Citation
The prenatal effects of stress and depression on immune functioning

Material Information

Title:
The prenatal effects of stress and depression on immune functioning
Creator:
Koehler, Angelina
Publication Date:
Language:
English
Physical Description:
46 leaves : ; 28 cm

Subjects

Subjects / Keywords:
Pregnancy -- Psychological aspects ( lcsh )
Depression in women ( lcsh )
Stress (Psychology) ( lcsh )
Pregnant women ( lcsh )
Immunity -- Psychological aspects ( lcsh )
Immune system ( lcsh )
Genre:
bibliography ( marcgt )
theses ( marcgt )
non-fiction ( marcgt )

Notes

Bibliography:
Includes bibliographical references (leaves 38-46).
Statement of Responsibility:
by Angelina Koehler.

Record Information

Source Institution:
University of Florida
Rights Management:
All applicable rights reserved by the source institution and holding location.
Resource Identifier:
55488724 ( OCLC )
ocm55488724
Classification:
LD1190.L645 2003m K63 ( lcc )

Downloads

This item has the following downloads:


Full Text
THE PRENATAL EFFECTS OF STRESS AND DEPRESSION
ON IMMUNE FUNCTIONING
by
Angelina Koehler
B. A., University of Massachusetts, Boston, 1995
A thesis submitted to the
University of Colorado at Denver
in partial fulfillment
of the requirements for the degree of
Master of Arts
Psychology
2003


This thesis for the Master of Arts
degree by
Angelina Koehler
has been approved
by
Annette Towler
ll-l% os
Date


Koehler, Angelina (M. A., Psychology)
The Prenatal Effects of Stress and Depression on Immune Functioning
Thesis directed by Professor Mary Coussons-Read
ABSTRACT
The purpose of this study is to examine the interaction between psychosocial stress
and depression during the prenatal period and alterations in maternal immune
functioning. The relationship between depressive scores on the Center for
Epidemiological Studies Depression Scale (CES-D) at various trimesters and on the
Denver Maternal Stress Inventory and proinflammatory cytokines circulating within
the blood was evaluated among 34 pregnant women and 24 non-pregnant women. A
positive correlation was found to exist between psychosocial stress, depression and
increased production of the proinflammatory cytokine, IL-6, during the prenatal
period. Increased production of IL-6 has been associated with depression, stress
preterm labor and preclampsia. Data also indicated significant differences between
the experience of psychosocial stress, social support and depression between pregnant
and non-pregnant women, and a trend toward significant relationships among these
factors and cytokine levels in pregnant women was observed. Moreover, specific
variables were more strongly related to certain components of stress, providing
in


further support for the transactional conceptualization of stress and the need to
include several measures to fully capture the pregnancy experience. There was an
association between pregnancy, stress, social support, and depression scores.
Whereas, non-pregnant women were found to have high levels of reported stress, but
lower reported levels of support and high reported levels of depression. These results
raise the possibility that among women of higher socioeconomic status interventions
may be highly affective.
This abstract accurately represents the content of the candidates thesis. I recommend
its publication.
Signe
IV


ACKNOWLEDGMENTS
I would like to thank Mary Coussons-Read for her support and guidance during the
several months I worked on my thesis project. I would also like to thank Michele
Okun for her generous assistance.


CONTENTS
Figures................................................... viii
Tables.................................................... ix
CHAPTER
1. INTRODUCTION............................................ 1
Stress and Immune Functioning............................ 2
Immune Functioning During Pregnancy...................... 6
Depression and Pregnancy.............................. 11
Relevance............................................... 14
2. METHODS................................................ 16
Subjects................................................ 16
Procedures.............................................. 18
Cytokine Assessment.................................. 18
Maternal Emotionality Measures.......................... 19
Measurement of Stress................................ 19
Measurement of Depression........................... 21
Statistical Treatment of Data.......................... 21
3. RESULTS................................................. 23
vi


4. DISCUSSION................................. 30
REFERENCES......................................... 28
Vll


FIGURES
Figure
3.1 Pregnant Women Report Less Stress............................. 23
3.2 Pregnant Women Report Less Depression........................ 24
3.3 Pregnant Women Report Less Social Support.................... 25
3.4 Social Support is Positively Related to Stress.............. 26
3.5 Depression Scores are Positively Related to Stress.......... 27
3.6 Increased IL6 Cytokine Production Correlated With Stress.... 28
3.7 Increased IL6 Cytokine Production Correlated With Depression.... 28
vm


TABLES
Table
2.1 Demographic Characteristics of Samples
IX


CHAPTER 1
Introduction
Current research has begun to clarify the negative impact that maternal stress
during pregnancy can have on fetal development as well as on the childs future
temperament and emotions. Stress during pregnancy is linked to preterm birth and
lower birth weight (Lobel, Dunkel-Schetter, & Scrimshaw, 1992; Groome, Swiber,
Bentz, Holland, & Atterbury, 1995). Similarly, depressive symptomatology appears
to be relatively common during pregnancy. In studies using self-report screening
scales, close to a quarter of all women surveyed admited to depressive symptoms
during the second trimester (Kelly, Russo, Katon, 2001) and 30% in the third
trimester (Klein & Essex, 1994/1995). Both stress and depression have been shown
to alter immune function in non-pregnant individuals, but to date these relationships
have not been addressed during pregnancy (Elenkov, & Chrousos, 1999; Conrad,
Miles, & Benyo, 1998; Benyo, Smarason, Redman, Sims, & Conrad, 2001; Miller,
1998). Several studies suggest that stress and depressive symptomatology have the
potential to reduce maternal immune functioning, thereby increasing susceptibility to
infection as well as altering cytokine production in a manner that negatively
contributes to pregnancy outcomes (Maes, Ombelet, De Jongh, Kenis, & Bosnian,
2001; Chung, Lau, Yip, Chiu, & Lee, 2001; Hoffman, & Hatch, 2000). Therefore, it
is believed that a womans emotional state as well as her stress level during
1


about changes in the in utero environment, which, in turn, may have a negative
impact on how the fetus and ultimately the child develops.
The general goal of the present study is to examine the extent to which higher
reported levels of stress scores predict greater reporting of depressive
symptomatology as well as impacting the level of cytokine production, while
accounting for relations between sociodemographic variables. It is hypothesized that
higher stress would be related to more depressive symptomatology. It is also
hypothesized that the greater the stress levels the further likelihood of depressive
symptoms. These two factors combined negatively impact the production of
cytokines causing the immune system to produce greater quantities that could
ultimately result in shorter periods of gestation, or increased risk of preclampsia or
low-birth weight infants.
Stress and Immune Functioning
Lazarus and Folkman (1994) view stress as a transaction between the
individual and his/her environment. A persons appraisal of stress is dependent upon
the environmental demands placed upon them, such as family and work obligations,
sleep deprivation, role strains and/or social isolation; plus the amount of resources
available to deal with the specific demand. Any immune challenge that threatens the
stability of the internal environment can be regarded as a stressor, thereby activating
2


the stress system. Moderate stress has been found to boost performance, both
physically and mentally (Baum & Posluszny, 1999). However, long-term stress has
been found to have a negative impact and impair proper immune functioning. It is the
effect of chronic stress on the immune system that this study will examine.
The neuroendocrine and immune systems play major roles in this transaction,
each regulating the other in situations of stress and infection. Recent research
indicates a bi-directional communication between the nervous system and immune
systems. This bi-directional system is thought to be an interaction between the
central nervous system (CNS), the endocrine system and the immune system. The
impact of behavior or stress on these interactions has implications for the disruption
of the functionality of this bi-directional system. Stress affects immunity through a
complex series of events occurring within the (CNS) in response to blood-borne,
neurosensory, and limbic signals (Baum, & Posluuszny, 1999; Chrousos, 1997;
Kaplan, 1999).
The peripheral limbs of the stress response are the hypothalamic-pituitary-
adrenal (HPA) axis and the systemic/adrenomedullary sympathetic nervous system
(SNS.) The HPA axis, which is responsible for the recognition of psychological or
physical stressors, is activated by signals from the CNS. The two main components
of the stress system are the corticotrophin-releasing hormone (CRH) and the locus
ceruleus norepinephrine (LC NE)/ autonomic (sympathetic) neurons of the
3


hypothalamus and brainstem (Elenkov, & Chrousos, 1999; Coussons-Read, Mazzeo,
Whitford, Schmitt, Moore, & Zamudio, 2003). Both of these mechanisms help
regulate the peripheral activities of the HP A axis and the SNS. CRH induces the
anterior pituitary gland to release adrenocorticotropin hormone (ACTH), which
causes cortisol to be released from the adrenal cortex. Ultimately, this leads to the
systemic secretion of glucocorticoids and catecholamines, mainly epinephrine (E) and
norepinephrine (NE), which in turn, influence immune response. This causes cell
products from an activated immune system, predominately the cytokines tumor
necrosis factor (TNF -a), interleukin 1 (IL 1) and IL 6, to stimulate CRH
secretion and, hence, activate both the HPA axis and the SNS (Coussons-Read,
Mazzeo, Whitford, Schmitt, Moore, & Zamudio; Elenkov & Chrousos, 1999).
Immune responses are regulated by antigen presenting cells (APCs), such as
monocytes/macrophages, dendritic cells and other phagocytic cells, which are
components of innate immunity, and by T helper cells (Th) lymphocyte subclasses Th
1 and Th 2, which are components of acquired immunity. Th 1 induces a
proinflammatory response resulting in cellular immunity, which provides protection
against intracellular bacteria, protozoa, fungi, several viruses. Th 2 prompts an
antiinflammatory response, which protects against multicellular parasites,
extracellular bacteria, some viruses, soluble toxins, and allergens. This is of
importance in understanding the role of stress on immune functioning, thereby
4


showing that stress does not uniformly suppress immune functioning, but may also
boost humoral immunity as well. Moreover, both depression and pregnancy
significantly alter immune function by inducing a suppression of the proinflammatory
response in order not to reject the pregnancy.
Numerous animal studies over the past 40 years have demonstrated that stress
is capable of causing numerous immune changes involving virtually every aspect of
the immune response. Studies have shown that a wide array of stressors such as
footshock, restraint, rotation, crowding, noise, forced exercise, and exposure to a
predator are capable of altering multiple immune parameters by detrimentally
effecting the distribution of lymphocytes and monocytes in various immune
compartments, lymphocyte proliferation and cytokine production, NK-cell activity,
phagocytic function, and antibody formation (Chrousos, 1997; Sheridan, Dobbs,
Brown, & Zwilling, 1994; Weiss & Sundar, 1992). Researchers have also found that
stress-induced changes in immune functioning can translate into disease exacerbation
(Miller, 1998). Ben-Eliahu and colleagues (1991) have shown that stress- induced
decreases in NK-cell activity in rats resulted in increased lung tumor colonization by
an NK-cell sensitive tumor cell line. Also, stress-induced decreases in cytotoxic T
cell functioning have been associated with increased viral disease in animals infected
with the Herpes simplex virus (Bonneau, Sheridan, Feng, & Glaser 1991; Kusnecov,
Grata, Schmidt, Bonneau, Sheridan, Glaser, et al., 1992).
5


Similar findings have occurred in human studies. Koenker (1994) found that
psychological stress could cause an increase in humans vulnerability to viral
infection as well. Subjects exposed to stress showed increases in infection rates from
74% to 90% and clinical colds rose from 27% to 47%. Earlier studies have shown
that medical students have an increased risk of mononucleosis during examination
periods (Glaser, Rabin, Chesney, Cohen, &Natelson, 1999). Stress also increases .
ones risk for diabetes, especially in overweight individuals, since psychological
stress alters the bodys need for insulin (Kaplan, 1999). In addition, wound healing
has been shown to be impaired due to the effects of psychological stress regardless of
ones age, education level or gender (Glaser, Rabin, Chesney, Cohen, & Natelson,
1999).
Immune Functioning During Pregnancy
The immune system takes on a different role during pregnancy. The maternal
immune system must be altered in order not to perceive the conceptus as a foreign
antigen thereby, rejecting it. Necessary changes made within the pregnant immune
system are separation of maternal and fetal circulation, protection of the uterus as an
immunologically privileged location as well as changes in maternal lymphocyte -
function and inflammatory responses (Coussons-Read, Mazzeo, Whitford, Schmitt,
Moore, & Zamudio, 2003).
6


During a normal pregnancy, cytokine production of IL-2 and INF-a decreases
while the production of IL-4 and IL-10 increases. In addition, IL-2 and IFN-a are at
their lowest levels in the third trimester of pregnancy, whereas IL-4 and IL-10 are at
their highest quantities (Clark, Arck, Jalali, Merali, Manuel, Chaouat, et al., 1996).
Elenkov and Chrousos (2002) have recently found that during the third trimester of
pregnancy, ex vivo monocytic IL-12 production was approximately threefold and
TNF-a production was approximately 40 % lower than postpartum values. This
suggests that Th 1, proinflammatory, cytokine production and cellular immunity are
suppressed and there is a Th 2, antiinflammatory, shift during normal pregnancy,
especially during the third trimester. Also, during the third trimester of pregnancy
there is an increase in urinary cortisol and NE excretion as well as marked elevations
of estradiol and progesterone. These are thought to ultimately suppress the Th
1/proimflammatory responses (IL-12, INF-y, and TNF-a) and stimulate the Th 2 /
antiinflammatory (IL-4 and IL-10) cytokine production.
Elevated levels of proinflammatory cytokines during pregnancy have been
linked to preclampsia, a serious vascular disease, which manifests as maternal
hypertension, organ system dysfunction, fetal distress and premature birth
(McCubbin, Lawson, Cox, Sherman, Norton, &, Read, (1996). It is hypothesized that
an abnormal increase in production of proinflammatory cytokines in response to
7


infection induces preterm labor (Gomez, Ghezzi, Romero, Munos, Tolosa, & Rojas,
1995). This occurs through a proliferation in the production of IL-6, IL-8 and TNF-
a, which is involved in the ripening of the cervix before delivery, and is associated
with premature labor and delivery (Zhang, Wang, Zhao, & Kang, 2000). IL 1-|3, also
a pro-inflammatory cytokine, has been found to induce premature labor and delivery
in laboratory animals as well as to be significantly elevated in the amniotic fluid of
women with intramniotic infections who deliver prematurely (Coussons-Read,
Mazzeo, Whitford, Schmitt, Moore, & Zamudio, 2003).
It is this inappropriate inflammatory and immunological response later in the
pregnancy that may cause the onset of preclampsia (Benyo, Smarason, Redman,
Sims, & Conrad, 2001). Moreover, Munno and colleagues (1999) found that there is
significantly more TNF-a, IL-6 and IL 1-0 produced by lymphocytes from
preclamptic women than those produced during a normal pregnancy. Also, women
who experience preterm labor and delivery have significantly higher levels of plasma
cortisol and CRH prior to onset of labor than women with normal deliveries
independent of medical risk (Sandman, Wadhwa, Chicz DeMet, Dunkel Schetter,
& Porto, 1997). It is this stress-related increase of CRH that may be responsible for
premature labor (Field, 1995). Sandman and colleagues (1999) found that womens
HPA axis dysregulation was related to levels of stress and anxiety during pregnancy
8


