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01.12.2021 | Review article | Ausgabe 1/2021 Open Access

Environmental Health and Preventive Medicine 1/2021

Association between exposure to ambient air pollution and hospital admission, incidence, and mortality of stroke: an updated systematic review and meta-analysis of more than 23 million participants

Zeitschrift:
Environmental Health and Preventive Medicine > Ausgabe 1/2021
Autoren:
Zhiping Niu, Feifei Liu, Hongmei Yu, Shaotang Wu, Hao Xiang
Wichtige Hinweise

Supplementary Information

The online version contains supplementary material available at https://​doi.​org/​10.​1186/​s12199-021-00937-1.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abbreviations
PM2.5
Particulate matter with aerodynamic diameter less than 2.5 μm
PM10
Particulate matter with aerodynamic diameter less than 10 μm
NO2
Nitrogen dioxide
SO2
Sulfur dioxide
CO
Carbon monoxide
O3
Ozone
OR
Odds ratio
HR
Hazard ratio
CI
Confidence interval
e.g.
For example
GBD
The Global Burden of Disease Study
CVD
Cardiovascular diseases
DALYs
Disability-adjusted life years
RR
Risk ratio
PRISMA
The Preferred Reporting Items for Systematic Review and Meta-analyses
NOx
Nitrogen oxides
IQR
Interquartile range
SD
Standard deviation
NOS
The Newcastle-Ottawa Scale
SE
Standard error
China-PAR
Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project
ICH
Intracerebral hemorrhage
IS
Ischemic stroke
REGARDS cohort
Reasons for Geographic and Racial Differences in Stroke Cohort
PPS
Primary prevention study
CNBSS
Canadian National Breast Screening Study
HS
Hemorrhagic stroke
ESCAPE Project
The European Study of Cohorts for Air Pollution Effects
AOD
Aerosol optic depth
ISSeP
The Scientific Institute of Public Services
CMAQ
Community Multiscale Air Quality model
QOED
The Qingyue Open Environmental Data Center
USEPA
The US Environmental Protection Agency
HBM
Hierarchical Bayesian Model
EPA
The Taiwanese Environmental Protection Administration
EPD
The Environmental Protection Department
LUR
Land-use regression model
IDW
Inverse distance weighting

Introduction

Stroke, characterized by acute cerebral blood circulation disorder, is caused by artery stenosis, occlusion, or rupture caused by various inducing factors in patients with cerebrovascular diseases [ 1]. Stroke has become a leading contributor to the global burden of disease and the second leading cause of death worldwide [ 2, 3]. According to the Global Burden of Disease Study (GBD) report, there were approximately 80.1 million stroke patients, and 5.5 million deaths were attributed to stroke in 2016 globally [ 4]. Considering stroke is characterized with high incidence, high mortality, and contribute to severe burden disease, identifying potential risk factor of stroke is of great significance for public health. In parallel, air pollution has also been regarded as one of the major environmental problems and a risk factor of many cardiovascular diseases (CVD), including stroke [ 5]. GBD 2019 showed that air pollution was globally the sixth leading cause of stroke death during 1990 to 2017, and 28.1% disability-adjusted life years (DALYs) of stroke attribute to environmental factors exposure [ 6, 7].
Air pollution is the most significant environmental risk factor for all-cause mortality [ 8]. Increasing number of human epidemiologic studies has been conducted to assess the potential association between air pollution exposure and stroke admission, incidence, and mortality in recent years. However, the results were inconsistent, and the associations between exposure to air pollution and stroke have not been fully understood. Some studies reported positive association between air pollution exposure and stroke hospital admission/incidence/mortality, whereas others did not [ 4, 914]. For example, Huang et al. 2019 indicated that exposure to PM 2.5 was associated with increased stroke incidence and the adjusted risk ratio (RR) was 1.130 (95%CI: 1.090, 82 1.170) for each increase of 10 μg/m 3 in n PM 2.5 concentration [ 4]. The adjusted risk ratio (RR) was 1.130 (95% CI 1.090, 1.170) for each increase of 10 μg/m 3 in PM 2.5 concentration, while Wing et al. suggested no association was found between PM 2.5 exposure and stroke incidence (RR = 0.950, 95% CI 0.710, 1.280) [ 11]. Previous meta-analyses have explored the associations between air pollution exposure and stroke [ 1519]. However, these studies were mainly focused on the studies of particulate matter (PM 2.5, particulate matter with aerodynamic diameter less than 2.5 μm; PM 10, particulate matter with aerodynamic diameter less than 10 μm) and stroke outcomes [ 1619]; results of gas air pollutants (NO 2, nitrogen dioxide; SO 2, sulfur dioxide; CO, carbon monoxide; O 3, ozone) were scarce. Moreover, to the best of our knowledge, more than 30 studies exploring the association between air pollution exposure and stroke, especially conducted from the multi-city level and with large sample sizes, were published after the most recent meta-analysis. The more recent and comprehensive studies should be included in the meta-analysis to conclude an updated pooled effect estimate.
We therefore conducted an updated systematic review and meta-analysis to assess the association between 6 main air pollutants (PM 2.5, PM 10, NO 2, SO 2, CO, and O 3) and 3 stroke outcomes (hospital admission, incidence, and mortality). This systematic review and meta-analysis was performed according to the guidelines of the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) criteria (Table S1).

