Sex Differences in Physical Activity and Incident Stroke: A Systematic Review

Tracy E Madsen; Mehrnoosh Samaei; Aleksandra Pikula; Amy Y X Yu; Cheryl Carcel; Erika Millsaps; Ria Sara Yalamanchili; Nicole Bencie; Adrienne N Dula; Michelle Leppert; Tatjana Rundek; Rachel P Dreyer; Cheryl Bushnell

doi:10.1016/j.clinthera.2022.02.006

. Author manuscript; available in PMC: 2023 Apr 11.

Published in final edited form as: Clin Ther. 2022 Apr 11;44(4):586–611. doi: 10.1016/j.clinthera.2022.02.006

Sex Differences in Physical Activity and Incident Stroke: A Systematic Review

Tracy E Madsen ^a, Mehrnoosh Samaei ^b, Aleksandra Pikula ^c, Amy Y X Yu ^d, Cheryl Carcel ^e, Erika Millsaps ^f, Ria Sara Yalamanchili ^g, Nicole Bencie ^h, Adrienne N Dula ⁱ, Michelle Leppert ^j, Tatjana Rundek ^k, Rachel P Dreyer ^l, Cheryl Bushnell ^m

PMCID: PMC9195871 NIHMSID: NIHMS1797369 PMID: 35418311

Abstract

Purpose:

Physical inactivity, a modifiable risk factor for cardiovascular disease, is independently associated with stroke. Though some prior data have suggested sex differences in levels of physical activity, whether there are sex differences in the role of physical activity in primary stroke prevention is largely unknown. Our objective was to conduct a systematic review to identify and describe recent findings on sex differences in the association between physical activity and incident (first-ever) stroke. We also aimed to describe current evidence for the strength of association between physical activity and reduced stroke risk in women in particular.

Methods:

Using a pre-specified search strategy, we searched PubMed/MEDLINE and Cochrane Central to identify observational studies or trials from 2000 to 2020 reporting sex differences in physical activity and incident stroke. To be included, among other criteria, studies had to include sex-specific effect estimates for women, men, or both. Authors screened titles, abstracts, and full-text articles to identify papers meeting criteria, and study authors abstracted adjusted sex-specific estimates of the association between physical activity and incident stroke for total stroke (ischemic plus hemorrhagic) or ischemic stroke.

Findings:

Thirty-seven studies met inclusion criteria. For total incident stroke (ischemic and hemorrhagic combined), 17 of those included both women and men. Among these 17 papers, 7 (41%) showed similar associations between physical activity and incident stroke between women and men, 6 (35%) of studies suggested a significant effect in women but not in men, and 3 (18%) of studies showed a significant effect in men but not in women. For ischemic stroke, of 10 papers including women and men, 5(50%) suggested similar effects in women and men, 4(40%) suggested a significant effect in women but not in men, and 1(10%) showed an effect in men but not women. For women specifically, the majority of included studies demonstrated a reduced risk of incident stroke with physical activity with relative risk reductions ranging from 11% to 72%, though most estimates fell between 20% and 40%.

Implications:

The majority of studies indicated a clear association between physical activity and reduction of stroke risk. Studies were split as to the potential for sex differences in this association. This should be further investigated prospectively to identify strategies for the use of increased physical activity for the primary stroke prevention, with sex-specific considerations as warranted. The sex-specific dose response relationship between physical activity and stroke risk is inconclusive and warrants more research.

Keywords: stroke, sex differences, physical activity, physical inactivity, women’s health

INTRODUCTION

In North America, women bear a greater burden of disease due to a higher lifetime risk of stroke,¹ a higher lifetime risk of death from stroke, and a higher risk of poor outcomes following stroke compared with men.^2–4 Though age is a major contributor, evidence is accumulating for important sex differences in key modifiable risk factors including diabetes^5–8 as well as the presence of sex-specific risk factors in women such as adverse pregnancy outcomes.⁹ Physical activity, a known protective risk factor for mortality and cardiovascular disease,¹⁰ is not only modifiable but is linked to other stroke risk factors such as diabetes and obesity, both of which have a stronger association with stroke in women than men.¹¹

The American Heart Association (AHA) recommends moderate to vigorous aerobic physical activity at least 40 min a day, 3 to 4 days per week, to prevent stroke.^12,13 This recommendation is mainly based on observational studies, and the lack of strong clinical trials leads to many knowledge gaps. Compared to coronary heart disease (CHD), there is less robust evidence indicating a causal relationship between physical inactivity and increased risk of stroke,¹⁴ and current studies are not consistent in supporting a dose-response relationship. Various mechanisms are suggested for favorable effects of physical activity, some of which are mediated by improving other known risk factors of cardiovascular disease such as hypertension, diabetes, and body weight. Additionally, physical activity could potentially slow the atherosclerotic process and endothelial dysfunction, improve cerebral blood flow (CBF),^15,16 decrease platelets’ aggregability, and increase insulin sensitivity.^17,18

Physical activity could be differentially related to stroke in men and women due to both sex-based (related to genetic differences) and gender-based (related to sociocultural or behavioral traits) differences. While many studies have explored the association between physical activity and cardiovascular disease, there is still a substantial lack of sex-stratified data for physical activity and stroke, and there is robust heterogeneity of physical activity measurements across studies. The Framingham study indicated that moderate or intense physical activity is protective against stroke in men but not in women.¹⁹ Other data showed favorable effects in both sexes;²⁰ however, the shape of the relationship (U-shape vs. linear association) and the strength of association are not well understood. To the authors’ knowledge, no systematic reviews with the primary purpose of reporting sex differences in the role of physical activity in primary stroke prevention have been published. In a past systematic review that included stroke as a secondary outcome,²¹ only data through 2010 were reported, reporting sex-specific estimates was an exploratory objective, and data on ischemic strokes was not reported separately. Also, this prior systematic review²¹ excluded papers that did not have at least 3 categories of physical activity, as the focus was on dose response. Other prior reviews have only investigated specific types of physical activity,^22,23 include only women,^24,25 or don’t report stroke outcomes separately.²⁶ The AHA guideline for preventing stroke in women identified physical inactivity as a risk factor with similar prevalence in men and women but with an unknown difference in effect by sex.¹³

Though it is unknown whether there are consistent sex differences in the link between physical activity and incident stroke, there are well known sex differences in the associations between key metabolic factors and stroke that would make it biologically plausible that physical activity may be more strongly associated with stroke among women than men. For example, given that inadequate physical activity is linked to the development of diabetes and metabolic syndrome, and the association between diabetes and fasting blood glucose and incident stroke is stronger in women than men,^8,11 lack of physical activity may also be a stronger predictor of stroke in women than men. In addition, if sex differences are observed in the association between physical activity and stroke, future guidelines for stroke prevention in women could include more targeted recommendations.

Objectives

To address the gap in knowledge of sex differences in the role of physical activity in primary stroke prevention, our objective was to perform a systematic review to evaluate sex differences in the association between physical activity and incident (first-ever) stroke. We planned to include estimates for ischemic stroke or a combination of ischemic or hemorrhagic stroke, but we excluded studies with estimates for hemorrhagic stroke only due to clear differences in pathophysiologic mechanism. Second, given the substantial number of prospective cohort studies comprised of only women, we aimed to assess the current evidence for the strength of association between physical activity and reduced stroke risk in women in particular, for both total and ischemic stroke.

