2Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
3Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam, Korea
4Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
*Corresponding author: Heejeong Yoo ,
Department of Psychiatry, Seoul National University Bundang Hospital, 82 Gumi-ro
173beon-gil, Bundang-gu, Seongnam 13620, Korea, E-mail:
hjyoo@snu.ac.kr
*
These authors contributed equally to this work.
• Received: August 19, 2024 • Revised: December 17, 2024 • Accepted: December 17, 2024
This is an Open-Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits
unrestricted non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Autism spectrum disorder involves challenges in social communication and
restricted, repetitive behaviors. Historically, males have received autism
diagnoses at comparatively high rates, prompting an underrepresentation of
females in research and an incomplete understanding of sex-specific symptom
presentations and comorbidities. This review examines sex differences in the
prevalence of common comorbidities of autism to inform tailored clinical
practices. These conditions include attention deficit hyperactivity disorder,
anxiety disorders, conduct disorder, depression, epilepsy, intellectual
disability, and tic disorders. Attention deficit hyperactivity disorder is
prevalent in both sexes; however, females may more frequently exhibit the
inattentive subtype. Anxiety disorders display inconsistent sex differences,
while conduct disorder more frequently impacts males. Depression becomes more
common with age; some studies indicate more pronounced symptoms in adolescent
girls, while others suggest greater severity in males. Epilepsy is more
prevalent in females, especially those with intellectual disabilities. Despite
displaying a male predominance, intellectual disability may exacerbate the
severity of autism to a greater degree in females. No clear sex differences have
been found regarding tic disorders. Overall, contributors to sex-based
differences include biases stemming from male-centric diagnostic tools,
compensatory behaviors like camouflaging in females, genetic and neurobiological
differences, and the developmental trajectories of comorbidities. Recognizing
these factors is crucial for developing sensitive diagnostics and sex-specific
interventions. Inconsistencies in the literature highlight the need for
longitudinal studies with large, diverse samples to investigate autism
comorbidities across the lifespan. Understanding sex differences could
facilitate earlier identification, improved care, and personalized
interventions, thus enhancing quality of life for individuals with autism.
Autism is a neurodevelopmental condition that affects an individual’s
ability to communicate and interact socially, often accompanied by restricted
and repetitive behaviors (RRBs). Its presentation varies widely across
individuals, leading to the popular saying, “If you’ve met one
person with autism, you’ve met one person with autism,” which
emphasizes the distinct strengths and challenges of each individual. Numerous
genetic and neurobiological studies have sought to understand the etiology
behind the observed sex differences in autism, but the multifactorial nature of
the condition has posed challenges. Historically, males with autism have been
over-represented compared to females. This disparity is largely reflected in
epidemiological research, with an analysis of data from 43 studies indicating a
mean male:female prevalence ratio of 4.2:1 [1].
The imbalanced ratio of males to females diagnosed with autism has resulted in an
incomplete understanding of core symptom presentations across sexes. Previous
studies comparing the social communication skills of males and females with
autism have yielded mixed results; some studies have identified distinct
challenges faced by each sex [2,3], while others have found no statistically
significant differences [4–6]. Similar inconsistencies have been
reported concerning RRBs, with certain studies suggesting greater severity in
males [4,6] and other research not corroborating these results [3,5].
A variety of factors could explain the observed or unobserved sex differences in
autism, ranging from the limitations of measurement tools to participant
characteristics such as the developmental stage of the individual, their overall
severity of autism, or the presence of comorbid conditions. Comorbidities, which
may include neurological, cognitive, psychiatric, and physical conditions,
increase the complexity of the person’s needs and underscore the critical
importance of seeking medical advice and interventions [7,8]. Moreover,
comorbid conditions may influence the manifestation of symptoms [9]. For instance, a study by Gu et al.
[10] revealed that boys were more
likely than girls to be diagnosed between the ages of 3 and 11, whereas girls
were more likely to receive a diagnosis either before age 3 or after age 11.
