Dose-Response Relationship Between Cigarette Smoking and
Risk of Ischemic Stroke in Young Women
Viveca M. Bhat, MD; John W. Cole, MD, MS; John D. Sorkin, MD, PhD;
Marcella A. Wozniak, MD, PhD; Ann M. Malarcher, PhD; Wayne H. Giles, MD, MS;
Barney J. Stern, MD; Steven J. Kittner, MD, MPH
Background and Purpose—Although cigarette smoking is known to be a risk factor for ischemic stroke, there are few data
on the dose-response relationship between smoking and stroke risk in a young ethnically diverse population.
Methods—We used data from the Stroke Prevention in Young Women Study, a population-based case-control study of risk
factors for ischemic stroke in women aged 15 to 49 years to examine the relationship between cigarette smoking and
ischemic stroke. Historical data, including smoking history, was obtained through standardized interviews. Odds ratios
(OR) were estimated using logistic regression. Cases (n?466) were women with stroke in the greater Baltimore-
Washington area, and controls (n?604) were women free of a stroke history identified by random digit dialing.
Results—After multivariable adjustment, the OR comparing current smokers to never smokers was 2.6 (P?0.0001); no
difference in stroke risk was observed between former smokers and never smokers. Adjusted OR increased with
increasing number of cigarettes smoked per day (OR?2.2 for 1 to 10 cigs/d; 2.5 for 11 to 20 cigs/d; 4.3 for 21 to 39
cigs/d; 9.1 for 40 or more cigs/d).
Conclusion—These results suggest a strong dose-response relationship between cigarette smoking and ischemic
stroke risk in young women and reinforce the need for aggressive smoking cessation efforts in young adults.
Key Words: stroke ? women ? smoking
amined this relationship among young ethnically diverse
populations.5Furthermore, some studies that have included
young adults have not addressed issues of dose response. In
2005, an estimated 20.7% of U.S. women ages 18 to 24 were
current cigarette smokers.6Given that the prevalence of
smoking in teenage girls and young women remains high and
has not changed substantially in the past several years, it is
important to further characterize the stroke risk associated
with smoking in this population.3We undertook this study to
assess the dose-response between cigarette smoking and risk
of ischemic stroke in young women.
urrent smoking is known to be an important risk factor
for ischemic stroke.1–4However, few studies have ex-
Subjects and Methods
The Stroke Prevention in Young Women Study (SPYW) is a
population-based case-control study initiated to examine risk factors
for ischemic stroke in young women. Study recruitment and data
collection occurred in 2 waves: SPYW-1 was conducted between
1992 and 1996 and SPYW-2 was conducted between 2001 and 2003.
Cases were women, aged 15 to 49 years, hospitalized with a first
cerebral infarction identified by discharge surveillance from one of
59 hospitals in the greater Baltimore-Washington area and direct
referral from regional neurologists. The methods for discharge
surveillance, chart abstraction, case adjudication, and assignment of
probable and possible underlying causes have been described else-
where.7,8Controls were women free of a history of stroke identified
by random-digit dialing and were frequency-matched to the cases by
age and geographic region of residence. For SPYW-1, recruitment
within 1 year of stroke was required for participation, whereas
recruitment within 3 years of stroke was required for SPYW-2.
We conducted interviews with both case patients and controls to
assess demographic (age, race, and educational level) and medical
(history of hypertension, diabetes, elevated total cholesterol and
coronary heart disease [angina and/or myocardial infarction]) char-
acteristics. For cases that were deceased or who had cognitive or
language impairment, proxies were interviewed. Women were con-
sidered to have hypertension, diabetes mellitus, elevated cholesterol,
or coronary heart disease if they responded affirmatively to whether
they had ever been told by a physician that they had the condition.
Body mass index (BMI) was based on self-report and calculated as
the weight in kilograms (kg) divided by the square of the height in
meters (m). Oral contraceptive (OC) use was based on reported use
of OC in the 30 days before stroke (cases) or interview (controls).
Analyses were restricted to participants with complete information
Received November 14, 2007; final revision received January 24, 2008; accepted January 28, 2008.
From the University of Maryland, School of Medicine, Departments of Neurology (V.M.B., J.W.C., M.A.W., B.J.S., S.J.K.) and Epidemiology and
Preventive Medicine (J.W.C., S.J.K.), Baltimore, Md; the Geriatrics Research, Education, and Clinical Center (J.D.S., S.J.K.), Claude D. Pepper Older
Americans Independence Center (J.D.S.), Medical Research Service (J.W.C., S.J.K.), Department of Veterans Affairs Medical Center, Baltimore, Md;
and the Centers for Disease Control and Prevention (W.H.G., A.M.M.), Atlanta, Ga.
Correspondence to Dr John W. Cole, Bressler Building, Room 12-006, University of Maryland, Baltimore, 655 W. Baltimore St, Baltimore, MD 21201.
