Nowadays, considerable literatures on epidemiology and clinical medicine has reported the association and adverse effects of ambient air pollution on adverse pregnancy outcomes (1, 2). Low birth weight (LBW), defined as weight at birth <2,500 g, is a major neonatal adverse outcome that is strongly related to infant mortality and even producing adverse effects on children's health in adulthood (3). Very low birth weight (VLBW) is defined as weight at birth <1,500 g (4). Many researchers have explored the association between maternal exposure to ambient air pollution and low birth weight or preterm birth (5–8). Among these significant results, it has been suggested ambient air pollution may increase the risk of low birth weight. However, few studies have yet specifically focused on the association between ambient air pollution and very low birth weight. Probably because of the low incidence of VLBW, these studies can be limited by sample size (9). However, further specific research is still essential to explore the ongoing risk of air pollutants on very low birth weight.

Many scholars in China have studied and published the relationship between exposure to air pollutants and birth outcomes (10–12); however, the association between exposure to ambient air pollutants and very low birth weight has been rarely reported. Chongqing is the largest municipality in China and is located along the Yangtze River. It is a huge industrial city with 40 districts and a permanent population of 31 million. From 2014 to the present, the air quality of Chongqing has greatly improved through years of efforts by local governments. These special air quality change trends in Chongqing offer a unique research environment for studying the effects of air pollution exposure on birth outcomes that is quite different from the environments found in Europe, America, Africa, and other countries and regions.

Given that few studies have explored the potential relationship between ambient air pollution and VLBW, this study sought to estimate the association between maternal exposure to ambient air pollutants (PM_2.5, PM₁₀, SO₂, O₃, NO₂, and CO) and the risk of VLBW in Chongqing, China. In doing so, it focused on the sensitive exposure time window of air pollutants for VLBW with a large sample size and also via precise individual exposure assessment.

In this study, we used a generalized additive model (GAM) to analyze the exposure-response association of air pollutants on the risk of very low birth weight. It revealed that maternal exposure to PM_2.5 and PM₁₀ in the first trimester of pregnancy was associated with increased risk of VLBW. In addition, a positive association with VLBW was linked to NO₂ exposure during the first and second trimesters of pregnancy. These results are a valuable supplement to the few previous association researches for maternal exposure to ambient air pollution and the risk of very low birth weight (19). Especially in China, such similarly related research is quite rare.

There are a lot of studies that have demonstrated that maternal exposure to fine ambient air pollution increases the risk of preterm birth and low birth weight (2, 20–22). Ghosh et al. (23) conducted a meta-regression and analysis related association of PM_2.5 pollution and adverse perinatal outcomes for 204 countries and territories. Its pooled estimates indicated 22 grams (95% UI: 12, 32) lower birth weight, and 11% greater risk of LBW (1.11, 95% UI: 1.07, 1.16) per 10 μg/m³ increment in ambient PM_2.5. Globally, an estimated 15.6% (95% UI: 15.6, 15.7) of all LBW infants were attributable to total PM_2.5 in 2019. A meta-analysis by Bekkar et al. (2) reported that positive associations between exposure to air pollution and LBW were found across all US geographic regions. Exposure to PM_2.5 or ozone was associated with an increased risk of LBW in 25 of 29 studies (86%). Niu et al. (24) carried out a cohort study in Los Angeles, California, and found early pregnancy to mid-pregnancy exposures to PM_2.5, PM₁₀, and NO₂ were associated with lower birth weight. Their result is highly consistent with our research. Still, some studies have suggested that the sensitive exposure period for NO₂ is throughout all of a pregnancy (12, 25). Although the stages of a sensitive window to air pollution exposure varied in the different literatures, the basic consensus is that maternal exposure to air pollution, particularly during the critical windows of pregnancy, significantly do increases the risk of LBW.

Over the past decade, numerous studies have been published on air pollutant exposure and low birth weight in China (12, 26, 27). The study by Yuan et al. (28) reported critical windows of gestational exposure to PM_2.5 were identified as 31st−34th gestational weeks for reduced birth weight, and 38th−42nd weeks for LBW, respectively. Liang et al. (29) conducted a study on 1,455,026 singleton births during 2014–2017 in nine cities of Guangdong, China, and found PM_2.5 was significantly associated with LBW in every trimester of pregnancy stage, with stronger effects on the first and third trimester for each 10 μg/m³ increase in PM_2.5 concentrations. The results of a cohort study performed in Changsha, China, further showed term LBW was significantly associated with exposure to ambient PM during pregnancy, with OR = 1.47 (95% CI: 1.00, 2.14) for per IQR increase after adjustment for the covariates and home environmental factors (3). Specifically, the authors identified a significant association in the early phase of pregnancy including conception month and the first trimester. Zou et al. (26) performed a retrospective observational study on 2,527 preschoolers in Shanghai, China, and indicated that exposure to NO₂ was a risk factor for LBW and T-LBW. The difference when compared to this study is that effects of exposures could be greater during early periods than during later periods of gestation.

