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

January 9, 2023 updated by: Johns Hopkins University
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.

Study Overview

Status

Completed

Conditions

Intervention / 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

Enrollment (Actual)

157

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Maryland
      • Baltimore, Maryland, United States, 21205
        • Women's Mood Disorders Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Sampling Method

Probability Sample

Study Population

Pregnant Women with or without mental health history.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
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)
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
healthy pregnant controls
100 matched healthy pregnant women. Participants are matched for age, parity, and gestational age at enrollment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3) 6 weeks postpartum; 4) 6 months postpartum
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.
4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum
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.
4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum
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.
4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum
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.
4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum
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.
4 study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation; 3)6 weeks postpartum; 4) 6 months postpartum
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.
Second study visit (32-36 weeks gestation)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
1st and 2nd study visits: 1) 22-26 weeks gestation; 2) 32-36 weeks gestation
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.
Second study visit (32-36 weeks gestation)
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.
Second study visit (32-36 weeks gestation)
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.
Study visit (22-36 weeks gestation)
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).
Study visit (22-36 weeks gestation)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johns Hopkins University

Collaborators

National Institute of Mental Health (NIMH)
Brain & Behavior Research Foundation

Investigators

  • Principal Investigator: Lauren Osborne, MD, Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 24, 2016

Primary Completion (Actual)

November 28, 2022

Study Completion (Actual)

November 28, 2022

Study Registration Dates

First Submitted

September 6, 2018

First Submitted That Met QC Criteria

September 7, 2018

First Posted (Actual)

September 10, 2018

Study Record Updates

Last Update Posted (Estimate)

January 10, 2023

Last Update Submitted That Met QC Criteria

January 9, 2023

Last Verified

June 1, 2022

More Information

Terms related to this study

Other Study ID Numbers

  • IRB00087653
  • 1K23MH110607-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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