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Adverse effects of exposure to air pollutants during fetal
development and early life with focus on pre-eclampsia, preterm
delivery, and childhood asthma
David Olsson
Department of Public Health and Clinical Medicine
Occupational and Environmental Medicine
Umeå University 2014
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This work is protected by the Swedish Copyright Legislation (Act
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ISBN: 978-91-7601-139-3
ISSN: 0346-6612
Elektronisk version tillgänglig på
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He få vål va he vejl
Sankte Per – Skapelseberättelsen, burträskarens uppkomst
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Table of Contents
Table of Contents i Abstract ii Abbreviations iv Enkel
sammanfattning på svenska v Original papers vi Introduction 1
Air pollution exposure 2 Air pollution and birth outcomes 2 Air
pollution and asthma 3
Aims of the thesis 5 Overall aims 5 Specific aims 5
Materials and methods 6 Study populations 6 Outcome definitions
6 Covariate definitions 7 Exposure assessment 8 Statistical
analysis 8
Results 13 Paper I 13 Paper II 14 Paper III 14 Paper IV 15
Discussion 17 Exposure assessment 17 Statistical modeling 17
Mechanism 18 Comparison of findings 18 Policy implications 20
Summary of findings 20 Future research 21 Conclusions 22
Acknowledgements 23 References 25
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Abstract
Background Air pollution exposure has been shown to have adverse
effects
on several health outcomes, and numerous studies have
reported
associations with cardiovascular morbidity, respiratory disease,
and
mortality. Over the last decade, an increasing number of studies
have
investigated possible associations with pregnancy outcomes,
including
preterm delivery. High levels of vehicle exhaust in residential
neighborhoods
have been associated with respiratory effects, including
childhood asthma,
and preterm birth is also associated with childhood asthma.
The first aim of this thesis was to investigate possible
associations between
air pollution exposure and pregnancy outcomes – primarily
preterm delivery
but also small for gestational age (SGA) and pre-eclampsia – in
a large
Swedish population (Papers I–III). The second aim was to study
any
association between exposure to high levels of vehicle exhaust
during
pregnancy and infancy and prescribed asthma medication in
childhood
(Paper IV).
Methods The study cohorts were constructed by matching other
individual
data to the Swedish Medical Birth Register. In the first two
studies, air
pollution data from monitoring stations were used, and in the
third and
fourth studies traffic intensity and dispersion model data were
used.
Preterm delivery was defined as giving birth before 37 weeks of
gestation.
SGA was defined as having a birth weight below the 10th
percentile for a
given duration of gestation. Pre-eclampsia was defined as having
any of the
ICD-10 diagnosis codes O11 (pre-existing hypertension with
pre-eclampsia),
O13 (gestational hypertension without significant proteinuria),
O14
(gestational hypertension with significant proteinuria), or O15
(eclampsia).
Childhood asthma medication was defined as having been
prescribed asthma
medication between the ages of five and six years.
Results We observed an association between ozone exposure during
the
first trimester and preterm delivery. First trimester ozone
exposure was also
associated with pre-eclampsia. The modeled concentration of
nitrogen
oxides at the home address was associated with pre-eclampsia,
but critical
time windows were not possible to investigate due to high
correlations
between time windows. We did not observe any association between
air
pollution exposure and SGA. High levels of vehicle exhaust at
the home
address, estimated by nitrogen oxides and traffic intensity,
were associated
with a lower risk of asthma medication.
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Conclusion Air pollution exposure during pregnancy was
associated with
preterm delivery and pre-eclampsia. We did not observe any
association
between air pollution levels and intrauterine growth measured as
SGA. No
harmful effect of air pollution exposure during pregnancy or
infancy on the
risk of being prescribed asthma medication between five and six
years of age
was observed.
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Abbreviations
ATC – Anatomical therapeutic chemical
BMI – Body mass index
CO – Carbon monoxide
ICD-10 – International Statistical Classification of Diseases,
version 10
LBW – Low birth weight NO2 – Nitrogen dioxide NOx – Nitrogen
oxides O3 – Ozone
OR – Odds ratio
PM10 – Particulate matter with a diameter
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Enkel sammanfattning på svenska
Ogynnsamma födelseutfall, exempelvis förtida födsel, har visats
öka risken
för sämre studieresultat och mer sjuklighet genom hela livet.
Astma under
barndomen kan leda till en lägre fysisk aktivitet eller ett
lägre psykosocialt
välbefinnande.
Denna avhandling har två huvudspår: (1) Att studera samband
mellan
luftföroreningshalter under graviditeten och ogynnsamma utfall,
främst
havandeskapsförgiftning, för tidigt födda barn samt
tillväxthämning. (2) Att
studera samband mellan luftföroreningshalter under graviditeten
eller
spädbarnstiden och astmamedicinering under barndomen.
