What are the risk factors for autism?

Risk Factors for Autism Spectrum Disorder

Autism spectrum disorder (ASD) has multiple genetic and environmental risk factors, with genetic factors being the most significant contributors, though environmental exposures during prenatal and early development periods also play important roles in triggering ASD development.

Genetic Risk Factors

• The high recurrence risk for autism in siblings and higher concordance in identical twins provides strong support for the importance of genetic factors 1
• Sibling recurrence risk varies considerably based on family composition, with risk estimates ranging from 6% on average to as high as 32% for a mother with two boys with ASD having another male child 1
• Multiple genes are involved in autism, with both common genetic variations and rare mutations contributing to risk 1
• Rare mutations with large effect sizes are the most robustly identified genetic risks for ASD 1
• Chromosomal microarray analysis is warranted and clinically indicated for all suspected cases of ASD, with a diagnostic yield of approximately 40% 1

Family and Parental Factors

• Advanced maternal and paternal age significantly increases risk of ASD 1, 2
• Female probands and families with multiple affected siblings increase the risk that subsequent children will have ASD 1
• High rates of learning/language problems and social disability have been noted in family members of individuals with ASD 1
• Closer spacing of pregnancies is associated with increased ASD risk 1

Prenatal and Perinatal Risk Factors

• Extremely premature birth (<26 weeks' gestational age) increases ASD risk 1
• Birth complications associated with trauma, ischemia, or hypoxia show strong links to ASD 2
• Maternal obesity, maternal diabetes, and cesarean section have shown significant associations with ASD risk 2
• Maternal infection during pregnancy, gestational diabetes, and maternal obesity are established risk factors 3
• Prenatal exposure to certain medications may increase risk:
  • Valproate intake during pregnancy significantly increases offspring vulnerability to ASD 4
  • Selective serotonin reuptake inhibitors during pregnancy are being investigated as potential risk factors 3

Environmental Exposures

• Environmental chemicals may target autism-related genes, including pesticides, heavy metals, bisphenol A (BPA), and phthalates 1
• Toxic chemical exposure, particularly to inorganic mercury and lead, has been associated with ASD risk 2
• The prenatal period is particularly sensitive, as the developing brain is susceptible to disruptions from environmental chemicals 1
• Chlorpyrifos, lead, and polychlorinated biphenyls (PCBs) have been recommended for systematic review regarding their relationship with ASD development 1

Neurobiological Factors

• Elevated peripheral levels of serotonin is one of the most frequently replicated neurochemical findings in autism 1
• Brain size increase and aberrations in white matter tract development have been observed in structural imaging studies 1
• Functional magnetic resonance imaging has identified difficulties in tasks involving social and affective judgments 1
• Neuropsychological correlates include impairments in executive functioning, weak central coherence, and deficits in theory-of-mind tasks 1

Sex-Related Factors

• Males are diagnosed with ASD 3-4.5 times more frequently than females 1
• The most parsimonious explanation for male predominance involves protective factors that reduce ASD risk in females 1
• Decreased second digit-to-fourth digit ratio, indicating increased fetal testosterone exposure, is associated with ASD diagnosis 1

Neurological Comorbidities

• Epilepsy occurs in 5-46% of children with ASD, with epileptiform abnormalities found in up to 60% 1
• Motor impairments including delayed motor milestones, apraxia, hypotonia, and malcoordination are common in ASD 1
• Sleep disturbances, particularly insomnia, affect 53-78% of individuals with ASD 1
• Specific genetic mutations are associated with both ASD and these neurological comorbidities 1

Important Caveats

• The dramatic rise in ASD prevalence (from 1 in 150 in 2002 to 1 in 59 in 2014) cannot be fully explained by genetics or changes in diagnostic criteria alone 1
• Vaccines have been extensively studied and epidemiological studies demonstrate no evidence for vaccination posing an autism risk 4, 2
• Many environmental risk factors are interrelated, and their identification might unveil common mechanisms of alteration on both contextual and molecular levels 5
• The early developmental period, particularly the prenatal period, represents a critical window of vulnerability 1, 3
• Studies of environmental risk factors have significant methodological limitations compared to genetic studies of ASD 2