Epidemiology/Population Ambient Air Pollution and Pregnancy-Induced Hypertensive Disorders A Systematic Review and Meta-Analysis Marie Pedersen, Leslie Stayner, Rémy Slama, Mette Sørensen, Francesc Figueras, Mark J. Nieuwenhuijsen, Ole Raaschou-Nielsen, Payam Dadvand Abstract—Pregnancy-induced hypertensive disorders can lead to maternal and perinatal morbidity and mortality, but the cause of these conditions is not well understood. We have systematically reviewed and performed a meta-analysis of epidemiological studies investigating the association between exposure to ambient air pollution and pregnancy-induced hypertensive disorders including gestational hypertension and preeclampsia. We searched electronic databases for English language studies reporting associations between ambient air pollution and pregnancy-induced hypertensive disorders published between December 2009 and December 2013. Combined risk estimates were calculated using random-effect models for each exposure that had been examined in ≥4 studies. Heterogeneity and publication bias were evaluated. A total of 17 articles evaluating the impact of nitrogen oxides (NO2, NOX), particulate matter (PM10, PM2.5), carbon monoxide (CO), ozone (O3), proximity to major roads, and traffic density met our inclusion criteria. Most studies reported that air pollution increased risk for pregnancy-induced hypertensive disorders. There was significant heterogeneity in meta-analysis, which included 16 studies reporting on gestational hypertension and preeclampsia as separate or combined outcomes; there was less heterogeneity in findings of the 10 studies reporting solely on preeclampsia. Metaanalyses showed increased risks of hypertensive disorders in pregnancy for all pollutants except CO. Random-effect meta-analysis combined odds ratio associated with a 5-µg/m3 increase in PM2.5 was 1.47 (95% confidence interval, 1.27–1.68) for combined pregnancy-induced hypertensive disorders and 1.30 (95% confidence interval, 1.11–1.48) for preeclampsia. Our results suggest that exposure to air pollution increases the risk of pregnancy-induced hypertensive disorders. (Hypertension. 2014;64:494-500.) Online Data Supplement
•
Key Words: air pollution
■
hypertension, pregnancy-induced
T
here is increasing evidence that exposure to ambient air pollution contributes to the risks of cardiovascular events in adults and the elderly.1 Maternal exposure to air pollution during pregnancy has been associated with increased risk of adverse birth outcomes such as low birthweight and preterm birth.2,3 Concern has recently been raised that ambient air pollution exposure may also increase the risk of hypertensive disorders during pregnancy.4 This is relevant because pregnant women are vulnerable to developing hypertensive disorders as a result of increased stress on the cardiovascular system5 and endothelium.6 Gestational hypertension and preeclampsia are the most common complications of pregnancy affecting 2% to 10%
■
pre-eclampsia
■
pregnancy
of pregnancies after 20 weeks of pregnancy.6,7 Gestational hypertension is usually diagnosed based on a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg in previously normotensive women.7 Preeclampsia is characterized by hypertension and protein in the urine.6,8 In addition to maternal mortality, preeclampsia and related conditions are a leading cause of maternal morbidity, perinatal death, placental abruption, preterm birth, and child growth restriction.6–8 The objective of this study was to systematically review epidemiological studies investigating associations between ambient air pollution and pregnancy-induced hypertensive disorders and to perform a meta-analysis of these studies.
