Over the last 20 years, numerous studies in

Canada and elsewhere have confirmed a positive

relation between air pollution and morbidity

and mortality (Burnett et al. 1997a, 1997b;

Pope et al. 2002; Samet et al. 2000; Schwartz

1994). Findings from animal studies have provided evidence of an association between air

pollution and reproductive and developmental

anomalies (Bignzmi et al. 1994; Falkner 1986;

Kavlock et al. 1979, 1980). Until recently, however, few epidemiologic studies have examined

the potential effects of ambient air pollution on

birth outcomes (Bobak 1999, 2000; Bobak and

Leon 1999; Dejmek et al. 1999; Dolk et al.

2000; Ritz and Yu 1999; Ritz et al. 2000;

Rogers et al. 2000; Sram et al. 1996; Wang et

al. 1997; Woodruff et al. 1997; Xu et al. 1995).

Birth weight, gestational age, and fetal

growth are important indicators of perinatal

health. Low birth weight (LBW), preterm birth,

or intrauterine growth retardation (IUGR) are

strongly associated with infant mortality and

morbidity. The etiology of these adverse birth

outcomes is complex but not yet well understood. In 1995, Xu et al. (1995) investigated

the association between maternal exposure to

air pollution during pregnancy and preterm

delivery in a prospective cohort in four urban

districts in Beijing, China. They found a

significant reduction in the duration of gestation with increasing levels of sulfur dioxide

and total suspended particulate (TSP). Wang

et al. (1997) reported a significant negative

association between maternal exposure to SO2

and TSP during the third trimester of pregnancy and infant birth weight. These results

indicate that TSP and SO2, or a more complex

mixture of these and other pollutants, may

contribute to an elevated risk of LBW in the

Beijing population. Results from similar studies in the United States, the Czech Republic,

Great Britain, and Brazil have subsequently

been reported (Bobak 1999, 2000; Bobak and

Leon 1999; Dejmek et al. 1999; Dolk et al.

2000; Ritz and Yu 1999; Ritz et al. 2000;

Rogers et al. 2000; Wang et al. 1997; Woodruff

et al. 1997).

A study in the Czech Republic (Bobak

1999) found that TSP, SO2, and nitrogen

oxides were all associated with LBW among

newborns. However, when the effects of all pollutants were assessed simultaneously in a multivariate statistical model, only SO2 demonstrated

a significant association with LBW. In Los

Angeles, California (USA), exposure to higher

levels of ambient carbon monoxide (CO; > 5.5

ppm averaged over 3 months) during the last

trimester was associated with a significantly

increased risk of LBW, after adjustment for

potential confounders (Ritz and Yu 1999). In a

study in Georgia (USA), exposures to environmental SO2 and TSP were associated with an

increased risk of very LBW (Rogers et al. 2000).

However, no association between LBW and

SO2 was found in a study in Great Britain

(Dolk et al. 2000).

In Canada, there have been several studies

of the association between ambient air pollution and adverse health outcomes over the last

decade (Burnett et al. 1997a, 1997b, 1998,

2000; Goldberg et al. 2001). These studies

have found positive and statistically significant

associations between the ozone–SO2 pollution

mix and hospital admissions for asthma, chronic

obstructive pulmonary disease, and infections

(Burnett et al. 1998) and between individual air

pollutants and hospitalization for respiratory

diseases (Burnett et al. 1997a) and hospital

admissions for congestive heart failure in the

elderly (Burnett et al. 1997b). Both gaseous and

particulate pollutants have also been associated

with increased mortality rates (Burnett et

al. 2000). A more recent investigation also

reported a positive association between tropospheric O3 and cause-specific mortality, including deaths from cancer, cardiovascular diseases,

and respiratory diseases in Montreal, Québec

(Goldberg et al. 2001). However, no report

has yet addressed associations between ambient

air pollution and birth outcomes in Canada. In

this study we examine this issue using data

from a major Canadian city:Vancouver, British

Columbia.

