Association between ambient particulate matter concentration and fetal growth restriction stratified by maternal employment

Fetal growth is assessed by comparing birthweight of the newborn with expected weight for the baby’s gestational age. Specifically, low birth weight (LBW, less than 2,500 g regardless of gestational age) [1] and small for gestational age (SGA, below the 10th percentile for the gestational age based on a birthweight-for-gestational-age measure in reference population) have been used as a proxy for perinatal health. Because LBW does not count for gestational age, the relationship between LBW and SGA differs by gestational term. For term births, given that 10th birthweight for 37 weeks of gestation is higher than 2,500 g, all LBW babies are SGA [2]. Being LBW or SGA is an important predictor of morbidity and mortality of newborns and infants and chronic diseases later in life [3, 4]. Proportion of LBW births including preterm ranges from 7.0% in high-income regions to 16.5% in low- and middle-income countries [1]. Prevalence of SGA births is approximately double the prevalence of LBW births globally [5].

Fetal growth restriction is mostly caused by utero-placental dysfunction leading to inadequate supply of nutrients and oxygen to support normal growth of the fetus [6, 7]. Female baby, firstborn, twins, congenital infection (e.g., malaria, HIV or syphilis), or obstetric complications such as hypertension are associated with retarded fetal growth and development, as well as the duration of pregnancy [8, 9]. Several environmental exposures during antenatal period are reported to be associated with higher risk of LBW. Living at high altitudes and exposure to recreational substance (e.g., alcohol, tobacco, or drug abuse) were also reported to be related with smaller fetal size [10, 11].

Among the physical environment, particulate matter (PM) air pollution is recognized as a risk factor for preterm birth and fetal grown disorders [12]. Previous animal and human studies have revealed that high PM exposure was associated with placental inflammatory reaction [13], abnormal trophoblast invasion [14], and reduced placental angiogenesis [15] which lead possible consequences for the impaired fetal growth. Still the underlying mechanism remains unclear [16, 17].

The estimates of term LBW risk for specific trimesters of pregnancy were not consistent [18‐20]. Previous systemic analyses revealed positive association between term LBW and ambient concentration of PM smaller than or equal to 10 and 2.5 μm in diameter (PM₁₀ and PM_2.5) exposed during the entire period of pregnancy which was not evident for the 1st or 2nd trimester [18, 20]. It has been attributed to different strategies for exposure assessment, variability of air pollution, and/or residual confounding [21‐23]. One of the potential factors that can result in inconsistent findings of air pollution and fatal grown restriction would be working status of mothers. Physical work demands and job stress in employed mothers were related with higher risk of LBW [24]. Longer time spent in transit among working mothers resulting in higher exposure to traffic-related air pollution and noise which is also related with less optimal fetal growth [25]. On the other hand, the actively employed are likely to have a more favorable health status possibly leading to lower risk of fatal growth restriction than general population at large [26]. In addition, there may be possible misclassification of exposure, given that air pollution exposure has been estimated based on mothers’ residential addresses in most epidemiological studies [27, 28].

Despite a potential influence of maternal employment, few studies investigated the role of mothers’ working status in the association between air pollution and fatal growth restriction at term. Common covariates included in many previous studies for adjustment were mother’s age, education, parity, prenatal care/health care coverage, race/ethnicity and the infant’s sex [20, 29‐31]. Several studies indicated effect modification in the association between air pollution and adverse birth outcomes by maternal age, smoking, pre-pregnancy BMI and socioeconomic status (SES) [32‐34].This study aimed to explore potential effect modification by employment of mothers in the association between PM air pollution exposed for different stages of pregnancy and fetal growth restriction. To confirm our findings, we used two outcomes, LBW and SGA, indicating more and less severe forms of growth restriction for term babies.

In our study population of 824,011 singleton term births, SGA and LBW comprised 11.2% (92,068) and 1.5% (12,764), respectively. The mean PM₁₀ concentrations of mothers during one year prior to birth, full pregnancy, the 1st, 2nd, and 3rd trimesters were 57.8 (standard deviation = 9.9), 57.3 (10.8), 58.2 (16.5), 57.2 (16.2), and 56.6 (16.6) μg/m³, respectively. PM_2.5 concentrations for births in 2008–2012 were 29.1 (6.7), 28.9 (7.0), 29.3 (8.7), 28.8 (8.5), and 28.4 (8.5) μg/m³. PM₁₀ concentrations for 1 year prior to birth were moderately correlated with those during the three trimesters (0.44 to 0.62), whereas the correlations of PM₁₀ concentrations between trimesters were weak (− 0.09 to 0.26) (Additional file 1: Table S2). In the simple regression of PM or fatal growth restriction on maternal employment, Maternal employment was associated with exposure (regression coefficients: -0.02, P < 0.001 for entire pregnancy PM₁₀ and − 0.02, P < 0.001 for entire pregnancy PM_2.5) and outcome (− 0.06, P < 0.001 for SGA and − 0.10, P < 0.001 for LBW) with adjustment for covariates.

