Association of Grandparental and Parental Age at Childbirth With Autism Spectrum Disorder in Children | Autism Spectrum Disorders | JAMA Network Open | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed. American Psychiatric Association; 1994.
Christensen  DL, Braun  KVN, Baio  J,  et al.  Prevalence and characteristics of autism spectrum disorder among children aged 8 years: Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2012.   MMWR Surveill Summ. 2018;65(13):1-23. doi:10.15585/mmwr.ss6513a1PubMedGoogle ScholarCrossref
Baio  J, Wiggins  L, Christensen  DL,  et al.  Prevalence of autism spectrum disorder among children aged 8 years: Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2014.   MMWR Surveill Summ. 2018;67(6):1-23. doi:10.15585/mmwr.ss6706a1PubMedGoogle ScholarCrossref
Hansen  SN, Schendel  DE, Parner  ET.  Explaining the increase in the prevalence of autism spectrum disorders: the proportion attributable to changes in reporting practices.   JAMA Pediatr. 2015;169(1):56-62. doi:10.1001/jamapediatrics.2014.1893PubMedGoogle ScholarCrossref
Lyall  K, Croen  L, Daniels  J,  et al.  The changing epidemiology of autism spectrum disorders.   Annu Rev Public Health. 2017;38:81-102. doi:10.1146/annurev-publhealth-031816-044318PubMedGoogle ScholarCrossref
Kim  JY, Son  MJ, Son  CY,  et al.  Environmental risk factors and biomarkers for autism spectrum disorder: an umbrella review of the evidence.   Lancet Psychiatry. 2019;6(7):590-600. doi:10.1016/S2215-0366(19)30181-6PubMedGoogle ScholarCrossref
Myrskylä  M, Silventoinen  K, Tynelius  P, Rasmussen  F.  Is later better or worse? association of advanced parental age with offspring cognitive ability among half a million young Swedish men.   Am J Epidemiol. 2013;177(7):649-655. doi:10.1093/aje/kws237PubMedGoogle ScholarCrossref
Durkin  MS, Maenner  MJ, Newschaffer  CJ,  et al.  Advanced parental age and the risk of autism spectrum disorder.   Am J Epidemiol. 2008;168(11):1268-1276. doi:10.1093/aje/kwn250PubMedGoogle ScholarCrossref
Grether  JK, Anderson  MC, Croen  LA, Smith  D, Windham  GC.  Risk of autism and increasing maternal and paternal age in a large north American population.   Am J Epidemiol. 2009;170(9):1118-1126. doi:10.1093/aje/kwp247PubMedGoogle ScholarCrossref
Lampi  KM, Hinkka-Yli-Salomäki  S, Lehti  V,  et al.  Parental age and risk of autism spectrum disorders in a Finnish national birth cohort.   J Autism Dev Disord. 2013;43(11):2526-2535. doi:10.1007/s10803-013-1801-3PubMedGoogle ScholarCrossref
Parner  ET, Baron-Cohen  S, Lauritsen  MB,  et al.  Parental age and autism spectrum disorders.   Ann Epidemiol. 2012;22(3):143-150. doi:10.1016/j.annepidem.2011.12.006PubMedGoogle ScholarCrossref
Wu  S, Wu  F, Ding  Y, Hou  J, Bi  J, Zhang  Z.  Advanced parental age and autism risk in children: a systematic review and meta-analysis.   Acta Psychiatr Scand. 2017;135(1):29-41. doi:10.1111/acps.12666PubMedGoogle ScholarCrossref
Iossifov  I, Ronemus  M, Levy  D,  et al.  De novo gene disruptions in children on the autistic spectrum.   Neuron. 2012;74(2):285-299. doi:10.1016/j.neuron.2012.04.009PubMedGoogle ScholarCrossref
Kong  A, Frigge  ML, Masson  G,  et al.  Rate of de novo mutations and the importance of father’s age to disease risk.   Nature. 2012;488(7412):471-475. doi:10.1038/nature11396PubMedGoogle ScholarCrossref
Sandin  S, Hultman  CM, Kolevzon  A, Gross  R, MacCabe  JH, Reichenberg  A.  Advancing maternal age is associated with increasing risk for autism: a review and meta-analysis.   J Am Acad Child Adolesc Psychiatry. 2012;51(5):477.e1-486.e1. doi:10.1016/j.jaac.2012.02.018PubMedGoogle ScholarCrossref
