Association between maternal exposure to ambient air pollutants during pregnancy and fetal growth restriction

Abstract

Previous research demonstrated consistent associations between ambient air pollution and emergency room visits, hospitalizations, and mortality. Effect of air pollution on perinatal outcomes has recently drawn more attention. We examined the association between intrauterine growth restriction (IUGR) among singleton term live births and sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and fine particles (PM2.5) present in ambient air in the Canadian cities of Calgary, Edmonton, and Montreal for the period 1985–2000. Multiple logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for IUGR, based on average daily levels of individual pollutants over each month and trimester of pregnancy after adjustment for maternal age, parity, infant gender, season, and city of residence. A 1 ppm increase in CO was associated with an increased risk of IUGR in the first (OR=1.18; 95% CI 1.14–1.23), second (OR=1.15; 95% CI 1.10–1.19) and third (OR=1.19; 95% CI 1.14–1.24) trimesters of pregnancy, respectively. A 20 ppb increase in NO2 (OR=1.16; 95% CI 1.09–1.24; OR=1.14; 95% CI 1.06–1.21; and OR=1.16; 95% CI 1.09–1.24 in the first, second, and third trimesters) and a 10 μg/m3 increase in PM2.5 (OR=1.07; 95% CI 1.03–1.10; OR=1.06; 95% CI 1.03–1.10; and OR=1.06; 95% CI 1.03–1.10) were also associated with an increased risk of IUGR. Consistent results were found when ORs were calculated by month rather than trimester of pregnancy. Our findings add to the emerging body of evidence that exposure to relatively low levels of ambient air pollutants in urban areas during pregnancy is associated with adverse effects on fetal growth.

Introduction

Fetal growth is an important indicator of perinatal health and early childhood development. Genetic, nutritional, environmental, uteroplacental, and fetal factors are major determinants of fetal growth. Multiple sociodemographic and clinical factors are also believed to influence fetal growth (Kramer, 2003). Intrauterine growth restriction (IUGR) is an important predictor of neonatal morbidity and mortality (Vorherr, 1982; Kramer, 1987). Severely growth restricted fetuses are at increased risk of stillbirth, and those born alive are at increased risk of neonatal death as well as short-term morbidity from hypoglycemia, hypocalcemia, and polycythemia (Kramer, 1987; Duvekot et al., 1995; Kramer, 2003). Over a longer term, IUGR infants tend to have small but permanent deficits in growth and neurocognitive development. Recent studies have demonstrated a relationship between impaired growth in the prenatal and early postnatal period and serious disease risks, including noninsulin-dependent diabetes, hypertension, and coronary heart disease (Duvekot et al., 1995; Kramer, 2003).

Previous research has demonstrated consistent associations between ambient air pollution and adverse health effects such as emergency room visits, hospitalizations, and mortality from respiratory and cardiovascular diseases (Dockery et al., 1993; Burnett et al., 1997, 2001). Recent studies have further demonstrated association between ambient air pollution and adverse pregnancy outcomes, including low birth weight, preterm birth, IUGR and birth defects in China (Xu et al., 1995; Wang et al., 1997), the Czech Republic (Bobak, 2000), the United States (Ritz and Yu, 1999; Ritz et al., 2000, 2002; Parker et al., 2005), and Korea (Lee et al., 2003). Recent Canadian studies have also provided evidence of a negative impact of air pollution on birth outcomes (Liu et al., 2003) and respiratory health among young children (Yang et al., 2003) in Vancouver. This present study further examines the impact of exposure to several ambient air pollutants on fetal growth, using data from multiple urban areas.

Methods

Air Pollution Exposure Data

Daily average concentrations and daily 1-h maximum concentrations of nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) were collected from each monitoring station located in Calgary, Edmonton, and Montreal for the period from 1 April 1985 to 31 December 1999. Data for small particles (PM2.5) were obtained from dichotomous samples with Teflon filters operating on a 6-day schedule in the three cities over the same period (Burnett et al., 2000). There were no changes in the placement of the monitoring stations or the monitoring instruments during the study period. Details on the number and location of monitoring stations in addition to the availability of data had been described elsewhere (Burnett et al., 2000). Data used in the present study were obtained from four, two, and eight monitoring stations in Calgary, Edmonton, and Montreal, respectively. The areas covered by the monitoring stations were defined according to census subdivision (CSD) boundaries, including CSDs 66025, 66070, 66020, 66140 for Montreal; 11061 for Edmonton; and 06016 for Calgary.

