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Environmental Pollution 237 (2018) 18e27

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Environmental Pollution
journal homepage: www.elsevier.com/locate/envpol

Effects of prenatal exposure to air pollution on preeclampsia in


Shenzhen, China
Qiong Wang a, b, 1, Huanhuan Zhang a, b, 1, Qianhong Liang c, Luke D. Knibbs d,
Meng Ren a, b, Changchang Li a, b, Junzhe Bao a, b, Suhan Wang a, b, Yiling He a, b, Lei Zhu a, b,
Xuemei Wang e, Qingguo Zhao f, g, *, Cunrui Huang a, b, **
a
Department of Health Policy and Management, School of Public Health, Sun Yat-sen University, China
b
Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, School of Public Health, Sun Yat-sen University, China
c
Department of Ultrasound, Panyu Maternal and Child Care Service Center of Guangzhou, China
d
School of Public Health, The University of Queensland, Herston, Australia
e
Institute of Environmental and Climate Research, Jinan University, China
f
Family Planning Research Institute of Guangdong Province, China
g
Family Planning Special Hospital of Guangdong Province, China

a r t i c l e i n f o a b s t r a c t

Article history: The impact of ambient air pollution on pregnant women is a concern in China. However, little is known
Received 17 September 2017 about the association between air pollution and preeclampsia and the potential modifying effects of
Received in revised form meteorological conditions have not been assessed. This study aimed to assess the effects of prenatal
1 February 2018
exposure to air pollution on preeclampsia, and to explore whether temperature and humidity modify the
Accepted 5 February 2018
effects. We performed a retrospective cohort study based on 1.21 million singleton births from the birth
registration system in Shenzhen, China, between 2005 and 2012. Daily average measurements of par-
ticulate matter <10 mm (PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), air temperature (T), and dew
Keywords:
Preeclampsia
point (Td) were collected. Logistic regression models were performed to estimate associations between
Air pollution air pollution and preeclampsia during the first and second trimesters, and during the entire pregnancy. In
Temperature each time window, we observed a positive gradient of increasing preeclampsia risk with increasing
Humidity quartiles of PM10 and SO2 exposure. When stratified by T and Td in three categories (<5th, 5th 95th, and
Modification >95th percentile), we found a significant interaction between PM10 and Td on preeclampsia; the adverse
effects of PM10 increased with Td. During the entire pregnancy, there was a null association between
PM10 and preeclampsia under Td < 5th percentile. Preeclampsia risk increased by 23% (95% CI: 19e26%)
when 5th < Td < 95th percentile, and by 34% (16e55%) when Td > 95th percentile. We also found that air
pollution effects on preeclampsia in autumn/winter seasons were stronger than those in the spring/
summer. This is the first study to address modifying effects of meteorological factors on the association
between air pollution and preeclampsia. Findings indicate that prenatal exposure to PM10 and SO2 in-
crease preeclampsia risk in Shenzhen, China, and the effects could be modified by humidity. Pregnant
women should limit air pollution exposure, particularly during humid periods.
© 2018 Elsevier Ltd. All rights reserved.

1. Introduction

Preeclampsia is a serious multisystem disorder of pregnancy,


most commonly defined as hypertension and proteinuria after 20
* Corresponding author. Family Planning Research Institute of Guangdong Prov- weeks of pregnancy. It complicates 1e4% of pregnancies globally
ince, Guangzhou 510600, China.
(Ananth et al., 2013; Roberts et al., 2011), and is a major cause of
** Corresponding author. Department of Health Policy and Management, School of
Public Health, Sun Yat-sen University, Guangzhou 510080, China.
maternal morbidity and mortality, intrauterine growth restriction,
E-mail addresses: zqgfrost@126.com (Q. Zhao), huangcr@mail.sysu.edu.cn preterm birth, and perinatal deaths. Additionally, preeclampsia has
(C. Huang). been associated with premature cardiovascular and metabolic
1
Author contributions: These authors contributed equally to this work.

https://doi.org/10.1016/j.envpol.2018.02.010
0269-7491/© 2018 Elsevier Ltd. All rights reserved.
Q. Wang et al. / Environmental Pollution 237 (2018) 18e27 19