However, after adjusting for comorbid neurodevelopmental and psychiatric
conditions, these age-related patterns were no longer significant. The
interaction between the core symptoms of autism and these additional challenges
emphasizes the necessity for a more comprehensive understanding of sex
differences. This understanding is crucial for the development of tailored
intervention strategies and could explain how a subset of the autistic
population could be overlooked.
Objectives
This review aims to explore the differences in the prevalence of comorbid
conditions between males and females with autism, establishing a necessary
foundation to understand the baseline disparities. These insights could guide
further investigation into sex-specific clinical presentations and targeted
interventions. By examining sex-based discrepancies, we intend to highlight
areas in need of additional research and suggest considerations for clinical
practice, thus fostering a more inclusive understanding of autism.
Ethics statement
This study is based solely on the review of published literature and did not involve
data collection, thus no informed consent was required
Sex differences in psychiatric and neurologic comorbidities
Attention deficit hyperactivity disorder
Attention deficit hyperactivity disorder (ADHD) is characterized by challenges in
maintaining attention, along with hyperactivity and impulsivity. It represents
one of the most common childhood neurodevelopmental disorders, with a weighted
prevalence of 10.47% in the United States from 2021 to 2022 [11]. Clinical observations have indicated
that a substantial number of children with autism also exhibit symptoms of ADHD,
with reported comorbidity rates ranging widely from 30% to 80% [12–14]. Additionally, the behavioral overlaps between these two
conditions suggest they may share a pathophysiological basis [15]. While ADHD has traditionally been
recognized to display a male predominance, with a male-to-female prevalence
ratio of 2.28 to 1 [16], a study by
Margari et al. [17] found no significant
sex differences in the prevalence of ADHD as a comorbid condition in adolescents
with autism. Notably, female sex was more frequently associated with the
predominantly inattentive presentation of ADHD, whereas male participants tended
to display the combined presentation.
Anxiety disorders
Anxiety disorders represent prevalent and chronic mental conditions, with
large-scale research suggesting that it may affect around 33.7% of the
population at some point in their lives [18]. Up to 40% of individuals with autism may experience at least
one comorbid anxiety disorder, most commonly specific phobia [19]. Although anxiety disorders are
generally more prevalent among females, research on individuals with autism has
yielded mixed results. Some studies have found comparable levels of anxiety
between sexes [17,20], while others have reported higher anxiety scores
[21] or more internalizing problems
in females with autism [22].
Conduct disorder
Conduct disorder is a complex behavioral disorder characterized by aggressive and
destructive behavior patterns. The lifetime prevalence of conduct disorder in
the general population is approximately 9.5% [23], and it increases to around 13% among individuals with autism
[24]. Regarding sex differences,
males typically exhibit higher rates of physical aggression [25]. Within the autism community, studies
indicate higher rates in males, with a greater manifestation of externalizing
problems [24,26]. Notably, however, this research has generally involved
small sample sizes, underscoring the need for further large-scale research to
fully understand the extent of conduct disorder comorbidity in autism.
Depression
The prevalence of depression among individuals with autism, particularly those
without intellectual disability, appears to increase with age. DeFilippis [27] noted that adolescents with autism
encounter substantial challenges as they navigate their identity and
interpersonal relationships. Oswald et al. [28] found that early adolescent girls with autism show more severe
depressive symptoms than either their male counterparts or girls without autism.
In a statistical analysis by Stacy et al. [29], the rates of mild and moderate/severe depression in girls with
autism were estimated at 7.2% and 3.6%, respectively, while boys with autism
experience these conditions at rates of 4.5% and 7.8%. These findings not only
emphasize the occurrence of depression among individuals with autism but also
highlight sex differences in its prevalence, suggesting that males tend to
experience more severe forms of depression.
Epilepsy
Epilepsy, a neurological condition characterized by recurrent seizures, affects
approximately 1.2% of the general population [30]. A comprehensive meta-analysis conducted by Liu et al. [31] revealed a disparity in the prevalence
of epilepsy between children (7%) and adults (19%) with autism. In a pooled
analysis of 14 studies, females with autism were found to have a higher
prevalence of epilepsy at 34.5%, compared to 18.5% in males [32]. Furthermore, Amiet et al. [32] observed that the incidence of epilepsy
is positively correlated with the severity of intellectual disability,
suggesting that an increase in cognitive impairment is associated with a
heightened risk of epilepsy.