Average ambient pollutant concentrations were calculated using measurements from the available monitoring stations on an hour-by-hour basis. Then from these hourly measurements, 24 h daily averages were computed. Any day with less than 22 out of 24 possible hours of available information was excluded from the analysis. As multi-site hourly averages were computed even if measurements were only available from one site (a rare occurrence), 24-h average daily pollutant concentrations were available throughout the entire study period. Missing pollutant data (<1% of the total number of daily observations) were imputed using linear interpolation methods, providing daily pollutant data throughout the study period.

Live Births and IUGR

All live births in the respective areas of CSDs were abstracted from the Canada Live Birth Database maintained by Statistics Canada for the period from 1 January 1986 to 30 June 2000. These data have been previously validated for the Canadian Perinatal Surveillance System and related research projects (Fair and Cyr, 1993). Information about live births was derived from birth certificates, including date of birth, birth weight, gestational age, parity, birth order, maternal age, father's age, and residence. Gestational age was determined by the responsible obstetrician, based on available information including date of last menstrual period, the mother's estimate of the date of conception, and more recently on ultrasound procedures. Previous work has indicated that gestational age information in this database is reliable (Kramer et al., 2000). Maternal residence during pregnancy was recorded at the CSD level. All singleton term live births for the selected CSDs in which air pollution was monitored were used in the present study.

Data on ambient air pollutant concentrations in the three cities of study were available at the census subdivision level. Air pollution exposure levels from conception through delivery were determined by linkage with the environmental database, which includes average daily concentrations of both gaseous pollutants and fine particles. Dates of the air pollution records were matched temporally to the dates of birth and length of gestation. For each live birth, average air pollutant concentrations were thus calculated throughout the whole period, in each month (9 months) and trimester (first, second, and third) of pregnancy. Maternal exposures to ambient SO2, NO2, CO, O3, and PM2.5 were determined by arithmetic means of all daily measurements by all monitoring stations in the residential area of each pregnant woman.

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 2000 (Kramer, 2003; Liu et al., 2003). All singleton live births at 37–42 weeks of gestation were included in this study.

Associations between IUGR and ambient air pollution were examined by using multiple logistic regression analysis. The effects of a single pollutant by month of pregnancy and trimester of pregnancy were first examined. For PM2.5, the effect was only estimated by trimester of pregnancy because this pollutant was measured every 6 days only, and was not available for a larger number of days compared with the gaseous pollutants. To examine the effects of maternal exposure to multiple pollutants, we then fit a logistic regression model including all (individually) significant pollutants simultaneously. Odds ratios (ORs) and 95% confidence intervals (CIs) for IUGR in relation to exposure to pollution were calculated based on average daily concentrations of pollutants, after controlling for maternal age (<20, 20–24, 25–29, 30–34, and 35+ years), parity, infant sex, season of birth, city of residence (Calgary, Edmonton, and Montreal) and time period of birth (1986–1989, 1990–1993, 1994–1996, and 1997–2000).

Results

The arithmetic means and selected percentiles of the concentrations of the five pollutants of interest are presented in Table 1, both for daily average and daily 1-h maximum levels (the latter is not available for PM2.5), based on the combined data among stations across the three cities (Calgary, Edmonton, and Montreal). Both daily average and daily 1-h maximum measurements varied considerably. For example, the mean daily concentration of NO2 was 24.0 ppb, while the 25th and 95th percentiles were 17.5 ppb and 40.5 ppb, respectively. Four of the air pollutants (SO2, NO2, CO, and PM2.5) were positively correlated each other, while O3 was negatively associated with the other pollutants (P<0.0001, Table 2).

Table 1 Mean concentrations and selected percentiles of gaseous air pollutants in Calgary, Edmonton, and Montreal, Canada 1985–1999
Table 2 Pearson correlation coefficients among daily average concentrations of gaseous air pollutants in Calgary, Edmonton, and Montreal, Canada 1985–1999

Temporal variations in the mean concentrations of three selected gaseous air pollutants (NO2, CO, and SO2) and in IUGR in Calgary are depicted in Figure 1, where considerable seasonal variations are apparent for all three gaseous pollutants. There was a slight decline in the average concentrations of CO during the study period, whereas NO2 generally stabilized over time. The contemporaneous IUGR risk also varied appreciably during this period.

