Markers of Inflammation in Midlife Women
with Intimate Partner Violence Histories
Tamara L. Newton, Ph.D.,1Rafael Fernandez-Botran, Ph.D.,2James J. Miller, Ph.D.,2
Douglas J. Lorenz, Ph.D.,3Vicki Ellison Burns, Ph.D.,4,5and Kimberly N. Fleming, B.A.1
Background: Lifetime occurrence of intimate partner violence (IPV) in women has been associated with in-
creased prevalence of aging-related chronic diseases, including those with a pathophysiology involving in-
flammation. To begin to identify potential biologic mediators of this relationship, this cross-sectional study
examined associations between past IPV and circulating levels of C-reactive protein (CRP) and interleukin-6
(IL-6)—measures linked with emergence of aging-related diseases—along with in vitro IL-6 production by
peripheral blood mononuclear cells (PBMC) stimulated with either phytohemagglutinin A (PHA) or lipopoly-
Methods: Apparently healthy, midlife women with divorce histories were recruited from the community.
Histories of intimate partner psychological aggression, physical assault, sexual coercion, and stalking were
assessed, along with current depression, posttraumatic stress symptoms, and health-related characteristics. At
two visits, blood was drawn for assessment of biologic measures; measures were averaged across visits.
multiple regression analysis that included body mass index (BMI) and current symptoms, this association was
attenuated by adjusting for BMI. Physical assault history was significantly negatively correlated with PHA-stimu-
lated IL-6 production. This was most apparent for severe assault and was not accounted for by BMI or symptoms.
Conclusions: IPV histories remitted for an average of 10 years were associated with biologic mediators of
inflammation. The profile was not uniformly proinflammatory, suggesting that in situations of traumatic or
chronic stress, different aspects of the inflammatory response are differentially regulated and subjected to
diverse compensatory mechanisms.
physical or sexual violence or threat of such violence between
current or former spouses or intimate partners. Acts of psy-
chological aggression and emotional maltreatment also
comprise IPV, particularly when there has been a history of
threats or physical or sexual aggression in a relationship.1
Women’s lifetime IPV rates sampled from 10 nations range
from 15% (Japan) to 71% (Ethiopia), with a rate of 25% in the
United States.2,3Compared with other examples of interper-
sonal victimization, such as a physical assault by a stranger,
the assaultive and aggressive acts in situations of IPV can
sometimes occur repeatedly over years. These acts may cause
ntimate partner violence (IPV), as defined by the Cen-
ters for Disease Control and Prevention (CDC), involves
injury, fear, and perceived life threat, the elements of trau-
matic stress. Further, between occurrences of discrete ag-
gressive incidents, a context of fear may persist. Thus, as a
stressor, IPV can be both chronic and traumatic.4In data from
a nationally representative U.S. sample, for example, two
thirds of women physically assaulted by an intimate partner
reported an average of 6.9 assaultive acts over 4.5 years.3In
a survey of female enrollees of a U.S. health maintenance
organization, nearly 50% reported ‡6 years of psychological
Two population-based, cross-sectional studies reveal the
significance of IPV for women’s health. Lifetime IPV occur-
rence predicted elevated prevalence of aging-related chronic
medical conditions, including conditions where the patho-
physiology involves inflammation (e.g., heart disease, stroke,
1Department of Psychological and Brain Sciences,2Department of Pathology and Laboratory Medicine,3School of Public Health and
Information Sciences, and4School of Nursing, University of Louisville, Kentucky.
5Present address: Lansing School of Nursing and Health Sciences, Bellarmine University, Louisville, Kentucky.
JOURNAL OF WOMEN’S HEALTH
Volume 20, Number 12, 2011
ª Mary Ann Liebert, Inc.
cancer, joint disease). These associations held after adjusting
for demographic and behavioral risks6and after establishing
the temporal precedence of IPV by excluding women for
whom disease onset preceded IPV.7
for a relative with dementia), there have been few efforts to
identify biologic mediators connecting IPV and poorer health.
cytokine interferon-c (IFN-c), an early mediator of the im-
munologic process that promotes inflammation.8IFN-c pro-
duction was significantly greater in a group comprising
women who reported either past or present partner violence,
compared to women reporting no abuse. This association was
fully mediated by current posttraumatic stress disorder
(PTSD) symptoms that were largely comorbid with depres-
sion. The present study approaches this problem by focusing
exclusively on women with past IPV and by considering the
biologic measures C-reactive protein (CRP) and interleukin-6
Although neither CRP nor IL-6 has been examined within
the context of IPV, both could plausibly contribute to its as-
sociation with multiple chronic conditions. CRP and IL-6 are
biologically linked, but they have distinct functions. CRP is
classified as an acute-phase protein; it assists in the recogni-
tion and elimination of pathogens and damaged cells9and is
widely used to index systemic inflammation. IL-6 is a cyto-
kine, a protein that facilitates communication between cells. It
stimulates CRP synthesis and is, therefore, generally consid-
ered proinflammatory, but it also has anti-inflammatory
properties.10,11Although there are exceptions,12some pro-
spective studies of apparently healthy persons reveal that el-
evated IL-6 and CRP circulating levels predict emergence of
multiple aging-related chronic conditions and mortality.13–15
Circulating CRP and IL-6 levels are also stress reactive. For
example, CRP and IL-6 elevations have been shown to ac-
and caregiving for a relative with dementia,17although again
there are exceptions.18,19The stress-reactive quality of IL-6
and CRP is consistent with data showing that key biologic
stress mediators, glucocorticoids and catecholamines, influ-
ence cytokine production.20Despite having some shared
correlates and despite being biologically linked, IL-6 and CRP
sometimes independently predict health risk,21and other
times they show divergent associations with both health
Especially pertinent to the present study is evidence that
chronic stress, even after it has remitted, is associated with
accelerated age-related increases in circulating IL-6.17Despite
daunting obstacles, many women leave violent relationships.