disease in later life (Behrens et al., 2016; Steegers et al., 2010). temperatures and precipitation for most of the year. The average
Common risk factors for preeclampsia include old maternal age temperature (and precipitation) is 22.6  C (153.8 mm), 28.5  C
(40 years old), obesity, multiple (twin) pregnancy, nulliparity, (340.2 mm), 24.7  C (111.6 mm) and 16.2  C (41.1 mm) in spring,
previous history of preeclampsia, family history, and pre-existing summer, autumn, and winter, respectively (Meteorological Bureau
diabetes (Duckitt and Harrington, 2005; Trogstad et al., 2011). of Shenzhen Municipality, 2017). Even though air quality in
Beyond individual-level risk factors, widespread environmental Shenzhen is better than other large Chinese cities, levels of air
exposures like air pollution have been associated with pre- pollutants during 2005e2012 were still above those recommended
eclampsia because pollutants can induce systemic inflammation, by the World Health Organization (WHO, 2006).
oxidative stress, and result in vascular endothelial injury (Montiel-
Davalos et al., 2010; Shah et al., 2013). Exposure to air pollution has 2.2. Study population
been associated with cardiovascular events in adults (Shah et al.,
2013), and there is increasing evidence that exposure to ambient This study was a retrospective cohort study, consisting of all
air pollution contributed to the risk of hypertensive disorders singleton births in Shenzhen from January 2005 to December 2012
during pregnancy (Pedersen et al., 2014). However, previous (a total of 1,270,656 cases). The data on both mothers and neonates
studies regarding the association between air pollution and pre- were obtained from Birth Registry Database and Maternal and
eclampsia have been inconsistent in their findings. Moreover, Children Health Information System in Shenzhen, which covered
almost all of these studies were conducted in areas with relatively all midwifery clinics and hospitals in the city.
low concentrations of air pollution (Dadvand et al., 2013, 2014; We excluded births with missing or outlier maternal age (<13 or
Malmqvist et al., 2013; Mendola et al., 2016; Nahidi et al., 2014; >50 years) (n ¼ 17,961; 1.41% of total births) according to the nat-
Pedersen et al., 2017; Yorifuji et al., 2015). A limited number of ural age at menarche (12.8 years) and menopause (50.8 years) in
studies were conducted in area with relatively high air pollution the Chinese population (Shao et al., 2014; Song et al., 2011), and
levels (Huang et al., 2015; Agrawal and Yamamoto, 2015). Eighty- those with missing or outlier gestational age (<20 or >44 weeks)
seven percent of the worlds population live in areas exceeding (n ¼ 1405; 0.11%) (Liang et al., 2016). The women with chronic hy-
WHO air quality guidelines for fine particles (Brauer et al., 2016), pertension (n ¼ 252; 0.002%) were also excluded because they
but very few studies have been conducted in such areas, including were not at risk for new-onset hypertension.
China. This study was approved by the medical ethics committee of
Recently, studies have shown that season (Coulibaly et al., 2015) School of Public Health, Sun Yat-sen University. Data used in the
and meteorological factors, including temperature and humidity, study were anonymous and individual consent was not required.
are implicated in air pollutants’ generation, transport (Csavina
et al., 2014; Li et al., 2014; Tian et al., 2014), and even chemical 2.3. Outcome and covariates
toxicity (Gordon, 2003; Gordon et al., 2014; Leon, 2008). This im-
plies that the season and meteorological conditions could modify Preeclampsia diagnoses were based on clinical guidelines in use
health effects of air pollution. Also, in the context of climate change, at the time of delivery in China. The clinical guidelines were pri-
the frequency and magnitude of extreme meteorological events marily based American College of Obstetricians and Gynecologists
(e.g., heat waves) are expected to increase (IPCC, 2013). This makes (ACOG), and preeclampsia was defined as sustained hypertension
investigations into meteorological factors and air pollution on hu- (140/90 mmHg) and proteinuria (urine protein concentrations of
man health are needed to better understand their combined effects. 30 mg/dL or 1 þ on two or more urine dipsticks) after 20th week of
A recent systematic review on air pollution and pregnancy gestation in previously normotensive women (ACOG, 2002). Based
induced hypertensive disorders (Pedersen et al., 2014) suggested on a previous study, we included women with eclampsia or the
that future studies should take into account more factors, especially HELLP syndrome (hemolysis, elevated liver enzymes, and low
air temperature to explore the modification effects. However, pre- platelets) in preeclampsia diagnosis (Weinberg et al., 2017) because
vious studies regarding effect modifiers of air pollution were they also generally present with hypertension and proteinuria.
mainly limited to body mass index (BMI) (Mobasher et al., 2013), Similar to other studies (Mendola et al., 2016; Wu et al., 2009), the
road noise (Pedersen et al., 2017), and asthma (Mendola et al., specific gestational age at preeclampsia diagnosis was not available.
2016). We are not aware of any studies focused on modification We collected covariates including maternal age, pre-pregnancy
of temperature or other meteorological factors on the association BMI, education levels, times of prenatal examination, parity,
between air pollution and preeclampsia. gestational age at birth, date of birth, birth weight, and infant sex.
In this study, we aimed to assess the effects of prenatal exposure The date of conception was calculated by subtracting the gesta-
to air pollution on preeclampsia, and further explore whether tional age at birth from the date of birth.
season and meteorological conditions could modify the effects of
air pollution. 2.4. Air pollution exposure assessment

2. Methods Daily (24-h) average air pollution data from January 2005 to
December 2012 were collected from environmental monitoring
2.1. Study area centers located within Shenzhen city (shown in Supplementary
Figs. 1 and 6 monitors from 2005 to 2007; 8 for 2008e2012). The
Shenzhen is a coastal city located within the Pearl River Delta of measured air pollutants were PM10, SO2 and NO2. According to
Guangdong Province, southern China. It was the first Special Eco- standard on ambient air quality (GB 3095-1996) established by
nomic Zone established as part of China's economic reform in the Environmental Protection Department of the People's Republic of
1980s. Within three decades, Shenzhen has developed from a China (1996), PM10 was determined by weighting, SO2 by formal-
relatively small town to one of the most developed cities in China. dehyde absorbing-pararosaniline spectrophotometric, and NO2 by
Until recently, Shenzhen has the highest population density and the N-(1-naphthyl)-ethylenediamine dihydrochloride spectrophoto-
highest Gross Domestic Product (GDP) per capita in China metric method. We assess the spatio-temporal variability of air
(Shenzhen, 2017). pollutants concentrations among the monitors (Supplementary
Shenzhen has a subtropical oceanic monsoon climate, with high Table S1).
20 Q. Wang et al. / Environmental Pollution 237 (2018) 18e27