Received March 13, 2014; first decision March 28, 2014; revision accepted May 21, 2014. From the Centre for Research in Environmental Epidemiology, Barcelona, Spain (M.P., L.S., M.J.N., P.D.); CIBER Epidemiología y Salud Pública, Madrid, Spain (M.P., M.J.N., P.D.); Universitat Pompeu Fabra, Barcelona, Spain (M.P., M.J.N., P.D.); INSERM, U823, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Institute Albert Bonniot, Grenoble, France (M.P., R.S.); Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago (L.S.); University Joseph Fourier, Institute Albert Bonniot, Grenoble, France (R.S.); Danish Cancer Society Research Center, Copenhagen, Denmark (M.S., O.R.-N.); and Department of Maternal-Foetal Medicine, ICGON, Hospital Clinic IDIBAPS, University of Barcelona, Barcelona, Spain (F.F.). The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 114.03545/-/DC1. Correspondence to Marie Pedersen, Centre for Research in Environmental Epidemiology, Doctor Aiguader 88, Barcelona 08003, Spain. E-mail [email protected] © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.114.03545
Downloaded from http://hyper.ahajournals.org/ at 494 CONS CALIFORNIA DIG LIB on December 7, 2014
Pedersen et al Air Pollution and Hypertensive Pregnancy Disorders 495
Methods Search Strategy Studies were identified using the electronic bibliographic databases PubMed and Web of Science using the following search terms (preeclampsia, eclampsia, pregnancy hypertension, gestational hypertension, or HELLP) and (air pollution, traffic, or criteria air pollutants: particulate matter [PM], nitrogen oxides [NOX], carbon monoxides [CO], or ozone [O3]). We also searched the reference lists of identified articles for additional publications. We limited the search to peerreviewed articles published in English between December 2009 and December 19, 2013. Full articles published in other languages and abstracts were excluded (Figure 1). A total of 17 studies were considered relevant to be included in the systematic review and meta-analysis. If not reported, we requested from the authors effect estimates for continuous exposure. Additional unpublished information was received for a Swedish study,9 which was included in our analyses. We excluded 1 small (n=2707) study conducted in Iran from the meta-analysis because only effect estimates of high versus low exposure to CO were reported.10 Finally, in the case of 2 publications that had overlapping study populations,11,12 we selected the results from the study that had the largest sample size.12 In a sensitivity analysis, we included the other study11 instead, because the 2 studies used different exposure assessment methods.
Statistical Analysis To allow comparison of effect estimates between different studies, the reported odds ratios (OR) and 95% confidence intervals (CIs) were converted to correspond to common exposure increments (Methods S1 in the online-only Data Supplement). Few estimates were available for trimester-specific exposure, and thus combined estimates were only estimated for the full pregnancy mean to secure sufficient number of studies for meta-analyses. Three studies13–15 did not report the effect of the exposure during the entire pregnancy, and so for these 3 studies we included the effect estimates related to exposure during the first trimester. Four studies only reported categorical effect estimates associated with exposure to residential proximity to major roads and traffic density,9,16–18 and for these studies we estimated the combined risk estimates related to the highest versus the lowest exposure category (Methods S2). We examined all studies on pregnancy-induced hypertensive disorders (ie, gestational hypertension and preeclampsia as separate outcomes or a combination of these conditions), irrespective of the definition used, to secure sufficient number of studies for random effect meta-analyses.19 Second, we restricted the meta-analyses to studies on preeclampsia because there is controversy whether gestational hypertension and preeclampsia are a spectrum or different diseases.6–8 There were an insufficient number of studies on gestational hypertension to analyze this as a separate outcome. To identify potential influential studies and examine the robustness of the findings of the meta-analysis to the exclusion of these studies, we conducted sensitivity analyses by repeating meta-analyses after removing 1 study at a time and comparing the combined estimates with and without that study. Publication bias was evaluated using Funnel plots and Egger tests.20 In the absence of bias, the funnel plot should resemble a symmetrical inverted funnel with larger studies being close to the pooled estimate, and smaller studies more widely, but evenly, scattered around the
pooled estimate. The Egger test provides a formal statistical evaluation of whether there is asymmetry in the study results that is related to their standard error. Stata S.E. version 12.1 was used for the statistical analyses (StataCorporation, TX).
Results Description of the Study Characteristics We identified 17 studies published between 2009 and 2013 for the systematic review that are summarized in Table S1 in the online-only Data Supplement.10–18,21–27 All studies with the exception of 1 case–control study28 were prospective cohorts or birth record–based retrospective cohorts. The studies were based on 298 to 468 517 pregnancies occurring during 1996 to 2008. Nine studies were conducted in the United States, 5 in Europe, and 3 in Iran, Japan, and Australia (Table S1). Most studies excluded multiple pregnancies, but not all.21,23 The applied inclusion and exclusion criteria varied between studies and so did the availability of potential confounders (Table S1).