Methods

Search strategy

Literature was searched in three databases (PubMed, Embase, and Web of Science), with published date until 1 February 2020. The search strategy was pairwise of combinations of terms concerning air pollution (e.g., air pollution, particulate matter, particles, PM 2.5, PM 10, nitrogen oxides (NOx), NO 2, SO 2, CO, and O 3) and stroke (e.g., stroke, cerebrovascular disease, cerebrovascular disorder, cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage).
We first selected articles by screening titles and abstracts and then the full texts of potentially eligible studies were further evaluated. Reference lists of all the included studies were also manually searched. Literature selection was finished by two independent authors (ZP N and FF L), and conflicts between the two authors were resolved by discussing with an arbitrator (H X).

Inclusion and exclusion criteria

Articles that met the following criteria were included: (1) provided quantitative measure of the associations between air pollution exposure with stroke admission, incidence, and/or mortality (relative risk (RR), odds ratio (OR), or hazard ratio (HR), and their 95% confidence interval (95%CI); (2) cohort, cross-sectional, time series, cross-sectional, case-control, case-crossover, or panel studies; (3) focused on outdoor (ambient) air pollution exposure but not indoor air pollution; (4) original peer-reviewed human subject research studies; (5) published in English. Studies were excluded if they were (1) toxicological studies, summaries, or reviews, and (2) articles without effect estimates after contacting the authors. In addition, for more than one article conducted from the same population, only the most recent studies were included.

Data extraction

Data were extracted from all eligible studies, including the following: (1) study characteristics (first author, published year, study location, and period); (2) study population (sample size, proportion of males, range of age, mean age); (3) outcome (type of stroke and outcome was admission, incidence, and/or mortality); (4) air pollution assessment method and increment of air pollution used in effect estimates (per interquartile range (IQR), standard deviation (SD), or per 10 μg/m 3); (5) effect estimates of the association between air pollution and stroke risk (OR, RR, HR with 95% CI). The effect estimates of single-pollutant model, generally called “main model” or “fully adjusted model,” were extracted [ 20].

Quality assessment

Two authors (ZP N and FF L) worked independently, and inconsistencies in quality assessment were resolved through discussion. We employed the Newcastle-Ottawa Scale (NOS) to evaluate the quality of included studies. The NOS Tool has designed 8 items to assess the critical appraisal of the potential risk of bias. Total score of NOS ranged from 0–9. Study score higher than or equal to 7 was regarded as high-quality; otherwise, the study was regarded as “low quality” [ 21].

Statistical analyses

This meta-analysis focused on examining the association between air pollution and three stroke outcomes, including admission, incidence, and/or mortality. We extracted effect estimates (OR, HR, RR, and 95%CI) from individual studies and then converted them into a standardized form of per 10 μg/m 3 increases in air pollution. The significance of the pooled OR, RR, or HR was determined by the Z test [ 22], and p value less than 0.05 was considered statistically significant. Standard error (SE) for each effect estimate was calculated by using the formula: (upper limit − lower limit)/3.92.
Heterogeneity among studies was evaluated using I 2 statistics and Q test [ 23]. If the values of I 2 > 50% or p < 0.01, the heterogeneity was “high” and random effect model was used to pool estimates. Otherwise, heterogeneity was considered as “low or moderate,” and fixed-effect model was used to pool estimates.
Begg’s test and Egger’s test were conducted to assess publication bias. The influence of individual studies on the pooled estimates was examined by removing each study from the analysis one by one. Moreover, we also performed sensitivity analysis and subgroup analysis to evaluate if the exposure period would change the significance of the pooled results. Because long-term studies were limited, sensitivity analysis was conducted by omitting long-term exposure (cohort) studies. Subgroup analysis was only performed if the number of short-term exposure studies or long-term exposure studies was more than 3. Publication bias and sensitivity analysis were only performed if the number of included studies was more than 5. All statistical analysis was performed in Stata version 15.0 (StataCorp, College Station, TX, USA).

