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Background: Identifying mental health disorders in migrant and refugee women during pregnancy provides an opportunity for interventions that may benefit women and their families. Evidence suggests that perinatal mental health disorders impact mother-infant attachment at critical times, which can affect child development. Postnatal depression resulting in suicide is one of the leading causes of maternal mortality postpartum. Routine screening of perinatal mental health is recommended to improve the identification of depression and anxiety and to facilitate early management. However, screening is poorly implemented into routine practice. This study is the first to investigate routine screening for perinatal mental health in a maternity setting designed for refugee women. This study will determine whether symptoms of depression and anxiety are more likely to be detected by the screening program compared with routine care and will evaluate the screening program's feasibility and acceptability to women and health care providers (HCPs). Objective: The objectives of this study are (1) to assess if refugee women are more likely to screen risk-positive for depression and anxiety than nonrefugee women, using the Edinburgh Postnatal Depression Scale (EPDS); (2) to assess if screening in pregnancy using the EPDS enables better detection of symptoms of depression and anxiety in refugee women than current routine care; (3) to determine if a screening program for perinatal mental health in a maternity setting designed for refugee women is acceptable to women; and (4) to evaluate the feasibility and acceptability of the perinatal mental health screening program from the perspective of HCPs (including the barriers and enablers to implementation). Methods: This study uses an internationally recommended screening measure, the EPDS, and a locally developed psychosocial questionnaire, both administered in early pregnancy and again in the third trimester. These measures have been translated into the most common languages used by the women attending the clinic and are administered via an electronic platform (iCOPE). This platform automatically calculates the EPDS score and generates reports for the HCP and woman. A total of 119 refugee women and 155 nonrefugee women have been recruited to evaluate the screening program's ability to detect depression and anxiety symptoms and will be compared with 34 refugee women receiving routine care. A subsample of women will participate in a qualitative assessment of the screening program's acceptability and feasibility. Health service staff have been recruited to evaluate the integration of screening into maternity care. Results: The recruitment is complete, and data collection and analysis are underway. Conclusions: It is anticipated that screening will increase the identification and management of depression and anxiety symptoms in pregnancy. New information will be generated on how to implement such a program in feasible and acceptable ways that will improve health outcomes for refugee women. International Registered Report Identifier (IRRID): DERR1-10.2196/13271 We help JMIR researchers to raise funds to pursue their research and development aimed at tackling important health and technology challenges. If you would like to show your support for this author, please donate using the button below. The funds raised will directly benefit the corresponding author of this article (minus 8% admin fees). Your donations will help this author to continue publishing open access papers in JMIR journals. Donations of over $100 may also be acknowledged in future publications. Suggested contribution levels: $20/$50/$100 [ABSTRACT FROM AUTHOR]