Key Points

Question Is the concentration of airborne particulate matter with a median diameter of 1 μm or less (PM 1 ) associated with the risk of preterm birth in China?

Findings This national cohort study of more than 1.3 million births found that increases in PM 1 concentration of 10 μg/m3 during the entire pregnancy as well as at each trimester were significantly associated with an increased risk of preterm birth.

Meaning Exposure to PM 1 air pollution is associated with an increased risk of preterm birth, and control measures to reduce PM 1 air pollution may lower the future incidence of preterm birth.

Abstract

Importance Airborne particulate matter pollution has been associated with preterm birth (PTB) in some studies. However, most of these studies assessed only populations living near monitoring stations, and the association of airborne particulate matter having a median diameter of 1 μm or less (PM 1 ) with PTB has not been studied.

Objective To evaluate whether PM 1 concentrations are associated with the risk of PTB.

Design, Setting, and Participants This national cohort study used National Free Preconception Health Examination Project data collected in 324 of 344 prefecture-level cities from 30 provinces of mainland China. In total, 1 300 342 healthy singleton pregnancies were included from women who were in labor from December 1, 2013, through November 30, 2014. Data analysis was conducted between December 1, 2016, and April 1, 2017.

Exposures Predicted weekly PM 1 concentration data collected using satellite remote sensing, meteorologic, and land use information matched with the home addresses of pregnant women.

Main Outcomes and Measures Preterm birth (<37 gestational weeks). Gestational age was assessed using the time since the first day of the last menstrual period. Cox proportional hazards regression analysis was used to examine the associations between trimester-specific PM 1 concentrations and PTB after controlling for temperature, seasonality, spatial variation, and individual covariates.

Results Of the 1 300 342 singleton live births at the gestational age of 20 to 45 weeks included in this study, 104 585 (8.0%) were preterm. In fully adjusted models, a PM 1 concentration increase of 10 μg/m3 over the entire pregnancy was significantly associated with increased risk of PTB (hazard ratio [HR], 1.09; 95% CI, 1.09-1.10), very PTB as defined as gestational age from 28 through 31 weeks (HR, 1.20; 95% CI, 1.18-1.23), and extremely PTB as defined as 20 through 27 weeks’ gestation (HR, 1.29; 95% CI, 1.25-1.34). Pregnant women who were older (30-50 years) at conception (HR, 1.13; 95% CI, 1.11-1.14), were overweight before pregnancy (HR, 1.13; 95% CI, 1.11-1.15), had a rural household registration (HR, 1.09; 95% CI, 1.09-1.10), worked as farmers (HR, 1.10; 95% CI, 1.09-1.11), and conceived in autumn (HR, 1.48; 95% CI, 1.46-1.50) appeared to be more sensitive to PM 1 exposure than their counterparts.

Conclusions and Relevance Results from this national cohort study examining more than 1.3 million births indicated that exposure to PM 1 air pollution was associated with an increased risk of PTB in China. These findings will provide evidence to inform future research studies, public health interventions, and environmental policies.

Introduction

The World Health Organization reported in 2010 that there were 12.9 million preterm births (PTBs) per year worldwide (9.6% of total births), and PTB has become the leading cause of perinatal mortality and morbidity.1,2 Preterm birth can lead to not only neonatal mortality but also lifelong disabilities that negatively contribute to a range of pulmonary, circulatory, and neurologic outcomes, resulting in $26.2 billion in medical costs per year in the United States alone.3 The etiology of PTB remains unclear, although biological, psychological, social, and environmental factors are thought to play significant roles.

An increasing number of studies have examined the association between particulate matter air pollution and PTB, including studies in Australia, Canada, England, the United States, South Korea, Spain, and China.4-11 However, those previous studies have primarily focused on airborne particulate matter with diameters of 10 μm (PM 10 ) or less or of 2.5 μm (PM 2.5 ) and greater. Compared with PM 2.5 or PM 10 , PM 1 (ie, an airborne particulate diameter of 1.0 μm or less) has a higher surface area to mass ratio and can reach the lung alveoli. Particulate matter of this size has been shown to activate multiple pathophysiological processes, which may in turn contribute to PTB.12,13 Although PM 1 contributes to nearly 80% of PM 2.5 ,14 no epidemiological study has examined the association between PM 1 and PTB to our knowledge. Thus, there is a critical need to investigate the association between PM 1 exposure during pregnancy and PTB.