Results

Literature search and characteristics of included studies

After removing duplicates, 737 records were identified in the initial literature search. By reviewing title and abstracts, 93 studies were downloaded for full-text reading. According to the inclusion and exclusion criteria, a total of 68 studies were included in our meta-analysis (Fig. 1).
Table 1 provides the characteristics of 68 studies included in meta-analysis. As for air pollution involved in the study, there were 26 studies that reported the association between air pollution exposure and stroke hospital admission, 19 reported air pollution exposure and stroke incidence, 19 reported air pollution exposure and stroke mortality, and 3 reported both stroke incidence and mortality. The sample size of included studies ranged between 407 and 8,834,533; more than 23 million participants were included in meta-analysis eventually. Furthermore, the studies included were conducted from 18 countries. Time-series and cross-sectional were the most commonly adopted study designs. In our meta-analysis, all 68 included studies were considered as “high quality,” and the average NOS score was 8.26 for all studies (Table S2)
Table 1
Descriptive summaries for all included studies
Reference
Study Location and period
Study population
Study design
Exposure
Exposure assessment method
Type of stroke
Outcome
Huang et al. [ 4]
15 provinces in China, 2000–2015
117,575 Chinese men and women without stroke from the Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project
Cohort
PM 2.5
A satellite-based spatiotemporal model, 1 × 1-km spatial resolution
All types of stroke
Incidence
Tian et al. [ 24]
172 cities in China, 2014–2016
2,032,667 hospital admissions for ischemic stroke in 172 cities in China
Time-series
PM 2.5
1–17 monitors in each city operated by the National Air Pollution Monitoring System
Ischemic stroke
Hospital admission
Chen et al. [ 25]
Jinan, China, 2013–2015
56,922 stroke admissions
Case-crossover
PM 2.5, PM 10, SO 2, NO 2, O 3
14 fix-sited monitoring stations in urban areas of Jinan operated by Jinan Environment Monitoring Center
All types of stroke
Hospital admission
Chen et al. [ 26]
China, 2007–2008
12,291 ischemic stroke patients from first national hospital-based prospective registry cohort of stroke in China
Cohort
PM 2.5, PM 10, NO 2
Monitoring data, satellite remote sensing, meteorological and land use information
Ischemic stroke
Mortality
Xue et al. [ 27]
China, 2013–2015
1356 first-ever stroke events
Case-crossover
O 3
1463 continuous air pollution monitoring sites operated by the China Environmental Protection Ministry
All types of stroke
Incidence
Qian et al. [ 28]
Shanghai, China, 2012–2014
5286 fatal intracerebral hemorrhage (ICH) case
Case-crossover
PM 2.5
The Shanghai Environmental Monitoring Center
Hemorrhagic stroke
Incidence
Tian et al. [ 12]
184 major cities in China, 2014–2017
8,834,533 hospital admissions for cardiovascular causes in 184 Chinese cities
Time-series
PM 2.5
The National Air Pollution Monitoring System
Ischemic, hemorrhagic stroke
Hospital admission
Tian et al. [ 10]
172 cities in China, 2014–2016
2,032,667 hospital admissions for ischemic stroke in 172 cities in China
Time-series
PM 2.5, SO 2, NO 2, O 3, CO
1–17 monitors in each city operated by the National Air Pollution Monitoring System
Ischemic stroke
Hospital admission
Dong et al. [ 1]
Changzhou, China, 2015–2016
32,840 ischemic stroke (IS) cases, 4028 IS deaths
Time-series
PM 2.5, PM 10, SO 2, NO 2, CO
10 air quality monitoring stations operated by the Changzhou Environmental Monitoring Center
Ischemic stroke
Mortality, incidence
Zhong et al. [ 29]
Changsha city, China, 2008–2009
1536 stroke patients
Case-crossover
PM 10, NO 2, SO 2
the Changsha Municipal Public Weather Information Service Website
All types of stroke
Hospital admission
Vivanco-Hidalgo et al. [ 30]
Barcelona, Spain, 2005–2014
27,421,536 stroke patients
Time-series
PM 2.5
An urban background research site located in southwest Barcelona
Ischemic stroke
Incidence
Yitshak-Sade et al. [ 31]
New England, 2001–2011
2,015,660 stroke admissions
Time-series
PM 2.5
Monitor PM data and aerosol optic depth (AOD) values (1 × 1 km)
Ischemic stroke
Hospital admission
Liu et al. [ 32]
272 cities in China, 2013–2015
294,199 deaths due to stroke in 272 Chinese cities
Time-series
CO
The National Urban Air Quality Real-time Publishing Platform
All types of stroke
Mortality
Wang et al. [ 33]
6 subtropical cities in China, 2013–2016
54,236 stroke deaths from six Chinese subtropical cities
Case-crossover
PM 2.5, PM 10
Municipal air monitoring system
All types of stroke
Mortality
Collart et al. [ 34]
Wallonia, Belgium, 2008–2011,
113,147 hospital admissions due to stroke
Time-series
NO 2
ISSeP (the Scientific Institute of Public Services)
All types of stroke
Hospital admission
Chen et al. [ 35]
30 counties in China, 2013–2015
49,669 stroke deaths
Time-series
PM 2.5
Fixed-site monitoring station operated by the closest spatial distance to the county center. Daily air pollution data for PM2.5 and O3 concentrations were collected from the National Air pollution Monitoring System
All types of stroke
Mortality
Wang et al. [ 36]
272 cities in China, 2013–2015
294,199 deaths due to stroke in 272 Chinese cities
Time-series
SO 2
The National Urban Air Quality Real-time Publishing Platform
All types of stroke
Mortality
Chen et al. [ 9]
272 cities in China, 2013–2015
294,199 deaths due to stroke in 272 Chinese cities
Time-series
PM 2.5
The National Urban Air Quality Real-time Publishing Platform
All types of stroke
Mortality
Yin et al. [ 37]
272 cities in China, 2013–2015
294,199 deaths due to stroke in 272 Chinese cities
Time-series
O 3
The National Urban Air Quality Real-time Publishing Platform
All types of stroke
Mortality
Ha et al. [ 38]
USA, 2002–2008
228,438 deliveries
Case-crossover
PM 2.5, PM 10, SO 2, O 3, CO
Community Multiscale Air Quality (CMAQ) models
