Happy Mother - Healthy Baby: Supplement Study on Biological Processes Underlying Anxiety During Pregnancy (HMHB-Bio)

Happy Mother - Healthy Baby: Supplement Study on Biological Processes Underlying Anxiety During Pregnancy

Biological Processes Underlying Anxiety During Pregnancy: A Substudy of an Anxiety-focused Early Prenatal Intervention for the Prevention of Common Mental Disorders in Pakistan

Human Development Research Foundation, Pakistan, Rawalpindi Medical College, Pakistan, University of Liverpool, National Institute of Mental Health (NIMH)

As a supplement to the ongoing randomized evaluation of the Cognitive Behavioral Therapy (CBT) anxiety prevention intervention in Pakistan (R01-MH111859), the investigators propose to explore potential biological mechanisms (related to inflammation and endocrine functioning) of antenatal anxiety through additional data collection with 300 pregnant women.

This study will leverage the ongoing randomized evaluation of the CBT anxiety prevention intervention in Pakistan (R01-MH111859) to explore potential biological mechanisms. This CBT intervention targets both sub-threshold anxiety symptoms and generalized anxiety disorder (GAD) in early- to mid- pregnancy, aiming to both prevent and treat Common Mental Disorders (CMDs) (GAD and major depressive episodes (MDE)) as well as improve birth outcomes. The study team proposes 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), the study will also include 100 healthy women without anxiety or depression. The aims are 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 allopregnanolone (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, 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, and 5) examine the effects of both anxiety and the intervention (including biomarkers) on infant development at six weeks postpartum.

Within women in a larger randomized trial (randomized to the intervention or enhanced care group), we propose to 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. These enrollment goals were modified after interruptions by the Covid-19 pandemic.

The principal investigators and outcomes assessors will be blind to the randomization status of the 200 anxious women assigned to the intervention and enhanced usual care groups.

100 pregnant women who have at least mild anxiety will be randomized to the intervention group where they will receive six one-on-one core sessions of Cognitive Behavioral Therapy during pregnancy (plus possible booster sessions)

100 pregnant women who have at least mild anxiety will be randomized to the enhanced usual care group. They will not receive intervention sessions but will receive transportation vouchers to come to the hospital and facilitation by study staff to attend to their regular antenatal care visits.

100 pregnant women who do not have symptoms of anxiety or depression be followed in the healthy control group. They will not receive intervention sessions but will receive transportation vouchers to come to the hospital and facilitation by study staff to attend to their regular antenatal care visits.

Women who are randomized to the intervention group will receive six core Cognitive Behavioral Therapy (CBT) sessions for anxiety during pregnancy (and possible booster sessions) to treat symptoms of anxiety.

We will measure differences in levels of peripheral inflammatory markers and change in these markers across time between anxious and healthy women, and between intervention and control women. Markers include IL-6, CCL3, CXCL8, Eotaxin, VEGF, and GM-CSF

We will measure differences in level of allopregnanolone at each time point and across time between anxious women and healthy women, and between intervention and control

We will measure differences in allopregnanolone levels at the second trimester between women who do and do not go on to develop postpartum depression.

We will measure the relationship between ALLO levels and levels of peripheral inflammatory markers across time, both concurrent and predictive

We will measure differences in birth outcomes (preterm birth, small or large for gestational age, low birth weight) between women with high inflammatory markers vs. those low in inflammatory markers, and also between anxious and healthy women.

We will measure differences in infant neurodevelopment using a standardized questionnaire between those high in inflammatory markers vs. those low, and also between anxious and healthy women

Inclusion Criteria: ability to understand spoken Urdu pregnant, ≤22 weeks' gestation age ≥18 years residence ≤20 km of Holy Family Hospital intent to reside in the study areas until the completion of the study Exclusion Criteria: Current major depressive episode (MDE on SCID) or life-threatening health conditions including e.g. active severe depression or suicidal ideation Self-report of past or current significant learning disability Self-report of past or current psychiatric disorder (e.g. bipolar disorder or schizophrenia) or psychiatric care (e.g. current use of anxiolytic drug and/or other psychotropic drug) medical disorders or severe maternal morbidity that require inpatient management that would preclude participation (101) ICU admission indicated by diagnosis (not only for assessment)

De-identified project data from the study will be posted on ClinicalTrials.gov and the National Institute of Mental Health (NIMH) data archive.

The study protocol, statistical analysis plan and informed consent form are available upon request now.

Atif N, Nazir H, Zafar S, Chaudhri R, Atiq M, Mullany LC, Rowther AA, Malik A, Surkan PJ, Rahman A. Development of a Psychological Intervention to Address Anxiety During Pregnancy in a Low-Income Country. Front Psychiatry. 2020 Jan 10;10:927. doi: 10.3389/fpsyt.2019.00927. eCollection 2019.

Rowther AA, Kazi AK, Nazir H, Atiq M, Atif N, Rauf N, Malik A, Surkan PJ. "A Woman Is a Puppet." Women's Disempowerment and Prenatal Anxiety in Pakistan: A Qualitative Study of Sources, Mitigators, and Coping Strategies for Anxiety in Pregnancy. Int J Environ Res Public Health. 2020 Jul 8;17(14):4926. doi: 10.3390/ijerph17144926.

Rauf N, Zulfiqar S, Mumtaz S, Maryam H, Shoukat R, Malik A, Rowther AA, Rahman A, Surkan PJ, Atif N. The Impact of the COVID-19 Pandemic on Pregnant Women with Perinatal Anxiety Symptoms in Pakistan: A Qualitative Study. Int J Environ Res Public Health. 2021 Aug 4;18(16):8237. doi: 10.3390/ijerph18168237.

Nazir H, Rowther AA, Rauf N, Atiq M, Kazi AK, Malik A, Atif N, Surkan PJ. 'Those whom I have to talk to, I can't talk to': Perceived social isolation in the context of anxiety symptoms among pregnant women in Pakistan. Health Soc Care Community. 2022 Nov;30(6):e5885-e5896. doi: 10.1111/hsc.14019. Epub 2022 Sep 19.

Surkan PJ, Hamdani SU, Huma ZE, Nazir H, Atif N, Rowther AA, Chaudhri R, Zafar S, Mullany LC, Malik A, Rahman A. Cognitive-behavioral therapy-based intervention to treat symptoms of anxiety in pregnancy in a prenatal clinic using non-specialist providers in Pakistan: design of a randomised trial. BMJ Open. 2020 Apr 15;10(4):e037590. doi: 10.1136/bmjopen-2020-037590.