Male:Female Ratio Is Related to Autism Spectrum Disorder in the Family and to Maternal Age

Background:

Research suggests that biological factors such as heredity, gender and parental ages may play a causal role in autism spectrum disorder (ASD).  Male:Female (M:F) ratio of 4:1 was documented in most studies. The prevalence of ASD among siblings of individuals with ASD ranges from 2% to 6% in comparison to 0.5-1% in the general population.  Increased autism risk was documented with both advanced maternal and paternal ages. 

Objectives:

1. To define gender ratio, prevalence of ASD in first and second relatives and maternal ages in a cohort with ASD. 2. To examine possible relationships between gender, familial genetic factors and maternal ages and autism severity, adaptive skills and developmental trajectories (developmental regression/non-regression)

Methods:

The study included 564 children who came to a tertiary autism center in Israel for a comprehensive evaluation. A pediatric neurologist obtained birth and developmental histories and performed a neurological examination. Evaluations of autism severity and of adaptive skills were performed using standardized tests [Autism Diagnosis Interview (ADI-R), Autism Diagnosis Observation Schedule (ADOS, the new ADOS severity scale and Vineland Adaptive Behavior Scales].

Results:

Of the 564 participants, 461 (81%) children, (M=39.8 months SD=26.3) were diagnosed with ASD.

Gender:  M:F ratio in ASD cohort was (6.8:1) which was significantly higher than the known ratio (4:1) (χ²=14.8, p<.001).   Autism severity was not different between boys (M=7.5, SD=2.0) and girls (M=7.4, SD=2.1). However Vineland composite scores were significantly better in boys (M=67.1, SD=10.0) than in girls (M=63.1, SD=13.1) [F(1,308)=4.7, p<.05, h²=.015]. Of the specific Vineland domains, only in motor skills boys showed significantly better scores (M=83.3, SD=13.9) than girls (M=73.7, SD=21.6) [F(1,276)=13.4, p<.001, h²=.015].  Developmental regression was significantly higher in girls (33%) than in boys (23%) (χ²=3.1, p<.05).

Familial genetics: Of 441 participants, 32 (6.8%) had a sibling diagnosed with ASD, and 51 more (12%) had a second-order relative diagnosed with ASD in the extended family. No difference was noted in adaptive skills, autism severity or developmental trajectories between the groups with and without ASD in the family.  Male/female ratio was significantly lower in the group with a first-order relative with ASD (2.5:1) than in the group without ASD in the family (7.5:1) (χ²=54.3, p<.001). 

Maternal ages: Mean maternal age of the ASD group at birth was 31.1 years (SD=5.8) which was significantly higher than the mean newborns maternal age (29.7y) in Israel (t=5.8, p<.001).  M:F ratio in the >35y group (N=100 ) was  4.5:1 which was significantly lower than M:F ratio of 11.2:1 in the < 25y group (N=49)  (χ².=12.9, p<.001).  The two maternal age groups did not differ significantly in the ADOS severity score, Vineland composite scores and developmental regression rates.
Conclusions:

Changes in Male:Female ratio is related to familial ASD and to maternal age.  Male predominance is observed in idiopathic ASD, while more females are affected in families with first-and second-order relatives with ASD and with advanced maternal age.  Females showed more delayed motor skills and developmental regression than males.  This pattern may suggest genetic and epigenetic influences in the etiology of ASD.