Paradoxically, violence sometimes continues or escalates after
separation.3,23This threat intensification, combined with the
possibility of enduring biologic consequences of remitted
chronic stress, underscores the relevance of research with
women who have experienced past IPV.
Accordingly, the present study evaluated CRP and IL-6
levels in women with histories of divorce or separation. All
women, midlife and postmenopausal, were at a biologic
transition characterized by increased risk for aging-related
chronic diseases. A prior report on this sample focused on
relations among circulating inflammatory mediators from
multiple biologic fluids.24CRP levels were higher among
women with histories of IPV (defined as one or more severe
instances of physical assault or sexual coercion) compared to
those without. The present article extends this prior report in
First, specific IPV types—physical assault, sexual coercion,
stalking, and psychological aggression—are the focus here.
The impetus for this is the multidimensional nature of IPV
and evidence from preclinical research for stressor-specific
biologic correlates.25This exploratory aim is designed to
move beyond a global, dichotomous measure of IPV and
generate new information about IPV types potentially most
relevant for biologic mediators of inflammation.
Second, in addition to CRP and IL-6 circulating levels,
which are products of multiple cell types, this article reports
on in vitro IL-6 production by stimulated peripheral blood
mononuclear cells (PBMCs), a model of the capacity of im-
mune system cells to produce IL-6 when challenged. To our
knowledge, this has not been evaluated in the context of re-
mitted chronic stress, but ongoing interpersonal stressors
persistent for 1–6 months show positive associations with
stimulated IL-6 production from PBMCs or whole blood.18,26
Third, this article evaluates whether relations between past
IPV and biologic measures are accounted for by current
symptoms of depression and PTSD. Symptoms of both dis-
production and IL-6 and CRP circulating levels in some
studies.27–30Despite this and despite the fact that such
symptoms arise in the context of life stressors, very few
studies of IL-6 and CRP have addressed stressors and
symptoms simultaneously.28,31,32In addition to its conceptual
advantages, this approach has practical relevance because
associations with symptoms could suggest potential avenues
Materials and Methods
Participant recruitment and selection
Mailings and community advertisements recruited women
ever divorced or separated from a stressful relationship. In-
clusion criteria were history of divorce or permanent sepa-
ration from a cohabitating partner, age (between 45 and 60),
and postmenopausal status (12-month cessation of menses
and follicle-stimulating hormone [FSH] levels ‡25 mIU/mL).
Exclusion criteria were absence of English language skills,
ongoing divorce-related legal issues, psychiatric hospitaliza-
tioninthepreceding 6 months,activesuicidalideation,current
IPV (IPV involving an ex-partner in the preceding year or any
IPV history with a current partner, defined by a score >1 on
three-item STaT33[slapped, threatened, and throw things]),
chronic disease other than unmedicated hypertension evi-
denced by self-report or eligibility laboratory tests, use of
prescription or over-the-counter (OTC) medications with in-
flammatory effects (including psychotropics and botanicals),
of street drugs evidenced by self-report (‡5 on the derived
Alcohol Use Disorders Identification Test [AUDIT-C] for
alcohol use disorders34) or eligibility laboratory tests.
A phone interview assessed initial inclusion and exclusion
criteria. Eligible participants were scheduled for research
visit 1. This visit included mental status interviews to confirm
1872NEWTON ET AL.
eligibility and a nursing evaluation to assess acute medical
conditions, signs of illness or infection, systolic (SBP) and di-
astolic blood pressure (DBP), and body measurements. Blood
was drawn via antecubital venipuncture and collected with
appropriate anticoagulants for assessment of IL-6 and CRP,
and the following eligibility laboratory tests: comprehensive
metabolic profile, FSH, thyroid -stimulating hormone (TSH),
ethanol, hemoglobin A1c (HbA1c), and complete blood
count (CBC). A urine sample was obtained for a toxicology
screen and urinalysis. Women then completed computer-
administered questionnaires and were compensated $60.00.
Eligible women were scheduled for research visit 2. After
mental status interviews and a nursing evaluation, blood was
drawn via antecubital venipuncture for IL-6 and CRP assays.
Women then completed computerized questionnaires and
interviews about anxiety symptoms and were compensated
$80.00. Data from interviews are not reported here.
Isolation of plasma and PBMCs.
(10mL) was centrifuged for 10min at 350 g; the plasma was
then separated by aspiration, aliquoted (0.25mL) into cryo-
vials, and stored frozen at -80?C until assay. Cells were re-
suspended to the original volume with Hank’s Balanced Salt
Solution (HBSS) containing 10% fetal bovine serum (FBS) and
layered on top of a 10-mL cushion of Histopaque (Sigma, St.
Louis, MO) in a 50-mL centrifuge tube. The tubes were
centrifuged at ambient temperature for 20min at 350 g, and
the cells at the resulting interface (PBMC) were aspirated and
washed twice with HBSS containing 1% FBS. After counting
and viability assessment (trypan blue), the PBMCs were re-
suspended to a cell density of 4·106cells/mL and used for
the in vitro stimulation cultures.
Culture and stimulation of PBMCs.
in 24-well plates at a final cell density of 2.5·106cells/mL
using RPMI 1640 medium supplemented with 10% heat-
inactivated FBS, 100U/mL penicillin, 100lg/mL streptomy-
cin, 2mM glutamine, 1mM sodium pyruvate, and 0.1mM
nonessential amino acids. Phytohemagglutinin A (PHA,
separately to the cultures (1mL final volume) to stimulate the
PBMCs. Cell mixtures were then cultured for 48 hours at
37?C/5% CO2. Supernatants were collected by aspiration and
centrifuged 10min at 300 g to remove cells and debris. Su-
pernatants were aliquoted (0.25mL) into cryovials and stored
frozen at -80?C until assayed by enzyme-linked immuno-
sorbent assay (ELISA).
