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Depressive symptoms predict exaggerated inflammatory responses
to an in vivo immune challenge among pregnant womenq
Lisa M. Christiana,b,c,d,*, Albert Francoe, Jay D. Iamsf, John Sheridanb,g,h, Ronald Glaserb,g,i
aDepartment of Psychiatry, The Ohio State University Medical Center, Columbus, Ohio, USA
bThe Institute for Behavioral Medicine Research, The Ohio State University Medical Center, Columbus, Ohio, USA
cDepartment of Psychology, The Ohio State University, Columbus, Ohio, USA
dDepartment of Obstetrics & Gynecology, The Ohio State University Medical Center, Columbus, Ohio, USA
eDepartment of Obstetrics & Gynecology, Carolinas Medical Center, Charlotte NC, USA
fDivision of Maternal Fetal Medicine, The Ohio State University Medical Center, Columbus, Ohio, USA
gDepartment of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Medical Center, Columbus, Ohio, USA
hDivision of Oral Biology, The Ohio State University, Columbus, Ohio, USA
iDepartment of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio USA
a r t i c l ei n f o
Received 10 February 2009
Received in revised form 8 May 2009
Accepted 15 May 2009
Available online 21 May 2009
Macrophage migration inhibitory factor
a b s t r a c t
Objective: Stress and depressive symptoms predict exaggerated inflammatory responses to a biological
challenge in nonpregnant humans and animals. The extent to which these findings generalize to preg-
nancy is unknown because the immune system exhibits substantial changes to support pregnancy. Nota-
bly, inflammatory responses to infectious agents play a causal role in the development of gestational
hypertension as well as risk for preterm birth. Thus, depressive symptoms may increase susceptibility
to these outcomes via sensitization of inflammatory processes. The current study was designed to test
the hypothesis that depressive symptoms would predict an exaggerated proinflammatory response to
an in vivo antigen challenge, influenza virus vaccination, among pregnant women.
Method: Twenty-two pregnant women completed two study visits: baseline and 1 week after receiving
influenza virus vaccination. Depressive symptoms were measured with the Center for Epidemiologic
Studies Depression Scale (CES-D) at baseline. Serum levels of macrophage migration inhibitory factor
(MIF) were determined using a high sensitivity immunoassay at both study visits.
Outcomes: Analyses demonstrated that, as compared to those in the lowest tertile of CES-D scores, those
in the highest tertile exhibited significantly higher levels of MIF 1 week after influenza virus vaccination
(p = .035).
Conclusions: Depressive symptoms predicted exaggerated MIF production following influenza virus vac-
cination during pregnancy. These data support the hypothesis that depressive symptoms are associated
with sensitization of the inflammatory response during pregnancy. Thus, women with greater depressive
symptoms may be more vulnerable to negative sequelae of infectious illness during pregnancy.
? 2009 Elsevier Inc. All rights reserved.
Conservatively, it is estimated that 25–40% of preterm births are
attributable intrauterine infection and associated inflammation
(Goldenberg et al., 2008). In addition, infections including peri-
odontal disease and urinary tract infection are associated with in-
creased risk of preeclampsia and preterm delivery (Conde-Agudelo
et al., 2008; Jeffcoat et al., 2001). Further, certain maternal infec-
tions, including influenza, predict increased risk of negative health
outcomes in offspring and inflammatory processes are implicated
in this link (Smith et al., 2007).
Stress and depressive symptoms predict exaggerated responses
to biological challenges in humans and animals. Rodents exposed
to repeated stressors evidence exaggerated inflammatory re-
sponses upon antigen exposure, higher levels of circulating inter-
leukin(IL)-6, and enhanced IL-6 and tumor necrosis factor (TNF)-
a production from myeloid cells (Avitsur et al., 2005; Johnson
et al., 2002; Stark et al., 2002). In human studies, lymphocytes from
depressed individuals show greater inflammatory responses upon
0889-1591/$ - see front matter ? 2009 Elsevier Inc. All rights reserved.
qThis project was supported by NIH training grant T32AI55411, APA Division 38
(Health Psychology) Graduate Student Research Award, the American Psychological
Foundation/Council of Graduate Departments of Psychology (APF/COGDOP) Schol-
arship Program, the OSU Department of Women’s Studies and the Coca-Cola Critical
Difference for Women Grant Program, the American Psychological Association
Dissertation Research Award, and the OSU Alumni Grants for Graduate Research
and Scholarship (LMC) as well as the OSU General Clinical Research Center (MO1-
* Corresponding author. Department of Psychiatry, The Ohio State University
E-mail address: Lisa.Christian@osumc.edu (L.M. Christian).