METHODS

Inclusion and Exclusion Criteria

We conducted a systematic review of manuscripts indexed in PubMed/MEDLINE or those included in Cochrane Central between January 1, 2000, and December 31, 2020. Criteria for inclusion for the study were determined a priori by study authors and included the following: 1) Inclusion of incident (first-ever) stroke as an outcome (either the primary or secondary study outcome); 2) inclusion of some measurement of physical activity or physical inactivity as an exposure variable with a reported effect estimate; and 3) reporting of sex-specific effect estimates of the association between physical activity (or inactivity) and incident stroke. No specific study designs or study populations were excluded; both observational (e.g., prospective cohort, case-control) and clinical trials were included. For the purposes of this study, we included a broad range of physical activity measurements including recreational or leisure time physical activity, occupational-related measures of activity, as well as measures of inactivity. Studies that included only women or only men were also included as they met criteria for reporting sex-specific effect estimates.

Exclusion criteria included studies that were only available in a language other than English, studies based on animal models rather than humans, studies that were only published as an abstract or conference proceeding rather than full text, or those that included participants who had experienced prior strokes, Papers on post-stroke measures of physical activity were also excluded (Figure 1). Recurrent strokes were not included, as the focus of this paper was on primary prevention. Finally, systematic reviews and meta-analyses were not included in the results but were included as comparisons in the introduction and discussion sections.

Figure 1: — Flow of article screening and inclusion in the review

Search Strategy

Our initial search strategy was an adaptation of a published PubMed search tool which has been previously validated to identify papers designed to identify either biologic sex or gender differences in particular disease states.²⁷ Further details of the validation of this search tool can be found in the original publication.²⁷ We made minor changes to field codes and added search terms specific to men to ensure the inclusion of papers that reported sex differences without mentioning it in the title as well as those that included men only. Our detailed search terms can be found in the Supplement. Following identification of candidate studies, titles and abstracts were first screened for possible inclusion by study authors. Following screening of titles and abstracts, each full text manuscript was evaluated by two study authors based on the inclusion and exclusion criteria stated above.

For included articles, data on the following variables were included: study year, geographic location, study design and population, and demographic variables of included participants including sex, age, race, and ethnicity distributions. In addition, we reported total sample size, number of stroke events, type of events for which effect estimates were included (total stroke and/or ischemic), and type of physical activity included as well as how physical activity was operationalized. To achieve our primary objectives, we abstracted the sex-specific effect estimates representing the association between physical activity and incident stroke in women, men, or both, depending on the specific study population, along with the type of effect estimate (e.g., hazard ratio for Cox proportional hazards models) and an estimate of the variability, usually a 95% confidence interval. We also abstracted any associated P-values for each effect estimate as well as P-values for sex by physical activity interaction terms when they were available. For each effect estimate, other covariates included in the models (i.e., confounders) were also reported. When multiple effect estimates were reported (i.e., unadjusted, partially adjusted, and fully adjusted), we reported the fully adjusted estimate. Crude effect estimates were not reported as these were often not reported by the primary articles, especially when physical activity was not the primary exposure variable.

For studies in which both female- and male-specific effect estimates were reported, we categorized studies as to whether there was evidence for a sex difference in the association between physical activity and risk of incident stroke. Studies demonstrating either a significant sex by physical activity interaction term (p<0.05), the presence of significant association (p<0.05) between physical activity and stroke in one sex category but not the other, or a 95% confidence interval that excluded the null value in one sex category but not the other were considered to provide evidence for a sex difference. If none of these criteria were met, the study as categorized as not providing evidence for a sex difference.

Relative risk reductions for the association between physical activity and stroke were also reported and were calculated directly by taking the difference between the effect estimate and the null, or reference value.

Covidence software²⁸ was used for abstract and manuscript screening. We did not attempt to pool data as this was not designed as a meta-analysis.

RESULTS

After applying all exclusion criteria described above, 37 full text articles were included for review (Figure 1, Table 1). Of the 37 articles, 24 included both women and men in the study,^29–52 though one of these articles only reported an effect estimate for men due to the small sample size of women.³⁸ Thirteen papers included women only,^53–65 and no studies included only men. Table 1 describes further characteristics of the studies including age distribution, study population, number of stroke events, total sample size, race and ethnicity data of study populations when available, and the specific measure and/or method of operationalizing physical activity for each of the studies. Twenty-nine papers included estimates for all strokes (ischemic and hemorrhagic), and 19 papers included effect estimates for ischemic strokes specifically. Of the 37 studies included, 31 were prospective cohort studies with the exception of 3 case control studies,^29,40,49 and 3 were other study types: one retrospective study from an administrative data set³¹ and two analyses using secondary analysis of clinical trial data.^55,64

Table 1:

