There is extensive evidence that ambient air

pollution affects human health (e.g.,

Brunekreef and Holgate 2002; Künzli et al.

2000; Pope et al. 2002). Most studies have

focused on the effects of air pollution on adult

mortality and respiratory morbidity (Dockery

et al. 1993; Schwartz and Marcus 1990).

However, some age groups appear to be more

susceptible than others. For example, it has

been shown that the effects are larger in the

elderly than in the general adult population

(Saldiva et al. 1995). Studies on childhood

health risks, such as respiratory symptoms or

hospital admissions for asthma, suggest that

the opposite end of the age spectrum is also

more vulnerable to air pollution than is the

general population (Dockery and Pope 1994;

Heinrich et al. 1999; Schwartz et al. 1994).

In addition to these “traditional” end points

in children, there is now emerging evidence

that air pollution is also associated with elevated risk of adverse pregnancy outcomes

(Glinianaia et al. 2004; Maisonet et al. 2004).

The study of birth outcomes is an important emerging field of environmental epidemiology. Birth outcomes are important in

their own right because they are important

indicators of the health of the newborns and

infants. In addition, low birth weight (LBW),

intrauterine growth retardation (IUGR), and

impaired growth in the first years of life are

known to influence the subsequent health 

status of individuals, including increased

mortality and morbidity in childhood and an

elevated risk of hypertension, coronary heart

disease, and non-insulin-dependent diabetes

in adulthood (Barker 1995; Osmond and

Baker 2000).

It is increasingly apparent that there is a

critical period of development when the timing of exposure and the dose absorption rate

can be even more important for the biologic

effects than is the overall dose (Axelrod et al.

2001). Fetuses, in particular, are considered to

be highly susceptible to a variety of toxicants

because of their exposure pattern and physiologic immaturity (Perera et al. 1999; Sˇrám

1999). Their developing organ systems can be

more vulnerable to environmental toxicants

during critical windows (sensitive periods of

development) because of higher rates of cell

proliferation or changing metabolic capabilities (Calabrese 1986). Therefore, prenatal

exposure to environmental pollution can

result in some adverse reproductive outcomes,

similar to the association between maternal

active and passive smoking and impaired

reproductive outcomes (Misra and Nguyen

1999; Salihu et al. 2004). The specific mechanisms that may account for the link between

ambient air pollution and adverse reproductive outcomes are also reviewed in this article.

The objective of this review is to examine

the evidence linking adverse birth outcomes

with ambient air pollution. For the purpose of

this review, birth outcomes have been divided

into five groups: a) mortality of fetuses and

infants, b) LBW, c) premature (preterm)

births, d) IUGR, and e) birth defects. In this

article we review the evidence on each of

these separately. For each of the outcomes, we

assess the three critical issues in interpreting

epidemiologic studies (random error, selection or measurement bias, and confounding);

issues related to all reviewed outcomes (e.g.,

publication bias or biologic plausibility) are

considered together at the end of the article.

By weighting the evidence, we attempt to

draw balanced conclusions about the relations

between air pollution and birth outcomes.

Materials and Methods

We searched all publications included in the

electronic databases PubMed (from 1966;

National Library of Medicine, Bethesda,

MD, USA) and the Science Citation Index

and Social Science Citation Index of the

Institute of Scientific Information, available

on the Web of Knowledge (from 1981;

Thompson Scientific, Philadelphia, PA,

USA). We searched for combinations of

either of the key words “air pollution” or

“pollution” with any of the following: “infant

mortality,” “postneonatal mortality,” “postneonatal mortality,” “birth weight,” “birthweight,” “intrauterine growth retardation,”

“IUGR,” “premature birth,” “prematurity,”

“fetal growth,” and “foetal growth.” We also

searched the reference lists of identified

papers for additional publications. We

excluded abstracts of conference presentations

because they did not contain sufficient information (but relevant conference abstracts that

were subsequently published as full papers

were included).

Environmental Health Perspectives • VOLUME 113 | NUMBER 4 | April 2005 375

Address correspondence to R.J. Sˇrám, Laboratory of

Genetic Ecotoxicology, Institute of Experimental

Medicine AS CR, 142 20 Prague 4, Vídeòská 1083,

Czech Republic. Telephone: 420-241-062-596. Fax:

420-241-062-785. E-mail: sram@biomed.cas.cz

We thank T. Damstra (World Health Organization,

Research Triangle Park, NC, USA) for her critical

comments. 

This work was supported by the grants from the

European Commission (QLRT-2001-02198,

ChildrenGenonetwork) and the Ministry of

Environment of the Czech Republic (VaV 740/5/03).

The authors declare they have no competing

financial interests.

Received 31 March 2003; accepted 4 January 2005.

Ambient Air Pollution and Pregnancy Outcomes: A Review of the Literature

Radim J. Sˇrám,1 Blanka Binková,1 Jan Dejmek,1 and Martin Bobak2

1Laboratory of Genetic Ecotoxicology, Institute of Experimental Medicine, Academy of Sciences, and Health Institute of Central

Bohemia, Prague, Czech Republic; 2Department of Epidemiology and Public Health, University College London, London, 

United Kingdom

Over the last decade or so, a large number of studies have investigated the possible adverse effects

of ambient air pollution on birth outcomes. We reviewed these studies, which were identified by a

systematic search of the main scientific databases. Virtually all reviewed studies were population

based, with information on exposure to air pollution derived from routine monitoring sources.

Overall, there is evidence implicating air pollution in adverse effects on different birth outcomes,

but the strength of the evidence differs between outcomes. The evidence is sufficient to infer a

causal relationship between particulate air pollution and respiratory deaths in the postneonatal

period. For air pollution and birth weight the evidence suggests causality, but further studies are

needed to confirm an effect and its size and to clarify the most vulnerable period of pregnancy and

the role of different pollutants. For preterm births and intrauterine growth retardation (IUGR) the

evidence as yet is insufficient to infer causality, but the available evidence justifies further studies.

Molecular epidemiologic studies suggest possible biologic mechanisms for the effect on birth

weight, premature birth, and IUGR and support the view that the relation between pollution and

these birth outcomes is genuine. For birth defects, the evidence base so far is insufficient to draw

conclusions. In terms of exposure to specific pollutants, particulates seem the most important for

infant deaths, and the effect on IUGR seems linked to polycyclic aromatic hydrocarbons, but the

existing evidence does not allow precise identification of the different pollutants or the timing of

exposure that can result in adverse pregnancy outcomes. Key words: air pollution, intrauterine

growth retardation, low birth weight, molecular epidemiology, PAHs, particulate matter, PM10,

premature birth, reproductive effects, SO2. Environ Health Perspect 113:375–382 (2005).

doi:10.1289/ehp.6362 available via http://dx.doi.org/ [Online 4 January 2005]

Research Review
Results

Air pollution and childhood mortality. The

possible impact of air pollution on children’s

health was first connected to early child mortality. One of the earliest reports was based on

an ecologic study of counties of England and

Wales in 1958–1964, with air pollution estimated from indices of domestic and industrial

pollution (Collins et al. 1971). The study

found significant correlations between air pollution and infant mortality, and infant respiratory mortality in particular. The Nashville

Air Pollution Study, conducted in the 1950s,

indicated that dust fall, a measure of air pollution estimated for each census tract, was

related to neonatal deaths with signs of prematurity, but the results were inconclusive

(Sprague and Hagstrom 1969). Another early

signal that air pollution may be associated

with deaths in infancy came from the extensive analyses of air pollution and mortality in

117 U.S. metropolitan areas in the 1960s

(Lave and Seskin 1977). Particulates and, to a

lesser degree, sulfate concentrations were positively associated with infant mortality; a 10%

increase in pollution was associated with a 1%

increase in infant mortality.