To further explore modification of meteorological conditions, (ORs) and 95% confidence intervals (CIs) were calculated based on
we collected air temperature and relative humidity from Shenzhen categories, within which exposure quartiles 2, 3, 4 were contrasted
Meteorological Bureau websites. Relative humidity is the routinely with quartile 1 as the reference. We did not have sufficiently ac-
reported meteorological factor to the public, but it represents the curate information on the women's historical exposure to control
extent to which air is saturated, not an atmospheric moisture var- for long-term exposures in our models.
iable (Davis et al., 2016). Therefore, we used a good approximation, For sensitivity analyses, we conducted multivariable logistic
the August-Roche-Magnus approximation (Alduchov and Eskridge, regression models to evaluate the association between PM10, SO2,
1996) to calculate dew point temperature ( C) as a humidity indi- NO2 and preeclampsia without exclusion of outliers of maternal age
cator. Therefore, daily mean air temperature (T,  C) and dew point (<13 or >50 years old) and gestational age (<20 or >44 weeks). We
temperature (Td,  C) were used as air temperature and humidity also added T and Td as adjusted covariates in above models for
indicators in this study. sensitivity analyses.
To assign air pollution exposure for each subject, we averaged In order to test effect modification by meteorological conditions,
daily PM10, SO2, and NO2 over all monitors. On the other hand, we we included a cross product interaction term between window-
used the estimated date of conception and date of birth to deter- specific air pollutants (in IQR: the differences between the 25th
mine the start and end date of each gestational week for each and 75th percentile) and season of conception, T and Td. Wald's
pregnancy. We then derived the weekly average PM10, SO2, and NO2 method was used to assess the presence of interaction on the
during each completed gestational week by averaging the daily multiplicative scale. Effect modification was considered statistically
mean PM10, SO2, and NO2 on the first day of the corresponding significant if the interaction term P value was less than 0.05. Then,
gestational week and the following 6 days. we calculated ORs (95% CIs) for per IQR increase in PM10, SO2 and
We used the same approach to estimate weekly average values NO2 and preeclampsia, stratified by season of conception (spring,
for T and Td. summer, autumn, winter), window-specific T and Td categories.
Although specific gestational age at preeclampsia diagnosis was Both T and Td were classified as three categories for each exposure
not available, by definition preeclampsia occurred after 20 weeks of time window: <5th percentile, 5th 95th percentile, and >95th
pregnancy. Therefore, weekly exposures were then averaged over percentile.
three exposure windows for each case: the first trimester (gesta- All analyses were performed using SAS software, version 9.4
tional week 1 through week 12), second trimester (week 13 to week (SAS Institute Inc., Cary, NC).
27), and the entire pregnancy. The first trimester time window will
always precede diagnosis, and most pregnancies also have a full 3. Results
second trimester window. Since preeclampsia diagnosis can trigger
a medically-indicated delivery at or near term, the entire pregnancy Of 1,208,559 mother-child pairs included in our study, 14,070
might be considered a proxy of an average exposure until diagnosis mothers were diagnosed as preeclampsia (1.16%). Distributions of
(Mendola et al., 2016). Since the specific gestational age at pre- selected characteristics between subjects with and without pre-
eclampsia diagnosis was not available, the length of preceding eclampsia are shown in Table 1. Compared with subjects without
exposure during the third trimester (week 28 to preeclampsia preeclampsia, those with preeclampsia were slightly older, more
onset) may vary substantially. We therefore did not assess t the likely to have lower gestational age, higher pre-pregnancy BMI, and
third trimester as an exposure window. having fewer occasions of prenatal examination. In addition, pre-
Those without exposure information (had exposure windows eclampsia was more frequently reported among women who had
occurring before 2005 when exposure assessment period started,
n ¼ 42,479, 3.4% of total cases) were excluded from final analyses.
Therefore, the remaining 1,208,559 records were included in our Table 1
Distributions of selected characteristics.
analyses.
Characteristics Preeclampsia Non-preeclampsia t/Chi-square (P)
2.5. Statistical analyses (n ¼ 14, 070) (n ¼ 1, 194, 489)

Gestational age 37.83 ± 2.58 38.94 ± 1.67 50.95 (<0.0001)