De viktigaste fynden är att förhöjda ozonhalter i ett tidigt
skede av
graviditeten ledde till en ökad risk för barnet att bli för
tidigt fött och för
mamman att drabbas av havandeskapsförgiftning. Bodde mamman i
ett
område med högre avgashalter hade hon en högre risk att drabbas
av
havandeskapsförgiftning, och mammor som bodde i områden med
lägst
avgashalter hade en mindre risk att föda ett tillväxthämmat
barn.
Det fanns inga tecken på att bo i områden med högre avgashalter
eller mer
trafikerade områden under graviditeten eller spädbarnstiden
ökade risken
för att barnet skulle behöva medicineras för astma före
skolåldern.
Alla fyra delarbeten i avhandlingen har omfattat Storstockholm.
Den första
studien baserades på alla kvinnor i området som var gravida
mellan 1988
och 1995. Det andra och tredje delarbetet utgår från alla
kvinnor som var
gravida mellan augusti 1997 och februari 2006. Det fjärde
delarbetet baseras
på alla födslar mellan juli 2000 och oktober 2005.
De luftföroreningar som studerades var ozon och kväveoxider,
där
kväveoxider användes som ett mått på trafikavgaser. Som ett
ytterligare mått
på trafik studerades det genomsnittliga antalet fordon som
passerade
hemadressen.
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Original papers
I: Olsson D, Ekström M, Forsberg B. Temporal variation in air
pollution
concentrations and preterm birth – a population based
epidemiological
study. Int. J. Environ. Res. Public Health, 2012, 9:272-285.
II: Olsson D, Mogren I, Forsberg B. Air pollution exposure in
early
pregnancy and adverse pregnancy outcomes: a register-based
cohort study.
BMJ Open, 2013, 3:e001955.
III. Olsson D, Mogren I, Eneroth K, Forsberg B. Traffic
pollution at home
address and pregnancy outcomes. Submitted.
IV. Olsson D, Bråbäck L, Forsberg B. Traffic pollution exposure
at home
during pregnancy and infancy and childhood asthma
medication.
Manuscript.
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Introduction
Adverse pregnancy outcomes such as a shorter period of gestation
and
intrauterine growth restriction have been shown to have an
effect on
morbidity throughout childhood, adolescence, and adult life1-2.
A shorter
period of gestation is also associated with decreased school
performance and
is an important predictor of lower socioeconomic status in
adulthood2-4.
Common proxies for intrauterine growth restriction in the
scientific
literature over the years have been low birth weight (LBW) at
term and small
for gestational age (SGA)5-6. LBW is defined as having a birth
weight lower
than 2,500 g, and SGA is commonly defined as having a birth
weight lower
than either the 10th percentile for a given gestational age or
lower than 2
standard deviations below the average birth weight for a given
gestational
age. LBW was the more common metric in earlier studies, but as
estimates of
gestational age have been increasingly reliable and more readily
available
SGA has become more common. Similarly, preterm delivery has also
been
more commonly studied as the reliability of gestational age
estimates have
improved, and preterm delivery is defined as being born before
the 37th week
of gestation7-9. Known risk factors for preterm delivery and LBW
are
smoking and pre-eclampsia.
Approximately 3%–8% of all pregnancies in Western countries
are
complicated by pre-eclampsia10-11. The main symptoms of
pre-eclampsia are
hypertension and proteinuria12. Pre-eclampsia is more common
among
nulliparous women and women with previous chronic
hypertension11.
A shorter period of gestation in particular is associated with a
higher rate of
asthma, possibly because the lung tissue might not be fully
developed at the
time of delivery13.
Childhood asthma and wheezing are heterogeneous conditions with
multiple
causes14, including environmental tobacco smoke and dampness in
the
home15. Wheezing in infants is often a transient condition that
is closely
associated with respiratory infections, but the causes of
persistent wheezing
remain unclear. Asthma is the most common chronic disease in
childhood
and can affect both physical fitness and psychosocial
wellbeing16.
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Air pollution exposure
Nitrogen oxides (NOx) consist of nitrogen dioxide (NO2, an
oxidant with
inflammatory effects17) and nitrogen oxide (NO). NOx are formed
at high
temperature in combustion engines and are, therefore, a marker
of vehicle
exhaust and traffic pollution.
Ground level ozone (O3, an oxidant with short-term effects on
lung function
and airway inflammation17) is formed along with NO through a
chemical
reaction between oxygen and NO2 under the influence of sunlight.
In areas
with high NO emissions, more O3 is consumed to oxidize NO to
NO2.
Long-term exposure to air pollution has been associated with
increased
mortality and incidence of chronic diseases, and there is
stronger evidence
for the negative effects of particulate matter than for NO2 and
O317-18.
Primary combustion particles, including soot particles and
elemental carbon,
are likely to be more harmful than particle mass in general.
However, black
carbon and elemental carbon are seldom measured by typical
monitoring
stations.
Exposure misclassification is always a potential problem in
epidemiological
studies using measured or modeled outdoor concentrations in the
area or at
home. This is because study subjects have different
time-activity patterns
and might have a true exposure that is lower or higher than what
the
exposure variable suggests. This type of exposure
misclassification will likely
dilute any association between exposure and outcome.