All types of stroke
Incidence
Huang et al. [ 39]
Beijing, China, 2013–2014
147,624 stroke admissions
Case-crossover
SO 2, NO 2, O 3, CO
The Centre of City Environmental Protection Monitoring Website Platform of Beijing
All types of stroke
Hospital admission
Guo et al. [ 5]
South China, 2013–2015
95,562 ischemic stroke cases
Time-series
PM 2.5, NO 2, SO 2, O 3, CO
The Qingyue Open Environmental Data (QOED) Center
Ischemic stroke
Hospital admission
Liu et al. [ 40]
14 large cities in China, 2014–2015
200,958 ischemic stroke and 41,746 hemorrhagic stroke hospitalizations
Case-crossover
PM 10, SO 2, O 3, CO, O 3
The National Air Pollution Monitoring System
Ischemic, hemorrhagic stroke
Hospital admission
Wing et al. [ 11]
Texas, USA, 2000–2012
3216 first-ever ischemic strokes
Case-crossover
PM 2.5, O 3
The Texas Commission on Environmental Quality’s Texas Air Monitoring Information System from a centrally located monitor
Ischemic stroke
Incidence
Liu et al. [ 41]
26 cities in China, 2014–2015
348,379 stroke admissions
Case-crossover
PM 2.5, PM 10
The National Air Pollution Monitoring System
Ischemic, hemorrhagic stroke
Hospital admission
McClure et al. [ 42]
USA, 2003–2011
30,239 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, 746 incidences
Case-crossover
PM 2.5
Moderate Resolution Imaging Spectroradiometer instrument on the NASA Aqua satellite (10 km × 10 km)
All types of stroke
Incidence
Tian et al. [ 43]
Beijing, China, 2010–2012
63,956 first hospital admissions due to stroke
Case-crossover
PM 2.5
An ambient air quality monitoring station on the rooftop of embassy building located in Chaoyang district, Beijing
Ischemic stroke
Hospital admission
Lin et al. [ 44]
6 low- and middle-income countries, 2007–2010
45,625 participants from the Study on Global Aging and Adult Health
Cohort
PM 2.5
Global estimates of ambient fine particulate matter concentrations from satellite-based aerosol optical depth
All types of stroke
Incidence
Hong et al. [ 45]
Changzhou, China, 2015–2016
32,840 ischemic stroke (IS) cases, 4028 IS deaths
Time-series
O 3
10 air quality monitoring stations operated by the Changzhou Environmental Monitoring Center
Ischemic stroke
Incidence, mortality
Stockfelt et al. [ 46]
Gothenburg, Sweden, 1990–2011
1391 cases of stroke from the Primary Prevention Study (PPS) cohort and GOT-MONICA cohort
Cohort
PM 2.5, PM 10
High-resolution dispersion modeling was performed for the period 1990–2011 over a Gothenburg region domain (93 × 112 km)
All types of stroke
Incidence
Qiu et al. [ 47]
Hong Kong, China, 1998–2010,
6,733 cases of incident stroke
Cohort
PM 2.5
Satellite-based aerosol optical depth (AOD) recordings and monitoring data from ground-based stations
All types of stroke
Incidence
Crichton et al. [ 48]
South London, England, 2005–2012
1800 incidence due to stroke
Time-series
PM 2.5, PM 10, NO 2, O 3
The KCLurban model developed at King’s College London
Ischemic, hemorrhagic stroke
Incidence
Huang et al. [ 49]
Beijing, China, 2013–2014
147,624 stroke admissions
Case-crossover
PM 2.5, PM 10
The Centre of City Environmental Protection Monitoring Website Platform of Beijing
Ischemic, hemorrhagic stroke
Hospital admission
Lin et al. [ 50]
Guangzhou, China, 2007–2011
9066 stroke deaths
Time-series
PM 2.5, PM 10
An automatic air monitoring system was installed on the rooftop of Panyu Meteorological Centre
All types of stroke
Mortality
Han et al. [ 51]
South Korea, 2004–2014
1,477 consecutive hemorrhagic stroke events
Case-crossover
PM 10, NO 2, O 3
The Climate and Air Quality Management Division of South Korea
Hemorrhagic stroke
Incidence
Montresor-López et al. [ 13]
South Carolina, USA, 2002–2006
21,301 stroke patients
Case-crossover
O 3
The US Environmental Protection Agency (USEPA), Hierarchical Bayesian Model (HBM)
All types of stroke
Hospital admission
Korek et al. [ 52]
Stockholm, Sweden, 1991–2010
22,587 individuals in four cohorts
Cohort
PM 10
The Airviro Air Quality Management System
All types of stroke
Incidence
Chang et al. [ 53]
Tropical City, Taiwan, 2006–2010
27,392 admissions due to stroke
Case-crossover
PM 2.5
6 air quality monitoring stations in Kaohsiung city operated by the Taiwanese Environmental Protection Administration (EPA)
All types of stroke
Hospital admission
Tian et al. [ 54]
Hong Kong, 2004–2011
140,774 emergency hospital admissions
Time-series
CO
4 general monitoring stations operated by the Environmental Protection Department (EPD) of Hong Kong
All types of stroke
Hospital admission
To et al. [ 55]
Canada, 1998–2006
89,835 women of the Canadian National Breast Screening Study (CNBSS)
Cohort
PM 2.5
Satellite-based estimates of surface concentrations of PM 2.5
All types of stroke
Incidence
Hoffmann et al. [ 56]
German, 2008–2009
4433 subjects from the German Heinz Nixdorf Recall cohort
Cohort
PM 2.5, PM 10
Land-use regression (LUR) models
All types of stroke
Incidence
Chen et al. [ 57]
Taiwan, 2006–2010
27,392 hospital admissions due to stroke
Case-crossover
PM 2.5, PM 10
6 air quality monitoring stations established in Kaohsiung city operated by the Taiwanese Environmental Protection Administration (EPA)
All types of stroke
Hospital admission
Amancio and Nascimento [ 58]
Brazil, 2005–2009
1,032 deaths due to stroke
Time-series
PM 10, SO 2
A measuring station in downtown São José dos Campos
All types of stroke
Mortality
Chen et al. [ 59]
Taiwan, 2004–2008,
12,982 ischemic, 3362 hemorrhagic stroke cases
Time-series
PM 2.5
The Sinjhuang Supersite located in the center of the Taipei metropolitan area
Hemorrhage, ischemic stroke
Hospital admission
Stafoggia et al. 2014 [ 60]
European, 2006–2010
99,446 study participants from 11 European Cohorts within the European Study of Cohorts for Air Pollution Effects (ESCAPE) Project
Cohort
PM 2.5, PM 10, NO 2
Land-use regression (LUR) models
All types of stroke
Incidence
Chiu et al. [ 61]
Taipei, Taiwan, 2006–2010
12,520 hemorrhagic stroke (HS) hospital admissions for the 47 hospitals
