Do Parental Medical and Psychiatric Conditions Have Sex-Differential Risk Effects for Autism?

Background: The male predominance in autism suggests that generally, the liability to developing autism may be sex/gender-differential. However, exact mechanisms contributing to this sex/gender-differential liability remain unclear. When investigating etiological-developmental mechanisms and risk/protective factors for autism, it is important to consider sex/gender-differential effects, rather than simply “controlling for” sex/gender. Both sex/gender-independent and -dependent effects should be tested in epidemiological and causal investigations. 

Objectives: To test whether parental medical and psychiatric conditions contribute to any sex-dependent and/or -independent risks for autism in offspring. 

Methods: Parent-report data from studies utilizing the medical history questionnaire of the Childhood Autism Risk from Genetics and Environment (CHARGE) study, publicly available on the National Database for Autism Research (NDAR) were analyzed, with a specific focus on testing for sex-differential risk effects. Parental conditions were grouped into 8 composite predictors: (1) maternal lifetime immune-dysregulation, (2) maternal immune-dysregulation during pregnancy, (3) maternal lifetime neuro/developmental conditions, (4) maternal lifetime psychiatric conditions, (5) maternal lifetime obesity, (6) paternal lifetime immune-dysregulation, (7) paternal lifetime neuro/developmental conditions, and (8) paternal lifetime psychiatric conditions. We used loglinear analysis to test for sex-differential risks of parental conditions to child ASD diagnosis, followed by logistic regression to evaluate odds ratio (OR). Finally, we calculated a fully adjusted logistic regression model, including all risk conditions and their interaction with child sex. 

Results: An initial 1,511 reports were collected. Only participants without missing data on the variables of interest were entered into the analysis, resulting in 867 reports (children with autism: 203 males, 41 females; control children: 468 males, 155 females). Loglinear analysis showed trends towards significant 3-way interactions among child ASD diagnosis, child sex, and (i) paternal lifetime immune-dysregulation (p=0.067), (ii) maternal lifetime obesity (p=0.066). Follow-up logistic regressions showed trends towards a significant “sex-paternal immune-dysregulation” multiplicative effect (p=0.070, male child plus the condition increased risk, OR=2.064), and a “sex-maternal obesity” multiplicative effect (p=0.074, female child plus the condition increased risk, OR=2.988). In the final model, maternal immune-dysregulation during pregnancy (p=0.013, OR=1.544, 95% CI=1.097-2.171) and paternal lifetime psychiatric condition (p=0.015, OR=1.639, 95% CI=1.099-2.445) increased autism risk independent of sex, while maternal lifetime obesity increased autism risk in a marginally sex-dependent manner, that female child plus the condition increased risk (p=0.052, OR=3.495, 95% CI=0.990-12.346). 

Conclusions: Maternal immune-dysregulation during pregnancy and paternal lifetime psychiatric conditions may increase risk for child ASD diagnosis independent of sex/gender, while maternal lifetime obesity confers a possible heightened risk for ASD in females. Sex/gender-differential effects should be regularly investigated in understanding the risk/protective factors and etiological-developmental mechanisms of autism.