Differences in selected characteristics between preeclampsia (years, Mean ± SD)
and non-preeclampsia subjects were examined with independent- Maternal age 28.77 ± 5.53 27.26 ± 4.71 32.29 (<0.0001)
(years, Mean ± SD)
sample T-tests for continuous variables and with chi-square tests Pre-pregnancy BMI 20.77 ± 2.34 20.1 ± 2.01 33.82 (<0.0001)
for categorical variables. Before T-tests, assumptions of normality as (Kg/m2, Mean ± SD)
well as of homogeneity of the variances were tested. The Wilcoxon- Prenatal examination 4.22 ± 3.56 4.96 ± 3.69 24.33 (<0.0001)
Mann-Whitney (WMW) test was used for non-normal data. If (times, Mean ± SD)
Years of education (n, %)
variances between two groups were not equal, the Satterthwaite
<¼6 1042 (7.41) 50,369 (4.22)
approximation was used. 7-9 5657 (40.21) 455,071 (38.1)
Pearson's correlation test was used to examine the correlation 10-12 4739 (33.68) 432,321 (36.19)
among PM10, SO2 and NO2; (Supplementary Table S2). Highly- >12 2632 (18.71) 256,728 (21.49) 432.24 (<0.0001)
correlated variables included in one model simultaneously may Season of conception (n, %)
Spring 3396 (24.14) 285,999 (23.94)
result in multicollinearity and unstable results. We therefore did Summer 3273 (23.26) 249,414 (20.88)
not t fit multi-pollutant model and instead presented results from Autumn 3361 (23.89) 299,855 (25.1)
single-pollutant models. Winter 4040 (28.71) 359,221 (30.07) 54.69 (<0.0001)
Multivariable logistic regression models were used to evaluate Parity (n, %)
Primiparous 8837 (62.81) 724,243 (60.63)
the association between PM10, SO2, NO2 and preeclampsia,
Multiparous 5202 (36.97) 465,780 (38.99)
adjusting for defined risk factors for preeclampsia (Duckitt and Missing 31 (0.22) 4466 (0.37) 34.25 (<0.0001)
Harrington, 2005; Trogstad et al., 2011), including gestational age, Infant sex (n, %)
maternal age, pre-pregnancy BMI, the number of prenatal exami- Male 7241 (51.46) 647,069 (54.17)
nation, education levels (6, 7e9, 10e12, >12 years), parity (pri- Female 6825 (48.51) 547,269 (45.82)
Missing 4 (0.03) 151 (0.01) 43.50 (<0.0001)
miparous, multiparous) and infant sex (male, female). Odds ratios
Q. Wang et al. / Environmental Pollution 237 (2018) 18e27 21

less education, were primiparous, conceived in spring/summer, and normal air temperature (5th < T < 95th percentile), 23% (19e26%)
who delivered girls. under normal humidity (5th < Td < 95th percentile), and 34%
Table 2 shows the summary statistics of PM10, SO2, NO2, T and Td (16e55%) under Td > 95th percentile, respectively. The equivalent
during each exposure time window. Their correlations are shown in effects for SO2 were 28% (25e32%), 26% (22e29%) and 17% (8e28%),
Supplementary Table S2. We observed moderate to high positive respectively.
correlation among PM10, SO2 and NO2 (Pearson's correlation co- For NO2, modifying effects were different to those for PM10 and
efficients ranged from 0.48 to 0.83), and also moderate to high SO2, and varied across exposure time windows. In the first
negative correlation between air pollutants (PM10, NO2) and trimester, except for null association were observed when
meteorological factors (T and Td) with coefficients from 0.47 conception in summer/autumn/winter seasons and under relative
to 0.83. low humidity (Td < 5th percentile), NO2 exposure showed an in-
Associations between air pollution and preeclampsia are pre- verse association with preeclampsia under other meteorological
sented in Table 3. Base models adjusted for the individual-level conditions. However, in the second trimester and entire pregnancy,
covariates described above showed a positive gradient increase in NO2 exposure tended to be positively associated with preeclampsia
risk of preeclampsia with quartiles of PM10 and SO2 exposure when conceived in autumn, under normal temperature and hu-
during the first, second trimester, and the entire pregnancy. midity, while inversely associated with preeclampsia under spring
Referring to Quartile 1, ORs increased with successive quartiles 2, 3, and relative high temperature strata.
and 4, ranging from 1.09 to 1.35 for PM10 and from 1.11 to 1.40 for
SO2. In models added T and Td as adjusted covariates for sensitivity
4. Discussion
analyses, the estimated ORs slightly changed, however the positive
gradient in associations remained.
Based on a large dataset in Shenzhen, China, our study is the first
There were inverse association between NO2 exposure in the
to examine the effect of air pollution on preeclampsia and modi-
first trimester and preeclampsia, null association in the second
fying effects of meteorological conditions. We observed that pre-
trimester and positive associations in the entire pregnancy. By
eclampsia risk increased gradually with quartiles of PM10 and SO2
additionally adjusting for meteorological factors, the estimated ORs
exposure, during the first trimester, second trimester and entire
for NO2 exposure did not change.
pregnancy. Also, significant interaction between PM10 and dew
In our sensitivity analyses without exclusion of maternal age
point temperature on preeclampsia were observed. Significant and
and gestational age outliers, we found similar associations between
stronger association between PM10 and preeclampsia were only
air pollution exposure and preeclampsia. The results are summa-
apparent under relative high humidity condition (>95th percentile
rized in Supplementary Table S3.
of dew point temperature). We also found that air pollution effects
Effect modification of season of conception and meteorological
on preeclampsia in autumn/winter seasons were much stronger
factors on associations between air pollution and preeclampsia are
than those in spring/summer seasons.
shown in Fig. 1 for PM10, Fig. 2 for SO2, and Fig. 3 for NO2. There
Among the participants in this study, preeclampsia incidence
were significant interactions between PM10, SO2 and season of
was 1.16%, which was relatively low compared with western
conception, as well PM10 and dew point temperature (interaction P-
countries (1.4%e4.0%) (Ananth et al., 2013; Roberts et al., 2011), and
value<0.05). For all time windows, positive associations between
also other Chinese populations (2.5%) (Li et al., 2013). Lower pre-
PM10, SO2 exposure and preeclampsia were solely observed under
eclampsia incidence in this study may partly due to geographic
specific season (conception in summer/autumn/winter seasons)
variation, as it was reported that preeclampsia incidence in
and the effects on preeclampsia in autumn/winter seasons were
Guangdong province (where Shenzhen located in) was lower than
stronger than those in summer. Positive associations were also
that in southwest China (Qiao et al., 2013). Also, we would not
observed in specific meteorological conditions: normal air tem-
exclude the possibility of underreporting by hospitals, which may
perature (5th < T < 95th percentile), normal and relative high hu-
potentially affect the pattern of association. There is the possibility
midity (5th < Td < 5th percentile and Td > 95th percentile strata).
that misclassification of preeclampsia cases as non-preeclampsia
Otherwise, the significant effects of air pollution were not present.
subjects biased associations towards the null (Savitz et al., 2015).
For example, during the entire pregnancy, with an IQR increase in
A large body of evidence suggests that air pollution can induce a
PM10, preeclampsia risk increased by 25% (95% CI: 21e29%) under
series of reactions, including systemic inflammation, oxidative