Methods

Air pollution exposure data. Continuous

sampling measures for air pollutants have

been compiled for the following 13 census

subdivisions in the great Vancouver area:

15004, 15011, 15015, 15018, 15022, 15025,

15029, 15034, 15038, 15039, 15043, 15051,

and 15803 (Statistics Canada 1997). These

data contain daily average and daily 1-hr concentrations of the gaseous pollutants SO2,

nitrogen dioxide, CO, and O3 for the period

1 April 1985 through 31 December 1998,

and of ambient particulate matter with aerodynamic diameters ≤ 10 μm (PM10) for the

Environmental Health Perspectives • VOLUME 111 | NUMBER 14 | November 2003 1773

Children’s Health Article

Association between Gaseous Ambient Air Pollutants and Adverse

Pregnancy Outcomes in Vancouver, Canada

Shiliang Liu,1 Daniel Krewski,1 Yuanli Shi,1 Yue Chen,1 and Richard T. Burnett1,2

1McLaughlin Centre for Population Health Risk Assessment, Institute of Population Health, and Department of Epidemiology and

Community Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; 2Environmental Health Science Bureau,

Healthy Environments and Consumer Safety Branch, Health Canada, Ottawa, Ontario, Canada

Address correspondence to S. Liu, McLaughlin

Centre for Population Health Risk Assessment,

Institute of Population Health, University of Ottawa,

1 Stewart St., Ottawa, Canada K1N 6N5. Telephone:

(613) 941-1284. Fax: (613) 941-9927. E-mail: Sliu@

uottawa.ca

This study was supported by the Toxic Substance

Research Initiative of Health Canada and the Canadian

Institutes of Health Research.

We declare that a conflict of interest related to this

study and submission of this manuscript for publication was reported.

Received 3 February 2003; accepted 4 August 2003.

The association between ambient air pollution and adverse health effects, such as emergency room

visits, hospitalizations, and mortality from respiratory and cardiovascular diseases, has been studied

extensively in many countries, including Canada. Recently, studies conducted in China, the Czech

Republic, and the United States have related ambient air pollution to adverse pregnancy outcomes. In

this study, we examined association between preterm birth, low birth weight, and intrauterine growth

retardation (IUGR) among singleton live births and ambient concentrations of sulfur dioxide (SO2),

nitrogen dioxide (NO2), carbon monoxide (CO), and ozone in Vancouver, Canada, for 1985–1998.

Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals

(CIs) for such effects. Low birth weight was associated with exposure to SO2 during the first month of

pregnancy (OR = 1.11, 95% CI, 1.01–1.22, for a 5.0 ppb increase). Preterm birth was associated with

exposure to SO2 (OR = 1.09, 95% CI, 1.01–1.19, for a 5.0 ppb increase) and to CO (OR = 1.08,

95% CI, 1.01–1.15, for a 1.0 ppm increase) during the last month of pregnancy. IUGR was associated with exposure to SO2 (OR = 1.07, 95% CI, 1.01–1.13, for a 5.0 ppb increase), to NO2 (OR =

1.05, 95% CI, 1.01–1.10, for a 10.0 ppb increase), and to CO (OR = 1.06, 95% CI, 1.01–1.10, for a

1.0 ppm increase) during the first month of pregnancy. In conclusion, relatively low concentrations of

gaseous air pollutants are associated with adverse effects on birth outcomes in populations experiencing diverse air pollution profiles. Key words: air pollution, intrauterine growth retardation, low birth

weight, preterm birth, risk assessment, sulfur dioxide. Environ Health Perspect 111:1773–1778 (2003).

doi:10.1289/ehp.6251 available via http://dx.doi.org/ [Online 4 August 2003]
period 1 January 1994 through 31 December

1998. The arithmetic means and selected percentiles of the distribution of these gaseous

pollutants are presented in Table 1, both for

daily average concentrations and for daily 1-hr

maximum concentrations.

Gaseous pollutant data were averaged across

the available monitoring stations hour by hour.

Daily averages (24 hr) were then computed

from these hourly measurements. Any day with

less than 22 of 24 possible hours of available

information was considered missing. Because

multisite hourly averages were computed even

if measurements were available from only one

site (a very rare occurrence), 24-hr average daily

pollutant concentrations were available for

the entire period covered by this study. We

estimated missing pollutant data (< 1% of the

total number of daily observations) using linear

interpolation methods so that daily pollutant

data were available throughout the 13-year

period of interest.

Live birth cohort. All live births were

obtained from the live birth database maintained by Statistics Canada (Fair and Cyr

1993) for the period 1 January 1986 through

31 December 1998. The quality of these data

has been previously validated for national

perinatal surveillance system and research

projects (Fair and Cyr 1993). The information in the database has been derived from

birth certificates and includes date of birth,

birth weight, gestational age, parity, birth

order, maternal and paternal age, and residence. Gestational age is determined by the

responsible obstetrician, based on all available

information, including date of last menstrual

period and the mother’s estimate of the date

of conception, and in recent years increasingly

including ultrasound dating. Previous research

suggests that gestational age information

in the database is reliable (Kramer et al. 2000).

Maternal residence during pregnancy is

recorded at the provincial census subdivision.