Almost two decades passed before a new

generation of studies addressed this question in

more detail. These newer studies, summarized

in Table 1, confirmed the early results. A small

ecologic study in the Rio de Janeiro, Brazil,

metropolitan area reported a positive association between annual levels of particulates and

infant mortality from pneumonia (Penna and

Duchiade 1991).

Bobak and Leon (1992) studied infant

mortality in an ecologic study in the Czech

Republic. The study found an association

between sulfur dioxide and total suspended

particles (TSP), and infant mortality, after

controlling for a number of potential confounding variables (at the ecologic level). The

effects were specific to respiratory mortality in

the postneonatal period. These results were

later confirmed in a nationwide case–control

study based on the Czech national death and

birth registers; this design allowed controlling

for social and biologic covariates at the individual level (Bobak and Leon 1999a). The

study found a strong effect of SO2 and TSP

on postneonatal mortality from respiratory

causes: the relative risks (RRs) per 50 μg/m3

increase in pollutant concentration were 1.95

[95% confidence interval (CI), 1.09–3.50] for

SO2 and 1.74 (95% CI, 1.01–2.98) for TSP.

Woodruff et al. (1997) analyzed the association between early postneonatal mortality and

PM10 (particulate matter < 10 μm) levels in

about 4 million babies born from 1989 through

1991 in the United States. Infants were categorized as having high, medium, or low exposures

based on tertiles of PM10. After adjustment for

other covariates, for total postneonatal mortality for the high-exposure (> 40 μg/m3) versus

low-exposure (< 28 μg/m3) groups was 1.10

(95% CI, 1.04–1.16). In infants of normal

birth weight, high PM10 exposure was associated with respiratory deaths (RR, 1.40; 95%

CI, 1.05–1.85) and sudden infant death syndrome (RR, 1.26; 95% CI, 1.14–1.39). The

results were similar in term and LBW infants.

Pereira et al. (1998) investigated the associations between daily counts of intrauterine

mortality in the city of São Paulo, Brazil, in

1991–1992 and daily measurements of several pollutants: nitrogen dioxide, SO2, carbon

monoxide, ozone, and PM10. The association

was strongest for NO2 (coefficient R =

0.0013/μg/m3; p < 0.01). A significant association was also observed with exposure combining the pollutants NO2, SO2, and CO

together (p < 0.01).

Loomis et al. (1999) conducted a timeseries study of infant mortality in the southwestern part of Mexico City in 1993–1995.

Exposure included NO2, SO2, O3, and particulate matter < 2.5 μm (PM2.5). A 10 μg/m3

increase in the mean level of fine particles

during the preceding 3 days was associated

with a 6.9% (95% CI, 2.5–11.3%) excess

increase in infant death.

Dolk et al. (2000) examined perinatal and

infant outcomes in populations residing near

22 coke works in Great Britain. Data on specific pollutants were not provided; the exposure was based on the proximity to pollution

sources. The ratios of observed to expected

cases for residence in proximity of the coke

works were 0.94 (95% CI, 0.78–1.12) for stillbirth, 0.95 (95% CI, 0.83–1.09) for infant

mortality, 0.86 (95% CI, 0.72–1.03) for

neonatal mortality, 1.10 (95% CI, 0.90–1.33)

for postneonatal mortality, 0.79 (95% CI,

0.30–1.46) for respiratory postneonatal mortality, and 1.07 (95% CI, 0.77–1.43) for sudden infant death syndrome in the postneonatal

period. This study, however, had a limited statistical power owing to the relatively small size

of the study.

A time-series analysis of daily deaths in

Seoul, South Korea, found a relatively specific

association between PM10 and total and respiratory mortality in the postneonatal period; the

RRs per 10 μg/m3 were 1.03 (1.02–1.04) and

1.18 (1.14–1.21), respectively (Ha et al. 2003).

The consistency of these studies, conducted in a range of different populations and

using both spatial and time-series study

designs, is remarkable. The three largest studies produced very similar estimates of RR

(Bobak and Leon 1992, 1999a; Woodruff

et al. 1997). Perhaps the only alternative

explanation that may affect the interpretation

Review | Sˇrám et al.

376 VOLUME 113 | NUMBER 4 | April 2005 • Environmental Health Perspectives

Table 1. Air pollution and child mortality.

Mortality Pollutant Results Reference

Postneonatal respiratory TSP AOR = 2.41 (95% CI, 1.10–5.28) Bobak and Leon 1992

mortality comparing highest vs. lowest quintile

AOR = 3.91 (95% CI, 0.90–3.50)

for 50 μg/m3 increase

Postneonatal respiratory TSP AOR = 1.95 (95% CI, 1.90–3.50) Bobak and Leon 1999a

mortality for 50 μg/m3 increase

SO2 AOR = 1.74 (95% CI, 1.01–2.98)

for 50 μg/m3 increase

NOx AOR = 1.66 (95% CI, 0.98–2.81) 

for 50 μg/m3 increase

Postneonatal infant PM10 AOR = 1.10 (95% CI, 1.04–1.16) Woodruff et al. 1997

mortality comparing high vs. low exposure

Respiratory death groups PM10 AOR = 1.40 (95% CI, 1.05–1.85) 

comparing high vs. low exposure

with normal birth weight 

Sudden infant death PM10 AOR = 1.26 (95% CI, 1.14–1.39)

comparing high vs. low exposure 

groups

Intrauterine mortality NO2 Strong association Pereira et al. 1998

(coefficient = 0.0013 μg/m3, p < 0.01)

SO2 NE

CO NE

Significant association using 

pollution index NOx + SO2 + CO

O3 NE

PM10 NE

Infant mortality NO2 NE Loomis et al. 1999

SO2 NE

CO NE

O3 NE

PM10 6.9% excess (95% CI, 2.5–11.3%) 

for 10 μg/m3 increase

Perinatal and infant mortality NE between residence near coke Dolk et al. 2000

works

Abbreviations: AOR, adjusted odds ratio; NE, no effect; PM10, particulate matter < 10 μm; TSP, total suspended particulate.
of these studies is confounding by maternal

smoking. It is likely that maternal smoking is

associated with children’s risk of respiratory

death, and none of the studies was able to

control for maternal smoking on the individual level. However, at least three observations

argue against this possibility. First, all recent

studies controlled for socioeconomic factors

and other potential confounders. Because

smoking in industrialized countries is strongly

socially patterned, adjustment for socioeconomic factors should at least partly adjust

for smoking. This would be reflected by

adjusted estimates being substantially smaller

than unadjusted ones. However, in most

instances the differences between the crude

and adjusted effect estimates were minimal.

This does not suggest a presence of residual

confounding.

Second, the results of spatial and timeseries studies were similar. It is highly unlikely

that the social composition or maternal smoking in the studied populations would change

substantially over the relatively short periods

covered by the time-series studies. In our

view, the time-series design practically precludes a presence of confounding by socioeconomic factors or maternal smoking.

Finally, the studies were conducted in

very different populations, ranging from

China to the United States and from Brazil to

the Czech Republic; it is unlikely that the distribution of socioeconomic disadvantage or

maternal smoking with respect to air pollution would be similar enough in these different countries to produce the same pattern of

results. We therefore conclude that the evidence is sufficient to infer causal relationship

between particulate air pollution and respiratory deaths in the postneonatal period.

Air pollution and birth weight. The potential effects of air pollutants on birth weight

were first examined in a small case–control

study by Alderman et al. (1987); the study did

not find any relationship between neighborhood ambient levels of CO during the third

trimester of pregnancy and LBW. Over the last

decade, this question has been investigated in a

number of studies (summarized in Table 2).