Table 2
Pollutant concentration and meteorological factors by gestational period.
a
Gestational period Pollutants/meteorological factors Mean SD Max 95th 75th 50th 25th 5th Min

1st trimester PM10 61.2 16.2 135.8 87.5 72.6 60.1 49.5 36.8 28.7
SO2 16.3 7.1 35.7 30.4 21.5 14.2 10.2 8.1 6.4
NO2 46.8 10.0 76.3 66.6 53.7 45.3 38.6 33.6 30.1
T 23.2 4.7 30.3 29.5 27.8 23.3 18.8 15.8 14.3
Td 16.7 5.6 25.1 24.3 22.1 16.9 11.7 7.8 6.3
2nd trimester PM10 58.0 14.6 92.8 83.9 69.4 56.3 46.1 37 32.8
SO2 15.4 6.9 35.4 29.9 19.7 13.6 9.7 7.8 6.4
NO2 45.5 9.5 75.6 64.9 51.2 43.5 37.8 33.7 30.4
T 24.1 4.4 30.0 29.4 28.3 25.0 20.0 16.6 14.9
Td 17.9 5.3 24.9 24.1 22.9 18.9 13.1 8.8 7.4
Entire pregnancy PM10 59.1 7.0 83.9 71.6 64.2 58.5 53.1 49.4 40.4
SO2 15.6 6.4 33.6 28.8 20.8 12.9 10.1 9.0 7.3
NO2 45.9 6.0 66.0 57.5 49.8 44.3 42.0 37.6 32.5
T 23.9 1.6 29.1 26.4 25.5 23.8 22.5 21.5 17.2
Td 17.6 2.0 23.8 20.6 19.3 17.5 15.9 14.3 9.6
a
T: Air temperature; Td: Dew point temperature; Units are microgram per cubic meter (ug/m3) for PM10, SO2 and NO2, degree Celsius ( C) for air temperature and dew point
temperature.
22 Q. Wang et al. / Environmental Pollution 237 (2018) 18e27

Table 3
Association between air pollutants and preeclampsia.

Gestational period PM10 SO2 NO2


a
Quartiles OR (95% CI)b OR (95% CI)c Quartiles a
OR (95% CI)b OR (95% CI)c Quartiles a
OR (95% CI)b OR (95% CI)c
st
1 trimester 49.5 1.00 1.00 10.2 1.00 1.00 38.6 1.00 1.00
49.5e60.1 0.89 (0.84e0.94) 0.89 (0.85e0.94) 10.2e14.2 0.91 (0.86e0.95) 0.87 (0.83e0.91) 38.6e45.3 0.79 (0.75e0.83) 0.81 (0.77e0.85)
60.1e72.6 1.04 (0.98e1.10) 1.07 (1.01e1.13) 14.2e21.5 1.01 (0.96e1.06) 0.98 (0.93e1.02) 45.3e53.7 0.76 (0.72e0.80) 0.77 (0.73e0.81)
72.6 1.17 (1.10e1.23) 1.17 (1.1e1.25) 21.5 1.12 (1.07e1.18) 1.06 (1.01e1.11) 53.7 0.77 (0.73e0.81) 0.76 (0.71e0.80)
2nd trimester 46.1 1.00 1.00 9.7 1.00 1.00 37.8 1.00 1.00
46.1e56.3 1.08 (1.03e1.14) 1.08 (1.03e1.13) 9.7e13.6 1.11 (1.05e1.17) 1.06 (1.01e1.12) 37.8e43.5 0.73 (0.69e0.76) 0.72 (0.69e0.76)
56.3e69.4 1.14 (1.08e1.19) 1.14 (1.08e1.20) 13.6e19.7 1.30 (1.24e1.37) 1.24 (1.17e1.30) 43.5e51.2 0.96 (0.92e1.01) 0.96 (0.92e1.01)
69.4 1.28 (1.22e1.34) 1.28 (1.21e1.35) 19.7 1.40 (1.33e1.47) 1.31 (1.24e1.38) 51.2 1.02 (0.97e1.07) 1.00 (0.95e1.05)
Entire pregnancy 53.1 1.00 1.00 10.1 1.00 1.00 42.0 1.00 1.00
53.1e58.5 1.04 (0.99e1.09) 1.01 (0.96e1.07) 10.1e12.9 0.98 (0.93e1.03) 0.93 (0.89e0.98) 42.0e44.3 0.98 (0.93e1.03) 0.99 (0.94e1.05)
58.5e64.2 1.35 (1.29e1.42) 1.34 (1.28e1.41) 12.9e20.8 1.30 (1.24e1.36) 1.20 (1.14e1.26) 44.3e49.8 1.04 (1.00e1.09) 1.05 (1.00e1.10)
64.2 1.31 (1.25e1.38) 1.32 (1.25e1.40) 20.8 1.26 (1.20e1.32) 1.16 (1.10e1.22) 49.8 1.10 (1.05e1.15) 1.10 (1.05e1.16)
a
Units are microgram per cubic meter (ug/m3) for PM10, SO2 and NO2.
b
Base models with single pollutant, adjusted for maternal age, gestational age, season of conception, prenatal examination times, pre-pregnancy body mass index, and
infant sex.
c
Base models adjusted for additional variables, air temperature and dew point temperature.

