Parental Age and the Risk of Autism Spectrum Disorders – Findings from a Swedish Population-Based Cohort

Background:  There is evidence that both maternal and paternal age are independently associated with increased risk for ASD. However, as it is increasingly apparent that ASD represent a heterogeneous group of disorders with potentially different etiologies, there is a need of studies of parental age effects on different phenotypes of ASD. To date, few studies have examined whether associations between parental age and ASD differ by intellectual disability (ID), which is the most frequent co-occurring condition in ASD and associated with poor outcome.

Moreover, the majority of previous studies of parental age and ASD have used categorical parameterizations of parental age. While categorical parameterizations allow for easily interpretable results, continuous parameterizations of age allow for flexible, non-linear associations that are frequently less biased and more efficient. We used penalized cubic regression smoothing splines implemented in generalized additive models (GAMs) to model the independent, and mutually dependent associations of maternal and paternal age and risk of offspring ASD, subtyped by co-morbid ID, using a large, Swedish total-population-based cohort. We estimated whether parental age effects were affected by adjustment for known and potential confounders, and tested whether our results were robust to influences from extreme parental age, or a genetic condition associated with advanced maternal age and ASD.

Objectives:  The objectives of this study were to examine the independent and dependent associations of maternal and paternal age and risk of offspring autism spectrum disorders (ASD), with and without intellectual disability (ID).

Methods:  The sample consisted of 417,303 Swedish children born 1984-2003. ASD case status (N=4746) was ascertained using national and regional registers. Smoothing splines in generalized additive models accounting for interactions of maternal and paternal were used to estimate associations of parental age with ASD.

Results:  While advancing parental age increased the risk of child ASD, maternal age effects were non-linear while paternal age effects were linear. Compared to mothers at the median age 29 years, those ≤29 had similar risk, while risk increased after age 30, with an OR of 1.76 (95% CI: 1.63-1.90) at ages 40-45. For fathers, compared to the median age 32 years, the OR for ages 55-59 was 1.39 (1.29-1.50).  In analyses stratified by co-parental age, increased risk due to advancing paternal age was evident only in mothers ≤ 35 years. In contrast, maternal age increased risk regardless of paternal age. Advancing parental age was more strongly associated with ASD with ID, compared to without ID.  

Conclusions:  We confirm prior findings that advancing parental age increases risk of ASD in a manner dependent on co-parental age. While recent attention has emphasized the effects of older fathers on ASD risk, an increase of N years in maternal age has greater implications for ASD risk than a similar increase in paternal age.