Background
Autism spectrum disorder (ASD) is a neurodevelopmental condition that manifests in early childhood. The term "spectrum" emphasizes the wide range of symptom severity and functional abilities among individuals.
Diagnosis of ASD, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Text Revision (DSM-5-TR), requires persistent deficits in two core areas: [1]
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Social communication and social interaction: This includes difficulties with social-emotional reciprocity (eg, failure of back-and-forth conversation, reduced sharing of interests), nonverbal communication (eg, abnormal eye contact, poor body language), and developing and maintaining relationships.
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Restricted, repetitive patterns of behavior, interests, or activities: This can manifest as stereotyped or repetitive motor movements (eg, hand flapping), insistence on sameness or rigid routines, highly fixated interests that are abnormal in intensity, and hyper or hyporeactivity to sensory input.
The prevalence of ASD has risen significantly over the past two decades. According to the Centers for Disease Control and Prevention (CDC), estimates suggest that about 1 in 31 children in the United States have been identified with ASD. [2] This increase is likely due to a combination of factors, including broader diagnostic criteria, greater public awareness, and improved screening tools.
Identifying ASD often requires a team approach involving various professionals, such as child psychiatrists, neurologists, psychologists, speech and language therapists, and pediatricians. Early recognition and intervention are critical to improving long-term outcomes. [3]
Motor and gaze anomalies have been reported in infancy and early childhood and may serve as early developmental markers; these are discussed in detail under Presentation.
Epidemiology
The global prevalence of autism spectrum disorder (ASD) is currently estimated to be around 1%, with a consistent male-to-female ratio of approximately 4:1. [4] The reasons for this are not fully understood, but it is thought to be due to a combination of genetic factors and the possibility that female-specific traits may be more subtle, leading to underdiagnosis in girls.
Additionally, reported rates have been rising significantly in many countries, including the United States. However, this is largely attributed to improved diagnostic practices, increased awareness, and changes to diagnostic criteria, rather than a true increase in the incidence of ASD. [5, 6]
The most reliable estimates of ASD prevalence in the United States come from the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network. According to their data, the prevalence of ASD is now 1 in 31 children aged 8 years, or 3.2%. This represents a significant increase from previous reports. [2]
Racial and health disparities
Despite progress, significant disparities in diagnosis and treatment persist. Studies show that Black and Hispanic children with ASD often experience a delay in diagnosis of several years, despite early parental concerns. This is linked to various health inequities, including misdiagnosis, excessive wait times for appointments, and barriers related to cost, scheduling, and transportation. [7] Additionally, the presence of a co-occurring condition like ADHD can contribute to these delays, as symptoms may be attributed to ADHD alone, masking the underlying ASD. This diagnostic delay can lead to a higher incidence of co-occurring intellectual disabilities, as it delays access to crucial early intervention services.
Culture and gender
When evaluating a child for ASD, cultural and gender considerations should be included, as there are cultural and familial differences in expectations regarding eye contact, play, social interaction, and pragmatic use of language. [8, 9] A healthcare provider must be able to distinguish between behaviors that are characteristic of ASD and those that are part of a child's cultural upbringing.
When English is not the family’s primary language, professionals should be conscious of finding ways to communicate effectively with the family, including finding professionals and/or translators who speak the primary language.
Etiology
The causes of autism spectrum disorder (ASD) are not fully understood. Current evidence supports a multifactorial origin, involving genetic vulnerability and environmental influences, but no single factor has been established as causative. [10, 11]
Several factors have been associated with an increased risk for ASD, including advanced maternal and paternal age, while observed differences by race or parental education likely reflect variations in access to health care and diagnostic practices rather than direct biological risk. [12, 13] Data from the CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network show that, for the first time, ASD prevalence among Black and Hispanic children has become similar to, and in some cases, surpassed that of White children, suggesting a narrowing of these diagnostic gaps. [5, 6, 2]
Genetic and familial factors
Familial clustering and twin studies demonstrate strong heritability of ASD. The recurrence risk is as high as 18.7% in siblings, and even higher in families with two or more affected children. [14, 15] Mutations or copy number variants in genes such as SHANK3 and syndromes such as fragile X and tuberous sclerosis are consistently associated with ASD. [16] [17, 18] Approximately 10% of individuals with ASD have an identifiable genetic alteration on testing. [19]
Prenatal and perinatal risk factors
Adverse obstetric events (eg, prematurity, low birth weight, preeclampsia, fetal distress) and perinatal complications are associated with increased ASD risk, although causality remains uncertain. [13, 20]
Maternal medication exposures
Valproate use during pregnancy is linked to a threefold increased risk of ASD and is contraindicated in women of childbearing potential whenever possible. [21] Epilepsy management during pregnancy requires balancing seizure control with teratogenic risk. Alternative anticonvulsants are generally preferred, but in some women valproate may still be necessary. Preconception counseling and documentation of informed discussion regarding risks and benefits are recommended.