Outcome Definition and Prevalence Ten of the 17 studies evaluated preeclampsia,9,11,12,16,21–25 5 studied a combination of gestational hypertension and preeclampsia without separating them,15,17,26–27 4 considered gestational hypertension,10,13,16,24 and one evaluated a combination of gestational hypertension and preeclampsia among women with preterm births.18 Few studies further evaluated subgroups of preeclampsia according to severity9,11,15 or early and late onset.21 The definition of outcomes varied among the studies (Table S2). In some studies, preeclampsia included the more severe outcomes such as eclampsia,11,12,24,26,27 and the definitions used were not described in detail in all studies.25,27 The reported prevalence for gestational hypertension ranged from 3.6%12 to 6.0%,13 preeclampsia ranged from 1.2%21 to 4.0%,22 and the combination of gestational hypertension and preeclampsia ranged from 2.7%14 to 4.7%.27
Air Pollution Exposure Half of all the included studies estimated the pollutant concentration in ambient air at the maternal home address at birth using environmental models (land-use regressions or dispersion),9,12,21–24 whereas routine air pollutant data from central air–pollution-monitoring stations were used in the other half of the studies.10,12,15,18,25–27 Most commonly, exposures were assigned using the monitoring station nearest to the maternal residence at the time of birth. Distance between the monitors and participant’s home addresses as well as the number and density of monitors differed across studies. Seven studies evaluated PM2.5, 6 NO2, 5 PM10, CO, or O3, and 4 evaluated NOX (Table S1). The mean pregnancy exposure
Figure 1. Study identification and selection.
Downloaded from http://hyper.ahajournals.org/ at CONS CALIFORNIA DIG LIB on December 7, 2014
496 Hypertension September 2014 (µg/m3) to PM2.5 and NO2 ranged from 10.123,27 to 17.312 and from 23.022 to 55.7,21 respectively. The ranges of the other air pollutant concentration also differed among studies (Table S3).
Combined Estimates of Air Pollution and the Risk of Hypertensive Disorders in Pregnancy The effect estimates of individual studies and the combined effect estimates for pregnancy-induced hypertensive disorders associated with PM2.5 and NO2 are presented in Figure 2. For all pollutants, heterogeneity as measured by the I2 was high, and there were highly significant Q tests when all pregnancyinduced hypertensive outcomes were combined (Table). For most pollutants, the heterogeneity among studies tended to be smaller when studies on preeclampsia only were considered (Table; Figure 2). Results from the individual studies on PM2.5 consistently reported increased risk of pregnancy-induced hypertensive disorders ranging from 11%13 to 398%27 associated with each 5-µg/ m3 increase in PM2.5 (Figure 2). Likewise for NO2, a consistent pattern of increased risks between 4%21 and 85%27 associated with each 10-µg/m3 increase in NO2 were reported (Figure 2). Increased risks were also observed in most, but not in all, of the individual studies on NOX, PM10, and O3 (Figure S1). Pregnancy-induced hypertensive disorders were statistically significantly associated with a 5 µg/m3 increment
in PM2.5 (OR=1.47; 95% CI, 1.27, 1.68; Table; Figure 2), a 10-µg/m3 increment in NO2 (OR=1.23; 95% CI, 1.04, 1.41; Table; Figure 2), and a 10-µg/m3 increment in PM10 (OR=1.11; 95% CI, 1.00, 1.21; Table). When all outcomes were combined, there were also marginally statistically significant associations with NOX and O3 but not with CO (Table). The forest plots of the other pollutants are presented in Figure S1.
Residential Proximity to Traffic, Traffic Density, and Hypertensive Disorders in Pregnancy One study reported effect estimates associated with increments in traffic density12 and 4 reported effect estimates of categorical proximity to major road.9,17,18,24 The individual studies have reported increased ORs for pregnancy-induced hypertensive disorders among women exposed to high traffic density,9,12 and among women living within 200 to 250 m from major roads,17,18 although not for all of the associations evaluated.16,17 The heterogeneity among the studies reporting effects of low versus high exposure to traffic indicators was not statistically significant. The random-effect meta-analysis suggested that pregnancy-induced hypertensive disorders were statistically significantly associated with higher exposure to traffic density (Table; Figure S1).