Brain, Behavior, and Immunity 24 (2010) 49–53
Contents lists available at ScienceDirect
Brain, Behavior, and Immunity
journal homepage: www.elsevier.com/locate/ybrbi
Author's personal copy
in vitro exposure to mitogens (Anisman et al., 1999; Maes, 1995,
1999). Similarly, in response to the in vivo antigen challenge of
influenza virus vaccination, older adults who reported more
depressive symptoms exhibited increases in serum IL-6 2 weeks
following vaccination while no increase was seen among those
with fewer depressive symptoms (Glaser et al., 2003). Providing
further evidence that depression primes inflammatory responding,
women with a history of major depression showed greater inflam-
matory responses following childbirth, a physical and psychologi-
cal stressor (Maes et al., 2001).
The extent to which such effects generalize to pregnancy is of
interest. The immune system demonstrates considerable changes
to support pregnancy and negative perinatal outcomes have con-
sistently been associated with an exaggerated inflammatory state
as compared to healthy pregnancy (Redman et al., 1999; Sargent
et al., 2006). Available data from pregnant women show that per-
ceived stress is associated with elevated maternal serum proin-
flammatory cytokines, lower antiinflammatory cytokines, and
exaggerated production of the proinflammatory cytokines by lym-
phocytes stimulated in vitro (Coussons-Read et al., 2005, 2007). Re-
cent data from our group demonstrate that current depressive
symptoms during pregnancy are associated with elevated maternal
serum IL-6 and TNF-a (Christian et al., in press). To our knowledge,
no studies have examined effects of distress (e.g., perceived stress
or depressive symptoms) on inflammatory responses to in vivo
antigen challenge in pregnancy. As described above, inflammatory
responses to infectious agents are associated with negative effects
for maternal health and pregnancy outcomes. Therefore, exagger-
ated inflammatory responses may have unique implications during
The role of macrophage migration inhibitory factor (MIF) in
inflammatory responses has gained increasing attention. In the
1960s, MIF was one of the first cytokines identified; however, it
was not until the mid-1990s that the functional properties of
MIF began to be elucidated. Notably, MIF has the unique ability
to counteract the anti-inflammatory properties of glucocorticoids
in a dose–response fashion (Calandra and Bucala, 1995; Flaster
et al., 2007). Due to its broad effects and essential role in both in-
nate and adaptive immune function, antagonism of MIF is now
being considered as a therapeutic target for many diseases with
an inflammatory component, including rheumatoid arthritis (Mor-
and et al., 2003), vascular diseases (Burger-Kentischer et al., 2006),
and multiple sclerosis (Denkinger et al., 2003).
In pregnancy, elevated MIF has been implicated in risk of pre-
eclampsia (Todros et al., 2005) and preterm delivery (Pearce
et al., 2008). Moreover, Pearce (2004) reported that, compared to
nondepressed pregnant women, clinically depressed pregnant wo-
men exhibited significantly higher serum levels of MIF. Due to its
unique proinflammatory properties and emerging links with peri-
natal outcomes, the effects of psychosocial factors on MIF during
pregnancy are of great interest.
The current study was designed to examine whether depressive
symptoms predict sensitization of MIF responses during preg-
nancy. To test this hypothesis, influenza virus vaccination was used
as an in vivo antigen challenge. It was hypothesized that women
reporting greater depressive symptoms would exhibit greater
MIF responses, indicating heightened sensitivity of the inflamma-
Of note, pregnant women evidence higher rates of influenza-re-
lated health complications and deaths than nonpregnant individu-
als. Given their high risk status, the American College of
Obstetricians and Gynecologists, American Academy of Family
Physicians, and Centers for Disease Control recommend that all
women who are pregnant or will be pregnant during influenza sea-
son be vaccinated (Fiore et al., 2008). Despite this recommenda-
tion, it is estimated that only 12–13% of pregnant women have
been vaccinated in recent years (Fiore et al., 2008). Thus, influenza
vaccination provides an excellent model for examining immune re-
sponses while promoting vaccination.