Measurement of IL-6 and CRP.
plasma or tissue culture supernatants were measured by two-
site ELISAs using Opti-EIA kits reagents (BD Pharmingen,
San Diego, CA) specific for human IL-6 according to the
manufacturer’s instructions. Assay sensitivity was 0.3pg/mL.
Each sample was tested in triplicate. To minimize and control
for interassay variability, analysis of the samples was deferred
until a minimum of plasma and supernatants from 15 partici-
pants could be run together. Intra-assay and interassay
coefficients of variation (CV) for the IL-6 ELISA were 6.9% and
9.6%, respectively. The minimum detection threshold was
Concentrations of IL-6 in
CRP was measured by turbidimetry on a Roche Integra
800 Analyzer. For the Roche Integra CRP assay, within-run
coefficients of variation are 0.9% and 0.7% at 3.3 and
8.0mg/L, respectively, and between-run coefficients of
variation are 3.5% and 2.2%, respectively. The limit of detec-
tion is 0.1mg/L.
Scale (CTS2)35assessed physical assault (12 items; Cronbach’s
a=0.86), sexual coercion (7 items; a=0.81), psychological ag-
gression (8 items; a=0.85), and IPV-related injury (6 items;
a=0.68). For each item, women rated frequency of occurrence
from 0 (never) to 6, (>20 times) with respect to their prior inti-
mate relationships collectively. Variety scores were computed
for each subscale by counting positively endorsed items.36
Items from the National Violence Against Women Survey3
assessed lifetime occurrence of stalking by an intimate part-
ner. These behaviorally specific items, based on the U.S. fed-
eral government’s model antistalking code,37,38are designed
to identify events that constitute legally defined forms of
stalking. Specifically, women reported yes/no if (1) a partner
or former partner had ever perpetrated any of eight events
(e.g., unsolicited phone calls, unsolicited correspondence,
fear, or (3) fear of bodily harm, threat of harm, or threat to
one’s own or another’s life. Following convention, women
meeting components 1–3 were classified as stalking vic-
tims.3,39Finally, for up to four relationships, women reported
duration, age at separation/divorce, and whether, to stay
safe, they had ever contacted police or filed an emergency
protective order (EPO) or sought shelter in the community or
with friends or family.
The Revised Conflict Tactics
of the Patient Health Questionnaire (PHQ-9)40assessed de-
pression symptoms in the past 2 weeks at research visits 1
(a=0.78, mean–standard deviation [SD]=4.57–4.19) and 2
visit (p=0.12) and were positively correlated (rS=0.64,
p<0.0001), they were averaged to form one score. The 17-item
Posttraumatic Stress Disorder Checklist-Civilian version
(PCL-C), administered at visit 2 (a=0.93), assessed past
month posttraumatic stress symptom severity.41The PCL-C
shows excellent reliability and validity in samples character-
ized by a variety of lifetime traumatic stressors (e.g., IPV,
physical and sexual assault, childhood maltreatment, motor
vehicle accidents)42–44and also has been used in samples se-
lected exclusively for IPV exposure.45
The 9-item depression module
Women reported their age, marital and employment
status, ethnicity, educational attainment, annual household
income, and whether they were regular smokers. A 48-item
checklist assessed past year stressful life events,46and the 4-
item Perceived Stress Scale (a=0.70) assessed perceptions of
stress in the past month.47Height and weight were used to
calculate body mass index (BMI). The Cook-Medley Hostility
Scale short-form48(a=0.80) assessed trait hostility and ag-
gression, and the National Women’s Study Event History
Module49assessed adversity before age 12 (e.g., attempted
PARTNER VIOLENCE AND INFLAMMATION MARKERS 1873
sexual molestation, physical attack), both of which have been
associated with IPV and systemic inflammation.31
Unstimulated IL-6 production levels were subtracted from
PHA-stimulated and LPS-stimulated levels. These change-
to reduce right skewness. Linear regression analyses were con-
ducted using the open-source R software package (R Founda-
tion for Statistical Computing, Vienna, Austria, 2009, www
.r-project.org/). Hypothesis tests were conducted at the 0.05
significance level. Spearman rank (rS) and rank biserial (rrb)
correlation coefficients are presented throughout.
study eligibility criteria, were able and willing to participate,
and were scheduled for research visit 1. An average of 3.49
weeks (SD-2.27) later, 69 women (100% of those eligible)
completed research visit 2. One participant unexpectedly
failed to show any PHA stimulation in her PBMC cultures,
resulting in technically improbable PHA-stimulated IL-6
change-scores that were lower than the baseline (-38.00 and
-160.00pg/mL), thus raising suspicion about the integrity of
the blood sample. Plasma from this woman also had IL-6
levels ‡5.52 SD from the sample mean (101.7 and 106.9pg/
mL). Because of the unusual profile, this participant was re-
moved from the sample, leaving 68 cases for analysis.