stress, and vascular endothelial injury (Montiel-Davalos et al., 2010; (Pedersen et al., 2017; Pereira et al., 2013), null findings (Dadvand
Shah et al., 2013). For pregnant women, these reactions may lead to et al., 2013; van den Hooven et al., 2011; Wu et al., 2011), as well
placental dysfunction, including decreasing placental blood flow, as inverse association (Savitz et al., 2015). In our study, NO2 expo-
disrupt trans-placental oxygenation, and imbalance between sure in the second trimester and entire pregnancy increased pre-
angiogenic placental growth factors and antiangiogenic proteins eclampsia risk (ORs ranged from 1.04 to 1.10).
(placenta growth factor, vascular endothelial growth factor, soluble Relatively high air pollution levels may be one explanation for
fms-like tyrosine kinase-1, and soluble endoglin) (van den Hooven the obvious positive associations in our study. The previous studies
et al., 2012). Placental dysfunction has been proposed to have a were mostly conducted in areas with relatively low concentrations
critical role in the pathogenesis of preeclampsia (Steegers et al., of air pollution. The median of PM10 exposure concentrations
2010; Trogstad et al., 2011). Thus, a link between ambient air ranged from 21.5 to 41.3 mg/m3 (Dadvand et al., 2013; Lee et al.,
pollution and preeclampsia is biologically plausible. 2013; Mendola et al., 2016), SO2 was around 9.4 mg/m3 (Mendola
Ambient air pollutants, either individually or as proxies for the et al., 2016), and NO2 was from 11.5 to 39.8 mg/m3 (Pedersen
complex mixture of urban air pollution, including PM2.5, PM10, CO, et al., 2017; van den Hooven et al., 2012; Wu et al., 2011), which
O3, NO2, and NOx, have been concerned to affect preeclampsia (Hu were all below the hazard level recommended by the WHO air
et al., 2014; Pedersen et al., 2014). Given the availability of data, we quality guidelines (50 mg/m3 for PM10 24 h concentration, 20 mg/m3
included PM10, SO2, and NO2 in our study. for SO2 24 h concentration, 40 mg/m3 for NO2 annual mean con-
Most previous studies assessing PM10 and risk of preeclampsia centration) (WHO, 2006). Concentration in these other studies,
have reported null associations. Dadvand et al. (2013) conducted a were far below those observed in our study, where medians of
study in Spain and found no statistically significant association PM10, SO2 and NO2 exposure during entire pregnancy reached 58.5,
between preeclampsia and PM10 exposure during entire pregnancy 12.9 and 44.3 mg/m3. In addition, there was a very large sample size
and different trimesters. Lee et al.'s study in the United States (1.21 million records included in the final analyses) in our study,
(2013) observed significant increase of 5%e8% in risk of gestational which was larger than all previous studies. The additional power
hypertension due to first trimester exposure to PM10, but no such associated with our large sample size may also explain our results
associations with preeclampsia. Mendola et al. (2016) examined air compared with those in previous studies.
pollution exposure and preeclampsia among US women with and Based on effect modification analyses, we found seasonal dif-
without asthma and found no significant effects. However, we ferences in associations between air pollution and preeclampsia.
found PM10 exposures in the first trimester, second trimester and Preeclampsia risk from PM10 and SO2 exposure was more apparent
entire pregnancy were positive gradient associated with pre- for conceptions in autumn and winter. The differences may be
eclampsia, with ORs ranged from 1.09 to 1.35, when highest quar- related to some seasonal pattern, including temperature, dietary
tiles were compared with the lowest quartiles. Our results were habits, seasonal infectious diseases, and so on. Also, vitamin D level
consistent with another study in China (Huang et al., 2015), which may be an important contributor. A recent meta-analysis based on
found PM10 exposure before 20 gestational weeks as well as the randomized controlled trials suggested that vitamin D supple-
entire pregnancy was significantly associated with preeclampsia. mentation could lower the risk of preeclampsia (Khaing et al.,
There were few studies focused on SO2 exposure and pre- 2017), especially during early pregnancy (Achkar et al., 2015).
eclampsia. We found two previous studies, one conducted in Japan Moreover, an in vitro study observed that sufficient vitamin D may
(Nahidi et al., 2014) and one in the United States (Mendola et al., counteract particle matter-driven inflammation (Mann et al., 2017).
2016), and both reported no significant relationships. In this In China, vitamin D level was reported to be significantly lower in
study, we found similar effects of SO2 as PM10. SO2 exposures in the winter than in summer (Yang and Zhang, 2017), which could
first trimester, second trimester and entire pregnancy were positive explain why we found stronger effects of air pollution in autumn
gradient associated with preeclampsia (highest quartiles compared and winter. Unfortunately, we do not have data on vitamin D. This
with the lowest quartiles: ORs ranged from 1.11 to 1.40). hypothesis could warrant further studies to test its plausibility.
Ambient NO2 concentration was usually used as a marker of It has been suggested that cold can cause arteriolar constriction,
traffic-related air pollution (Pereira et al., 2013). The literature on increased peripheral resistance and lead to apro-hypertensive
NO2 is more extensive, including a number of positive reports status that may be more vulnerable to external stimuli such as air
Q. Wang et al. / Environmental Pollution 237 (2018) 18e27 23