The association between air pollution exposure and health
outcome might be
confounded by risk factors that are correlated with both
exposure and
outcome. Potential confounders must vary together in the
same
dimension(s) as the exposure, for example, if the exposure
varies over time,
then potential confounders must also vary over time.
Air pollution and birth outcomes
Early studies on the effects of air pollution on birth outcomes
focused mainly
on long-term average exposures in different districts within the
study area.
The main outcome of interest was LBW5-6,19-22, but preterm
delivery and SGA
were also studied23. The air pollutants investigated in those
studies were
mainly carbon monoxide (CO), sulfur dioxide (SO2), NOx, and
total
suspended particles. Most studies reported that elevated levels
of SO2 were
associated with increased odds of LBW5,20-23.
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Later studies focused on preterm delivery as the outcome of
interest to a
much larger extent than the earlier studies, although LBW was
still
frequently studied7-9,24-33. Long-term air pollution averages
were still the
most common exposure metric used, but the exposure assessment
shifted
from area averages to using the nearest monitoring station and
including
only subjects living within a certain distance from the
monitoring station.
There were some studies that used modeling approaches in the
exposure
assessment, including kriging32, dispersion modelling29 and
land-use
regression25. Particulate matter with an average diameter less
than 10 µm
(PM10) or 2.5 µm (PM2.5) were the most commonly studied air
pollutants,
although others such as NO2, NOx, SO2, O3, and CO were also
studied. Most
studies showed positive associations between air pollution
exposure and the
studied birth outcome. However, the critical timing of the
exposure varied
across the different study populations.
In more recent studies, preterm delivery, SGA, and LBW have been
the most
commonly studied outcomes, although a few studies have used
pre-
eclampsia as the outcome34-44. The exposure assessments were
similar to
those of the earlier studies, i.e., measuring exposure levels
from the nearest
monitoring station within a certain radius or using a dispersion
model to
estimate the level of exposure at the home address. As in
earlier studies,
higher levels of air pollution were positively associated with
preterm
delivery, LBW, and SGA. Higher levels of PM10 and NO2 have
been
associated with an increased risk of pre-eclampsia37,40, but
higher levels of
CO were associated with a decreased risk of pre-eclampsia44.
A potential pathway through which ambient air pollution could
lead to
adverse pregnancy outcomes is through systemic
inflammation45.
Proinflammatory cytokines could disrupt trophoblastic invasion
during
placentation leading to suboptimal function of the
placenta46-47. This could in
turn lead to pre-eclampsia, preterm delivery, or intrauterine
growth
restriction48.
Air pollution and asthma
Air pollution exposure and proximity to traffic have been linked
to asthma or
asthma symptoms in several studies49-55, and air pollution
exposure has also
been linked to hospital admissions and emergency room visits for
asthma56-
57. Associations between early life exposure to air pollution
and childhood
asthma have been reported in several studies58-63, and there is
some evidence
that exposure to air pollution during gestation might be
associated with an
increased risk of developing asthma during childhood64. These
findings are
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inconsistent52, however, and an association between air
pollution exposure
during childhood and asthma has not always been found65-66.
Air pollution exposure might lead to epigenetic reprogramming
that could
potentially lead to an elevated risk of developing respiratory
diseases in
general67. Alternatively, air pollution exposure during periods
of rapid
development of lung tissue, such as during the last stage of
pregnancy or
during infancy, might cause disruption in the development of the
respiratory
organs that could lead to a higher risk for asthma59,67.
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Aims of the thesis
Overall aims
The overall aims of this thesis were (1) to assess any possible
association
between air pollution exposure during pregnancy and important
adverse
pregnancy outcomes and (2) to assess any possible associations
between air
pollution exposure during pregnancy or infancy and asthma
medication
during childhood.
Specific aims
In Paper I, the aim was to study any association between O3 and
NO2
exposure during the first and second trimesters and the last
week of
gestation and preterm delivery and duration of gestation.
Paper II aimed to assess the association between first trimester
levels of O3
and NOx and preterm delivery in a different cohort as well as to
study pre-
eclampsia and SGA as outcomes.
The aim of Paper III was to study any association between
traffic pollution at
the home address during pregnancy, as indicated by NOx and
traffic
intensity, and preterm delivery, pre-eclampsia, and SGA.
Paper IV studied the association between traffic pollution
during pregnancy
and from birth to the first birthday, as indicated by NOx and
traffic intensity,
and being prescribed asthma medication between five and six
years of age.
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Materials and methods
Study populations
All four studies were performed on study populations in the
greater
Stockholm area. Paper I was based on all singleton births
conceived between
1988 and 1995. Papers II and III were based on all singleton
births conceived
between August 1997 and February 2006 and delivered at one of
the five
hospitals in the greater Stockholm area (Danderyd, Huddinge,
Karolinska,
Södersjukhuset, and Södertälje). The third study was further
restricted to
include only women who did not change addresses during pregnancy
and
who had a delivery that started spontaneously. The fourth study
was based
on all singleton births between July 1, 2000, and October 30,
2005.