As shown in Table 1, participants were midlife women
who self-identified as European American or African Amer-
ican. Few were currently partnered. Almost half had com-
pleted at least a college degree; most were employed, with an
annual household income <$40,000.00. Levels of FSH con-
firmed women’s postmenopausal status. Average TSH values
and white blood cell counts were within their respective ref-
erence ranges;average HbA1c wasinthenormalrange. Blood
pressure was in the prehypertensive (SBP) or normotensive
(DBP) range, and BMI was in the overweight range. Women
reported an average of 4.59 past year stressful life events;
perceived stress scores were about 1 point higher than age-
matched U.S. norms.47Childhood adversity was reported by
29.41%. Few women were current smokers, and a minority
a urinary tract infection at visit 1.
most recent divorce or separation an average of 10.73–7.61
years before study participation and had been in distressed
marriages or partnerships an average of 17.51–9.01 years. As
shown in Table 2, all women reported histories of psycho-
logical aggression. Physical assault and sexual coercion were
prevalent, as were IPV-related injury. Stalking, police contact
or filing an EPO, and sheltering for safety were each reported
by at least half of the women.
Women experienced their
correlated across visits 1 and 2 (rSCRP=0.88; rSIL-6=0.79;
0.0005). Levels did not differ significantly between visits
(Wilcoxon signed rank test, p‡0.15), except that the LPS-
stimulated IL-6 change was greater at visit 1 than visit 2
(p=0.04). Descriptive statistics for biologic measures aver-
Biologic measures were positively
Study eligibility and enrollment diagram. FSH, follicle-stimulating hormone; HbAlc, hemoglobin Alc; IPV, intimate
1874NEWTON ET AL.
for interlaboratory comparisons, the median level was com-
parable to that from studies of healthy, midlife Americans
(median, interquartile range [IQR]: 1.50, 0.60–3.50mg/L),13
while the IQR extended somewhat higher.
chological symptoms are shown in Table 3. Median depres-
sion severity was minimal,40and median posttraumatic stress
symptom severity was lower than the average for women
without current syndromal PTSD.44
Descriptive statistics for psy-
Associations among IPV types, psychological
symptoms, and biologic measures
chological symptoms, were significantly correlated with bio-
Table 3 shows that IPV types, but not psy-
logic measures. As illustrated in Figure 2, PHA-stimulated
IL-6 change-scores were significantly negatively associated
with physical assault history (p=0.03), and circulating CRP
levels were significantly positively associated with stalking
history (p=0.008). This latter association was further evalu-
ated by established CRP risk levels. Histories of being stalked
were reported by 80% of women with very high CRP levels
(>10mg/L) and by 71% with high levels (>3mg/L), com-
pared to 52% and 35% with moderate (1–3mg/L) or low
levels (<1mg/L), respectively (Fisher’s exact test, p<0.09).
Although very high CRP levels provide prognostic informa-
tion for morbidity and mortality,50some argue they could
indicate acute inflammatory processes rather than habitual
levels.51To evaluate this possibility, between-visit percent
changein CRP wascalculated for the 5 women withvery high
levels. The degree of between-visit change (13% to 38%) was
less than that which would be considered significant and
possibly indicative of a developing or resolving acute in-
flammatory process (i.e., 117%).*
Multiple regression analyses.
stimulated IL-6 change-scores, linear regression models of the
visit averages evaluated relations with IPV type (stalking or
physical assault history, respectively), depression symptom
severity, and posttraumatic stress symptom severity. BMI, a
well-recognized correlate of inflammatory markers, was in-
cluded a priori. Because IL-6 has a circadian rhythm, correla-
tions between time of blood draw (ranging from 8:11 am to
change-scores were computed; there were no significant as-
sociations at either visit 1(rs=0.03, p=0.79) or visit 2 (rs= -
0.01, p=0.93), and, therefore, draw time was not included in
the regression model.
Neither depression nor posttraumatic stress symptoms
wereassociated with thetwo biologic measures, whereas BMI
was positively associated with both (Table 4). After adjusting
for BMI and symptoms, physical assault history was signifi-
cantly negatively associated with PHA-stimulated IL-6
change-scores; stalking history was marginally positively as-
sociated with CRP. In a model excluding BMI, women with
stalking histories had significantly higher CRP levels than
those without (p=0.05). Thus, BMI attenuated the correlation
between stalking history and CRP, but its lack of significant
association with stalking (Table 3) indicates that this was not
due to confounding or mediation.
For CRP levels and PHA-
ducted. First, the role of IPV severity was evaluated. For
physical assault, separate variety scores were computed for
severe (e.g., beat me up, 64.71% of women, 1.88–1.88) and
minor assault (e.g., grabbed me, 76.47% of women,
2.68–1.87). Severe physical assault (rs= -0.32, p=0.007), not
minor (rs= -0.15, p=0.21), was significantly correlated with
PHA-stimulated IL-6 change-scores, a difference that ap-
proached statistical significance (p=0.06). When the adjusted
regression model was refit with severe physical assault, it
Three follow-up analyses were con-
Table 1. Sociodemographics and Health-Related
Characteristics for Total Sample
or % (n) Median
European American or white
College graduate or beyond
Employed full-time or part-time
Annual household income
White blood cell count (103/lL)
Systolic blood pressurea(mm Hg)
Diastolic blood pressurea(mm Hg)
Body mass index
Stressful life events in past year
Perceived stress in past month
Current regular smoker
Signs of acute conditionc
Urinary tract infection at visit 1
n=68, except for annual household income and follicle-stimulating
hormone (n=67), years postmenopausal, and hemoglobin A1c
(HbA1c) (n=66). Medians are provided for skewed variables.
aAverage of measurements taken during visits 1 and 2.
bOne woman was enrolled with an Alcohol Use Disorder
Identification Test (AUDIT-C) score of 5 due to a scoring error
during a phone interview, and 4 were taking exclusionary medica-
tions—estradiol (n=2), testosterone (n=1), and a biophosphonate
(n=1). Assessments of health behaviors preceding both research
visits served as additional checks on exclusionary medications; 4
women reported morning use of such medications (i.e., acetamin-
ophen, both acetaminophen and a ‘‘cholesterol medication,’’ baclo-
fen, and loratadine). Finally, 1 woman disclosed an exclusionary
medical condition during a research visit, and because of an
emergent health condition, another was prescribed daily aspirin
and a statin drug between visits 1 and 2. Collectively, 10 participants
accounted for these cases.
cEleven women showed signs of skin rash, upper respiratory tract
infection, allergic reaction, or enlarged submandibular nodes or
glands at one of the research visits.