Fig. 1. Association between PM10 and preeclampsia by gestational period. Logistic regression models were used to test the interaction between PM10 during each exposure
windows (the first, second trimester, or entire pregnancy) and season of conception, daily mean ambient temperature (T) as well as dew point temperature (Td), and also to calculate
the odds ratios (ORs) and 95% confidence intervals (CIs) for associations between PM10 (per IQR increase) and preeclampsia, stratified by season of conception, T and Td categories.
Both T and Td were classified as three categories for each exposure time window: <5th percentile, 5th 95th percentile, and >95th percentile. All models were adjusted for maternal
age, gestational age, season of conception, prenatal examination times, pre-pregnancy body mass index, and infant sex.

pollution (Wu et al., 2015). While high ambient temperatures can and SO2, were specifically observed under relatively high humidity
result in skin blood flow increasing and moistening of the skin (>95th percentile) conditions. Also, the results were robust in
surface, which may further exacerbate the toxicity of exposed different trimesters. Little empirical research has examined
chemicals (Gordon et al., 2014; Leon, 2008). We anticipated to whether humidity modify air pollution and health relationship, if
observe elevated risk effects of air pollution under relative low and any, and health outcomes were limited to infections (Song, 2015) or
high temperatures; however, we did not. The null finding might be respiratory disease (Leitte et al., 2009; Sunyer et al., 1997). The
explained by behavioral adaptation, as pregnant women in China positive associations observed with PM10 and SO2 under relative
are more likely to stay indoors during cold and hot days, which high humidity may have a plausible explanation. High air moisture
therefore could reduce their exposure to outdoor air pollution. may lead to elevated concentrations of water-soluble inorganic ions

In addition to air temperature, we calculated dew point tem- (SO2 4þ
4 , NO3 , NH ) for PM10 (Gao et al., 2015) and increased acid
perature as an indicator of humidity to examine its modification. aerosol (H2SO4) formation from ambient SO2 (Bernstein et al.,
Interestingly, increased risks of air pollution, especially for PM10 2004). This could be important because some studies suggest that
24 Q. Wang et al. / Environmental Pollution 237 (2018) 18e27

Fig. 2. Association between SO2 and preeclampsia by gestational period. Logistic regression models were used to test the interaction between SO2 during each exposure
windows (the first, second trimester, or entire pregnancy) and season of conception, daily mean ambient temperature (T) as well as dew point temperature (Td), and also to calculate
the odds ratios (ORs) and 95% confidence intervals (CIs) for associations between SO2 (per IQR increase) and preeclampsia, stratified by season of conception, T and Td categories.
Both T and Td were classified as three categories for each exposure time window: <5th percentile, 5th 95th percentile, and >95th percentile. All models were adjusted for maternal
age, gestational age, season of conception, prenatal examination times, pre-pregnancy body mass index, and infant sex.

health worsens on days with high aerosolized acid levels (Bernstein associated with preeclampsia among the women without asthma
et al., 2004). (Mendola et al., 2016). The authors considered the effects were
Unexpectedly, we observed protective associations between chance findings or related to the negative correlations among
preeclampsia and air pollution exposure for some time windows, pollutants. We do not anticipate increases in air pollution exposure
especially for NO2. Similar findings were reported by two previous biologically confer protection, neither consider our results are
studies. One was conducted in New York (Savitz et al., 2015), which chance findings because of our very large sample size and observed
observed inverse association between PM2.5, NO2 and preeclamp- stable effects for PM10 and SO2. The inverse associations may be
sia, with ORs ranged from 0.64 to 0.94, and the protective effects in related to some important confounding effect of asthma or some
their study mainly referred to mild preeclampsia. The other study other air pollutants correlated with NO2 (Mendola et al., 2016). We
was based on 12 centers across the United States, and found NOX, suggest that the relationship of NO2 or NOx with preeclampsia re-
SO2 and volatile organic compounds (benzene and cyclohexane) quires more in-depth studies in the future.
exposure in per IQR increase during early pregnancy were inversely There are several major strengths of our study. This is the first
Q. Wang et al. / Environmental Pollution 237 (2018) 18e27 25

Fig. 3. Association between NO2 and preeclampsia by gestational period. Logistic regression models were used to test the interaction between NO2 during each exposure
windows (the first, second trimester, or entire pregnancy) and season of conception, daily mean ambient temperature (T) as well as dew point temperature (Td), and also to calculate
the odds ratios (ORs) and 95% confidence intervals (CIs) for associations between NO2 (per IQR increase) and preeclampsia, stratified by season of conception, T and Td categories.
Both T and Td were classified as three categories for each exposure time window: <5th percentile, 5th 95th percentile, and >95th percentile. All models were adjusted for maternal
age, gestational age, season of conception, prenatal examination times, pre-pregnancy body mass index, and infant sex.