Depending on the timing of the exposure of interest in the
fourth study, the
inclusion criteria were altered. When studying exposure during
pregnancy,
only children born to women who did not change addresses
during
pregnancy were included. When studying exposure during infancy,
those
who did not change addresses between birth and their first
birthday were
included in one datset and those who did not change address
during infancy
but whose mothers changed addresses during pregnancy were
included in a
separate dataset.
Outcome definitions
Duration of gestation was based on ultrasound examination or the
date of
the last menstrual period (Paper I). Preterm delivery was
defined as having a
gestational period shorter than 37 weeks (Papers I–III). SGA was
defined as
having a birth weight below the 10th percentile for the given
duration of
gestation in days (Papers II and III) and according to sex
(Paper III). Pre-
eclampsia was defined as having any of the ICD-10 (International
Statistical
Classification of Diseases, version 10) diagnoses of O11
(pre-existing
hypertension with pre-eclampsia), O13 (gestational hypertension
without
significant proteinuria), O14 (gestational hypertension with
significant
proteinuria), or O15 (eclampsia) (Papers II and III). Two
different
definitions of childhood asthma medication were used. The first
included
any prescribed asthma medication between the ages 5 and 6
years
(Anatomical Therapeutical Chemical (ATC) codes R03AC, R03AK,
R03BA,
R03BC, R03CC, or R03DC), and the second included being
prescribed anti-
inflammatory medicines or leukotriene antagonists on two or
more
occasions between the ages of 5 and 6 years (ATC codes R03AK,
R03BA or
R03DC) (Paper IV).
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Covariate definitions
The Swedish Medical Birth Register contains data on a number of
different
covariates such as smoking habits, family situation, and
parity.
In Paper I we included maternal smoking habits (non-smoker,
moderate
smoker (1–9 cigarettes/day) and heavy smoker (10 or more
cigarettes/day)),
maternal parity (0, 1, 2, 3, or more para), and infant sex
(male, female). The
date of conception was used to adjust for possible confounding
from
temporal and seasonal trends, and data on temperature (°C) and
relative
humidity (%) were used in the modeling.
Paper II used the same covariates as Paper I, but it also
included data on
maternal age, maternal asthma status, highest level of maternal
education,
BMI (kg/m2) at antenatal care registration, family situation,
and maternal
region of origin in the statistical modeling. Maternal age was a
continuous
variable. Maternal asthma status was a dichotomous factor
defined as a case
if the mother was prescribed any asthma medication between July
2005 and
December 2011 (ATC codes R03AC, R03AK, R03BA, R03BC, R03CC,
or
R03DC) or had ever received hospital care for asthma bronchiale
since 1997.
Highest level of education had five category levels (pre-upper
secondary
school (
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of times the child changed addresses up to the age of four was
followed
yearly resulting in 5 possible discrete states of 0–4 address
changes.
Exposure assessment
The City of Stockholm Environment and Health Administration
provided
time-series of air pollution measurements for all studies. The
modeled
annual averages for the 100 m × 100 m squares where the home
addresses of
the study population were located were provided for Papers III
and IV. NO2
(1-hour maxima, Paper I) and NOx (daily mean, Paper II) were
measured
daily at rooftop level at three monitoring stations. O3 (8-hour
maxima,
Papers I and II) was measured at rooftop level at two monitoring
stations,
Figure 1. In the case where one station had a missing value, the
data were
imputed from the other stations by linear regression. The
time-series from
the monitoring stations were used to create citywide averages
that were used
to calculate time-dependent averages over weeks and trimesters
(12 weeks).
If there were more than 19 days of missing data, no trimester
average was
calculated.
Annual average NOx levels were estimated at the location of the
home
address using the SMHI-Airviro Gauss dispersion model68, Figure
2. The
input to the model was provided by the emission inventory of the
City of
Stockholm Environment and Health Administration and the Uppsala
Air
Quality Management System, which consist of road traffic NOx
emissions
(i.e. traffic flow, vehicle fleet composition, emission factors
and
meteorology). The ratio between the estimated annual averages at
the
location of the home address and the annual city average from
the
monitoring stations were used to estimate trimester, pregnancy,
and first-
year exposures for each study subject in the third and fourth
studies.
Annual daily average traffic flow at the location of the home
address was
used as an alternative vehicle exhaust exposure metric in Papers
III and IV.
These data were also provided by the City of Stockholm
Environment and
Health Administration.
Statistical analysis
Logistic regression was used for the main analyses in Papers I,
II, and IV.
Linear regression was used for the continuous outcomes in Paper
I. Mixed-
model logistic regression was used in Paper III. All analyses
were performed
in R programming software69.
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Figure 1. Monthly average NO2 and O3 levels.
In Paper I, each time window was studied separately (first
trimester, second
trimester, last week of gestation, and last week at risk for
preterm delivery).
For each outcome, the estimated air pollution effect was modeled
in three
steps. First, unadjusted models were fitted. Next, the models
were adjusted
for maternal smoking, parity, sex of the infant, temperature,
relative
humidity, season, and long-term trend. The last model estimated
the effects
of the air pollutants simultaneously. The seasonal patterns were
accounted
for by fitting the day of the year of conception as a cyclic
spline function. A
cubic regression spline was fitted to the conception year to
adjust for long-
term trends.