Figure 1
figure1

Variations in mean concentrations of air pollutants and IUGR (%) by month, Calgary, Canada, 1985–1999.

There were 386,202 singleton term live births between 1986 and 2000 in the CSDs in which monitoring stations were located. Overall, 10.9% of the live births were qualified as IUGR births. The risk of IUGR varied by season of birth, infant sex, maternal age, period of birth, and city of residence. For example, IUGR risks among young women were as high as 13.8% and 12.5% for mothers 20–24 and 25–29 years of age, respectively. In addition, IUGR risk for Calgary was highest (11.6%) among the cities of study (Table 3).

Table 3 Intrauterine Growth Retardation (IUGR) among Singleton Live Births Calgary, Edmonton and Montreal, Canada 1986–2000

In general, there were no significant differences in ORs between the adjusted and unadjusted models, thus the former are shown and interpreted as follows. The risk of IUGR associated with maternal exposure to SO2 was not elevated overall, and decreased slightly during the first 3 months of pregnancy (Figure 2). The risk of IUGR in relation to exposure to NO2 increased significantly throughout the entire period of pregnancy, particularly in the early and later periods of pregnancy. By the ninth month of pregnancy, the risk of IUGR increased by 14% for a 20.0 ppb increase in NO2 (Figure 3). An increased risk of IUGR among live births was also associated with maternal exposure to CO during pregnancy, with greater risks observed in the early and later periods of gestation. For example, a 1.0 ppm increase in the concentration of ambient CO was associated with an increased risk of IUGR of approximately 16% and 23% in the first month and the ninth month of pregnancy, respectively (Figure 4). However, no increase in the risk of IUGR in relation to exposure to O3 during pregnancy was noted (Figure 5).

Figure 2
figure2

Adjusted OR and 95% CI for IUGR, exposure to SO2 by month of pregnancy. Note: 1. Adjusted for maternal age, parity, infant sex, season of birth, and residence of city. 2. ORs were estimated based on an increase (3.0 ppb) of pollutant SO2.

Figure 3
figure3

Adjusted OR and 95% CI for IUGR, exposure to NO2 by month of pregnancy. Note: 1. Adjusted for maternal age, parity, infant sex, season of birth, and residence of city. 2. ORs were estimated based on an increase (20.0 ppb) of pollutant NO2.

Figure 4
figure4

Adjusted OR and 95% CI for IUGR, exposure to CO by month of pregnancy. Note: 1. Adjusted for maternal age, parity, infant sex, season of birth, and residence of city. 2. ORs were estimated based on an increase (1.0 ppb) of pollutant CO.

Figure 5
figure5

Adjusted OR and 95% CI for IUGR, exposure to O3 by month of pregnancy. Note: 1. Adjusted for maternal age, parity, infant sex, season of birth, and residence of city. 2. ORs were estimated based on an increase (15.0 ppb) of pollutant O3.

ORs were also calculated by trimester of pregnancy. The patterns in risks of IUGR for the four gaseous pollutants by trimester are consistent with those by month of pregnancy: maternal exposure to elevated NO2 and CO levels over the three trimesters of pregnancy was significantly associated with IUGR, while SO2 and O3 were not (Figure 6). IUGR was significantly associated with an increased PM2.5 exposure during pregnancy: specifically, the OR increased by an average of 6 percent per 10 μg/m3 increase in fine particulate matter over the three trimesters (Figure 6). Logistic regression modelling including all the above three (individually) significant pollutants (NO2, CO, and PM2.5) showed that the robustness was only observed for the association between IUGR and exposure to CO during the entire gestation, while effects of NO2 and PM2.5 were no longer observed (Figure 7).

Figure 6
figure6

Adjusted OR and 95% CI for IUGR, exposure to pollutants by trimester of pregnancy. Note: 1. Adjusted for maternal age, parity, infant sex, season of birth, and residence of city. 2. ORs were estimated based on an increase of individual pollutants (SO2 — 3.0 ppb, NO2 — 2.0 ppb, CO — 1.0 ppm, O3 — 15.0 ppb and PM2.5 — 10 μg/m3.

