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Pregnancy and Anxious Thoughts: The Role of the Immune and Endocrine Systems

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ClinicalTrials.gov Identifier: NCT03664128
Recruitment Status : Recruiting
First Posted : September 10, 2018
Last Update Posted : September 11, 2019
Sponsor:
Collaborators:
Brain & Behavior Research Foundation
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
Johns Hopkins University

Tracking Information
First Submitted Date September 6, 2018
First Posted Date September 10, 2018
Last Update Posted Date September 11, 2019
Actual Study Start Date June 24, 2016
Estimated Primary Completion Date June 15, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 7, 2018)
  • Changes in the level of interleukin 6 (IL-6) [ Time Frame: 4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3) 6 weeks postpartum; 4) 6 months postpartum ]
    The MesoScale Discovery Pro-Inflammatory Multiplex Assay will be used to measure concentrations of IL-6 in pg/mL. Concentration will be log-transformed.
  • Changes in the level of Interleukin 15 (IL-15) [ Time Frame: 4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum ]
    The MesoScale Discovery Pro-Inflammatory Multiplex Assay will be used to measure concentrations of IL-15 in pg/mL. Concentration will be log-transformed.
  • Changes in the level of Granulocyte macrophage colony stimulating factor (GM-CSF) [ Time Frame: 4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum ]
    The MesoScale Discovery Pro-Inflammatory Multiplex Assay will be used to measure concentrations of GM-CSF in pg/mL. Concentration will be log-transformed.
  • Changes in the level of Granulocyte colony stimulating factor (G-CSF) [ Time Frame: 4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum ]
    The MesoScale Discovery Pro-Inflammatory Multiplex Assay will be used to measure concentrations of G-CSF in pg/mL. Concentration will be log-transformed.
  • Changes in the level of Chemokine C-X-C motif ligand 8 (CXCL8) [ Time Frame: 4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum ]
    The MesoScale Discovery Pro-Inflammatory Multiplex Assay will be used to measure concentrations of C-X-CL8 in pg/mL. Concentration will be log-transformed.
  • Changes in the level of Chemokine C-C motif ligand 3 (CCL3) [ Time Frame: 4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum ]
    The MesoScale Discovery Pro-Inflammatory Multiplex Assay will be used to measure concentrations of CCL3 in pg/mL. Concentration will be log-transformed.
  • Leukocyte subpopulation [ Time Frame: Second study visit (32-36 weeks gestation) ]
    The investigators will use flow cytometry and fluorescence activated cell-sorting analysis to determine the percentages of leukocyte subpopulations, namely T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells.
Original Primary Outcome Measures Same as current
Change History
Current Secondary Outcome Measures
 (submitted: September 7, 2018)
  • Relationship of changes in levels of allopregnanolone (ALLO) to pro-inflammatory markers [ Time Frame: 1st and 2nd study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation ]
    The investigators will use enzyme-linked immunosorbent assay (ELISA) to measure levels of ALLO in ng/mL, across pregnancy and calculate the rate of change across pregnancy to determine if there is any correlation between the level of ALLO at second and third trimesters and levels of the pro-inflammatory markers listed above.
  • Heart Rate Variability [ Time Frame: Second study visit (32-36 weeks gestation) ]
    The investigators will measure high-frequency heart rate variability (in length of R to R interval in milliseconds, using electrocardiogram in Biopac Data Acquisition System) at baseline and in response to a stressor. This will be analyzed to see if there is a change comparing women with elevated inflammation and decreased ALLO to those without these features.
  • Electrodermal Activity [ Time Frame: Second study visit (32-36 weeks gestation) ]
    The investigators will measure electrodermal activity on the hands at baseline and in response to a stressor, using Biopac Data Acquisition System and electrodermal activity electrodes. The investigators will analyze these data to assess any changes when comparing women with elevated inflammation and decreased ALLO to those without these features.
  • Feasibility of a mindfulness-based cognitive behavioral therapy intervention as assessed by participant retention number [ Time Frame: Study visit (22-36 weeks gestation) ]
    The investigators will measure feasibility of this intervention by enrollment and retention of participants in a mindfulness-based cognitive behavioral therapy intervention for perinatal anxiety (CALM pregnancy). The intervention will be deemed feasible if the investigators successfully enroll at least 6 participants, and all participants complete at least 6 of the 8 sessions.
  • Acceptability of a mindfulness-based cognitive behavioral therapy intervention as assessed by a Likert scale [ Time Frame: Study visit (22-36 weeks gestation) ]
    The investigators will measure acceptability of the CALM pregnancy intervention to participants using a Likert scale (1-5, with 1 being not at all acceptable and 5 being very acceptable).
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Pregnancy and Anxious Thoughts: The Role of the Immune and Endocrine Systems
Official Title Pregnancy and Anxious Thoughts: The Role of the Immune and Endocrine Systems
Brief Summary The aim of the proposed research is to identify the clinical and biological phenotypes that define perinatal anxiety. The importance of this research to public health is that it will help to identify women at high risk, and will also serve as the basis for further studies that would identify genetic and epigenetic markers of risk and lead to research to identify novel treatment targets. The research is based upon preliminary data demonstrating a relationship between inflammatory cytokines and Trait anxiety in pregnancy; between progesterone and postpartum anxiety; and between allopregnanolone and obsessive symptoms in pregnancy. The proposed research will build upon these preliminary findings by prospectively examining the clinical features of anxiety in a cohort of pregnant women and healthy matched controls, and by analyzing blood samples from the same cohort for inflammatory cytokines, reproductive hormones, and immune cell types. The proposed study will therefore identify the clinical and biological phenotypes that characterize perinatal anxiety and will identify potential novel targets for treatment.
Detailed Description