and that womens CRH level was negatively correlated with an index of fetal CNS
development. These findings suggest that stress and anxiety during pregnancy alter a
womens HPA axis functioning which, in turn, has an impact on fetal CNS
development. Moreover, Erickson and colleagues (2001) found that the total plasma
CRH concentrations are elevated during the second trimester in pregnant women who
experienced preterm delivery. Similarly, bacteria infectious diseases as well as
growth-restricted fetal development have been associated with elevated levels of total
plasma CRH and preterm labor and delivery (Goldenberg, Hauth, & Andrews, 2000;
Golans, Jozak, Warren, Stark, Jozak, & Conwell, 1993).
High levels of psychosocial stress during pregnancy are also associated with a
significant risk of lower birth weight and pre-term birth (Lobel, Dunkel-Schetter, &
Scrimshaw, 1992; Wadhwa, Sandman, Porto, Dunkel-Schetter, & Garite, 1993;
Hedegaard, Henriksen, Sabroe, & Secher, 1993). In a nationwide, multicenter study
of 2,593 pregnant women, stress predicted preterm birth and low birth weight even
after control of confounding risk factors such as race, maternal age, marital status,
education, tobacco and alcohol use (Copper, Goldenberg, Das, Elder, Swain, Norman,
et al., 1996). In addition, Hedegaard and colleagues (1993) reported a significant
association between self-reported general distress at 30 weeks and an increased risk
of preterm delivery, defined as <37 weeks, however, the effects of distress early in
pregnancy on obstetric outcome was not significant. Whereas, Lou et al (1992) found
9


that women who experience severe stressful events during pregnancy showed a 50%
increase in marked premature delivery (prior to 34 weeks).
Recent data on social support during pregnancy is consistent with these
results. In a study by Feldman et al. (2000), pregnant women who reported more
social support in their lives gave birth to babies who weighed more. Moreover, Rini
(1999) and colleagues confirmed that women with stronger resources had higher birth
weight babies, whereas those reporting more stress had shorter gestations. The
amount of resources available to the women were also associated with lower stress,
such as being married, being White, and a having higher income and education.
Animal research also indicates that offspring whose mother was exposed to
acute stressors during pregnancy (e.g., electric shock, heat, light, restraint, and
unpredictable noise) versus controls exhibit long-term changes in behavior and HPA
axis regulation. Prenatally stressed animals show inhibited, anxious and fearful
behavior throughout their lifespan. It is hypothesized that this is a result of excessive
levels of endogenous arousal (Takahashi & Kalin, 1991; Glover & OConnor, 2002).
Moreover, the offspring of rats exposed to an acute stressor during pregnancy
compared to offspring of nonstressed controls also had elevated ACTH stress
responses as preweanlings (Takahashi & Kalin) and have increased stress-induced
corticosterone secretion as adults (Vallee, Mayo, Dellu, Le Moal, Simon, & Maccari,
10


1997). These findings indicate that experienced-based alterations in maternal
physiology are sufficient to influence fetal and post-birth development.
Depression and Pregnancy
Recent research has also begun to explore the effects of prenatal depression on
infant development. There is evidence that major depression is accompanied by an
activation of the inflammatory response system, as indicated by signs of increased
serum and urinary concentrations of neopterin, increased number of leukocytes,
neutrophils and activated T cells. There is also in vitro immunosuppression
characterized by decreased mitogen-induced lymphocyte proliferation and blunted
NK-cell activity. In addition, there is an increase in the secretion of proinflammatory
cytokines, such as IL-1, IL-6 and INF-a as well as cytokine receptors or receptor
antagonists (Maes, Ombelet, De Jongh, Kenis, & Bosnian, 2001). Overall, it is
believed that the response of IL-6 and sIL-IRA following delivery are amplified in
women who previously suffered from major depression. This suggests that major
depression is accompanied by the sensitization of the inflammatory response system.
Furthermore, TNF-a, IL-1, IL-6 and LIF, either alone or in conjunction with
components of the stress system and the classic stress hormones, induces symptoms
11


very similar to those manifested during depression such as fever, sleepiness, fatigue,
loss of appetite and decreased libido (Miller, 1998).
In a study of pregnant womens anxiety and depression, Ponirakis and
colleagues (1998) found that elevated levels of anxiety and depression during
pregnancy predicted reduced infant heart rate variability (HRV) a noninvasive
index of cardiac autonomic modulation linked in children and adults to differences in
affect regulation (Monk, Fifer, Myers, Sloan, Trien, & Hurtado, 1999). Babies of
mothers who report depressive symptomatology at the time of the childs birth have
lower motor tone and endurance, are less active, less robust, and more irritable on
neurobehavioral exam (Abrams, Field, Scafidi, & Prodromidis, 1995). Furthermore,
depressive symptoms, measured at prenatal intake, were a significant predictor of
newborn fussiness and nonsoothability, even after controlling for adverse health
behaviors and low socioeconomic status (Zuckerman, Bauchner, Parker, & Cabral,
1990). In another study, maternal depression, which was characterized by elevated
norepinephrine and cortisol, and reduced dopamine levels assessed during the third-
trimester of the pregnancy predicted newborns elevated norepinephrine and cortisol
levels as well as inferior orienting and reflex skills (Lundy, Jones, Field, Nearing,
Davalos, Pietro, 1999).
However, it is still not know whether mood disturbance has any adverse effect
on fetal growth or the duration of gestation. Among well-designed studies using
12


general population samples, most have found no association (Brooke, Anderson,
Bland, Peacock, & Stewart, 1989; Nordentoft, Lou, Hansen, Nim, Pryds, Rubin,
1996; Peacock, Bland, & Anderson, 1995). There was a moderate relationship
between elevated distress scores and preterm delivery in one large population-based
study in Denmark (Hedegaard, Henricksen, Sabroe, & Secher, 1993), but no
relationship between elevated scores and fetal growth retardation (Hedegaard,
Henricksen, Sabroe, & Secher, 1996). In studies that used measures more specific to
depressive symptoms on general populations no association with adverse pregnancy
outcomes were found (Copper, Goldenberg, Das, Elder, Swain, Norman, 1996;
Jacobsen, Schei, & Hoffman, 1997).
It is also important to note that depressed women often take poor care of
themselves and participate in adverse health behaviors (Zuckerman, Amaro,
Bauchner, & Cabral, 1989). Depressed pregnant women have a higher likelihood of
smoking cigarettes and using toxic substances, such as alcohol and cocaine
(Zuckerman, Amaro, Bauchner, & Cabral et al.). These substances may be important
mediators of the effects of psychological stress on low birth weight and prematurity
in the infant (Ponirakis, Susman, & Stifter, 1998). Depressed pregnant mothers also
may experience weight loss and poor appetite. The effects of inadequate weight gain
increases the risk of giving birth to a low-birth-weight infant, having a preterm birth
delivery, and having a small for gestational age infant (Steer, Scholl, Hediger, &
13


Fischer, 1992; Hedegaard, Henricksen, Sabroe, & Secher, 1993). Although the
specific mechanism involved in the direct or indirect effects of depression during
pregnancy and infant outcomes are unknown, the conclusions are the same across
numerous studies depression is related to negative effects on immune functioning
during pregnancy as well as poor infant outcomes.
Relevance
Taken together, this emerging body of work suggests that heightened levels of
stress, anxiety, and depression during pregnancy are associated with poor immune
functioning. This ultimately can alter infant neurobehavioral development and have
negative long-term effects on the behavioral and emotional development of the infant,
by extension; these alterations arose and can be detected in the fetal period. This is
important to note because low-birth weight infants are at higher risk for morbidity
and rehospitalization during the first year of life (Feldman, Dunkel-Schetter,
Sandman, & Wadhwa, 2000). In addition, recent studies have shown that reduced
fetal growth predicts the development of hypertension, coronary heart disease, and
non-insulin-dependent diabetes in adulthood (Erickson, Thorsen, Chrousos,
Grigoriadis, Khongsaly, McGregor, et al., 2001; Field, 1995; Monk, 2001). Thus it is
important to examine the relationship between stress, depression and immune
function during the prenatal period in order to effectively introduce interventions that
14


improve the rate of detection of maternal disturbances as well as facilitate treatment
options that could potentially impact neonatal and infant outcomes in a positive
manner. This is especially critical since recent investigations have found that
psychiatric disorders and stress related complications are under recognized and under
treated by obstetric providers (Kelly, Russo, & Katon, 2001).
15


CHAPTER 2
METHODS
Subjects
The sample consisted of 34 pregnant and 24 non-pregnant women. The
complete samples of pregnant and nonpregnant women were equivalent in their
demographic characteristics and composition. The women ranged in age from 23 to
37 years of age (M= 30.82) in the pregnant group and 23 to 39 years of age in the
nonpregnant group (M= 28.37). Eighty-eight percent of the pregnant sample were
married whereas, only 42% pf the nonpregnant sample were married. Both samples
were predominately Caucasian and the average number of years educated for both
groups was 18 years. Almost all of the women from both samples were employed
either part or full time. The subjects were recruited through an e-mail advertisement
issued through the University of Colorado internet system. Inclusion criteria for
pregnant women were that subjects were primiparous, healthy, and without chronic
conditions predisposing to preclampsia such as renal disease, diabetes or obesity.
Pregnant women were asked to participate at any time from the first through the third
trimester, non-pregnant women were asked to participate only once. The women
were assessed during early pregnancy [less than or equal to 16 weeks gestation (first
trimester)], the second trimester, and/or the third trimester of pregnancy.
16


Table 2.1 presents selected demographic variables for the two groups,
pregnant and non-pregnant. There was little difference between the two groups
except for the high number of women married in the pregnant group as opposed to the
non-pregnant group.
Table 2.1 Demographic Characteristics of Samples
Pregnant women n = 34 Non-pregnant women N = 24
Maternal age 30.82 28.38
Marital status 88% married (30) 9% unmarried (3) 3% divorced (1) 42% married (10) 58% unmarried (14)
Race 76% Caucasian (26) 3% African American (1) 12% Hispanic (3) 6% Other (2) 92% Caucasian (22) 4% Asian (1) 4% Hispanic (1)
Years of education 17.71 18.08
Employment 18% Employed, part time 8% Employed, part time
status 76% Employed, full time 84% Employed, full-time
Within the pregnant sample, seventeen women (50%) provided data for only
one trimester, 12 (35%) had data collected during multiple trimesters, and five
women (15%) had data collected during all three trimesters.
17


Procedures
The women were asked to complete several self-reported measures that
obtained information on demographics, social support, stress level and daily hassles
as well as a depression inventory. They were also asked to give two samples of blood
to be immediately processed at the University of Colorado at Denvers lab. One
sample was collected into sodium heparin-coated Vacutainer for the leukocyte
extreaction procedure and the other sample was collected in a non-heparinized tube
for serum extraction. Blood samples collected in non-heparinized tubes were allowed
to clot at room temperature for 30 minutes after collection. Samples were then
centrifuged and 0.5 ml aliquots of serum were frozen at -70 C until analysis. All
blood samples were processed within two hours of collection to assure cell viability
and consistency of processing.
Cytokine Assessments
Levels of TNF-a, IL-6, IL-4, and IL-10 in serum were determined using
commercially available enzyme-linked immunosorbent assay (ELISA) kits
(Biosource Europe). Undiluted serum samples were tested in duplicate and according
to the directions provided by the manufacturer. Optical density at 450 nm was
assessed using an automatic micro plate reader (Biotek 310), and the amount of
cytokine in each sample was determined using the standard curve generated with each
18


assay according to the manufacturers instruction. Detection limits for the assays
were .1 pg/ml for TNF-a, .104 pg/ml for IL-6, .1 pg/ml for IL-4, and .2 pg/ml for IL-
10. The mean of the duplicates was used as the unit of analysis for statistical
evaluation of these data. To facilitate statistical analysis, cytokine values for this
timepoint for this subject were estimated using a computerized program for
replacement of missing values based on the mean of other values in that experimental
group for each dependent variable.
Maternal Emotionality Measures
Measurement of Stress
Coussons Read developed and validated an assessment tool that measures
stress, social support, and self-efficacy. The self-reported questionnaire includes
validation scales and items that assure reliability and validity of the instrument. The
questionnaire is based upon the Meikle, Orleans, Leff, Shain, & Gibbs assessment
tool (1995). The DMHA differs from the original measure in that it includes stress
factors and can be administered in a short period of time. DMHA provides
demographic information, current health status, measures of family environment,
social support, daily hassles, stressors and self efficacy. The main purpose of the
measure is to assess the participants levels of stress using a Life Stress subscale.
19


This subscale includes items that focus on personal habits, time constraints, work,
money, and relationships with partner and family. Items on the Life Stresses
subscales use a 7-point Likert scale, with responses ranging from not a stress at all to
major stress. Participants could also endorse the does not apply response, which
excluded the item from the analysis. The Social Readjustment Rating Scale (SRR
scale) has been used to measure the convergent validity of the DMHAs ability to
assess life stress, Life Stresses subscale. The SRR scale has been used for over 30
years, and has been shown to be a valid and reliable instrument.
Womens responses to each item were entered into a spreadsheet (Excel), and
each item response was assigned a numerical value. Higher scores were indicative of
more of the construct being tested. Thus, whereas a score of 4 on items relating to
quality of relationships indicated more social support than a score of 1 on these items,
scores of 4 on the stress items indicated more stress caused by given events than a
score of 1. The sum of scores for items in each section is computed to provide a
support core, a stress score, and a self-efficacy score of each woman. Thus, three
DHMA scores were generated for each woman each time she took the survey. Higher
total scores of the support portion of the DHMA indicate more social support, higher
scores on the stress portion indicate more psychosocial stress, and higher scores on
the self-efficacy portion represent higher self-efficacy and better coping skills.
20


Measurement of Depression
Depressive symptoms were measured using the Center for Epidemiological
Studies Depression Scale (CES -D; Radloff, 1977), a 20 item screening instrument
tapping symptoms in the previous week. Scores can range from 0 to 60, with the
outpoint of 16 generally used to indicate clinically significant elevations (Weissman,
Sholomskas, Pottenger, Prussoff, & Locke, 1977). Because some symptoms of
pregnancy may be indistinguishable from somatic manifestations of depression
(Huffman, Lamour, Bryan, & Pederson, 19990: Klein & Essex, 1994/1995) and
standard scores for pregnant women are unavailable, 4 items from the scale, 2 items
assessing fatigue, and 1 each assessing loss of appetite and difficulty sleeping) were
excluded. These pregnancy modified scores were proportionally reinflated using
the equation [(original CES -D 4 items) x 1.25 = new CES D] so the standard
cutpoint of 16 could be applied (Hoffman & Hatch, 2000). The range of original
scores was 1 to 20; that of the pregnancy-modified scores, 0 to 17; and that of the
reinflated scores, 0 to 20. To evaluate whether this adjustment influenced the results,
we repeated analyses with original scores.
Statistical Treatment of Data
All statistical assessments were made using a computerized program for data
analysis (SPSS, SPSS Inc.). Demographic variables were analyzed using a
21


multivariate analysis of variance (ANOVA) in which DEPRESSION, STRESS,
SOCIAL SUPPORT, SELF-EFFICACY, IL-6, IL-4, IL-10, AND TNF-a were the
variables of interest. ANOVAs were conducted in which the within-subjects factor
was the TRIMESTER of pregnancy when the sample was taken (first, second or
third) and the between-subject factor was PREGNANCY (pregnant vs. nonpregnant).
Variables were then analyzed using a correlation matrix in which DEPRESSION,
STRESS, SOCIAL SUPPORT, IL-6, IL-4, IL-10, AND TNF-a were the variables of
interest. The data was collapsed across the three trimesters to compensate for missing
data within each trimester. Planned contrasts were conducted when the correlation
indicated that it was appropriate and when they were supported by a priori
hypotheses. The significance level for all statistical tests conducted was set at 0.05.
The results were then collapsed and a correlational matrix was run to better establish
the relationship between the numerous variables.
22


