Abstract
To examine associations between early-pregnancy exposure to ambient air pollutants and spontaneous abortion (SA), identify lag windows using distributed lag non-linear models (DLNM), and explore the potential mechanisms via network toxicology. A hospital-based case-control study was conducted in Changzhi, Shanxi Province. Individual daily exposures were estimated using inverse distance weighting (IDW) based on residential geocoding and monitoring data. Multivariable logistic regression models were adjusted for BMI, gestational age, gravidity, and parity. DLNM were applied to pollutants showing statistical significance in the logistic model. Network toxicology was used to identify overlapping targets, construct PPI networks, and perform GO/KEGG enrichment analyses. O₃ Q3 (vs. Q1) was inversely associated with SA (OR = 0.42, 95% CI: 0.211–0.824). SO₂ showed positive gradient associations (Q3 vs. Q1: OR = 2.124, 95% CI: 1.068–4.291; Q4 vs. Q1: OR = 2.992, 95% CI: 1.536–5.946). DLNM suggested a lag-dependent SO₂ effect, peaking at lag 28 days (OR = 1.242, 95% CI: 1.0077–1.5363), with a significant association observed during lag 22–28 days, whereas O₃ displayed weak and inconsistent lag patterns. Network toxicology highlighted inflammation/immune-related pathways (e.g., Toll-like receptor and IL-17 signaling). SO₂ exposure was associated with increased SA risk with a more evident late-lag effect, while the inverse association for O₃ should be interpreted cautiously. Inflammation-related immune activation may be a plausible mechanistic pathway.
Data availability
Data will be made available on request. For data requests, please contact the first author Yingying Zhang (email address: zhangyingying@sxmu.edu.cn).
References
Saraiya, M., Berg, C. J., Shulman, H., Green, C. A. & Atrash, H. K. Estimates of the annual number of clinically recognized pregnancies in the United States, 1981–1991. Am. J. Epidemiol. 149, 1025–1029 (1999).
Magnus, M. C., Wilcox, A. J., Morken, N. H., Weinberg, C. R. & Håberg, S. E. Role of maternal age and pregnancy history in risk of miscarriage: prospective register based study. BMJ 364, l869 (2019).
Tong, F. et al. The epidemiology of pregnancy loss: global burden, variable risk factors, and predictions. Hum. Reprod. 39, 834–848 (2024).
Hertz-Picciotto, I. & Samuels, S. J. Incidence of early loss of pregnancy. N Engl. J. Med. 319, 1483–1484 (1988).
Li, S. & Shorey, S. Psychosocial interventions on psychological outcomes of parents with perinatal loss: A systematic review and meta-analysis. Int. J. Nurs. Stud. 117, 103871 (2021).
Rasmark Roepke, E., Christiansen, O. B., Källén, K. & Hansson, S. R. Women with a history of recurrent pregnancy loss are a high-risk population for adverse obstetrical outcome: A retrospective cohort study. J. Clin. Med. 10, 179 (2021).
Hao, F., Zhou, X. & Jin, L. Natural killer cells: functional differences in recurrent spontaneous abortion. Biol. Reprod. 102, 524–531 (2020).
Guan, D., Sun, W., Gao, M., Chen, Z. & Ma, X. Immunologic insights in recurrent spontaneous abortion: Molecular mechanisms and therapeutic interventions. Biomed. Pharmacother. 177, 117082 (2024).
He, Y. et al. Common mental disorders and risk of spontaneous abortion or recurrent spontaneous abortion: A two-sample Mendelian randomization study. J. Affect. Disord. 354, 258–266 (2024).
Health Effects Institute. State of Global Air. (2025). https://www.healthdata.org/research-analysis/library/state-global-air-2025 (2025).
Chen, J. et al. Associations of adverse pregnancy outcomes with high ambient air pollution exposure: Results from the Project ELEFANT. Sci. Total Environ. 761, 143218 (2021).