2.1. Study design and participants
Twenty-two pregnant women were recruited from the Ohio
State University (OSU) General Perinatal Medical Clinic. Partici-
pants completed two study visits: baseline and 1 week after influ-
enza virus vaccination. Depressive symptoms were assessed at
baseline and serum levels of macrophage migration inhibitory fac-
tor (MIF) were assessed at both study visits. Women were ex-
cluded from participation if they reported recent acute illness,
chronic health conditions with implications for immune function,
or if fetal anomaly or preeclampsia was indicated per medical re-
cords. Participants received compensation for their participation
at each study visit. The study was approved by The OSU Biomedical
Institutional Review Board. Data were collected from November
2006 to April 2007.
2.2. Demographic and psychosocial measures
Information regarding height, current weight, pre-pregnancy
weight, age, race, education level, marital status, income, and
employment status was collected. The following health behaviors
were assessed: cigarette use, participation in regular physical
activity (i.e., at least 1 h per week of vigorous activity), the number
of hours of sleep in the previous night, frequency of prenatal vita-
min use, and receipt of influenza virus vaccination in the prior
Depressive symptoms were assessed prior to vaccination using
the Center for Epidemiologic Studies Depression Scale (CES-D),
which demonstrates good test–retest reliability and excellent con-
struct validity (Radloff, 1977). In addition, women were asked if
they had ever been diagnosed with and/or treated for a mood dis-
order (i.e., major depression, dysthymia or minor depression, or
bipolar disorder) by a healthcare provider.
2.3. Cytokine measurements
At both study visits, whole blood was collected into vacutainer
tubes between 9:30 am and 1:30 pm while subjects were in a
seated position. Post-vaccination samples were collected between
6 and 9 days following vaccination. Samples were immediately
centrifuged, aliquoted, and placed in ?80 ?C freezer storage until
analysis. Serum levels of MIF were assayed in duplicate by using
a Quantikine High Sensitivity ELISA kit (R&D Systems Minneapolis,
MN) per kit instructions.
2.4. Influenza virus vaccination
Each woman received Fluarix vaccine (GlaxoSmithKline) during
the 2006–2007 influenza season. Vaccines were administered
within 30 min after blood sampling. Each 0.05 mL dose contained
45 lg hemagglutinin (HA), with 15 lg HA of each of the following
three virus strains: A/New Caledonia/20/99 (H1N1), A/Wisconsin/
67/2005 (H3N2), and B/Malaysia/2506/2004.
2.5. Analytic strategy
bution. Data points P3 standard deviations from the mean were
considered to be outliers and were excluded from analyses. One-
L.M. Christian et al./Brain, Behavior, and Immunity 24 (2010) 49–53
Author's personal copy
as low, moderate, and high in depressive symptoms in terms of
demographic and behavioral factors. A repeated measures general
on changes in serum MIF over time, with levels of MIF as the depen-
dent variable and tertiles of depressive symptoms (low, moderate,
high) as the independent variable. One-way analysis of variance
(ANOVA) and post-hoc tests of least significant difference were uti-
lized to test simple main effects post-vaccination. Data analyses
were performed using SPSS statistical software (SPSS 16.0).
3.1. Demographic and descriptive characteristics
After excluding data from one participant with outlying MIF
values, data were available from 22 women. Demographic and
descriptive data are presented in Table 1. Participants were 25
(SD = 4.6) years of age and at an average of 17 (SD = 9) weeks ges-
tation. Participants were primarily African–American (n = 14),
unmarried (n = 16), had completed high school or less education
(n = 17), and reported a total annual family income of less than
$15,000 per year (n = 15).