Individual data of all singleton live births for

the 13 census subdivisions in the Vancouver

area noted above were abstracted from the

database and used in the present study.

Linkage of the two databases. Environmental air pollution data were available at the

census subdivision level. Exposure levels from

conception through delivery were determined

by linkage with this environmental database,

which includes daily average concentrations

of the gaseous pollutants of interest. Dates on

the air pollution records were matched temporally to the date of birth and length of gestation. For each live birth, therefore, average air

pollution concentrations were retrospectively

calculated for the first, second, and third

month; the last and the next to last month of

pregnancy; or for the first, second, or third

trimester. For preterm birth and LBW, the

maternal exposure window was expressed in

months, because preterm or LBW births may

involve only 6–8 months of gestation. For

IUGR births, the exposure window was

expressed in both months and trimesters.

Maternal exposures in each month or

trimester of pregnancy were calculated for

ambient SO2, NO2, CO, and O3. These were

estimated by the arithmetic means of all daily

measurements by all monitors in the residential area of each mother. There were no

changes in the placement of the monitoring

stations or the monitoring instruments during

the study period.

A preterm birth is defined as a live birth

with < 37 complete weeks of gestation. An

LBW infant is defined as a live-birth infant

weighing < 2,500 grams at birth. Live-birth

infants with birth weights < 500 g or gestational ages < 22 weeks were excluded from all

analyses. An IUGR birth is defined as an

infant whose birth weight falls below the 10th

percentile, by sex and gestational week, of all

singleton live births in Canada between 1986

and 1998 (Health Canada 2000). In examining this indicator of pregnancy outcome, we

included only live births at 37–42 weeks of

gestation (i.e., full-term births).

Statistical analysis. The fundamental

hypothesis in this study is that temporal variation in ambient air pollution levels is associated

with temporal variation in pregnancy outcomes.

Adverse pregnancy outcomes, including preterm

birth, LBW, and IUGR, defined as dichotomous categories, represent dependent variables

in the analysis. Daily average concentrations of

ambient SO2, NO2, CO, and O3 represent

independent variables. We examined the association between individual-level dependent variables and independent variables by multiple

logistic regression. Initial analyses focused on

the effects of a single pollutant; we then assessed

the robustness of these effects using multiple

pollutant models. Odds ratios (ORs) and 95%

confidence intervals (CIs) for adverse pregnancy

outcomes in relation to exposure to ambient air

pollutants were calculated after controlling for

maternal age (< 20, 20–24, 25–29, 30–34 and

≥ 35 years), parity, infant sex, gestational age or

birth weight, and month of birth.

Results

The concentrations of all pollutants varied

appreciably, both for daily average and for

daily 1-hr maximum concentrations (Table 1).

Children’s Health | Liu et al.

1774 VOLUME 111 | NUMBER 14 | November 2003 • Environmental Health Perspectives

Table 1. Mean and selective percentiles of gaseous air pollutants: Vancouver, Canada, 1985–1998.

Percentile

Pollutant (unit) Mean 5th 25th 50th 75th 95th 100th

SO2 (ppb)

Daily average 4.9 1.5 2.8 4.3 6.3 10.5 30.5

Maximuma 13.4 4.3 7.8 11.7 16.8 28.3 128.5

NO2 (ppb)

Daily average 19.4 11.5 15.1 18.1 22.3 31.9 70.0

Maximuma 34.1 21.0 26.7 31.4 38.3 56.2 124.5

CO (ppm)

Daily average 1.0 0.5 0.7 0.8 1.2 2.2 5.6

Maximuma 2.2 0.8 1.2 1.8 2.7 5.1 12.8

O3 (ppb)

Daily average 13.4 3.2 8.2 13.1 18.2 25.1 41.3

Maximuma 27.9 9.7 19.8 27.6 35.1 47.2 105.5

aMaximum 1-hr concentrations within a day.

Figure 1. Variations in mean concentrations of air pollutants in Vancouver, by month, 1985–1998.

100

10

1

0.1

1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151

Month

Mean concentration

SO2 (ppb)

CO (ppm)

NO2 (ppb)

O3

 (ppb)
For example, the mean daily concentration of

SO2 was 4.9 ppb, with the 5th and 95th percentiles being 1.5 ppb and 10.5 ppb, respectively. The mean concentrations of all four

pollutants are shown in Figure 1. All pollutants

exhibit a clear seasonal variation. In addition,

there were steady declines in the average concentrations of SO2, NO2, and CO, whereas O3

showed a slight increase over time.