Figure 7
figure7

Adjusted OR and 95% CI for IUGR, exposure to multi-pollutants (NO2, CO, and O3) by trimester of pregnancy. Note: 1. Adjusted for maternal age, parity, infant sex, season of birth, and residence of city. 2. ORs were estimated based on increases of multiple pollutants (NO2 — 2.0 ppb, CO — 1.0 ppm and PM2.5 — 10 μg/m3.

Discussion

Growing evidence of adverse effects of air pollution on human health has raised concerns about possible effects on the developing fetus. Several recent epidemiological studies have reported associations between elevated levels of air pollutants (SO2, CO, NO2, particulate matter, and polycyclic aromatic hydrocarbons) and adverse pregnancy outcomes, such as low birth weight, preterm, and IUGR (Xu et al., 1995; Landgren, 1996; Wang et al., 1997; Dejmek et al., 1999; Parker et al., 2005). While the magnitude of these observed effects varied greatly by study, other studies have yielded non-significant results (Landgren, 1996; Smrcka and Leznarova, 1998). Results varied with the type of pollutant, pollutant concentration, period of pregnancy, and indicator of birth outcome.

Our data from three major Canadian cities showed that fetal growth restriction was positively associated with maternal exposure during pregnancy to the gaseous pollutants NO2 and CO and to fine particles, with the highest risks observed for exposures occurring early and late in gestation. While these three significant pollutants were presumed to be exposed simultaneously, CO was shown to have a particularly robust effect on fetal growth. Similar associations between air pollution and fetal growth restrictions were observed for maternal exposures estimated either by month or by trimester of pregnancy. The present findings are consistent with those in our previous report on the association between gaseous air pollutants and IUGR based on data from Vancouver (Liu et al., 2003), as well as those in studies conducted by other investigators (Dejmek et al., 1999; Bobak, 2000; Maroziene and Grazuleviciene, 2002; Parker et al., 2005).

The present study is one of the few large-scale studies of potential adverse effects of maternal exposure to ambient air pollution during pregnancy on fetal growth. Our study has several strengths. First, data used cover a large population across three major Canadian cities with an access to a publicly administered and funded health care system, including comparable prenatal and perinatal services. Second, gestational age and birth weight, on which determination of IUGR was based, are reliably recorded in the Canada Live Birth Database (Kramer et al., 2000), which affords the ability to adjust for several potential confounding factors for fetal growth, including maternal age, parity, and season and period of birth. Third, we have access to reliable measurements of daily SO2, NO2, CO, O3, and PM2.5 levels that have been used in previous studies of the association between air pollution and morbidity (Burnett et al., 1997, 2001; Yang et al., 2003) and mortality (Burnett et al., 2000) by members of our research team. Unfortunately, information on some known risk factors for fetal growth development, such as maternal race, education, cigarette smoking, caloric intake, alcohol consumption, paternal weight and height, and socioeconomic status was not available. However, these risk factors are likely to vary independently of changes in ambient pollutant levels, and therefore should not confound the associations between air pollution and fetal growth restrictions observed here (Rothman, 1993; Schwartz and Morris, 1995; Liu et al. 2004).

An important limitation of our study is misclassification of maternal exposure to air pollution due to ecological measurements of ambient pollutant concentrations. Our estimates of individual exposure to air pollution were based on average pollutant concentrations for residents living in the vicinity of monitoring stations located in specified geographic areas. Nonetheless, Janssen et al. (1998, 1999) argue that air pollution levels from outdoor monitoring stations can provide useful surrogates for personal exposure. As exposure misclassification due to use of fixed site ambient monitors rather than personal dosimeters is probably non-differential, it is possible that the effects of air pollution on birth outcomes reported in this study may have been underestimated (Rothman, 1993; Zeger et al., 2000; Mallick et al., 2002).