Wang et al. (1997) examined the effects

of SO2 and TSP on birth weight in a timeseries study in four relatively highly polluted

residential areas of Beijing, China. A spectrum of potential confounding factors was

adjusted for in multivariate analysis. A graded

dose–effect relationship was found between

maternal exposure to SO2 and TSP during

the third trimester and infant birth weight.

The mean birth weight was reduced by 7.3

and 6.9 g for each 100-μg/m3 increase in SO2

and TSP, respectively. The RRs of LBW associated with a 100-μg/m3 increase in SO2 and

TSP were 1.11 (95% CI, 1.06–1.16) and

1.10 (95% CI, 1.05–1.14), respectively. The

authors speculated that SO2 and particles, or

some complex mixtures associated with these

pollutants, during late gestation contributed

to the LBW risk in the studied population.

Bobak and Leon (1999b) conducted an

ecologic study of LBW and levels of nitrous

oxides (NOx), SO2, and TSP in 45 districts of

the Czech Republic in 1986–1988. After controlling for socioeconomic factors, the RRs of

LBW associated with an increase of 50 μg/m3

in the annual mean concentrations were 1.04

(95% CI, 0.96–1.12) for TSP, 1.10 (95% CI,

1.02–1.17) for SO2, and 1.07 (95% CI,

0.98–1.16) for NOx. When all pollutants were

included in one model, only SO2 remained

related to LBW [odds ratio (OR), 1.10; 95%

CI, 1.01–1.20].

In a subsequent study, Bobak (2000) analyzed individual-level data on all single live

births in the Czech Republic that occurred in

1991 in the 67 districts where at least one

pollutant (NOx, SO2, or TSP) was monitored.

The risk of LBW was analyzed separately for

each trimester of pregnancy. The association

between LBW and pollution was strongest for

pollutant levels during the first trimester of

pregnancy. The RRs of LBW per 50 μg/m3

increase in the mean concentration of SO2

and TSP during the first trimester were 1.20

(95% CI, 1.11–1.30) and 1.15 (95% CI,

1.07–1.24), respectively.

In a population-based study in Southern

California, Ritz and Yu (1999) examined the

influence of pollution levels during the third

trimester on LBW risk in a cohort of 126,000

term births. The exposure to O3, NO2, and

PM10 in the last trimester was estimated from

continuous monitoring data. After adjustment

for potential confounders, the risk of LBW

was associated with maternal exposure to

> 5.5 ppm CO during the third trimester (RR,

1.22; 95% CI, 1.03–1.44). The association

Review | Air pollution and pregnancy outcome

Environmental Health Perspectives • VOLUME 113 | NUMBER 4 | April 2005 377

Table 2. Air pollution and birth weight.

Outcome Pollutant Results Reference

LBW SO2 AOR = 1.21 (95% CI, 1.06–1.16) Wang et al. 1997

for 100 μg/m3 increase

TSP AOR = 1.10 (95% CI, 1.05–1.14)

for 100 μg/m3 increase

LBW TSP OR = 1.04 (95% CI, 0.96–1.12) Bobak and Leon 1999b

for 50 μg/m3 increase

SO2 OR = 1.10 (95% CI, 1.02–1.17)

for 50 μg/m3 increase

NOx OR = 1.07 (95% CI, 0.98–1.16)

for 50 μg/m3 increase

LBW NOx NE Bobak 2000

SO2 AOR = 1.20 (95% CI, 1.11–1.30)

for 50 μg/m3 increase in the first trimester

TSP AOR = 1.15 (95% CI, 1.07–1.24)

for 50 μg/m3 increase in the first trimester

LBW O3 NE Ritz and Yu 1999

NO2 NE

PM10 NE

CO OR = 1.22 (95% CI, 1.03–1.44)

for CO > 5.5 ppm in the first trimester

VLBW TSP + SO2 AOR = 2.88 (95% CI, 1.16–7.13) Rogers et al. 2000

comparing highest vs. lowest 

exposure groups (56.7 vs .9.9 μg/m3)

LBW CO AOR = 1.43 (95% CI, 1.18–1.74) Maisonet et al. 2001

for 1 ppm increase in first trimester 

AOR = 1.75 (95% CI, 1.50–2.04)

for 1 ppm increase in first trimester

in African Americans

SO2 AOR = 1.18/1.20 (95% CI, 1.02–1.36)

ppm increase in all trimesters in whites

LBW SO2 + NO2 + PM10 AOR = 1.77 (95% CI, 1.00–3.12) Lin et al. 2001b

comparing petrochemical and

control municipalities

LBW CO AOR = 1.08 (95% CI, 1.04–1.12) Ha et al. 2001

in the first trimester

NO2 AOR = 1.07 (95% CI, 1.03–1.11)

in the first trimester

SO2 AOR = 1.06 (95% CI, 1.02–1.10)

in the first trimester

TSP AOR = 1.04 (95% CI, 1.00–1.08)

in the first trimester

LBW POM OR = 1.31 (95% CI, 1.21–1.43) Vassilev et al. 2001b

comparing highest vs. lowest

exposure groups

Abbreviations: AOR, adjusted odds ratio; NE, no effect; VLBW, very low birth weight (< 1,500 g).
between LBW risk and pollution exposure during earlier gestational stages was not significant.

In a population-based case–control study

in Georgia (USA), Rogers et al. (2000) analyzed the combined effect on very low birth

weight (VLBW) (< 1,500 g) of SO2 and TSP

levels, using annual exposure estimates. The

risk of VLBW was increased in babies of

mothers who were exposed to concentrations

of the combined pollutants above the 95th

percentile of the exposure distribution

(56.8 μg/m3); the RR was 2.88 (95% CI,

1.16–7.13).

Maisonet et al. (2001) examined the

association between term LBW and ambient

levels of SO2, PM10, and CO in six large cities

in the northeastern United States. Their results

suggested that the effects of ambient CO and

SO2 on the risk of term LBW may differ by

ethnic group. In Caucasians (n ~ 36,000), the

risk of LBW associated with a 10-ppm increase

in SO2 was 1.18 (95% CI, 1.12–1.23) in the

first trimester, 1.18 (95% CI, 1.02–1.35) in

the second, and 1.20 (95% CI, 1.06–1.36) in

the third. By contrast, in African Americans

(n ~ 47,000) LBW was associated with CO;

a 1-ppm increase in CO concentration was

associated with an RR of 1.43 (95% CI,

1.18–1.74) in the first trimester and 1.75 (95%

CI, 1.50–2.04) in the third trimester. No

effects were seen in Hispanics (n ~ 13,000),

although this may have been due to a lower statistical power in this group.

Lin et al. (2001b) compared the rates of

adverse pregnancy outcomes in an area polluted by the petrochemical industry and in a

control area in Taiwan. The exposed and control areas differed substantially in the levels of

air pollution; for example, the differences in

the mean concentrations of PM10 was

26.7 μg/m3. The RR of term LBW, when the

petrochemical municipality was compared

with the control municipality, was 1.77 (95%

CI, 1.00–3.12).

Ha et al. (2001) examined full-term births

from 1996 through 1997 in Seoul, South

Korea, to determine the association between

LBW and exposure to CO, SO2, NO2, TSP,

and O3 in the first and third trimesters. They

found that ambient CO, SO2, NO2, and TSP

concentrations during the first trimester of

pregnancy were associated with LBW; the RRs

were 1.08 (95% CI, 1.04–1.12) for CO, 1.06

(95% CI, 1.02–1.10) for SO2, 1.07 (95% CI,

1.03–1.11) for NO2, and 1.04 (95% CI,

1.00–1.08) for TSP.

Vassilev et al. (2001b) used U.S.