CHAPTER 3
Results
Analysis of the demographic data indicated that there were no differences in
demographic variables between the pregnant and non-pregnant samples, except that
significantly more women were married in the pregnant sample then the nonpregnant
sample. An analysis of variance (ANOVAs) of psychosocial stress and pregnancy
revealed significant group differences [F (1,57) = 28.335, p< .000]. The means for
the pregnant group was M = 21.09 and M = 36.40 for the non-pregnant group.
Therefore, women who were pregnant reported lower psychosocial stress in their day
to-day lives than women who were not pregnant. .
Figure 3.1 Pregnant Women Report Less Stress
Pregnant Women Report Less Stress
50
Pregnant Non-Pregnant
23


Pregnant women were also found to report less depressive symptomatology
than non-pregnant women. The means for pregnant women were M 4.49 and M =
5.52 for non-pregnant women.
Figure 3.2 Pregnant Women Report Less Depression
Pregnant Women Report Less Depression
7
Pregnant Non-Pregnant
However, pregnant women were found to report lower levels of social support
than non-pregnant women. The means of the two groups were M = 7.85 for pregnant
women and M = 11.56 for non-pregnant women [F (1, 57) = 11.12, p < .002].
24


Figure 3.3 Pregnant Women Report Less Social Support
Pregnant Women Report Less Support
14
Pregnant Non-Pregnant
Overall, pregnant women reported less psychosocial stress and depressive
symptomatology than their non-pregnant counterparts. However, they did report
lower levels of perceived social support than the non-pregnant sample.
After examining the difference between pregnant and non-pregnant samples it
was thought to be an unrealistic comparison due to the enormous changes that occur
during the prenatal period. Therefore, the data was collapsed and correlational
analyses were conducted to determine if there were any associations between any of
the dependent measures assessed. As previously mentioned, the three DHMA scores
25


were generated for each woman: social support, psychosocial stress, and self-efficacy.
All three-stress measures were found to significantly correlated. Social support was
positively related to psychosocial stress r = .598, p< .01. Coping, the third
component of the inventory, was also positively correlated to psychosocial stress as
well as social support, r = .802, p< .01, and r = .766, p< .01, respectively. This
further validates the DHMA measure by exemplifying the interaction that exists
between the three measures.
Figure 3.4 Social Support is Positively Related to Stress
Social Support is Positively Related to Stress
26


A significant correlation was also found to exist between depression and
psychosocial stress, r = .432, p< .01. This correlation was not surprising given the
established theoretical relationship between these two variables from previous
studies.
Figure 3.5 Depression Scores Positively Related to Stress
Depression Scores are Positively Related to Stress
More importantly, a positive correlation was found to exist between IL-6 cytokine
production and psychosocial stress, r = .392, p< .05.
27


Figure 3.6 Increased IL6 Cytokine Production Correlated With Stress
IL-6 was also found to be positively correlated with a pregnant womens self-
reported score on the CES-D, r = .333, p<.05.
Figure 3.7 Increased IL6 Cytokine Production Correlated With Depression
Taken together, these two correlations show that women who report high levels of
psychosocial stress and depression are more likely to produce higher levels of the IL-
28


6 proinflammatory cytokine. There was also a positive correlation between IL-4 and
IL-10 production within the pregnant women studied, r = .539. This was an expected
result, since production of both cytokines normally increases during pregnancy. A
negative correlation was found between the amount of social stress and IL-10
production, r = -.297. Women who reported higher amounts of social support
produced less IL-10 cytokines.
29


CHAPTER 4
Discussion
The goal of this study was to examine the relationships among psychosocial
stress, depression and cytokine production during the prenatal period. It was
hypothesized that women reporting higher levels of prenatal stress and lower social
support during pregnancy would also exhibit more depressive symptoms, and that
these factors would be related to higher levels of proinflammatory cytokines in
maternal circulation. Data indicated significant differences between the experience of
psychosocial stress, social support and depression between pregnant and non-
pregnant women, and a trend toward significant relationships among these factors and
cytokine levels in pregnant women was observed. Moreover, specific variables were
more strongly related to certain components of stress, providing further support for
the transactional conceptualization of stress and the need to include several measures
to fully capture the pregnancy experience.
Previous studies have shown that various maternal psychosocial
characteristics such as stress, depression, self-efficacy, and poor social support
increase a womans risk for low birth weight and pregnancy complications (Copper,
Goldenberg, Das, Elder, Swain, Norman, G. et al., 1996; Da Costa, Larouche, Drista,
& Brender, 2000; Hedegaard, Henriksen, Secher, Hatch, & Sabroe, 1996; Lou,
30


Nordentofit, & Jensen, 1992; Wadhwa, Sandman, Porto, Dunkel-Schetter, & Garite,
1993). Although some studies have shown minimal effects of prenatal stress on
pregnancy (Brooke, Anderson, Bland, Peacock, & Stewart, 1989), the majority of
studies show that stress experienced throughout pregnancy can negatively affect
pregnancy and infant outcomes. For example, Carmichael and Shaw (2000) noted
that significant stress around conception (e.g., death of a loved one, divorce) resulted
in greater chances of delivering an infant with conotruncal heart defects, neural tube
defects, and isolated clef lip. Glynn et al. (2001) found that trauma from an
earthquake had a greater negative effect on gestational length if experienced earlier in
the pregnancy. Several investigators have shown that stress experienced later in
pregnancy is related to lower birth weights, reduced gestational length, and preterm
labor and delivery (Groome, Swiber, Bentz, Holland, & Atterbury, 1995; Wadhwa,
Porto, Garite, Chicz-DeMet, & Sandman, 1998). Moreover, infants of stressed
pregnancies have higher rates of childhood allergies and asthma, and perinatal stress
appears to contribute to respiratory illness in infancy (Monk, 2001).
In this study we used several tools that simultaneously addressed numerous
components of psychosocial stress by combining elements that had previously been
examined separately. It was hoped that a more comprehensive and accurate picture of
what contributes to poor immune function during pregnancy would result. Due to this
approach an interesting picture emerged; stress was positively associated to both,
31


psychosocial stress and depression. More importantly, increased production of IL-6
was also positively correlated to both variables. These analyses provide further
evidence for an emerging pattern of results linking multidimensional measures of
prenatal stress, and now depression, to poor immune functioning.
This is significant since increased production of IL-6 has been linked with
contributing to higher levels of plasma cortisol and CRH prior to the onset of labor
(Erickson, Thorsen, Chrousos, Grigoriadis, Khongsaly, McGregor, et al., 2001).
CRH and cortisol have also been implicated in the suppression of the immune system,
which may lead to infections that increase the risk of preterm labor (Wadhwa, Porto,
Garite, Chicz-DeMet & Sandman, 1998) and contribute to the onset of preclampsia in
response to infection (Zhang, Wang, Zhao, & Kang, 2000). However, TNF-a, which
is also associated with these phenomena, was not found to be elevated. Therefore, it
is uncertain as to the extent IL-6 alone could trigger these results. Further research
needs to be done in this area.
Increased production of IL-6 has also been associated with depression. Maes
and colleagues (2001) found that women who previously suffered from major
depression had increased levels of the IL-6, proinflammatory cytokine. This
increased production, in conjunction with stress hormones, can induce symptoms
similar to depression. It is believed that increased stress can activate the release of
proinflammatory cytokines. This is important because proinflammatory cytokines
32


stimulate HPA activity, alter glucocorticoids receptor function and alter monoamine
neurotransmission in the CNS (Miller, 1998). Again, it wise to interpret these results
cautiously because no other proinflammatory cytokine was found to be significant.
Overall, IL-6 is strongly associated with not only depression, but also with
premature labor, stress, and preeclampsia. This is significant for pregnant women
because the effects of psychosocial stress and depression, alone or together, can
negatively affect fetal development and can lead to poor birth outcomes by
stimulating increased production of IL-6. Therefore, major depression could induce
an increase in proinflammatory response due to the stresses associated with childbirth
(Maes, Ombelet, De Jongh, Kenis, & Bosnian, 2001). This bi-directional loop is
important to recognize due the tremendous impact it has on the both, the mother and
the developing fetus. Hoffman et al (2000) note that increases in IL-6 production
might also contribute to retarded fetal growth through a catecholamine-mediated
decrease in placental perfusion.
Many of the variables we believed would be significant, such as increased
reporting of depressive symptomatology as well as increased psychosocial stress
during the prenatal period, were low. There are several factors that could have
contributed to these results. First, the population sampled was unique. The women
who participated in this study had several skewed sociodemographic variables. For
example, they were exceptionally well educated, came from a higher SES, were
33


employed, predominantly married, and Caucasian. All of these factors have been
found to significantly lower a womans risk for developing complications during
pregnancy (Feldman, Dunkel-Schetter, Sandman, & Wadhwa, 2000). Moreover,
these numerous variables reduce a womans stress level, thereby lowering her risk for
prenatal depression and increase immune function. Women that are well educated as
well as married have greater access to social and dispositional (e.g., mastery,
optimism, and self-esteem) resources during pregnancy and in turn have better birth
outcomes (Da Costa, Larouche, Dritsa, & Brender, 1999).
These factors may have influenced the results in an unexpected manner.
Studies have shown that women of lower SES are at increased risk for lower birth
weight as well as having a propensity to participate in adverse health behaviors
(Cunningham, 2002). It has also been found that women with less education and
lower incomes had fewer personal resources, which predicted less fetal growth
compared with women with more education and higher incomes (Rini, Dunkel-
Schetter, Wadhwa, & Sandman, 1999). African American and Hispanic women are
at high risk of depression and postpartum parenting problems in contrast to Caucasian
women (Cunningham). Lastly, Ponirakis and colleagues (1998) found that pregnant
adolescent women had higher concentrations of cortisol and gave birth to infants that
scored lower on responsivity measures as well as had an increased need for
resuscitation measures to be performed on the infant.
34


Women from a higher SES may face different types of stressors than our
inventoiy measured. Given that these women were recruited from a research,
hospital-based community, they may have realized what was being asked of them and
gave responses that placed them in the best possible light. Although these women did
not claim to be significantly depressed or to suffer from the effects of psychosocial
stress, they did have elevated levels of IL-6 in their blood. Perhaps, what these
women view as stress may be different then what was being measured.
Our results indicate that overall, a higher self-reported depression score was
associated with higher levels of perceived psychosocial stress. This highlights the
complex interaction the two factors play in contributing to the negative progression of
the other. Secondly, the greater the amounts of perceived social support the lower
their self-reported psychosocial stress scores. Interestingly, pregnant women in our
sample reported lower levels of stress as well as depressive symptomatology than
non-pregnant women. This manifestation could reflect changes in overall perception
of what stressful may mean to them. As previously mentioned, women within this
sample were well-educated and currently employed. They also all had health
insurance, which may have contributed to a lower stress score. Also, it is very likely
that a majority of the pregnancies within this sample were planned, and not
unexpected.
35


Pregnant women did, however, report lower levels of perceived social support
then non-pregnant women. This could reflect changes in perception and the
realization of upcoming changes in lifestyle and demands. Women within this
sample could believe that their partner needs to provide more support then they had in
the past. This factor could also be a sign of marital discord, as women who are more
adjusted in their relationship may be getting more support from their partner, which
serves to reduce stress (Brown, 1994). There is some evidence from this study to
suggest that the effect of marital adjustment is more likely related to its supportive
role rather than as a stressor. However, caution should be used when interpreting the
role of marital adjustment as a predictor of lower reported social support scores. The
inclusion of a measure assessing womens perceptions of support in various domains
by the partner would be necessary to untangle this complicated relationship.
Some limitations of this study must be acknowledged. The trimester
subgroups were too small to be examined separately, a larger sample size would
allow for differences between the trimesters to emerge and should be tested in the
future. Also, the sample size limited the ability to detect relationships with
dichotomous clinical outcome variables, which would be important to observe for the
purposes of risk assessment and intervention.
The present findings indicate that research on the effects of maternal
depression and stress and intervention techniques need to begin during the prenatal
36


period. Determining early predictors of women at risk of experiencing high levels of
psychosocial stress as well as depression during pregnancy would allow us to identify
women early in the pregnancy that may benefit from cost-effective interventions
aimed at reducing stress. Women that are more depressed and stress during
pregnancy would most likely experience this postpartum as well. Da Costa and
colleagues (2000) found that the best predictor of postpartum depressed mood was
prepartum depressed mood. It is believed that almost 25% of cases of postpartum
depression start during pregnancy (Evans, Heron, Francomb, Oke, & Golding, 2001).
Women who are depressed take poor care of themselves as well as the child and this
in turn can lead to problems bonding with the child and could create developmental
delays (Evans, 2001). This is an important area of research to explore and the
component of depression should not be overlooked.
37


REFERENCES
Abrams, S. M., Field, T., Scafidi, F., & Prodromidis, M. (1995). Maternal
depression effects on infants Brazelton Scale performance. Infant Mental
Health Journal, 16, 231-235.
Baum, A. & Posluuszny, D. (1999). Health psychology: Mapping biobehavioral
contributions to health and illness. American Psychologist, 47, 1597-1611.
Ben-Eliyahu, S., Yirmiya, R., Liebeskind, J. C., Taylor, A. N., & Gale, R. P. (1991).
Stress increases metastatic spread of mammary tumor in rats: Evidence for
mediation by the immune system. Brain, Behavior, & Immunity, 5(2), 193-
205.
Benyo, D. F., Miles, T. A., & Conrad, K. P. (1997). Hypoxia stimulates cytokine
production by villous explants from the human placenta. The Journal of
Clinical Endocrinology and Metabolism, 82(5), 1582-1588.
Benyo, D. F., Smarason, A., Redman, C. W., Sims, C., & Conrad, K. P. (2001).
Expression of inflammatory cytokine in placentas from women with
preclampsia. The Journal of Clinical Endocrinology and Metabolism, 86(6),
2505-2512.
Bonneau, R. H., Sheridan, J. F., Feng, N. G., & Glaser, R. (1991). Stress-induced
suppression of herpes simplex virus (HSV)-specific cytotoxic T lymphocyte
and natural killer cell activity and enhancement of acute pathogenesis
following local HSV infection. Brain, Behavior, & Immunity, 5(2), 170-92.
Brooke, O. G., Anderson, H. R., Bland, J. M., Peacock, J. L., & Stewart, C. M.
(1989). Effects on birth weight of smoking, alcohol, caffeine, socioeconomic
factors, and psychosocial stress. British Medical Journal, 298, 795-801.
Brown, M. (1994). Marital discord during pregnancy: A family systems approach.
Family Systems Medicine, 12, 2221 -234.
Carmichael, S. L., & Shaw, G. M. (2000). Maternal life event stress and congenital
anomalies. Epidemiology, 11, 30 35.
38