3.2. Depressive symptoms
Scores on the CES-D ranged from 2 to 37 with an average score
of 16 (SD = 10). For the purposes of analyses, CES-D scores were
split into tertiles. Women were classified as having no/minimal
depressive symptoms (scores ranging 0–10; n = 8), mild/moderate
depressive symptoms (11–21; n = 8), and significant depressive
symptoms (P22; n = 6). Three women reported that they had pre-
viously been diagnosed with major depression (n = 2) or bipolar
disorder (n = 1) by a healthcare provider. All three were in the
highest tertile in terms of current depressive symptoms and had
previously been treated with antidepressant or mood stabilizing
medications. No women in the study were currently taking psy-
3.3. Group characteristics
One-way ANOVAs demonstrated that women in the three ter-
tiles of depressive symptoms did not differ in terms of age
(p = .31), pre-pregnancy BMI (p = .73), education (p = .23), income
(p = .67), gravidity (p = .64), parity (p = .46), or weeks gestation at
the time of vaccination (p = .67). Chi-square analyses demon-
strated no group differences marital status (v2(2) = 3.3 p = .19) or
race (v2(2) = 1.9, p = .38). As further confirmation of lack of racial
difference in depressive symptoms, t-tests comparing CES-D scores
among African–American versus Caucasian women demonstrated
no significant difference (p = .67). In terms of health behaviors,
groups did not differ in terms of hours of sleep the night prior to
vaccination (p = .32) or post-vaccination session (p = .70). In addi-
tion, chi-square analyses showed that groups did not differ in
terms of cigarette smoking (v2(2) = 1.7, p = .92) or endorsement
of regular vigorous physical activity (P1 h per week (v2(2) = 1.7,
p = .44). One participant reported receiving influenza virus vaccina-
tion during the prior influenza season. Repeated measures ANOVA
and tests for simple main effects indicated no significant differ-
ences as compared to participants who had not been vaccinated
in the previous season in terms of MIF levels at baseline or post-
vaccination (ps P .13).
Analyses revealed a statistically significant difference in the
days from vaccination to post-vaccination follow-up between wo-
men with low depressive symptoms versus moderate depressive
symptoms (p = .03). The post-vaccination visit was completed at
an average of 7.13 (SD = .64) days among those with low depres-
sive symptoms, 8.13 (SD = .99) among those with moderate
depressive symptoms and 7.33 (.82) among those with high
depressive symptoms. Based on these analyses, days to post-vacci-
nation visit was used as a covariate in subsequent analyses.
3.4. Depressive symptoms and MIF responses
Next, analyses were conducted to examine relationships be-
tween depressive symptoms and MIF levels. Repeated measures
analyses controlling for days to post-vaccination visit demon-
strated no main effect for change in MIF from pre to post-vaccina-
tion (F(1, 18) = 1.25, p = .28). Post-hoc univariate ANOVAs were
conducted to test for simple main effects at baseline and post-vac-
cination. Results demonstrated that, controlling for days to post-
vaccination visit, women who scored in the top tertile on the
CES-D (scores P 22) exhibited significantly higher levels of macro-
phage MIF at 1 week post-vaccination as compared to those scor-
ing in the bottom tertile (scores 0–10) (p = .035; Fig. 1).
The current data provide evidence that depressive symptoms
predict sensitization of inflammatory responses to an in vivo im-
Mean: 25 (SD = 4.6) range: 18–37
Less than high school: 4
High school: 13
Greater than high school: 5
<$ 15,000: 15
Body mass index (kg/m2)
Mean: 26.8 (SD = 6.0) range: 18.2–38.7
Mean: 28.9 (SD = 6.3) range: 20.2–42.9
Mean: 17 (SD = 9) range: 5–36
Mean: 3.2 (SD = 1.5) range: 1–7
Mean: 1.9 (SD = 1.3) range: 0–5
Fig. 1. Macrophage migration inhibitory factor (MIF) levels prior to and 1 week
post-influenza virus vaccination. As compared to women in the lowest tertile of
CES-D scores (n = 8), those in the highest tertile (n = 6) exhibited significantly
higher levels macrophage MIF at 1 week after vaccination (p = 0.035).
L.M. Christian et al./Brain, Behavior, and Immunity 24 (2010) 49–53
Author's personal copy
mune challenge during pregnancy. Women scoring in the highest
tertile of depressive symptoms as measured by the CES-D exhib-
ited significantly higher MIF at 1 week following influenza virus
vaccination as compared to women in the lowest tertile. Groups
did not differ in demographic characteristics (e.g., age, BMI, race,
income) or health behaviors (e.g., sleep, smoking, regular exercise)
assessed, suggesting that these factors did not account for the ef-
fects of depressive symptoms.
The absence of an increase in MIF levels at 1 week post-vaccina-
tion among women with lower depressive symptoms is consistent
with previous evidence that influenza virus vaccination does not
generally cause an extended inflammatory response (Glaser et al.,
2003; Posthouwer et al., 2004; Tsai et al., 2005). Thus, we suggest
that the inflammatory response seen among the more depressed
individuals at 1 week post-vaccination indicates dysregulation of
normal inflammatory processes.
relevant to maternal health, preterm delivery, and fetal develop-
pregnancy may experience greater inflammatory responses upon
exposure to other immune challenges including infectious agents,
matory responses to influenza vaccination are mild as compared to
responses to influenza infection (e.g., Hayden et al., 1998; Tsai
et al., 2005), supporting the clinical utility of vaccination.