During the study period from 2002 through 2012, mean birth weight decreased consistently (β = − 0.005, P < 0.001). The proportion of employed mothers increased from 23.6% in 2002 to 44.7% in 2012. Whereas percentage of LBW increased from 1.4% in 2002 to 1.7% in 2012 (P for trend < 0.001 for both), percentage of SGA was consistent over time (11.2 to 11.4%, P for trend = 0.880) (Fig. 1).

At the time of birth, 34.0% of mothers (279,856) were employed and 66.0% (544,155) were non-employed (Table 1). Proportions of SGA and LBW between employed and non-employed mothers were 12.7 and 12.8% and 1.5 and 1.6%, respectively. Although there was only 1% difference between the two groups, these differences were statistically significant due to the large size of population. SGA and LBW were more likely to occur in female babies in both employed and non-employed mothers. Employed mothers with SGA and LBW tended to have no previous pregnancy experience compared to non-employed mothers with SGA and LBW. Average residential concentrations for PM₁₀ and PM_2.5 were slightly higher in non-employed mothers than in employed mothers for all five gestational periods (Additional file 1: Figure S3).

ORs of SGA and LBW were generally higher in non-employed mothers than employed mothers (Table 2). ORs of SGA and LBW were close to null in employed mothers for all exposure periods. For non-employed mothers, 13.7 μg/m³ (IQR in the full pregnancy period) increase in PM₁₀ for one year before birth was associated with 2% increase in odds of SGA (OR = 1.02, 95% confidence intervals (CI): 1.00–1.04, P = 0.028). The positive association of PM₁₀ for the full pregnancy period and the 3rd trimester with SGA did not reach statistical significance. RERIs indicating additive interaction by maternal employment did not show statistical significance. ORs of LBW were also higher in non-employed mothers than employed mothers, but RERIs were not significant.

The positive association was not found when we used coarse exposure assessment applying citywide Seoul-mean concentration. ORs were lower both for SGA and LBW than those in our primary analysis using district-means and became negative for some exposure periods. Our findings were similar, when we applied mixed models to account for additional variability at the district group level (Additional file 1: Table S2 and S3). Increased odds for SGA per 13.7 μg/m³ increase of PM₁₀ during one year before birth in non-employed mothers remained significant.

For PM_2.5, we generally found consistent patterns to those for PM₁₀. However, most effect estimates gave null association for both employed and non-employed mothers (Table 3).

We observed positive associations between PM₁₀ concentrations during one year before birth and SGA at term only in non-employed mothers. This association was not evident in those employed. Although we reached different conclusions between employed and non-employed mothers, there was lack of evidence indicating additive interaction by maternal employment status in the association between air pollution and fetal growth restriction. This pattern was consistent but weak for LBW which is stricter definition of fetal growth restriction for term birth. This finding implies that the association between air pollution and fetal growth restriction can be close to null if we use more severe of fetal growth restriction. Based on the homogeneity in the effect estimates across maternal employment strata which is also one of the evidences of confounding [44], our finding indicates a possible role of maternal employment as a confounder in the association between air pollution and fetal growth restriction.

Although there is lack of evidence for maternal employment as an effect modifier, we generally found higher ORs in non-employed mothers than employed mothers. Average estimated concentrations of PM of their residential addresses were slightly higher in mothers without employment compared to those employed consistently across all five antenatal periods. As people living closer to major roads or pollutant-producing facilities were more likely to be at lower SES [45, 46], higher exposure estimates of PM in non-employed mothers may confirm generally lower SES for non-employed mothers than for employed mothers. However, this tendency of exposure to higher air pollution in more socioeconomically deprived group is not universal. In largely populated and congested cities such as Seoul, people may prefer living close to major roads that allow easy access to transportation. A recent study in Seoul showed that children with higher SES were found to be living closer to major roads [43]. As a proxy of social and individual characteristics, maternal employment or working during pregnancy would mean better or worse socioeconomic condition. The adverse health effect of air pollution could be stronger in the socioeconomically deprived people than their counterpart, possibly due to high air pollution exposure, nutritional deficiency, and/or limited access to health care [45]. Several studies found stronger association between air pollution and adverse birth outcomes for mothers living in deprived neighborhoods compared to those in affluent neighborhoods [47, 48], though this finding was not replicated in another study [49]. Considering potential hazard of working such as more work demands, job stress, and higher exposure to traffic-related air pollution, the average effect of lower PM exposure might have been blunted. Future studies should elucidate the pathways between air pollution, fetal growth restriction, and employment focusing on each possible factor.