Chrousos, G. P. (1997). Stressors, stress, and neuroendocrine integration of the
adaptive response. Annals New York Academy of Sciences, 311 -335.
Chung, T. K., Lau, T. K., Yip, A. S., Chiu, H. F., & Lee, D. T. (2001). Antepartum
depressive symptomatology is associated with adverse obstetric and neonatal
outcomes. Psychosomatic Medicine, 63, 830 834.
Clark, D. A., Arck, P. C., Jalali, R., Merali, F. S., Manuel, J., Chaouat, G., et al.
(1996). Psycho-neuro-cytokine/endocrine pathways in immunoregulation
during pregnancy. American Journal of Reproductive Immunology, 35, 330-
337.
Conrad, K. P., Miles, T. M., & Benyo, D. F. (1998). Circulating levels of
immunoreactive cytokine in women with preclampsia. American Journal of
Reproductive Immunology, 40,102-111.
Copper, R. L., Goldenberg, R. L., Das, A., Elder, N., Swain, M., Norman, G. et al.
(1996). Obstetrics: The preterm prediction study: Maternal stress is associated
with spontaneous preterm birth at less than thirty-five weeks gestation.
American Journal of Obstetrics and Gynecology, 175, 5, 1286 1292.
Coussons-Read, M. E., Mazzeo, R. S., Whitford, M. H., Schmitt, M., Moore, L. G., &
Zamudio, S. (2003). High altitude residence during pregnancy alters cytokine
and catecholamine levels. The American Journal of Reproductive
Immunology.
Cunningham, M., & Zayas, L. H. (2002). Reducing depression in pregnancy:
Designing multimodal interventions. Social Work, 27(2), 114-124.
Da Costa, D., Larouche, J., Drista, M., & Brender, W. (1999). Variations in stress
levels over the course of pregnancy: Factors associated with elevated hassles,
state anxiety and pregnancy-specific stress. Journal of Psychosomatic
Research, 47(6), 609-621.
Da Costa, D., Larouche, J., Drista, M., & Brender, W. (2000). Psychosocial
correlates of prepartum and postpartum depressed mood. Journal of Affective
Disorders, 59, 31 -40.
39


Dejin-Karlsson, E., Hanson, B. S., Ostergren, P. 0., Lindgren, A., Sjober, N. O., &
Marsal, K. (2000). Association of a lack of psychosocial resources and the
risk of giving birth to small for gestational age infants: A stress hypothesis.
British Journal of Gynecology, 707(1), 89-100.
Dunkel-Schetter, C., Stanton, A. L., & Wadhwa, P. D. (2000). Stress and
reproduction: Introduction to the special section. Health Psychology, 19(6),
507-509.
Elenkov, I. A., & Chrousos, G. P. (1999). Stress hormones, Th 1/Th2 patterns,
pro/anti-inflammatory cytokines and susceptibility to disease. Trend in
Endocrinology and Metabolism, 10(9), 359-368.
Elenkov, I. A., & Chrousos, G. P. (2002). Stress hormones, proinflammatory and
antiinflammatory cytokines, and autoimmunity. Annals New York Academy of
Sciences, 966,290-303.
Erickson, K., Thorsen, P., Chrousos, G., Grigoriadis, D. E., Khongsaly, O.,
McGregor, J. et al. (2001). Preterm birth: Associated neuroendocrine,
medical, and behavioral risk factors. The Journal of Clinical Endocrinology
and Metabolism, 86(6), 2544-2552.
Evans, J., Heron, J., Francomb, H., Oke, S., & Golding, J. (2001). Cohort study of
depressed mood during pregnancy and after childbirth. British Medical
Journal, 323, 257-260.
Feldman, P. J., Dunkel-Schetter, C., Sandman, C. A., & Wadhwa, P. A. (2000).
Maternal social support predicts birth weight and fetal growth in human
pregnancy. Psychosomatic Medicine, 62,1X3- 725.
Field, T. (1995). Infants of depressed mothers. Infant Behavior and Development,
18, 1-13.
Glaser, R., Rabin, B., Chesney, M., Cohen, S., & Natelson, B. (1999). Stress-induced
immunomodulation. Implications for infectious diseases? Journal of
American Medical Association, 281(24), 2268-2270.
Glover, V. & OConnor, T. G. (2002). Effects of antenatal stress and anxiety. British
Journal of Psychiatry, 180, 389-391.
40


Glynn, L. M., Wadhwa, P.D., Dunkel-Schetter, C., Chicz-DeMet, A., & Sandman, C.
(2001). When stress happens matters: Effects of earthquake timing on stress
responsivity in pregnancy. American Journal of Obstetrics and Gynecology,
184(4), 637-642.
Goland, R. S., Jozak, S., Warren, W. B., Conwell, J. M., Stark, R. I., & Tropper, P. J.
(1993). Elevated levels of umbilical cord plasma corticotropin-releasing
hormone in growth-retarded fetuses. Journal of Clinical Endocrinology and
Metabolism, 77,1174-1179.
Goldenberg, R. L., Hauth, J. C., & Andrews, W. W. (2000). Intrauterine infection
and preterm delivery. New England Journal of Medicine, 342, 1500-1507.
Gomez, R., Ghezzi, F., Romero, R., Munos, H., Tolosa, J. E., & Rojas, I. (1995).
Premature labor and intra-amniotic infection. Clinical aspects and role of the
cytokines in diagnosis and pathophysiology. Clinics in Perinatology, 22, 281-
342.
Groome, L. J., Swiber, M. J., Bentz, L. S., Holland, S. B., & Atterbury, J. L. (1995).
Maternal anxiety during pregnancy: Effect on fetal behavior at 38 to 40 weeks
of gestation. Developmental and Behavioral Pediatrics, 16(6), 391-395.
Hedegaard, M., Henriksen, T. B., Sabroe, S., & Secher, N. J. (1993). Psychological
distress in pregnancy and increased uterine artery resistance index: Cohort
based study. British Medical Journal, 318,153-157.
Hedegaard, M., Henriksen, T. B., Secher, N. J., Hatch, M. C., & Sabroe, S. (1996).
Do stressful life events affect the duration of gestation and risk of preterm
delivery? Epidemiology, 7, 339-345.
Hoffman, S., & Hatch, M. C. (2000). Depressive symptomatology during pregnancy:
Evidence for an association with decreased fetal growth in pregnancies of
lower social class women. Health Psychology, 19(6), 535 543.
Jacobsen, G., Schei, B., & Hoffman, H. J. (1997). Psychosocial factors for small-for-
gestational-age infants among Scandinavian women. Acta Obstetricia et
Gynecologica Scaninavica, 76 (Suppl. 165), 14-20.
41


Kaplan, A. (1999). Implications of stress, psychosocial factors on the immune system.
Psychiatric Times, XVI( 10), 1-9. Abstract received October 15, 2003, from
PsycINFO database.
Kelly, R. H., Russo, J., & Katon, W. (2001). Somatic complaints among pregnant
women cared for in obstetrics: Normal pregnancy or depressive and anxiety
symptoms amplification revisited? General Hospital Psychiatry, 23,107 -
113.
Klein, M. H., & Essex, M. J. (1994/1995). Pregnant or depressed? The effect of
overlap between symptoms of depression and somatic complaints of
pregnancy on rates of major depression in the second trimester. Depression,
2, 308-314.
Koenker, H. (1994). Stress and the immune system. Retrieved September 18, 2003,
from http://www.econ.uiuc.edu.
Kusnecov, A. V., Grota, L. J., Schmidt, S.G., Bonneau, R. H., Sheridan, J. F., Glaser,
R., et al. (1992). Decreased heipes simplex viral immunity and enhanced
pathogenesis following stressor administration in mice. Journal of
Neuroimmunology, 38, 129.
Lazarus, R. S., & Folkman, S. (1994). Stress, appraisal and coping. New York:
Springer.
Lobel, M. (1994). Conceptualizations, measurement, and effects of prenatal maternal
stress on birth outcomes. Journal of Behavioral Medicine, 17(3), 225-272.
Lobel, M., Dunkel-Schetter, C., & Scrimshaw, S. C. (1992). Prenatal maternal stress
and prematurity: A prospective study of socioeconomically disadvantaged
women. Health Psychology, 77,32-40.
Lou, H. C., Nordentoft, M., & Jensen, F. (1992). Psychosocial stress and severe
prematurity. Lancet, 340, 54.
Lundy, B. L., Jones, N. A., Field, T., Nearing, G., Davalos, M., Pietro, P. A. et al.
(1999). Prenatal depression effects on neonates. Infant Behavior &
Development, 22(1), 119 129.
42


McCubbin, J. A., Lawson, E. J., Cox, S., Sherman, J. J., Norton, J. A., & Read, J. A.
(1996). Prenatal maternal blood pressure response to stress predicts birth
weight and gestational age: A preliminary study. American Journal of
Obstetrics and Gynecology, 175(3), 706-712.
Maes, M., Libbrecht, I., Lin, A., Goossens, F., Ombelet, W., Stevens, K., et al.
(2000). Effects of pregnancy and delivery serum prolyl endopeptidase (PEP)
activity: Alterations in serum PEP are related to increased anxiety in the early
puerperium and to postpartum depression. Journal of Affective Disorders, 57,
125-137.
Maes, M., Ombelet, W., De Jongh, R., Kenis, G., & Bosnian, E. (2001). The
inflammatory response following delivery is amplified in women who
previously suffered from major depression, suggesting that major depression
is accompanied by a sensitization of the inflammatory response system.
Journal of Affective Disorders, 63,1-3, 85-92.
Meikle, T. H., Orleans, M., Leff, M., & Gibbs, S. (1995). Womens reasons for not
seeking prenatal care: Racial and ethnic factors. Birth, 22(2), 81-86.
Miller, A. H. (1998). Neuroendocrine and immune system interactions in stress and
depression. Psychoneuroendocrinology, 21(2), 443-463.
Monk, C. (2001). Stress and mood disorders during pregnancy: Implications for child
development. Psychiatric Quarterly, 72(A), 347-357.
Monk, C., Fifer, W. P., Myers, M. M., Sloan, R. P., Trien, L., & Hurtado, A. (1999).
Maternal stress responses and anxiety during pregnancy: Effects on fetal
heart rate. Developmental Psychobiology, 36, 76-77.
Munno, I., Chiechi, L. M., Lacedra, G., Berardesca, C., Patimo, C., Marcuccio, L., et
al. (1999). Evaluation of nonspecific immunity and plasma levels of
interferon-gamma, interleukin-6 and tumor necrosis factor-alpha in
preclampsia. Immunopharmacology Immunotoxicology, 21, 551-564.
Nordentoft, M., Lou, H. C., Hansen, D., Nim, J., Pryds, O., Rubin, P., et al. (1996).
Intrauterine growth retardation and premature delivery: The influence of
maternal smoking and psychosocial factors. American Journal of Public
Health, 56,347-354.
43


Peacock, J. L., Bland, J. M., & Anderson, H. R. (1995). Preterm delivery: Effects of
socioeconomic factors, psychological stress, smoking, alcohol, and caffeine.
British Medical Journal, 311, 531-536.
Ponirakis, A., Susman, E. J., & Stifter, C. A. (1998). Negative emotionality and
cortisol during adolescent pregnancy and its effects on infant health and
autonomic nervous system reactivity. Developmental Psychobiology, 33, 163-
174.
Radloff, L. S. (1977). The CES-D scale: A self-report depression scale for research
in the general population. Journal of Applied Psychological Measures, 1,
385-401.
Rini, C. K., Dunkel-Schetter, C., Sandman, C. A., & Wadhwa, P. D. (1999).
Psychological adaptation and birth outcomes: The role of personal resources,
stress, and sociocultural context in pregnancy. Health Psychology, 75(4),
333-345.
Rini, C. K., Sandman, C. A., & Wadhwa, P. D. (1999). Psychological
adaptation and birth outcomes: The role of personal resources, stress, and
sociocultural context in pregnancy. Health Psychology, 75(4), 333-345.
Sandman, C. A., Wadhwa, P. D., Chicz-DeMet, A., & Dunkel-Schetter, C. (1997).
Maternal stress, HPA activity, and fetal/infant outcome. Annals of the New
York Academy of Science, 814,266-275.
Sandman, C. A., Wadhwa, P. D., Chicz-DeMet, A., Porto, M., & Garite, T. J. (1999).
Maternal corticotropin releasing hormone and habituation in the human
fetus. Developmental Psychobiology, 34, 163-173.
Sheridan, J. F., Dobbs, C., Brown, D.,& Zwilling B. (1994).
Psychoneuroimmunology: Stress effects on pathogenesis and immunity during
infection. Clinical Microbiology Reviews, 7(2), 200-212.
Steer, R. A., Scholl, T. O., Hediger, M. L., & Fischer, R. (1992). Self-reported
depression and negative pregnancy outcomes. Journal of Clinical
Epidemiology, 45,1093-1099.
44


Takahashi, L. K., & Kalin, N. H. (1991). Early developmental and temporal
characteristics of stress-induced secretion of pituitary-adrenal hormones in
prenatally stress rat pups. Brain Research, 558,75-78.
Teixeira, J. M., Fisk, N. M., & Glover, V. (1999). Association between maternal
anxiety in pregnancy and increased uterine artery resistance index based
study. British Medical Journal, 318, 153-157.
Vallee, M., Mayo, W., Dellu, F., Le Moal, M., Simon, H., & Maccari, S. (1997).
Prenatal stress induces high anxiety and postnatal handling induces low
anxiety in adult offspring: Correlation with stress-induced corticosterone
secretion. The Journal of Neuroscience, 17(1), 2626-2636.
Wadhwa, P. D., Dunkel-Schetter, C., Chicz-DeMet, A., Porto, M., & Sandman, C. A.
(1996). Prenatal psychosocial factors and the neuroendocrine axis in human
pregnancy. Psychosomatic Medicine, 58(5), 432-446.
Wadhwa, P. D., Porto, M, Garite, T. J., Chicz-DeMet, A.,& Sandman, C. A. (1998).
Maternal corticotropin-releasing hormone levels in the early third trimester
predict length of gestation in human pregnancy. American Journal of
Obstetrics and Gynecology, 179, 1079-1085.
Wadhwa, P. D., Sandman, C. A., Porto, M., Dunkel-Schetter, C., & Garite, T. J.
(1993). The association between prenatal stress and infant birth weight and
gestational age at birth: A prospective investigation. American Journal of
Obstetrics and Gynecology, 169, 858-65.
Weiss, J. M., & Sundar, S. (1992). Effects of stress on cellular immune responses in
animals. Washington, DC: American Psychiatric Press, Inc.
Zhang, W., Wang, L., Zhao, Y., & Kang, J. (2000). Changes in cytokine (IL-8, IL-6,
and TNF-a) levels in the amniotic fluid and maternal serum in patients with
premature rupture of membranes. Chung Hua I. Hsueeh Tsa Chih (Taipei),
63, 311-315.
Zuckerman, B., Amorao, H., Bauchner, H., & Cabral, H. (1989). Depressive
symptoms during pregnancy: Relationship to poor health behaviors.
American Journal of Obstetric Gynecology, 160,1107-1 111.
45


