Prenatal Exposure to Air Pollution and Autism Spectrum Disorder: Sensitive Windows of Exposure and Sex Differences

Abstract

Background: Studies have shown that air pollution exposures during pregnancy are associated with an increased risk of autism spectrum disorder (ASD) in children, and the risk appears to be greater for boys. However, studies assessing gestational windows of susceptibility have been mostly limited by trimesters.

Objective: We identified sensitive windows of exposure to regional air pollution and risk of ASD and examined sex differences in a large birth cohort.

Methods: This population-based retrospective cohort study included 294,937 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California (KPSC) hospitals from 2001 to 2014. Children were followed using electronic medical records until clinical ASD diagnosis, non-KPSC membership, death, or 31 December 2019, whichever came first. Weekly mean fine particulate matter [PM with an aerodynamic diameter of $\le 2.5\mu m$ (${\mathrm{PM}}_{2.5}$)], nitrogen dioxide (${\mathrm{NO}}_2$), and ozone ($O_3$) pregnancy exposures were estimated using spatiotemporal prediction models. Cox proportional hazard models with distributed lags were used to estimate weekly pollutant exposure associations with ASD risk for the entire cohort, and separately for boys and for girls. Models were adjusted for child sex (for full cohort), maternal race/ethnicity, maternal age at delivery, parity, maternal education, maternal comorbidities, medical center, census tract median household income, birth year, and season.

Results: There were 5,694 ASD diagnoses (4,636 boys, 1,058 girls). Sensitive ${\mathrm{PM}}_{2.5}$ exposure windows associated with ASD were found early in pregnancy, statistically significant throughout the first two trimesters [1-27 wk of gestation, cumulative $\text{hazard ratio}\left(\text{HR}\right)=1.14$ [95% confidence interval (CI): 1.06, 1.23] per interquartile range (IQR) ($7.4\text{-}{\mu g/m}^3$) increase]. $O_3$ exposure during 34-37 wk of gestation was associated with increased risk [$\text{HR}=1.06$ (95% CI: 1.01, 1.11) per IQR ($17.4\text{ppb}$) increase] but with reduced risk during 20-28 wk of gestation [$\text{HR}=0.93$ (95% CI: 0.89, 0.98)]. No associations were observed with ${\mathrm{NO}}_2$. Sex-stratified early gestational ${\mathrm{PM}}_{2.5}$ associations were stronger among boys [boys $\text{HR}=1.16$ (95% CI: 1.08, 1.26); girls $\text{HR}=1.06$ (95% CI: 0.89, 1.26)]. $O_3$ associations in later gestation were observed only in boys [boys $\text{HR}=1.10$ (95% CI: 1.04, 1.16); girls $\text{HR}=0.94$ (95% CI: 0.84, 1.05)].

Conclusions: Exposures to ${\mathrm{PM}}_{2.5}$ in the first two gestational trimesters were associated with increased ASD risk in children, with stronger associations observed for boys. The role of $O_3$ exposure on ASD risk merits further investigation. https://doi.org/10.1289/EHP9509.

Figure 1.

Weekly associated hazard ratios (HRs) associated with weekly ${\mathrm{PM}}_{2.5}$, ${\mathrm{NO}}_2$, and ${\mathrm{O}}_3$ exposures over gestation with risk of ASD in the overall cohort ($n=\mathrm{294,937}$), and separately among boys ($n=\mathrm{150,009}$) and girls ($n=\mathrm{144,928}$). Gray shade indicates 95% confidence intervals; dashed vertical lines demarcate trimesters. All the models were adjusted for maternal race/ethnicity, maternal age at delivery, parity, education, maternal comorbidities, medical centers, household income, birth year, and season; the model for the Overall cohort was further adjusted for child sex. Note: ASD, autism spectrum disorder; ${\mathrm{NO}}_2$, nitrogen dioxide; ${\mathrm{O}}_3$, ozone; ${\mathrm{PM}}_{2.5}$, fine particulate matter.