The Sex Ratio in Autism Spectrum Disorder and Its Relationship with Risk Factors and Associated Features

Background: The higher prevalence of autism spectrum disorder (ASD) among males compared to females is well documented but poorly understood. A better understanding of the ASD sex ratio may provide valuable insight into the underlying neurobiological and genetic mechanisms of the disorder. Factors such as cognitive functioning, diagnostic subtype, comorbid disorders, birth weight, and parental age at birth have been found to affect the sex ratio, suggesting that males and females with ASD may be differentially impacted by associated risk factors and underlying neurobiology.

Objectives: This study had three main aims: 1) estimate the ASD sex ratio among children enrolled in EarlySteps, Louisiana’s statewide early intervention program; 2) examine changes in the ASD sex ratio across specific phenotypes, risk factors, and associated features; 3) examine whether males and females with ASD are differentially impacted by factors associated with increased risk for ASD.

Methods: Participants (n= 12,598) were children aged 17-37 months (M = 25.43, SD) enrolled in EarlySteps, the State of Louisiana’s early intervention program. The Baby and Infant Screen for Children with aUtism Traits- Part 1 (BISCUIT- Part 1) and Battelle Developmental Inventory, Second Edition (BDI-2) were administered to parents/caregivers as part of the EarlySteps assessment protocol. Diagnostic classifications were made through review of EarlySteps assessment results using DSM-5 criteria for ASD. Bivariate analyses were conducted to examine the male/female (M/F) ratio across factors (i.e., race/ethnicity, ASD symptom severity, developmental delay, cognitive delay, maternal age, paternal age, birth weight, premature birth, multiple births, multiplex families, global developmental delay, Down syndrome, seizure disorder, cerebral palsy) and to examine difference in the mean number of risk factors between males and females with ASD. Hierarchical logistical regression models were used to examine risk factors in relation to ASD classification outcomes, with interaction terms between risk factors and sex allowing for the analysis of differential risk between the sexes.

Results: The overall ASD M/F ratio was 3.15. Significant differences in the M/F ratio were found: between cases with (3.05) and without cognitive impairment (3.26); between cases with (1.97) and without (3.41) advanced maternal age; across birth weight categories (<1500 g: 1.90, 1500-2499 g: 2.05, ≥2500 g: 3.79); and between cases with (1.62) and without (3.28) seizure disorder. Females with ASD had a significantly higher mean of risk factors compared to their male counterparts. Advanced maternal age was found to significantly increase the risk of ASD for females but not males (OR = 1.628, 95% CI [1.034-2.564],p = .035).

Conclusions: The found ASD M/F ratio of 3.15 is lower than many previous estimates, but similar to other recent population-level studies. The differential impact of risk factors such as advanced maternal age may have important implications for understanding underlying genetic mechanisms. Further research is needed examining the relationship between specific risk factors for ASD and the ASD sex ratio.