Risk Factors in Autism Spectrum Disorders Are More Prevalent in Affected Females

Background:  The association between specific risk factors and autism spectrum disorder (ASD) has been documented in previous studies. Among these risk factors are genetic predisposition, parental age, birth order, prematurity, and low birth weight (LBW). The main risk factor for ASD is by far male sex. Male predominance in ASD has been noted in all epidemiological studies with Male:Female (M:F) ratio of 4-5:1.  It is proposed that females are more protected from ASD compared with males and need to have a more severe aberration in order to show the autistic phenotype.

Objectives:  To examine M:F ratio in several known risk factors for autism spectrum disorder (ASD), including, parental age, family history of ASD, birth order, low birth weight and prematurity.

Methods:  The study included 611 participants aged 15 months to 18 years (mean=42.6m, SD=28.4m) referred for diagnosis of ASD to a national autism center.  The diagnosis of ASD was obtained using two standardized tests, the Autism Diagnosis Interview-Revised (ADI-R) and the Autism Diagnosis Observation Schedule (ADOS), and meeting criteria for autism/ASD based on DSM-IV criteria. Detailed birth, familial, medical and developmental histories were obtained from the parents.

Results:  The M:F ratio in the ASD group (n=537) was 6.8:1 higher than the 2.7:1 in the group that did not meet criteria for ASD (n=74) (p=.001). Regarding M:F ratio in different parental age groups,  22.9% of the ASD group had mothers with an advanced age (≥35 years). The M:F ratio (4.4:1) in the ≥35 years maternal age group was significantly lower than the M:F ratio (7.9:1) in the  younger <35 years maternal age group (p<.05)   Regarding paternal age, 21.9% of the ASD individuals had fathers with an advanced age (≥38 years). The M:F ratios in paternal age ≥38 years (5.9:1) and  paternal age <38y (6.8:1) groups were not significantly different.  Of the ASD participants, 7.0% had a first-order relative diagnosed with ASD.  In these multiplex families, the M:F ratio (2.3:1) was significantly lower than the M:F ratio (7.5:1) in the group of simplex cases (without ASD in first-order relatives) (p<.001).  Comparing the sex ratio between the first and the third born groups in mothers <34y, there was a significantly higher M:F ratio in the first born group (8.9:1) than in the third born group (3.1:1) (p<.01).  Regarding LBW, 31.6% of the ASD group had a birth weight ≤2500 g. The M:F ratio in the LBW (6.1:1) and in the>2500 g (7.9:1) groups was not significantly different. Regarding prematurity, 14% of the ASD group had a gestational age (GA) <36 weeks. No significant difference in M:F ratio was noted between the GA <36w (7.6:1) and the GA ≥36w (6.7:1) groups

Conclusions:  The existence of certain risk factors, namely advanced maternal age, positive family history and birth order, increases the representation of females in ASD. These findings suggest that there is an essential difference between the sexes regarding at least some etiologies of the condition. Possibly, 'female ASD' is associated with specific genetic and environmental factors that may lower the basic female "immunity" from autism.