SD, standard deviation.
*Relative change value (95% confidence interval [CI]=(21/2)
(1.96)(CVp2+CVi2+CVa2)1/2, where CVp is the preanalytical change
value (considered to be negligible), CVi is the intraindividual change
value (42.2%, from www.westgard.com/biodatabase1.htm), and CVa
is the between-run analytical change value (2.2% at 8mg/L).
PARTNER VIOLENCE AND INFLAMMATION MARKERS1875
accounted for 14% of the variance in PHA-stimulated IL-6
change-scores (b= -0.17; p=0.0008). For stalking, a less se-
vere form was defined as the occurrence of any stalking be-
havior regardless of fear or life threat; the zero-order
correlation with CRP was not statistically significant (rrb=
Second, the role of potentially confounding health-related
and sociodemographic characteristics was evaluated. Neither
stalking nor physical assault history was significantly asso-
ciated withyearsdivorced oryearsin adistressed marriageor
any of the sociodemographic or health-related characteristics
(rrbor Fisher’s exact test, p‡0.13). There were trends for as-
sociations between physical assault history and trait hostility
(rs=0.21,p=0.09) andchildhood adversity(rrb=0.29,p=0.06).
When these variables were added to the regression model for
PHA-stimulated IL-6 change-scores, the effect for physical
assault history remained statistically significant (p=0.003);
neither trait hostility (p=0.10) nor childhood adversity
(p=0.62) reached statistical significance.
Third, the 10 women with exclusionary biomedical condi-
tions (medication use, medical history, or possible substance
use disorder) were omitted, and analyses with and without
these women were compared. In terms of patterns of statis-
tical significance, zero-order correlations among biologic
measures, IPV types, and psychological symptoms were
identical in both cases. The two regression models were also
identical in both cases, with one exception: when the 10 wo-
men with exclusionary conditions were omitted, the effect for
stalking history and CRP was statistically significant (b=1.80,
This study examined correlations between remitted IPV
and biologic mediators of inflammation in healthy midlife
women. Women who reported intimate partner stalking his-
tories showed higher CRP levels than those without. This was
apparent only when stalking was defined as a traumatic
stressor, engendering fear and perceived life threat. After
adjusting for BMI, this effect was attenuated and was mar-
ginally statistically significant. Nonetheless, in the adjusted
model, the magnitude of the relation between stalking history
and CRP (r=0.22) exceeded a previously reported effect size
Table 2. Descriptive Statistics for Relationship Experiences and Correlations Among
Intimate Partner Violence Types
Police contact/EPO for safety
Sheltered for safety
aPrevalence refers to the percentage of women who endorsed at least one item on a given measure. Correlations for psychological
aggression, physical assault, and sexual coercion are based on variety scores.
bSpearman rank correlation coefficients.
cRank biserial correlation coefficients.
EPO, emergency protective order.
Table 3. Descriptive Statistics for Biologic and Symptom Measures and Zero-Order Correlations
with Intimate Partner Violence Types
Median (IQR)IL-6 PHA LPSPCL-C PHQ BMI
1. CRP, mg/L
2. IL-6, pg/mL
3. PHA, pg/mL
4. LPS, pg/mL
0.22 0.37** 0.43**
0.35** -0.06 -0.06
Descriptive statistics for biologic measures are nontransformed and averaged across visits.
Correlations for IPV types other than stalking are based on variety scores. Except for stalking, where rank biserial correlation coefficients
are used, Spearman rank correlation coefficients are presented.
BMI, body mass index; CRP, C-reactive protein; IL-6, interleukin-6; IQR, interquartile range; LPS, lipopolysaccharide; PCL-C,
Posttraumatic Stress Disorder Checklist (posttraumatic stress symptoms); PHA, phytohemagglutinin A (LPS-stimulated production
change-scores); PHQ, Patient Health Questionnaire (depression symptoms).
1876 NEWTON ET AL.
d=0.28).31Sample size and consequent limitations in statisti-
cal power, plus the strong association between BMI and CRP,
likely hampered the study’s ability to detect this effect. Also,
follow-up analyses showed that the presence of women with
exclusionary conditions masked this effect.
Intimate partner stalking, with a lifetime prevalence of 5%
among U.S. women,3has been relatively neglected in IPV
research. The few exceptions suggest that even among se-
verely battered women, stalking intensifies and extends
women’s fear, anxiety, sadness, and sleep disruption and
further dampenswomen’sperceivedsafety.52,53Although not
exclusively a postrelationship event, intimate partner stalking
is more likely to occur after, rather than before, relationship
dissolution,3making it particularly relevant for the health of
postabused women. Because stalking was the only IPV type
measured with appraisals of fear and perceived life threat,
however, resultsattributed toit couldbe due toitsassessment
as a traumatic stressor. As recently argued, routine mea-
surement of stress appraisals for all IPV types might benefit
this research area.54
Because the cytokine IL-6 is often highlighted as a primary
no statistically significant association between stalking his-
tory and circulating IL-6 levels. Other studies have similarly
reported that the associations of CRP and IL-6 with chronic
stress do not always converge,19and some have reported null
or inverse associations with psychosocial factors.18,55Offering
one possible explanation, other cytokines, such as IL-1b and
tumor necrosis factor-a (TNF-alpha;), along with the adipo-
kine resistin, play a role in CRP synthesis.56,57
Physical assault history was significantly correlated with
in vitro production of the cytokine IL-6 by PBMCs, but only
when stimulated with PHA. Similar to the results for stalking,
minor, physical assault. Further, it was not accounted for by
BMI, trait hostility, or childhood adversity. Thus, in the
present sample, a history of intimate partner physical assault
emerged as an independent correlate of the capacity of im-
mune system cells to produce IL-6 when stimulated in vitro.
