women abused. However, to date no studies have used genome- wide data to address this question. Our proposed study is uniquely suited to greatly expand our understanding of how childhood abuse affects health across generations and to inform interventions to protect the healthy development of children. This information is critical to establish public health priorities and to determine the optimal type and timing of interventions to prevent neurodevelopmental harm to children.

Project Narrative/Public Health Relevance The proposed research will examine three biological pathways which may account for the association of maternal childhood abuse with offspring neurodevelopmental deficits: 1) endocrine dysfunction during pregnancy, 2) inflammation during pregnancy, and 3) genetic loading for neurodevelopmental disorders. Neurodevelomental deficits, including autism and attention deficit hyperactivity disorder (ADHD), are major causes of disability, morbidity, and unemployment across the life course. Ascertaining the mechanisms by which mother's abuse affects offspring neurodevelopment will have a profound impact on the design of public health interventions to protect the healthy development of children, specifically: 1) identify targets for potential prenatal and perinatal interventions, 2) improve screening in prenatal and pediatric care, and 3) identify children who will benefit from early intervention.