Environmental Protection Agency (EPA)

Cumulative Exposure Project data to investigate the association between outdoor airborne

polycyclic organic matter (POM) and adverse

reproductive outcomes in New Jersey for newborns born in 1991–1992. The RR of LBW

in term babies, comparing the highest and the

lowest exposure groups, was 1.31 (95% CI,

1.21–1.43).

Bobak et al. (2001) tested the hypothesis

that air pollution is related to LBW on data

from a British 1946 cohort. They found a

strong association between birth weight and air

pollution index based on coal consumption.

After controlling for a number of potential

confounding variables, babies born in the most

polluted areas (annual mean concentration of

smoke > 281 μg/m3) were on average 82 g

(95% CI, 24–140) lighter than those born in

the areas with the cleanest air (mean smoke

concentration < 67 μg/m3).

Chen et al. (2002) examined the association between PM10, CO, and O3 and birth

weight in northern Nevada (USA) from 1991

through 1999. The results suggested that a

10-μg/m3 increase in the mean PM10 concentrations during the third trimester of pregnancy was associated a reduction in birth

weight of 11 g (95% CI, 2.3–19.8).

Wilhelm and Ritz (2003) studied the effect

on LBW of residential proximity to heavy traffic in Los Angeles County, California (USA) in

1994–1996. The risk of term LBW increased

by 19% for each 1 ppm increase in the mean

annual concentration of background CO. In

addition, an elevated risk was observed for

women whose third trimester fell during the

fall/winter months (RR, 1.39; 95% CI,

1.16–1.67); this is probably due to the more

stagnant air conditions during the winter

period. Overall, the study reported an approximately 10–20% increase in the risk of term

LBW in infants born to women exposed to

high levels of traffic-related air pollution.

A time-series study in Vancouver, Canada,

found that LBW was associated with SO2 in

the first month of pregnancy (OR per 5 ppb

increase, 1.11; 95% CI, 1.01–1.22); NO2,

CO, and O3 were not independently associated with LBW (Liu et al. 2003). Particles

were not measured.

A time-series study in Sao Paulo, Brazil,

found that birth weight was inversely related

to CO in the first trimester; after controlling

for potential confounders, a 1-ppm increase in

the mean CO concentration in the first

trimester was associated with a 23-g (95% CI,

5–41 g) reduction in birth weight (Gouveia et

al. 2004).

The results of studies of outdoor exposures

are complemented by studies of indoor and

personal exposures (not included in Table 2).

Boy et al. (2002) compared the association

between birth weight and the type of fuel

(open fires with wood smoke, chimney stove,

and electricity/gas) used in kitchens by mothers in rural Guatemala during pregnancy. The

use of open fire produced average levels of

24-hr PM10 of about 1,000 μg/m3. Babies of

mothers using wood fuel and open fires were

on average 63 g (95% CI, 0.4–126 g) lighter

than those of women using electricity/gas.

Perera et al. (2003) evaluated the effects of

prenatal exposure to airborne carcinogenic

polycyclic aromatic hydrocarbons (PAHs)

monitored during pregnancy by personal air

sampling in a sample of 263 nonsmoking

African-American and Dominican women in

New York. The mean total PAH exposure was

3.7 ng/m3 (range, 0.4–36.5 ng/m3). Among

African Americans, high prenatal exposure to

PAHs was associated with lower birth weight

(p = 0.003) and smaller head circumference

(p = 0.01). No such effects were observed

among Dominican women.

Several methodologic issues should be

considered in the interpretation of these studies. First, could chance (random error) play a

role here? In several of the studies reviewed

above, there is a potential problem of multiple

comparisons. The more comparisons that are

made, the higher the probability that some of

them will be “statistically significant.” In some

instances, a more stringent use of statistical

testing would be useful. Especially in studies

where exposures to different pollutants at different pregnancy periods were analyzed, some

of the associations could be chance findings.

In addition, exposures in different pregnancy

periods and concentrations of different pollutants are mutually correlated, and efforts to

separate their effects are not reliable.

Second, as with infant mortality, confounding by socioeconomic factors and maternal smoking could affect the results. Overall,

however, this seems unlikely for the same reasons as those listed above in “Air pollution and

childhood mortality.” In addition, some of the

studies were able to control for social conditions and maternal smoking at the individual

level, and the results were essentially identical.

In terms of the magnitude of the effect,

the results were consistent in suggesting that

the effects are relatively small. For comparison,

it has been estimated that active smoking in

pregnancy leads to a reduction in birth weight

by approximately 150–200 g (Adriaanse et al.

1996), and exposure to environmental tobacco

smoke in pregnancy results in birth weight

reduction by approximately 20–30 g

(Windham et al. 1999). There were also substantial inconsistencies in the results with

respect to the importance of individual pollutants and the timing of critical exposure. The

extent of the inconsistencies was such that the

studies were not “combinable” into a formal

meta-analysis to produce pooled effect estimates, although it is possible that the mix of

pollutants differs between different settings and

that this underlies the discrepancies in results.

The evidence suggests causality of the effect

of air pollution on birth weight. However,

given the potential problem with multiple

comparisons and the heterogeneity of results,

further studies are needed to confirm that the

Review | Sˇrám et al.

378 VOLUME 113 | NUMBER 4 | April 2005 • Environmental Health Perspectives
effect is indeed causal, to clarify the most vulnerable periods of pregnancy and the role of

individual pollutants, and to examine whether

the impaired reproductive outcomes have any

long-term consequences on child health.

Air pollution and premature births.

Perhaps the first study that suggested a possible association between air pollution and

preterm births was the Nashville Air Pollution

Study; the results suggested that dust fall (a

measure of particulate pollution) was associated with neonatal deaths among premature

births (Sprague and Hagstrom 1969).

However, the study did not address the question of preterm births specifically, and there

were concerns about confounding by socioeconomic variables. It was only in the 1990s

when this issue was investigated in more

detail (Table 3).

The first “modern” investigation of the

possible influence of air pollution on premature birth was a time-series study in

Beijing, China, conducted by Xu et al. (1995).

The study found an inverse relationship

between gestational age and the concentration

of SO2 and TSP; the RRs of premature birth

associated with a 100-μg/m3 increase in the

mean SO2 and TSP concentrations during

pregnancy, after controlling for potential confounders, were 1.21 (95% CI, 1.01–1.45) and

1.10 (95% CI, 1.01–1.20), respectively.

Trimester-specific effects were not studied.

Bobak (2000) examined the relation

between premature birth and ambient NOx,

SO2, and TSP during each trimester. The association was strongest for SO2, weaker for TSP,

and only marginal for NOx. For exposures during the first trimester, the RRs associated with

a 50-ng/m3 increase in pollutant concentrations were 1.27 (95% CI, 1.16–1.39) and 1.18

(95% CI, 1.05–1.31) for SO2 and TSP,

respectively. The effects of pollutants on premature births in the later two trimesters were

weak.

The possible impact of CO, NO2, O3,

and PM10 on premature birth was studied by

Ritz et al. (2000) in Southern California. After

adjustment for a number of biologic, social,

and ethnic covariates, premature births were

associated with CO and PM10 in the first gestational month and during late pregnancy.

The RR associated with PM10 during the first

gestational month was 1.16 (95% CI,

1.06–1.26); exposure in the last 6 weeks of

gestation was associated with an RR of 1.20

(95% CI, 1.09–1.33). The association of 

premature birth with CO levels was not consistent throughout the study area.

In a study in a petrochemically polluted

area in Taiwan, Lin et al. (2001a) found an

RR of preterm birth in the polluted area,

compared with the clean area, of 1.41 (95%

CI, 1.08–1.82), after controlling for potential

confounders.