Zuckerman, B., Bauchner, H., Parker, S., & Cabral, H. (1990). Maternal depressive
symptoms during pregnancy and newborn irritability. Journal of
Developmental Behavioral Pediatrics, 11,190-194.
46


Full Text

PAGE 1

THE PRENATAL EFFECTS OF STRESS AND DEPRESSION ON IMMUNE FUNCTIONING by Angelina Koehler B. A., University of Massachusetts, Boston, 1995 A thesis submitted to the University of Colorado at Denver in partial fulfillment of the requirements for the degree of Master of Arts Psychology 2003

PAGE 2

This thesis for the Master of Arts degree by Angelina Koehler has been approved by 1/ 12>-03 Date

PAGE 3

Koehler, Angelina (M. A., Psychology) The Prenatal Effects of Stress and Depression on Immune Functioning Thesis directed by Professor Mary Coussons-Read ABSTRACT The purpose of this study is to examine the interaction between psychosocial stress and depression during the prenatal period and alterations in maternal immune functioning. The relationship between depressive scores on the Center for Epidemiological Studies Depression Scale (CES-D) at various trimesters and on the Denver Maternal Stress Inventory and proinfiammatory cytokines circulating within the blood was evaluated among 34 pregnant women and 24 non-pregnant women. A positive correlation was found to exist between psychosocial stress, depression and increased production of the proinfiammatory cytokine, IL-6, during the prenatal period. Increased production ofIL-6 has been associated with depression, stress preterm labor and preclampsia. Data also indicated significant differences between the experience of psychosocial stress, social support and depression between pregnant and non-pregnant women, and a trend toward significant relationships among these factors and cytokine levels in pregnant women was observed. Moreover, specific variables were more strongly related to certain components of stress, providing III

PAGE 4

further support for the transactional conceptualization of stress and the need to include several measures to fully capture the pregnancy experience. There was an association between pregnancy, stress, social support, and depression scores. Whereas, non-pregnant women were found to have high levels of reported stress, but lower reported levels of support and high reported levels of depression. These results raise the possibility that among women of higher socioeconomic status interventions may be highlyaffective. This abstract accurately represents the content of the candidate's thesis. I recommend its publication. IV

PAGE 5

ACKNOWLEDGMENTS I would like to thank Mary Coussons-Read for her support and guidance during the several months I worked on my thesis project. I would also like to thank Michele Qkun for her generous assistance.

PAGE 6

. CONTENTS Figures ......................................................... V1l1 Tables............................................................................. IX CHAPTER 1. INTRODUCTION..................................................... .... 1 Stress and hnmune Functioning. .... ....... .. .. .. ... .. ... .. .. .. ... 2 Immune Functioning During Pregnancy. ........ .. .. ... ... .. ... ... 6 Depression and Pregnancy .............................................. 11 Relevance. .. ... .. .. .. .. .. .. ... ... .. ...... ... .. .. .. .. ....... ... 14 2. METHODS................................................................. 16 Subjects... ............... ...... ..................... ............ ............. 16 Procedures............... ...... ............................................... 18 Cytokine Assessment.. ... .. ... ...... .. .. ... ... ..... .. .. ... ..... 18 Maternal Emotionality Measures........................................ 19 Measurement of Stress............................................ .... 19 Measurement of Depression.......................................... 21 Statistical Treatment of Data........................ ...................... 21 3. RESULTS................................................................... 23 VI

PAGE 7

4 DISCUSSION.................. ......................................... ... 30 REFERENCES................ .......................................... ...... ......... 28 VB

PAGE 8

FIGURES Figure 3.1 Pregnant Women Report Less Stress.: ............... ... .. .. .. ... 23 3.2 Pregnant Women Report Less Depression.... .. ... .. . .. ... .. ........ 24 3.3 Pregnant Women Report Less Social Support.... ....... ............. 25 3.4 Social Support is Positively Related to Stress.... ........ ........ ..... 26 3.5 Depression Scores are Positively Related to Stress ................... 27 3.6 Increased IL6 Cytokine Production Correlated With Stress.......... 28 3.7 Increased IL6 Cytokine Production Correlated With Depression.... 28 Vlll

PAGE 9

TABLES Table 2.1 Demographic Characteristics of Samples .................................. 17 IX

PAGE 10

I CHAPTER 1 Introduction Current research has begun to clarify the negative impact that maternal stress during pregnancy can have on fetal development as well as on the child's future temperament and emotions. Stress during pregnancy is linked to pretenn birth and lower birth weight (Lobel, Dunkel-Schetter, & Scrimshaw, 1992; Groome, Swiber, Bentz, Holland, & Atterbury, 1995). Similarly, depressive symptomatology appears to be relatively common during pregnancy. In studies using self-report screening scales, close to a quarter of all women surveyed admited to depressive symptoms during the second trimester (Kelly, Russo, Katon, 2001) and 30% in the third trimester (Klein & Essex, 1994/1995). Both stress depression have been shown to alter immune function in non-pregnant individuals, but to date these relationships have not been addressed during pregnancy (Elenkov, & Chrousos, 1999; Conrad, Miles, & Benyo, 1998; Benyo, Smarason, Redman, Sims, & Conrad, 2001; Miller, 1998). Several studies suggest that stress and depressive symptomatology have the potential to reduce maternal immune functioning, thereby increasing susceptibility to infection as well as altering cytokine production in a manner that negatively contributes to pregnancy outcomes (Maes, Ombelet, De Jongh, Keriis, & Bosman, 2001; Chung, Lau, Yip, Chiu, & Lee, 2001; Hoffman, & Hatch, 2000). Therefore, it is believed that a woman's emotional state as well as her stress level during 1

PAGE 11

about changes in the in utero environment, which, in turn, may have a negative impact on how the fetus and ultimately the child develops. The general goal of the present study is to e.xamine the extent to which higher reported levels of stress scores predict greater reporting of depressive symptomatology as well as impacting the level of cytokine production, while accounting for relations between sociodemographic variables. It is hypothesized that higher stress would be related to more depressive symptomatology. It is also hypothesized that the greater the stress levels the further likelihood of depressive symptoms. These two factors combined negatively impact the production of cytokines causing the immune system to produce greater quantities that could ultimately result in shorter periods of gestation, or increased risk of preclampsia or low-birth weight infants. Stress and Immune Functioning Lazarus and Folkman (1994) view stress as a transaction between the individual and hislher environment. A person's appraisal of stress is dependent upon the environmental demands placed upon them, such as family and work obligations, sleep deprivation, role strains and/or social isolation; plus the amount of resources available to deal with the specific demand. Any immune challenge that threatens the stability of the internal environment can be regarded as a stressor, thereby activating 2

PAGE 12

the stress system. Moderate stress has been found to boost performance, both physically and mentally (Baum & Posluszny, 1999). However, long-tenn stress has been found to have a negative impact and impair proper immune functioning. It is the effect of chronic stress on the immune system that this study will examine. The neuroendocrine and immune systems play major roles in this transaction, each regulating the other in situations of stress and infection. Recent research indicates a bi-directional communication between the nervous system and immune systems. This bi-directional system is thought to be an interaction between the I central nervous system (CNS), the endocrine system and the immune system. The impact of behavior or stress on these interactions has implications for the disruption of the functionality of this bi-directional system. Stress affects immunity through a complex series of events occurring within the (CNS) in response to blood-borne, neurosensory, and limbic signals (Baum, & Posluuszny, 1999; Chrousos, 1997; Kaplan, 1999) The peripheral limbs of the stress response are the hypotbalamic-pituitaryadrenal (HPA) axis and the systemic/adrenomedullary sympathetic nervous system (SNS.) The HPA axis, which is responsible for the recognition of psychological or physical stressors, is activated by signals from the CNS. The two main components of the stress system are the corticotrophin-releasing hormone (CRH) and the locus ceruleus norepinephrine (LC -NE)I autonomic (sympathetic) neurons of the 3

PAGE 13

hypothalamus and brainstem (Elenkov, &,. Chrousos, 1999; Coussons-Read, Mazzeo, Whitford, Schmitt, Moore, & Zamudio, 2003). Both of these mechanisms help regulate the peripheral activities of the HP A axis and the SNS. CRR induces the anterior pituitary gh:md to release adrenocorticotropin hormone (ACTH), which causes cortisol to be released froIl1the adrenal cortex. Ultimately, this leads to the systemic secretion of glucocorticoids and catecholamines, mainly epinephrine (E) and norepinephrine (NE), which in turn, influence immune response. This causes cell products from an activated in:nnune system, predominately the cytokines tumor necrosis factor (TNF -a), interleukin -1 (IL 1) and IL 6, to stimulate CRH secretion and, hence, activate both the HPA axis and the SNS (Coussons-Read, Mazzeo, Whitford, Schmitt Moore, & Zamudio; Elenkov & Chtousos, 1999). Immune responses are regulated by antigen presenting cells (APCs), such as monocytes/macrophages, dendritic cells and other phagocytic cells, which are components of innate immunity, and by T helper cells (Th) lymphocyte subclasses Th 1 and Th 2, which are components of acquired immunity. Th 1 induces a proinflammatory response reSUlting in cellular immunity, which provides protection against intracellular bacteria, protozoa, fungi, several viruses. Th 2 prompts an antiinflammatory response, which protects against multicellular parasites extracellular bacteria, some viruses, soluble toxins, and allergens. This is of importance in understanding the role of stress on immune functioning, thereby 4

PAGE 14

I showing that stress does not uniformly suppress immune functioning, but may also boost humoral immunity as well. Moreover, both depression and pregnancy significantly alter immune function by inducing a suppression of the proinfiammatory response in order not to reject the pregnancy. Numerous animal studies over the past 40 years have demonstrated that stress is capable of causing numerous immune changes involving virtually every aspect of the immune response. Studies have shown that a wide array of stressors such as footshock, restraint, rotation crowding, noise, forced exercise, and exposure to a predator are capable of altering multiple immune parameters by detrimentally effecting the distribution of lymphocytes and monocytes in various immune compartments, lymphocyte proliferation and cytokine production, NK-cellactivity, phagocytic function, and antibody formation (Chrousos, 1997; Sheridan, Dobbs, Brown, & Zwilling, 1994; Weiss & Sundar, 1992). Researchers have also found that stress-induced changes in immune functioning can translate intodisease exacerbation (Miller, 1998). Ben-Eliahu and colleagues (1991) have shown that stressinduced decreases in NK-cell activity in rats resulted in increased lung tumor colonization by an NK-cell sensitive tumor cell line. Also, stress-induced decreases in cytotoxic T cell functioning have been associated with increased viral disease in animals infected with the Herpes simplex virus (Bonneau, Sheridan, Feng, & Glaser 1991; Kusnecov, Grota, Schmidt, Bonneau, Sheridan, Glaser, et aI., 1992). 5

PAGE 15

Similar findings have occurred in human studies. Koenker (1994) found that psychological stress could cause an increase in human's vulnerability to viral ; infection as well. Subjects exposed to stress showed increases in infection rates from 74% to 90% and clinical colds rose from 27% to 47% Earlier studies have shown that medical students have an increased risk of mononucleosis during examination periods (Glaser, Rabin, Chesney, Cohen, & Nate1son, 1999). Stress also increases one's risk for diabetes, especially in overweight individuals, since psychological stress alters the body's need for insulin (Kaplan, 1999). In addition, wound healing has been shown to be impaired due to the effects of psychological stress regardless of ones age, education level or gender (Glaser, Rabin, Chesney, Cohen, & Nate1son, 1999). Immune Functioning During Pregnancy The immune system takes on a different role during pregnancy. The maternal immune system must be altered in order not to perceive the conceptus as a foreign antigen thereby, rejecting it. Necessary changes made within the pregnant immune system are separation of maternal and fetal circulation, protection of the uterus as an immunologically privileged location as well as changes in matemallymphocyte function and inflammatory responses (Coussons-Read, Mazzeo, Whitford, Schmitt, Moore, & Zamudio, 2003). 6

PAGE 16

During a normal pregnancy, cytokine production ofIL-20 and INF-a. decreases while the production ofIL-4 and IL01O increases. In addition, IL-2 and IFN-a. are at their lowest levels in the third trimester of pregnancy, whereas IL-4 and IL-I0 are at their highest quantities (Clark, Arck, Jalali, Merali, Manuel, Chaouat, et al., 1996). Elenkov and Chrousos (2002) have recently found that during the third trimester of pregnancy, ex vivo monocytic IL-12 production was approximately threefold and TNF-a. production was approximately 40 % lower than postpartum values. This suggests that Th 1, proinflammatory;c)rtokine production and cellular immunity are suppressed and there o is a Th 2,antiinflammatory, shift during normal pregnancy, especially during the third trimester. Also, during the third trimester of pregnancy there is an increase in urinary cortisol and NE excretion as well as marked elevations of estradiol and progesterone. These are thought to ultimately suppress the Th lIproimflammatory responses (IL-12, INF-y, and 1NF-a.) and stimulate the Th 2/ antiinflammatory (IL-4 and IL-l 0) cytokine production. Elevated levels of proinflammatory cytokines duri ng pregnancy have been linked to prec1ampsia, a serious vascular disease, which manifests as maternal hypertension, organ system dysfunction, fetal distress and premature birth (McCubbin, Lawson, Cox, Sherman, Norton, &, Read, (1996). It is hypothesized that an abnormal increase in production of proinflammatory cytokines in response to 7

PAGE 17

infection induces preterm labor (Gomez, Ghezzi, Romero, Munos, Tolosa, & Rojas, 1995). This occurs through a proliferation in the production ofIL-6, IL-8 and TNF. a, which is involved in the ripening of the cervix before delivery, and is associated with premature labor and delivery (Zhang, Wang, Zhao, & Kang, 2000). IL also a pro-inflammatory cytokine, has been found to induce premature labor and delivery in laboratory animals as well as to be significantly elevated in the amniotic fluid of women with intramniotic infections who deliver prematurely (Coussons-Read, Mazzeo, Whitford Schmitt,Moore, & Zamudio, 2003). It is this inappropriate inflammatory and immunological response later in the pregnancy that may cause the onset ofpreclampsia (Benyo, Smarason, Redman, Sims, & Conrad, 2001). Moreover, Munno and colleagues (1999) found that there is significantly more TNF-a, IL-6 and IL produced by lymphocytes from preclamptic women than those produced during a normal pregnancy. Also, women who experience preterm labor and delivery have significantly higher levels of plasma cortisol and CRR prior to onset of labor than women with normal deliveries independent of medical risk (Sandman, Wadhwa, Chicz DeMet, Dunkel-Schetter, & Porto, 1997). It is this stress-related increase of CRR that may be responsible for premature labor (Field, 1995). Sandman and colleagues (1999) found that women's HP A axis dysregulation was related to levels of stress and anxiety during pregnancy 8