There were 229,085 singleton live births

in the Vancouver study area between 1986

and 1998. The average LBW, preterm birth,

and IUGR rates were 4.0, 5.3, and 9.4%,

respectively. These rates varied by season of

birth, infant sex, parity, maternal age, and

time period of birth. IUGR rates among nonparous and younger (< 25 years) women were

much higher (Table 2).

LBW and preterm birth rates appeared to

be increasing slightly over the study period.

Although IUGR rates show considerable variation as with LBW and preterm birth, a secular

trend in IUGR does not appear in the data

because that proportion of infants with IUGR

is calculated relative to the national fetal growth

curve during the same period (Figure 2).

Correlations among these pollutants are

given in Table 3. Strong positive correlations

were observed among SO2, NO2, and CO,

with coefficients ranging from 0.61 to 0.72

(p < 0.0001). However, O3 was inversely correlated with other pollutants, with coefficients

of –0.35, –0.25, and –0.49 (p < 0.0001) for

SO2, NO2 and CO, respectively.

Crude and adjusted ORs for LBW and

preterm birth in relation to exposure to gaseous

air pollution are given in Tables 4 and 5,

respectively, for the first and last months of

pregnancy. Overall, there were only slight differences between the crude and adjusted estimates of risk. Statistically significant increased

adjusted ORs were observed for LBW and

maternal exposure to SO2 during first month

of pregnancy (OR = 1.11, 95% CI, 1.01–1.22,

for a 5.0 ppb increase), for preterm birth and

SO2 (OR = 1.09, 95% CI, 1.01–1.19, for a

5.0 ppb increase) or CO exposure (OR = 1.08,

95% CI, 1.01–1.15, for a 1.0 ppm increase)

during the last month of pregnancy.

As shown in Table 6, increased risk of

IUGR was observed to be caused by maternal

exposure to three gaseous pollutants during

the first month of pregnancy (OR = 1.07,

95% CI, 1.01–1.13, for a 5.0 ppb increase of

SO2; OR = 1.05, 95% CI, 1.01–1.10, for a

10.0 ppb increase of NO2; OR = 1.06, 95%

CI, 1.01–1.10, for a 1.0 ppm increase of CO).

No significant elevation in risk was observed

with O3. Using pregnancy trimester to characterize the maternal exposure time window,

IUGR is associated with exposure to SO2

(OR = 1.07, 95% CI, 1.00–1.14, for a 5.0 ppb

increase) and exposure to CO (OR = 1.05, 95%

CI, 1.00–1.10, for a 1.0 ppm increase) during

the first trimester of pregnancy, and exposure to

O3 (OR = 1.08, 95% CI, 1.01–1.15 for a

10.0 ppb increase) during the second trimester

of pregnancy (Table 7).

To examine the robustness of adjustment

for exposure to copollutants, we fit logistic

regression models including each of the other

pollutants individually, and then including all

three additional gaseous pollutants simultaneously. The increased risk of LBW associated

with exposure to SO2 during the first month of

pregnancy (OR = 1.11, 95% CI, 1.01–1.22)

persisted after adjustment for NO2 (OR = 1.22,

95% CI, 1.09–1.39), CO (OR = 1.23, 95%

CI, 1.07–1.42), or O3 (OR = 1.16, 95% CI,

1.04–1.28), as well as after adjustment for

NO2, CO, and O3 simultaneously (OR = 1.29,

95% CI, 1.12–1.50).

Similarly, the elevated risks for preterm

birth associated with SO2 (OR = 1.09, 95%

CI, 1.01–1.20) and CO (OR = 1.08, 95% CI,

1.00–1.20) during the last month of pregnancy

remained elevated after adjustment for other

gaseous copollutants, although not all adjusted

risk estimates remained statistically significant.

Elevated risks for IUGR associated with SO2,

NO2, and CO during the first month of pregnancy also tended to persist after adjustment

for copollutant exposure. This robustness was

also observed for the association between

IUGR and exposure to SO2 and CO during

the first trimester of pregnancy.

Discussion

In our study, LBW was associated with maternal exposure to SO2 during the first month of

Children’s Health | Ambient air pollution and adverse pregnancy outcome

Environmental Health Perspectives • VOLUME 111 | NUMBER 14 | November 2003 1775

Table 2. LBW (< 2,500 g), preterm birth (< 37 weeks’ gestation), and IUGR among singleton live births,

Vancouver, Canada, 1986–1998.

