Background: This study aimed to explore the main effects of environmental risk factors as well as their interaction effects with miRNA on the risk of autism spectrum disorder (ASD). Methods: One hundred fifty-nine ASD children (ASD group) and 159 healthy children (control group), aged 2-6 years, were included in this study. ASD diagnoses were based on DSM-5 criteria. The extensive medical and demographic characterization of the two groups were recorded. MicroRNAs (miRNAs) in serum were detected by qRT-PCR. Results: Compared with the control group, the ASD group had significantly higher rates of maternal stress during pregnancy (p < 0.001), maternal drinking during pregnancy (p = 0.006), threatened abortion (p = 0.011), pregnancy-induced hypertension (p = 0.032), gestational diabetes (p = 0.039), maternal anemia during pregnancy (p < 0.001), umbilical cord knot (p < 0.001), neonatal jaundice (p < 0.001), family psychiatric history (p = 0.001), and much lower birth weight (p = 0.012). Furthermore, the ASD group had much lower expression levels of hsa-miR-181b-5p (p < 0.001) and hsa-miR-320a (p < 0.001) and significantly higher levels of hsa-miR-19b-3p (p < 0.001). The interactions of hsa-miR-320a and maternal stress during pregnancy (OR = 39.42, p < 0.001), hsa-miR-19b-3p and neonatal jaundice (OR = 2.44, p < 0.001), and hsa-miR-181b-5p and family psychiatric history (OR = 8.65, p = 0.001) could increase ASD risk. Conclusions: The dysregulation of hsa-miR-181b-5p, hsa-miR-320a, and hsa-miR-19b-3p could interact with environmental factors, such as maternal stress during pregnancy, neonatal jaundice, and family psychiatric history, to impact the risk of ASD.