Study characteristics

Author/Year	Description/ Study Design	Study Population	Women, Men, or Both	Race/Ethnicity	Age Distribution (Years)	Number of strokes/Total sample size	Measure of Physical Activity	Method of obtaining Information on Physical Activity	Types of Strokes
Prospective cohort studies
Armstrong, 2015 ¹	Prospective cohort of Million Women Study, UK	Women aged 50–64 enrolled from breast cancer screening clinics in the UK	Women	NR	55.9 (4.8)	17822/1,119,230	Inactive vs. any exercise, Inactive vs. strenuous exercise	Self-report	Total, Ischemic
Autenrieth, 2013 ²	Prospective cohort of the Atherosclerosis Risk in Communities Study	Adults in 4 U.S. communities (community-based)	Both	13.0–36.6% African American depending on quartile of PA, 87.0% – 63.3% White	Across PA levels, mean 53.7 (SD 5.7) – 54.2 (5.8)	648/613,069	Baecke PA questionnaire, then categorized as poor, intermediate, and ideal	Self-report	Total, Ischemic
Barengo, 2017 ³	Population based cohort study	Population/community based in 5 Finnish provinces	Both	Finish	65–74	226/2456	LTPA: low, moderate and high	Self-report	Total
Blomstrand, 2014 ⁴	Prospective population study of women in Sweden	Population/community sample, women >32 years gold	Women	Swedish	5 age strata, range from 38 to 89	184 / 1462	LTPA classified on a scale of 1–4 (low, intermediate, high and very high).	Self-report	Total, Ischemic
Calling, 2006 ⁵	Prospective cohort	Women and men age 45–73, community/population based sample	Both	Swedish	54.9–59.5 depending on body fat quartile	538 / 26,942	LTPA obtained via self-report, divided into quartiles, operationalized into low vs physically active	Self-report	Ischemic
Chomistek, 2018 ⁶	Prospective cohort study	Observational component of Women’s Health Study; healthy women ≥45 years old enrolled from community	Women	NR	Mean 52.3 (SD 4.8) – 66.8 (SD 7.2) depending on estimated stroke risk	650/ 27536	LTPA (>500 kcal/week vs. <500 kcal/week)	Self-report	Total
Chomistek, 2013 ⁷	Prospective cohort study	Post-menopausal women, free of CVD, enrolled in the Women’s Health Initiative Study	Women	Differs across PA level: (80–86% White, 7–9% African American, 26% Hispanic, 5% Other)	Differs across PA level: Mean 60.9 (SD 7.2) – 63.8 (SD 7.1)	2050 / 71018	LTPA by questionnaire and hours of sitting her day	Self-report	Total
Cuthbertson, 2019 ⁸	Prospective cohort study	Adults in 4 U.S. communities (community-based)	Both	Differs across exposure level: 60.9 (7.2) – 63.8 (7.1)	54.4 (5.7)	1144/13534	LTPA (none, < median, > median, Television viewing (seldom/never, sometimes, often)	Self-report	Total non-fatal strokes
Fan, 2019 ⁹	Prospective cohort study (China)	Adults recruited from Chinese communities	Both	Chinese	Mean 44.3 (SD 6.7) – 49.1 (SD 9.1) across categories of commuting	5498 / 104,170	Commuting categories: Non-active, work at/near home, walking, cycling	Self-report	Ischemic
Hall, 2019 ¹⁰	Prospective cohort study	Community based recruitment of healthy women who had sisters with breast cancer (U.S., Puerto Rico)	Women	For those with no event: 82.4% NH White, 10.3% NH Black, 4.7% Hispanic, 2.6% other; For those with stroke/TIA: 79.7% NH White, 13.1% NH Black, 4.2% Hispanic, 3.0% Other	Those w/out strokes: 53.0 (7.6), Those w/strokes; 57.7 (8.0)	567/ 31270	LTPA: MET-hours/ week in categories, occupational PA measured via questionnaire	Self-report	Total
Hu, 2000 ¹¹	Prospective cohort study	Community-based enrollment of healthy (free of CVD and cancer) adult women (Nurses’ Health Study)	Women	NR	No specific age distribution reported, but participants of Nurses’ Health Study were 40–65 years old at enrollment	407 / 72,488	METs per week calculated based on self-reported type of PA and pace of walking, categorized by MET-hours/week	Self-report	Total, Ischemic
Hu, 2001 ¹²	Prospective cohort Study	Female nurses with diabetes (subset of Nurses’ Health Study)	Women	NR	Mean age 50 years	98 /5125	Average hours of moderate or vigorous PA / week	Self-report	Total, Ischemic
Hu, 2005 ¹³	Prospective cohort	Population/community based study of Finnish adults	Both	Finnish	Women: 42.8 y non-stroke; 49.5 stroke; Men: 43.5 y non-stroke, 52.0 y stroke	2863 / 44,858	Leisure-time (low, moderate, and high) PA; Occupational (light, moderate or standing and walking, or active or walking, lifting, heavy manual labor, industrial/farm work); Commuting (using motorized transportation or no work, walking or bicycling 1–29 minutes, walking or bicycling for >30 minutes.	Self-report	Total
Huerta, 2013 ¹⁴	Prospective cohort	Adults recruited from community (European Prospective Investigation in Cancer and Nutrition Cohort, Spain)	Both	Total Hispanic White	Across levels of PA, 50.1 to 50.8 for men, 47.4 – 48.0 for women	652 / 32992	Validated PA questionnaire to assess MET × hours/week by type of PA [Occupational, recreational, household (for those not working)]	Self-report	Ischemic
Jain, 2020 ¹⁵	Prospective cohort study/Simulated intervention in the Nurses’ Health Study to simulate effect of behavior change on stroke risk	Community-based enrollment of healthy (free of CVD and cancer) adult women (Nurses’ Health Study)	Women	95% White	Mean 52 (SD 7.2)	2349 / 59,727	Moderate to vigorous intensity exercise at least 30 min/day	Simulated intervention	Total, Ischemic
Kim, 2019 ¹⁶	Prospective cohort study	Random sample of South Korean adults from the National Health Insurance Cohort Data	Both	South Korean	Mean 50.7 (SD 8.7)	16134/257854	Self-report frequency of exercise	Self-report	Total
Larsson, 2014 ¹⁷	Prospective cohort study	Community based cohort of women free from CVD and cancer (Swedish Mammography Cohort)	Women	NR	Mean 60.0 to 61.6 across lifestyle factor quintiles	1554 / 31696	> 40 min/day walking/bicycling and >1 h/week exercise vs less	Self-report	Total, Ischemic
Lv, 2017 ¹⁸	Prospective cohort	Adults free of heart disease, stroke, diabetes (China Kadoorie Biobank cohort)	Both	Chinese	Mean 50.7 (10.7)	19,348 / 461,211	Type and duration of physical activity (self-report), in occupational, commuting, domestic, and leisure-time domains in past 12 months. Daily level of PA calculated by multiplying METs value for activity by hours spent per day and summing the MET-hours for all activities.	Self-report	Ischemic
McDonnell, 2013 ¹⁹	Prospective cohort, Reasons for Geographic and Racial Differences in Stroke Study	Community-based study of U.S adults ≥45 years old	Both	40% Black, 60% White	Mean 64.6 (SD 9.4)	918 / 27,348	Questionnaire asking about moderate to vigorous physical activity, categorized as none, 1–3x/week or at least 4 times per week	Self-report	Total
Mokhayeri 2019 ²⁰	Prospective cohort,	Community based study (U.S.) (MESA)	Both	For men: 39.1% white, 12.1% Asian, 26.3% African-American, 22.5% Hispanic. For women: 37.8% White, 11.5% Asian, 29.1% African American, 21.5% Hispanic	Men: Mean 62.2 (SD 10.2), Women: 62.1 (SD 10.3)	NR/ 6809	Hypothetical intervention: exercise at least 210 minutes/ week	See previous column	Ischemic
Myint 2009 ²¹	Prospective Cohort Study (UK), EPIC-Norfolk Study	Community based study of adults in UK	Both	99.5% White	Men: Mean 58.6 (SD 9.2), Women: Mean 58.0 (SD 9.2)	599 / 20,040	Physically inactive vs. physically not inactive	Self-report	Total
Myint 2006 ²²	Prospective cohort, EPIC-Norfolk Study	Community based study of adults in UK	Both	NR	Depending on PA level: Men: Mean 56 (SD 9) – 62 (9), Women: 55 (9) – 62 (9)	361 / 22,602	Combined habitual work and leisure activity short EPIC-physical activity questionnaire, 4 categories: 1=inactive, 2=moderately inactive, 3 = moderately active, 4 = active	Self-report	Total
Ng, 2020 ²³	Prospective cohort	Community based study of Canadian adults (Canadian Community Health Survey)	Both	NR	Mean 45.9 (SD 16.1)	112,870	LTPA: No physical activity: 0 MET-hour/day, slightly active: 0 to 1.5 MET/ day Moderately active: 1.5 to 3 MET/ day Active: ≥ 3 MET/ day	Self-report	Total
Paganini-Hill, 2001 ²⁴	Prospective cohort	Residents of a southern California retirement community	Both	NR	Range 44 – 101, median 74	1984 / 13,074	Health survey, self-report	Self-report	Total, ischemic
Qiao, 2012 ²⁵	Prospective cohort	Random sample of Finnish adults	Both	NR	Mean age by specific cohort ranges from 42 (11) to 44 (11)	840 / 30,361	Self-report, nor explained with details, only 1 category: regular physical activity	Self-report	Ischemic
Sattelmair, 2010 ²⁶	Prospective cohort	Healthy women ≥45 years old enrolled from community	Women	NR	Across LTPA (kcal/week) categories, Mean is approximately 54 (SD 7)	579 / 39,315	Self-report, average time spent on 8 groups of recreational activities, <200, 200–599, 600–1499, ≥1500	Self-report	Total, Ischemic
Soares-Miranda, 2016 ²⁷	Prospective cohort	Community based study of U.S. adults (Cardiovascular Health Study)	Both	78% White	Mean 73 (SD 6)	563 / 4207	Walking score (combination of walking pace and number of blocks walked/ peer), LTPA in kcal/week, exercise intensity	Self-report	Total
Tikk, 2014 ²⁸	Prospective cohort	Community based study of adults in Heidelberg (Nutrition Heidelberg Cohort)	Both	NR	Women: Median 48.9 (IQR 37.7–61.5), Men: 52.8 (IQR 42.3–62.1)	551/23,927	Physical Activity Index	Self-report	Total
Willey, 2009 ²⁹	Prospective cohort study,	Population-based sample of adults free from stroke (Northern Manhattan Study)	Both	52.3% Hispanic, 24.4% NH Black, 21.0% NH White	Mean 69.2 (10.3)	238 / 3298	LTPA via questionnaire	Self-report	Ischemic
Willey, 2017 ³⁰	Prospective cohort study,	Current and retired female teachers in CA (California Teacher’s Study)	Women	88% Non-Hispanic White	Mean 53 (SD 14)	987 / 61,256	LTPA at baseline and 10 years follow-up, based on AHA recommendations of either 150 min/week of moderate PA or 75 min/week of strenuous PA	Self-report	Total, Ischemic
Williams, 2009 ³¹	Prospective cohort study, National Runner’s Study	Community based recruitment of adult runners	Both (but only effect estimate for men reported)	NR	Mean 44.8 (SD 10.3)	100 / 29,279	Running (km/day), self-reported	Self-report	Total
Clinical Trials (Secondary analysis of trial data)
Kurth, 2006 ³²	Secondary analysis of women in a clinical trial data	Women enrolled in Women’s Health Study, a clinical trial of aspirin every other day and vitamin E for primary prevention of CVD and cancer	Women	94.4% White, 2.1% Black, 3.5% other	Mean 54.6 (SE 0.04)	450 / 37,636	Self-report frequency/week: rarely/never, < once, once, 2–3 times, >4 times/week	Self-report	Total
Mora 2007 ³³	Secondary analysis of women in a clinical trial data	Women enrolled in Women’s Health Study, a clinical trial of aspirin every other day and vitamin E for primary prevention of CVD and cancer	Women	NR	Mean 55 (SD 7)	266 / 27055	Self-reported activity operationalized into kcal/week	Self-report	Ischemic
Case Control
Aigner, 2017 ³⁴	Case control study of patients in Stroke in Young Fabry Patients/German Health Update	Adults age 18–55; Stroke cases from hospital sample; controls from community	Both	NR	Median 47 (IQR 41–51) for cases	2125 cases, 8500 controls	Low, moderate, high categories	Self-report	Total
Guo, 2018 ³⁵	Case-control	Chinese adults with diabetes	Both	Chinese	5 groups spanning 40 – ≥ 80	353 / 632,228	Insufficient vs. sufficient PA	Self-report	Total, Ischemic
O’Donnell, 2016 ³⁶	Case-control study	Hospitalized stroke patients matched with community or hospital based controls (Interstroke)	Both	NR	Cases: Mean 62.2 (SD 13.6)	13447/26919	Self-report/questionnaire: Regular involvement in moderate / strenuous activity (at least 4 times per week)	Self-report	Total
Other
Lee, 2018 ³⁷	Retrospective administrative dataset,	Sample of adults from Korean National Health Insurance Screening Data	Both	Korean	Included adults > age 20	640,804 / 5,715,311	Low physical activity (self-reported as none) vs moderate (1–4 times/week) vs high (5 to 7 times/week)	Self-report	Total