Characteristics No. of live births LBW (%) Preterm birth (%) IUGRa

Total 229,085 (100%) 4.0 5.3 9.4

Season of birth

Spring 59,168 (25.8) 3.9 5.2 9.2

Summer 58,942 (25.7) 3.9 5.0 9.6

Autumn 56,695 (24.8) 3.9 5.2 9.4

Winter 54,280 (23.7) 4.3 5.8 9.5

Male 118,072 (51.5) 3.8 5.8 9.6

Parity

0 108,419 (47.3) 4.7 5.7 11.8

1 80,215 (35.0) 3.3 4.7 7.4

≥ 2 40,451 (17.7) 3.6 5.2 7.0

Maternal age (years)

< 20 7,507 (3.3) 5.5 6.7 11.9

20–24 36,592 (16.0) 4.4 5.2 11.9

25–29 77,650 (33.9) 3.8 4.9 9.5

30–34 73,387 (32.0) 3.7 5.0 7.9

≥ 35 33,949 (14.8) 4.5 6.4 8.1

Period of birth

1986–1989 63,953 (27.9) 3.8 5.1 9.5

1990–1992 52,718 (23.0) 4.0 5.4 9.4

1993–1995 56,912 (24.8) 4.1 5.4 9.6

1996–1998 55,502 (24.2) 4.1 5.4 9.2

aThere are a total of 216,988 births after excluding all those with gestational age < 37 weeks.

Figure 2. Temporal trends in LBW, preterm birth, and IUGR by month in Vancouver, 1986–1998.

12

10

8

6

4

2

0

1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151

Month

Rate (%)

Preterm Low birth weight IUGR
pregnancy, and preterm birth was associated

with SO2 and CO during the last month.

Fetal growth retardation was consistently associated with maternal exposure to SO2, NO2,

and CO in the first month of pregnancy. The

positive association between fetal growth retardation and exposure to gaseous air pollution

persisted when maternal exposure was evaluated during the first trimester of pregnancy

but was slightly weaker.

These results are generally consistent with

the findings from China, the United States,

and the Czech Republic. Our estimates of the

effects of gaseous air pollution on birth weight

and gestational age categorized as dichotomous

variables are comparable with those found in

the studies from China (Wang et al. 1997; Xu

et al. 1995). These associations were not attenuated by adjustment for potential confounding

factors, including season of birth. There are

some differences between the results from

the studies reported to date, however. In one

Chinese study (Wang et al. 1997), LBW was

associated with SO2 and TSP in the last

trimester of pregnancy, with ORs of 1.11

(95% CI, 1.06–1.16) and 1.10 (95% CI,

1.05–1.14) for a 100 μg/m3 increase in SO2

and TSP. However, exposures in earlier

trimesters were not associated with birth outcomes. In a Czech study (Bobak 2000), IUGR

was not associated with any of the pollutants

measured, although the effects on LBW and

preterm birth were statistically significant for

exposures to SO2 in the first trimester.

The present study is one of only a few studies using a large sample to assess the potential

effects of maternal exposures to ambient air

pollutants during pregnancy on birth weight,

preterm birth, and IUGR. Our study has several strengths. First, this community-based

investigation is less likely to suffer selection

bias, healthy worker effects, or attribution

than are occupationally based studies. Second,

British Columbia birth registration is generally

considered complete and reliable, with individual information on both mothers and

infants recorded on birth certificates, including data on birth weight and gestational age.

These data are recorded by a single, welldeveloped vital statistics registry and have been

verified to be accurate for perinatal research

purposes (Fair and Cyr 1993). Third, reliable

measurements of daily SO2, NO2, CO, and

O3 concentrations obtained independently,

from air monitoring stations, have previously

been used in studies of the association between

air pollution and morbidity (Burnett et al.

1997a, 1997b) and mortality (Burnett et al.

1998, 2000; Goldberg et al. 2001; Villeneuve

et al. In press). Finally, the present analysis

enjoys the strength of the time-series approach

while offsetting limitations inherent in many

previous time-series studies—notably, the lack

of individual information on potential confounding or modifying factors and reliable

information on the size of the population

from which the cases were derived.

Although no information on socioeconomic status was available at the individual

level, it is unlikely that socioeconomic status is

an important confounder in this study for the

following reasons. First, there is no evidence

that socioeconomic factors are associated with

air pollution in the Vancouver area. Second,

another analysis of the same air pollution data

set revealed that socioeconomic status measured

at the community level did not modify association between air pollution and mortality in

Vancouver (Villeneuve et al. In press). Third,

adjustment for individual characteristics such

as maternal age, parity, and time period of

birth did not attenuate the risk estimates,

providing evidence against the possibility of

residential confounding. In addition, we controlled for month of birth to avoid seasonal

bias. Maternal smoking is a well-known risk

factor for adverse pregnancy outcomes, but it is

unlikely to be associated with air pollution

independently from maternal socioeconomic

status. Other unmeasured factors may vary

over the study period, although it is not clear

to what extent these factors might confound

the observed association between gaseous air

pollution and adverse birth outcomes.

