American Journal of Epidemiology Vol. 168, No. 11 ª 2008 The Authors DOI: 10.1093/aje/kwn250 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, Advance Access publication October 21, 2008 distribution, and reproduction in any medium, provided the original work is properly cited.
Original Contribution
Advanced Parental Age and the Risk of Autism Spectrum Disorder
Maureen S. Durkin, Matthew J. Maenner, Craig J. Newschaffer, Li-Ching Lee, Christopher M. Cunniff, Julie L. Daniels, Russell S. Kirby, Lewis Leavitt, Lisa Miller, Walter Zahorodny, and Laura A. Schieve
Initially submitted March 21, 2008; accepted for publication July 16, 2008.
This study evaluated independent effects of maternal and paternal age on risk of autism spectrum disorder. A case-cohort design was implemented using data from 10 US study sites participating in the Centers for Disease Control and Prevention’s Autism and Developmental Disabilities Monitoring Network. The 1994 birth cohort in- cluded 253,347 study-site births with complete parental age information. Cases included 1,251 children aged 8 years with complete parental age information from the same birth cohort and identified as having an autism spectrum disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria. After adjustment for the other parent’s age, birth order, maternal education, and other covariates, both maternal and paternal age were independently associated with autism (adjusted odds ratio for maternal age 35 vs. 25–29 years ¼ 1.3, 95% confidence interval: 1.1, 1.6; adjusted odds ratio for paternal age 40 years vs. 25–29 years ¼ 1.4, 95% confidence interval: 1.1, 1.8). Firstborn offspring of 2 older parents were 3 times more likely to develop autism than were third- or later-born offspring of mothers aged 20–34 years and fathers aged <40 years (odds ratio ¼ 3.1, 95% confidence interval: 2.0, 4.7). The increase in autism risk with both maternal and paternal age has potential implications for public health planning and investigations of autism etiology.
autistic disorder; birth order; maternal age; paternal age
Abbreviations: ASD, autism spectrum disorder; PDD-NOS, pervasive developmental disorders-not otherwise specified.
This paper examines the relation between parental age at autism risk, with at least 3 studies reporting firstborn chil- delivery and the prevalence of autism spectrum disorder dren to be at increased risk of autism (1, 2, 4). The goal of (ASD). The possibility that autism is more common in off- this study was to determine, in a large, population-based spring of older parents has generated considerable interest cohort of US children, whether advancing maternal and (1–6). Confirmation of such an association could have im- paternal age each independently increase a child’s risk of portant public health implications in light of increasing developing autism after controlling for the other parent’s trends in recent decades regarding both maternal and pater- age, birth order, and other risk factors. nal age (7). In addition, evidence of paternal and maternal age effects on autism risk may provide clues to the etiology of a class of neurodevelopmental disorder that is still poorly MATERIALS AND METHODS understood and thought to be complex and multifactoral. Study design and sample In evaluating the association between parental age and autism risk, it is important to account for other variables We implemented a population-based, case-cohort design related to both parental age and autism or that may modify in which the comparison group was a cohort of all livebirths the association. Birth order is a potentially confounding in 1994 in 10 geographically defined study areas participating factor because it is positively associated with parental age in the Centers for Disease Control and Prevention’s Autism and has been reported in some studies to be associated with and Developmental Disabilities Monitoring Network (8). The
Correspondence to Dr. Maureen Durkin, Waisman Center and Departments of Population Health Sciences and Pediatrics, University of Wisconsin School of Medicine and Public Health, 789 WARF, 610 Walnut Street, Madison, WI 53726 (e-mail: [email protected]).
1268 Am J Epidemiol 2008;168:1268–1276 Parental Age and Autism 1269
Table 1. Characteristics of the 1994 Birth Cohort and ASD Cases, 10 Study Sites From the US Centers for Disease Control and Prevention’s Autism and Developmental Disabilities Monitoring Network
All Children Full Birth Birth Cohort Aged 8 Years ASD Cases ASD Cases Cohort: All With Complete With ASD With Any Birth With Complete Livebirths in Information on Residing in Certificate Information on the 10 Study Parental Age the 10 Study Information Parental Age Areas Areas in 2002 No. (%) 326,785 (100) 253,347 (77.5) 2,142 (100) 1,517 (70.8) 1,251 (58.4) Median maternal age, years 27 28 29 29 Median paternal age, years 30 31 Maternal age <20 years, % 13.8 8.5 8.0 5.4 Maternal age 35 years, % 10.9 12.6 16.2 17.2 Boys, % 51.2 51.4 81.2 81.7 81.8 White, % 60.1 67.6 63.1 65.5 69.0 Black, % 23.7 16.5 22.1 22.7 17.2 Hispanic, % 12.0 11.1 10.5 9.3 9.2 Gestational age <37 weeks, % 9.8 8.7 13.6 12.5 Gestational age <28 weeks, % 0.8 0.6 1.9 1.5 Autistic disorder, % 81.0 80.8 80.7 Confirmed intellectual 32.4 32.7 30.9 impairment, %a Confirmed normal 43.2 42.1 43.2 intelligence, %a
Abbreviation: ASD, autism spectrum disorder. a Information to confirm intellectual functioning was missing for approximately 25% of ASD cases.