McCarthy  DM, Morgan  TJ  Jr, Lowe  SE,  et al.  Nicotine exposure of male mice produces behavioral impairment in multiple generations of descendants.   PLoS Biol. 2018;16(10):e2006497. doi:10.1371/journal.pbio.2006497PubMedGoogle Scholar
Sampino  S, Juszczak  GR, Zacchini  F,  et al.  Grand-paternal age and the development of autism-like symptoms in mice progeny.   Transl Psychiatry. 2014;4:e386. doi:10.1038/tp.2014.27PubMedGoogle Scholar
Choi  CS, Gonzales  EL, Kim  KC,  et al.  The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy.   Sci Rep. 2016;6:36250. doi:10.1038/srep36250PubMedGoogle ScholarCrossref
Golding  J, Ellis  G, Gregory  S,  et al.  Grand-maternal smoking in pregnancy and grandchild’s autistic traits and diagnosed autism.   Sci Rep. 2017;7:46179. doi:10.1038/srep46179PubMedGoogle ScholarCrossref
Kioumourtzoglou  MA, Coull  BA, O’Reilly  EJ, Ascherio  A, Weisskopf  MG.  Association of exposure to diethylstilbestrol during pregnancy with multigenerational neurodevelopmental deficits.   JAMA Pediatr. 2018;172(7):670-677. doi:10.1001/jamapediatrics.2018.0727PubMedGoogle ScholarCrossref
Frans  EM, Sandin  S, Reichenberg  A,  et al.  Autism risk across generations: a population-based study of advancing grandpaternal and paternal age.   JAMA Psychiatry. 2013;70(5):516-521. doi:10.1001/jamapsychiatry.2013.1180PubMedGoogle ScholarCrossref
Frans  EM, McGrath  JJ, Sandin  S,  et al.  Advanced paternal and grandpaternal age and schizophrenia: a three-generation perspective.   Schizophr Res. 2011;133(1-3):120-124. doi:10.1016/j.schres.2011.09.027PubMedGoogle ScholarCrossref
Schendel  DE, Overgaard  M, Christensen  J,  et al.  Association of psychiatric and neurologic comorbidity with mortality among persons with autism spectrum disorder in a Danish population.   JAMA Pediatr. 2016;170(3):243-250. doi:10.1001/jamapediatrics.2015.3935PubMedGoogle ScholarCrossref
Bliddal  M, Broe  A, Pottegård  A, Olsen  J, Langhoff-Roos  J.  The Danish medical birth register.   Eur J Epidemiol. 2018;33(1):27-36. doi:10.1007/s10654-018-0356-1PubMedGoogle ScholarCrossref
Munk-Jørgensen  P, Kastrup  M, Mortensen  PB.  The Danish psychiatric register as a tool in epidemiology.   Acta Psychiatr Scand Suppl. 1993;370:27-32. doi:10.1111/j.1600-0447.1993.tb05358.xPubMedGoogle ScholarCrossref
Nissen  J, Powell  S, Koch  SV,  et al.  Diagnostic validity of early-onset obsessive-compulsive disorder in the Danish Psychiatric Central Register: findings from a cohort sample.   BMJ Open. 2017;7(9):e017172. doi:10.1136/bmjopen-2017-017172PubMedGoogle Scholar
Maenner  MJ, Schieve  LA, Rice  CE,  et al  Frequency and pattern of documented diagnostic features and the age of autism identification.   J Am Acad Child Adolesc Psychiatry. 2013;52(4):401-413. doi:10.1016/j.jaac.2013.01.014PubMedGoogle ScholarCrossref
Li  J, Vestergaard  M, Obel  C, Cnattingus  S, Gissler  M, Olsen  J.  Cohort profile: the Nordic Perinatal Bereavement Cohort.   Int J Epidemiol. 2011;40(5):1161-1167. doi:10.1093/ije/dyq127PubMedGoogle ScholarCrossref
Lee  BK, McGrath  JJ.  Advancing parental age and autism: multifactorial pathways.   Trends Mol Med. 2015;21(2):118-125. doi:10.1016/j.molmed.2014.11.005PubMedGoogle ScholarCrossref
Sandin  S, Schendel  D, Magnusson  P,  et al.  Autism risk associated with parental age and with increasing difference in age between the parents.   Mol Psychiatry. 2016;21(5):693-700. doi:10.1038/mp.2015.70PubMedGoogle ScholarCrossref
Idring  S, Magnusson  C, Lundberg  M,  et al.  Parental age and the risk of autism spectrum disorders: findings from a Swedish population-based cohort.   Int J Epidemiol. 2014;43(1):107-115. doi:10.1093/ije/dyt262PubMedGoogle ScholarCrossref