Our estimates of individual exposure to air

pollution were based on average measures for

residents living in proximity of air monitoring

stations. Therefore, individual maternal exposure is inevitably misclassified. However, such

misclassification is most likely random, leading to underestimation of the actual effects of

air pollution (Burnett et al. 2000; Dolk et al.

2000). Variation in exposure to ambient air

pollution due to residential mobility is also

likely to lead to random exposure misclassification and underestimation of risk. A further

complication of using the ecologic measurements of ambient air pollution over a 13-year

period is that although mothers may be

exposed to similar levels of air pollution at the

same point in time, considerable daily and seasonal variation exists. Despite these well-recognized sources of exposure misclassification,

which can be expected to bias risk estimates

toward the null value of zero, associations

between ambient air pollution and adverse

birth outcomes observed in this study are

unlikely to be due to chance.

Other studies have found that LBW, preterm birth, or IUGR is also associated with

PM10. However, this difference can be related

to the availability of measurements of particulate air pollution. We only have 5 years of

data available on PM10, and our analysis did

not indicate its association with any indicator

of the birth outcomes under study. This negative finding may be due to the small number

of live births over the 5-year period. In our

study, SO2 demonstrated the strongest association with IUGR. Sulfur oxides may be a

Children’s Health | Liu et al.

1776 VOLUME 111 | NUMBER 14 | November 2003 • Environmental Health Perspectives

Table 3. Pearson correlation coefficients among

daily average concentrations of gaseous air pollutants, Vancouver, 1985–1998.

Pollutant SO2 NO2 CO O3

SO2 1.00

NO2 0.61* 1.00

CO 0.64* 0.72* 1.00

O3 –0.35* –0.25* –0.49* 1.00

*p-Value < 0.0001.

Table 4. Crude and adjusted ORs and 95% CIs for LBW attributable to maternal exposure to SO2, NO2, CO,

and O3 by month of pregnancy.

Pollutant Period of pregnancy Crude OR (95% CI)a Adjusted OR (95% CI)a,b

SO2 First month 0.95 (0.89–1.02) 1.11 (1.01–1.22)

Last month 0.99 (0.92–1.07) 0.98 (0.89–1.08)

NO2 First month 0.96 (0.90–1.01) 0.98 (0.90–1.07)

Last month 0.99 (0.93–1.06) 0.94 (0.85–1.04)

CO First month 1.01 (0.96–1.06) 1.01 (0.93–1.09)

Last month 1.04 (0.98–1.09) 0.96 (0.88–1.04)

O3 First month 1.07 (1.02–1.12) 1.04 (0.95–1.13)

Last month 1.03 (0.98–1.07) 1.01 (0.92–1.11)

aORs were estimated based on a certain increase of pollutant: SO2, 5.0 ppb; NO2, 10.0 ppb; CO, 1.0 ppm; O3, 10.0 ppb. bAdjusted for maternal age, parity, infant sex, gestational age, and season of birth.

Table 5. Crude and adjusted ORs and 95% CIs for preterm birth attributable to maternal exposure to SO2,

NO2, CO, and O3 by month of pregnancy.

Pollutant Period of pregnancy Crude OR (95% CI)a Adjusted OR (95% CI)a,b

SO2 First month 1.00 (0.95–1.06) 0.95 (0.88–1.03)

Last month 1.06 (0.99–1.13) 1.09 (1.01–1.19)

NO2 First month 0.95 (0.91–1.00) 1.01 (0.94–1.07)

Last month 1.08 (1.01–1.14) 1.08 (0.99–1.17)

CO First month 0.99 (0.95–1.03) 0.95 (0.89–1.01)

Last month 1.09 (1.04–1.15) 1.08 (1.01–1.15)

O3 First month 1.08 (1.04–1.12) 0.98 (0.89–1.03)

Last month 1.00 (0.97–1.04) 0.93 (0.86–1.00)

aORs were estimated based on a certain increase of pollutant: SO2, 5.0 ppb; NO2, 10.0 ppb; CO, 1.0 ppm; O3, 10.0 ppb. bAdjusted for maternal age, parity, infant sex, birth weight, and season of birth.
good indirect measure of small respirable particles that may underlie the observed association with IUGR.