In addition, even in those studies examining PM 2.5 and PM 10 , variability in the exposure estimates and analysis methods has led to inconsistent results. Because most of the studies have been conducted in developed countries with relatively lower levels of PM air pollution and smaller exposure ranges,4 the power to generate robust results may have been restricted. Furthermore, most studies have been based on birth record data, meaning that the studies were unable to take into account the mother’s socioeconomic and behavioral characteristics, which can contribute to the estimates of the effects of PM air pollution.15 Most previous studies have treated PTB as a binary variable instead of using multiple categories, raising some limitations when trying to associate PTB with each degree of prematurity. The resulting gap in evidence limits the formulation of effective policies regulating air pollution, especially in areas with a wide range of PM pollution.

In the present study, we obtained estimated concentrations of PM 1 by using satellite-based aerosol optical depth data, land use information, and meteorologic data and applied these to a national birth cohort across mainland China that included both urban and rural areas. The primary objective was to evaluate whether PM 1 pollution levels were associated with the risk of PTB in a cohort of 1 300 342 births in China from December 1, 2013, to November 30, 2014. We also aimed to identify subgroups of pregnant women vulnerable to PM 1 .

Methods

Study Design and Participants

Data for this national cohort study were extracted from the National Free Preconception Health Examination Project (NFPHEP), which was launched by the Chinese National Health and Family Planning Commission and Ministry of Finance in 2010 to provide free preconception health examinations and follow-up of pregnancy outcomes for couples of childbearing age throughout China. The detailed study design, organization, and implementation have been described elsewhere.16 We collected NFPHEP database data regarding the preconception examination, early gestation follow-up, and postpartum follow-up for all of the 1 535 545 nulliparous women who were in labor from December 1, 2013, through November 30, 2014. A flowchart (eFigure 1 in the Supplement) of the exclusion criteria for the birth cohort is provided in the Supplement (see eTable 1 in the Supplement for additional information on PTB rates). The final analyses included 1 300 342 singleton live births and was conducted between December 1, 2016, and April 1, 2017. The institutional review board of the National Research Institute for Family Planning, Beijing, China, approved this study. All participants provided written informed consent.

Outcome Definition

As recommended by the World Health Organization, PTB was defined as a gestational age from 20 through 36 completed weeks. We also categorized very PTB as a gestational age from 28 through 31 weeks and extremely PTB as 20 through 27 weeks. The time since the first day of the last menstrual period was used to assess gestational age. Women’s responses to inquiries about the date were recorded during the early gestation follow-up visit (conducted no later than 12 weeks after conception) by an obstetrician. After delivery, each woman was asked again about the date of the last menstrual period, after which gestational age was determined at the postpartum follow-up visit (conducted no later than 6 weeks after delivery).

Exposure Assessment

Weekly PM 1 concentrations were predicted at a 0.1° × 0.1° spatial resolution for mainland China during the research period by using satellite remote sensing, meteorologic, and land use information (see the eAppendix in the Supplement for more detailed information).17 Each woman’s address information at the township level was collected during the preconception examination, early gestation follow-up, and postpartum follow-up records. The 3 addresses were compared, and those women who moved during pregnancy were excluded. In total, 24 444 township-level locations were geocoded, including both urban and rural areas (41 636 township-level units existed in China during the study period). Each woman’s address information was geocoded into longitude and latitude and matched to the centroid of the nearest 0.1° × 0.1° grid cell location of predicted PM 1 . Trimester-specific mean PM 1 concentrations were calculated using the weekly concentration. The data were categorized as trimester 1 (1-13 weeks’ gestation), trimester 2 (14-26 weeks’ gestation), trimester 3 (27 weeks to delivery), and the entire pregnancy (see eTable 2 in the Supplement for additional information).

Statistical Analysis

Cox proportional hazards regression analyses were conducted by using generalized additive mixed models to estimate the association of trimester-specific PM 1 exposure with PTB.15 Gestational age was fitted as the time scale, and the event was defined as PTB (medically induced labor data were removed from the analysis). Trimester-specific PM 1 levels were fitted as time-independent variables. A literature review was conducted, and a directed acyclic graph was used to create a least biased estimate of the association.1,10,18 The data in the model were adjusted for the following individual variables: maternal age from 16 to 50 years by 5-year intervals; household registration19 (rural, urban); completed educational level (primary school or below, junior high school, senior high school, or college or higher); occupation (farmers, workers, or others); body mass index calculated as the weight in kilograms divided by height in meters squared (≤18.5, 18.6-23.9, or ≥24); organic solvent, heavy metal, or pesticide exposure (yes, no); alcohol consumption and cigarette smoking of mother or partner (still, quit, or never); mode of delivery (vaginal, cesarean); sex of the neonate (male, female); and season of conception (summer, June through August; fall, September through November; winter, December through February; or spring, March through May). A spline with 4 df was used to control for trimester-specific mean temperature.20 A random contribution of province was fitted to control for potential spatial variation.15 Only PM 1 and the random contribution of province were included in the crude models. All the aforementioned covariables were then used to build the adjusted models. The restricted maximum likelihood method was used to fit the models, and hazard ratios (HRs) associated with a 10-μg/m3 increase in PM 1 were reported.