Fetal growth is influenced by maternal, placental, and fetal factors. The biological mechanisms by which air pollutants may influence the developing fetus remain largely unknown. Several mechanisms have been hypothesized, including maternal susceptibility to infection, oxidative stress, hematological factors such as blood viscosity, and the direct effect of specific pollutants on fetal development or on DNA and its transcription (Perera et al., 1998, 1999). Perera et al. (1998) found that fetal development was adversely associated with PAH-DNA adduct levels, and that transplacental exposure to PAHs in ambient air could compromise fetal development. Air pollution may affect maternal respiratory function or general health, which may in turn impair uteroplacental and umbilical blood flow, transplacental glucose, and total insulin, all of which are important determinants of fetal growth (Vorherr, 1982). Ambient air pollution or its effective constituents could be inhaled and absorbed into the maternal bloodstream, and subsequently interfere with nutritional development of the fetus. It is known that some related toxicants are able to cross the placenta and directly affect fetal development (Rutledge, 2000).

Previous studies have showed that NO2 can oxidize tissue components such as proteins and lipids, and suppress antioxidant protection systems. Exposure to NO2 during pregnancy is associated with an increased lipid peroxidation in the placenta, elevated postimplantation embryonic lethality, and disturbances of postnatal development (Tabacova et al., 1998). It has also been demonstrated that maternal exposure to NO2 can increase the risk of pregnancy complications as a consequence of initiation of the formation of cell-damaging lipid peroxides and a decrease in maternal antioxidant reserves (Tabacova et al., 1998). Moison et al. (1993) found that an increased lipid peroxidation of surfactants in maternal or fetal tissue compartments has been associated with preterm birth.

Exposure to CO during the third trimester was previously found to be associated with low birth weight (Ritz and Yu, 1999) and preterm birth (Ritz et al., 2002) in Southern California, and the North-Eastern United States (Maisonet et al., 2001). The risk of cardiac ventricular septal defects in fetuses has also been shown to be associated with an increased CO exposure in the second month of pregnancy in Southern California (Ritz et al., 2002). Several hypotheses have been advanced concerning the biological mechanisms by which such effects may be induced. First, exposure to low levels of ambient CO during pregnancy may result in tissue hypoxia by increasing maternal and fetal carboxyhaemoglobin concentrations and decreasing fetal O2 tensions or O2 carrying capacity (Longo, 1976). Second, CO may interfere with metabolic and transport functions of the placenta and concentrate more in the fetus than in its mother and consequently affect the fetus more severely than the mother with respect to oxygenation of tissues (Longo, 1976). Third, the fetus may be particularly susceptible to hypoxia following in utero exposure to CO, even if the maternal blood level of CO is non-toxic.

Ambient fine particles (PM2.5) are a complex mixture of different substances, many of which are toxic, including metals and organic matter such as polycyclic aromatic hydrocarbons (Dejmek et al., 2000). Maternal exposure to fine particles during pregnancy may result in adverse birth outcomes either by direct effects on the fetus through in utero exposure or indirectly as a consequence of maternal toxicity. Fine particles have been shown to be associated with a number of cardiovascular and respiratory outcomes in both adults and children (Janssen et al., 1999; Burnett et al., 2000), as well as effects on fetal growth and birth weight (Dejmek et al., 1999; Dejmek et al., 2000; Jedrychowski et al., 2004; Parker et al., 2005).

In conclusion, the present data confirm the adverse effects of ambient air pollution on pregnancy found in our previous study in Vancouver, and are consistent with other reports from China, Europe, the United States, and Korea. Specifically, our findings demonstrate that prenatal maternal exposure to CO, NO2, and PM2.5 is associated with adverse effects on the fetal growth. Although the mechanisms underlying these associations are not well understood, these results add to the emerging body of evidence that relatively low concentrations of ambient air pollutants present in urban centers are associated with adverse effects on fetal growth in populations experiencing diverse air pollution exposures.

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Acknowledgements

We are grateful to Environment Canada for air pollutant data and Statistics Canada for live birth data.

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Correspondence to Shiliang Liu.

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Liu, S., Krewski, D., Shi, Y. et al. Association between maternal exposure to ambient air pollutants during pregnancy and fetal growth restriction. J Expo Sci Environ Epidemiol 17, 426–432 (2007). https://doi.org/10.1038/sj.jes.7500503

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Keywords

  • air pollution
  • fetal growth restriction
  • pregnancy
  • risk assessment

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