Case-crossover
PM 2.5
Air quality monitoring stations operated by the Taiwanese Environmental Protection Administration (EPA)
Hemorrhagic stroke
Hospital admission
Chen et al. [ 62]
8 cities in China, 1996–2008
4820,000 subjects of 8 Chinese cities, approximately
Time-series
PM 10, SO 2, NO 2
2–12 monitoring stations in each city operated by the Ministry of Environmental Protection of China
All types of stroke
Mortality
Carlsen et al. [ 63]
Reykjavík, Iceland, 2003–2009
24,439 emergency hospital admissions due to stroke
Time-series
PM 10, NO 2, O 3
The Environmental Branch of the Municipality of Reykjavík (2003–2008) and the Icelandic Environmental Protection Agency (2009)
All types of stroke
Hospital admission
Johnson et al. [ 64]
Canada, 2007–2009
4,696 stroke (cases) and 37,723 injury patients (controls)
Case-crossover
NO 2
Land-use regression (LUR) model for the city of Edmonton
All types of stroke
Hospital admission
Atkinson et al. [ 65]
England, 2003–2007
836,557 patients
Cohort
PM 10, NO 2, NO 2, O 3
Air dispersion models (1 × 1-km grids)
All types of stroke
Incidence
Xu et al. [ 66]
Pennsylvania, USA, 1994–2000
26,210 hospital admissions due to stroke
Case-crossover
O 3
The repository of ambient air quality database of the US Environmental Protection Agency
All types of stroke
Hospital admission
Xiang et al. [ 67]
Wuhan, China, 2006–2008
10,663 stroke hospital admissions from 4 major hospitals
Case-crossover
PM 10, SO 2, NO 2
9 fixed-site stations operated by the Wuhan Environmental Monitoring Center
All types of stroke
Hospital admission
Yorifuji et al. [ 68]
Shizuoka, Japan, 1999–2009
14,001 elderly residents
Cohort
NO 2
Land use regression (LUR) model
Hemorrhage, ischemic stroke
Mortality
Qian et al. [ 69]
Shanghai, China, 2003–2008
66,366 stroke deaths for adults aged over 65
Case-crossover
PM 10, SO 2, NO 2
6 fixed-site stations operated by Shanghai Environmental Monitoring Center
All types of stroke
Mortality
Andersen et al [ 70]
Denmark, 1971–2006
52,215 participants of the Danish Diet, Cancer and Health cohort
Cohort
NO 2
The Danish geographic information system-based air pollution and human exposure modeling system
All types of stroke
Incidence, Mortality
Nascimento et al. [ 71]
São Paulo State, Brazil, 2007–2008,
407 hospitalizations due to stroke
Time-series
PM 10, SO 2, O 3
Measuring station of the São Paulo State Environmental Agency
All types of stroke
Hospital admission
OʼDonnell et al. [ 72]
Canada, 2003–2008,
9202 patients hospitalized due to ischemic stroke
Case-crossover
PM 2.5
19 monitoring stations in the vicinity of the 11 regional stroke centers participating in the Registry
Ischemic Stroke
Incidence
Lipsett et al. [ 73]
California, USA, 1996–2005,
124,614 women living in California
Cohort
PM 2.5, PM 10, SO 2, NO 2, CO, O 3
Fixed-site monitors, inverse distance weighting (IDW) interpolation
All types of stroke
Incidence
Yorifuji et al. [ 68]
Tokyo, Japan, 2003–2008
41,440 deaths due to stroke
Time-series
PM 2.5, NO 2
2 monitoring stations in Tokyo’s 23 wards
Hemorrhagic stroke
Mortality
Ren et al. [ 74]
Massachusetts, USA, 1995–2002
157,197 non-accident deaths aging 35 years or older
Case-crossover
O 3
The Environmental Protection Agency, USA
All types of stroke
Mortality
Zanobetti and Schwartz [ 75]
USA, 1999–2005
330,613 deaths for stroke in 112 US cities
Time-series
PM 2.5
Air Quality System Technology Transfer Network
All types of stroke
Mortality
Kettunen et al. [ 76]
Helsinki, Finland, 1998–2004
3265 deaths due to stroke
Time-series
PM 2.5, PM 10, NO 2, CO, O 3
The Environmental Protection Agency, USA
All types of stroke
Mortality
Franklin et al. [ 77]
USA,1997–2002
1310,781 deaths in 27 US communities
Case-crossover
PM 2.5
National, State, and Local Ambient Monitoring Stations
All types of stroke
Mortality
Qian et al. [ 78]
Wuhan, China, 2001–2004
89,131 non-accidental death cases
Time-series
PM 10
Wuhan Environmental Monitoring Center
All types of stroke
Mortality
Villeneuve et al. [ 79]
Edmonton, Canada, 1992–2002
12,422 stroke visits
Time-series
PM 2.5, PM 10, SO 2, NO 2, CO, O 3
Fixed-site monitoring stations maintained by Environment Canada
All types of stroke
Hospital admission
Henrotin et al. [ 80]
Dijon, France, 1994–2004
1487 patients with ischemic stroke and 220 patients with hemorrhagic stroke
Case-crossover
PM 10, SO 2, CO, O 3
The monitoring station located in the town center, Dijon
Hemorrhage, ischemic stroke
Incidence
Tsai et al. [ 81]
Kaohsiung, Taiwan, 1997–2000
23,179 hospital admissions due to stroke
Case-crossover
PM 10, SO 2, NO 2, CO, O 3
6 air-quality monitoring stations operated by the Environmental Protection Administration (EPA)
All types of stroke
Hospital admission
Yu et al. [ 14]
Seoul, Korea, 1991–1997
7137 ischemic deaths due to stroke
Time-series
SO 2, NO 2, CO, O 3
20 monitoring site and data operated by the Department of the Environment (Seoul)
Ischemic stroke
Mortality
PM 2.5 particulate matter with aerodynamic diameter less than 2.5 μm, PM 10 particulate matter with aerodynamic diameter less than 10 μm, SO 2 sulfur dioxide, NO 2 nitrogen dioxide, CO carbon monoxide, O 3 ozone, China-PAR Atherosclerotic Cardiovascular Disease Risk in China (China-PAR) project, ICH intracerebral hemorrhage, IS ischemic stroke, REGARDS Cohort Reasons for Geographic and Racial Differences in Stroke Cohort, PPS primary prevention study, CNBSS Canadian National Breast Screening Study, HS hemorrhagic stroke, ESCAPE Project the European Study of Cohorts for Air Pollution Effects, AOD aerosol optic depth, ISSeP the Scientific Institute of Public Services, CMAQ Community Multiscale Air Quality model, QOED the Qingyue Open Environmental Data Center, USEPA the US Environmental Protection Agency, HBM Hierarchical Bayesian Model, EPA the Taiwanese Environmental Protection Administration, EPD the Environmental Protection Department, LUR land use regression model, IDW inverse distance weighting
.

