Identifying susceptible exposure windows for ambient nitrogen dioxide before and during pregnancy and increased risks of small/large for gestational age

[Background] Exposure to ambient nitrogen dioxide (NO₂) could increase the risks of small for gestational age (SGA) and large for gestational age (LGA). Nevertheless, previous published studies usually use a time period over relatively long durations as the exposure window, such as trimester-specific or gestational months, to identify adverse pregnancy outcomes related susceptible exposure windows for ambient air pollution. At present, no study has explored associations of weekly-specific ambient air NO₂ exposure around pregnancy with SGA and LGA. [Objective] To evaluate the associations of exposure to ambient NO₂ over the preconception and entire pregnancy period with risks of SGA and LGA, as well as to explore critical windows of NO₂ exposure by refining exposure period to specific weeks. [Methods] Based on a birth cohort established by the project Environmental and LifEstyle FActors iN metabolic health throughout life-course Trajectories (ELEFANT) situated in Tianjin, 10 916 singleton pregnant women whose dates of the last menstrual period and delivery were both between June 2014 and June 2016, and whose gestational age were within 24-42 completed gestational weeks were included in this study. Each pregnant woman's exposures to ambient NO₂ throughout 12 weeks before pregnancy and pregnancy period were matched with daily average NO₂ concentrations obtained from the Chinese air quality reanalysis datasets (CAQRA). Distributed lag models incorporated in Cox proportional hazard regression models were applied to explore the associations of maternal exposure to weekly ambient NO₂ throughout 12 weeks before pregnancy and pregnancy period with risks of SGA and LGA after controlling for potential confounders including maternal age, ethnicity, educational level, occupation, body mass index before pregnancy, residence, times of gravidity and parity, smoking, alcohol consumption, husband smoking, and season of conception. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated per 3 μg·m⁻³ increase in ambient NO2 concentrations. [Results] The average levels of maternal exposure to NO₂ over the preconception, first trimester, second trimester, third trimester, and entire pregnancy periods were (39.6±10.8), (42.7±10.5), (44.8±12.7), (37.7±11.1), and (41.6±4.8) μg·m⁻³, respectively. For a 3 μg·m⁻³ increase in NO₂ over the first trimester, the risk of SGA increased by 19.0% (95%CI: 8.0%-32.0%). For a 3 μg·m⁻³ increase in NO₂ over the preconception, first trimester, and entire pregnancy, the associated risks of LGA increased by 7.0% (95%CI: 1.0%-13.0%), 37.0% (95%CI: 29.0%-46.0%) and 19.0% (95%CI: 9.0%-31.0%), respectively. For SGA, the susceptible exposure windows for NO₂ were observed during the 7th to 12th preconceptional weeks and the 6th to 12th gestational weeks, with the strongest association found at the 12th preconceptional week, when the risk of SGA increased by 6.0% (95%CI:3.2%-8.9%) for a 3 μg·m⁻³ increase in NO₂. For LGA, the susceptible exposure windows for NO₂ were observed during the 1st to 12th preconceptional weeks and the 1st to 6th gestational weeks, with the strongest association found at the 12th preconceptional week, when the risk of LGA increased by 6.1% (95%CI: 4.5%-7.8%) for a 3 μg·m⁻³ increase in NO₂. [Conclusion] Exposure to ambient NO₂ is associated with increased risks of both SGA and LGA, and the most susceptible weekly exposure windows are nested within the 12 weeks before pregnancy and early pregnancy.