The Vancouver time-series study found

that the risk of preterm birth was associated

with SO2 and CO during the last month of

pregnancy; the ORs were 1.09 (1.01–1.19 per

5-ppb increase) and 1.08 (1.01–1.15 per

1-ppm increase), respectively (Liu et al. 2003).

The interpretation of the studies of

preterm birth is complicated by similar issues

as in the case of birth weight: the issue of multiple comparisons, and the inconsistency of the

results in terms of the role of individual pollutants and the timing of exposure. In addition,

there have been fewer studies of premature

birth than of birth weight. We therefore conclude that the evidence, as yet, is insufficient to

infer causality, but further studies are justified.

Air pollution and IUGR. IUGR is defined

as birth weight below the 10th percentile of

birth weight for gestational age and sex. IUGR

is an interesting end point that may predict

functional changes in adulthood, such as

hypertension and coronary heart disease. The

studies of the relationship between IUGR and

air pollution are summarized in Table 4.

Dejmek et al. (1999) examined the

impact of PM10 and PM2.5 on IUGR in a

highly polluted area of northern Bohemia

(Teplice District). The mean concentration of

pollutants in each month of gestation for each

mother were estimated from continuous

monitoring data. A significantly increased risk

of giving birth to a child with IUGR was

established for mothers who were exposed to

PM10 levels > 40 μg/m3 or PM2.5 > 27 μg/m3

during the first month of gestation. The

adjusted odds ratio (AOR) associated with a

10-μg/m3 increase in PM10 was 1.25 (95%

CI, 1.08–1.56); a similar, although weaker,

association was seen for PM2.5. There was no

association between IUGR and particulate

levels in later gestational months or with SO2,

NOx, or O3 (Dejmek et al. 1996).

The question of IUGR was addressed again

in a reanalysis of an extended data set (Dejmek

et al. 2000). Compared with exposure to the

mean PM10 of < 40 μg/m3 during the first

month of gestation, the AOR was 1.44 (95%

CI, 1.03–2.02) for the medium-exposure

group (PM10 40 to < 50 μg/m3) and 2.14

(95% CI, 1.42–3.23) for PM10 of ≥ 50 μg/m3.

Using a continuous exposure, the AOR of

IUGR was 1.19 (CI, 1.06–1.33) per 10-μg/m3

increase of PM10 in the first gestational month.

In further analyses of this cohort, Dejmek

et al. (2000) investigated the association

between carcinogenic PAHs and IUGR in

Review | Air pollution and pregnancy outcome

Environmental Health Perspectives • VOLUME 113 | NUMBER 4 | April 2005 379

Table 3. Air pollution and premature births.

Pollutant Results Reference

SO2 AOR = 1.21 (95% CI, 1.01–1.45) for 100 μg/m3 increase Xu et al. 1995

TSP AOR = 1.10 (95% CI, 1.01–1.20) for 100 μg/m3 increase

SO2 AOR = 1.27 (95% CI, 1.16–1.39) for 50 μg/m3 increase in the 1st trimester Bobak 2000

TSP AOR = 1.18 (95% CI, 1.05–1.31) for 50 μg/m3 increase in the 1st trimester

CO NE Ritz et al. 2000

NO2 NE

O3 NE

PM10 RR = 1.16 (95% 1.06–1.26) for 50 μg/m3 increase in the 1st trimester

SO2 + NO2 + PM10 AOR = 1.41 (91% CI, 1.08–1.82) comparing petrochemical and control Lin et al. 2001a

municipalities

Abbreviations: AOR, adjusted odds ratio; NE, no effect.

Table 4. Air pollution and IUGR.

Outcome Pollutant Results Reference

IUGR SO2 NE Dejmek et al. 1996

NOx NE

O3 NE

IUGR PM10 AOR = 2.64 (95% CI, 1.48–4.71) comparing Dejmek et al. 1999

PM10 > 50 μg/m3 with PM10 < 40 μg/m3

in the first month of pregnancy

PM2.5 AOR = 2.11 (95% CI, 1.20–3.70) comparing

PM2.5 > 37 μg/m3 with PM2.5 < 27 μg/m3

in the first month of pregnancy

IUGR PM10 AOR = 2.14 (95% CI, 1.42–3.23) comparing Dejmek et al. 2000

PM10 > 50 μg/m3 with PM10 < 40 μg/m3

in the first month of pregnancy

PM2.5 AOR = 1.96 (95% CI, 1.02–3.11) comparing

PM2.5 > 37 μg/m3 with PM2.5 < 27 μg/m3

in the first month of pregnancy

carc-PAHs AOR = 2.15 (95% CI, 1.27–3.63) comparing 

carc-PAHs > 30 μg/m3 with carc-PAHs < 15 μg/m3

in the first month of pregnancy

SGA POM AOR = 1.22 (95% CI, 1.16–1.27) comparing Vassilev et al. 2001a

highest vs. lowest exposure groups for the term birth

Abbreviations: AOR, adjusted odds ratio; carc-PAHs, carcinogenic-PAHs; NE, no effect; SGA, small for gestational age.
two Czech districts: Teplice and Prachatice.

In the Teplice data, there was a highly significant increase of IUGR with exposures to

carcinogenic PAHs (benz[a]anthracene,

benzo[b]fluoranthene, benzo[k]fluoranthene,

benzo[g,h,i]perylene, benzo[a]pyrene, chrysene, dibenz[a,h]anthracene, and indeno[1,2,3-

c,d]pyrene) above 15 ng/m3. Again, the effect

was specific for the first gestational month. The

AORs were 1.59 (95% CI, 1.06–2.39) for

medium levels of carcinogenic PAHs and 2.15

(95% CI, 1.27–3.63) for high exposure levels.

Using a continuous measure of exposure, a

10 ng/m3 increase in carcinogenic PAH level

was associated with an AOR of 1.22 (95% CI,

1.07–1.39). Although there was no effect of

PM10 on IUGR found in Prachatice, the association between carcinogenic PAHs and IUGR

was close to that found in Teplice. Again, the

only consistent association between carcinogenic PAHs and IUGR was observed in the

first gestational month: compared with the

lowest category of exposure to carcinogenic

PAHs, the AOR of IUGR was 1.63 (95% CI,

0.87–3.06) in the medium category and 2.39

(95% CI, 1.01–5.65) in the highest category.

The analysis of the Czech national birth

register linked with air pollution data did not

reveal any significant association between

IUGR and ambient levels of NOx, SO2, and

TSP (Bobak 2000). The discrepancy between

the Czech studies is probably related to exposure measurement. PAHs appear to be the

critical exposure for IUGR, but PAHs were not

measured by the national monitoring system

used for exposure estimation by Bobak (2000).

Vassilev et al. (2001a) examined the association of POM in outdoor air with “small for

gestational age” (SGA) births (the definition

of SGA is identical to that of IUGR).

Information from birth certificates in New

Jersey (USA) from 1991 through 1992 was

combined with data on air toxicity derived

from the U.S. EPA Cumulative Exposure

Project, using the predicted POM concentrations from annual exposure estimates. The

AOR for term SGA in the highest exposure

tertile (0.61–2.83 μg/m3, which includes

about 89% of the state’s births) was 1.22

(95% CI, 1.16–1.27), suggesting that residential exposure to airborne POM is associated

with an increased prevalence of IUGR.

In the Vancouver study, using the timeseries approach, SO2, NO2, and CO in the

first month of pregnancy were associated

with IUGR; the ORs were 1.07 (95% CI,

1.01–1.13) per 5-ppb increase, 1.05 (95%

CI, 1.01–1.10) per 10-ppb increase, and 1.06

(95% CI, 1.01–1.10) per 1-ppm increase,

respectively (Liu et al. 2003). Data on exposures to particles or PAHs were not available

in that study.