Air pollution and stroke hospital admission

A total of 29 studies were performed to assess the association for air pollution and stroke hospital admission, and the results were inconsistent. Most studies showed a positive correlation between exposure to air pollution and the risk of hospital admission for stroke. In meta-analysis, we enrolled 13 studies on PM 2.5, 11 studies on PM 10 and NO 2, 10 studies on SO 2 and O 3, and 6 studies on CO with stroke hospital admission and suggested an increased stroke hospital admission risk after air pollution exposure. The pooled odds ratio (OR) of stroke with a 10 μg/m 3 increase in PM 2.5, PM 10, SO 2, NO 2, CO, and O 3 was 1.008 (95% CI 1.005, 1.011), 1.004 (95% CI 1.001, 1.006), 1.013 (95% CI 1.007, 1.020), 1.023 (95% CI 1.015, 1.030), 1.000 (95% CI 1.000, 1.001), and 1.002 (95% CI 1.000, 1.003), respectively (Table 2, Figure S1- S6). Heterogeneity among studies was significant ( I 2 ≥ 50%, p < 0.001).
Table 2
Association between exposure to air pollution and stroke hospital admission (per 10 μg/m 3 increment)
Air pollution
Hospital admission
Heterogeneity
NO.
HR (95% CI)
I 2 (%)
P
PM 2.5
19
1.008 (1.005, 1.011)
96.6
0.000
PM 10
15
1.004 (1.001, 1.006)
92.7
0.000
SO 2
13
1.013 (1.007, 1.020)
94.5
0.000
NO 2
15
1.023 (1.015, 1.030)
92.6
0.000
CO
8
1.000 (1.000, 1.001)
92.7
0.000
O 3
15
1.002 (1.000, 1.003)
80.2
0.000
HR hazard ratio, NO. number, PM 2.5 particulate matter with aerodynamic diameter less than 2.5 μm, PM 10 particulate matter with aerodynamic diameter less than 10 μm, SO 2 sulfur dioxide, NO 2 nitrogen dioxide, CO carbon monoxide, O 3 ozone

Air pollution and stroke incidence

Twenty-three studies have investigated the association of air pollution on stroke incidence (Table 1). For meta-analysis, we extracted 18 studies on PM 2.5, 13 studies on PM 10, 10 studies on O 3, 7 studies on NO 2, and 4 studies on SO 2 and CO. Ten of these studies suggested increased risks for stroke incidence for at least one of the investigated pollutants. Meta-analysis showed that exposure to PM 2.5, SO 2, and NO 2 was associated with increased risks of stroke incidence, and the pooled HR with a 10 μg/m 3 increase was 1.048 (95% CI 1.020, 1.076), 1.002 (95% CI 1.000, 1.003), 1.002 (95% CI 1.000, 1.003), respectively. However, no significant differences were found in associations of PM 10, CO, O 3, and stroke incidence (Table 3, Figure S7- S12).
Table 3
Association between exposure to air pollution and stroke incidence (per 10 μg/m 3 increment)
Air pollution
Incidence
Heterogeneity
NO.
OR (95% CI)
I 2 (%)
P
PM 2.5
18
1.048 (1.020, 1.076)
82.3
0.000
PM 10
13
1.017 (0.981, 1.055)
51.9
0.010
SO 2
4
1.002 (1.000, 1.003)
20.3
0.288
NO 2
7
1.002 (1.000, 1.003)
0.0
0.512
CO
5
0.999 (0.997, 1.001)
0.0
0.763
O 3
10
0.999 (0.999, 1.000)
34.1
0.135
OR odds ratios, NO. number, PM 2.5 particulate matter with aerodynamic diameter less than 2.5 μm, PM 10 particulate matter with aerodynamic diameter less than 10 μm, SO 2 sulfur dioxide, NO 2 nitrogen dioxide, CO carbon monoxide, O 3 ozone