Figure 2. Associations between air pollution with PM2.5, NO2, and pregnancy-induced hypertensive disorders. Odds ratio (OR) and 95% confidence intervals (CI) from the individual studies and the combined meta-analysis result indicated by vertical points of the diamonds and 95% CIs by horizontal points per 5 µg/m3 for PM2.5 (upper) and 10 µg/m3 for NO2 (lower), respectively.
Downloaded from http://hyper.ahajournals.org/ at CONS CALIFORNIA DIG LIB on December 7, 2014
Pedersen et al Air Pollution and Hypertensive Pregnancy Disorders 497 Table. Random-Effect Meta-Analyses of Studies on Air Pollution, Traffic, and Hypertensive Disorders in Pregnancy Exposure and Outcomes
Studies
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19 139
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•
Key Words: air pollution
■
hypertension, pregnancy-induced
T
here is increasing evidence that exposure to ambient air pollution contributes to the risks of cardiovascular events in adults and the elderly.1 Maternal exposure to air pollution during pregnancy has been associated with increased risk of adverse birth outcomes such as low birthweight and preterm birth.2,3 Concern has recently been raised that ambient air pollution exposure may also increase the risk of hypertensive disorders during pregnancy.4 This is relevant because pregnant women are vulnerable to developing hypertensive disorders as a result of increased stress on the cardiovascular system5 and endothelium.6 Gestational hypertension and preeclampsia are the most common complications of pregnancy affecting 2% to 10%
■
pre-eclampsia
■
pregnancy
of pregnancies after 20 weeks of pregnancy.6,7 Gestational hypertension is usually diagnosed based on a systolic blood pressure of ≥140 mm Hg or a diastolic blood pressure of ≥90 mm Hg in previously normotensive women.7 Preeclampsia is characterized by hypertension and protein in the urine.6,8 In addition to maternal mortality, preeclampsia and related conditions are a leading cause of maternal morbidity, perinatal death, placental abruption, preterm birth, and child growth restriction.6–8 The objective of this study was to systematically review epidemiological studies investigating associations between ambient air pollution and pregnancy-induced hypertensive disorders and to perform a meta-analysis of these studies.
Received March 13, 2014; first decision March 28, 2014; revision accepted May 21, 2014. From the Centre for Research in Environmental Epidemiology, Barcelona, Spain (M.P., L.S., M.J.N., P.D.); CIBER Epidemiología y Salud Pública, Madrid, Spain (M.P., M.J.N., P.D.); Universitat Pompeu Fabra, Barcelona, Spain (M.P., M.J.N., P.D.); INSERM, U823, Team of Environmental Epidemiology Applied to Reproduction and Respiratory Health, Institute Albert Bonniot, Grenoble, France (M.P., R.S.); Division of Epidemiology and Biostatistics, School of Public Health, University of Illinois at Chicago (L.S.); University Joseph Fourier, Institute Albert Bonniot, Grenoble, France (R.S.); Danish Cancer Society Research Center, Copenhagen, Denmark (M.S., O.R.-N.); and Department of Maternal-Foetal Medicine, ICGON, Hospital Clinic IDIBAPS, University of Barcelona, Barcelona, Spain (F.F.). The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA. 114.03545/-/DC1. Correspondence to Marie Pedersen, Centre for Research in Environmental Epidemiology, Doctor Aiguader 88, Barcelona 08003, Spain. E-mail [email protected] © 2014 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.114.03545
Downloaded from http://hyper.ahajournals.org/ at 494 CONS CALIFORNIA DIG LIB on December 7, 2014
Pedersen et al Air Pollution and Hypertensive Pregnancy Disorders 495
Methods Search Strategy Studies were identified using the electronic bibliographic databases PubMed and Web of Science using the following search terms (preeclampsia, eclampsia, pregnancy hypertension, gestational hypertension, or HELLP) and (air pollution, traffic, or criteria air pollutants: particulate matter [PM], nitrogen oxides [NOX], carbon monoxides [CO], or ozone [O3]). We also searched the reference lists of identified articles for additional publications. We limited the search to peerreviewed articles published in English between December 2009 and December 19, 2013. Full articles published in other languages and abstracts were excluded (Figure 1). A total of 17 studies were considered relevant to be included in the systematic review and meta-analysis. If not reported, we requested from the authors effect estimates for continuous exposure. Additional unpublished information was received for a Swedish study,9 which was included in our analyses. We excluded 1 small (n=2707) study conducted in Iran from the meta-analysis because only effect estimates of high versus low exposure to CO were reported.10 Finally, in the case of 2 publications that had overlapping study populations,11,12 we selected the results from the study that had the largest sample size.12 In a sensitivity analysis, we included the other study11 instead, because the 2 studies used different exposure assessment methods.