Trimester-specific associations between very PTB, extremely PTB, and exposure were also assessed using the same approach. A potential association of dose was explored by fitting PM 1 as a spline function with 4 df in the models. The exposures during the entire pregnancy were categorized into 4 quartiles, and the HRs for each higher exposure group compared with the lowest exposure group were reported. In addition, because previous studies have shown that the socioeconomic status of women and the season of conception can modify the effects of PM pollution,10,20,21 subgroup analyses were conducted to assess which subgroups were associated with increased risk of PTB.

Sensitivity analyses were conducted by fitting a random contribution of city. A single model adjusted for exposures during each trimester was created as a sensitivity analysis for trimester-specific contributions. All analyses were performed using R, version 3.3.3 (R Core Team). All statistical tests were 2-sided, and P values <.05 were considered statistically significant.

Results

In total, 1 300 342 singleton live births at the gestational ages of 20 to 45 weeks were included in this study that covered 324 of 344 prefecture-level cities from the 30 provinces in mainland China (eFigure 2 in the Supplement). Among the live births, 104 585 (8.0%) were PTBs (eTable 3 in the Supplement). The demographic profiles of women with preterm deliveries differed from those with term deliveries (Table 1). Women with preterm deliveries were more likely to be younger than 20 years at conception (11.0%), come from rural areas (8.1%), have primary school or below educational attainment (9.1%), and be farmers (8.3%). Women who were overweight before their pregnancy (9.1%), smoked cigarettes (9.1%) or consumed alcohol after conception (8.6%), underwent cesarean delivery (8.3%), delivered a boy (8.4%), or conceived in winter (9.1%) were more likely to deliver preterm.

The median PM 1 exposure over the entire pregnancy for all mothers was 46.0 μg/m3 with a wide interquartile range (14.3-127.6 μg/m3) (eTable 4 in the Supplement). Figure 1 shows the distribution of quartered mean PM 1 exposure over the entire pregnancy for each prefecture-level city in mainland China. We found that women living in the Beijing, Tianjin, and Hebei regions, the Yangtze River delta, the Sichuan Basin, and the Pearl River delta experienced relatively high PM 1 exposure (>52.7 μg/m3) over the entire pregnancy.

Table 2 provides the crude and adjusted HRs (and 95% CIs) of PTB associated with maternal exposure to PM 1 . In the crude models, we found that an increase in PM 1 exposure in each trimester and over the entire pregnancy was significantly associated with an increased risk of PTB. In the adjusted analyses, a PM 1 exposure increase of 10 μg/m3 in trimester 1 (HR, 1.07; 95% CI, 1.06-1.07), trimester 2 (HR, 1.10; 95% CI, 1.09-1.10), trimester 3 (HR, 1.04; 95% CI, 1.03-1.04), and over the entire pregnancy (HR, 1.09; 95% CI, 1.09-1.10) was significantly associated with an increased risk of PTB. The risks associated with PM 1 for very and extremely PTBs were higher than those for PTB. For very PTB, an increased PM 1 exposure of 10 μg/m3 over the entire pregnancy provided an HR of 1.20 (95% CI, 1.18-1.23), reaching 1.29 (95% CI, 1.25-1.34) for extremely PTB. The HRs associated with PM 1 exposure during the first and second trimester were greater than those of the third trimester.

After fitting the contribution of PM 1 exposure over the entire pregnancy as a spline function, the association between PM 1 exposure and risk of PTB was log linear (eFigure 3 in the Supplement). When we compared the risk of PTB associated with the categorized PM 1 exposure, we found that mothers in the highest exposure group (group 4, >52.7 μg/m3) had a higher risk of PTB (HR, 1.36; 95% CI, 1.33-1.39) than mothers in the lowest exposure group (group 1, <38.4 μg/m3) (Figure 2).