PAGE 18

and that women's CRR level was negatively correlated with ari index of fetal CNS development. These findings suggest that stress and anxiety during pregnancy alter a women's HP A axis functioning which, in tum, haS an impact on fetal CNS development. Moreover, Erickson and colleagues (2001) found that the total plasma CRR concentrations are elevated during the second trimester in pregnant women who experiencedpretenn delivery. Similarly, bacteria infectious diseases as well as growth-restricted fetal development have been associated with elevated levels aftotal plasma CRR and preterm labor and delivery (Goldenberg, Hauth, & Andrews, 2000; Golans, Jozak, Warren, Stark, Jozak, & Conwell, 1993). High levels. of psychosocial stress during pregnancy are also associated with a significant risk of lower birth weight and pre-term birth (Lobel, Dunkel-Schetter, & Scrimshaw, 1992; Wadhwa, Sandman, Porto, Dunkel-Schetter, & Garite, 1993; Hedegaard, Henriksen, Sabroe, & Secher, 1993). In a nationwide, multicenter study of 2,593 pregnant women, stress predicted preterm birth and low birth weight even after control of confounding risk factors such as race, maternal age, marital status, education, tobacco and alcohol use (Copper, Goldenberg, Das, Elder, Swain, Norman, et al., 1996). In addition, Hedegaard and colleagues (1993) reported fl significant association between self-reported general distress at 30 weeks and an increased risk of preterm delivery, defined as <37 weeks, however, the effects of distress early in pregnancy on obstetric outcome was not significant. Whereas, Lou et al (1992) found 9

PAGE 19

that women who experience severe stressful events during pregnancy showed a 50% increase in marked premature delivery (prior to 34 weeks). Recent data on social support during pregnancy is consistent with these results. In a study by Feldman et al. (2000), pregnant women who reported more social support in their lives gave birth to babies who weighed more. Moreover, Rini (1999) and colleagues confirmed that women with stronger resources had higher birth weight babies, whereas those reporting more stress had shorter gestations. The amount of resources available to the women were also associated with lower stress, such as being married, being White, and a having higher income and education. Animal research also indicates that offspring whose mother was exposed to acute stressors during pregnancy (e.g., electric shock, heat, light, restraint, and unpredictable noise) versus controls exhibit long-term changes in behavior and HP A axis regulation. Prenatally stressed animals show inhibited, anxious and fearful behavior throughout their lifespan. It is hypothesized that this is a result of excessive levels of endogenous arousal (Takahashi & Kalin, 1991; Glover & O'Connor, 2002). Moreover, the offspring of rats exposed to an acute stressor during pregnancy compared to offspring of nonstressed controls also had elevated ACTH stress responses as preweanlings (Takahashi & Kalin) and have increased stress-induced corticosterone secretion as adults (Vallee, Mayo, Dellu, Le Moal, Simon, & Maccari, 10

PAGE 20

1997). These findings indicate that experienced-based alterations in maternal physiology are sufficient to influence fetal and post-birth development. Depression and Pregnancy Recent research has also begun to explore the effects of prenatal depression on infant development. There is evidence that major depression is accompanied by an activation of the inflaInmatory response system, as indicated by signs of increased serum and urinary concentrations of neopterin, increased number of leukocytes, neutrophils and activated T cells. There is also in vitro immunosuppression characterized by decreased mitogen-induced lymphocyte proliferation and blunted NK-cell activity. In addition, there is an increase in the secretion ofproinfiammatory cytokines, such as IL-l, IL-6 and INF-a as well as cytokine receptors or receptor antagonists (Maes, Ombelet, De Jongh, Kenis, & Bosman, 2001). Overall, it is believed that the response of IL-6 and slL-l RA following delivery are amplified in women who previously suffered from major depression. This suggests that major depression is accompanied by the sensitization of the inflammatory response system. Furthennore, 1NF-a, IL-l, IL-6 and LIF, either alone or in conjunction with components of the stress system and the classic stress honnones, induces symptoms 11

PAGE 21

very similar to those manifested during depression such as fever, sleepiness, fatigue, loss of appetite and decreased libido (Miller, 1998). In a study of pregnant women's anxiety and depression, Ponirakis and colleagues (1998) found that elevated levels of anxiety and depression during pregnancy predicted reduced infant heart rate variability (HRV)-a noninvasive index of cardiac autonomic modulation linked in children and adults to differences in affect regulation (Monk, Fifer, Myers, Sloan, Trien, & Hurtado, 1999). Babies of mothers who report depressive symptomatology at the time of the child's birth have lower motor tone and endurance, are less active, less robust, and more irritable on neurobehavioral exam (Abrams, Field, Scafidi, & Prodromidis, 1995). Furthermore, depressive symptoms, measured at prenatal intake, were a significant predictor of newborn fussiness and nonsoothability, even after controlling for adverse health behaviors and low socioeconomic status (Zuckerman, Bauchner, Parker, & Cabral, 1990). In another study, maternal depression, which was characterized by elevated norepinephrine and cortisol, and reduced dopamine levels assessed during the third trimester of the pregnancy predicted newborns' elevated norepinephrine and cortisol levels as well as inferior orienting and reflex skills (Lundy, Jones,Field, Nearing, Davalos, Pietro, 1999). However, it is still not know whether mood disturbance has any adverse effect on fetal growth or the duration of gestation. Among well-designed studies using 12 -,

PAGE 22

general population samples, most have found no association (Brooke, Anderson, Bland, Peacock, & Stewart, 1989; Nordentoft, Lou, Hansen, Nim, Pryds, Rubin, 1996; Peacock, Bland, & Anderson, 1995). There was a moderate relationship between elevated distress scores and preterm delivery in one large population-based study in Denmark (Hedegaard, Henricksen, Sabroe, & Secher, 1993), but no relationship between elevated scores and fetal growth retardation (Hedegaard, Henricksen, Sabroe, & Secher, 1996). In studies that used measures more specific to depressive symptoms on general populations no association with adverse pregnancy outcomes were found (Copper, Goldenberg, Das, Elder, Swain, Norman, 1996; Jacobsen, Schei, & Hoffman, 1997). It is also important to note that depressed women often take poor care of themselves and participate in adverse health behaviors (Zuckerman, Amaro, Bauchner, & Cabral, 1989). Depressed pregnant women have a higher likelihood of smoking cigarettes and using toxic substances, such as alcohol and cocaine (Zuckerman, Amaro, Bauchner, & Cabral et al.). These substances may be important mediators of the effects of psychological stress on low birth weight and prematurity in the infant (ponirakis, Susman, & Stifter, 1998). Depressed pregnant mothers also may experience weight loss and poor appetite. The effects of inadequate weight gain increases the risk of giving birth to a low-birth-weight infant, having a preterm birth delivery, and having a small for gestational age infant (Steer, Scholl, Hediger, & 13

PAGE 23

Fischer, 1992; Hedegaard, Henricksen, Sabroe, & Secher, 1993). Although the specific mechanism involved in the direct or indirect effects of depression during pregnancy and infant outcomes are unknown, the conclusions are the same across numerous studies depression is related to negative effects on immune functioning during pregnancy as well as poor infant outcomes. Relevance Taken together, this emerging body of work suggests that heightened levels of stress, anxiety, and depression during pregnancy are associated with poor iniIllune functioning. This ultimately can alter infant neurobehavioral development and have negative long-tenn effects on the behavioral and emotional development of the infant, by extension; these alterations arose and can be detected in the fetal period. This is important to note because low-birth weight infants are at higher risk for morbidity and rehospitalization during the first year oflife (Feldman, Dunkel-Schetter, Sandman, & Wadhwa, 2000). In addition, recent studies have shown that reduced fetal growth predicts the development of hypertension, coronary heart disease, and non-insulin-dependent diabetes in adulthood (Erickson, Thorsen Chrousos, Grigoriadis, Khongsaly, McGregor, et aI., 2001; Field, 1995; Monk, 2001). Thus it is important to examine the relationship between stress, depression and immune function during the prenatal period in order to effectively introduce interventions that 14

PAGE 24

improve the rate of detection of maternal disturbances as well as facilitate treatment options that could potentially impact neonatal and infant outcomes in a positive manner. This is especially critical since recent investigations have found that psychiatric disorders and stress related complications are under recognized and under treated by obstetric providers (Kelly, Russo, & Katon, 2001). 15

PAGE 25

CHAPTER 2 METHODS Subjects The sample consisted of 34 pregnant and 24 non-pregnant women. The complete samples of pregnant and nonpregnant women were equivalent in their demographic characteristics and composition. The women ranged in age from 23 to 37 years of age (M= 30.82) in the pregnant group and 23 to 39 years of age in the nonpregnant group (M= 28.37). Eighty-eight percent of the pregnant sample were married whereas, only 42% pfthe nonpregnant sample were married. Both samples were predominately Caucasian and the average number of years educated for both groups was 18 years. Almost all of the women from both samples were employed either part or full time. The subjects were recruited through an e-mail advertisement issued through the University of Colorado internet Inclusion criteria for pregnant women were that subjects were primiparous, healthy, and without chronic conditions predisposing to preclampsia such as renal disease, diabetes or obesity. Pregnant women were asked to participate at any time from the first through the third trimester, non-pregnant women were asked to participate only once. The women were assessed during early pregnancy [less than or equal to 16 weeks gestation (first trimester)], the second trimester, and/or the third trimester of pregnancy. 16

PAGE 26

Table 2.1 presents selected demographic variables for the two groups, pregnant and non-pregnant. There was little difference between the two groups except for the high number of women married in the pregnant group as opposed to the non-pregnant group. Table 2.1 Demographic Characteristics of Samples Pregnant women Non-pregnant women n =34 N=24 Maternal age 30.82 28.38 Marital status 88% married (30) 42% married (l0) 9% unmarried (3) 58% unmarried (14) 3 % divorced (1) Race 76% Caucasian (26) 92% Caucasian (22) 3% African American (1) 4% Asian (1) 12% Hispanic (3) 4% Hispanic (1) 6% Other (2) Years of 17.71 18.08 education Employment 18% Employed, part time 8% Employed, part time status 76% Employed, full time 84% Employed, full-time Within the pregnant sample, seventeen women (50%) provided data for only one trimester, 12 (35%) had data collected during multiple trimesters, and five women (15%) had data collected during all three trimesters. 17

PAGE 27

Procedures The women were asked to complete several self-reported measures that obtained information on demographics, social support, stress level and daily hassles as well as a depression inventory. They were also asked to give two samples of blood to be immediately processed at the University of Colorado at Denver's lab. One sample was collected into sodium heparin-coated Vacutainer for the leukocyte extreaction procedure and the other sample was collected in a non-heparinized tube for serum extraction. Blood samples collected in non-heparinized tubes were allowed to clot at room temperature for 30 minutes after collection. Samples were then centrifuged and 0.5 ml aliquots of serum were frozen at -700 C until analysis. All blood samples were processed within two hours of collection to assure cell viability and consistency of processing. Cytokine Assessments Levels of1NF-a, IL-6, IL-4, and IL-I0 in serum were determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits (Biosource Europe). Undiluted serum samples were tested in duplicate and according to the directions provided by the manufacturer. Optical density at 450 nm was assessed using an automatic micro plate reader (Biotek 310), and the amount of cytokine in each sample was determined using the standard curve generated with each 18

PAGE 28

assay according to the manufacturer's instruction. Detection limits for the assays were.1 pg/ml for TNF-a, .104 pg/ml for IL-6,.1 pg/ml for IL-4, and.2 pg/ml for IL10. The mean of the duplicates was used as the unit of analysis for statistical evaluation of these data. To facilitate statistical analysis, cytokine values for this timepoint for this subject were estimated using a computerized program for replacement of missing values based on the mean of other values in that experimental group for each dependent variable. Maternal Emotionality Measures Measurement of Stress Coussons Read developed and validated an assessment tool that measures stress, social support, and self-efficacy. The self-reported questionnaire includes validation scales and items that assure reliability and validity of the instrument. The questionnaire is based upon the Meikle, Orleans, Leff, Shain, & Gibbs assessment tool (1995). The DMHA differs from the original measure in that it includes stress factors and can be administered in a short period of time. DMHA provides demographic information, current health status, measures of family environment, social support, daily hassles, stressors and self efficacy. The main purpose ofthe measure is to assess the participants' levels of stress using a Life Stress subscale. 19

PAGE 29

This subscale includes items that focus on personal habits, time constraints, work, money, and relationships with partner and family. Items on the Life Stresses subscales use a 7-point Likert scale, with responses ranging from not a stress at all to major stress. Participants could also endorse the does not apply response, which excluded the item from the analysis. The Social Readjustment Rating Scale (SRR scale) has been used to measure the convergent validity of the DMHA's ability to I assess life stress, Life Stresses subscale. The SRR scale has been used for over 30 I I years, and has been shown to be a valid and reliable instrument. Women's responses to each item were entered into a spreadsheet (Excel), and each item response was assigned a numerical value Higher scores were indicative of more of the construct being tested. Thus, whereas a score of 4 on items relating to quality of relationships indicated more social support than a score of 1 on these items, scores of 4 on the stress items indicated more stress caused by given events than a score of 1. The sum of scores for items in each section is computed to provide a support core,a stress score, and a self-efficacy score of each woman. Thus, three DHMA scores were generated for each woman each time she took the survey. Higher total scores of the support portion of the DHMA indicate more social support, higher scores on the stress portion indicate more psychosocial stress, and higher scores on the self-efficacy portion represent higher self-efficacy and better coping skills. 20

PAGE 30

Measurement of Depression Depressive symptoms were measured using the Center for Epidemiological Studies Depression Scale (CES -D; Radloff, 1977), a 20 item screening instrument tapping symptoms in the previous week. Scores can range from 0 to 60, with the cutpoint of 16 generally used to indicate clinically significant elevations (Weissman, Sholomskas, Pottenger, Prussoff, & Locke, 1977). Because some symptoms of pregnancy may be indistinguishable from somatic manifestations of depression (Huffman, Lamour, Bryan, & Pederson, 19990: Klein & Essex, 1994/1995) and standard scores for pregnant women are unavailable, 4 items from the scale, 2 items assessing fatigue, and 1 each assessing loss of appetite and difficulty sleeping) were excluded. These pregnancy modified scores were proportionally reinflated using the equation [ (original CES -D -4 items) x 1.25 = new CES D] so the standard cutpoint of 16 could be applied (Hoffman & Hatch, 2000). The range of original scores was 1 to 20; that of the pregnancy-modified scores, 0 to 17; and that of the reinflated scores, 0 to 20. To evaluate whether this adjustment influenced the results, we repeated analyses with original scores. Statistical Treatment of Data All statistical assessments were made using a computerized program for data analysis (SPSS, SPSS Inc.). Demographic variables were analyzed using a 21

PAGE 31

multivariate analysis of variance (ANOV A) in which DEPRESSION, STRESS, SOCIAL SUPPORT, SELF-EFFICACY, IL-6, IL-4, IL-lO, AND TNF-a were the variables of interest. ANOV As were conducted in which the within-subjects factor was the TRIMESTER of pregnancy when the sample was taken (first, second or third) and the between-subject factor was PREGNANCY (pregnant vs. nonpregnant). Variables were then analyzed using a correlation matrix in which DEPRESSION, STRESS, SOCIAL SUPPORT, IL-6, IL-4, IL-IO, AND TNF-a were the variables of interest. The data was collapsed across the three trimesters to compensate for missing data within each trimester. Planned contrasts were conducted when the correlation indicated that it was appropriate and when they were supported by a priori hypotheses. The significance level for all statistical tests conducted was set at 0.05. The results were then collapsed and a correlational matrix was run to better establish the relationship between the numerous variables. 22 ..

