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

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.

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.

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.