Intellectual disability
Intellectual disability is a lifelong condition characterized by below-average
cognitive functioning. A systematic review conducted in 2016 examined the
prevalence and incidence of intellectual disabilities, yielding prevalence
estimates ranging from 0.05% to 1.55% [33]. Among six studies that compared sex differences, five reported
higher rates of intellectual disability in males [33]. Intellectual disability is also a common comorbid
condition in children with autism, with an estimated prevalence of 21.7% [9]. Among individuals with autism, the
male-to-female ratio of comorbid intellectual disability was 1.9:1 [34]. In a meta-analysis, Saure et al.
[35] found that intellectual
disability tends to exacerbate the severity of autism symptoms more in females
than in males. These findings indicate that phenotypic differences in autism may
be influenced by the level of cognitive functioning.
Tic disorders
Tic disorders are characterized by sudden, rapid motor movements or vocal
outbursts and are estimated to affect between 5 and 6 per 1,000 school-aged
children [36]. Among individuals with
autism, tic disorders are a common comorbidity, affecting approximately 18% to
22% [37,38]. Generally, females with tic disorders are diagnosed less
frequently than males and typically report a later age of symptom onset [39]. Kim et al. [38] found no significant sex differences between a group of
individuals with autism alone and one with both autism and tic disorders, based
on parental reports. However, further research is warranted. Studies that
utilize clinician assessments to evaluate the type and severity of tics by sex
could provide a deeper understanding of their manifestation in individuals with
autism.
Potential factors contributing to sex differences in prevalence
The exploration of sex-based differences in the prevalence of comorbid conditions
among individuals with autism is complex. It involves diagnostic and reporting
biases, sex-specific symptom presentations, biological factors, and distinct
patterns of comorbidity. In the present exploration of current research, we aim to
provide a thorough understanding of these contributing factors.
Measurement bias
Concerns have arisen regarding the measurement tools used in autism diagnosis,
which are often developed with a male-centric bias due to the disproportionate
representation of the sexes. This bias toward the male autism phenotype may
result in the misclassification of female patients. In an investigation of
potential sex biases in widely used diagnostic instruments, Belcher et al.
[40] conducted a confirmatory factor
analysis on the Autism Spectrum Quotient using data from a large UK adult
cohort. Their findings revealed that all but two items showed sex biases,
notably indicating that women were more likely than men to endorse items related
to social skills and communication. Similarly, Kalb et al. [41] examined the Autism Diagnostic
Observation Schedule-2 via differential item functioning analysis and identified
five items with significant differential item functioning. This suggests that
these items function differently for males and females, potentially impacting
diagnostic accuracy [42]. Furthermore,
there is a clear deficiency in accurate and reliable tools for assessing the
wide range of psychiatric comorbid conditions in individuals with autism.
Although efforts have been made to validate modified screening tools for
psychopathology in children and adolescents with autism, research specifically
addressing sex differences remains scarce.
Compensatory behaviors
The term “camouflaging” refers to the use of compensatory behaviors
or coping strategies by individuals with autism to mask their autistic traits
and conform to social norms. These methods often involve mimicking the behaviors
and interests of others or deliberately making eye contact. Camouflaging is
commonly reported among females and is considered a key reason why this
demographic is often overlooked. Such masking strategies contribute to a higher
likelihood of misdiagnosis in females with autism compared to their male
counterparts [43]. In their research,
Cage and Troxell-Whitman [44] underscore
the critical need for clinicians to recognize the impact of camouflaging.
Acknowledging these behaviors is essential for improving the well-being of
individuals with autism, especially when addressing comorbid mental health
conditions.
Different trajectories of comorbid conditions
Considering an individual’s age and developmental stage is crucial when
examining psychiatric conditions. It is well-established that certain
internalizing and externalizing disorders manifest at different times, often
influenced by sex-specific developmental trajectories. For example, in the
general population, boys are more likely to experience externalizing problems,
such as aggression, hyperactivity, and conduct problems, and these patterns tend
to remain stable across adolescence [45].