As with studies of birth weight and

preterm births, the reviewed studies of IUGR

produced inconsistent results, and the interpretation is complicated by multiple comparisons (Bobak 2000; Liu et al. 2003) and

mutual correlations of exposures. The results

by Dejmek et al. (1999, 2000) and Liu et al.

(2003) suggest that the first month was the

most sensitive period for the effect of air pollutants, but further studies should clarify this

issue. Data by Dejmek et al. (2000) and

Vassilev et al. (2001a) imply a critical role of

PAHs. It is possible that carcinogenic PAHs

are responsible for the biologic activity of

complex mixtures adsorbed to respirable air

particles that can result in IUGR. With the

increase in traffic, the significance of PAHs in

Europe is growing, but their monitoring

remains scarce. At present, the evidence is

insufficient to infer causality, but further

studies are required.

Air pollution and birth defects. At present,

the evidence on the relation between outdoor

air pollution and birth defects is limited to

only one report. Ritz et al. (2002) evaluated

the effect of CO, NO2, O3, and PM10 on the

occurrence of birth defects in Southern

California for the period 1987–1993. The

average monthly exposure for each pollutant

throughout pregnancy was calculated. Dose–

response patterns were observed for CO exposure in the second month of gestation and

ventricular septal defects (AOR for the highest

vs. lowest quartile of exposure, 2.95; 95% CI,

1.44–6.05) and for exposure to O3 in the second month and aortic artery and valve defects

(AOR, 2.68; 95% CI, 1.19–6.05).

Given the lack of studies on air pollution

and birth defects, the evidence base available

so far is insufficient to draw conclusions

about causality. Further studies are required

to support these results by Ritz et al. (2002).

Discussion

The studies reviewed above indicate that

ambient air pollution is inversely associated

with a number of birth outcomes. This is a

relatively new area of environmental epidemiology; most reports have emerged over the last

10 years. A critical assessment of the evidence

is therefore timely. Issues pertinent to different

studies were considered separately above.

Here, we consider questions common to all

reproductive outcomes: publication bias, measurement of exposure, and the biologic plausibility of the effects on birth weight, IUGR,

and preterm births.

Publication bias. Negative studies are less

likely to be published, and studies published in

non-English journals are less likely to be

included in reviews. We included all studies we

were able to identify. We cannot exclude the

possibility that some negative studies, especially

in the earlier period, remain unpublished.

However, given the recent interest in this

topic, it is likely that most studies over the last

decade have been published or at least presented at conferences.

Measurement of exposure. Most studies

relied on routine monitoring of air pollution in

large areas. Extrapolation from citywide or

areawide measurements to individual exposures

can be problematic. In this context, molecular

epidemiologic studies are particularly valuable

for the interpretation of the epidemiologic

data. The molecular epidemiologic studies

used biomarkers of exposure, mainly as the

DNA adducts measured by 32P-postlabeling

and PAH–DNA adducts assessed by enzymelinked immunosorbent assays (Sˇrám and

Binková 2000). Overall, these studies suggest

that DNA adduct levels in maternal blood and

placentas are higher in areas with higher pollution levels (Sˇrám et al. 1999; Whyatt et al.

1998), and significant district and seasonal differences in DNA adducts were found in subgroups with the GSTM1 null genotype

(Topinka et al. 1997a, 1997b). The increase in

the levels of DNA adducts related to pollution

is similar to, but smaller in magnitude than,

the differences between smoking and nonsmoking mothers. All this indicates that ambient air pollution levels do translate to higher

individual exposures, even for unborn babies.

This provides support for the validity of the

epidemiologic studies reviewed above.

DNA adducts in placentas and the impact

of PAHs on IUGR are consistent with findings of in vitro studies that exposure to extracts

of urban air PM increased DNA adducts and

embryotoxicity (Binková et al. 1999, 2003).

These findings indicate that particle-bound

carcinogenic PAH concentrations may be

taken as an index of the biologically active

components in samples of particulates in air.

Biologic plausibility. The molecular epidemiologic studies suggest biologic mechanisms for the effect of air pollution on birth

outcomes. It has been shown that the levels

of DNA adducts are positively related to risk

of IUGR (Dejmek at al 2000; Sˇrám et al.

1999), birth weight, birth length, and head

circumference (Perera et al. 1998, 1999), and

hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus mutation frequency in

infants (Perera et al. 2002).

PAHs and/or their metabolites may bind

to the aryl hydrocarbon receptor (AhR) and

accumulate in the nucleus of cells, resulting in

increased rates of mutagenesis. Because PAHs

bind to the AhR, it may result in antiestrogenic activity through increased metabolism and the depletion of endogenous

estrogens (Carpenter et al. 2002), thus disrupting the endocrine system by altering

steroid function. Bui et al. (1986) hypothesized that benzo[a]pyrene exposure may interfere with uterine growth during pregnancy

because of its antiestrogenic effects, thereby

disrupting the endocrine system. Fetal toxicity

Review | Sˇrám et al.

380 VOLUME 113 | NUMBER 4 | April 2005 • Environmental Health Perspectives
may be further caused by DNA damage resulting in activation of apoptotic pathways (Nicol

et al. 1995) or binding to receptors for placental growth factors resulting in decreased

exchange of oxygen and nutrients (Dejmek

et al. 2000).

The finding of higher DNA adduct levels

in the infant compared with the mother suggests an increased susceptibility of the developing fetus to DNA damage (Perera et al. 1999).

With respect to IUGR, it appears that the

increased risk is principally due to exposure to

carcinogenic PAHs. This finding is consistent

with the idea of a primary role for carcinogenic

PAHs in fetal growth modulation (Guyda

1991; MacKenzie and Angevine 1981; Rigdon

and Rennels 1964; Zhang et al. 1995). Perera

et al. (2003) labeled PAHs as significant independent determinants of birth outcomes. In

addition, there appears to be an interaction

between exposure to PAHs and genotypes that

produce DNA adducts (Whyatt et al. 2001).

Although the specific steps of these pathways need to be further clarified, the molecular epidemiology studies and the similarity of

effects of air pollution to those of smoking

(Adriaanse et al. 1996; Windham et al. 1999)

support the biologic plausibility of the

effects.

Conclusions

Overall, there is evidence implicating air pollution in adverse effects on different birth outcomes, but the strength of the evidence differs

between outcomes. The evidence is sufficient

to infer a causal relationship between particulate air pollution and respiratory deaths in the

postneonatal period. For air pollution and

birth weight, the evidence is suggestive of

causality, although further studies are needed.

For preterm births and IUGR, the evidence as

yet is insufficient to infer causality, but the

available evidence justifies further studies.

Molecular epidemiologic studies suggest possible biologic mechanisms for the effect on birth

weight, premature birth, and IUGR and support the view that the relation between pollution and these birth outcomes is genuine. For

birth defects, the evidence base so far is insufficient to draw conclusions. In terms of exposure

to specific pollutants, particulates seem the

most important for infant deaths, and the

effect on IUGR seems linked to PAHs, but the

existing evidence does not allow precise identification of the different pollutants and the timing of exposure that can result in adverse

pregnancy outcomes.

On the basis of this review, we suggest

several priorities for future research. First, it

remains to be confirmed that the effects on

birth weight, prematurity, and IUGR are genuine and causal. Second, it is important to

identify the most vulnerable period of exposure in pregnancy. Third, the contribution of

different pollutants needs to be established.

Fourth, the biologic pathways require further

clarification. And finally, with the increasing

attention to the life course, it would be interesting to examine whether early exposures and

impaired reproductive outcome have any

long-term consequences in later life.

