SUMMARY While pregnant women frequently suffer from common mental health disorders (CMDs), research on anxiety has been relatively neglected (compared to depression), despite associations with poor pregnancy outcomes and long-term child developmental problems. We previously identified immune and endocrine mechanisms associated with antenatal anxiety, including inflammatory dysfunction and modulation of the progesterone metabolite allopregnanolone (ALLO). Cognitive behavioral therapy (CBT) interventions are highly effective for anxiety and have been shown to affect immune processes, but have not been studied in the context of pregnancy. We now propose leveraging the ongoing randomized evaluation of our CBT anxiety prevention intervention in Pakistan (R01-MH111859) to explore potential biological mechanisms. Our CBT intervention targets both sub-threshold anxiety symptoms and generalized anxiety disorder (GAD) in early- to mid- pregnancy, aiming to both prevent and treat CMDs (GAD and major depressive episodes (MDE)) as well as improve birth outcomes. In this revision application, we propose to additionally study biological correlates of antenatal anxiety (i.e., immune and endocrine functioning) in 300 women: in addition to 200 drawn from our randomized trial (100 intervention, 100 usual care), we will also include 100 healthy women without anxiety or depression. We aim to 1) characterize the “immune phenotype” of anxious women across the peripartum, specifically by measuring the relation among anxiety symptoms and peripheral markers of inflammation within and across women (both anxious and healthy) and between those receiving the intervention and control; 2) determine the relation between levels of ALLO in pregnancy and concurrent anxiety symptoms and future symptoms of postpartum depression (PPD), 3) examine the relation between changes in immune functioning and ALLO levels in anxious pregnancy across time, and 4) examine whether immune function and/or ALLO are mediators or moderators of the association between antenatal anxiety and preterm birth and/or small-for- gestational age. By taking advantage of the ongoing study and routine hospital blood draws, we will minimize participant burden while elucidating the links between perinatal anxiety, correlated biological markers, and the effect(s) of CBT. Perinatal anxiety and its negative impacts on mother and babies, can be ameliorated through greater understanding of its biology.

NARRATIVE Immune and endocrine mechanisms associated with antenatal anxiety, including immune dysregulation modulation of the progesterone metabolite allopregnanolone (ALLO) may be influenced by anxiety prevention interventions, such Cognitive Behavioral Therapy (CBT). We propose leveraging our ongoing CBT anxiety prevention intervention and randomized controlled trial (RCT) in Pakistan (R01-MH111859) to additionally study biological correlates of antenatal anxiety in women with and without anxiety. By taking advantage of the ongoing study and routine hospital blood draws (minimizing participant burden) and creating the first and largest trial to date that connects a perinatal anxiety intervention to its potential biological effects, our study has the potential of helping two vulnerable populations (pregnant women and their infants).