Given the results in Paper I, only exposures to NOx and O3
during the first
trimester were studied in Paper II. The modeling was performed
in six steps.
First, unadjusted models were fitted for each pollutant
separately. Then
maternal age (as a cubic regression spline), parity, highest
level of education,
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region of origin, maternal asthma, and seasonal trend (as a
cyclic spline)
were added to the model. In the third step, a cubic regression
spline to
account for any long-term trend was added. The fourth step was
to study the
exposures simultaneously. First-trimester temperature and
relative humidity
were added in the fifth step. Finally, maternal smoking habits,
family
situation, and BMI at the first antenatal visit were added.
Additionally, we
explored if maternal asthma acted as an effect modifier for O3
by adding an
interaction term in the modeling procedure.
Figure 2. Modeled annual NOx means over the study area
The modeling approach in Paper III was similar to that of the
previous
papers. The initial model consisted of home address NOx levels
or traffic
flow and a random intercept for home municipality. In the second
modeling
step, a set of maternal variables was added (asthma status,
level of
education, region of origin, age and parity), along with
conception date, first
trimester O3, and temperature. In the third and final step,
maternal smoking
status, family situation, and BMI at the first antenatal visit
were included in
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the model. Additional analysis was performed on the subset of
the study
population that had complete information for all explanatory
variables in
order to investigate if changes in estimates were due to
adjustment for
additional factors or due to restriction of the study
population.
Similarly to the other studies, the statistical analyses in
Paper IV were
performed in a forward stepwise fashion. Initially, a crude
model including
only outcome and exposure was fitted. In the second step, older
siblings,
parental asthma, maternal region of origin, maternal age and
level of
education at the time of delivery, number of address changes,
birth month,
and date of birth were added to the model. Pregnancy outcomes
(duration of
gestation (cubic regression spline), pre-eclampsia, and SGA)
were added in
the third step. In the last step, maternal BMI at the first
antenatal visit was
added. The modeling approach for those who changed address
differed in
step 2 in that older siblings, level of education, and number of
address
changes were excluded.
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Table 1. Outcome frequencies and selected mean exposure levels
across
studies.
Paper Ia Number (%) Mean first trimester NO2 (sd), µg/m3
Mean first trimester O3 (sd), µg/m3
Preterm delivery, Yes
6,154 (5.3) 38.4 (5.4) 57.6 (13.4)
No 109,434 38.5 (5.4) 57.1 (13.1) Paper IIa Number (%) Mean
first
trimester NOx (sd), µg/m3
Mean first trimester O3 (sd), µg/m3
Pre-eclampsia delivery, Yes
3,239 (2.7) 96.6 (16.3) 68.6 (13.3)
No 117,516 96.9 (16.3) 67.8 (13.3) Preterm delivery, Yes
5,341 (4.4) 96.7 (16.3) 68.4 (13.2)
No 115,404 96.9 (16.3) 67.8 (13.3) SGAb, Yes 11,334 (9.4) 97.0
(16.2) 67.6 (13.2) No 109,216 96.9 (16.3) 67.9 (13.3) Paper IIIc
Number (%) Mean first
trimester NOx (sd), µg/m3
Pre-eclampsia delivery, Yes
2,774 (2.7) 15.4 (7.6)
No 99,994 15.1 (7.4) Preterm delivery, Yes
2,823 (2.8) 15.3 (7.5)
No 98,220 15.1 (7.4) SGAb, Yes 9,977 (9.8) 14.9 (7.2) No 91,960
15.1 (7.4) Paper IVc Number (%) Mean first
year NOx (sd), µg/m3
Two prescriptions of anti-inflammatory medicine or leukotriene
antagonists
2,354 (3.0) 13.2 (6.2)
Any prescribed asthma medication
7,614 (9.7) 13.1 (6.1)
No prescribed asthma medication
70,526 13.4 (6.4)
aAir pollution data from monitoring stations. bSmall for
gestational age. cAir
pollution data from dispersion model.
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Results
The proportion of preterm deliveries was higher in the earlier
cohort (all
singleton children who were conceived between 1988 and 1995,
Paper I)
than in the later cohort (all singleton children conceived
between August
1997 and February 2006, Paper II) (Table 1). Almost 3% of the
pregnant
women suffered from pre-eclampsia and pregnancy-induced
hypertension.
The average O3 levels increased from the first study cohort to
the second, but
the average difference in first trimester O3 levels between
preterm and term
deliveries were consistently 0.5–0.6 µg/m3.
Figure 3. Annual average O3 and proportion of preterm delivery
between
1988 and 1995.
Paper I
Higher first trimester O3 levels were associated with slightly
increased odds
of preterm delivery and a shorter period of gestation in both
the unadjusted
and adjusted models. The second trimester and last week of
gestation O3
levels were not associated with an altered risk of preterm
delivery, but were
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weakly associated with a shortened period of gestation. Figure 3
indicates a
co-variation between O3 levels and preterm delivery during the
study period,
in this case without any adjustment.