Although stimulated IL-6 production has not been identified
as a risk factor for poorer health outcomes per se, these results
nonetheless clearly link IPV history to a specific functional
effect in the immune system.
Notably, this significant effect did not extend to LPS-stim-
ulated IL-6 production, although the latter was also nega-
tively correlated with physical assault. This somewhat
different pattern could reflect the cell types being stimulated.
Atconcentrations used in thisstudy, LPS stimulatesprimarily
monocytes, the main producers of proinflammatory cyto-
kines, including IL-6. In contrast, PHA stimulates exclusively
T lymphocytes, which can also produce IL-6. This suggests
that the stress of intimate partner physical assault may have
differential, rather than uniform, effects on the various cells of
the immune system. It is interesting that in a population of
PTSD patients, the sensitivity of PHA-stimulated but not LPS-
stimulated cytokine production by whole blood to the
phytohemagglutinin A (PHA)-stimulated interleukin-6 (IL-6)
change-scores and physical assault history and between (B)
raw (nontransformed) C-reactive protein (CRP) circulating
levels and stalking history.
Associations between (A) raw (non-transformed)
Table 4. Analyses Predicting Biologic Measures from Stalking History (for C-Reactive Protein)
or Physical Assault History (for Phytohemagglutinin A-Stimulated Interlekin-6 Change-Score)
After Adjusting for Body Mass Index and Current Posttraumatic Stress and Depression Symptoms
bc(95% CI) pr2
p value Predictor
Body mass index
Physical assault history
Body mass index
-0.06 (-0.16-0.03) 0.03
-0.01 (-0.08-0.06)0.0020.730.12 (-0.15-0.40) 0.010.38
-0.08 (-0.14--0.03) 0.120.0051.39 (-0.17-2.94) 0.050.08
aModel R2=0.24, p=0.001.
bModel R2=0.33, p<0.0001.
cb=standardized regression coefficient.
PARTNER VIOLENCE AND INFLAMMATION MARKERS 1877
further suggesting that traumatic stress and its emotional af-
termath might affect immune system cells differentially.
In the present sample, psychological symptoms were not
significantly associated with biologic measures. This is con-
sistent with some prior research30,55,58and might partially re-
flect the low symptom levels in the present sample. The more
for connections between remitted IPV and inflammation
markers.Another plausible mediator,BMI,wassimilarlyruled
out by the present results. It was not significantly correlated
with stalking history, and despite its positive correlation with
physical assault history, it did not account for the connection
mediators—psychological, biologic, or both—will need to be
considered to explain the observed correlations between re-
mitted IPV and markers of inflammation.
The present study has certain limitations. First, because
many potential participants were disqualified for already
having developed chronic diseases, women with sufficient
stress-buffering resources to maintain good midlife health
despite severe stress histories may comprise thepresent study
sample. Therefore, these results should not be generalized to
all women with IPV histories. Second, although women were
carefully screened for medical conditions, subclinical disease
cannot be ruled out as a factor in the results. Third, there is
precedent for using IPV measures to assess cumulative
lifetime IPV,3but the reliability and validity of these retro-
spective reports are naturally a question. Finally, the cross-
sectional study design limits causal inferences, and it is
prudent to acknowledge trends for histories of physical as-
sault and psychological aggression to correlate with CRP and
PHA-stimulated IL-6, respectively, rather than to draw pre-
mature conclusions about the specificity of links between IPV
types and biologic measures.
This article began by considering whether IL-6 and CRP
might play a role in the relationship between IPV and aging-
related chronic diseases. Results show that healthy midlife
women with IPV histories present a complex inflammatory
profile that may not be uniformly ‘‘proinflammatory’’ when
all measures are taken into consideration. It may seem sur-
prising for stressor history to be related to both increased CRP
and decreased stimulated IL-6 production. Whereas plasma
levels of CRP reflect chronic, systemic inflammation that is a
cumulative downstream product of multiple mediators and
celltypes, stimulated IL-6 productionreflects theacutein vitro
response of a particular type of leukocyte (e.g., monocytes vs.
T cells) in response to a given stimulation. The present results
as IPV, although the overall balance of the system may be
biased in favor of increased systemic inflammation, different
aspects of the inflammatory response may be differentially
regulated and subjected to diverse compensatory mecha-
nisms (such as glucocorticoids).32Future studies should ad-
dress the factors, such as specific stressor experiences,59that
might contribute to this differential regulation and to its
persistence despite stressor remission.
This research was funded by the National Institute on
Aging and conducted with support from the University of
Louisville Hospital Clinical Research Center. We thank Heidi
Resnick for her support and consultation, Kristen Allison,
Jeanne Cundiff, Cristina Fernandez, and Rebecca Weigel for
assisting with data collection, and the study participants.
No competing financial interests exist.
1. Saltzman LE, Fanslow JL, McMahon PM, Shelley GA. In-
timate partner violence surveillance: Uniform definitions
and recommended data elements, version 1.0. Atlanta, GA:
National Center for Injury Prevention and Control, Centers
for Disease Control and Prevention, 2002.
2. Garcia-Morena C, Jansen HAFM, Ellsberg M, Heise L, Watts
C. WHO Multi-country study on women’s health and do-
mestic violence against women: Initial results on prevalence,
health outcomes and women’s responses. Geneva: World
Health Organization, 2005.