Figure 3 summarizes the associations between PM 1 exposure during the entire pregnancy and PTB stratified by maternal age, household registration, educational level, occupation, prepregnancy body mass index, and season of conception. Mothers who were older (30-50 years) at conception (HR, 1.13; 95% CI, 1.11-1.14), were overweight before pregnancy (HR, 1.13; 95% CI, 1.11-1.15), resided in rural areas (HR, 1.09; 95% CI, 1.09-1.10), worked as farmers (HR, 1.10; 95% CI, 1.09-1.11), or conceived in autumn (HR, 1.48; 95% CI, 1.46-1.50) had a higher risk of PTB associated with PM 1 exposure.

When we conducted sensitivity analyses by fitting the random contribution of city or creating a single model adjusted for exposure during each trimester, the results did not change (eTables 5 and 6 in the Supplement).

Discussion

The present cohort study of 1.3 million births in China from December 1, 2013, through November 30, 2014, provides compelling evidence that exposure to PM 1 air pollution is associated with increased risk of PTB. To our knowledge, no study has reported associations between PM 1 and PTB, very PTB, or extremely PTB. However, some studies have reported positive associations between PM 2.5 , PM 10 , and suspended particulates and the risk of PTB.8,10 Two national-level studies also used estimated or satellite-based estimates of PM 2.5 exposures to examine pregnancy outcomes, although their results were inconsistent. Stieb et al5 reported negative associations between satellite-derived PM 2.5 and PTB in Canada for an unadjusted model (odds ratio [OR], 0.96; 95% CI, 0.93-0.98) and a model adjusted for the maternal demographic characteristics and socioeconomic status (OR, 0.96; 95% CI, 0.93-0.99). Fleischer et al4 found that PM 2.5 was not associated with PTB when using a global sample, but the highest quartile of exposure in China was associated with PTB. This result indicates that the difference in exposure range could be a reason for the inconsistent results. In addition, some studies conducted in small areas (eg, at the city level) have also reported positive associations between PTB and PM 2.5 or PM 10 based on data from Asian populations.6,9,11

A previous study reported that PM 1 contributed to nearly 80% of PM 2.5 in China,14 and PM 1 and PM 2.5 have similar components. But few studies worldwide have focused on airborne PM 1 owing to the unavailability of air monitoring data. Thus, few studies have estimated the health effects of PM 1 . Previous studies examining PM 2.5 have suggested that it results in inflammation and oxidative stress.12,22 However, another previous study23 has indicated that inflammation may be related to the creation of reactive oxygen species. Reactive oxygen species can lead to DNA damage, cell damage, irreversible protein modifications, disruption of cellular processes, or alterations in cellular signaling.23 Whether these alterations would lead to PTB is not clear, but they may disrupt normal gestational processes. Studies have reported that the mean concentration of PM 1 in Australia is 16 μg/m3, in Athens is 18.5 μg/m3, and in Milan is 16.4 μg/m3, which are lower than the PM 1 exposure in our study.21,24,25 Although, to our knowledge, no study to date has investigated the association between PM 1 exposure and pregnancy outcomes, the present study found significant positive associations between PM 1 exposure at each trimester as well as for the entire pregnancy and PTB. This evidence can be used to inform future research studies, public health interventions, and environmental policies.

The present study showed that mothers who conceived in the autumn appeared to be more sensitive to PM 1 exposure than those who conceived in other seasons. A study in China reported a higher incidence of PTB in women who conceived in the autumn.26 The reason for this finding may be that some women engage in more outdoor activities in autumn, for example, farmers tend to their harvest during this season.5,27,28 In addition, we found that mothers from rural areas who were farmers appeared to be particularly sensitive to PM 1 exposure. Their lower socioeconomic status, excess exposure due to outdoor work, and shortage of protective measures (eg, use of a mask or air purifier and building design) could be reasons for the apparent enhanced risk.10,29 Regarding educational attainment, we found that pregnant women with a high school educational level appeared to be more sensitive to PM 1 exposure than those with a college educational level, which may also be explained by their socioeconomic status.10,29

Our study has important clinical and public health implications. Preterm birth not only is the leading cause of death throughout the world for neonates, infants, and children younger than 5 years30,31 but also has long-term consequences. Numerous studies have shown that individuals born prematurely can have lifelong health problems in multiple organs or systems, including asthma and metabolic disorders, causing tremendous strain on families and the medical system and resulting in enormous annual medical costs worldwide.32,33 In the present study, we found an increased PTB risk of 9% associated with an increase in PM 1 concentration of 10 μg/m3 over the entire pregnancy. Compared with less polluted areas (PM 1 <38.4 μg/m3), an increased PTB risk of 36% was found in areas with higher levels of air pollution (PM 1 >52.7 μg/m3) in China. To our knowledge, the present air pollution standards in both the United States and China do not include regulations for PM 1 ; thus, there is an urgent need to improve these related policies. Effective strategies, such as improving indoor air quality or wearing a mask outdoors, should be considered in protecting mothers from the risks associated with PM pollution.