REFERENCES

Adriaanse HP, Knottnerus JA, Delgado LR, Cox HH, Essed GGM.

1996. Smoking in Dutch women and birth weight. Patient

Educ Couns 28:25–30.

Alderman BW, Baron AE, Saviz DA. 1987. Maternal exposure to

neighborhood carbon monoxide and risk of low infant birth

weight. Public Health Rep 102:410–414.

Axelrod D, Davis DL, Hajek RA, Jones LA. 2001. It’s time to

rethink dose: the case for combining cancer, and birth and

developmental defects [Editorial]. Environ Health Perspect

109:A246–A249.

Barker DJP. 1995. The fetal and infant origins of disease. Eur J

Clin Invest 25:457–463.

Binková B, Cerna M, Pastorkova A, Jelinek R, Benes I, Novak

J, et al. 2003. Biological activities of organic compounds

adsorbed onto ambient air particles: comparison between

the cities of Teplice and Prague during the summer and

winter seasons 2000–2001. Mutat Res 525:43–59.

Binková B, Vesely D, Veselá D, Jelínek R, Sˇrám RJ. 1999.

Genotoxicity and embryotoxicity of urban air particulate matter collected during winter and summer period in two different districts of the Czech Republic. Mutat Res 440:45–58.

Bobak M. 2000. Outdoor pollution, low birth weight, and prematurity. Environ Health Perspect 108:173–176.

Bobak M, Leon DA. 1992. Air pollution and infant mortality in

the Czech Republic, 1986–88. Lancet 310:1010–1014.

Bobak M, Leon DA. 1999a. The effect of air pollution on infant

mortality appears specific for respiratory causes in the

postneonatal period. Epidemiology 10:666–670.

Bobak M, Leon DA. 1999b. Pregnancy outcomes and outdoor

air pollution: an ecological study in districts of the Czech

Republic. Occup Environ Med 56:539–543.

Bobak M, Richards M, Wadsworth M. 2001. Air pollution and

birth weight in Britain in 1946. Epidemiology 12:358–359.

Boy E, Bruce N, Delgado H. 2002. Birth weight and exposure to

kitchen wood smoke during pregnancy in rural Guatemala.

Environ Health Perspect 110:109–114.

Brunekreef B, Holgate ST. 2002. Air pollution and health.

Lancet 360:1233–1242.

Bui QQ, Tran MB, West WL. 1986. A comparative study of the

reproductive effects of methadone and benzo[a]pyrene in

the pregnant and pseudopregnant rat. Toxicology 42:195–204.

Calabrese EJ. 1986. Age and Susceptibility to Toxic Substances.

New York:Wiley & Sons.

Carpenter DO, Arcaro K, Spink DC. 2002. Understanding the

human health effects of chemical mixtures. Environ Health

Perspect 110(suppl 1):25–42.

Chen L, Yang W, Jennison BL, Goodrich A, Omaye ST. 2002. Air

pollution and birth weight in northern Nevada, 1991–1999.

Inhal Toxicol 14:141–157.

Collins JJ, Kasap HS, Holland WW. 1971. Environmental factors

in child mortality in England and Wales. Am J Epidemiol

93:10–22.

Dejmek J, Selevan SG, Benesˇ I, Solansky I, Sˇrám RJ. 1999. Fetal

growth and parental exposure to particulate matter during

gestation. Environ Health Perspect 107:475–480.

Dejmek J, Selevan SG, Benesˇ I, Sˇrám RJ. 1996. Impact of

selected air pollutants on the prevalence of low birth

weight and prematurity [Abstract]. Epidemiology 7:S26.

Dejmek J, Solansky I, Benesˇ I, Lenícˇek J, Sˇrám RJ. 2000. The

impact of polycyclic aromatic hydrocarbons and fine particles on pregnancy outcome. Environ Health Perspect

108:1159–1164.

Dockery DW, Pope CA III. 1994. Acute respiratory effects of particulate air pollution. Annu Rev Public Health 15:107–132.

Dockery DW, Pope CA III, Xu X, Spengler JD, Ware JH, Fay ME,

et al. 1993. The association between air pollution and mortality in six U.S. cities. N Engl J Med 329:1753–1759.

Dolk H, Pattenden S, Vrijheid M, Thakrar B, Armstrong B. 2000.

Perinatal and infant mortality and low birth weight among

residents near cokeworks in Great Britain. Arch Environ

Health 55:26–30.

Glinianaia SV, Rankin J, Bell R, Pless-Mulloli, Howel D. 2004.

Particulate air pollution and fetal health. A systematic

review of the epidemiologic evidence. Epidemiology

15:36–45.

Gouveia N, Bremner SA, Novaes HM. 2004. Association

between ambient air pollution and birth weight in Sao

Paulo, Brazil. J Epidemiol Community Health 58(1):11–17.

Guyda HJ. 1991. Metabolic effects of growth factors and polycyclic aromatic hydrocarbons on cultured human placental cells of early and late gestation. J Clin Endocrinol

Metab 72:718–723.

Ha EH, Hong YC, Lee BE, Woo BH, Schwartz J, Christiani DC.

2001. Is air pollution a risk factor for low birth weight in

Seoul? Epidemiology 12:643–648. 

Ha EH, Lee JT, Kim H, Hong YC, Lee BE, Park HS, et al. 2003.

Infant susceptibility of mortality to air pollution in Seoul,

South Korea. Pediatrics 111:284–290.

Heinrich J, Hoelscher B, Wjst M, Ritz B, Cyrys J, Wichmann H.

1999. Respiratory diseases and allergies in two polluted

areas in East Germany. Environ Health Perspect 107:53–62. 

Künzli N, Kaiser R, Medina S, Studnicka M, Chanel O, Fillinger P,

et al. 2000. Public-health impact of outdoor and trafficrelated air pollution: a European assessment. Lancet

356:795–801.

Lave LB, Seskin EP. 1977. Air Pollution and Human Health.

Baltimore, MD:Johns Hopkins University Press.

Lin MC, Chiu HF, Yu HS, Tsai SS, Cheng BH, Wu TN, et al. 2001a.

Increased risk of preterm delivery in areas with air pollution from a petroleum refinery plant in Taiwan. J Toxicol

Environ Health 64:637–644.

Lin MC, Yu HS, Tsai SS, Cheng BH, Hsu TY, Wu TN, et al. 2001b.

Adverse pregnancy outcome in a petrochemical polluted

area in Taiwan. J Toxicol Environ Health 63:565–574.

Liu S, Krewski D, Shi Y, Chen Y, Burnett RT. 2003. Association

between gaseous ambient air pollutants and adverse pregnancy outcomes in Vancouver, Canada. Environ Health

Perspect 111:1773–1778.

Loomis D, Castillejos M, Gold RG, McDonnell W, Borja-Aburto VH.

1999. Air pollution and infant mortality in Mexico City.

Epidemiology 10:118–123.

MacKenzie KM, Angevine DM. 1981. Infertility in mice exposed

in utero to benzo(a)pyrene. Biol Reprod 24:183–191.

Maisonet M, Bush TJ, Correa A, Jaakkola JJK. 2001. Relation

between ambient air pollution and low birth weight in the

northeastern United States. Environ Health Perspect

109(suppl 3):351–356.

Maisonet M, Correa A, Misra D, Jaakkola JJK. 2004. A review

of the literature on the effects of ambient air pollution on

fetal growth. Environ Res 95:106–115.

Misra DP, Nguyen RH. 1999. Environmental tobacco smoke and

low birth weight: a hazard in the workplace? Environ

Health Perspect 107(suppl 6):897–904.