© 2008 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.orgDOI: 10.1161/STROKEAHA.107.510073
for analysis variables leaving an analysis sample of 466 cases,
including 10 cases with proxy interviews, and 604 controls.
A detailed smoking history was obtained during the face-to-face
interview. Women were classified according to their smoking status
as never smokers, former smokers, and current smokers. Never
smokers (n?500) were defined as those who had never smoked
greater than 100 cigarettes or 5 packs of cigarettes in their lifetime.
Current smokers (n?386) were defined as those who had smoked
greater than 100 cigarettes in their lifetime and also had smoked in
the 30 days preceding their stroke (for cases) or their interview (for
controls). Former smokers (n?184) were defined as those who had
smoked greater than 100 cigarettes in their lifetime, but had not
smoked in the 30 days before their stroke/interview (cases/controls).
Amount of current smoking (cigarettes/d) was stratified into 4
categories: 1 to 10 cigs/d, 11 to 20 cigs/d, 21 to 39 cigs/d, and 40?
cigs/d. Data on measurements of serum cotinine or other markers for
objectively validating smoking status were not available.
Statistical analyses were conducted using SAS v9 (SAS Institute).
?2tests were used to compare proportions. Logistic regression was
used to estimate the odds ratio (OR) for ischemic stroke comparing
women in different smoking categories to the reference group of
never smokers while controlling for potential confounders. In regres-
sion analyses, we performed age-adjusted and multivariate analyses
(adjusted for study period, age, race, education category, hyperten-
sion, diabetes mellitus, coronary heart disease, elevated total choles-
terol, OC use and BMI). We tested whether each of the variables
used in adjustment modified the dose-response relationship between
amount of smoking and stroke by including interaction terms in the
logistic regression. Model parameter estimates were computed using
maximum-likelihood and 95% confidence intervals (CI) were based
on the standard error of the model coefficients. All probability values
were 2-sided and P?0.05 was considered statistically significant.
Table 1 demonstrates the demographics and other selected
characteristics of the studied population. Also shown is the
percentage of controls that are current smokers and former/
never smokers and corresponding probability values within
Table 2 demonstrates the odds ratios for stroke risk
between cases and controls by smoking status and by ciga-
rettes smoked daily. Former smokers did not have an in-
creased stroke risk. Current smokers had a multivariate-
adjusted OR of 2.6 (P?0.0001). Multivariate-adjusted
analysis showed increasing OR with increasing number of
cigarettes smoked per day: 2.2 for 1 to 10 cigs/d; 2.5 for 11
to 20 cigs/d; 4.3 for 21 to 39 cigs/d; 9.1 for 40 or more cigs/d.
The risk associated with smoking even 1 to 10 cigarettes per
day was statistically significant and the test for trend using
logistic regression was also highly significant (P?0.0001).
The dose-response relationship between smoking amount and
stroke risk was not modified by any of the covariates,
Stroke risk compared to never smokers also increased with
increasing pack years of smoking. The multivariate-adjusted
OR for 1 to 10 pack years was 2.1 (P?0.0004), for 11 to 20
pack years was 2.7 (P?0.0001), and for 21? pack years it
was 4.8 (P?0.0001). When smoking amount and smoking
duration were both included in a multivariate logistic model,
smoking amount remained highly significant (P?0.002) but
smoking duration was not statistically significant (P?0.6).
Were Current Smokers or Former and Never Smokers (Total Cases, n?466; Total Controls, n?604)
Demographics and Other Selected Characteristics of Studied Population, Including Percentage of Control Subjects Who
FactorCategoryCases n (%) Controls n (%)P*
Smokers† n (%)
Never Smokers† n (%)P*
Coronary artery disease
Body Mass Index 0.00060.4903
Oral contraceptives0.0581 0.1259
There is prior evidence for a dose-response between amount
of smoking in middle-aged to older adults and stroke risk4but
few data to document a dose-response in young adults.9,10
Our study extends this finding to young women in an
ethnically-diverse population. In addition, we found a steeper
dose response than has been reported in other populations
with OR of 2.3 for 1 to 10 cigarettes/d and 9.4 for 40 or more
cigarettes per day. The study by Love9in young adults did
report that in young adults 15 to 45 years of age, the number
of cigarettes smoked daily was a significant risk factor
(P?0.028) for cerebral infarction with risk increasing by a
factor of 1.014 for each additional cigarette smoked and an
OR of 1.035 per each additional pack year of smoking (with
a quadratic relationship). In the Nurses Health Study, among
women ages 30 to 55 years of age, the multivariate-adjusted
relative risk for ischemic stroke was 1.8 for 1 to 14 ciga-
rettes/d and 4.0 for 35 or more cigarettes per day.11,12Other
studies have reported a dose response among middle-aged to
older men13,14and both men and women15,16, but none have
shown a dose-response as strong as our study suggests. Our
study also found that there were a high number of blacks who
were smokers in both our cases and controls (Table 1), which
emphasizes that smoking is an under-recognized public
health problem in this population.
