The perinatal period (pregnancy and the first postnatal year) (O'Hara & Wisner, 2014) involves important changes and considerable challenges for parents (Milgrom & Gemmill, 2015). As a result, perinatal mental health (PMH) disorders are highly prevalent. It is estimated that 1 in 5 women meet criteria for mental health disorders during the perinatal period (Van Damme et al., 2018). These psychological problems not only significantly impact (expectant) mother's own wellbeing, but also that of their children, partners, and their support networks. Additionally, PMH problems are associated with significant financial burden. For instance, In the UK perinatal depression and anxiety are estimated to cost approximately £8.1 billion per annual birth cohort (Bauer, 2015). Prevention of these problems is therefore essential. Unfortunately, in up to 75% of women symptoms of depressive or anxiety disorders are not detected timely, and only 10% of these women receive appropriate help (Kingston et al., 2015).

This study proposes a novel approach to intervention by investigating the effectiveness of psychosocial treatments for (expectant) mothers identified to be at moderate risk of developing perinatal depression based on a novel statistical risk modeling approach. Specifically, we will investigate the clinical and cost-effectiveness of (a) an online self-help program and (b) a brief face-to-face (FTF) intervention for expectant mothers with a moderate risk of developing perinatal depression, compared to (c) standard care (treatment as usual). We expect both active treatments to be superior compared to standard care and similar in effectiveness to each other. In addition, we expect both online self-help and the brief FTF intervention to be more cost-effective compared to usual care. Moreover, we will also investigate the effects of the three treatments on a range of other important outcomes, participants' satisfaction with the treatments, the credibility of the treatments and expected effects as rated by patients. Finally, in a small qualitative study, we will investigate the subjective experiences of participants in the brief FTF intervention specifically.

Introduction The perinatal period, encompassing pregnancy and the first year postpartum (O'Hara & Wisner, 2014), represents a time of significant physiological, psychological and social change, necessitating considerable adaptation by expectant parents (Milgrom & Gemmill, 2015). This transitional phase is characterized by a coexistence of intense positive emotions-such as joy, hope, and excitement-and challenging negative emotions, including insecurity, anxiety and depression. As a result, both the transition to parenthood and the early stages of parenting are associated with increased vulnerability to emotional difficulties.

Mental health problems are highly prevalent in the perinatal period, affecting approximately one in five expectant or new mothers (Van Damme et al., 2018). Among these, perinatal depression (PD)-which includes both minor and major depressive episodes-is one of the most common complications during pregnancy and postpartum (Wisner et al., 2013). The point prevalence of major depressive disorder during pregnancy ranges from 3.1% to 4.9%, increasing to approximately 5% in the first three months postpartum. Minor depression affects an estimated 11% of pregnant women and 13% of women in the first three months after childbirth. The period prevalence of any depression during pregnancy and the first three postpartum months is estimated at 18.4% and 19.2%, respectively, with 12.7% and 7.1% meeting criteria for major depression during those timeframes (Gavin et al., 2005). Notably, one-third of postpartum depression cases begin during pregnancy, and 27% have onset prior to pregnancy (Wisner et al., 2013). Depression during the second and third trimesters increases the likelihood of postpartum depression by factors of 3.2 and 6.6, respectively (Heron et al., 2004). Mental health disturbances during pregnancy are therefore strong predictors of postpartum mental health status (Robertson et al., 2004).

Although most women recover from postnatal depression within a few months, approximately 30% remain clinically depressed beyond the first postpartum year (Goodman, 2004), and 40% may develop a chronic depressive disorder (Vliegen et al., 2014).

The consequences of perinatal depression extend beyond the individual, significantly affecting the mother-infant relationship and the child's socio-emotional development (Atif et al., 2015). For instance, the perinatal period is critical for the establishment of a secure attachment, which is fundamental to a mother's capacity to recognize and respond to her infant's emotional cues (Rosenboom, 2018). Maternal mental health issues may interfere with mothers' emotional availability and responsiveness, which may in turn compromise children's development.

Consistent with these assumptions, epidemiological and longitudinal studies have demonstrated that children of parents with depression have significantly elevated risks of developing depression themselves (Rosenboom, 2018). For example, Weissman et al. (2006) found that offspring of depressed parents were three to four times more likely to develop depression compared to children of non-depressed parents, with up to 50% affected by age 20.

Perinatal mental health (PMH) problems are associated with a high socio-economic burden. According to a UK report by Bauer et al. (2015), the annual cost of PMH problems in the United Kingdom was estimated at £8.1 billion per birth cohort, with 72% of this cost attributed to adverse impacts on child development (Sutter-Dallay et al., 2016). Early identification and intervention are therefore critical for reducing both the prevalence and economic burden of PMH issues (Sutter-Dallay et al., 2016).

Despite robust evidence on the impact of PD and broader PMH disorders on maternal, infant and family well-being, early detection and prevention remain problematic. Approximately 75% of women experiencing perinatal anxiety or depression go undiagnosed, and only about 10% of expectant and new mothers receive adequate treatment (Kingston et al., 2015). In this context, brief and low-intensity interventions show promise, with meta-analytic evidence supporting the efficacy of brief (preventative) interventions, including digital formats (Loughnan et al., 2019).