study to address modification of both air temperature and humidity 20 and 34 of pregnancy) and late-onset (diagnosed after week 34 of
on association between air pollution and preeclampsia. We calcu- pregnancy) according to the time of diagnosis, and also as mild and
lated dew point temperature as a humidity indicator. In China, severe according to its severity. There are possibly different path-
relative humidity is a routinely reported meteorological factor to ogenesis and risk factors for different types (Pedersen et al., 2017;
the public, but it represents the extent to which air is saturated, not Valensise et al., 2008). In this study, however, we could not
an atmospheric moisture variable (Davis et al., 2016). Therefore, we examine the possible differences due to data not being available.
used the August-Roche-Magnus approximation to calculated dew Second, we used city-wide average air pollutant concentrations, air
point temperature ( C) as a humidity indicator. Furthermore, we temperature and dew point temperature to assign individual
have included about 1.21 million births spanned from 2005 to 2012. exposure, which may result in exposure misclassification and
The sample size was far larger than any previous study, which therefore bias effect estimates toward the null. Also, we only
contributed increased power to detect associations. focused on PM10, SO2, and NO2 in our study, because measurements
Several limitations should also be mentioned. First, pre- of other pollutants were not available. Third, we did not have data
eclampsia can be divided as early-onset (diagnosed between weeks on exercise and diet, smoking (including active smoking and
26 Q. Wang et al. / Environmental Pollution 237 (2018) 18e27

environmental tobacco smoke), previous history of preeclampsia, Duckitt, K., Harrington, D., 2005. Risk factors for pre-eclampsia at antenatal
booking: systematic review of controlled studies. BMJ 330, 565.
pre-existing diabetes (Duckitt and Harrington, 2005; Trogstad et al.,
Environmental Protection Department of the People's Republic of China, 1996.
2011), and road noise (Pedersen et al., 2017), which may confound Standard on ambient air quality (GB 3095-1996). Available: http://www.zhb.
our conclusions. A prospective birth cohort study will be helpful to gov.cn. (Accessed 21 July 2017).
address the above concerns. Gao, J.J., Tian, H.Z., Cheng, K., Lu, L., Zheng, M., Wang, S.X., et al., 2015. The variation
of chemical characteristics of pm2.5 and pm10 and formation causes during
In conclusion, we observed a positive gradient in associations two haze pollution events in urban Beijing, China, 2015; 107: 108 Atmos. En-
between PM10, SO2 exposures and preeclampsia, in the first viron. 107, 1e8.
trimester, second trimester and entire pregnancy. We found the Gordon, C.J., 2003. Role of environmental stress in the physiological response to
chemical toxicants. Environ. Res. 92, 1e7.
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of high levels air pollution on preeclampsia, which has important Huang, X., Qiu, J., Zhang, Y.Q., Qiu, W.T., He, X.C., Wang, Y.X., et al., 2015. Ambient air
public health implications. Pregnant women should aim to limit air pollutant PM10 and risk of pregnancy-induced hypertension in urban China.
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pollution exposures, particularly during humid periods. IPCC, 2013. Climate change 2013: the physical science basis. Contribution of
Working Group Ⅰ to the Fifth Assessment Report of the Intergovernmental Panel
Conflicts of interest on Climate Change. Cambridge university Press, Cambridge, United Kingdom
and New York, NY, USA.
Khaing, W., Vallibhakara, S.A., Tantrakul, V., Vallibhakara, O., Rattanasiri, S.,
None declared. McEvoy, M., et al., 2017. Calcium and vitamin D supplementation for prevention
of preeclampsia: a systematic review and network Meta-analysis. Nutrients 10
pii: E1141.
Sources of financial support Lee, P.C., Roberts, J.M., Catov, J.M., Talbott, E.O., Ritz, B., 2013. First trimester expo-
sure to ambient air pollution, pregnancy complications and adverse birth
The results reported herein correspond to specific aims of grant outcomes in Allegheny County, PA. Matern. Child Health J. 17, 545e555.
Leitte, A.M., Petrescu, C., Franck, U., Richter, M., Suciu, O., Ionovici, R., et al., 2009.
81602819 to investigator QW from National Natural Science Respiratory health, effects of ambient air pollution and its modification by air
Foundation of China, and grant A2015443 to investigator QW from humidity in Drobeta-Turnu Severin, Romania. Sci. Total Environ. 407,
Medical Scientific Research Foundation of Guangdong Province. 4004e4011.
Leon, L.R., 2008. Thermoregulatory responses to environmental toxicants: the
This work was also supported by grants 2016A030313216 from the interaction of thermal stress and toxicant exposure. Toxicol. Appl. Pharmacol.
Nature Science Foundation of Guangdong Province, CRRP2016- 233, 146e161.
10MY-Huang from Asia-Pacific Network for Global Change Li, Z., Ye, R., Zhang, L., Li, H., Liu, J., Ren, A., 2013. Folic acid supplementation during
early pregnancy and the risk of gestational hypertension and preeclampsia.
Research.
Hypertension 61, 873e879.
Li, L., Qian, J., Ou, C.Q., Zhou, Y.X., Guo, C., Guo, Y., 2014. Spatial and temporal
Appendix A. Supplementary data analysis of air pollution index and its timescale-dependent relationship with
meteorological factors in Guangzhou, China, 2001-2011. Environ. Pollut. 190,
75e81.
Supplementary data related to this article can be found at Liang, Z., Lin, Y., Ma, Y., Zhang, L., Zhang, X., Li, L., et al., 2016. The association be-
https://doi.org/10.1016/j.envpol.2018.02.010. tween ambient temperature and preterm birth in Shenzhen, China: a distrib-
uted lag non-linear time series analysis. Environ. Health 15, 84.
Malmqvist, E., Jakobsson, K., Tinnerberg, H., Rignell-Hydbom, A., Rylander, L., 2013.
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