The timing and intensity of exposure to

gaseous pollutants such as SO2 and CO during pregnancy are important in understanding

the mechanisms by which adverse birth outcomes are induced. Although a range of social

and behavioral determinants have been identified, neither the biologic mechanisms leading

to LBW, preterm delivery, and retarded fetal

growth nor the critical period of vulnerability

is as yet well understood (Berkowitz and

Papiernik 1993; Kramer 1987), and it is generally believed that different mechanisms may

be involved at different stages of pregnancy.

The observation that maternal alcohol consumption and cigarette smoking in pregnancy

affect birth outcome suggests that exposures

during early or late gestational period are very

important.

Acute effects that provoke premature labor

are not the only mechanisms by which adverse

health outcomes may be induced. Chronic

exposure and associated adverse birth effects

could be considered for the following reasons.

First, the known determinants of preterm

birth include intrauterine infection (Berkowitz

and Papiernik 1993; Kramer 1987). Previous

studies have indicated that maternal illness

due to respiratory infection during pregnancy

may also be involved, although most of them

focused on genitourinary infections (Gibbs et

al. 1992). Second, air pollution may affect

DNA or its transcription. DNA adducts have

commonly been observed in areas with high

levels of pollution, with placental DNA adducts

more common among mothers exposed to high

levels of outdoor air pollution (Perera et al.

1998, 1999; Petruzzelli et al. 1998; Topinka et

al. 1997). There may be a link between DNA

adducts and fetal growth: Newborns with more

adducts have lower birth weight and length

(Perera et al. 1998). The effects of air pollution

on DNA adduct levels seem similar to the

effects of cigarette smoking (Petruzzelli et al.

1998; Topinka et al. 1997). Third, the potential mechanisms could be related to hematologic factors. There are reports of increased

blood viscosity and plasma fibrinogen (related

to blood coagulation) during air pollution

episodes (Peters et al. 1997). Rheologic variables, including blood viscosity, influence

blood perfusion of the placenta (Peters et al.

1997; Petruzzelli et al. 1998), and one could

speculate that chronic exposure to high pollution levels may influence placental functions.

In addition, it is postulated there is a parallel

with maternal smoking, an established risk

factor for LBW (Windham et al. 1999, 2000),

despite the fact that the underlying biologic

mechanisms of toxicity are not well understood. Although the fetal exposures to air pollution are probably much lower than to

constituents of cigarette smoke, the biologic

mechanisms such as rheologic factors and

DNA damage may be somewhat similar.

Although a full understanding of biologic

mechanisms is important in understanding

the effects of environmental health hazards

such as air pollution and cigarette smoke, the

lack of a confirmed mechanistic hypothesis

does not preclude a meaningful epidemiologic

assessment of risk.

The time, intensity, and duration of the

adverse factors affecting fetal growth will manifest themselves in different ways. Peak growth

in fetal length occurs first, around the 20th

week of gestation, whereas peak growth in

weight occurs around the 33rd week of gestation (Falkner 1986). It is also estimated that by

the 28th week, a fetus has reached 71% of the

mean length at 41 weeks, whereas weight is

only 32% of full-term infant weight. Thus,

growth in length is determined predominantly

in the first two trimesters. In the present study

we consistently found that maternal exposures

to SO2 and CO during early pregnancy are the

best predictors of early fetal adverse development. The effects of air pollution on pregnancy outcomes may differ with the timing of

exposure, with early exposures likely to be

more important for pregnancy end points such

as spontaneous abortion and birth defects

(Antipenko and Kogut 1993; Hansteen et al.

1987). A recent study (Ritz et al. 2002) evaluated the effects of air pollution on the occurrence of birth defects in neonates and fetuses

in Southern California during the period

1987–1993. In that study, the risk of cardiac

ventricular, aortic artery and valve defects,

and pulmonary artery and valve anomalies

increased with maternal CO and O3 exposures

during the second month of pregnancy, representing a link between air pollution and

human malformation during a vulnerable window of development. Thus, maternal exposure

to air pollution during pregnancy may also

affect other pregnancy end points such as

spontaneous abortion, fetal growth, and even

fetal death.

To a certain extent, effects during early

pregnancy are consistent with current knowledge on the etiology of IUGR. Nutrient and

oxygen supply to the fetus during gestation are

key factors in fetal development. Several new

findings on this topic suggest that the pathogenesis resulting in IUGR is triggered by an

abnormal reaction between trophoblast and

uterine tissues in the first few weeks of pregnancy (Duvekot et al. 1995; Khong et al.