Croen  LA, Najjar  DV, Fireman  B, Grether  JK.  Maternal and paternal age and risk of autism spectrum disorders.   Arch Pediatr Adolesc Med. 2007;161(4):334-340. doi:10.1001/archpedi.161.4.334PubMedGoogle ScholarCrossref
Golding  J, Steer  C, Pembrey  M.  Parental and grandparental ages in the autistic spectrum disorders: a birth cohort study.   PLoS One. 2010;5(4):e9939. doi:10.1371/journal.pone.0009939PubMedGoogle Scholar
Girard  SL, Bourassa  CV, Lemieux Perreault  LP,  et al.  Paternal age explains a major portion of de novo germline mutation rate variability in healthy individuals.   PLoS One. 2016;11(10):e0164212. doi:10.1371/journal.pone.0164212PubMedGoogle Scholar
Gratten  J, Wray  NR, Peyrot  WJ, McGrath  JJ, Visscher  PM, Goddard  ME.  Risk of psychiatric illness from advanced paternal age is not predominantly from de novo mutations.   Nat Genet. 2016;48(7):718-724. doi:10.1038/ng.3577PubMedGoogle ScholarCrossref
Ni  G, Gratten  J, Wray  NR, Lee  SH; Schizophrenia Working Group of the Psychiatric Genomics Consortium.  Age at first birth in women is genetically associated with increased risk of schizophrenia.   Sci Rep. 2018;8(1):10168. doi:10.1038/s41598-018-28160-zPubMedGoogle ScholarCrossref
Mehta  D, Tropf  FC, Gratten  J,  et al; Schizophrenia Working Group of the Psychiatric Genomics Consortium, LifeLines Cohort Study, and TwinsUK.  Evidence for genetic overlap between schizophrenia and age at first birth in women.   JAMA Psychiatry. 2016;73(5):497-505. doi:10.1001/jamapsychiatry.2016.0129PubMedGoogle ScholarCrossref
Sharma  R, Agarwal  A, Rohra  VK, Assidi  M, Abu-Elmagd  M, Turki  RF.  Effects of increased paternal age on sperm quality, reproductive outcome and associated epigenetic risks to offspring.   Reprod Biol Endocrinol. 2015;13:35. doi:10.1186/s12958-015-0028-xPubMedGoogle ScholarCrossref
Puleo  CM, Reichenberg  A, Smith  CJ, Kryzak  LA, Silverman  JM.  Do autism-related personality traits explain higher paternal age in autism?   Mol Psychiatry. 2008;13(3):243-244. doi:10.1038/ ScholarCrossref
McGrath  JJ, Petersen  L, Agerbo  E, Mors  O, Mortensen  PB, Pedersen  CB.  A comprehensive assessment of parental age and psychiatric disorders.   JAMA Psychiatry. 2014;71(3):301-309. doi:10.1001/jamapsychiatry.2013.4081PubMedGoogle ScholarCrossref
Alio  AP, Mbah  AK, Grunsten  RA, Salihu  HM.  Teenage pregnancy and the influence of paternal involvement on fetal outcomes.   J Pediatr Adolesc Gynecol. 2011;24(6):404-409. doi:10.1016/j.jpag.2011.07.002PubMedGoogle ScholarCrossref
Boden  JM, Fergusson  DM, John Horwood  L.  Early motherhood and subsequent life outcomes.   J Child Psychol Psychiatry. 2008;49(2):151-160. doi:10.1111/j.1469-7610.2007.01830.xPubMedGoogle ScholarCrossref
Huber  S, Bookstein  FL, Fieder  M.  Socioeconomic status, education, and reproduction in modern women: an evolutionary perspective.   Am J Hum Biol. 2010;22(5):578-587. doi:10.1002/ajhb.21048PubMedGoogle ScholarCrossref
Durkin  MS, Maenner  MJ, Meaney  FJ,  et al.  Socioeconomic inequality in the prevalence of autism spectrum disorder: evidence from a U.S. cross-sectional study.   PLoS One. 2010;5(7):e11551. doi:10.1371/journal.pone.0011551PubMedGoogle Scholar
Yeshurun  S, Hannan  AJ.  Transgenerational epigenetic influences of paternal environmental exposures on brain function and predisposition to psychiatric disorders.   Mol Psychiatry. 2019;24(4):536-548. doi:10.1038/s41380-018-0039-zPubMedGoogle ScholarCrossref
Lauritsen  MB, Jørgensen  M, Madsen  KM,  et al.  Validity of childhood autism in the Danish Psychiatric Central Register: findings from a cohort sample born 1990-1999.   J Autism Dev Disord. 2010;40(2):139-148. doi:10.1007/s10803-009-0818-0PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    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.