My preliminary data from the Viral Immunity in Pregnancy Study found a strong association in 49 pregnant women between levels of anxiety and of cytokines. When the investigators controlled for clinical confounders, some of those associations disappeared - but there was still a strong correlation between anxiety score and the cytokine interleukin (IL) 6.

Hypothesis: Anxious pregnant women (as determined by a score > 21 on the Perinatal Anxiety Screening Scale (PASS)) will have elevated pro-inflammatory cytokines in pregnancy (at second and third trimesters) and will demonstrate greater continued elevation at 6 weeks and 6 months postpartum when compared to healthy controls. Leukocyte subpopulation analysis in anxious women will show a higher ratio of T-helper 1-type (Th1) to T-helper 2- type (Th2) cells and a greater monocyte activation across the perinatal period than that in healthy controls.

Hypothesis: There will be a negative correlation between allopregnanolone (ALLO) and pro-inflammatory markers (as listed above in primary outcome measure) in pregnancy, and between allopregnanolone (ALLO) in pregnancy and pro-inflammatory markers in the postpartum.

Hypothesis: Women with a pro-inflammatory immune fingerprint and low levels of allopregnanolone (ALLO) as determined by outcomes 1 and 2 will show increased attentional bias to threat, as demonstrated by measurement of autonomic reactivity in response to a validated pregnancy-specific modified Stroop task.

Hypothesis: Anxious pregnant women will find it feasible and acceptable to engage in a mindfulness-based cognitive behavioral therapy intervention for perinatal anxiety.

For each of these, the investigators will compare the outcome between anxious and non-anxious women.

The current study has 2 parts. The initial part, funded by Brain and Behavior Foundation, was designed to collect general information about the immune and endocrine mechanisms of perinatal anxiety and to test following aims:

Aim 1: To determine if obsessional anxiety in pregnancy corresponds to changes in immune functioning.

Aim 2: To determine if symptoms of obsessional anxiety in pregnancy are associated with changes in the levels of progesterone and its metabolites.

Aim 3: To determine feasibility and acceptability of mindfulness-based cognitive behavioral intervention designed to ameliorate prenatal anxiety and the accompanying inflammatory dysregulation.

I next expanded the study to obtain more detailed biological data; There is no intervention in the expansion for this phase.

I plan to recruit a group of 200 pregnant women (100 who screen positive for anxiety and 100 healthy controls). Subjects will answer questionnaires about mood and anxiety symptoms and have participants' blood drawn at four visits across pregnancy and the postpartum; in the second visit, participants will also perform a computer task designed to test how well participants can inhibit responses. A small subset of subjects will enroll in a group mindfulness intervention as well. This study is designed to achieve the following aims:

  1. To compare the "immune fingerprint" of women with significant perinatal anxiety with that of a cohort of healthy matched controls.
  2. To determine how perinatal changes in the "immune fingerprint" relate to changes in levels of progesterone metabolites (specifically, allopregnanolone) across pregnancy.
  3. To identify how changes in the "immune fingerprint" and progesterone metabolites are related to changes in maternal response to threat.

