Maternal Exposure to Ambient Ozone and Fetal Critical Congenital Heart Disease in China: A Large Multicenter Retrospective Cohort Study

The relevance of O₃ exposure in critical congenital heart disease (CCHD) remains uncertain and requires further investigation. The present study aims at quantitatively assessing the association between ambient O₃ exposure during the early pregnancy period with fetal CCHD and identifying possible susceptible exposure windows. A retrospective cohort study involving 24,516 pregnant women was conducted using data from the Maternal-Fetal Medicine Consultation Network, which encompassed 1313 medical centers across China from 2013 to 2021. We extracted daily O₃ concentrations from a validated grid dataset with a spatial resolution of 0.1° at each participant's residential county to assess ambient O₃ exposure, followed by calculating the average exposure levels in the periconceptional period, embryonic period, first trimester, and preconception period. The diagnosis of CCHD was based on fetal echocardiography. Exposure-response analyses were carried out using logistic regression models. During the study period, a total of 1541 (17.4%) subjects were diagnosed with fetal CCHD. Each 10 µg/m³ increase in ambient O₃ exposure in the periconceptional period was associated with a 26.0% increase in the odds of CCHD (odds ratio [OR]: 1.260, 95% confidence interval [CI]: 1.189, 1.335; <i>p</i> < 0.001). Importantly, the association was not modified by factors including maternal age and occupation status, paternal age and smoking status, conception mode, and the presence of risk factors. In the sensitivity analysis, significant associations were observed between O₃ exposure and CCHD in the embryonic period, first trimester, and preconception period, which was consistent with the results of the main analyses. These findings suggest that lowering ambient O₃ exposure in the preconception and early pregnancy periods may be beneficial in reducing the risk of fetal CCHD, especially in regions with elevated O₃ levels.