Bekkar, B., Pacheco, S., Basu, R. & DeNicola, N. Association of air pollution and heat exposure with preterm birth, low birth weight, and stillbirth in the US: A systematic review. JAMA Netw. Open. 3, e208243 (2020).
Cao, M. et al. Relationship between exposure to air pollutants in the first trimester and spontaneous abortion in pregnant women in the river valley city. Sci. Rep. 14, 27609 (2024).
Wang, B. et al. Nitrogen dioxide exposure during pregnancy and risk of spontaneous abortion: a case-control study in China. J. Matern Fetal Neonatal Med. 35, 3700–3706 (2022).
Nyadanu, S. D. et al. Prenatal exposure to ambient air pollution and adverse birth outcomes: An umbrella review of 36 systematic reviews and meta-analyses. Environ. Pollut. 306, 119465 (2022).
Jiang, D. et al. Coexposure to ambient air pollution and temperature and its associations with birth outcomes in women undergoing assisted reproductive technology in Fujian, China: A retrospective cohort study. J. Hazard. Mater. 481, 136539 (2025).
Quenby, S. et al. Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss. Lancet 397, 1658–1667 (2021).
Yang, L. et al. Nonlinear effect of air pollution on adult pneumonia hospital visits in the coastal city of Qingdao, China: A time-series analysis. Environ. Res. 209, 112754 (2022).
Blum, J. L., Chen, L. C. & Zelikoff, J. T. Exposure to ambient particulate matter during specific gestational periods produces adverse obstetric consequences in mice. Environ. Health Perspect. 125, 077020 (2017).
Yang, Y. et al. Effects of relative humidity on childhood hand, foot, and mouth disease reinfection in Hefei, China. Sci. Total Environ. 630, 820–826 (2018).
Doubilet, P. M. et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl. J. Med. 369, 1443–1451 (2013).
Xu, Q. et al. Effect of short-term ambient air pollution exposure on early miscarriage and pregnancy hormones with critical window identification. J. Hazard. Mater. 460, 132328 (2023).
Kanehisa, M. Toward understanding the origin and evolution of cellular organisms. Protein Sci. 28 (11), 1947–1951 (2019).
Kanehisa, M., Furumichi, M., Sato, Y., Matsuura, Y. & Ishiguro-Watanabe, M. KEGG: biological systems database as a model of the real world. Nucleic Acids Res. 53 (D1), D672–D677 (2025).
Kanehisa, M. & Goto, S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28 (1), 27–30 (2000).
Ng, K. H., Lai, S. Y., Jamaludin, N. F. M. & Mohamed, A. R. A review on dry-based and wet-based catalytic sulphur dioxide (SO2) reduction technologies. J. Hazard. Mater. 423, 127061 (2022).
Mohorovic, L., Petrovic, O., Haller, H. & Micovic, V. Pregnancy loss and maternal methemoglobin levels: an indirect explanation of the association of environmental toxics and their adverse effects on the mother and the fetus. Int. J. Environ. Res. Public. Health. 7, 4203–4212 (2010).
Dastoorpoor, M. et al. Correction to: Prenatal exposure to ambient air pollution and adverse pregnancy outcomes in Ahvaz, Iran: a generalized additive model. Int. Arch. Occup. Environ. Health. 95, 1805 (2022).
Dastoorpoor, M. et al. Prenatal exposure to ambient air pollution and adverse pregnancy outcomes in Ahvaz, Iran: a generalized additive model. Int. Arch. Occup. Environ. Health. 94, 309–324 (2021).
Yu, B., Yuan, Z., Yang, X. & Wang, B. Prodrugs of persulfides, sulfur dioxide, and carbon disulfide: important tools for studying sulfur signaling at various oxidation states. Antioxid. Redox Signal. 33, 1046–1059 (2020).
He, P., Ren, X., Zhang, Y., Tang, B. & Xiao, C. Recent advances in sulfur dioxide releasing nanoplatforms for cancer therapy. Acta Biomater. 174, 91–103 (2024).
Checa Vizcaíno, M. A., González-Comadran, M. & Jacquemin, B. Outdoor air pollution and human infertility: a systematic review. Fertil. Steril. 106, 897–904 (2016).