Conversely, males have a lower risk of internalizing problems, such as mood and
anxiety issues [46], with the onset of
such conditions typically occurring at a later age compared to females.
Therefore, the inherent characteristics of these comorbid conditions may
meaningfully impact the observed sex differences in individuals with autism.
Implications
In the context of autism, understanding sex-based differences in prevalence is
critical, as it can lead to the creation of more sensitive screening and
diagnostic tools, as well as the development of therapeutic plans tailored to
individual needs.
Sensitive measurement tools
Early and accurate identification of autism is crucial for improving outcomes in
young children. However, research has shown that girls are consistently
diagnosed later than boys, highlighting the need for diagnostic tools that are
sensitive to sex differences. Additionally, females with autism often have a
higher incidence of comorbid conditions compared to males [14], including internalizing behaviors that result in
anxiety, depression, and social withdrawal [47]. The overlap between these psychiatric comorbidities and the
core features of autism can complicate the diagnostic process, potentially
leading to delayed diagnoses in female patients.
Sex-specific intervention planning
Creating a sex-specific intervention strategy for autism requires a nuanced
understanding of the ways in which the condition presents in females versus
males. Females with autism often demonstrate better communication and social
interaction skills and exhibit fewer RRBs than their male counterparts. The use
of compensatory mechanisms, such as masking, may further complicate the
development of effective intervention strategies, as these behaviors can conceal
the true extent of the challenges these individuals face. For females with
autism, creating a sex-specific intervention strategy could involve focusing on
the management of psychiatric comorbidities through a combination of various
therapies and self-advocacy education. By customizing interventions to address
both shared characteristics and sex-specific differences in autism, we can
improve support for individuals, helping them to realize their full
potential.
Conclusion
This review examines the prevalence of various comorbid conditions among males and
females with autism. The current body of research on comorbidities is mixed, with
some studies finding no significant differences between sexes and others reporting
certain conditions as more common in one sex. These inconsistencies may stem from
differences in measurement tools, masking behaviors that complicate diagnosis, and
the age of study participants. The recognition of distinct patterns of comorbidity
could indicate the presence of subgroups within the autism spectrum. Consequently,
longitudinal studies with larger sample sizes are required to explore comorbid
conditions from a life-course perspective, considering the developmental
trajectories of both sexes. Given our preliminary findings on the differences in the
prevalence of common comorbid conditions among individuals with autism, it is
imperative that future research expand upon this work by examining potential sex
differences in their manifestation. A deeper understanding of these patterns could
support earlier autism diagnosis and improve access to care, enabling the creation
of more personalized intervention plans that improve quality of life for those on
the autism spectrum.
Authors' contributions
Project administration: Yoo H
Conceptualization: Yoo H
Methodology & data curation: Hong YH, Song DY
Funding acquisition: Yoo H
Writing – original draft: Hong YH, Song DY
Writing – review & editing: Hong YH, Song DY, Yoo H
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Funding
This research was supported by the Bio & Medical Technology Development
Program of the National Research Foundation (NRF), funded by the Korean
government (MSIT) (No. 2021M3E5D9021878).
Data availability
Not applicable.
Acknowledgments
Not applicable.
Supplementary materials
Not applicable.
References
1. Fombonne E. Epidemiology of pervasive developmental disorders. Pediatr Res 2009;65(6):591-598.
3. Song DY, Kim SY, Bong G, Kim YA, Kim JH, Kim JM, et al. Exploring sex differences in the manifestation of autistic traits
in young children. Res Autism Spectr Disord 2021;88:101848
4. Mandy W, Chilvers R, Chowdhury U, Salter G, Seigal A, Skuse D. Sex differences in autism spectrum disorder: evidence from a
large sample of children and adolescents. J Autism Dev Disord 2012;42(7):1304-1313.
5. Sutherland R, Hodge A, Bruck S, Costley D, Klieve H. Parent-reported differences between school-aged girls and boys on
the autism spectrum. Autism 2017;21(6):785-794.
6. Wilson CE, Murphy CM, McAlonan G, Robertson DM, Spain D, Hayward H, et al. Does sex influence the diagnostic evaluation of autism spectrum
disorder in adults? Autism 2016;20(7):808-819.