Smoking is known to promote atherosclerosis and a pro-
coagulant state.4It has been established in older adults that
the stroke risk associated with cigarette smoking falls to the
lowest levels within 5 years of smoking cessation,15,17sug-
gesting that induction of a procoagulant state is the primary
mechanism. Cigarette smoking causes vascular endothelial
dysfunction18–20with associated alteration in hemostatic and
inflammatory markers.17Smoking also increases fibrinogen
concentration,21reduces fibrinolytic activity,22increases
platelet aggregability,23and causes polycythemia.24
Our study has several limitations. Recall bias remains
possible, given the retrospective design. Objective markers of
smoking exposure, such as serum cotinine levels, were not
available. In addition, we did not control for factors such as
alcohol consumption and physical activity in our model,
which may have resulted in unmeasured or residual con-
founding of our risk estimates.
Our study also has several strengths. It is one of the largest
studies of early-onset stroke in young women. The large
sample size allowed relatively precise estimates of dose-
response. The study population was ethnically diverse with
roughly 50% blacks.
Almost 120 000 women and 105 000 men in America
under the age of 45 have suffered a stroke.25Despite the
evidence that smoking is a risk factor for many diseases,
including stroke,120.9% (45.1 million) of the United States
population defined themselves as current smokers in 2005,6
and every year, nearly 750 000 young people become regular
smokers.26Smoking prevalence in the United States among
young women age 18 to 24 years was 20.7% and was 21.4%
among women age 25 to 44 years. According to the CDC,
almost all smokers begin smoking as teenagers, and if current
trends continue, more than 6 million young people who are
regular smokers will eventually die from a tobacco-related
Cigarette smoking remains prevalent, even among young
stroke survivors. Arquizan et al assessed the control of risk
factors in young patients with cryptogenic stroke and found
that 54% to 58% still smoked during follow-up, demonstrat-
ing that management of vascular risk factors is not achieved
after stroke in the young.27
Stroke risk decreases significantly 3 years after cessation
of cigarette smoking and is at the level of nonsmokers by 5
years.11,15,28Although smoking cessation has major and
immediate health benefits for men and women of all ages,29
the benefit is greater the earlier in life one quits. Persons who
quit before the age of 35 years have a life expectancy that is
similar to nonsmokers.30There is strong evidence that sus-
tained mass media campaigns and increased price of tobacco
products are effective in reducing initiation and promoting
cessation of cigarette smoking among adolescents and young
Our study supports the need to target smoking as a prevent-
able and modifiable risk factor for cerebrovascular disease in
young women. The dose-response relationship between num-
ber of current cigarettes smoked and ischemic stroke risk in a
young ethnically-diverse population of women makes large-
Table 2. Odds Ratio for Ischemic Stroke by Smoking Status and, in Current Smokers, by Cigarettes Smoked Daily
Cases (n)Controls (n)
Model 1†Model 2‡
OR 95% CIP OR95% CIP
? ? ?
? ? ?? ? ?
? ? ?
? ? ? ? ? ?
*Reference is never smokers.
†Model 1 is adjusted for age only.
‡Model 2 is adjusted for study period, age, race, education, HTN, DM, CAD, hyperlipidemia, OC use, and BMI.
Bhat et al Cigarette Smoking and Stroke in Young Women
scale public health campaigns promoting smoking abstinence,
cessation, and reduction imperative.