Evidence also suggests that individuals experiencing greater
stress are more susceptible to infection. For example, chronic stress
among pregnant women has been associated with approximately
two times greater risk of bacterial vaginosis (BV) (Culhane et al.,
2001). Therefore distress may contribute to inflammation during
pregnancy by increasing both susceptibility and response to infec-
To our knowledge, there are no prior studies examining
whether distress predicts priming of MIF responses to biological
challenge. However, data from animal models indicates that MIF
rises in response to acute behavioral stress (Calandra et al., 1995)
and elevations in MIF have previously been associated with
depressive symptoms among young men (Hawkley et al., 2006)
and pregnant women (Pearce, 2004).
In the current investigation, depressive symptoms did not pre-
dict differences in MIF prior to vaccination, although a trend to-
wards this effect equivalent to a medium effect size was
suggested. Thus, additional research with a larger sample size is
needed to confirm the present results and to further examine asso-
ciations of depressive symptoms with MIF prior to vaccination.
Although the CES-D is a valid and reliable measure of depressive
symptomatology, it does not allow for diagnosis of clinical depres-
sion. It is estimated that 40–50% of those scoring at or above the
commonly used cut-off of 16 on the CES-D meet criteria for major
depression as determined by clinical interview (Weissmann et al.,
1977). A variety of higher cut-offs have been suggested to provide
greater specificity and to identify more severe cases (e.g., Radloff,
1991). In the current sample, exaggerated inflammatory responses
were seen among those scoring in the top third (P22). Research in
which diagnostic clinical interviews are utilized in conjunction
with questionnaire measures would allow for better determination
of the predictive validity of assessing depressive symptoms versus
clinical depression. Also, in the current study, three women classi-
fied as the highest tertile of depressive symptoms reported that
they had previously been diagnosed with and treated for a mood
disorder. The study sample size did not allow for analyses of effects
of current versus recurrent depressive symptoms which could be
addressed in a larger sample with more comprehensive assess-
ment of psychiatric history.
Of note, our ability to detect effects of interest within a small
sample was largely a function of the notably high rate of depressive
symptoms in our study population. This rate was similar to other
studies of pregnant women from lower socioeconomic back-
grounds, highlighting the importance of delineating effects of
depressive symptoms during pregnancy. For example, Seguin and
colleagues (1995) found that 47% of pregnant women whose in-
comes were below the poverty line scored at or above a clinical
cut-off for depressive symptoms as compared to 20% of pregnant
women from higher socioeconomic backgrounds.
The current study does not address the dynamics of change in
MIF over time. The follow-up timepoint of 1 week post-vaccination
was selected to capture relatively extended inflammatory re-
sponses; because prolonged responses are not generally expected
in the context of vaccination, such responses may provide an indi-
cation of immune dysregulation. However, research examining the
dynamics of inflammatory responses over time, including time-
points more immediately post-vaccination, would be highly infor-
mative. In addition, the extent to which inflammatory responses to
vaccination predict health outcomes (e.g., preterm delivery, pre-
eclampsia, antibody response to vaccination) should be addressed
in future studies.
These data do not allow for examination of the effects of stage
of pregnancy on inflammatory responses. In addition, because ef-
fects of depressive symptoms during pregnancy were of primary
interest, a nonpregnant comparison group was not included in this
study. Future research utilizing a larger sample size and more com-
prehensive assessment of health behaviors will allow for more
thorough analysis of demographic and behavioral factors which
may mediate and/or moderate effects noted in the current
In sum, the current data provide evidence that depressive
symptoms predict exaggerated inflammatory responses to an
in vivo antigen challenge during pregnancy. These findings impli-
cate a novel and plausible pathway by which depressive symptoms
may affect maternal health (e.g., preeclampsia), pregnancy out-
comes (e.g., preterm delivery), and offspring health.
These data were collected as part of the first author’s doctoral
dissertation. I would like to thank my advisor, Janice Kiecolt-Glaser
for her support of this project, my dissertation committee mem-
bers for their helpful input, and my undergraduate research assis-
tants for their efforts. Portions of this study were previously
presented at the 2009 annual meeting of the Psychoneuroimmun-
ology Research Society in Breckenridge, Colorado.
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