Among all term singleton births of this study, the proportion of LBW was relatively low. Previous studies reported wide ranges of LBW rate across countries or regions within a country. Prevalence of LBW at term birth was as low as 3.4% in U.S. [50] and 3.0% in U.K. [51], whereas high prevalence was seen as 8.2% in Nepal and 10% in Ethiopia [52]. Across the different regions of U.K., the prevalence ranged widely from 2.6 to 4.0% [51]. In Japan, LBW was 2.7% in 1979 which increased to 5.3% in 2010 [53]. As we restricted our population to those living in Seoul, the capital city with best access to health care, the relatively lower rate of LBW in our study would result from easy healthcare access compared to mothers living in other areas [54]. This considerably low prevalence of LBW, representing a more severe outcome, in our population could have made it difficult to find an association of PM compared to studies that reported associations in other populations. In contrast, SGA, comprising around 10% of the population and regarded as less strict definition of LBW for term births in our study, yielded positive association in non-employed mothers consistent with those in previous studies. This finding suggests that SGA would be a practical measure for fetal birth restriction in the populations with extremely low LBW rate.

The magnitude of the relationship between PM₁₀ or PM_2.5 and LBW at term was lower in our study than in previous studies which employed population-based birth record data [55‐57]. In addition to lower LBW, this might be due to potential misclassification driven by the restricted address information in our data. [58]. We used district-averages of air pollution as individual exposures of mothers, given the limited data availability to district-level addresses. This limitation may have affected underestimation of risk estimates, although the urban background monitoring sites mostly located at the community-service centers in largely populated residential areas may well represent the exposure level of residents of the corresponding districts. A study of SGA and LBW using a birth cohort in Vancouver, Canada, showed that fine spatial-scale individual exposures based on full address information and individual exposure assessment approach yielded stronger associations than those based on crude exposures [59], Our finding of lower risk estimates using city-wide average concentrations than those using district-means also suggests the possibility of increasing risks when it is replaced by spatially refined individual exposures. Future studies using extended address information will allow us to assess the association with high validity.

We found negative associations between the 2nd trimester increase in PM₁₀ and LBW estimated by Seoul-mean concentrations in non-employed mothers. In general, ORs for the 1st and 2nd trimesters were also slightly lower than those for one year before and entire pregnancy. Considering the result of district-based analysis, this may be incidental finding due to multiple comparison and/or residual confounding effect by spatial variation of exposure by districts. This counter-intuitive association for Seoul-mean may support the value of district-mean as more precise exposure estimate compared to citywide mean.

There are other several limitations in this study. First, there is possible information bias because we did not verify mothers’ self-reported working status during pregnancy. Some of the mothers classified as employed might have taken maternity leave during pregnancy and some of the unemployed might have left their job just before birth. As a retrospective study of birth registry data, we could not assess the duration of employment during pregnancy for each mother. Future studies based on prospectively collected data could minimize this possible misclassification bias. Second, because we used the administrative data, some key individual confounders related to smoking intensity, previous pregnancy history, and type of LBW (constitutional or pathological, and severe or mild) were not available. As there were previous findings of associations between exposure to PM air pollution and smoking intensity, smoking might have confounded air pollution-related health effect [60]. Considering that the smoking rate of women in South Korea is only 5–8% [61], smoking rate in pregnant women would likely be lower and thus smoking would have a negligible impact on our results. Late-onset fetal growth restriction probably represents a more heterogeneous group with less characteristic histological changes [7]. If parts of LBW births are early-onset, exploring the association with 2nd or 3rd trimester PM would not be appropriate. As we included only term births, our LBW cases are presumed to be largely late-onset. Considering the potential heterogeneity in our LBW at term cases, future studies should subdivide the births into several groups by potential causes or severity and look at the association. Third, there can be misclassification bias in estimating maternal exposure based on residential address at the time of birth. According to previous report of a population-based sample cohort in Korea, proportion of relocation across district (gu) or province was 8–25% during the same period of our study period (2003–2012) [62]. Relocation rate for less than one year could be much smaller particularly in pregnant women. Fourth, maternal PM exposure based on district might have contributed to the general null finding. However, since temporal variability is much larger than spatial variability in daily averages of air pollution exposures in our data [63], the impact of exposure measurement error resulting from spatial misclassification may not be substantial. More refined individual exposure measure would improve the precision of effect estimates. Lastly, generalizability of the findings would be limited because mothers in our study are mostly residents in Seoul which less represent deprived socio-economic conditions which also contribute to poor fetal growth [64].

Exposure to high ambient PM air pollution during one year before birth tended to increase the risk of SGA at term in non-employed mothers living in Seoul, Korea. Despite potential difference due to mothers’ health status, socioeconomic condition, and exposure misclassification related to their employment status, there was no evidence of effect modification by maternal employment in the association between PM concentration and fetal growth restriction. Futures studies using refined metrics would be helpful to confirm this finding.