Mid-to-late pregnancy: A critical window for the protective effect of green space against autism spectrum disorder (ASD).

Introduction: Green space exposure during pregnancy and the early postnatal period is associated with lower autism spectrum disorder (ASD) risk. However, averaged exposure studies may miss time-specific sensitive windows spanning prenatal to early postnatal periods. Whether PM2.5 mediates or modifies this relationship remains unclear. This study aimed to identify critical windows of green space exposure and examine PM2.5's role.

Methods: A 1:3 matched case-control study was conducted, including 207 children with ASD and 621 healthy controls individually matched by age and sex. Participants were recruited from a tertiary maternal and child health hospital in central China. Monthly residential normalized difference vegetation index (NDVI), a satellite-derived metric of vegetation greenness, and fine particulate matter (PM2.5) levels from 10 months before to 3 months after birth were estimated for each participant based on maternal residential addresses. A distributed lag nonlinear model (DLNM) was used to quantify the association between monthly NDVI exposure and ASD risk and to detect critical windows for the protective effects of green space. Product terms were incorporated into conditional logistic regression models to test multiplicative interactions between NDVI and PM2.5. The bootstrap method was used to evaluate mediating effects, and Bonferroni correction was applied to account for multiple testing.

Results: Children with ASD had consistently lower monthly NDVI values than controls across all 14 months (from 10 months before birth to 3 months after birth; all FDR-adjusted P values < 0.01). A critical window was identified from 6 months to 1 month before birth (lags -6 to -1), during which higher NDVI was associated with lower odds of ASD. For this window, each interquartile range (IQR) increase in window-averaged NDVI was associated with a 46.6% reduction in the odds of ASD (OR = 0.534, 95% CI: 0.415-0.688). No significant multiplicative interaction between NDVI and PM2.5 was observed for any month (all P > 0.05 after correction), and mediation analyses revealed no evidence of mediation by PM2.5.

Conclusions: Green space exposure during mid-to-late pregnancy (corresponding to 6 to 1 month before birth for term births) is associated with substantially lower odds of ASD, independent of PM2.5. These findings suggest that prenatal care providers should consider advising pregnant women to increase green space contact during mid-to-late pregnancy. The identification of this temporally specific window also supports urban planning efforts to prioritize green space preservation in residential areas with high concentrations of pregnant women.