PAGE 32

CHAPTER 3 Results Analysis of the demographic data indicated that there were no differences in demographic variables between the pregnant and non-pregnant samples, except that significantly more women were married in the pregnant sample then the nonpregnant sample. An analysis of variance (ANOVAs) of psychosocial stress and pregnancy revealed significant group differences [F (1,57) = 28.335, p< .000]. The means for the pregnant group was M = 21.09 and M = 36.40 for the non-pregnant group. Therefore, women who were pregnant reported lower psychosocial stress in their dayto-day lives than women who were not pregnant. Figure 3.1 Pregnant Women Report Less Stress 50 40 -w U) 30 tJ en en 20 ... U) 10 Pregnant Women Report Less Stres. s 0 ....... ---Pregnant Non-Pregnant 23

PAGE 33

Pregnant women were also found to report less depressive symptomatology than non-pregnant women. The means for pregnant women were M = 4.49 and M = 5.52 for non-pregnant women. Figure 3.2 Pregnant Women Report Less Depression Pregnant Women Report Less Depression 7 -6 w en .I 5 QI I-0 4 () en c 3 0 CIt CIt QI 2 l-e.. QI 0 1 0 Pregnant Non-Pregnant However, pregnant women were found to report lower levels of social support than non-pregnant women. The means of the two groups were M = 7.85 for pregnant women and M = 11.56 for non-pregnant women [F (1, 57) = 11.12, p < .002]. 24

PAGE 34

Figure 3.3 Pregnant Women Report Less Social Support Pregnant Women Report Less Support 14 12 10 w VI =tJ 8 0 6 rn 4 2 0 Pregnant Non-Pregnant Overall, pregnant women reported less psychosocial stress and depressive symptomatology than their non-pregnant counterparts. However, they did report lower levels of perceived social support than the non-pregnant sample. After examining the difference between pregnant and non-pregnant samples it was thought to be an unrealistic comparison due to the enormous changes that occur during the prenatal period. Therefore, the data was collapsed and correlational analyses were conducted to determine if there were any associations between any of the dependent measures assessed. As previously mentioned, the three DHMA scores 25

PAGE 35

were generated for each woman: social support, psychosocial stress, and self-efficacy. All three-stress measures were found to significantly correlated. Social support was positively related to psychosocial stress r = 598, p< .01. Coping, the third component of the inventory, was also positively correlated to psychosocial stress as well as social support, r = .802, p< .01, and r = .766, p< .01, respectively. This further validates the DHMA measure by exemplifying the interaction that exists between the three measures. Figure 3.4 Social Support is Positively Related to Stress Social Support is Positively Related to Stress 18 16 .. 14 IV 12 I-0 fA 10 1:: 0 8 Q. Q. :::J 6 fA 4 2 0 5 10 15 20 25 30 35 40 45 Stress Score 26

PAGE 36

, A significant correlation was also found to exist between depression and psychosocial stress, r = .432, p< .01. This correlation was not surprising given the established theoretical relationship between these two variables from previous studies. Figure 3.5 Depression Scores Positively Related to Stress Depression Scores are Positively Related to Stress 10 8 c V) w u 6 "0 !E 4 '0 0 :E 2 0 5 10 15 20 25 30 35 40 45 Stres s Sc ore More importantly, a positive correlation was found to exist between IL-6 cytokine production and psychosocial stress, r = .392; p< .05. 27

PAGE 37

Figure 3.6 Increased IL6 Cytokine Production Correlated With Stress 0.4 0.35 0.3 0.25 0.2 0.15 0.1 0.05 o 20 .. '..30 .6 .... .. I 40 Stress ... ...... ... 50 60 IL-6 was also found to be positively correlated with a pregnant women's selfreported score on the CES-D, r = .333, p<.05. ,Figure 3.7 Increased IL6 Cytokine Production Correlated With Depression 0.4 0.35 0.3 .. 0.25 CD 0.2 ...J 0.15 0.1 .... .' ....... .... 0.05 0 o 5 10 15 20 25 30 Depression Taken together, these two correlations show that women who report high levels of psychosocial stress and depression are more likely to produce higher levels of the IL-28

PAGE 38

6 proinflammatory cytokine. There was also a positive correlation between IL-4 and IL-IO production within the pregnant women studied, r = .539. This was an expected result, since production of both cytokines normally increases during pregnancy. A negative correlation was found between the amount of social stress and IL-I 0 production, r = -.297. Women who reported higher amounts of social support produced less IL-I 0 cytokines. 29

PAGE 39

CHAPTER 4 Discussion The goal of this study was to examine the relationships among psychosocial stress, depression and cytokine production during the prenatal period. It was hypothesized that women reporting higher levels of prenatal stress and lower social support during pregnancy would also exhibit more depressive symptoms, and that these factors would be related to higher levels of proinflammatory cytokines in maternal circulation. Data indicated significant differences between the experience of psychosocial stress, social support and depression between pregnant and non pregnant women, and a trend toward significant relationships among these factors and cytokine levels in pregnant women was observed. Moreover, specific variables were more strongly related to certain components of stress, providing further support for the transactional conceptualization of stress and the need to include several measures to fully capture the pregnancy experience. Previous studies have shown that various maternal psychosocial characteristics such as stress, depression, self-efficacy, and poor social support increase a woman's risk for low birth weight and pregnancy complications (Copper, Goldenberg, Das, Elder, Swain, Norman, G. et al., 1996; Da Costa, Larouche, Drista, & Brender, 2000; Hedegaard, Henriksen, Secher, Hatch, & Sabroe, 1996; Lou, 30

PAGE 40

Nordentoft, & Jensen, 1992; Wadhwa, Sandman, Porto, Dunkel-Schetter, & Garite, 1993). Although some studies have shown minimal effects of prenatal stress on pregnancy (Brooke, Anderson, Bland, Peacock, & Stewart, 1989), the majority of studies show that stress experienced throughout pregnancy can negatively affect pregnancy and infant outcomes. For example, Carmichael and Shaw (2000) noted that significant stress around conception (e.g., death of a loved one, divorce) resulted in greater chances of delivering an infant with conotruncal heart defects, neural tube defects, and isolated cleflip. Glynn et al. (2001) found that trauma from an earthquake had a greater negative effect on gestational length if experienced earlier in the pregnancy. Several investigators have shown-that stress experienced later in pregnancy is related to lower birth weights, reduced gestational length, and preterm labor and delivery (Groome, Swiber, Bentz, Holland, & Atterbury, 1995; Wadhwa, Porto, Garite, Chicz-DeMet, & Sandman, 1998). Moreover, infants of stressed pregnancies have higher rates of childhood allergies and asthma, and perinatal stress appears to contribute to respiratory illness in infancy (Monk, 2001). In this study we used several tools that simultaneously addressed numerous components of psychosocial stress by combining elements that had previously been examined separately. It was hoped a more comprehensive and accurate picture of what contributes to poor immune function during pregnancy would result. Due to this approach an interesting picture emerged; stress was positively associated to both, 31

PAGE 41

psychosocial stress and depression. More importantly, increased production of IL-6 was also positively correlated to both variables. These analyses provide further evidence for an emerging pattern of results linking multidimensional measures of prenatal stress, and now depression, to poor immune functioning. This is significant since increased production of IL-6 has been linked with contributing to higher levels of plasma cortisol and CRH prior to the onset of labor (Erickson, Thorsen, Chrousos, Grigoriadis, Khongsaly, McGregor, et al., 2001). CRH and cortisol have also been implicated in the suppression of the immune system, which may lead to infections that increase the risk of pre term labor (Wadhwa, Porto, Garite, Chicz-DeMet & Sandman, 1998) and contribute to the onset ofpreclampsia in response to infection (Zhang, Wang, Zhao, & Kang, 2000). However, 1NF-a, which is also associated with these phenomena, was not found to be elevated. Therefore, it is uncertain as to the extent IL-6 alone could trigger these results. Further research needs to be done in this area. Increased production of IL-6 has also been associated with depression. Maes and colleagues (2001) found that women who previously suffered from major depression had increased levels of the IL-6, proinflammatory cytokine. This increased production, in conjunction with stress hormones, can induce symptoms similar to depression. It is believed that increased stress can activate the release of pro inflammatory cytokines. This is important because proinflarnmatory cytokines 32

PAGE 42

stimulate HPA activity, alter glucocorticoids receptor function and alter monoamine neurotransmission in the eNS (Miller, 1998). Again, it wise to interpret these results cautiously because no other proinflammatory cytokine was found to be significant. Overall, IL-6 is strongly associated with not only depression, but also with premature labor, stress, and preeclampsia. This is significant for pregnant women because the effects of psychosocial stress and depression, alone or together, can negatively affect fetal development and can lead to poor birth outcomes by stimulating increased production of IL-6. Therefore, major depression could induce an increase in pro inflammatory response due to the stresses associated with childbirth (Maes, Ombelet, De Jongh, Kenis, & Bosman, 2001). This bi-directionalloop is important to recognize due the tremendous impact it has on the both, the mother and the developing fetus. Hoffman et al (2000) note that increases in IL-6 production might also contribute to retarded fetal growth through a catecholamine-mediated decrease in placental perfusion Many of the variables we believed would be significant, such as increased reporting of depressive symptomatology as well as increased psychosocial stress during the prenatal period, were low. There are several factors that could have contributed to these results. First, the population sampled was unique. The women who participated in this study had several skewed sociodemographic variables. For example, they were exceptionally well educated, came from a higher SES, were 33

PAGE 43

employed, predominantly married, and Caucasian. All of these factors have been found to significantly lower a woman's risk for developing complications during pregnancy (Feldman, Dunkel-Schetter, Sandman, & Wadhwa, 2000). Moreover, these numerous variables reduce a woman's stress level, thereby lowering her risk for prenatal depression and increase immune function. Women that are well educated as well as married have greater access to social and dispositional (e.g., mastery, optimism, and self-esteem) resources during pregnancy and in turn have better birth outcomes (Da Costa, Larouche, Dritsa, & Brender, 1999). These factors may have influenced the results in an unexpected manner. Studies have shown that women of lower SES are at increased risk for lower birth weight as well as having a propensity to participate in adverse health behaviors (Cunningham, 2002). It has also been found that women with less education and lower incomes had fewer personal resources, which predicted less fetal growth compared with women with more education and higher incomes (Rini, Dunkel Schetter, Wadhwa, & Sandman, 1999). African American and Hispanic women are at high risk of depression and postpartum parenting problems in contrast to Caucasian women (Cunningham). Lastly, Ponirakis and colleagues (1998) found that pregnant adolescent women had higher concentrations of cortisol and gave birth to infants that scored lower on responsivity measures as well as had an increased need for resuscitation measures to be performed on the infant. 34

PAGE 44

Women from a higher SES may face different types of stressors than our inventory measured. Given that these women were recruited from a research, hospital-based community, they may have realized what was being asked of them and gave responses that placed them in the best possible light. Although these women did not claim to be significantly depressed or to suffer from the effects of psychosocial stress, they did have elevated levels of IL-6 in their blood. Perhaps, what these women view as stress may be different then what was being measured. Our results indicate that overall, a higher self-reported depression score was associated with higher levels of perceived psychosocial stress. This highlights the complex interaction the two factors play in contributing to the negative progression of the other. Secondly, the greater the amounts of perceived social support the lower their self-reported psychosocial stress scores. Interestingly, pregnant women in our sample reported lower levels of stress as well as depressive symptomatology than non-pregnant women. This manifestation could reflect changes in overall perception of what 'stressful' may mean to them. As previously mentioned, women within this sample were well-educated and currently employed. They also all had health insurance, which may have contributed to a lower stress score. Also, it is very likely that a majority of the pregnancies within this sample were planned, and not unexpected. 35

PAGE 45

Pregnant women did, however, report lower levels of perceived social support then non-pregnant women. This could reflect changes in perception and the realization of upcoming changes in lifestyle and demands. Women within this sample could believe that their partner needs to provide more support then they had in the past. This factor could also be a sign of marital discord, as women who are more adjusted in their relationship may be getting more support from their partner, which serves to reduce stress (Brown, 1994). There is some evidence from this study to suggest that the effect of marital adjustment is more likely related to its supportive role rather than as a stressor. However, caution should be used when interpreting the role of marital adjustment as a predictor of lower reported social support scores. The inclusion of a measure assessing women's perceptions of support in various domains by the partner would be necessary to untangle this complicated relationship. Some limitations of this study must be acknowledged. The trimester subgroups were too small to be examined separately, a larger sample size would allow for differences between the trimesters to emerge and should be tested in the future. Also, the sample size limited the ability to detect relationships with dichotomous clinical outcome variables, which would be important to observe for the purposes of risk assessment and intervention. The present findings indicate that research on the effects of maternal depression and stress and intervention techniques need to begin during the prenatal 36

PAGE 46

period. Determining early predictors of women at risk of experiencing high levels of psychosocial stress as well as depression during pregnancy would allow us to identify women early in the pregnancy that may benefit from cost-effective interventions aimed at reducing stress. Women that are more depressed and stress during pregnancy would most likely experience this postpartum as well. Da Costa and colleagues (2000) found that the best predictor of postpartum depressed mood was prepartum depressed mood. It is believed that almost 25% of cases of postpartum depression start during pregnancy (Evans, Heron, Francomb, Oke, & Golding, 2001). Women who are depressed take poor care of themselves as well as the child and this in turn can lead to problems bonding with the child and could create developmental delays (Evans, 2001). This is an important area of research to explore and the component of depression should not be overlooked. 37

PAGE 47

REFERENCES Abrams, S. M., Field, T., Scafidi, F., & Prodromidis, M. (1995). Maternal "depression" effects on infants' Brazelton Scale performance. Infant Mental Health Journal, 16, 231-235. Baum, A. & Posluuszny, D. (1999). Health psychology: Mapping biobehavioral contributions to health and illness. American Psychologist, 47, 1597-1611. Ben-Eliyahu, S., Yinniya, R, Liebeskind, J. C., Taylor, A. N., & Gale, R. P. (1991). Stress increases metastatic spread of mammary tumor in rats: Evidence for mediation by the immune system. Brain, Behavior, & Immunity, 5(2), 193205. Benyo, D. F., Miles, T. A., & Conrad, K. P. (1997). Hypoxia stimulates cytokine production by villous explants from the human placenta. The Journal of Clinical Endocrinology and Metabolism, 82(5), 1582-1588. Benyo, D. F., Smarason, A., Redman, C. W., Sims, C., & Conrad, K. P. (2001). Expression of inflammatory cytokine in placentas from women with preclampsia. The Journal of Clinical Endocrinology and 86(6), 2505-2512. Bonneau, R H., Sheridan, J. F., Feng, N. G., & Glaser, R (1991). Stress-induced suppression of herpes simplex virus (HSV)-specific cytotoxic T lymphocyte and natural killer cell activity and enhancement of acute pathogenesis following local HSV infection. Brain, Behavior, & Immunity, 5(2), 170-92. Brooke, O. G., Anderson, H. R, Bland, 1. M., Peacock, 1. L., & Stewart, C. M. (1989). Effects on birth weight of smoking, alcohol, caffeine, socioeconomic factors, and psychosocial stress. British Medical Journal, 298, 795-801. Brown, M. (1994). Marital discord during pregnancy: A family systems approach. Family Systems Medicine, 12, 2221-234. Carmichael, S. L., & Shaw, G. M. (2000). Maternal life event stress and congenital anomalies. Epidemiology, 11, 30 35. 38