Air pollution and stroke mortality

Twenty-two population-based studies have explored the association for exposure to air pollution and stroke mortality. As for meta-analysis, 11 articles on PM 2.5, 10 articles on NO 2, 9 articles on PM 10, 6 articles on O 3, and 4 articles on CO exposure were included. Meta-analysis showed that exposure to ambient PM 2.5 (OR = 1.008 95% CI 1.005, 1.012, per 10 μg/m 3 increment), PM 10 (OR = 1.006, 95% CI 1.003, 1.010, per 10 μg/m 3 increment), SO 2 (OR = 1.006, 95% CI 1.005, 1.008, per 10 μg/m 3 increment), and NO 2 (OR = 1.009, 95% CI 1.003, 1.016, per 10 μg/m 3 increment) was associated with increased risks of mortality due to stroke. No significant difference was shown in association between CO, O 3 exposure, and stroke mortality (Table 4, Figure S13- S18).
Table 4
Association between exposure to air pollution and stroke mortality (per 10 μg/m 3 increment)
Air pollution
Mortality
Heterogeneity
NO.
OR (95% CI)
I 2 (%)
P
PM 2.5
12
1.008 (1.005, 1.012)
89.2
0.000
PM 10
10
1.006 (1.003, 1.010)
83.3
0.000
SO 2
6
1.006 (1.005, 1.008)
45.8
0.100
NO 2
10
1.009(1.003, 1.016)
70.1
0.000
CO
5
1.045 (0.980, 1.115)
50.6
0.091
O 3
6
1.005 (0.999, 1.010)
84.8
0.000
OR odds ratios, NO. number, PM 2.5 particulate matter with aerodynamic diameter less than 2.5 μm, PM 10 particulate matter with aerodynamic diameter less than 10 μm, SO 2 sulfur dioxide, NO 2 nitrogen dioxide, CO carbon monoxide, O 3 ozone

Publication bias and sensitivity analysis

Publication bias of studies on PM 10 exposure and stroke hospital admission may exist, since p values of Begg’s test were less than 0.05. Publication bias of studies was remarkable in association of exposure to PM 2.5 and O 3 and stroke incidence according to funnel plots and Egger’s test. For PM 2.5 and stroke mortality, the p value of Egger’s test was 0.009, suggesting publication bias may exist. Other publication bias test indicated that no substantial publication bias of studies was observed according to funnel plots, Begg’s test, and Egger’s test (Table S3, Figure S19- 34).
Sensitivity analysis showed that the relation of exposure to CO and stroke hospital admission might be influenced by Tian et al.’s study [ 10]. And the association between exposure to NO 2 and stroke incidence may be influenced by Dong et al.’s study [ 1]. The pooled OR of exposure to air pollution and stroke mortality might be influenced by some studies (PM 2.5: Wang et al.’s study [ 33]; O 3: Yin et al.’s study [ 37]). We recalculated the pooled OR/HR and 95% CI after removing those studies (Table S3). Due to limited studies after excluding those studies, the pooled estimated effects of SO 2 and stroke incidence and O 3 and stroke mortality were not recalculated. Other sensitivity analyses indicated that excluding each individual study did not change the results, suggesting the results of the meta-analysis were stable (Table S4, Figure S35- 50). Sensitivity analyses by exposure period found that the pooled effect estimates were not changed significantly after excluding the long-term (cohort) studies (Table S5). Subgroup analysis suggested that both short-term and long-term exposure to air pollution would increase the risk of stroke incidence (PM 2.5, PM 10, and NO 2) and mortality (NO 2) (Table S6).