However, access to these interventions is often restricted to individuals with subthreshold symptoms or those highly motivated to seek care. Interventions that match the risk status of individuals may be more effective than a 'one-size-fits-all' approach. For instance, for women with more complex and persistent depression, targeted intensive approaches may be most effective (Howard & Khalifeh, 2020). Women with less severe clinical presentations may respond well to brief, scalable interventions, including online self-help programs and brief face-to-face (FTF) psychological interventions (Loughnan et al., 2019), and these interventions may also be cost-effective.

The present study This study will be the first to evaluate the clinical and cost-effectiveness of an online self-help intervention compared to a brief 8-session FTF intervention, both offered alongside usual care, for pregnant women at moderate risk for developing PD based on an analytical epidemiological approach aligned with precision medicine principles relying on a concentration-of-risk prediction modeling approach.

The primary aim of this study is to assess whether an online self-help program and a brief FTF intervention, in conjunction with usual care, is superior to usual care alone in reducing severity of depression from baseline to end-of-treatment (primary outcome). It is hypothesized that both interventions will be superior to usual care and that online self-help is non-inferior to the brief FTF intervention.

Secondary aims are to assess whether online self-help and brief FTF intervention are more effective than usual care in reducing parental stress, and in fostering mother-infant bonding, child socio-emotional development, and quality of life (secondary outcomes).

In addition, treatment credibility and expectancy of and satisfaction with the three treatments will be investigated, as well as their cost-effectiveness.

A qualitative study will be embedded within the trial to investigate mothers' experience of the brief FTF intervention.

References

Atif, N., Lovell, K., & Rahman, A. (2015). Maternal mental health: The missing "m" in the global maternal and child health agenda. Seminars in Perinatology, 39, 345-352. https://doi.org/10.1053/j.semperi.2015.06.007 Bauer, A., Pawlby, S., Plant, D. T., King, D., Pariante, C. M., & Knapp, M. (2015). Perinatal depression and child development: exploring the economic consequences from a South London cohort. Psychological Medicine, 45(1), 51-61. https://doi.org/10.1017/S0033291714001044 Berry, J. O., & Jones, W. H. (1995). The Parental Stress Scale: Initial Psychometric Evidence. Journal of Social and Personal Relationships, 12(3), 463-472. https://doi.org/10.1177/0265407595123009 Bouwmans, C., De Jong, K., Timman, R., Zijlstra-Vlasveld, M., Van der Feltz-Cornelis, C., Tan, S. S., & Hakkaart-van Roijen, L. (2013). Feasibility, reliability and validity of a questionnaire on healthcare consumption and productivity loss in patients with a psychiatric disorder (TiC-P). BMC Health Services Research, 13(1), 217. https://doi.org/10.1186/1472-6963-13-217 Condon, J. T., & and Corkindale, C. J. (1998). The assessment of parent-to-infant attachment: Development of a self-report questionnaire instrument. Journal of Reproductive and Infant Psychology, 16(1), 57-76. https://doi.org/10.1080/02646839808404558 Cox, J. L., Holden, J. M., & Sagovsky, R. (1987). Detection of postnatal depression. Development of the 10-item Edinburgh Postnatal Depression Scale. Br J Psychiatry, 150, 782-786. https://doi.org/10.1192/bjp.150.6.782 Devilly, G. J., & Borkovec, T. D. (2000). Psychometric properties of the credibility/expectancy questionnaire. J Behav Ther Exp Psychiatry, 31(2), 73-86. https://doi.org/10.1016/s0005-7916(00)00012-4 Feinberg, M. E., D., B. L., & and Kan, M. L. (2012). A Multi-Domain Self-Report Measure of Coparenting. Parenting, 12(1), 1-21. https://doi.org/10.1080/15295192.2012.638870 Gavin, N. I., Gaynes, B. N., Lohr, K. N., Meltzer-Brody, S., Gartlehner, G., & Swinson, T. (2005). Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol, 106(5 Pt 1), 1071-1083. https://doi.org/10.1097/01.AOG.0000183597.31630.db Goodman, J. H. (2004). Postpartum Depression Beyond the Early Postpartum Period. Journal of Obstetric, Gynecologic & Neonatal Nursing, 33(4), 410-420. https://doi.org/https://doi.org/10.1177/0884217504266915 Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., Bonsel, G., & Badia, X. (2011). Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res, 20(10), 1727-1736. https://doi.org/10.1007/s11136-011-9903-x Heron, J., O'Connor, T. G., Evans, J., Golding, J., & Glover, V. (2004). The course of anxiety and depression through pregnancy and the postpartum in a community sample. Journal of Affective Disorders, 80(1), 65-73. https://doi.org/https://doi.org/10.1016/j.jad.2003.08.004 Howard, L. M., & Khalifeh, H. (2020). Perinatal mental health: a review of progress and challenges. World Psychiatry, 19(3), 313-327.