3. Tjaden P, Thoennes N. Extent, nature, and consequences of
intimate partner violence. Washington, DC: U.S. Depart-
ment of Justice, National Institute of Justice, 2000.
4. Kaysen D, Resick PA, Wise D. Living in danger: The impact
of chronic traumatization and the traumatic context on
posttraumatic stress disorder. Trauma Violence Abuse 2003;
5. Thompson RS, Bonomi AE, Anderson M, et al. Intimate
partner violence: Prevalence, types, and chronicity in adult
women. Am J Prev Med 2006;30:447–457.
6. Breiding MJ, Black MC, Ryan GW. Chronic disease and
health risk behaviors associated with intimate partner
violence—18 U.S. states/territories, 2005. Ann Epidemiol
7. Coker AL, Davis KE, Arias I, et al. Physical and mental
health effects of intimate partner violence for men and wo-
men. Am J Prev Med 2002;23:260–268.
8. Woods AB, Page GG, O’Campo P, Pugh LC, Ford D,
Campbell JC. The mediation effect of posttraumatic stress
disorder symptoms on the relationship of intimate partner
violence and IFN-gamma levels. Am J Community Psychol
9. Gabay C, Kushner I. Mechanisms of disease: Acute-phase
proteins and other systemic responses to inflammation. N
Engl J Med 1999;340:448–454.
10. Maggio M, Guralnik JM, Longo DL, Ferrucci L. Interleukin-6
in aging and chronic disease: A magnificent pathway. J
Gerontol Med Sci 2006;61A:575–584.
11. Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK.
IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans.
Am J Physiol Endocrinol Metab 2003;285:E433–E437.
12. Pai JK, Pischon T, Ma J, et al. Inflammatory markers and the
risk of coronary heart disease in men and women. N Engl J
13. Ridker PM. Clinical application of C-reactive protein for
cardiovascular disease detection and prevention. Circulation
14. Teunissen CE, van Boxtel MPJ, Bosma H, et al. Inflammation
markers in relation to cognition in a healthy aging popula-
tion. J Neuroimmunol 2003;134:142–150.
15. Weaver JD, Huang MH, Albert M, Harris T, Rowe JW,
Seeman TE. Interleukin-6 and risk of cognitive decline:
MacArthur Studies of Successful Aging. Neurology 2002;59:
1878 NEWTON ET AL.
16. Melamed S, Shirom A, Toker S, Berliner S, Shapira I. Asso-
ciation of fear of terror with low-grade inflammation among
apparently healthy employed adults. Psychosom Med 2004;
17. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C,
Malarkey WB, Glaser R. Chronic stress and age-related in-
creases in the proinflammatory cytokine IL-6. Proc Natl
Acad Sci 2003;100:9090–9095.
18. Davis MC, Zautra AJ, Younger J, Motivala SJ, Attrep J, Irwin
MR. Chronic stress and regulation of cellular markers of
inflammation in rheumatoid arthritis: Implications for fa-
tigue. Brain Behav Immun 2008;22:24–32.
19. von Kanel R, Dimsdale JE, Mills PJ, et al. Effect of Alzheimer
caregiving stress and age on frailty markers interleukin-6, C-
reactive protein, and D-dimer. J Gerontol Med Sci 2006;61A:
20. Elenkov IJ, Chrousos GP. Stress hormones, Th1/Th2 pat-
terns, pro/anti-inflammatory cytokines and susceptibility to
disease. Trends Endocrinol Metabol 1999;10:359–368.
21. Bermudez EA, Rifai N, Buring J, Manson JE, Ridker PM.
reactive protein, and traditional cardiovascular risk factors
in women. Arterioscler Thromb Vasc Biol 2002;22:1668–
22. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive
protein and other markers of inflammation in the prediction
of cardiovascular disease in women. N Engl J Med 2000;
23. Campbell JC, Webster D, Koziol-McLain J, et al. Risk factors
for femicide in abusive relationships: Results from a multi-
site case control study. Am J Public Health 2003;93:1089–
24. Fernandez-Botran R, Miller JJ, Burns VE, Newton TL. Cor-
relations among inflammatory markers in plasma, saliva
and oral mucosal transudate in post-menopausal women
with past intimate partner violence. Brain Behav Immun
25. Avitsur R, Powell N, Padgett DA, Sheridan JF. Social inter-
actions, stress, and immunity. Immunol Allergy Clin North
26. Miller GE, Rohleder N, Cole SW. Chronic interpersonal
stress predicts activation of pro- and anti-inflammatory
signaling pathways 6 months later. Psychosom Med 2009;71:
27. Maes M, Scharpe S, Meltzer HY, et al. Relationships between
interleukin-6 activity, acute phase proteins, and function of
the hypothalamic-pituitary-adrenal axis in severe depres-
sion. Psychiatry Res 1993;49:11–27.
28. Gill J, Vythilingam M, Page GG. Low cortisol, high DHEA,
and high levels of stimulated TNF-a, and IL-6 in women
with PTSD. J Trauma Stress 2008;21:530–539.
29. Howren MB, Lamkin DM, Suls J. Associations of depression
with C-reactive protein, IL-1, and IL-6: A meta-analysis.
Psychosom Med 2009;71:171–186.
30. Pace TWW, Heim CM. A short review on the psychoneur-
oimmunology of posttraumatic stress disorder: From risk
factors to medical comorbidities. Brain Behav Immun 2011;
31. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R,
Caspi A. Elevated inflammation levels in depressed adults
with a history of childhood maltreatment. Arch Gen Psy-
32. de Kloet CS, Vermetten E, Bikker A, et al. Leukocyte glu-
cocorticoid receptor expression and immunoregulation in
veterans with and without post-traumatic stress disorder.