Discussion

We conducted a systematic review and meta-analysis of 68 epidemiological studies and performed a comprehensive evaluation on exposure ambient air pollution and stroke, which were conducted from more than 23 million participants. Most studies suggested that exposure to a higher level of air pollution was associated with increased stroke risk. Meta-analysis showed that exposures to air pollutants were associated with increased risk of stroke hospital admission (PM 2.5, PM 10, SO 2, NO 2, CO, and O 3), incidence (PM 2.5, SO 2, and NO 2), and mortality (PM 2.5, PM 10, SO 2, and NO 2). Although the high heterogeneity may reduce the credibility of the pooled evidence to some extent, the large number of studies included and the consistency of the results indicated that our conclusions were credible to some extent.
The positive associations between exposure to PM 2.5, PM 10, SO 2, NO 2, CO, and O 3, and stroke hospital admission were observed in other meta-analysis. Yang et al. meta-analyzed 34 case-crossover and time series studies and reported significant associations for PM 10 (per 10 μg/m 3 increment: RR = 1.007, 95% CI 1.001, 1.013) and O 3 (per 10 ppb increment: RR = 1.036, 95% CI 1.016, 1.056), but non-significant association for PM 2.5, SO 2, NO 2, and CO [ 15]. The meta-analysis performed by Yang et al. was not consistent with our current study completely, which might be caused by the different number of the included studies. To our knowledge, more than 16 studies have been published after 2014, and studies included in Yang et al.’s study were mainly conducted in Europe and North America. Data from more recent studies, especially low- and middle-income countries were not considered. Moreover, many studies conducted from the multi-city level and with large sample sizes have been published in recent years, which were more likely to find a significant association between air pollution and stroke hospital admission. For example, Tian et al. performed a time-series of more than 2 million hospital admissions for ischemic stroke in 172 cities in China and suggested that elevated incidence of ischemic stroke hospital admissions was associated with exposure to higher level of PM 2.5 (RR = 1.003, 95% CI 1.002, 1.005, per 10 μg/m 3 increment), SO 2 (RR = 1.013, 95% CI 1.011, 1.017, per 10 μg/m 3 increment), and NO 2 (RR = 1.018, 95% CI 1.015, 1.022, per 10 μg/m 3 increment) [ 24].
Three meta-analyses were conducted to examine the association between exposure to particulate matter (PM 2.5 and PM 10) and stroke incidence, whereas no meta-analysis of gas air pollutants was published before the current study. Li et al. performed a meta-analysis to explore the association between PM 10 and stroke incidence in time-series studies and case-crossover studies. These studies indicated that PM 10 was not associated with stroke incidence in the time-series design (HR = 1.002, 95% CI 0.999, 1.005, per 10 μg/m 3 increment), but significantly associated in case-crossover studies (HR = 1.028, 95% CI 1.001, 1.057, per 10 μg/m 3 increment). Meanwhile, PM 2.5 exposure was related to an increased risk of stroke incidence in time-series design (HR = 1.006, 95% CI 1.002, 1.010, per 10 μg/m 3 increment), but no significant association in case-crossover studies (HR = 1.016, 95% CI 0.937, 1.097, per 10 μg/m 3 increment) [ 16]. Only 12 studies published before 2010 were included in Li et al.’s study. We updated the literature search up to 2020, which generated more than 10 studies. Moreover, Li et al. separately analyzed the data from time-series and case-crossover studies, which would reduce the number of studies calculated the pooled estimates. These might explain the inconsistency in between our study and Li et al.’s study. Yu et al. updated the literature search before 2012 and identified 19 studies [ 19]. Yu et al. found that exposure to PM 10 was associated with an increased risk of stroke incidence (HR = 1.004, 95% CI 1.001, 1.008, per 10 μg/m 3 increment), but exposure to PM 2.5 was not significantly associated with stroke incidence (HR = 0.999, 95% CI 0.994, 1.003, per 10 μg/m 3 increment) [ 19]. The results of these published meta-analyses were not exactly the same as our study, which might be due to more than 15 studies published after Yu et al.’s study. Moreover, we conducted a meta-analysis of gas air pollutants and stroke incidence and found that exposure to a higher level of SO 2 and NO 2 was associated with higher risk of stroke incidence, which may fill the gap of meta-analysis of gas air pollutants and stroke incidence. We also found that compared to short-term exposure, long-term exposure to air pollution may be associated with a higher risk of stroke incidence (PM 2.5, PM 10, and NO 2), which may be explained by different pathophysiological pathways.
Studies investigating the association between exposure to air pollution and stroke mortality have been partly analyzed in two meta-analysis [ 15, 17]. Yang et al. evaluated the association between all 6 pollutants and suggested that stroke mortality increased 1.34% (95% CI 0.27, 2.42) per 10 μg/m 3 increase in PM 2.5, 0.65% (95% CI 0.54, 0.77) per 10 μg/m 3 increase in PM 10, 2.45% (95% CI 1.83, 3.07) per 10 parts per billion (ppb) increase in SO 2, 7.78% (95% CI 4.49, 11.60) per 1 ppm increase in CO, and 1.50% (95% CI 0.37, 2.63) per 10 ppb increase in NO 2, respectively [ 15]. Consistent with Yang et al.’s study, our meta-analysis also indicated that exposure to a higher level of PM 2.5, PM 10, SO 2, and NO 2 was related to higher risk of stroke mortality. No association was observed in both our study and Yang et al.’s study. However, Yang et al. reported a positive association in CO, whereas our study did not, which may be explained by the limited number of included studies. Scheers et al. performed a meta-analysis of exposure to PM 10 and stroke events (mortality and incidence) and suggested that exposure to PM 10 was positively associated with overall stroke events (mortality and incidence) (HR = 1.061, 95% CI 1.018, 1.105), but no significant association were observed in stroke mortality (HR = 1.080, 95% CI 0.992, 1.177) [ 17]. Inconsistency of Scheers et al.’s study and current study could be explained that Scheers et al.’s study included the studied estimated exposure to PM 10 from studies using PM 2.5, which may cause estimation bias to some extent.
Although accurate mechanisms of air pollution exposure and stroke remain unclear, several pathways including systemic inflammation, oxidative stress, thrombosis, and vascular endothelial dysfunction have been proposed [ 1, 9, 15, 82]. Vascular function injury may be central to mechanisms for air pollution-related stroke, which could lead to raised level of blood pressure and plasma viscosity [ 26]. It has been showed that exposure to air pollution was associated with increased thrombosis and vascular endothelial dysfunction by provoking oxidative stress and releasing systemic inflammatory cytokines [ 83]. Moreover, evidence also suggested that exposure to air pollution can lead to dysfunction of the autonomic system, which has been found as the major pathway that could result in air pollution-related adverse cardiovascular outcomes, such as stroke [ 84]. In addition, stroke status may aggravate the susceptibility of population to air pollution and increase the adverse cardiovascular effects of air pollution circularly [ 62].
A major strength of our meta-analysis is that our systematic review and meta-analysis covered six main air pollutants (PM 2.5, PM 10, NO 2, SO 2, CO, O 3) and a rich set of stroke outcomes (hospital admission, incidence, and mortality), which may be difficult to obtain from individual studies or isolated reviews or meta-analyses. However, some limitations should be acknowledged. Firstly, high heterogeneity existed in some meta-analysis, which may be due to different study designs, difference in exposure assessment method and population demographics, and the varied covariable adjustment strategies in different studies. Secondly, our study failed to perform the association between different subtypes of stroke (ischemic stroke, hemorrhagic stroke) and air pollution exposure separately because most included studies (48 out of 68 articles) did not report subtypes of stroke or results of ischemic stroke and hemorrhagic stroke specifically. Finally, the correlation between different air pollutants was not examined in our study because different air pollutants were controlled in different studies, and the results of those studies could not be pooled directly.

Conclusion

Our study demonstrated that exposure to air pollution was positively associated with an increased risk of stroke hospital admission (PM 2.5, PM 10, SO 2, NO 2, CO, and O 3), incidence (PM 2.5, SO 2, and NO 2), and mortality (PM 2.5, PM 10, SO 2, and NO 2). Given the great global burden of stroke and air pollution, our findings could provide some scientific evidence to accurate prevention and treatment of stroke and air pollution exposure.

Acknowledgments

The authors acknowledge all the participants and administrators of this study.

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors consent for publishing this work.

Competing interests

The authors declare that they have no competing interests.
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