This study is an effort to further characterize the role of the immune system in common psychiatric symptomatology and the likely bidirectional relationship between the immune system and reproductive hormones that may be related to disease flares among a subset of patients. This work could eventually extend to the gene signatures responsible for immune pathways, to epigenetic studies, and/or to brain imaging studies examining differences in brain region function as affected by inflammation. Ultimately, this would allow the investigators to augment the traditional psychopharmacological focus on serotonin modification with new treatment targets, including cytokines, intracellular inflammatory mediators, neurogenesis, or glial cell activation.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Participants' blood will be drawn (up to 55 ml) at all four sessions by a study clinician or a trained research assistant. Blood will be collected in sodium-heparin tubes for immune cell preparation. Peripheral blood mononuclear cell (PBMC) suspensions will be prepared within 8 hours of blood collection by low-density gradient centrifugation via a Hermle Z 300 K #55085010, to avoid erythrophagy-related activation of the monocytes. PBMCs will be frozen and stored at -80° C using 10% dimethylsulfoxide, thereby allowing all samples to be analyzed in parallel.
Sampling Method Probability Sample
Study Population Pregnant Women with or without mental health history.
Condition Perinatal Anxiety
Intervention Other: Coping with Anxiety through Living Mindfully (CALM) Pregnancy
Mindfulness-based Cognitive Behavioral Therapy (CBT) for perinatal anxiety on a subset (8 participants); no intervention for other participants
Study Groups/Cohorts
  • pregnant women positive for anxiety

    100 pregnant women who screen positive for anxiety symptoms (>21 on the Perinatal Anxiety Screening Scale). Participants are matched for age, parity, and gestational age at enrollment.

    Coping with Anxiety through Living Mindfully (CALM) Pregnancy: Mindfulness-based Cognitive Behavioral Therapy (CBT) for perinatal anxiety on a subset (8 participants)

    Intervention: Other: Coping with Anxiety through Living Mindfully (CALM) Pregnancy
  • healthy pregnant controls
    100 matched healthy pregnant women. Participants are matched for age, parity, and gestational age at enrollment.
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: September 7, 2018)
200
Original Estimated Enrollment Same as current
Estimated Study Completion Date June 15, 2022
Estimated Primary Completion Date June 15, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria for all:

  • Pregnant and <27 weeks gestation
  • Age 18 or above
  • Able to provide written consent
  • Healthy pregnancy.

Additional inclusion criteria specific to anxiety group:

  • Significant anxiety symptoms as measured by a score of > 21 on the Perinatal Anxiety Screening Scale (PASS)
  • a diagnosis of current anxiety disorder by Structured Clinical Interview for Diagnostic And Statistical Manual Of Mental Disorders (DSM) V Diagnoses (SCID), or a diagnosis of a current anxiety disorder by a clinician interview using DSM-V criteria.

Exclusion Criteria for all:

  • Multifetal pregnancy
  • Autoimmune or endocrine disease
  • Meeting criteria for a major depressive episode at study entry
  • Active suicidal ideation at study entry
  • Bipolar disorder or primary psychotic disorder
  • Recent or current substance abuse.

Additional exclusion criteria for healthy controls:

  • No history of an anxiety or depressive disorder as determined by Structured Clinical Interview for DSM-V Diagnoses (SCID)
  • No current use of an antidepressant.
Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Lauren Osborne, MD 410-955-9986 lmosborne@jhmi.edu
Contact: Samantha Meilman, LCSW-C 410-502-2586 smeilma1@jhmi.edu
Listed Location Countries United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT03664128
Other Study ID Numbers IRB00087653
1K23MH110607-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party Johns Hopkins University
Study Sponsor Johns Hopkins University
Collaborators
  • Brain & Behavior Research Foundation
  • National Institute of Mental Health (NIMH)
Investigators
Principal Investigator: Lauren Osborne, MD Johns Hopkins University
PRS Account Johns Hopkins University
Verification Date September 2019