10 areas are all sites with deidentified birth certificate infor- were excluded because of missing paternal age. The cohort mation on parental age and other relevant variables included in serving as the comparison group thus included the 253,347 the Network database and include sites in Alabama, Arizona, livebirths with complete information on parental age and Arkansas, Colorado, Georgia, Maryland, Missouri, New Jersey, other key variables (Table 1). North Carolina, and Wisconsin. The total number of children aged 8 years residing in the The cohort serving as the comparison group includes all study areas in 2002 determined by the Autism and livebirths to mothers residing in any 1 of the study areas in Developmental Disabilities Monitoring Network surveillance 1994, with complete information available from birth cer- system to have an ASD was 2,142. Birth certificate infor- tificates on maternal and paternal age, birth order, and mation was available for 1,517 (70.8%) of these children, other variables. We used 2 data sources to construct the who were born in the same state as their state of residence in cohort: 1994 deidentified birth records for the Wisconsin 2002. The remaining 29.2% of cases were excluded from study area provided by the Wisconsin Department of this analysis because of missing birth certificate informa- Health and Family Services and, for the remaining sites, tion. The case group for the present analysis was further the National Center for Health Statistics public use natality restricted to the 1,251 children (58.4% of the total ASD case data files (9). The public use file includes county of resi- group) for whom information on both parents’ age as well as dence for births in densely populated counties, which en- birth order and gestational age was available. Our final sam- abled us to ascertain deidentified birth information for all ple was comparable to the total population of ASD cases births in most of the counties. We were unable to precisely regarding demographic factors and ASD case characteristics obtain counts of births occurring in sparsely populated (Table 1). counties in which 13,043 (4.1%) of the study-area births occurred in 1994. For these counties, we obtained county- Case definition level aggregate information on the total number of births in 1994 and their distribution by variables such as maternal ASDs include behaviorally defined neurodevelopmental marital status, ethnicity, and age and selected a stratified disorders diagnosed through clinical observation, and they random sample of deidentified birth records (equal in num- encompass impairments in social, communicative, and be- ber and similar in distribution by maternal marital status, havioral development, often accompanied by abnormalities ethnicity, and age to all livebirths occurring in the respec- in intellectual functioning, learning, attention, and sensory tive counties in 1994) from sparsely populated counties of processing. For this study, children with ASD included the state in which the study area was located. The full co- members of the birth cohort residing in the study area in hort included 326,785 livebirths, of which 73,438 (22.5%) 2002 who met Diagnostic and Statistical Manual of Mental
Am J Epidemiol 2008;168:1268–1276 1270 Durkin et al.
Disorders, Fourth Edition, Text Revision criteria for autistic tinuous variable with the odds ratio scaled to reflect a 10-year disorder; pervasive developmental disorders-not otherwise difference in age (4). Although we found the association specified (PDD-NOS (http://www.cdc.gov/ncbddd/autism/ between parental age and autism risk to be similar across overview_diagnostic_criteria.htm), including atypical au- the 10 sites, to adjust for potential site-to-site variability we tism); or Asperger’s disorder (10) based on a comprehensive included site dummy variables in all multivariable models. review of educational and clinical records by trained clini- To evaluate interaction or modifying effects of each covariate cians. Children were classified by clinician reviewers as and of ASD subtypes on the associations between parental having an ASD if they had either a documented previous age and ASD, we performed stratified analyses. We also tested classification of ASD (65%) or an evaluation record from an interaction terms for maternal age by paternal age and 2-way educational or medical setting indicating unusual behaviors and 3-way interaction terms for each parent’s age by the other consistent with ASD (35%). For children previously identi- covariates in the regression models, but we identified no fied as having an ASD, case status was confirmed on the significant interactions. SAS version 9.1.3 software (SAS basis of evaluation records. For children without a docu- Institute, Inc., Cary, North Carolina) was used for all statis- mented ASD classification, data were abstracted on all rel- tical analyses. evant ASD and developmental behaviors from education or This research involved secondary analysis of deidentified medical evaluations to determine whether behaviors de- data and was approved by the University of