Kingston, D., Austin, M.-P., Heaman, M., McDonald, S., Lasiuk, G., Sword, W., Giallo, R., Hegadoren, K., Vermeyden, L., van Zanten, S. V., Kingston, J., Jarema, K., & Biringer, A. (2015). Barriers and facilitators of mental health screening in pregnancy. Journal of Affective Disorders, 186, 350-357. https://doi.org/https://doi.org/10.1016/j.jad.2015.06.029 Loughnan, S. A., Joubert, A. E., Grierson, A., Andrews, G., & Newby, J. M. (2019). Internet-delivered psychological interventions for clinical anxiety and depression in perinatal women: a systematic review and meta-analysis. In (Vol. 22, pp. 737-750): Springer-Verlag Wien.

Milgrom, J., & Gemmill, A. W. (2015). Identifying Perinatal Depression and Anxiety: Evidence-Based Practice in Screening, Psychosocial Assessment, and Management. John Wiley & Sons. https://doi.org/10.1002/9781118509722 O'Hara, M. W., & Wisner, K. L. (2014). Perinatal mental illness: Definition, description and aetiology. Best Practice & Research Clinical Obstetrics & Gynaecology, 28(1), 3-12. https://doi.org/https://doi.org/10.1016/j.bpobgyn.2013.09.002 Robertson, E., Grace, S., Wallington, T., & Stewart, D. E. (2004). Antenatal risk factors for postpartum depression: a synthesis of recent literature. General Hospital Psychiatry, 26(4), 289-295. https://doi.org/https://doi.org/10.1016/j.genhosppsych.2004.02.006 Rosenboom, T. (2018). De eerste 1000 dagen: het fundamentele belang van een goed begin vanuit biologisch, medisch en maatschappelijk perspectief. de Tijdstroom.

Squires, J., Bricker, D., Twombly, E., Hoselton, R., Murphy, K., Dolata, J., Yockerlson, S., Schoen Davis, M., & Kim, Y. (2015). A Parent-Completed Child Monitoring System for Social-Emotional Behaviors Ages & Stages Questionnaires: Social-Emotional.

Sutter-Dallay, A.-L., Glangeaud-Freudenthal, N. M.-C., Guedeney, A., & Riecher-Rössler, A. (2016). Joint Care of Parents and Infants in Perinatal Psychiatry (1st ed.). Springer International Publishing Switzerland.

Van Damme, R., Van Parys, A.-S., Vogels, C., Roelens, K., & Lemmens, G. (2018). Screening en detectie van perinatale mentale stoornissen: richtlijn als leidraad voor het ontwikkelen van een zorgpad. UZ Gent; Universiteit Gent; Karus, Vlaanderen is zorg.

Vliegen, N., Casalin, S., & Luyten, P. (2014). The Course of Postpartum Depression: A Review of Longitudinal Studies. Harvard Review of Psychiatry, 22(1). https://journals.lww.com/hrpjournal/fulltext/2014/01000/the\_course\_of\_postpartum\_depression\_\_a\_review\_of.1.aspx Weissman, M. M., Wickramaratne, P., Nomura, Y., Warner, V., Pilowsky, D., & Verdeli, H. (2006). Offspring of depressed parents: 20 years later. Am J Psychiatry, 163(6), 1001-1008. https://doi.org/10.1176/ajp.2006.163.6.1001 Wisner, K. L., Sit, D. K. Y., McShea, M. C., Rizzo, D. M., Zoretich, R. A., Hughes, C. L., Eng, H. F., Luther, J. F., Wisniewski, S. R., Costantino, M. L., Confer, A. L., Moses-Kolko, E. L., Famy, C. S., & Hanusa, B. H. (2013). Onset Timing, Thoughts of Self-harm, and Diagnoses in Postpartum Women With Screen-Positive Depression Findings. JAMA Psychiatry, 70(5), 490-498. https://doi.org/10.1001/jamapsychiatry.2013.87

Inclusion Criteria:

Participants will be drawn from the broader PRIL (Perinatal mental health Profiling and Intervention in Leuven) study, who consented to being contacted for the intervention trial and who meet criteria for moderate risk for perinatal depression based on an analytical epidemiological approach aligned with precision medicine principles, specifically a concentration-of-risk prediction modeling approach. Based on a comprehensive assessment of biological, psychological and social risk and protective factors, concentration-of-risk models will be developed and validated to stratify respondents in terms of risk for future perinatal depression, namely (1) not, (2) mildly, (3) moderately and (4) highly at risk of developing perinatal depression. Mothers falling into the moderate risk profile are eligible to participate

Exclusion Criteria:

• Receiving concurrent psychological guidance in perinatal mental health problems;
• Not consenting to (a) audiorecording of the first two face-to-face sessions and/or (b) paying the appropriate fee, in case of randomization to the face-to-face intervention arm.

The study results will be owned by the Sponsor. The sponsor will have access to the study data. After the publication of results focusing on primary and secondary outcomes/endpoints, anonymized data will be made available to researchers who provide a methodologically sound proposal.

After the publication of results focusing on primary and secondary outcomes/endpoints, anonymized data will be made available to researchers who provide a methodologically sound proposal within a reasonable time frame.