A Systematic Review and Meta-Analysis Reveals Sex Differences in Rrbis in School Age Children with ASD without ID

Background: The consensus that autism spectrum disorders (ASDs) are found four times as often in males as females has remained strikingly consistent despite evolving diagnostic criteria.  The possible reasons for this sex difference in prevalence of ASDs are a topic of vigorous debate.  First, although typical social, communication, and play behavior develops differently in boys and girls, the ASD diagnostic criteria are not sex-specific, and may systematically underdiagnose girls.  Second, the higher prevalence of externalizing behaviors in boys may lead to an ascertainment bias, with boys more frequently taken for diagnostic evaluation due to their disruptive behavior.  Finally, biological and environmental factors including genetics, hormones, and neuro-immune processes may act differentially in boys and girls, leading to true phenotypic differences by sex.

Objectives: Quantify sex differences in social, communication, and repetitive behavior and restricted interests (RRBI) symptom severity in individuals diagnosed with ASDs, and the potential mediating impacts of age and IQ. 

Methods: PubMed was searched for relevant peer-reviewed articles published before September 29, 2015.  Included studies reported core (social, communication, and/or RRBI) ASD symptom severity by sex in subjects diagnosed with ASDs.  Meta-analyses were performed using random effects models. To account for measurement heterogeneity, separate meta-analyses were run by symptom domain for studies using the ADOS vs. the ADI vs. any other instrument.  The effects of age and IQ were examined by rerunning meta-analyses stratified by subject age (in 5 year increments) and IQ (≤70 and >70). 

Results: A total of 39 studies providing data on 9,005 subjects were included (Table 1).  Males had significantly higher RRBI on all instruments, including the ADI and ADOS (OR 1.92, 95% CI 1.32-2.87, p=0.001; Table 2). Neither the ADI nor the ADOS, which were used in approximately two-thirds of the studies of social symptoms, revealed sex differences for social problems, although other instruments (eg. AQ, RBQ II, BISCUIT, and DASH-II) did indicate more social symptoms in males than females (OR 1.30, 95% CI 1.01-1.67, p=0.044).  The ADI, but not the ADOS or other instruments, revealed more severe communication problems in males (OR 1.40, 95% CI 1.07-1.83, p=0.014).  As only RRBI analyses were stable by measurement instrument, and as numbers of studies were inadequate to stratify by both age/IQ and instrument, only RRBI results were stratified by age and IQ.  Boys aged 11-15 had significantly worse RRBI symptoms (OR 2.82, 95% CI 1.45-5.48, p=0.002), as did males with IQ>70 (OR 1.83, 95% CI 1.26-2.37, p=0.001). 

Conclusions: This meta-analysis did not find any consistent sex differences in social deficit severity.  Males had significantly worse communication deficits on parent report measures, and RRBI intensity on all measures.  Early adolescent boys, and boys without intellectual disability (ID), showed higher RRBI severity than corresponding girls. These findings indicate that in non-ID school-aged children with ASD, current measurement tools are capturing more severe RRBI difficulties in boys.  Whether this reflects inadequacy of the tools to comprehensively capture RRBI in girls, or relatively lower RRBI severity in girls, is a question for future research.