Statistical Analysis To allow comparison of effect estimates between different studies, the reported odds ratios (OR) and 95% confidence intervals (CIs) were converted to correspond to common exposure increments (Methods S1 in the online-only Data Supplement). Few estimates were available for trimester-specific exposure, and thus combined estimates were only estimated for the full pregnancy mean to secure sufficient number of studies for meta-analyses. Three studies13–15 did not report the effect of the exposure during the entire pregnancy, and so for these 3 studies we included the effect estimates related to exposure during the first trimester. Four studies only reported categorical effect estimates associated with exposure to residential proximity to major roads and traffic density,9,16–18 and for these studies we estimated the combined risk estimates related to the highest versus the lowest exposure category (Methods S2). We examined all studies on pregnancy-induced hypertensive disorders (ie, gestational hypertension and preeclampsia as separate outcomes or a combination of these conditions), irrespective of the definition used, to secure sufficient number of studies for random effect meta-analyses.19 Second, we restricted the meta-analyses to studies on preeclampsia because there is controversy whether gestational hypertension and preeclampsia are a spectrum or different diseases.6–8 There were an insufficient number of studies on gestational hypertension to analyze this as a separate outcome. To identify potential influential studies and examine the robustness of the findings of the meta-analysis to the exclusion of these studies, we conducted sensitivity analyses by repeating meta-analyses after removing 1 study at a time and comparing the combined estimates with and without that study. Publication bias was evaluated using Funnel plots and Egger tests.20 In the absence of bias, the funnel plot should resemble a symmetrical inverted funnel with larger studies being close to the pooled estimate, and smaller studies more widely, but evenly, scattered around the
pooled estimate. The Egger test provides a formal statistical evaluation of whether there is asymmetry in the study results that is related to their standard error. Stata S.E. version 12.1 was used for the statistical analyses (StataCorporation, TX).
Results Description of the Study Characteristics We identified 17 studies published between 2009 and 2013 for the systematic review that are summarized in Table S1 in the online-only Data Supplement.10–18,21–27 All studies with the exception of 1 case–control study28 were prospective cohorts or birth record–based retrospective cohorts. The studies were based on 298 to 468 517 pregnancies occurring during 1996 to 2008. Nine studies were conducted in the United States, 5 in Europe, and 3 in Iran, Japan, and Australia (Table S1). Most studies excluded multiple pregnancies, but not all.21,23 The applied inclusion and exclusion criteria varied between studies and so did the availability of potential confounders (Table S1).
Outcome Definition and Prevalence Ten of the 17 studies evaluated preeclampsia,9,11,12,16,21–25 5 studied a combination of gestational hypertension and preeclampsia without separating them,15,17,26–27 4 considered gestational hypertension,10,13,16,24 and one evaluated a combination of gestational hypertension and preeclampsia among women with preterm births.18 Few studies further evaluated subgroups of preeclampsia according to severity9,11,15 or early and late onset.21 The definition of outcomes varied among the studies (Table S2). In some studies, preeclampsia included the more severe outcomes such as eclampsia,11,12,24,26,27 and the definitions used were not described in detail in all studies.25,27 The reported prevalence for gestational hypertension ranged from 3.6%12 to 6.0%,13 preeclampsia ranged from 1.2%21 to 4.0%,22 and the combination of gestational hypertension and preeclampsia ranged from 2.7%14 to 4.7%.27
Air Pollution Exposure Half of all the included studies estimated the pollutant concentration in ambient air at the maternal home address at birth using environmental models (land-use regressions or dispersion),9,12,21–24 whereas routine air pollutant data from central air–pollution-monitoring stations were used in the other half of the studies.10,12,15,18,25–27 Most commonly, exposures were assigned using the monitoring station nearest to the maternal residence at the time of birth. Distance between the monitors and participant’s home addresses as well as the number and density of monitors differed across studies. Seven studies evaluated PM2.5, 6 NO2, 5 PM10, CO, or O3, and 4 evaluated NOX (Table S1). The mean pregnancy exposure
Figure 1. Study identification and selection.