Mol Psychiatry 2007;12:443–453.
33. Paranjape A, Rask K, Liebschutz J. Utility of STaT for the
identification of recent intimate partner violence. J Natl Med
34. Dawson DA, Grant BF, Stinson FS, Zhou Y. Effectiveness of
the Derived Alcohol Use Disorders Identification Test
(AUDIT-C) in screening for alcohol use disorders and risk
drinking in the US general population. Alcoholism Clin Exp
35. Straus MA, Hamby SL, Warren WL. The Conflict Tactics
Scales handbook. Los Angeles, CA: Western Psychological
36. Moffitt TE, Caspi A, Krueger RF, et al. Do partners agree
about abuse in their relationship? A psychometric evalua-
tion of interpartner agreement. Psychol Assess 1997;9:47–56.
37. National Criminal Justice Association. Project to develop a
model anti-stalking code for states. Washington, DC: U.S.
Department of Justice, National Institute of Justice, 1993.
38. Tjaden P, Thoennes N, Allison CJ. Comparing stalking vic-
timization from legal and victim perspectives. In: Davis KE,
Frieze IH, Maiuro RD, eds. Stalking: Perspectives on victims
and perpetrators. New York: Springer, 2002:9–30.
39. Baum K, Catalano S, Rand M, Rose K. Stalking victimization
in the United States. Bureau of Justice Statistics Special Re-
port. Washington, DC: U.S. Department of Justice, 2009.
40. Kroenke K, Spitzer RL, Williams JBW. The PHQ-9: Validity
of a brief depression severity measure. J Gen Intern Med
41. Weathers F, Litz B, Herman D, Huska J, Keane T. The PTSD
Checklist (PCL): Reliability, validity, and diagnostic utility.
San Antonio, TX: International Society for Traumatic Stress
42. Dobie DJ, Kivlahan DR, Maynard C, et al. Screening for
post-traumatic stress disorder in female Veteran’s Affairs
patients: Validation of the PTSD Checklist. Gen Hosp Psy-
43. Ruggiero KJ, Del Ben K, Scotti JR, Rabalais AE. Psychometric
properties of the PTSD Checklist—Civilian version. J Trau-
ma. Stress 2003;16:495–502.
44. Walker EA, Newman E, Dobie DJ, Ciechanowski P, Katon
W. Validation of the PTSD Checklist in an HMO sample of
women. Gen Hosp Psychiatry 2002;24:375–380.
45. Krause ED, Kaltman S, Goodman LA, Dutton MA. Long-
itudinal factor structure of posttraumatic stress symptoms
related to intimate partner violence. Psychol Assess 2007;19:
46. Spurgeon A, Jackson CA, Beach JR. The Life Events In-
ventory: Re-scaling based on an occupational sample. Occup
47. Cohen S, Williamson GM. Perceived stress in a probability
sample of the United States. In: Spacapan S, Oskamp S, eds.
The social psychology of health. Beverly Hills, CA: Sage,
48. Barefoot JC, Dodge KA, Peterson BL, Dahlstrom WG, Wil-
liams RB. The Cook-Medley Hostility Scale: Item content
and ability to predict survival. Psychosom Med 1989;51:46–
49. Resnick H. Psychometric review of National Women’s Study
(NWS) Event History—PTSD module. In: Stamm BH, ed.
Measurement of stress, trauma, and adaptation. Lutherville,
MD: Sidran Press, 1996.
50. Hamer M, Chida Y, Stamatakis E. Association of very highly
elevated C-reactive protein concentration with cardiovascular
PARTNER VIOLENCE AND INFLAMMATION MARKERS1879
events and all-cause mortality. Clin Chem 2010;56:132–
51. Pearson TA, Mensah GA, Alexander RW, et al. Markers of
inflammation and cardiovascular disease: Application to
clinical and public health practice. A statement for health-
care professionals from the Centers for Disease Control and
Prevention and the American Heart Association. Circulation
52. Logan TK, Shannon L, Cole J, Walker R. The impact of dif-
ferential patterns of physical violence and stalking on mental
health and help-seeking among women with protective or-
ders. Violence Women 2006;12:866–886.
53. Logan TK, Walker R. Toward a deeper understanding of the
harms caused by partner stalking. Violence Vict 2010;25:
54. Martinez-Torteya C, Bogat GA, von Eye A, Levendosky AA,
Davidson WS. Women’s appraisals of intimate partner vio-
lence stressfulness and their relationship to depressive and
posttraumatic stress disorder symptoms. Violence Vict 2009;
55. Steptoe A, Kunz-Ebrecht SR, Owen N. Lack of association
between depressive symptoms and markers of immune and
vascular inflammation in middle-aged men and women.
Psychol Med 2003;33:667–674.
56. Calabro P, Chang DW, Willerson JT, Yeh ETH. Release of C-
reactive protein in response to inflammatory cytokines by
human adipocytes: Linking obesity to vascular inflamma-
tion. J Am Coll Cardiol 2005;46:1112–1113.
57. Eklund CM. Proinflammatory cytokines in CRP baseline
regulation. Adv Clin Chem 2009;48:111–136.
58. Cyranowski JM, Marsland AL, Bromberger JT, Whiteside
TL, Chang Y, Matthews KA. Depressive symptoms and
production of proinflammatory cytokines by peripheral
blood mononuclear cells stimulated in vitro. Brain Behav
59. Kemeny ME. The psychobiology of stress. Curr Dir Psychol
Address correspondence to:
Tamara L. Newton, Ph.D.
Department of Psychological and Brain Sciences
University of Louisville
317 Life Sciences
Louisville, KY 40292
1880 NEWTON ET AL.