Wisconsin scribed in the evaluations by clinical reviewers were consis- Institutional Review Board. tent with the diagnostic criteria. Because case status was determined solely on the basis of information contained in evaluation records, and because Diagnostic and Statistical RESULTS Manual of Mental Disorders, Fourth Edition, Text Revision criteria are less well defined for PDD-NOS than for autistic In unadjusted analyses, both mean maternal age and mean disorder, the surveillance protocol for determining whether paternal age were significantly higher for ASD cases than a child could be classified as having PDD-NOS required for the birth cohort as a whole (Table 2). Table 2 also shows documentation of at least 1 behavior considered to be an that mean parental ages differed significantly in unadjusted ASD discriminator, such as being oblivious to others when analyses across categories of birth order, maternal educa- there is a clear social opportunity or demonstrating atypical tion, ethnicity, multiple birth, gestational age, and birth and persistent focus on sensory input (11). weight for gestational age, but not for gender. With parental Of the 1,251 ASD cases, 80.7% were determined to meet age 25–29 years as the reference group, the odds of develop- criteria for autistic disorder, while there was insufficient in- ing ASD was significantly reduced for parental age <20 years formation for those remaining to distinguish between autis- and increased for maternal age 35 and paternal age 40 tic disorder, Asperger’s disorder, or PDD-NOS. Information years (Table 3, unadjusted odds ratios). We therefore used from standardized intelligence tests was available for ap- these age cutoffs (maternal age 35, paternal age 40 years) proximately 75% of the ASD cases. On the basis of this to classify each parent’s age as ‘‘older’’ versus ‘‘younger.’’ information, children with ASD were classified as having Other significant predictors of ASD in unadjusted analyses intellectual impairment (an IQ of <70) versus normal in- included low birth order, male gender, advanced maternal telligence. Further details regarding the 2002 Autism and education, and preterm birth (Table 3). Developmental Disabilities Monitoring Network sample and methodology have been reported previously (8, 11). Multivariable analysis of parental ages modeled as categorical variables Analytic strategy and statistical methods After we adjusted for the other parent’s age and other Potential for confounding effects of birth order, gender, covariates, the increases in ASD risk associated with mater- and other variables was evaluated by first examining un- nal age 35 years and paternal age 40 years (relative to adjusted associations between each potential confounder and age 25–29 years) were slightly reduced compared with the the independent variables of maternal and paternal age as unadjusted analysis (Table 3). In contrast, the results for well as the dependent variable, ASD case status. Variables birth order suggest that the decline in ASD risk associated were considered to be potentially confounding factors if with increasing birth order is somewhat stronger in the ad- they were associated with both parental age and ASD. Un- justed analysis than in the unadjusted analysis (Table 3). In adjusted odds ratios with confidence intervals were com- addition, the apparent increase in ASD risk associated with puted to evaluate the magnitude of these associations, and higher levels of maternal education in the unadjusted anal- unconditional logistic regression models were fit to estimate ysis is no longer evident in the adjusted model, suggesting adjusted odds ratios and 95% confidence intervals. Statisti- that the apparent maternal education effect is due to its cal significance was evaluated by using chi-square tests for association with parental age (Table 3). categorical variables and analysis of variance for continuous variables. Parental ages modeled as continuous variables To enhance the comparability of our findings with those from other studies, we fit 2 types of models, 1 with parental In unadjusted analyses, the risk of developing ASD in- ages categorized into 6 categories: <20, 20–24, 25–29, 30–34, creased significantly with each 10-year increase in both ma- 35–39, 40 years; and the other with parental age as a con- ternal age and paternal age. After adjustment for age of the
Am J Epidemiol 2008;168:1268–1276 Parental Age and Autism 1271
Table 2. Unadjusted Mean Maternal and Paternal Ages at Delivery for ASD Cases Compared With the Cohort as a Whole, and in the Cohort as a Whole Stratified by Covariate Categories, 1994 Birth Cohort From 10 Study Sites From the US Centers for Disease Control and Prevention’s Autism and Developmental Disabilities Monitoring Network
Mean Age, years No. % Maternal Paternal ASD case status ASD cases 1,251 29.0a 31.4a Birth cohort (comparison group) 253,347 28.0a 30.1a Birth order 1st 105,140 41.3 26.1a 28.3a 2nd 88,065 34.6 28.5a 30.7a 3rd 39,902 15.7 30.0a 32.0a 4th 21,491 8.4 31.5a 33.5a Gender Boys 131,258 51.6 28.0 30.2 Girls 123,340 48.4 28.0 30.1 Maternal education