Elevated NO2 levels during the first and second trimester were
not associated
with an increased risk of preterm delivery, but they were
associated with a
slightly longer period of gestation. Elevated NO2 levels during
the late stage
of pregnancy were associated with an increased risk of preterm
delivery.
Paper II
Higher levels of first trimester O3 were again associated with
higher odds of
preterm delivery in a new cohort. The association was stronger
when elective
Caesarean sections were excluded from the analysis. There was
some
evidence of effect modification by maternal asthma status where
the
association between O3 and preterm delivery was stronger among
asthmatic
mothers than non-asthmatic mothers. Higher levels of NOx did not
appear
to have an effect on the risk of having a preterm delivery.
There was no evidence of any increased risk of SGA by having
elevated first
trimester levels of O3 or NOx, in fact, nearly all estimated
associations
indicated a slightly decreased risk of SGA.
Increased first trimester O3 was associated with higher odds of
pre-
eclampsia. The association was slightly weaker when excluding
elective
Caesarean sections; however, having an elective Caesarean
section is a likely
outcome of having pre-eclampsia. Increased levels of first
trimester NOx did
not exhibit any association with pre-eclampsia.
Paper III
Due to high correlation between the NOx levels at the home
location through
all periods of pregnancy, it was difficult to identify periods
of increased
susceptibility. The NOx level at the home address was positively
correlated
with a slight, but not statistically significant, increased risk
of preterm
delivery. Higher levels of NOx were associated with an increased
risk of SGA
when comparing any of quartiles 2, 3, or 4 with the first
quartile. There was,
however, no difference in estimated effect among quartiles 2, 3,
and 4. There
was a marked association between home address NOx and
pre-eclampsia
with an OR of 1.17 per 10 µg/m3 increase in NOx in the fully
adjusted model.
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15
There were no associations between average traffic intensity and
preterm
delivery or SGA. Traffic intensity was associated with slightly
increased odds
of pre-eclampsia, but the association was close to the null.
Figure 4. Main findings of the studies in terms of ORs per 10
µg/m3 increase in air pollution level. Exposure periods were the
first trimester in Papers I, IIand III and the pregnancy period in
Paper IV. The results for Paper I are from the multi-pollutant
model in Table 4 of Paper I. For Paper II, the results were
collected from Model 4 in Paper II as shown in Tables 1, 3, and 4
of Paper II for the non-restricted study population. The results
from Papers III and IV were collected from Model 2 in Table 2 of
Papers III and IV.
Paper IV
Higher levels of NOx during pregnancy or during infancy were
associated
with a lower risk of using asthma medication between the ages
five and six
-
16
years. When restricting the analysis to only those who changed
addresses
prior to delivery, the protective association remained but were
not as marked
as for those who remained at the same address throughout their
pregnancy.
Traffic intensity showed a similar pattern of association with
asthma
medication as NOx, although for those who changed address there
was
neither a protective nor a harmful effect.
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17
Discussion
Exposure assessment
Papers I and II used city-wide fluctuations in urban background
air pollution
values over time to estimate individual exposure. In other
words, individual
exposure was a function of conception date only, and two women
who
conceived on the same day would have been assigned the same
levels of
exposure regardless of where they lived. This can lead to
exposure
misclassification, particularly for pollutants with important
local sources,
such as NO2 and NOx, which vary both in time and strongly in
space because
they are formed primarily through combustion in vehicle engines.
This is less
of an issue for O3 that, although it is consumed by locally
emitted NO,
depends mainly on incoming air masses and varies seasonally over
time70.
This means that there was a greater chance to detect an
association between
O3 and pregnancy outcomes than between NO2 or NOx and
pregnancy
outcomes in Papers I and II. Papers III and IV were better
designed to
estimate associations between spatially varying traffic air
pollution and the
studied outcome. However, due to the exposure assessment it was
possible to
separate between effects of exposure during different time
windows.
Statistical modeling
The statistical models in the four papers include several
covariates, some of
which might be considered confounders and some of which might
be
important determinants but unlikely confounders. For example,
parity
would not be considered a confounder in the papers that focus on
the
correlation between the temporal variation of exposure and
pregnancy
outcomes unless one suspects that families with different
numbers of
children are differentially prone to plan for a child at a
certain time during
the year and that parity is associated with the outcome. In the
papers
focusing on spatial variation, parity could be a confounder if
families of
different sizes have different probabilities of living in
environments with
certain air pollution concentrations.
In the first two papers, the potential confounders of interest
were time-
varying variables – such as season of conception and the
meteorological
variables – because they could affect the outcome and because O3
varies with
season. In Papers III and IV, the confounders that were
identified were the
proxies for socioeconomic status, i.e. level of education and
maternal region
of origin. The reason why they could be confounders is that
people with a
higher level of education tend to live in the central areas in
Stockholm where
traffic air pollution levels are higher; therefore, neglecting
to adjust for
socioeconomic status might lead to the conclusion that living in
more
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18
polluted areas might have a beneficial effect on pregnancy
outcomes and
childhood asthma medication.