1986). The altered growth may arise from

defective trophoblast invasion, resulting in placental implantation and maternal hemodynamic maladaptation (Duvekot et al. 1995;

Roberts et al. 1991). These changes could

result in reduced growth and fetal adaptation

to undernutrition, with subsequent changes in

the structure and function of a range of organs

and tissues (Barker et al. 1993; Godfrey et al.

1996). Because ultrasound studies (Greisen

1992) have shown that preterm infants weigh

Children’s Health | Ambient air pollution and adverse pregnancy outcome

Environmental Health Perspectives • VOLUME 111 | NUMBER 14 | November 2003 1777

Table 6. Crude and adjusted ORs and 95% CIs for IUGR attributable to maternal exposure to SO2, NO2, CO,

and O3 by month of pregnancy.

Pollutant Period of pregnancy Crude OR (95% CI)a Adjusted OR (95% CI)a,b

SO2 First month 1.07 (1.02–1.12) 1.07 (1.01–1.13)

Last month 1.01 (0.96–1.06) 1.00 (0.94–1.06)

NO2 First month 1.06 (1.02–1.10) 1.05 (1.01–1.10)

Last month 0.97 (0.92–1.02) 0.98 (0.92–1.03)

CO First month 1.06 (1.02–1.10) 1.06 (1.01–1.10)

Last month 0.97 (0.91–1.05) 0.98 (0.94–1.03)

O3 First month 0.98 (0.95–1.01) 0.99 (0.93–1.04)

Last month 0.99 (0.96–1.02) 0.99 (0.94–1.04)

aORs were estimated based on a certain increase of pollutant: SO2, 5.0 ppb; NO2, 10.0 ppb; CO, 1.0 ppm; O3, 10.0 ppb. bAdjusted for maternal age, parity, infant sex, and season of birth.

Table 7. ORs and 95% CIs for IUGR attributable to maternal exposure to SO2, NO2, CO, and O3 by trimester

of pregnancy.

Pollutant Period of pregnancy Crude OR (95% CI)a Adjusted OR (95% CI)a,b

SO2 1st trimester 1.07 (1.01–1.14) 1.07 (1.00–1.14)

2nd trimester 0.98 (0.92–1.04) 0.98 (0.91–1.04)

3rd trimester 1.02 (0.96–1.09) 1.03 (0.96–1.10)

NO2 1st trimester 1.04 (0.99–1.10) 1.03 (0.98–1.10)

2nd trimester 0.96 (0.91–1.01) 0.94 (0.88–1.00)

3rd trimester 0.96 (0.91–1.02) 0.98 (0.92–1.06)

CO 1st trimester 1.06 (1.01–1.10) 1.05 (1.00–1.10)

2nd trimester 0.97 (0.94–1.01) 0.97 (0.92–1.01)

3rd trimester 0.97 (0.93–1.01) 0.97 (0.93–1.02)

O3 1st trimester 0.99 (0.96–1.03) 1.02 (0.95–1.08)

2nd trimester 1.04 (1.00–1.08) 1.08 (1.01–1.15)

3rd trimester 1.01 (0.97–1.05) 0.99 (0.93–1.06)

aORs were estimated based on a certain increase of pollutant: SO2, 5.0 ppb; NO2, 10.0 ppb; CO, 1.0 ppm; O3, 10.0 ppb. bAdjusted for maternal age, parity, infant sex, and season of birth.
less than infants who remain in utero at the

same gestational age, a fetus with restricted

growth may exhibit a greater susceptibility to

events that trigger premature labor. CO may

interfere with metabolic and transport functions of the placenta and, after crossing the placental barrier, concentrates more in the fetus

than in the mother.

It is important to recognize that ambient air

pollution is a complex mixture involving multiple components. In the present study, associations between individual gaseous pollutants and

adverse pregnancy outcomes tended to persist

after adjustment for copollutant exposure in

multiple-pollutant models. Overall, the associations among SO2 and LBW, preterm birth, and

IUGR appear to be most robust against copollutant adjustment. These results suggest that

the effects of air pollutants on birth outcomes

are likely related to more than one component

of the complex mix of air pollutants present in

urban environment.

In summary, our data from Vancouver,

Canada, confirm previous reports from China,

Europe, and the United States about the

adverse effects of ambient air pollution on

birth outcomes. Although there are some differences in strength of these associations, it is

increasingly evident that relatively low concentrations of ambient air pollution are associated

with adverse birth outcomes in populations

experiencing diverse air pollution profiles.

Although the mechanisms underlying these

associations are not yet clear, these effects

require further examination in other populations. Further research also needs to be conducted with more detailed information on

personal exposures, effect modifiers, and other

adverse pregnancy outcomes such as birth

defects and spontaneous abortion.

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