Preeclampsia Research on Vitamin D, Inflammation, & Depression

Background information

The PROVIDE study tests the hypothesis that low vitamin D levels and increased inflammatory
activity in pregnant women contributes to increased risk of preeclampsia and postpartum
depression (PPD). Preeclampsia is a multisystem disorder of pregnancy commonly characterized
by hypertension that occurs after 20 weeks of gestation in a woman with previously normal
blood pressure accompanied by proteinuria. One pathway thought to lead to preeclampsia is
chronic subclinical inflammation. Likewise, inflammation is elevated in women with major
depressive disorder (MDD) and PPD and may therefore be a common physiological pathway
connecting depression with preeclampsia. In addition, vitamin D deficiency, which is common
in pregnancy and the postpartum period is associated with depressive symptomatology, prenatal
inflammation and adverse birth outcomes, particularly preeclampsia. Research has shown that
vitamin D acts as an anti-inflammatory agent regulating placental function to promote
tolerance of the fetus. Prior work demonstrated that among women with elevated prenatal
inflammation, higher prenatal vitamin D status was associated with lower PPD symptoms. This
research tests the hypothesis that vitamin D deficiency places women with higher levels of
inflammatory cytokines at highest risk for preeclampsia and PPD. Findings will have
substantial impact providing new information about inflammatory mechanisms implicated in the
development of preeclampsia and PPD, and will support future research, such as vitamin D
supplementation to reduce risk for preeclampsia and depression.

The study also seeks a better understanding of several important biopsychosocial consequences
of developing preeclampsia. In pregnancy, 8-13% of women are diagnosed with MDD, which can
lead to postpartum depression (PPD) and adverse birth outcomes, specifically low birth weight
and preeclampsia. Although maternal depression is associated with negative consequences for
the mother, her infant and family, low rates of diagnosis and treatment for perinatal
depression are common in medical settings. Rapid diagnosis and treatment is essential because
the episodes are lengthy and psychosocial symptoms (including anxiety) increase with the
duration of the disorder. Screening is important because it is the first step in the pathway
to treatment. This study tests the acceptability and benefits of a mental health screening,
education and referral program in women with and without preeclampsia. With assistance from a
community partner, Maternal Mental Health-NOW (formerly the L.A. County Perinatal Mental
Health Task Force), findings will provide valuable patient centered qualitative and
quantitative data that can be used in future services planning. This is timely work. In 2015
ACOG recommended that clinicians screen patients at least once during the perinatal period
for depression and anxiety symptoms. Post-traumatic stress symptoms are particularly common
after experiencing an adverse pregnancy outcome, and approximately 9% develop Post-traumatic
stress disorder (PTSD). Increased risk of major depression (40-50%) comorbid with PTSD can
lead to decreased maternal bonding with infant and other long term adverse mental and
physical health repercussions for the mother, child and family. Screening therefore must be
coupled with appropriate follow-up and treatment when indicated, and systems should be in
place to ensure follow-up for diagnosis and treatment. Most recently (2016), the US
Preventive Services Task Force (USPSTF) made perinatal depression screening recommendations,
adding that data are lacking on both the accuracy of screening and the benefits and harms of
treatment in pregnant women. The authors highlight that research is needed to assess barriers
to establishing adequate systems of care and how these barriers can be addressed.

Very little is known from the patient perspective regarding acceptance and benefits of mental
health screening. There is even less understanding of the variation in preferences and need
for these services in women who experience preeclampsia, for whom PPD rates are even higher.
The perinatal period is an opportune time for screening and mental health education due to
the frequency of contact with health care providers, unfortunately rates of diagnosis and
treatment for perinatal depression are low in medical settings. New parents are often highly
motivated to seek help in effecting change for the sake of their offspring and potential
reduction in intergenerational family dysfunction. The perinatal period thus provides
clinicians with a unique opportunity to consider universal psychosocial assessment as part of
mainstream maternity and postnatal care. Early identification and treatment of psychosocial
morbidity are especially important in relation to the functioning of the family unit and the
critical parent-infant relationship with potential to positively impact on the health of the
next generation. Routine depression screening and referral has been supported by RCTs in
Primary Care. RCT work has not been conducted in the perinatal period or in the OB/GYN
setting, however screening, education, and referral programs in obstetric settings have been
well accepted by patients. Overall, mental health care might be most acceptable if provided
as part of routine obstetrical care. Mental health screening and treatment might also be more
beneficial in the subset of women who experience adverse pregnancy complications. Results
from this mental health screening program will allow for early identification and
intervention at a time when women are at highest risk for mental health complications, after
an adverse complication such as preeclampsia.

Objectives and purpose

To our knowledge, no studies have comprehensively investigated the anti-inflammatory role of
vitamin D in depressed reproductive aged women, and its association with adverse pregnancy
outcomes. Findings will have substantial impact providing new information about inflammatory
mechanisms implicated in the development of preeclampsia and PPD, and will support future
intervention research, including vitamin D supplementation, focused on alleviating these
effects. Additionally, testing the acceptability and effectiveness of a new mental health
screening, education and referral program at Cedars-Sinai Medical Center (CSMC) will provide
valuable patient centered qualitative and quantitative data that can be used in future
services planning.

PROVIDE study hypotheses will be tested in a new cohort (N=200) recruited in the third
trimester from CSMC Childbirth and Education classes, the Prenatal Diagnostic Center (PDC),
or in the Maternal-Fetal Care Unit (MFCU, for those diagnosed with Preeclampsia); and
followed through delivery and 2 time points (4 weeks and 3 months) postpartum. A targeted
sampling strategy over a two-year period will result in 100 women who experience preeclampsia
and 100 women who do not.

Specific Aim 1: Determine to what extent prenatal vitamin D deficiency (defined clinically as
serum 25(OH)D < 20 ng/ml48) will be associated with increases in prenatal inflammatory
cytokines (e.g. hs-CRP and Interleukin-6), prenatal depressive symptoms, and preeclampsia.

Hypothesis: Women who experience lower prenatal vitamin D levels will exhibit an increased
likelihood of experiencing prenatal depression, preeclampsia, and postpartum depression.
These effects will be greatest in those with high levels of prenatal inflammatory cytokines.

Specific Aim 2: Determine to what extent women who have preeclampsia will have increases in
postpartum inflammatory cytokines, vitamin D deficiency and PPD.

Hypothesis: Compared to those who do not experience preeclampsia, women with preeclampsia
will have higher postpartum levels of inflammatory cytokines, lower postpartum vitamin D
levels, and increased symptoms of PPD.

Specific Aim 3: Determine to what extent a mental health program that includes screening,
education and referral is acceptable to pregnant women and effective in reducing symptoms of
postpartum depression, anxiety and/or stress following preeclampsia.

Hypothesis: Women in the preeclampsia + depression group will rate the mental health program
as more acceptable and beneficial, and will follow up on referral suggestions more than
depressed-only group.

Inclusion Criteria:

- Female

- Minimum 18 years of age

- Patient at Cedars Sinai Medical Center, Los Angeles, CA

- Between 20 and 40 weeks gestation (majority recruited at start of 3rd trimester
between 26-32 weeks)

- English or Spanish language preference

Exclusion Criteria:

- Any diagnosis of psychosis, past or current (evident by either meds taken via medical
intake, or in clinical assessment - SCID)

- Current substance abuse (evident either via medical intake, or in clinical assessment
- SCID)