The following individuals sponsored the Stroke Prevention in Young
Women Study at their institution: Frank Anderson, MD; Clifford
Andrew, MD, PhD; Merrill Ansher, MD; Brian Avin, MD; Harjit
Bajaj, MD; Robert Baumann, MD; Christopher Bever, MD; David
Buchholz, MD; Nicholas Buendia, MD; Young Ja Cho, MD; James
Christensen, MD; Kevin Crutchfield, MD; Remzi Demir, MD; Terry
Detrich, MD; Mohammed Dughly, MD; Boyd Dwyer, MD; Chris-
topher Earley, MD; John Eckholdt, MD (Deceased); Nirmala Fern-
back, MD (Deceased); Jerold Fleishman, MD; Benjamin Frishberg,
MD; Stuart Goodman, MD, PhD; Adrian Goldszmidt, MD; Kalpana
Hari Hall, MD; Norman Hershkowitz, MD, PhD; Aleem Iqbal, MD;
Constance Johnson, MD; Luke Kao, MD, PhD; Walid Kamsheh, MD;
Andrew Keenan, MD; John Kelly, MD; Harry Kerasidis, MD; Mehrul-
lah Khan, MD; Ramesh Khurana, MD; Ruediger Kratz MD; John
Kurtzke, MD; Somchai Laowattana, MD; William Leahy, MD; Alan
Levitt, MD; William Lightfoote II, MD; Bruce Lobar, MD; Paul
Melnick, MD; Michael Miller, MD, PhD; Harshad Mody, MBBS;
Marvin Mordes, MD; Seth Morgan, MD; Howard Moses, MD; Francis
Mwaisela, MD; Sivarama Nandipati, MD; Mark Ozer, MD; Roger
Packer, MD; Maciej Poltorak, MD; Thaddeus Pula, MD; Phillip
Pulaski, MD; Naghbushan Rao, MD; Marc Raphaelson, MD; Neelupali
Reddy, MD; Perry Richardson, MD; Solomon Robbins, MD; David
Satinsky, MD; Elijah Saunders, MD; Michael Sellman, MD, PhD;
Arthur Siebens, MD (Deceased); Barney Stern, MD; Harold Stevens,
MD, PhD; Jack Syme, MD; Richard Taylor, MD; Dean Tippett, MD;
Michael Weinrich, MD; Roger Weir, MD; Richard Weisman, MD;
Laurence Whicker, MD; Robert Wityk, MD; Don Wood, MD (De-
ceased); Robert Varipapa, MD; James Yan, MD; Mohammed Yaseen,
MD; and Manuel Yepes, MD.
In addition, the study could not have been completed without the
support from the administration and medical records staff at the
following institutions: In Maryland, Anne Arundel Medical Center;
Atlantic General Hospital; Bon Secours Hospital; Calvert Memorial
Hospital; Carroll Hospital Center; Chester River Hospital; Church
Hospital; Civista Medical Center; Department of Veterans Affairs
Medical Center in Baltimore; Doctors Community Hospital;
Dorchester Hospital; Franklin Square Hospital Center; Frederick
Memorial Hospital; Good Samaritan Hospital; Greater Baltimore
Medical Center; Harbor Hospital Center; Hartford Memorial Hospi-
tal; Holy Cross Hospital; Howard County General Hospital; Johns
Hopkins Bayview; The Johns Hopkins Hospital; Kernan Hospital;
Kennedy Krieger Institute; Laurel Regional Hospital; Liberty Med-
ical Center; Maryland General Hospital; McCready Memorial Hos-
pital; Memorial Hospital at Easton; Mercy Medical Center; Mont-
gomery General Hospital; Montebello Rehabilitation Hospital; North
Arundel Hospital; Northwest Hospital Center; Peninsula Regional
Medical Center; Prince George’s Hospital Center; Saint Agnes
Hospital; Saint Joseph Medical Center; Saint Mary’s Hospital; Shady
Grove Adventist Hospital; Sinai Hospital of Baltimore; Southern
Maryland Hospital Center; Suburban Hospital; The Union Memorial
Hospital; Union Hospital Cecil County; University of Maryland
Medical System; Upper Chesapeake Medical Center; Washington
Adventist Hospital and Washington County Hospital; in Washington
DC: Children’s National Medical Center; District of Columbia
General Hospital; Greater Southeast Community Hospital; The
George Washington University Medical Center; Georgetown Uni-
versity Hospital; Hadley Memorial Hospital; Howard University
Hospital; National Rehabilitation Hospital; Providence Hospital;
Sibley Memorial Hospital; Veteran’s Affairs Medical Center and the
Washington Hospital Center; in Pennsylvania: Gettysburg Hospital
and Hanover General Hospital.
We are indebted to the following members of the Stroke Prevention
in Young Women research team for their dedication: Kathleen
Caubo, Mark Dobbins, Barbara Feeser, James Gardner, Mohammed
Huq, Tamar Pair, Mary Simmons, Mary J. Sparks, Mark Waring,
Latasha Williams, and Nancy Zappala.
Sources of Funding
This material is based upon work supported in part by the Office
of Research and Development, the Medical Research Service and the
Research Enhancement Award Program in Stroke, the Geriatrics
Research, Education, and Clinical Center, and the Baltimore VAMC
Center for Excellence in Robotics, Department of Veterans Affairs;
the American Heart Association (Grant 0665352U); a Cooperative
Agreement with the Cardiovascular Health Branch, Division of
Adult and Community Health, Centers for Disease Control; the
National Institute of Neurological Disorders and Stroke (NINDS)
and the NIH Office of Research on Women’s Health (ORWH)
(Grant R01 NS45012); the National Institute on Aging (NIA) Pepper
Center (Grant P60 12583); the University of Maryland General
Clinical Research Center, General Clinical Research Centers Pro-
gram, National Center for Research Resources (NCRR), NIH (Grant
M01 RR 165001); and the Clinical Nutrition Research Unit of the
University of Maryland.
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Bhat et al Cigarette Smoking and Stroke in Young Women