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NR: Not reported, PA: Physical activity, ICH: intracerebral hemorrhage; LTPA: Leisure Time Physical Activity; MET: Metabolic Equivalents

There was substantial heterogeneity in the constructs used to measure physical activity (Table 1). All studies obtained data on physical activity using participant self-report (e.g., questionnaires); none of the studies used objectively measured physical activity (i.e., measurement using devices). Leisure time physical activity was the most commonly measured type of physical activity, though some studies had variables which included both physical activity from leisure time and occupational physical activity, some included a broad measure of ‘exercise,’ some included estimates for physical activity related to participants’ occupation or commute to work, and some measured sedentary time and/or inactivity. Effect estimates were mostly relative measures of the association between physical activity and incident stroke (either hazard ratios or relative risks), though 3 papers^29,34,47 reported absolute measures of effect such as population attributable risk percents.

Sex differences in the association between physical activity and total stroke

For our first objective, sex differences in the association between physical activity and overall (total) incident stroke, data from articles that included both women and men are displayed in Figure 2 and Supplemental Table 1. Among 17 papers that included both women and men and reported effect estimates for total stroke, 7 (41%) showed similar associations between physical activity and incident stroke between women and men,^{31,33,38,40,47,50,52} 6 (35%) of studies^{36,39,42,44,45,49} suggested a significant effect in women but not in men, and 3 (18%) of studies^30,35,41 showed a significant effect in men but not in women. One paper²⁹ (of the 17) demonstrated a higher population attributable risk of stroke due to physical inactivity in women than men (63.8% vs. 57.6%), but the difference was not tested for statistical significance. Of the 7 papers showing similar effect estimates by sex, ^{31,33,38,40,47,50,52} 5 papers demonstrated reduced risk of total stroke with increasing physical activity,^{31,40,47,50,52} and in some cases, moderate frequencies of physical activity were more protective than every day exercise.⁵²

Data for total strokes by sex are graphically displayed in Figure 2, though three (of 17) studies are excluded from this figure. Two were not displayed on the figure as they reported absolute measures of effect which could not be shown on a Forest plot.^29,47 The third³⁸ was not displayed because the sex-specific estimate for women was not reported due to small case numbers. Six papers reported the testing of a sex by physical activity interaction term;^{33,38,40,41,50,52}, all showing non-significant interactions.

Sex differences in the association between physical activity and ischemic stroke

Similarly, for ischemic stroke, among 10 papers, 5 (50%) of studies^{30,32,34,46,48} suggested similar effects in women and men, 4 (40%) suggested a significant effect in women but not in men,^42,43,49,51 and 1 (10%)³⁷ showed an effect in men but not women.³⁷ (Supplemental Table 1a) Few papers (n=3) reported that they tested interaction terms or conducted a hypothesis test of a sex by physical activity interaction,^32,37,48 and one demonstrated a significant sex interaction (P for interaction <0.05).³⁷

Association between physical activity and stroke risk in women

Our second objective was to evaluate the current evidence for the strength of association between physical activity and reduced stroke risk in women specifically. There were 29 studies that reported a measure of association between physical activity and incident total stroke (studies with either only women or those with both women and men, Table 1). One study³⁸ did not report the effect estimate for women due to small case numbers; and this study was not included in Table 2. Of the 28 studies in Table 2, Nineteen studies (68%) reported estimates indicating a protective effect of physical activity on risk of stroke, either supported by a significant P-value for the trend across physical activity categories, relative effect estimates with confidence intervals that do not cross the null value, or both.^{29,31,36,39,40,42,44,45,47,49,50,52–54,57–61} One study (4%) reported a borderline association,⁶³ and eight (29%) reported a non-significant association between physical activity and incident total stroke.^{30,33,35,41,56,62,64,65}

Table 2:

Association between Physical Activity and Incident Stroke in Women

Author/Year	Adjusted effect estimate for women	P-value^*	Adjustment Factors	Evidence for an association between PA and stroke (Y/N)

