Identifying Unique and Shared Pre- and Perinatal Risk Factors in Simplex Versus Multiplex ASD and ADHD Families

Background: Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) are highly heritable, heterogeneous neurodevelopmental disorders that co-occur frequently. Some studies show that the high co-morbidity is caused by shared genetic factors, but it is also possible that the high co-morbidity rates of ASD and ADHD are caused by shared pre- and perinatal risk factors. A more complete understanding of the complex etiologies of ASD and ADHD may be helpful in improving treatment and prevention.

Objectives: The current study aims to a) identify pre- and perinatal risk factors associated with ASD, ADHD, or both disorders and b) examine whether these factors are unique, i.e., only found in affected offspring, or shared, i.e. also present in non-affected offspring, by stratifying into simplex (SPX; one affected individual within a family) and multiplex (MPX; two or more affected individuals) families, respectively. So far, studies have suggested that in ASD, pre- and perinatal risk factors are more unique to the affected child (likely to be found in SPX families), whereas in ADHD, risk factors were more often shared between affected and unaffected siblings (likely to be found in MPX families).

Methods: Pre- and perinatal data were collected in 56 ASD and 31 ADHD SPX families (including: 56/31 probands and 81/55 unaffected siblings, respectively) and 59 ASD and 171 ADHD MPX families (including 96/270 probands and 55/128 unaffected siblings, respectively) and 203 control families (408 children), using retrospective parent-report questionnaires. Thirteen pre- and perinatal risk factors were examined, including miscarriages/bleeding, maternal diseases, infections or intoxications during pregnancy, stress during pregnancy, labor/parturition, prematurity (<37 weeks), suboptimal condition of the child at birth, being firstborn, artificial pregnancy, maternal and paternal age at conception, and birth weight.

Results: No pre- and perinatal risk factors were related to both disorders. The risk factors stress during pregnancy, suboptimal condition of child at birth, maternal infections and labor/parturition were identified for ASD. The first two factors emerged only in SPX probands, whilst the latter two risk factors were observed only in MPX probands. In ADHD families, the risk factors low parental age (present in both SPX and MPX families) and maternal diseases during pregnancy (MPX families only) were identified. These factors were shared between affected and unaffected siblings.

Conclusions: Our results suggest that the high co-morbidity of ASD and ADHD cannot be explained by shared pre- and perinatal risk factors. Instead, these factors might have a formative influence on which disorder (ASD or ADHD) a person will develop. Particularly in ASD, pre-and perinatal risk factors differed between the SPX-MPX families. As expected, risk factors in ASD families were not shared between affected and unaffected siblings, which indicated that these factors may have a unique, possible determining effect on the development of the disorder. In ADHD, risk factors were shared between siblings, suggesting that these factors might increase familial risk for ADHD.