Strengths and Limitations

Our study had many strengths. First, it included a very large sample size (>1.3 million mothers), which is important for generating robust findings. Second, the satellite-based exposure estimates used in the present study allowed us to include rural areas. Third, exposure was assessed based on home addresses recorded from preconception, early gestation follow-up, and postpartum follow-up records, which minimized potential exposure misclassification resulting from residential mobility. By contrast, most previous studies have used residence at birth to assign exposure for the entire pregnancy. Finally, because this was a prospective cohort study, we minimized recall bias for the dates of the last menstrual period and birth, which helped ensure the accuracies of gestational age and PTB assessments.

The study also had several limitations. Although we used a satellite-based comprehensive model and assigned exposures according to the mothers’ addresses at the township level, there could have been misclassification of the exposure. The pollutant levels at microenvironmental levels (eg, indoor, outdoor, or associated with commuting) or maternal activity patterns may have contributed to a misclassification. In addition, specific components and their proportions could not be considered separately but rather were grouped as PM 1 . The specific components might have had different chemical structures and might be associated with different health concerns. Future studies are needed to investigate PM components and their sources.

Conclusions

Exposure to PM 1 air pollution during pregnancy was associated with an increased risk of PTB. The mothers who were older at conception, were overweight before pregnancy, were registered as a rural household, worked as farmers, or conceived in autumn had a greater risk of PTB associated with PM 1 exposure. Further studies to examine the mechanisms accounting for increased vulnerability to PM 1 are warranted. Public policies and guidelines should be improved to protect pregnant women from risks associated with PM 1 air pollution.

Back to top Article Information

Corresponding Authors: Hai-Jun Wang, PhD, Department of Maternal and Child Health, School of Public Health, Peking University, No. 38 Xueyuan Rd, Beijing 100191, China (whjun1@bjmu.edu.cn) and Xu Ma, MS, National Research Institute for Family Planning, No. 12 Dahuishi Rd, Beijing 100081, China (nfpcc_ma@163.com).

Accepted for Publication: October 25, 2017.

Correction: This article was corrected on March 5, 2018, to correct the degree for Qin Li from PhD to MMSc in the Byline, revise how Mr Li is addressed in the Author Contributions and Funding/Support sections, and replace the maps of China in Figure 1 as well as eFigure 2 in the Supplement to fix a portion of the country’s western border.

Published Online: January 2, 2018. doi:10.1001/jamapediatrics.2017.4872

Author Contributions: Drs Y.-y. Wang and Guo and Mr Q. Li contributed equally and are considered co–first authors; Dr H.-J. Wang and Prof Ma contributed equally, had full access to all of the study data, and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Y.-y. Wang, Q. Li, Guo, H.-J. Wang, Ma.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Y.-y. Wang, Q. Li, Guo.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Y.-y. Wang, Q. Li, Guo, Zhou, X. Wang, Q. Wang, Shen, Yiping Zhang, Yan, Ya Zhang, H. Zhang, S. Li, Chen, Zhao, He, Yang, Xu, Y. Wang, Peng.

Study supervision: H.-J. Wang, Ma.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Y.-y. Wang and Prof Ma are supported by grants 2016YFC1000300 and 2016YFC1000307 from the National Key Research and Development Program. Mr Q. Li and Dr H.-J. Wang are supported by grants 81573170 from the National Natural Science Foundation of China and 11-064 from the China Medical Board. Dr Guo is supported by Career Development Fellowship APP1107107 from the Australian National Health and Medical Research Council (NHMRC). Dr S. Li is supported by Early Career Fellowship APP1109193 from the Australian NHMRC and seed grant APP1030259 from the Centre of Research Excellence–Centre for Air Quality and Health Research and Evaluation.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Tami R. Bartell, MPH, the Mary Ann & J. Milburn Smith Child Health Research, Outreach, and Advocacy Center, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, contributed to revising an early draft of the manuscript. Ms Bartell was not financially compensated. We thank the health professionals in 30 provinces across China for their assistance with this National Free Preconception Health Examination Project.