Total Incident Strokes (Ischemic and Hemorrhagic Combined)
Aigner, 2017	PAR 63.8 (95% CI 58.0–69.6)	NR	HTN, HLD, DM, CAD, smoking, alcohol use, BMI, cases and controls were matched by age and sex	Y
Armstrong, 2015	Strenuous Activity: None: 1.0 (REF) 1x/week: RR 0.83 (0.80–0.85), 2–3x / week: RR 0.81 (0.78–0.84), 4–6x/ week: RR 0.87 (0.80–0.95), Daily: RR 0.96 (0.89–1.04)	<0.001	Stratified by SES and region, BMI by age, alcohol by age, smoking by age	Y
	Any exercise: None: 1.0 (REF) 1x/week: 0.87 (0.84–0.90), 2–3x / week: 0.80 (0.77–0.83), 4–6x week: 0.83 (0.79–0.88), Daily: 0.88 (0.86–0.91)	<0.001	Stratified by SES and region, BMI by age, alcohol by age, smoking by age	Y
Autenrieth, 2013	HR, Poor PA: 1.0 (REF) Intermediate PA: 0.98 (0.75–1.29) Ideal PA: 0.94 (0.67–1.33)	0.735	Age, race-center, cigarette years, education, WHR, SBP, use of antihypertensives, diabetes, LVH, HDL, LDL, lipoprotein(a), fibrinogen, vWF, WBC	N
Barengo, 2017	HR (95%CI): Low PA: 1.0 (REF) Moderate PA: 0.61 (0.36–1.03) High PA: 0.48 (0.19–1.22)	0.12	Age, study area, study year, BMI, total cholesterol, SBP, smoking, education, marital status, self-reported inability to practice PA	N
Blomstrand, 2014	Physical Inactivity (vs. physical activity) HR 1.49 (1.14–1.96)	p<0.05	Age and baseline data concerning hypertension, BMI, smoking, physical inactivity, cholesterol, triglycerides, mental stress and educational level	Y
Chomistek, 2018	Being physically active (500 kcal/week) (vs. physically inactive) HR 0.78 (0.66, 0.91)	NR	Adjusted for age; randomized treatment assignment; smoking status; consumption of alcohol, saturated fat, fiber, fruits, and vegetables; menopausal status; postmenopausal hormone use.	Y
Chomistek, 2013	Sedentary Time, HR: <=5 hours/day: 1.00 (REF) 5.1–9.9 hours/ day: 1.03 (0.94–1.14) > 10 hours/day: 1.18 (1.04–1.34)	0.008	Stratified by age, includes sedentary time and physical activity simultaneously as well as race, education, income, marital status, smoking, family history of myocardial infarction, depression, alcohol intake, hours of sleep, intake of total calories, saturated fat, fiber, HTN, DM, high cholesterol	Y
	PA (MET-hour/week) High 1.00 (REF) Medium 1.08 (0.95, 1.23) Low 1.19 (1.04, 1.36) Inactive 1.30 (1.13, 1.50)	<0.001	Stratified by age, includes sedentary time and physical activity simultaneously as well as race, education, income, marital status, smoking, family history of myocardial infarction, depression, alcohol intake, hours of sleep, intake of total calories, saturated fat, fiber, HTN, DM, high cholesterol	Y
Cuthbertson, 2019	Disease-free expected years from age 50, (95%CI): LTPA> median (13.2 MET hours/week) and low TV time: 27.1 (26.4–27.7) No LTPA and high TV time: 24.6 (24.1–25.1) (REF) Difference 2.4 (95%CI, 1.7–3.2)	NR	Age, urban/rural address, marital status, ethnic group, HTN, a fib, abnormal lipids, TIA hx, family hx of stroke, SBP, DBP, use of antihypertensive, glucose lower agent, and cholesterol lowering agents	Y
Guo, 2018	OR (95%CI) Insufficient PA: 1.50 (1.02–2.21)	<0.05	Age, urban/rural address, marital status, ethnic group, HTN, a fib, abnormal lipids, TIA hx, family hx of stroke, SBP, DBP, use of antihypertensive, glucose lower agent, and cholesterol lowering agents	Y
Hall, 2019	HR: No LTPA: 1.0 (REF) All activity <3 MET: 0.97 (0.62–1.51) Insufficient activity to meet requirements: 0.82 (0.65–1.04) 3-<6 MET at ≤150 min/ week: 0.72 (0.44–1.19) ≤6 MET for at least 75 min / week: 0.64 (0.44–0.94)	NR	Age, OPA, alcohol, smoking, BMI, discrimination at work, night work, rate pressure	Y
Hu, 2000	MET Quintiles (REF is Q1) RR 0.66 (0.47–0.91)	0.005	Cigarette smoking, BMI, menopausal status, parental hx MI before age 60, alcohol consumption, aspirin use, hx htn, hx DM, or hx hypercholesterolemia	Y
Hu, 2001	>7 (vs. <1 h/wk): RR 0.75 (0.22–2.51)	0.17	Cigarette smoking, BMI, menopausal status, parental hx MI before age 60, alcohol consumption, aspirin use, hx htn, hx DM, or hx hypercholesterolemia, MVI supplement, Vit E supplement	N
Hu, 2005	Leisure activity: High (vs. low): HR 0.77 (95% CI 0.62–0.97) Occupational activity Act (vs. light): HR 0.89 (95% CI 0.78–1.03) Commuting >30 min (vs. 0 min): HR 0.87 (95%CI 0.75–1.01)	Leisure model: 0.013; Occupational model: 0.28; Commuting model: 0.093	Age, area, study year, BMI, SBP, cholesterol, education, smoking, alcohol consumption, diabetes, other 2 types of PA.	Y
Jain, 2020	Population Risk Ratio, Effect of exercising ≤ 30 min/day 0.80 (0.59 to 1.00)	NR	Age, history of cardiovascular disease at age ≤60 y in first-degree relatives, smoking and oral contraceptive use before 1980, marital status, education, employment, race, BMI at 18 y of age, stress in daily life and work; and time-varying covariates: cigarettes smoked, statin use, postmenopausal hormone use, aspirin use, physical activity, intake of nuts, whole grains, refined grains, fruits and vegetables, fish, unprocessed red meat, processed red meat, poultry, alcohol, calories, BMI, high serum cholesterol, high blood pressure, menopause, cancer, diabetes mellitus, and coronary artery disease	B
Kim, 2019	HR (95%CI): No Exercise: 1.0 (REF) 1–2x/week: 0.89 (0.84–0.94), 3–4x/week: 0.82 (0.76–0.89), 5–6x/ week: 0.79 (0.68–0.92), Almost every day: 0.94 (0.86–1.02)	NR	Age, BMI, SBP, FBG, total cholesterol, family history stroke/ HTN, heart disease, smoking, alcohol use	Y
Kurth, 2006	Rarely or Never: HR 1.0 (REF) < Once/week: HR 1.13 (0.88–1.45); Once/wk: HR 1.02 (0.72–1.43); 2–3 times/wk: HR 0.89 (0.68–1.17); >4 times/wk: HR 0.98 (0.70–1.37)	p>0.05	Age, components of health index: diet, alcohol consumption, smoking, BMI. Note that the overall Health Index score and stroke had many other covariates for the two models	N
Larsson, 2014	Walking/bicycling ≥40 min/d and exercise ≥1 h/wk (vs. less) HR: 0.94 (0.84–1.05)	NS	Age, education, aspirin use, history of DM, diagnosis of afib, fam hx MI before age 60, total energy intake, non-recommended Food Score, smoking, BMI, alcohol	N
Lee, 2018	Low PA: HR 1.0 (REF) Moderate PA: HR 0.88 (95% CI 0.866–0.894) High PA: HR: 0.891 (95% CI 0.872–0.910)	<0.0001 for both categories	Age, past hx HTN, history of heart disease, fam hx heart disease, fam hx stroke, alcohol, cholesterol (total), smoking, diabetes, BMI	Y
McDonnell, 2013	At least 4 times per week: 1.0 (REF), 1–3x / week: 0.99 (0.75–1.30) None: 1.10 (0.85–1.43)	0.4	Age, race, age by race, income, education, diabetes, hypertension, BMI, alcohol use, smoking	N
Myint, 2009	Physically inactive (vs. not inactive) RR 1.37 (1.08–1.73)	0.0009	Age, sex, BMI, SBP, cholesterol, ASA use, DM, social class	Y
Myint 2006	Inactive: 1.0 (REF) Moderately inactive: RR 0.81 (95% CI 0.57–1.14) Moderately active = RR 0.82 (95%CI 0.53–1.26) Active = RR 0.71 (95% CI 0.41–1.26)	0.50	Age, smoking, SBP, BMI, cholesterol, history of DM	N
Ng, 2020	HR (95%CI) Active: 1.0 (REF) Moderately active: 1.44 (1.11–1.88) Slightly active: 1.38 (1.07–1.78) No physical activity: 0.96 (0.68–1.35)	NR	Ethnicity, immigrant status, rural residence, education level, income, marital status, self-rated health, life stress, asthma and high blood pressure, alcohol, BMI, cigarettes smoked, daily fruit and vegetable consumption	Y