PAGE 48

Chrousos, G. P. (1997). Stressors, stress, and neuroendocrine integration of the adaptive response. Annals New York Academy of Sciences, 311-335. Chung, T. K., Lau, T. K., Yip, A. S., Chiu, H. F., & Lee, D. T. (2001) Antepartum depressive symptomatology is associated with adverse obstetric and neonatal outcomes. Psychosomatic Medicine, 63, 830 834. Clark, D. A., Arck, P. C., Jalali, R., Merali, F. S., Manuel, J., Chaouat, G., et al. (1996). Psycho-neuro-cytokine/endocrine pathways in immunoregulation during pregnancy. American Journal of Reproduciive Immunology, 35, 330337. Conrad, K. P., Miles, T. M., & Benyo, D. F. (1998). Circulating levels of immunoreactive cytokine in women with prec1ampsia. American Journal of Reproductive Immunology, 40, "102-111. Copper, R. L., Goldenberg, R. L., Das, A., Elder, N., Swain, M., NOIman, G. et al. (1996). Obstetrics: The preterm prediction study: Maternal stress is associated with spontaneous preterm birth at less than thirty-five weeks' gestation. American Journal of Obstetrics and Gynecology, 175, 5, 1286 -1292. Coussons-Read, M. E., Mazzeo, R. S., Whitford, M. H., Schmitt, M., Moore, L. G., & Zamudio, S. (2003). High altitude residence during pregnancy alters cytokine and catecholamine levels. The American Journal of Reproductive Immunology. Cunningham, M., & Zayas, L. H. (2002). Reducing depression in pregnancy: Designing multimodal interventions. Social Work, 27(2), 114-124. Da Costa, D., Larouche, J., Drista, M., & Brender, W. (1999) Variations in stress levels over the course of pregnancy: Factors associated with elevated hassles, state anxiety and pregnancy-specific stress. Journal of Psychosomatic Research, 47(6), 609-621. Da Costa, D., Larouche, J., Drista, M., & Brender, W. (2000). Psychosocial correlates of prepartum and postpartum depressed mood. Journal of Affective Disorders, 59, 31-40. 39

PAGE 49

Dejin-Karlsson, E., Hanson, B. S., Ostergren, P.O., Lindgren, A., Sjober, N. 0., & Marsal, K. (2000). Association of a lack of psychosocial resources and the risk of giving birth to small for gestational age infants: A stress hypothesis. British Journal of Gynecology, 107(1), 89-100. Dunkel-Schetter, C., Stanton, A. L., & Wadhwa, P. D. (2000). Stress and reproduction: Introduction to the special section. Health Psychology, 19(6), 507 509. Elenkov, I. A., & Chrousos, G. P. (1999). Stress hormones, Th I1Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trend in Endocrinology and Metabolism, 10(9), 359-368. Elenkov, I. A., & Chrousos, G. P. (2002). Stress hormones, pro inflammatory and antiinflammatory cytokines, and autoimmunity. Annals New YorkAcademy of Sciences, 966, 290-303. Erickson, K., Thorsen, P., Chrousos, G., Grigoriadis, D.E., Khongsaly, 0., McGregor, J. et al. (2001). Preterm birth: Associated neuroendocrine, medical, and behavioral risk factors .. The Journal of Clinical Endocrinology and Metabolism, 86(6), 2544-2552. Evans, J., Heron, J., Francomb, H., Oke, S., & Golding,J. (2001). Cohort study of depressed mood during pregnancy and after childbirth. British Medical Journal, 323, 257-260. Feldman, P. J., Dunkel-Schetter, C., Sandman, C. A., & Wadhwa, P. A. (2000). Maternal social support predicts birth weight and fetal growth in human pregnancy. Psychosomatic Medicine, 62, 715 -725. Field, T. (1995). Infants of depressed mothers. Infant Behavior and Development, 18, 1-13. Glaser, R., Rabin, B., Chesney, M., Cohen, S., & Natelson, B. (1999). Stress-induced immunomodulation. Implications for infectious diseases? Journal of American Medical Association, 281(24), 2268-2270. Glover, V. & O'Connor, T. G. (2002). Effects of antenatal stress and anxiety. British Journalo/Psychiatry, 180,389-391. 40

PAGE 50

Glymi, L. M., Wadhwa, P.D., Dunkel-Schetter, C., Chicz-DeMet, A., & Sandman, C. (2001). When stress happens matters: Effects of earthquake timing on stress responsivity in pregnancy. American Journal of Obstetrics and Gynecology, 184(4),637-642. Goland, R S., Jozak, S., Warren, W. B., Conwell, J. M., Stark, R 1., & Tropper, P. J. (1993). Elevated levels of umbilical cord plasma corticotropin-releasing honnone in growth-retarded fetuses. Journal of Clinical Endocrinology and Metabolism, 77, 1174-1179. Goldenberg, R. L., Hauth, J. C., & Andrews, W. W. (2000). Intrauterine infection and preterm delivery. New England Journal of Medicine, 342, 1500-1507. Gomez, R, Ghezzi, F., Romero, R, Munos, H., Tolosa, J. E., & Rojas, 1. (1995). Premature labor and intra-amniotic infection. Clinical aspects and role of the cytokines in diagnosis and pathophysiology. Clinics in Perinatology, 22, 281-342. Groome, L. J., Swiber, M. J., Bentz, L. S., Holland, S. B., & Atterbury, J. L. (1995). Maternal anxiety during pregnancy: Effect on fetal behavior at 38 to 40 weeks of gestation. Developmental and Behavioral Pediatrics, 16(6),391-395. Hedegaard, M., Henriksen, T. B., Sabroe, S., & Secher, N. J. (1993). Psychological distress in pregnancy and increased uterine artery resistance index: Cohort based study. British Medical Journal, 318, 153-157. Hedegaard, M., Henriksen, T. B.,Secher, N: J., Hatch, M. C., & Sabroe, S. (1996). Do stressful life events affect the duration of gestation and risk of preterm delivery? Epidemiology, 7,339-345. Hoffman, S., & Hatch, M. C. (2000). Depressive symptomatology during pregnancy: Evidence for an association with decreased fetal growth in pregnancies of lower social class women. Health Psychology, 19(6), 535 543. Jacobsen, G., Schei, B., & Hoffinan, H. J. (1997). Psychosocial factors for small-for gestational-age infants among scandinavian women. Acta Obstetricia et Gynecologica Scaninavica, 76 (Suppl. 165), 14-20. 41

PAGE 51

Kaplan, A. (1999). Implications of stress, psychosocial factors on the immune system. Psychiatric Times, XVI(10), 1-9. Abstract received October 15,2003, from PsycINFO database. Kelly, R. H., Russo, J., & Katon, W. (2001). Somatic complaints among pregnant women cared for in obstetrics: Nonnal pregnancy or depressive and anxiety symptoms amplification revisited? General Hospital Psychiatry, 23, 107113. Klein, M. H., & Essex, M. J. (1994/1995). Pregnant or depressed? The effect of overlap between symptoms of depression and somatic complaints of pregnancy on rates of major depression in the second trimester. Depression, 2,308-314. Koenker, H. (1994). Stress and the immune system. Retrieved September 18,2003, from http://www.econ.uiuc.edu. Kusnecov, A. V., Grota, L. J., Schmidt, S.G., Bonneau, R H., Sheridan, J. F., Glaser, R, et al. (1992). Decreased herpes simplex viral immunity and enhanced pathogenesis following stressor administration in mice. Journal of Neuroimmunology, 38, 129. Lazarus, R S., & Folkman, S. (1994). Stress, appraisal and coping. New York: Springer. Lobel, M. (1994). Conceptualizations, measurement, and effects of prenatal maternal stress on birth outcomes. Journal of Behavioral Medicine, 17(3), 225-272. Lobel, M., Dunkel-Schetter, C., & Scrimshaw, S. C. (1992). Prenatal maternal stress and prematurity: A prospective study of socioeconomically disadvantaged women Health Psychology, 11, 32-40. Lou, H. C., Nordentoft, M., & Jensen, F. (1992). Psychosocial stress and severe prematurity. Lancet, 340, 54. Lundy, B. L., Jones, N. A., Field, T., Nearing, G., Davalos, M., Pietro, P. A. et al. (1999). Prenatal depression effects on neonates. Infant Behavior & Development, 22(1), 119 129 42

PAGE 52

McCubbin, J. A., Lawson, E. J., Cox, S., Shennan, J. J., Norton, J. A., & Read, J. A. (1996). Prenatal maternal blood pressure response to stress predicts birth weight and gestational age: A preliminary study. American Journal of Obstetrics and Gynecology, 175(3), 706-712. Maes, M., Libbrecht, I., Lin, A., Goossens, F., Ombelet, W., Stevens, K., et al. (2000). Effects of pregnancy and delivery serum prolyl endopeptidase (PEP) activity: Alterations in serum PEP are related to increased anxiety in the early puerperium and to postpartum depression. Journal of Affective Disorders, 57, 125-137. Maes, M., Ombelet, W., De Jongh, R., Kenis, G., & Bosman, E. (2001). The inflammatory response following delivery is amplified in women who previously suffered from major depression, suggesting that major depression is accompanied by a sensitization of the inflammatory response system. Journal of Affective 63, 1-3,85-92. Meikle, T. H., Orleans, M., Leff, M., & Gibbs, S. (1995). Women's reasons for not seeking prenatal care: Racial and ethnic factors. Birth, 22(2), 81-86. Miller, A. H. (1998). Neuroendocrine and immune system interactions in stress and depression. Psychoneuroendocrinology, 21(2), 443-463. Monk, C. (2001). Stress and mood disorders during pregnancy: Implications for child development. Psychiatric Quarterly, 72(4),347-357. Monk, C., Fifer, W. P., Myers, M. M., Sloan, R. P., Trien, L., & Hurtado, A. (1999). Maternal stress responses and anxiety during pregnancy: Effects on fetal heart rate. Developmental Psychobiology, 36, 76-77. Munno, 1., Chiechi, L. M., Lacedra, G., Berardesca, C., Patimo, c., Marcuccio, L., et al. (1999). Evaluation of nonspecific immunity and plasma levels of interferon-gamma, interleukin-6 and tumor necrosis factor-alpha in preclampsia. Immunopharmacology Immunotoxicology, 21, 551-564. Nordentoft, M., Lou, H. C., Hansen, D., Nim, J., Pryds, 0:, Rubin, P., et al. (1996). Intrauterine growth retardation and premature delivery: The influence of maternal smoking and psychosocial factors. American Journal of Public Health, 86, 347-354. 43

PAGE 53

Peacock, J. L., Bland, J. M., & Anderson, H. R. (1995). Pretenn delivery: Effects of socioeconomic factors, psychological stress, smoking, alcohol, and caffeine. British Medical Journal, 311,531-536. Ponirakis, A., Susman, E. J., & Stifter, C. A. (1998). Negative emotionality and cortisol during adolescent pregnancy and its effects on infant health and autonomic nervous system reactivity. Developmental Psychobiology, 33, 163174. Radloff, L. S (1977). The CES-D scale: A self-report depression scale for research in the general population. Journal of Applied Psychological Measures, 1, 385-401. Rini, C. K., Dunkel-Schetter, C., Sandman, C. A., & P. D. (1999). Psychological adaptation and birth outcomes: The role of personal resources, stress, and sociocultural context in pregnancy. Health Psychology, 18(4), 333-345. Rini, C. K., Sandman, C. A., & Wadhwa, P. D. (1999). Psychological adaptation and birth outcomes: The role of personal resources, stress, and sociocultural cOntext in pregnancy. Health Psychology, 18(4),333-345. Sandman, C. A., Wadhwa, P. D., Chicz-DeMet, A., & Dunkel-Schetter, C. (1997). Maternal stress, HP A activity, and fetal/infant outcome. Annals of the New YorkAcademy of Science, 814, 266-275. Sandman, C. A., Wadhwa, P. D., Chicz-DeMet, A., Porto; M., & Garite, T. J. (1999). Maternal corticotropin releasing honnone and habituation in the human fetus. Developmental Psychobiology, 34, 163.,173 Sheridan, J. F., Dobbs, C., Brown, 0.,& Zwilling B. (1994). Psychoneuroimmunology: Stress effects on pathogenesis and immunity during infection. Clinical Microbiology Reviews, 7(2),200-212. Steer, R. A., Scholl, T. 0., Hediger, M. L., & Fischer, R. (1992). Self-reported depression and negative pregnancy outcomes. Journal of Clinical Epidemiology, 45, 1093-1099. 44

PAGE 54

Takahashi, L. K., & Kalin, N. H. (1991). Early developmental and temporal characteristics of stress-induced secretion of pituitary-adrenal hormones in prenatally stress rat pups. Brain Research, 558, 75-78. Teixeira, J. M., Fisk, N. M., & Glover, V. (1999). Association between maternal anxiety in pregnancy and increased uterine artery resistance index based study. British Medical Journal, 318, 153-157. Vallee, M., Mayo, W" Dellu, F., Le Moal, M., Simon, R., & Maccari, S. (1997). Prenatal stress induces high anxiety and postnatal handling induces low anXiety in adult offspring: Correlation with stress-induced corticosterone secretion. The Journal of Neuroscience, 17(7), 2626-2636. Wadhwa, P. D., Dunkel-Schetter, C.,Chicz-DeMet, A., Porto, M., & Sandman, C. A (1996). Prenatal psychosocial factors and the neuroendocrine axis in human pregnancy. Psychosomatic Medicine, 58(5), 432-446. Wadhwa, P. D., Porto, M, Garite, T. J., Chicz-DeMet, A.,& Sandman, C. A. (1998). Maternal corticotropin-releasing hormone levels in the early third trimester predict length of gestation in human pregnancy. American Journal of Obstetrics and Gynecology, 179, 1079-1085. Wadhwa, P. D., Sandman, C. A., Porto, M., Dunkel-Schetter, C., & Garite, T. J (1993). The association between prenatal stress and infant birth weight and gestational age at birth: A prospective investigation. American Journal of Obstetrics and Gynecology, 169, 858-65. Weiss, J. M., & Sundar, S. (1992). Effects of stress on cellular immune responses in animals. Washington, DC: American Psychiatric Press, Inc. Zhang, W., Wang, L., Zhao, Y., & Kang, J. (2000). Changes in cytokine (lL-8, IL-6, and 1NF-a) levels in the amniotic fluid and maternal serum in patients with premature rupture of membranes. Chung Hua 1 Hsueeh Tsa Chih (Taipei), 63,311-315. Zuckerman, B., Amorao, H., Bauchner, R., & Cabral, H. (1989). Depressive symptoms during pregnancy: Relationship to poor health behaviors. American Journal of Obstetric Gynecology, 160, 1107-1111. 45

PAGE 55

Zuckennan, B., Bauchner, H., Parker, S., & Cabral, H. (1990). Maternal depressive symptoms during pregnancy and newborn irritability. Journal of Developmental Behavioral Pediatrics, 11, 190-194. 46