Selective serotonin reuptake inhibitors (SSRIs), especially with first-trimester exposure, have been associated with a modestly increased risk, though findings are inconsistent. [22, 23, 24]
Some observational studies have suggested a possible association between prenatal acetaminophen use and ASD risk, but evidence is inconclusive and confounding factors make causation uncertain. [25] It is important to note that major medical organizations, including the American College of Obstetricians and Gynecologists (ACOG), continue to state that acetaminophen is considered a safe option for managing pain and fever during pregnancy and that pregnant individuals should not avoid it when necessary. [26] This position is based on the lack of definitive causal evidence from human studies, which is critical for making clinical recommendations.
Maternal medical conditions
Severe early-gestation hypothyroxinemia has been linked to a nearly fourfold increased ASD risk. [27, 28] Maternal infections such as rubella also confer risk, and vaccination has largely eliminated this cause in high-income countries. [14] Other prenatal infections have been investigated, but evidence remains limited.
Environmental associations
Associations have been reported with prenatal exposure to pesticides, traffic-related air pollution, and certain airborne toxins (eg, styrene, chromium, arsenic). [29, 30, 31] These remain correlational and not proven causative.
Parental age
Older parental age has been reported as a risk factor, though findings are mixed. Some studies suggest increased ASD incidence in younger parents of children with an affected sibling. [12]
Vaccination
Large population studies consistently show no association between childhood vaccines and ASD. [32, 33, 34, 35, 36] The 1998 Wakefield study suggesting a link with MMR vaccination was retracted due to fraudulent data. [37] Parents should be encouraged to adhere to routine immunization schedules.
Emerging research and other proposed factors
Beyond the established genetic and environmental risk factors, other areas of emerging research offer new insights into the complex etiology of ASD. The field of epigenetics is particularly promising, as it explores how environmental influences, such as diet or exposure to toxins, can modify gene expression without altering the underlying DNA sequence. This could explain how a gene predisposed to a certain function is "turned on" or "turned off" by environmental factors. [38] Additionally, researchers are investigating the role of the gut microbiome and the gut–brain axis. Studies have found differences in the gut bacteria of individuals with ASD and are exploring how these microbial imbalances may influence brain function and behavior through metabolic, immune, and neural pathways. [39] Another area of focus is maternal immune activation (MIA), where a mother's immune response to an infection during pregnancy may release inflammatory molecules that affect fetal brain development, contributing to an increased risk for ASD. [40]
Large-scale genetic and developmental research suggests that ASD may represent multiple biologically distinct subtypes rather than a single disorder. A 2025 genome-wide analysis identified differing genetic architectures and developmental trajectories among individuals diagnosed in early childhood versus those diagnosed later. Early-diagnosed cases were enriched for rare deleterious variants in constrained genes, whereas later-diagnosed individuals showed higher polygenic risk for traits such as educational attainment, ADHD, and depression. These findings indicate that age at diagnosis may reflect meaningful biological subtypes within the spectrum, further emphasizing the heterogeneity of ASD. [41]
Pathophysiology
The pathophysiology of autism spectrum disorder (ASD) is complex and not fully understood. Evidence from neuroimaging, neuropathology, and biochemical studies suggests that atypical brain development, altered neural connectivity, and imbalances in excitatory and inhibitory signaling contribute to core features of ASD.