O’Donnell, 2016	Regular involvement in moderate or strenuous activity (vs no regular involvement): OR (99% CI) 0.65 (0.5–0.85)	NR	Sex and age matched, adjusted for geographic region	Y
Paganini-Hill, 2001	PA per day RR < 0.5 hours/day minutes: 1.0 (REF) < 0.1 hours/day: 0.88 > 1 hour/day: 0.83 (0.73–0.95)	<0.01	Age, others not specified	Y
Sattelmair, 2010	Kcal/ week, RR <200: 1.0 (REF) 200–599: 1.16 (0.91–1.48) 600–1499: 0.93 (0.72–1.20) ≥1500: 0.89 (0.68–1.17	0.21	Age, randomized treatment assignment, plus smoking; alcohol; saturated fat, iruit and vegetable, and fiber intake, postmenopausal hormone therapy; menopausal status, parental history of myocardial infarction, and migraine aura, BMI, history of diabetes, history of elevated cholesterol, and history of hypertension.	N
Soares-Miranda, 2016	I (REF), II: 0.63 (0.48–0.83), III: 0.51 (0.37–0.69), IV: 0.52 (0.35–0.76)	<0.001	Age, race, education, income, clinical sites, smoking, BMI	Y
Tikk, 2014	HR Inactive: 1.0 REF, Moderately inactive: 0.49 (0.34–0.71), Moderately active: 0.53 (0.35–0.79), Active: 0.50 (0.32–0.77)	NR	BMI, waist circumference, physical activity, smoking status, alcohol consumption, diet	Y
Willey, 2017	HR Neither recommendation met: 1.0 (REF) Either recommendation met: 0.83 (0.73–0.94)	NR	Age, race, SES, tobacco use, alcohol use, BMI, HTN, DM, hyperlipidemia	Y
Incident Ischemic Stroke Only
Armstrong, 2015	Strenuous Activity Inactive: 1.00 (REF) 1x/week: RR 0.88 (0.84–0.92) 2–3x / week: RR 0.81 (0.75–0.88) 4–6x/ week: RR 0.86 (0.74–1.01) Daily: RR 0.92 (0.80–1.05)	<0.001	Stratified by SES and region, BMI by age, alcohol by age, smoking by age	Y
	Any exercise Inactive: 1.00 (REF) 1x/week: 0.89 (0.84–0.94) 2–3x / week 0.82 (0.77–0.87) 4–6x week 0.83 (0.76–0.92) Daily: 0.91 (0.86–0.97)	<0.001	Stratified by SES and region, BMI by age, alcohol by age, smoking by age	Y
Autenrieth, 2013	HR (95% CI): Poor PA: 1.0 (REF) Intermediate PA: 1.05 (0.79–1.41) Ideal PA: 0.87 (0.591.28)	0.654	Age, race-center, cigarette years, education, WHR, SBP, use of antihypertensives, diabetes, LVH, HDL, LDL, lipoprotein(a), fibrinogen, vWF, WBC	N
Blomstrand, 2014	Physical Inactivity (vs. Physical activity) HR 1.35 (0.99–1.85)	>0.05	Age and baseline data concerning hypertension, BMI, smoking, physical inactivity, cholesterol, triglycerides, mental stress and educational level	B
Calling, 2006	Physically active (vs. low PA): For those with low BF%): HR 0.65 (0.37–1.13), For those with high BF%: HR 0.68 (0.50–0.93)	>0.05, <0.05	Age, smoking status, high alcohol intake, height, DM, SBP, BP medications, lipid-lowering drugs	Y
Guo, 2018	OR, 95%CI Insufficient PA (vs. sufficient PA): 1.57 (1.04–2.36)	<0.05	Age, urban/rural address, marital status, ethnic group, HTN, a fib, abnormal lipids, TIA hx, family hx of stroke, SBP, DBP, use of antihypertensive, glucose lower agent, and cholesterol lowering agents	Y
Fan, 2019	HR (95%CI) Non-active commuting: 1.0 (REF) Work near home: 1.04 (0.90–1.20) Walking: 1.03 (0.92–1.16) Cycling: 0.96 (0.82–1.12)	NR	Education, marital status, income, occupation, alcohol consumption, smoking status, intake of red meat, fresh fruit, vegetables, leisure time sedentary activity, family history of heart attack, BMI, hypertension, DM, pollution, passive smoking, other types of PA	N
Hu, 2000	MET Quintiles (5^th vs. 1^st quintile) RR 0.52 (0.33–0.80)	0.003	Cigarette smoking, BMI, menopausal status, parental hx MI before age 60, alcohol consumption, aspirin use, hx htn, hx DM, or hx hypercholesterolemia	Y
Hu, 2001	>7 (vs <1) h/wk: RR: 0.38 (0.17–0.82)	0.01	Cigarette smoking, BMI, menopausal status, parental hx MI before age 60, alcohol consumption, aspirin use, hx htn, hx DM, or hx hypercholesterolemia, MVI supplement, Vit E supplement,	Y
Huerta, 2013	HR (95%CI) PA at work (manual/heavy vs sedentary) 1.97 (0.58–6.67) Household PA (high vs low MET-h/wk): 0.77 (0.43–1.39)	>0.05 >0.05 <0.01	Stratified by age and center and adjusted by baseline education, selfreported HTN or hyperlipidemia, DM, smoking, age at start of smoking, alcohol, total energy intake, BMI, waist circumference, consumption of protein, lipids, vegetables, red meat, and fish, mutual adjustment of all PA variables	Y
	Recreational (Active vs inactive): HR 0.45 (0.22–0.90) Vigorous PA (> 2 h/wk vs none) HR 1.17 (0.61–2.24).	>0.05
Jain, 2020	Population Risk Ratio, Effect of exercising ≤ 30 min/day 0.71 (0.49 to 0.95)	NR	Age, history of cardiovascular disease at age ≤60 y in first-degree relatives, smoking and oral contraceptive use before 1980, marital status, education, employment, race, BMI at 18 y of age, stress in daily life and work; and time-varying covariates: cigarettes smoked, statin use, postmenopausal hormone use, aspirin use, physical activity, intake of nuts, whole grains, refined grains, fruits and vegetables, fish, unprocessed red meat, processed red meat, poultry, alcohol, calories, BMI, high serum cholesterol, high blood pressure, menopause, cancer, diabetes mellitus, and coronary artery disease	Y
Larsson, 2014	Walking/bicycling ≥40 min/d and exercise ≥1 h/wk (vs. less) HR: 0.91 (0.81–1.04)	NS	Age, education, aspirin use, history of DM, diagnosis of afib, fam hx MI before age 60, total energy intake, non-recommended Food Score, smoking, BMI, alcohol	N
Lv, 2017	Physical activity, MET-hours/day <11.0: 1.00 (REF) 11–18.0: 0.95 (0.90–0.99) 18.0–29.5: 0.89 (0.83, 0.95) ≥ 29.5: 0.86 (0.80, 0.93)	<0.001	All lifestyle factors, age, sex, education, marital status, family hx heart disease or stroke, prevalent hypertension, menopausal status for women	Y
Mora, 2007	< 200 kcal/ week: 1.00 (REF) 200–599 kcal/ week: 0.68 (0.49–0.95) 600–1499 kcal/week: 0.69 (0.5–.95) >1500 kcal/week: 0.72 (0.51–1.01)	0.16	Age, treatment arm	Y
Mokhayeri 2019	Hypothetical intervention 210 min/week (compared w/no intervention) Risk Difference −0.06 (−0.63–0.38); PAF %: 2.60 (−18.74–26.10)	NR	TG, DM, CAD, BP medications, lipid lowering medications, aspirin, age, race, alcohol use, anger index, anxiety index, stroke history of parents, stroke history of siblings, homocystine, fibrinogen, CRP	N
Paganini-Hill, 2001	PA per day (RR, RR 0.5 hours/day: 1.0 (REF) 0.1 hours/day: 0.95 > 1 hour/day: 0.81	p>0.05	Age, others not specified	N
Qiao, 2012	Regular PA (vs. no regular PA) HR : 0·80 (0.64–0.99)	NR	Age, smoking, History of diabetes, antihypertensive treatment, incapable of walking 500 m, happy marriage, vegetable and/or fruit at least once a week, SBP, BMI	Y
Sattelmair, 2010	Kcal/ week, RR <200: 1.0 200–599: 1.11 (0.85–1.46) 600–1499: 0.87 (0.66–1.16) ≥1500: 0.88 (0.65–1.19)	0.22	Age, randomized treatment assignment, plus smoking; alcohol; saturated fat, fruit and vegetable, and fiber intake, postmenopausal hormone therapy; menopausal status, parental history of myocardial infarction, and migraine aura, BMI, history of diabetes, history of elevated cholesterol, and history of hypertension.	N
Willey, 2009	HR (95%CI) Moderate to heavy activity vs. none: 0.92 (0.57–1.50)	NR	Age, race, education, insurance status, hypertension, diabetes, alcohol intake, tobacco use	N
Willey, 2017	HR for physical activity recommendations per AHA Neither recommendation met: 1.0 (REF) Either recommendation met: 0.82 (0.70–0.96)	NR	Age, race, SES, tobacco use, alcohol use, BMI, HTN, DM, hyperlipidemia	Y