7. de Bruin EI, Ferdinand RF, Meester S, de Nijs PFA, Verheij F. High rates of psychiatric co-morbidity in PDD-NOS. J Autism Dev Disord 2007;37(5):877-886.
8. Joshi G, Petty C, Wozniak J, Henin A, Fried R, Galdo M, et al. The heavy burden of psychiatric comorbidity in youth with autism
spectrum disorders: a large comparative study of a psychiatrically referred
population. J Autism Dev Disord 2010;40(11):1361-1370.
9. Khachadourian V, Mahjani B, Sandin S, Kolevzon A, Buxbaum JD, Reichenberg A, et al. Comorbidities in autism spectrum disorder and their
etiologies. Transl Psychiatry 2023;13(1):71
10. Gu Z, Dawson G, Engelhard M. Sex differences in the age of childhood autism diagnosis and the
impact of co-occurring conditions. Autism Res 2023;16(12):2391-2402.
11. Li Y, Yan X, Li Q, Li Q, Xu G, Lu J, et al. Prevalence and trends in diagnosed ADHD among US children and
adolescents, 2017-2022. JAMA Netw Open 2023;6(10):e2336872.
12. van der Meer JMJ, Oerlemans AM, van Steijn DJ, Lappenschaar MGA, de Sonneville LMJ, Buitelaar JK, et al. Are autism spectrum disorder and attention-deficit/hyperactivity
disorder different manifestations of one overarching disorder? Cognitive and
symptom evidence from a clinical and population-based sample. J Am Acad Child Adolesc Psychiatry 2012;51(11):1160-1172.E3.
13. Gnanavel S, Sharma P, Kaushal P, Hussain S. Attention deficit hyperactivity disorder and comorbidity: a
review of literature. World J Clin Cases 2019;6(17):2420-2426.
14. Vadukapuram R, Elshokiry AB, Trivedi C, Abouelnasr A, Bataineh A, Usmani S, et al. Sex differences in psychiatric comorbidities in adolescents with
autism spectrum disorder: a national inpatient sample
analysis. Prim Care Companion CNS Disord 2022;24(5):21m03189
16. Ramtekkar UP, Reiersen AM, Todorov AA, Todd RD. Sex and age differences in attention-deficit/hyperactivity
disorder symptoms and diagnoses: implications for DSM-V and
ICD-11. J Am Acad Child Adolesc Psychiatry 2010;49(3):217-228.e1-e3.
17. Margari L, Palumbi R, Peschechera A, Craig F, de Giambattista C, Ventura P, et al. Sex-gender comparisons in comorbidities of children and
adolescents with high-functioning autism spectrum disorder. Front Psychiatry 2019;10:159
19. van Steensel FJA, B Bens SM, Perrin S. Anxiety disorders in children and adolescents with autistic
spectrum disorders: a meta-analysis. Clin Child Fam Psychol Rev 2011;14(3):302-317.
20. Sukhodolsky DG, Scahill L, Gadow KD, Arnold LE, Aman MG, McDougle CJ, et al. Parent-rated anxiety symptoms in children with pervasive
developmental disorders: frequency and association with core autism symptoms
and cognitive functioning. J Abnorm Child Psychol 2008;36(1):117-128.
21. Solomon M, Miller M, Taylor SL, Hinshaw SP, Carter CS. Autism symptoms and internalizing psychopathology in girls and
boys with autism spectrum disorders. J Autism Dev Disord 2012;42(1):48-59.
22. Prosperi M, Turi M, Guerrera S, Napoli E, Tancredi R, Igliozzi R, et al. Sex differences in autism spectrum disorder: an investigation on
core symptoms and psychiatric comorbidity in preschoolers. Front Integr Neurosci 2021;14:594082
23. Nock MK, Kazdin AE, Hiripi E, Kessler RC. Prevalence, subtypes, and correlates of DSM-IV conduct disorder
in the National Comorbidity Survey Replication. Psychol Med 2006;36(5):699-710.