Mechanisms
In the studies of preterm delivery, pre-eclampsia was thought of
as a possible
intermediate step along the causal pathway between air pollution
exposure
and preterm delivery. In Paper II this was explored by adjusting
the models
in the main analysis for pre-eclampsia. This proposed that the
previously
observed association would be masked by adding pre-eclampsia as
a factor in
the model. This did not change the estimated association
indicating that pre-
eclampsia is not an important intermediate step between air
pollution
exposure and preterm delivery.
In a similar manner, the adverse pregnancy outcomes studied in
the first
three papers could be possible pathways through which air
pollution
exposure during pregnancy could lead to childhood asthma. Being
born after
a shorter gestational period or being growth restricted were
associated with
an increased risk of asthma medication (Paper IV, Table 1). If
air pollution
levels during pregnancy were associated with both pregnancy
outcomes and
the need to use asthma medication, it is possible that the
relationship
between air pollution exposure and childhood asthma medication
would be
masked by adjusting for pregnancy outcomes. However, no
adverse
association between traffic pollution during pregnancy (or
infancy) and
asthma medication was apparent, and no changes in the
estimated
association were observed after adjusting for birth
outcomes.
Comparison of findings
There was an association between elevated O3 levels during the
first
trimester of pregnancy and preterm birth in Paper I and Paper
II. This
association has been reported previously in a few other
studies9,36-37,47,71, but
other studies have found no such association24,33,72. In one of
the studies,
however, the association did not remain after adjustment for
possible
confounders71. The differing results might be explained in part
by different
timing and intensity of the seasonal O3 peaks, for example, in
Stockholm and
Shanghai9 the highest levels of O3 are found during spring73,
while the
highest levels of O3 in the US and London are found during
summer36,74-75.
Vitamin D status varies with the season – with a trough in the
spring76-80 –
and a lower level of vitamin D status is associated with
increased sensitivity
to inflammation81. Higher O3 levels have been reported to be
associated with
inflammation in early pregnancy45, and inflammation during
early
-
19
pregnancy has been associated with a higher prevalence of
preterm
delivery82.
High NO2 levels late in pregnancy were associated with preterm
delivery in
Paper I, but no association was observed in the other stages of
pregnancy.
The association between elevated levels of late-pregnancy NO2
and preterm
delivery is in agreement with previous studies33,47,71-72,83.
Higher levels of
NOx early in pregnancy were not associated with preterm delivery
in Paper
II. In Paper III, only the results for the average levels of NOx
during the first
trimester were reported because the NOx levels were highly
correlated
between different pregnancy time windows. No statistically
significant
association between elevated NOx levels and preterm delivery was
observed.
The problem with correlated exposure estimates over different
time windows
have been reported elsewhere26,29. Although no statistically
significant
associations between early pregnancy or pregnancy NOx levels and
preterm
delivery were observed in Papers II and III, the observed
tendencies are in
the same direction as previously published results25,29,84.
Similarly to Paper II, a study from Pennsylvania reported a
tendency that
higher levels of first trimester O3 led to an increased risk of
pre-eclampsia37.
A study from California reported similar associations as in
Paper II for O3
and pre-eclampsia in Orange County but not in Los Angeles85. The
differing
results for Los Angeles might be because they reported entire
pregnancy
exposure associations only. A few studies have reported
associations between
vehicle exhaust and pre-eclampsia, and these associations were
of similar
magnitude as reported in Paper III37,85-87.
The association between late pregnancy levels of NO2 (Paper I)
and preterm
delivery and between pregnancy average levels of NOx and
pre-eclampsia
(Paper III) suggest that vehicle exhaust exposure in Stockholm
could be high
enough to cause adverse effects on pregnancy outcomes.
The observed association between NOx and SGA in Paper III –
where
mothers who resided in areas with NOx levels exceeding the 1st
quartile were
more likely to give birth to an SGA infant – supports the
conclusion of small
or no effect in a review by Glinianaia et al., although that
review focused on
particulate matter88. No association between O3 or NOx and SGA
was
observed in Paper II, which might be because only the exposure
in the first
trimester was studied and effects on fetal growth are likely to
occur later in
pregnancy89.
No positive association between NOx levels at home and being
prescribed
asthma medication was found, and similar studies have
reported
-
20
inconsistent results59,90. Several smaller studies have,
however, reported an
association between traffic air pollution and incident or
new-onset asthma61-
63. The differing results might be because a more accurate
exposure
assessment is possible in a smaller study population62 or
because the studied
population was likely to be more sensitive to airway insults
than the general
population61. A possible explanation for the negative
associations observed
in Paper IV and in the other Swedish study by Lindgren et al.91
is that in
populations living in a relatively clean environment there is
some beneficial
adaptation among children living in neighborhoods with
moderately higher
levels of air pollution.