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P-values refer to those for the associations between measures of physical activity and stroke.

Abbreviations: ASA: acetylsalicylic acid, BMI: body mass index, BP : blood pressure CAD: coronary artery disease, CI: confidence interval, DBP: diastolic blood pressure, DM: diabetes mellitus, FBG: fasting blood glucose, HDL: high-density lipoprotein; HLD: hyperlipidemia, HR: hazard ratio, HTN: hypertension: history, LDL: low-density lipoprotein, LTPA: leisure time physical activity, LVH: left ventricular hypertrophy, MET: metabolic equivalents, NR: not reported, NS: not significant; OR: odds ratio, PA: physical activity, PAR: Population attributable risk, REF: Reference, RR: relative risk, SBP: systolic blood pressure, TIA: transient ischemic attack

For estimates of the association between measures of physical activity and incident ischemic stroke among women, of 19 papers, 11 (58%)^{32,43,46,49,51,53,55,57,61–63} reported evidence for a protective effect of physical activity, one study (5%) demonstrated a trend towards a protective effect,⁵⁴ and 7 (37%) demonstrated no evidence for reduced risk of incident stroke associated with physical activity.^{30,34,37,42,48,56,65} Models were commonly adjusted for age, demographic, comorbidities, BMI and other lifestyle factors (Table 2). Excluding those studies that measured only occupational-physical activity, commuting, or those that only reported an absolute measure of effect, the relative risk reduction for stroke was apparent, but widely varied across studies and level of physical activity from 11% to 51% for total stroke and from 11% to 72% for ischemic stroke.

Types of physical activity

Although the majority of studies included primarily recreational or leisure time physical activity, five studies specifically investigated occupational-related physical activity or commuting activity,^{32,35,48,50,60} either as the primary objective or in addition to investigating leisure time activity. Other studies included occupational-related physical activity in the total physical activity estimates. Some studies reported differing effects between leisure time physical activity and occupational⁵⁰ or commuting activity and reported reduced stroke risk with leisure time physical activity but no reduced stroke risk associated with increased occupational activity or commuting.

DISCUSSION

In this review of sex differences in the association between physical activity and incident total and ischemic stroke, we found that among women, the majority of the studies demonstrated a reduced risk of incident stroke associated with physical activity with estimates ranging from 11% to 72%, though most estimates fell in the 20% to 40% range. Estimates varied depending on the study population, the way that physical activity was quantified (e.g., two level vs. multi-level variable), and other study characteristics. Studies were conflicted as to whether the association between physical activity and incident stroke differed by sex, with 35% of the studies on total stroke demonstrating a significant association in women but not in men and fewer demonstrating a stronger association in men than women.

Our results are generally supported by prior studies with respect to the degree of stroke risk reduction associated with physical activity. For example, in a large systematic review and meta-analysis that included 21 prospective studies, the pooled relative risk of stroke for moderate vs. low physical activity was 0.73 for men and 0.89 for women after adjusting for age, other stroke risk factors, and menopausal status.²¹ Similarly, in a meta-analysis by Oguma that included only women, physical activity was associated with approximately 30% reduction in stroke risk.²⁴ Our results also support recommendations found in stroke prevention guidelines,^12,13 that moderate to vigorous physical activity at a moderate frequency (3–4 times per week) reduces risk of stroke.

With respect to a potential dose-response, though not a primary objective of our study, papers that compared multiple levels of physical activity largely demonstrated that even moderate intensity and/or frequency of physical activity was beneficial in decreasing stroke risk and that the benefit of physical activity did not always increase with higher levels of physical activity frequency, though there was a wide degree of heterogeneity with respect to definitions of low, moderate, and high physical activity. Further prospective and possible interventional studies may be needed to more definitively determine the optimal level of physical activity for risk reduction in women and men.

In the majority of included studies, findings of reduced risk of incident total stroke and ischemic stroke remained despite adjustment for multiple covariates. However, approximately 1/3 of the studies demonstrated no significant association in adjusted estimates, which may be due to a variety of factors. The wide degree of heterogeneity of how physical activity was categorized, along with differing study populations and potentially differing covariates in the models, may contribute to conflicting results between studies, though there may also be biologic explanations for studies demonstrating no significant association between physical activity and incident stroke. These findings could also be due to having mediators included in the adjusted models. For example, some of the benefit of regular physical activity may be in the modification of other risk factors such as obesity, hypertension, and the development of metabolic syndrome, with reduced stroke risk being a downstream effect of having fewer of these comorbidities.