Tong, M. et al. The short-term effect of ozone on pregnancy loss modified by temperature: Findings from a nationwide epidemiological study in the contiguous United States. Sci. Total Environ. 902, 166088 (2023).
Wesselink, A. K. et al. Ambient air pollution and rate of spontaneous abortion. Environ. Res. 246, 118067 (2024).
Zhang, C. & Stevenson, D. Characteristic changes of ozone and its precursors in London during COVID-19 lockdown and the ozone surge reason analysis. Atmos. Environ. 273, 118980 (2022).
Kim, C. S. & Rohr, A. C. Review and analysis of personal-ambient ozone measurements. J. Air Waste Manag Assoc. 71, 1333–1346 (2021).
Cai, Z. et al. TNF-α-positive patients with recurrent pregnancy loss: The etiology and management. Technol. Health Care. 32, 4581–4591 (2024).
Kaislasuo, J. et al. IL-10 to TNFα ratios throughout early first trimester can discriminate healthy pregnancies from pregnancy losses. Am. J. Reprod. Immunol. 83, e13195 (2020).
Chan, H. Y. et al. Toll-like receptor-4 null mutation causes fetal loss and fetal growth restriction associated with impaired maternal immune tolerance in mice. Sci. Rep. 11, 16569 (2021).
Lan, R., Yang, Y., Song, J., Wang, L. & Gong, H. Fas regulates the apoptosis and migration of trophoblast cells by targeting NF-κB. Exp. Ther. Med. 22, 1055 (2021).
Tang, C. & Hu, W. The role of Th17 and Treg cells in normal pregnancy and unexplained recurrent spontaneous abortion (URSA): New insights into immune mechanisms. Placenta 142, 18–26 (2023).
Lestari, B., Fukushima, T., Utomo, R. Y. & Wahyuningsih, M. S. H. Apoptotic and non-apoptotic roles of caspases in placenta physiology and pathology. Placenta 151, 37–47 (2024).
Wesselink, A. K. et al. Exposure to ambient heat and risk of spontaneous abortion: A case-crossover study. Epidemiology 35, 864–873 (2024).
Asamoah, B., Kjellstrom, T. & Östergren, P. O. Is ambient heat exposure levels associated with miscarriage or stillbirths in hot regions? A cross-sectional study using survey data from the Ghana Maternal Health Survey 2007. Int. J. Biometeorol. 62, 319–330 (2018).
Funding
This study was supported by National Science Foundation of China (No. 82103938 No. 82574195), Research Project Supported by Shanxi Scholarship Council of China (No. 2022 − 113), Shanxi Basic Research Program Project (No. 202303021221126), Startup Foundation for Doctors of Shanxi Province (SD1916), Startup Foundation for Doctors of Shanxi Medical University (XD1916), Shanxi Province Higher Education Billion Project Science and Technology Guidance Project (BYBLD002), Shenzhen Ripson Institute of Stem Cell Regenerative Medicine Special R&D Project (JCYJ202003010103), Youth Science and Technology Research Foundation of Shanxi Province (20210302124038), Scientific and Technological Innovation Programs of Higher Education Institutions in Shanxi (2020L0176).
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All contributing authors participated in the development of this research article and endorsed the final version prior to submission. Study concept and design: Yingying Zhang. Acquisition of data: All authors. Analysis and interpretation of data: Yingying Zhang, Wen Sun. Drafting of the manuscript: Zhiwei Zou, Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: All authors. Obtained funding: Yingying Zhang, Lijian Lei. Administrative, technical, or material support: Yingying Zhang, Lijian Lei, Wenxia Song. Study supervision: Lijian Lei, Wenxia Song.
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Zhang, Y., Zou, Z., Dai, H. et al. A case-control study identifying critical exposure windows in the association between ambient air pollution and spontaneous abortion. Sci Rep (2026). https://doi.org/10.1038/s41598-026-44655-6
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DOI: https://doi.org/10.1038/s41598-026-44655-6