25. Moffitt TE, Caspi A, Rutter M, Silva PA. Sex differences in antisocial behaviour: conduct disorder, delinquency,
and violence in the Dunedin Longitudinal Study; Cambridge: Cambridge University Press; 2001
26. Napolitano A, Schiavi S, La Rosa P, Rossi-Espagnet MC, Petrillo S, Bottino F, et al. Sex differences in autism spectrum disorder: diagnostic,
neurobiological, and behavioral features. Front Psychiatry 2022;13:889636
28. Oswald TM, Winter-Messiers MA, Gibson B, Schmidt AM, Herr CM, Solomon M. Sex differences in internalizing problems during adolescence in
autism spectrum disorder. J Autism Dev Disord 2016;46(2):624-636.
29. Stacy ME, Zablotsky B, Yarger HA, Zimmerman A, Makia B, Lee LC. Sex differences in co-occurring conditions of children with
autism spectrum disorders. Autism 2014;18(8):965-974.
30. Zack MM, Kobau R. National and state estimates of the numbers of adults and
children with active epilepsy: United States, 2015. MMWR Morb Mortal Wkly Rep 2017;66(31):821-825.
31. Liu X, Sun X, Sun C, Zou M, Chen Y, Huang J, et al. Prevalence of epilepsy in autism spectrum disorders: a systematic
review and meta-analysis. Autism 2022;26(1):33-50.
32. Amiet C, Gourfinkel-An I, Bouzamondo A, Tordjman S, Baulac M, Lechat P, et al. Epilepsy in autism is associated with intellectual disability and
gender: evidence from a meta-analysis. Biol Psychiatry 2008;64(7):577-582.
33. McKenzie K, Milton M, Smith G, Ouellette-Kuntz H. Systematic review of the prevalence and incidence of intellectual
disabilities: current trends and issues. Curr Dev Disord Rep 2016;3(2):104-115.
35. Saure E, Castras M, Mikkola K, Salmi J. Intellectual disabilities moderate sex/gender differences in
autism spectrum disorder: a systematic review and
meta-analysis. J Intellect Disabil Res 2023;67(1):1-34.
36. Scahill L, Specht M, Page C. The prevalence of tic disorders and clinical characteristics in
children. J Obsessive Compuls Relat Disord 2014;3(4):394-400.
38. Kim YR, Song DY, Bong G, Han JH, Kim JH, Yoo HJ. Clinical characteristics of comorbid tic disorders in autism
spectrum disorder: exploratory analysis. Child Adolesc Psychiatry Ment Health 2023;17(1):71
40. Belcher HL, Uglik-Marucha N, Vitoratou S, Ford RM, Morein-Zamir S. Gender bias in autism screening: measurement invariance of
different model frameworks of the autism spectrum quotient. BJPsych Open 2023;9(5):e173.
41. Kalb LG, Singh V, Hong JS, Holingue C, Ludwig NN, Pfeiffer D, et al. Analysis of race and sex bias in the autism diagnostic
observation schedule (ADOS-2). JAMA Netw Open 2022;5(4):e229498.
42. Brickhill R, Atherton G, Piovesan A, Cross L. Autism, thy name is man: exploring implicit and explicit gender
bias in autism perceptions. PLoS One 2023;18(8):e0284013.
43. Lai MC, Lombardo MV, Ruigrok ANV, Chakrabarti B, Auyeung B, Szatmari P, et al. Quantifying and exploring camouflaging in men and women with
autism. Autism 2017;21(6):690-702.
44. Cage E, Troxell-Whitman Z. Understanding the reasons, contexts and costs of camouflaging for
autistic adults. J Autism Dev Disord 2019;49(5):1899-1911.
45. Fernandez Castelao C, Kröner-Herwig B. Developmental trajectories and predictors of externalizing
behavior: a comparison of girls and boys. J Youth Adolesc 2014;43(5):775-789.
46. Kovess-Masfety V, Woodward MJ, Keyes K, Bitfoi A, Carta MG, Koç C, et al. Gender, the gender gap, and their interaction; analysis of
relationships with children's mental health problems. Soc Psychiatry Psychiatr Epidemiol 2021;56(6):1049-1057.
