SUMMARY: Common mental disorders (CMDs) such as anxiety and depression occur frequently in pregnancy and the postnatal period in lower- and middle income countries (LMICs). Prenatal anxiety, both subthreshold and clinical, adversely affects maternal wellbeing and outcomes among offspring, and is a major predictor of subsequent depression. Preventive approaches have enormous potential to reduce the negative effects of postnatal mental disorders in mothers and improve child outcomes. We propose to create a scalable and sustainable early prevention intervention focusing on anxiety symptoms in pregnant women, to be delivered by non-specialist providers (Aim 1). We will evaluate this preventive intervention through a trial by randomizing 1100 pregnant women from a public hospital in Islamabad Pakistan to either our Cognitive Behavioral Therapy- based (CBT-based) early-in-pregnancy program or to usual care. We will study the effects of the intervention on 1) CMDs in the 3rd trimester of pregnancy and at 6 weeks postpartum (Aim 2) and on 2) fetal and newborn small-for-gestational age (SGA) outcomes (Aim 3). We will also examine if interpersonal violence, perceived stress and social support mediate and/or modify the intervention effects on CMDs and perinatal outcomes (Aim 4). Finally, we will conduct a cost-effectiveness evaluation, comparing costs and healthcare utilization for women in the prenatal intervention and enhanced usual care groups (Aim 5). Focusing on anxiety reduction is a major innovation; anxiety has not been addressed within prenatal intervention packages in LMICs, despite its association with increased postpartum depression and suboptimal fetal and infant outcomes. Pakistan has high prevalence of both women with prenatal anxiety (35% to 49%) and SGA newborns (~47%), providing an ideal research opportunity. Our CBT-based approach, appropriate given its indication for anxiety and depression, is grounded in our preliminary work in this population, where we have previously successfully reduced postpartum depression. Intervening early in pregnancy is a further innovation that is critical for building the evidence base for preventative approaches to reduce maternal CMDs and related perinatal outcomes. Our proposed mediation and effect modification analyses will improve understanding of mechanism(s) of action and help identify subpopulations for programmatic targeting. The use of non-specialized providers and integration within the primary care environment will guide scale up, while incorporating a cost-effectiveness analysis will aid policy-makers in resource allocation decisions. This study will inform the integration of preventive strategies that target anxiety with existing approaches for treatment of perinatal depression to further the evidence-base for transdiagnostic mental health initiatives globally, and will inform policies to support lifelong maternal mental health and resilience across generations.