Related studies have suggested different sensitive windows worldwide. The differences may be due to study design, air pollution level, regional disparity, components of PM, and sample size, etc. However, most of the sensitive time windows are concentrated in the first trimester. For example, in a study of seven states in the U.S. (30) for associations between maternal exposure to PM_2.5 and the risk of LBW, showed a statistically significant correlation during the entire stage of pregnancy and all specific trimesters in New York, for the full gestation, the first and third trimesters in Minnesota, and for the entire pregnancy and first trimester in New Jersey.

The current study focused on associations between maternal exposure to ambient air pollution and VLBW, which was unique to our study. We observed that the first trimester may be the sensitive window for PM_2.5 and PM₁₀, consistent with a few previous studies on LBW (29, 31). Meanwhile, the first and second trimesters constituted the susceptible exposure window for NO₂. On the other hand, a few studies have shown different staging methods with consequently different results. For example, several researchers divided pregnancy into months or weeks to evaluate the relationship between exposure and outcomes. Our large sample size and the exposure evaluation mode of individual assessment allowed us to reliably estimate the associations. However, the effect of exposure sensitive time does need to be further explored, and personal exposure measurements need to be more widely utilized.

Few studies have evaluated the disease burdens of PM exposure on LBW worldwide. We found 17.89% (95% CI: 10.5%, 24.26%) of VLBW was attributable to a higher PM_2.5 exposure (PM_2.5 ≥ 35 μg/m³) relative to the Chinese Class I Standard after adjusting for covariates. The ARP of PM₁₀ for VLBW was 36.81% (95% CI: 25.69%, 46.01%), calculated for PM₁₀ exposure concentration higher than 50 μg/m³. These results were statistically sufficient to demonstrate the harmful effects of high PM exposure on very low birth weight. Liu et al. (4) estimated the LBW burden caused by outdoor PM_2.5 exposure in Shanghai, China, in 2013, according to Shanghai's Class I Standard (15 μg/m³). Those results showed that 23.36% (95%CI: 3.86%, 40.02%) of LBW could be attributed to PM_2.5 exposure. Our results provided a particular estimate of attribution analysis of PM exposure on VLBW in China.

There are several possible biologic mechanisms through which ambient air pollution can cause LBW (32, 33). Yet, no studies have specifically focused on the mechanisms that cause very low birth weight. Current research reports mainly include systemic oxidative stress and inflammatory response that induces premature birth; maternal endocrine disorder; the release of inflammatory factors and entering into the placenta; direct toxicity to the placenta or fetus, etc. (7, 34, 35). Studies on the effects of different components of PM_2.5 on birth outcomes have shown that the component elements of carbon, calcium, copper, nickel, titanium, zinc, aluminum, and antimony are associated with low birth weight (36). The toxicological effects of metal components are inferred as well, mainly by increasing oxidative stress (37). The biological mechanisms related to VLBW, however, need to be further investigated and explored in the future.

This study did have some limitations. First, due to the large sample size, it was difficult to obtain comprehensive and complete information. Some potential risk factors were not considered in this study, such as maternal nutritional status, pregnancy complications, and life behaviors, genetic information, etc. These factors may have confounded the association results. However, previous similar studies have found little change in efficacy estimates based on whether or not these factors are adjusted (33). Second, as with most related studies, exposure measurement errors were inevitable. The type of area, proximity of green/blue area and the “quality” of neighborhood can also be important in assessment of exposure level. However, due to the absence of these variables in the original data, we did not conduct further analysis about this. The proximity principle from nearby air quality monitoring stations was applied to serve as the estimates of individual air pollution exposure. Moreover, we limited the exposure concentration assessment to within 10 km of the monitoring station. We did not assess the movement of pregnant women during pregnancy. Fortunately, the large sample size used for this study balanced that situation to some extent. Third, the composition of PM is complex, and that composition was not obtained and analyzed in this study. It is possible that different pollutant components can have inconsistent effects on VLBW. The risk effects caused by specific components will be explored in subsequent relevant studies.

In conclusion, this study provides special evidence on the associations between air pollutant exposure during pregnancy and VLBW using a retrospective birth cohort study. We estimated that maternal exposure to high levels of PM_2.5, PM₁₀, NO₂, and O₃ during pregnancy may increase the risk of very low birth weight. The sensitive period for that exposure window is likely to be the first and second trimesters. Reducing the risk of early maternal exposure to ambient air pollution is thus necessary for pregnant women.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

WZ, XM, JC, and XZ: conceptualization. XM and JC: methodology. YY: software. YY and YH: validation. ZH: formal analysis. XM and HC: investigation. WZ: resources, project administration, and funding acquisition. HC and YL: data curation. WZ and XM: writing—original draft preparation. JC and XZ: writing—review and editing. XM and ZH: visualization. JC: supervision. All authors have read and agreed to the published version of the manuscript.