Estimating the risk and burden of stillbirth related to prenatal nitrogen dioxide exposure in a birth cohort of 3.98 million mother-baby pairs.
Despite mounting evidence linking ambient air pollution to adverse birth outcomes, the nexus between stillbirth risk and prenatal nitrogen dioxide (NO2) exposure remains limited and inconsistent, particularly in low- and middle-income countries (LMICs). We examined 3982304 mother-infant pairs recorded in Iran during 2013-2018. Pregnancy-average NO2 concentrations were assigned using satellite-based gridded estimates averaged within 10-km buffers around delivery hospitals. Logistic regression models were fitted in single-, bi-, and tri-pollutant frameworks, with analyses conducted in parallel under the Iranian (≥ 22 gestational weeks) and WHO (≥ 28 gestational weeks) stillbirth definitions. In the single-pollutant model, per 10-μg/m3 increase in prenatal NO2 was associated with an elevated stillbirth odds of 1.206 (95% confidence interval: 1.192, 1.220) under the Iranian definition and 1.106 (1.088, 1.125) under the WHO definition. Co-pollutant analyses estimated generally unchanged associations after adjustment of PM2.5 or/and ozone. In both stillbirth definitions, we observed a monotonic increasing exposure-response function, with stronger associations at lower NO2 concentrations. Assuming causality, achieving an annual NO2 concentration of 10 μg/m3 was associated with 7686 (7242, 8127) potentially avoidable stillbirths under the Iranian definition and 2114 (1780, 2445) under the WHO definition, corresponding to attributable fractions of 25.8% (24.3%, 27.3%) and 14.0% (11.8%, 16.2%), respectively. Associations were stronger among mothers with lower educational attainment, whereas attributable burdens were larger among urban and highly educated mothers because of higher exposure levels. This study provides nationwide cohort evidence for increased risk of stillbirth associated with prenatal NO2 exposure, emphasizing the potential for stricter air quality regulations to reduce the stillbirth burden, particularly in LMICs.