Policy implications
In the recent WHO REVIHAAP (2013) report, O3 was “upgraded” as a
health
problem18. Climate change will increase O3 exposure assuming
that
everything else stays the same. The increased proportion of
diesel cars in
countries like Sweden is changing the ratio between NO and NO2
in local
emissions and is increasing O3 levels in the cities92. The local
regulations for
O3 could be stricter, but large-scale measures would have to be
undertaken
in order to effectively reduce concentrations.
In Paper I it was estimated that 129 cases (7.8%) of preterm
delivery could be
attributed to being exposed to the highest quartile of O3
instead of the lowest
quartile. Similarly, 138 cases (5.5%) of pre-eclampsia and 211
cases (5.2%) of
preterm delivery could be attributed to being exposed to O3
levels exceeding
the 25th percentile in Paper II. Being exposed to the highest
quartile of NO2
was associated with 85 cases (5.2%) of preterm delivery in Paper
I. Stronger
regulations of air pollution might lead to substantial monetary
savings from
a public point of view partly because preterm infants are more
likely to spend
a prolonged time in the hospital before being discharged and
women
suffering from pre-eclampsia need more medical attention prior
to delivery,
and partly because preterm children have increased morbidity.
Supporting
this it was shown that preterm children were prescribed more
asthma
medication than term children (Table 1 in Paper IV).
Summary of findings
Papers I and II showed a consistent association between first
trimester O3
exposure and preterm delivery. These results support previous
findings9,47,71
and have been repeated in later publications36-37. Paper II was
one of the first
papers reporting an association between first trimester O3 and
pre-
eclampsia37,85,87. The strong observed association between
traffic-based air
pollution and pre-eclampsia in Paper III adds additional
strength to the few
previously published findings37,85-87.
-
21
Future research
Future research should strive to explore if the spatial pattern
of O3 is
associated with birth outcomes or childhood morbidity.
Spatiotemporal
models should be implemented in order to improve the exposure
assessment
of traffic-related air pollution and O3. Instead of using
proxies for traffic
pollution, such as NO2 and NOx, more biologically active
substances, such as
soot and elemental carbon, should be used. In order to further
improve the
exposure assessment, occupational exposure and exposure levels
during
commuting should be accounted for.
-
22
Conclusions
First trimester O3 was associated with an increased likelihood
of
preterm delivery. There was some evidence of an association
between higher early pregnancy O3 levels and pre-eclampsia.
Traffic pollution at the home address during gestation was
strongly
associated with pre-eclampsia.
There was an indication that traffic pollution at the home
address
during gestation could lead to an increased risk of preterm
delivery.
Living in a neighborhood with levels of traffic pollution above
the 1st
quartile was associated with SGA.
There was no increased likelihood of being prescribed asthma
medication between five and six years of age among children
living
in more polluted areas during their first year or among
children
having a mother who lived in a more polluted area during
pregnancy.
-
23
Acknowledgements
I would like to thank:
My main supervisor Bertil Forsberg for guiding me through the
process of
conducting scientific research, for your never-ending enthusiasm
and
constant flow of ideas. A special thanks for every time I have
been stuck on a
problem and you told me “But if you tried this…”, solving the
issue.
My co-supervisors Magnus Ekström and Anders Bucht for all your
help with
the conception and birth of the studies.
My co-authors Ingrid Mogren and Lennart Bråbäck for your
brilliance and
contagious enthusiasm.
All the people at the Environment and Health Administration
in
Stockholm who provided me with exposure data, in particular
Christer
Johansson, Boel Löwenheim and my co-author Kristina Eneroth.
Lars Rylander, Eva Rönmark and Joacim Rocklöv for reviewing
my
manuscripts and your helpful comments at the mid-seminar.
The administrators at the unit, Thomas Kling, Jenny Bagglund and
Kristina
Lindblom for all your help.
My fellow PhD students over the years for listening to my
complaints about
my lack of progress, allowing me to win a set or two when
playing squash,
grabbing a sparkling beverage after work, and helping with my
work.
My colleagues for your fantastic tirades about subjects ranging
from
fireplaces to statistics and for telling me what’s what.
My friends from the crown of creation, Burträsk, whom I would
name if I
wasn’t certain someone would be unintentionally omitted.
-
24
My parents, Bosse and Barbro, and sisters, Sofia and Johanna,
with families
for all your love and support, additional thanks to my sister
for teaching me
to read and write, so I wouldn’t have trouble keeping up with
the curriculum
once school started, and for teaching me to chew with my mouth
closed.
The Norlunds for babysitting and whatnot.
Edith and Imre for all the joy you give me, there is no feeling
in the world
like when I come home and am met with a big smile and a
delighted ‘Da’ or
‘Pappa’.
Sofia for letting me love you. Or in the words of Dylan:
“There’s beauty in the
silver, singin’ river, There’s beauty in the sunrise in the sky;
But none of
these and nothing else, can match the beauty That I remember in
my true
love’s eyes”.
This thesis was funded by the Centre for Environmental Research
in Umeå
(CMF) and is a part of the SIMSAM project.
-
25
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