Though age may be a key factor in the role of physical activity in stroke prevention, it is unclear if the strength of association between physical activity and incident stroke varies predictably over the lifespan. The baseline ages of participants varied fairly widely among the studies included in this review, with mean ages ranging from approximately 40 to over 70 years of age. As mentioned, there was also a wide degree of heterogeneity with respect to the physical activity constructs, race/ethnicity, and other differences in study populations, making it difficult to separate out the effect of age in our study. Additional biologic considerations would be sex differences in the ability to participate in strenuous activity at older ages as well as the potential for hormonal changes to affect the role of physical activity on cerebrovascular disease. Future work should investigate the role of physical activity across the lifespan and sex differences in optimal levels of physical activity across the lifespan as other risk factors increase in prevalence.

Limitations

Our study has several limitations. First, studies indicating a lack of sex difference in the association of interest might be underpowered to detect sex differences, pointing to the need for future studies specifically designed to test sex differences. Similarly, few of the studies that reported sex-specific estimates conducted formal hypothesis testing to determine whether sex differences were significant. As a result, we may have underreported the number of studies with true sex differences. In addition, we did not pool effect estimates or perform a meta-analysis. There was a wide degree of heterogeneity with respect to how physical activity was measured and categorized; data from future prospective studies with standardized definitions of physical activity may add additional information. All physical activity data from included studies were obtained from self-report. Though self-report may be affected by recall or reporting bias, self-report of physical activity is still a valid method, especially in observational and population-based studies.⁶⁶ We did not separately investigate hemorrhagic strokes in our analysis; this should be the topic of a future study. Finally, data on race and ethnicity of participants in some of the studies was not complete; future studies should report race and ethnicity of participants and ensure adequate enrollment of those from minoritized groups.

Conclusions

In conclusion, we found that the majority of studies indicated a clear association between physical activity and reduction of stroke risk. In women, the benefit of regular physical activity in some populations was associated with as much as 70% reduction in stroke risk, though the majority of studies reported more modest risk reductions. Studies were split as to the potential for sex differences in this association, and this should be further explored prospectively and in the context of factors like age, BMI, and other comorbidities. The sex-specific dose response relationship between physical activity and stroke risk is inconclusive but warrants further investigation. Regardless, physical activity continues to be a modifiable lifestyle factor that should be included in stroke prevention strategies for both women and men.

Supplementary Material

NIHMS1797369-supplement-1.docx^{(45.5KB, docx)}

Acknowledgments

Declaration of Interest: TEM is funded by the NHLBI (K23 HL140081–01A1). AP is funded by the Canadian Institutes of Health Research (CIHR). AYXY is funded by a National New Investigator Award from Heart and Stroke Foundation of Canada. CC is funded by the National Heart Foundation Australia (Award ID 102742). AND is funded by Lone Star Stroke Research Consortium and American Heart Association AHA 847469. ML is funded by NIH/NCATS Colorado CTSA KL2 (TR002534). TR is funded by the grants from National Institutes of Health (R01 MD012467, R01 NS029993, R01 NS040807, U24 NS107267), the National Center for Advancing Translational Sciences (UL1 TR002736, KL2 TR002737), and the Florida Department of Health. RPD is funded by the Canadian Institutes of Health Research (CIHR) and the American Heart Association. CB is funded by grants from National Institutes of Health (U24NS107235, UL2TR001420), Agency for Healthcare Research Quality (1R01HS025723), and Patient Centered Outcomes Research Institute (Phased Large Awards for Comparative Effectiveness Research or PLACER). MS, EM, RSY, and NB have no disclosures to report.

Footnotes

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Supplementary Materials

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[R24] 24.Oguma Y, Shinoda-Tagawa T. Physical activity decreases cardiovascular disease risk in women: review and meta-analysis. Am J Prev Med. 2004;26(5):407–418. doi: 10.1016/j.amepre.2004.02.007 [DOI] [PubMed] [Google Scholar]

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[R27] 27.Song MM, Simonsen CK, Wilson JD, Jenkins MR. Development of a PubMed based search tool for identifying sex and gender specific health literature. J Women’s Heal. 2016;25(2):181–187. doi: 10.1089/jwh.2015.5217 [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R32] 32.Lv J, Yu C, Guo Y, et al. Adherence to Healthy Lifestyle and Cardiovascular Diseases in the Chinese Population. J Am Coll Cardiol. 2017;69(9):1116–1125. doi: 10.1016/j.jacc.2016.11.076 [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R34] 34.Mokhayeri Y, Hashemi-Nazari SS, Khodakarim S, et al. Effects of Hypothetical Interventions on Ischemic Stroke Using Parametric G-Formula. Stroke. 2019;50(11):3286–3288. doi: 10.1161/strokeaha.119.025749 [DOI] [PubMed] [Google Scholar]

[R35] 35.Myint PK, Luben RN, Wareham NJ, et al. Combined work and leisure physical activity and risk of stroke in men and women in the European prospective investigation into Cancer-Norfolk Prospective Population Study. Neuroepidemiology. 2006;27(3):122–129. doi: 10.1159/000095551 [DOI] [PubMed] [Google Scholar]

[R36] 36.Myint PK, Luben RN, Wareham NJ, Bingham SA, Khaw KT. Combined effect of health behaviours and risk of first ever stroke in 20,040 men and women over 11 years’ follow-up in Norfolk cohort of European Prospective Investigation of Cancer (EPIC Norfolk): prospective population study. Bmj. 2009;338:b349. doi: 10.1136/bmj.b349 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] 37.Willey JZ, Moon YP, Paik MC, Boden-Albala B, Sacco RL, Elkind MS. Physical activity and risk of ischemic stroke in the Northern Manhattan Study. Neurology. 2009;73(21):1774–1779. doi: 10.1212/WNL.0b013e3181c34b58 [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] 38.Williams PT. Reduction in incident stroke risk with vigorous physical activity: evidence from 7.7-year follow-up of the national runners’ health study. Stroke. 2009;40(5):1921–1923. doi: 10.1161/strokeaha.108.535427 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Sex Differences in Physical Activity and Incident Stroke: A Systematic Review

Tracy E Madsen, MD, PhD

Mehrnoosh Samaei, MD, MPH

Aleksandra Pikula, MD

Amy Y X Yu, MD, MSc

Cheryl Carcel, MD, PhD

Erika Millsaps, RN, MSN

Ria Sara Yalamanchili, MS

Nicole Bencie, BA

Adrienne N Dula, PhD

Michelle Leppert, MD, MBA

Tatjana Rundek, MD PhD

Rachel P Dreyer, Ph.D.

Cheryl Bushnell, MD, MHS

Abstract

Purpose:

Methods:

Findings:

Implications:

INTRODUCTION

Objectives

METHODS

Inclusion and Exclusion Criteria

Figure 1:

Search Strategy

RESULTS

Table 1:

Sex differences in the association between physical activity and total stroke

Figure 2:

Sex differences in the association between physical activity and ischemic stroke

Association between physical activity and stroke risk in women

Table 2:

Types of physical activity

DISCUSSION

Limitations

Conclusions

Supplementary Material

Acknowledgments

Footnotes

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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