Downloaded from http://hyper.ahajournals.org/ at CONS CALIFORNIA DIG LIB on December 7, 2014
496 Hypertension September 2014 (µg/m3) to PM2.5 and NO2 ranged from 10.123,27 to 17.312 and from 23.022 to 55.7,21 respectively. The ranges of the other air pollutant concentration also differed among studies (Table S3).
Combined Estimates of Air Pollution and the Risk of Hypertensive Disorders in Pregnancy The effect estimates of individual studies and the combined effect estimates for pregnancy-induced hypertensive disorders associated with PM2.5 and NO2 are presented in Figure 2. For all pollutants, heterogeneity as measured by the I2 was high, and there were highly significant Q tests when all pregnancyinduced hypertensive outcomes were combined (Table). For most pollutants, the heterogeneity among studies tended to be smaller when studies on preeclampsia only were considered (Table; Figure 2). Results from the individual studies on PM2.5 consistently reported increased risk of pregnancy-induced hypertensive disorders ranging from 11%13 to 398%27 associated with each 5-µg/ m3 increase in PM2.5 (Figure 2). Likewise for NO2, a consistent pattern of increased risks between 4%21 and 85%27 associated with each 10-µg/m3 increase in NO2 were reported (Figure 2). Increased risks were also observed in most, but not in all, of the individual studies on NOX, PM10, and O3 (Figure S1). Pregnancy-induced hypertensive disorders were statistically significantly associated with a 5 µg/m3 increment
in PM2.5 (OR=1.47; 95% CI, 1.27, 1.68; Table; Figure 2), a 10-µg/m3 increment in NO2 (OR=1.23; 95% CI, 1.04, 1.41; Table; Figure 2), and a 10-µg/m3 increment in PM10 (OR=1.11; 95% CI, 1.00, 1.21; Table). When all outcomes were combined, there were also marginally statistically significant associations with NOX and O3 but not with CO (Table). The forest plots of the other pollutants are presented in Figure S1.
Residential Proximity to Traffic, Traffic Density, and Hypertensive Disorders in Pregnancy One study reported effect estimates associated with increments in traffic density12 and 4 reported effect estimates of categorical proximity to major road.9,17,18,24 The individual studies have reported increased ORs for pregnancy-induced hypertensive disorders among women exposed to high traffic density,9,12 and among women living within 200 to 250 m from major roads,17,18 although not for all of the associations evaluated.16,17 The heterogeneity among the studies reporting effects of low versus high exposure to traffic indicators was not statistically significant. The random-effect meta-analysis suggested that pregnancy-induced hypertensive disorders were statistically significantly associated with higher exposure to traffic density (Table; Figure S1).
Figure 2. Associations between air pollution with PM2.5, NO2, and pregnancy-induced hypertensive disorders. Odds ratio (OR) and 95% confidence intervals (CI) from the individual studies and the combined meta-analysis result indicated by vertical points of the diamonds and 95% CIs by horizontal points per 5 µg/m3 for PM2.5 (upper) and 10 µg/m3 for NO2 (lower), respectively.
Downloaded from http://hyper.ahajournals.org/ at CONS CALIFORNIA DIG LIB on December 7, 2014
Pedersen et al Air Pollution and Hypertensive Pregnancy Disorders 497 Table. Random-Effect Meta-Analyses of Studies on Air Pollution, Traffic, and Hypertensive Disorders in Pregnancy Exposure and Outcomes
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19 139
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