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    Original Investigation
    April 15, 2020

    Association of Grandparental and Parental Age at Childbirth With Autism Spectrum Disorder in Children

    Author Affiliations
    • 1Department of Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    • 2Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
    • 3Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut
    • 4Yale Center for Perinatal, Pediatric, and Environmental Epidemiology, Yale School of Public Health, New Haven, Connecticut
    • 5The Ministry of Education–Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
    JAMA Netw Open. 2020;3(4):e202868. doi:10.1001/jamanetworkopen.2020.2868
    Key Points español 中文 (chinese)

    Question  Is grandparental age at the time of birth of the parent associated with the risk for autism spectrum disorders (ASDs) in the grandchildren?

    Findings  This Danish national population-based cohort study across 3 generations observed transgenerational associations suggesting that ASD risk in children was elevated if their mothers were born to young (≤19 years) grandparents or if their fathers were born to young (≤19 years) and older (≥40 years) grandparents, compared with children whose parents were born to grandparents aged 25 to 29 years. These associations observed for grandparental hage were independent of possible parental age associations with ASD risk in children.

    Meaning  These findings suggest that the risk of ASD associated with young or advanced grandparental age might be transmitted across generations, which should be considered in future research of the causes of ASD.


    Importance  Advanced parental age has been associated with autism spectrum disorders (ASDs) in children. However, little is known about the association between grandparental age at the time of birth of the parent and the risk of ASD in the grandchildren.

    Objective  To estimate the associations between parental and grandparental age and ASD risk in children.

    Design, Setting, and Participants  This population-based, multigenerational cohort study used data from Danish national health registries. A parental age cohort was constructed to evaluate the association between parental age and ASD in 1 476 783 singleton children born from 1990 to 2013, and a multigenerational cohort was also constructed including 362 438 fathers and 458 234 mothers born from 1973 to 1990 for whom information on grandparental age was available. Data analyses were conducted from November 1, 2018, through February 7, 2020.

    Exposures  Parental age at childbirth and grandparental age at the time of the birth of the parent.

    Main Outcomes and Measures  Diagnoses of ASD in children were obtained from the Danish Psychiatric Central Register (1994-2017). Logistic regression analysis was used to estimate the associations between parental or grandparental age and ASD in children.

    Results  Of the 1 476 783 children born from 1990 to 2013, 758 066 (51.3%) were male, and 27 616 (1.9%) had ASD (20 467 [74.1%] were male). Advanced paternal or maternal age over 30 years was monotonically associated with increased ASD risk, with odds ratios (ORs) of 1.56 (95% CI, 1.45-1.68) for maternal age 40 years and older and 1.57 (95% CI, 1.39-1.78) for paternal age 50 years and older, compared with parents aged 25 to 29 years. In the multigenerational cohort, 9364 grandchildren (1.7%) had ASD. This study found U-shaped associations, in that ASD risk was higher among grandchildren of younger (≤19 years) maternal grandmothers (OR, 1.68; 95% CI, 1.52-1.85), younger maternal grandfathers (OR, 1.50; 95% CI, 1.26-1.78), and younger paternal grandmothers (OR, 1.18; 95% CI, 1.04-1.34), and older (≥40 years) paternal grandmothers (OR, 1.40; 95% CI, 1.03-1.90) compared with the grandchildren of grandparents who were aged 25 to 29 years at the time of giving birth to the parents.

    Conclusions and Relevance  These findings corroborate previous studies suggesting that advanced parental age is independently associated with increased ASD risk in children. This study also found that children with young maternal grandparents and children with young and old paternal grandparents had elevated ASD risk. Possible transmission of ASD risk across generations should be considered in etiological research on ASD.