Nicol CJ, Harrison ML, Laposa RR, Gimelshtein IL, Wells PG. 1995.

A teratologic suppressor role for p53 in benzo[a]pyrenetreated transgenic p53-deficient mice. Nat Genet 10:181–187.

Osmond C, Baker DJP. 2000. Fetal, infant and childhood growth

are predictors of coronary heart disease, diabetes, and

hypertension in adult men and women. Environ Health

Perspect 18:545–553.

Penna MLF, Duchiade MP. 1991. Air pollution and infant mortality

from pneumonia in the Rio de Janeiro metropolitan area.

Bull Pan Am Health Organ 25:47–54.

Pereira LA, Loomis D, Conceicao GMS, Braga ALF, Arcas RM,

Kishi HS, et al. 1998. Association between air pollution and

intrauterine mortality in Sao Paulo, Brazil. Environ Health

Perspect 106:325–329.

Perera FP, Hemminki K, Jedrychowski W, Whyatt R,

Campbell U, Hsu Y, et al. 2002. In utero DNA damage from

environmental pollution is associated with somatic gene

mutation in newborns. Cancer Epidemiol Biomarkers Prev

11:1134–1137.

Perera FP, Jedrychowski W, Rauh V, Whyatt RM. 1999. Molecular

epidemiologic research on the effect of environmental pollutants on the fetus. Environ Health Perspect 107:451–460.

Perera FP, Rauh V, Tsai WY, Kinney P, Camann D, Barr D, et al.

2003. Effects of transplacental exposure to environmental

pollutants on birth outcomes in a multiethnic population.

Environ Health Perspect 111:201–205.

Perera FP, Whyatt RM, Jedrychowski W, Rauh V, Manchester D,

Santella RM, et al. 1998. Recent developments in molecular

epidemiology. A study of the environmental polycyclic aromatic hydrocarbons on birth outcomes in Poland. Am J

Epidemiol 147:309–314.

Pope CA, Burnett RT, Thun MJ, Calle MJ, Krewski D, Ito K,

Review | Air pollution and pregnancy outcome

Environmental Health Perspectives • VOLUME 113 | NUMBER 4 | April 2005 381
et al. 2002. Lung cancer, cardiopulmonary mortality, and

long-term exposure to fine particulate air pollution. JAMA

287:1132–1141.

Rigdon RH, Rennels EG. 1964. Effect of feeding benzpyrene on

reproduction in the rat. Experientia 20:224–226.

Ritz B, Yu F. 1999. The effect of ambient carbon monoxide on low

birth weight among children born in Southern California

between 1989 and 1993. Environ Health Perspect 107:17–25.

Ritz B, Yu F, Chapa G, Fruin S. 2000. Effect of air pollution on

preterm birth among children born in Southern California

between 1989 and 1993. Epidemiology 5:502–511.

Ritz B, Yu F, Fruin S, Chapa G, Shaw GM, Harris JA. 2002.

Ambient air pollution and risk of birth defects in Southern

California. Am J Epidemiol 155:17–24.

Rogers JF, Thompson SJ, Addy CL, McKeown RE, Cowen DJ,

Decoufle P. 2000. Association of very low birth weight with

exposures to environmental sulfur dioxide and total suspended particulates. Am J Epidemiol 151:602–613.

Saldiva PHN, Pope CA III, Schwartz J, Dockery DW,

Lichtenfels AJF, Salge JM, et al. 1995. Air pollution and

mortality in elderly people: a time series study in São

Paulo, Brazil. Arch Environ Health 50:159–163.

Salihu HM, Shumpert MN, Aliyu MH, Alexander MR, Kirby RS,

Alexander GR. 2004. Stillbirths and infant deaths associated

with maternal smoking among mothers aged ≥ 40 years: a

population study. Am J Perinatol 21:121–9.

Schwartz J, Dockery DW, Neas LM, Wypij D, Ware JH,

Spengler JD, et al. 1994. Acute effects of summer air pollution on respiratory symptom reporting in children. Am J

Respir Crit Care Med 150:1234–1242.

Schwartz J, Marcus A. 1990. Mortality and air pollution in

London: a time series analysis. Am J Epidemiol 131:185–194. 

Sprague HA, Hagstrom R. 1969. The Nashville Air Pollution

Study: mortality multiple regression. Arch Environ Health

18:503–507.

Sˇrám RJ. 1999. Impact of air pollution on reproductive health

[Editorial]. Environ Health Perspect 107:A542–A543.

Sˇrám RJ, Binková B. 2000. Molecular epidemiology studies on

occupational and environmental exposure to mutagens and

carcinogens, 1997–1999. Environ Health Perspect 108:57–69.

Sˇrám RJ, Binková B, Rössner P, Rubesˇ J, Topinka J, Dejmek J.

1999. Adverse reproductive outcomes from exposure to

environmental mutagens. Mutat Res 428:203–215.

Topinka J, Binková B, Mracˇková G, Stávková Z, Benesˇ I, Dejmek J,

et al. 1997a. DNA adducts in human placenta as related to air

pollution and to GSTM1 genotype. Mutat Res 390:59–68.

Topinka J, Binková B, Mracˇková G, Stávková Z, Peterka V,

Benesˇ I, et al. 1997b. Influence of GSTM1 and NAT2 genotypes on placental DNA adducts in an environmentally

exposed population. Environ Mol Mutagen 30:184–195.

Vassilev ZP, Robson MG, Klotz JB. 2001a. Association of polycyclic organic matter in outdoor air with decreased birth

weight: a pilot cross-sectional analysis. J Toxicol Environ

Health 64:595–605.

Vassilev ZP, Robson MG, Klotz JB. 2001b. Outdoor exposure to

airborne polycyclic organic matter and adverse reproductive outcomes: a pilot study. Am J Ind Med 40:255–262.

Wang X, Ding H, Ryan L, Xu X. 1997. Association between air

pollution and low birth weight: a community-based study.

Environ Health Perspect 105:514–520.

Whyatt RM, Jedrychowski W, Hemminki K, Santella RM,

Tsai WY, Yang K, et al. 2001. Biomarkers of polycyclic aromatic hydrocarbon-DNA damage and cigarette smoke

exposure in paired maternal and newborn blood samples

as a measure of differential susceptibility. Cancer

Epidemiol Biomarkers Prev 10:581–588.

Whyatt RM, Santella RM, Jedrychowski W, Garte SJ, Bell DA,

Ottman R, et al. 1998. Relationship between ambient air

pollution and DNA damage in Polish mothers and newborns. Environ Health Perspect 106:821–826.

Wilhelm M, Ritz B. 2003. Residential proximity to traffic and

adverse birth outcomes in Los Angeles County, California,

1994–1996. Environ Health Perspect 111:207–216.

Windham GC, Eaton A, Hopkins B. 1999. Evidence for an association between environmental tobacco smoke exposure

and birthweight: a meta-analysis and new data. Paediatr

Perinat Epidemiol 13:35–57.

Woodruff T, Grillo J, Schoendorf KC. 1997. The relationship

between selected causes of postnatal infant mortality and

particulate air pollution in the United States. Environ Health

Perspect 105:608–612.

Xu X, Ding H, Wang X. 1995. Acute effects of total suspended particles and sulfur dioxides on preterm delivery; a communitybased cohort study. Arch Environ Health 50:407–415.

Zhang L, Connor EE, Chegini N, Shiverick KT. 1995. Modulation

by benzo[a]pyrene of epidermal growth factor receptors,

cell proliferation, and secretion of human chorionic

gonadotropin in human placental lines. Biochem Pharmacol

50:1171–1180.

Review | Sˇrám et al.

382 VOLUME 113 | NUMBER 4 | April 2005 • Environmental Health Perspectives