Neuroanatomic and connectivity findings
Neuroimaging and postmortem studies show abnormalities in several brain regions, including the frontal and temporal lobes, cerebellum, amygdala, and hippocampus. Enlargements of the amygdala and hippocampus are common in childhood, and increased neuron numbers have been observed in the prefrontal cortex of children with ASD compared with controls. [42] MRI studies demonstrate atypical connectivity in frontal regions, thinning of the corpus callosum, and region-specific differences in myelination and gray matter density. [43, 44, 45, 46]
Neurotransmitter imbalances
Imbalances in key neurotransmitters, particularly gamma-aminobutyric acid (GABA) and glutamate, are implicated in ASD. GABA is the brain's primary inhibitory neurotransmitter, and its dysregulation can lead to an imbalance between excitatory and inhibitory signaling. Magnetic resonance spectroscopy (MRS) studies often show reductions in GABA levels in the sensorimotor cortex of individuals with ASD, which correlates with impaired behavioral inhibition. [47, 48, 49] Postmortem studies demonstrate reductions in GABAB receptors in the cingulate cortex and fusiform gyrus, regions important for social cognition and facial recognition. [50] Findings, however, are not entirely consistent across cohorts. [51, 52]
Alterations in glutamatergic signaling have also been implicated, with hypotheses focusing on disrupted excitatory connectivity between parietal and occipital cortices during prenatal development. [43, 44]
Metabolic and oxidative stress markers
Oxidative stress is hypothesized to contribute to ASD pathogenesis. MRS studies have demonstrated reduced glutathione (GSH), creatine (Cr), and myoinositol (MI) in the dorsal anterior cingulate cortex of individuals with ASD. [47, 53] Diminished N-acetylaspartate (NAA), a marker of neuronal activity, has been observed in multiple brain regions including the frontal, parietal, and temporal lobes, amygdala, hippocampus, and thalamus. [47, 54, 55, 56] Children with ASD also show lower plasma levels of cysteine, glutathione, and methionine, and altered methylation ratios, suggesting abnormal redox and energy metabolism. [57, 58, 59]
Mitochondrial dysfunction
Some children with ASD show biochemical or clinical features of mitochondrial disorders, such as elevated lactate or carnitine deficiency. [58, 59, 60, 61] While these findings suggest disturbed neuronal energy metabolism in a subset of individuals, they are not universal.
Neuroinflammation
Immune dysregulation may play a role in ASD. Low concentrations of anti-inflammatory cytokines and excess pro-inflammatory cytokines have been observed. [62] Maternal infection during pregnancy can trigger cytokine release that crosses the placenta, potentially contributing to fetal brain inflammation. [63]
Prognosis
The prognosis in patients with autism spectrum disorder (ASD) is highly correlated with their ability to communicate using language, as so many aspects of everyday life depend on the ability to communicate.
Prognosis is also closely linked to cognitive functioning. Individuals with significant intellectual disability may require lifelong support and are unlikely to live independently, although the level of independence can vary depending on early interventions and ongoing support. Individuals with higher cognitive and adaptive functioning may achieve independent living, hold employment, and form long-term relationships, including marriage and parenthood. Complete remission of ASD symptoms has been reported in anecdotal case reports, but this is extremely rare.
Comorbid disorders
Children and adults with ASD frequently experience comorbid medical and psychiatric conditions. Gastrointestinal disorders, particularly constipation and chronic diarrhea, are more common in ASD, and the risk tends to increase with greater severity of autism symptoms. [64] Other conditions reported more frequently in individuals with ASD include cancer, [65] cerebral palsy, [66] attention-deficit/hyperactivity disorder, [67] insomnia and other sleep disorders, [68] and epilepsy. [69]
Psychiatric conditions are common in individuals with ASD, with anxiety disorders, depression, and obsessive-compulsive disorder (OCD) being the most frequently reported, [70, 71] while psychotic disorders occur less commonly. [72, 73]
Patient Education
Children and adults with autism spectrum disorder (ASD) are at increased risk for safety concerns that require proactive supervision and planning. Elopement, or wandering away from safe environments such as home or school, occurs in a substantial proportion of individuals with ASD; parents and caregivers should implement safety measures and ensure vigilant supervision. [8, 74] Individuals with ASD are also at higher risk for sexual abuse, particularly those with more severe cognitive or functional impairments. Families should provide age-appropriate education on personal safety and strategies to recognize and respond to potentially abusive situations.
Clinicians should guide families in advocating for appropriate educational and legal supports, including individualized education plans and access to services that meet the child’s specific needs. [75] Awareness of cognitive, social, and communication challenges in ASD is essential when evaluating decision-making capacity, including for healthcare decisions, advance directives, or acting as a surrogate decision-maker. [9] Clinicians should ensure that individuals with ASD are supported to understand choices and participate in decisions to the extent possible.
Families and caregivers may also benefit from structured interventions or training programs that enhance social and safety skills, particularly for interactions with unfamiliar adults or in community settings. Individuals with ASD may be especially vulnerable in encounters with law enforcement due to communication and social difficulties, with heightened risks reported among some groups such as Black adolescents; anticipatory guidance and safety planning may be warranted. [76, 8, 74]
