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    Autismo

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    9 views7 pages

    Idade Paterna e Autismo

    Uploaded by

    Clara Nascimento
    Autismo

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
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    — Advancing Paternal Age and Autism Abraham Reichenberg, PhD; Raz Gross, MD, MPH: Mark Weiser, MD; Michealine Bresnahan, PhD: Jeremy Silverman, PhD; Susan Harlap, MBBS, Jonathan Rabinowitz, PhD; Cory Shulman, PhD: Dolores Malaspina, MD; Gad Lubin, MD; Haim Y. Knobler, MD; Michael Davidson, MD; Ezra Susser, MD, DrPH Context: Maternal and paternal ages are associated with neurodevelopmental disorders Objective: To examine the relationship between ad- vancing paternal age at birth of offspring and their risk of autism spectrum disorder (ASD). Design: Historical population-based cohort study Setting: Identification of ASD cases from the Israeli draft board medical registry Partleipants: We conducted a study of Jewish per- sons born in Israel during 6 consecutive years. Virtually all men and about three quarters of women in this co- hort underwent draft board assessment at age 17 years. Paternal age at bitth was obtained for most of the co- hort: maternal age was obtained for a smaller subset, We used the smaller subset (n=132 271) with data on both paternal and maternal age for the primary analysis and the larger subset (n=318 506) with data on paternal but not maternal age for sensitivity analyses. Main Outcome Measures: Information on persons coded as having International Classification of Diseases, 10th Revision ASD was obtained from the registry. The registry identified 110 cases of ASD (incidence, 8.3 cases per 10000 persons), mainly autism, in the smaller sub- set with complete parental age data Results: There was a significant monotonic association between advancing paternal age and risk of ASD. Off- spring of men 40 years or older were 5.75 times (05% con- fidence interval, 2.5-12.40; P<.001) more likely to have ASD compared with ollspring of men younger than 30 years, alter controlling for year of birth, socioeconomic status, and ‘maternal age. Advancing maternal age showed no associ tion with ASD after adjusting for paternal age. Sensitivity analyses indicated that these findings were not the resul of bias due to missing data on maternal age Conelusions: Advanced paternal agewas associated with, increased risk of ASD. Possible biological mechanisms include de novo mutations associated with advancing age or alterations in genetic imprinting, Arch Gen Psychiatry. 2006;63:102 I STUDY INVESTIGATED whether advancing pater- nal age at birth of offspring fs associated with an in- creased risk of autism spec- {s partly artifactual, owing to improved di- ‘agnostic accuracy, changes in diagnostic cri teria, earlier detection, and increased aware- ness of types of ASD other than autism However, it may also partly reflect a true snerease in the incidence of ASD." Author Affiliations are listed at the end of this article trum disorder (ASD) in offspring, Autism {sa chronie disorder with an onset by age 3 years, characterized by the following 3 ‘main sets of behavioral disturbances: so- cial abnormalities, language abnormali- ties, and stereotyped, repetitive patterns of behavior." In the International Classfiea- tion of Diseases, 10th Revision (ICD-10), ASD. also includes atypical autism, Asperger syn- drome, Rett syndrome, overreactive disor- der, childhood disintegrative disorder, and. pervasive developmental disorders, which are believed tobe etiologically related to au- ism, Prevalence estimates of ASD in- creased dramatically during the past 2 de- * from approximately 5 cases 10 50 ceases per 10000 children.°* The increase “Maternal and paternal ages have been as- sociated with other neurodevelopmental disorders and have been considered in some previous studies of ASD. Advancing ma- {eral age increases the risk of chromo- somal abnormalities such as Down syn- drome” and has been associated with the risk of brain damage during pregnancy,” dyslexia," and mental retardation of known cause.” Studies?™ on the associa- tion between advancing maternal age and risk of ASD have reported mixed results Among 5 recent epidemiological studies,3 studies!" did not find advancing mater nal age to be a risk factor for ASD, while the other 2 studies!” did (among the lat (©2006 American Medical Association. AI rights reserved, ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/18914/ on 05/08/2017 ter 2 studies, only the study by Glasson etal adjusted for paternal age) Older age of the father at birth of offspring has been associated with several congenital disorders, including ‘Apert syndrome," craniosynostosis,” situs inversus” syn- dactyly" cleft lip oF cleft palate," and hydrocepha- Jus" Advaneing paternal age hasalso been associated with an increased risk of schizophrenia?” and with de- creased intellectual eapacity®” in offspring. In some in- stances (eg, Apert syndrome), the association is ex- plained by the increased risk of de novo genetie mutations in the germline of older fathers." Therefore, one of the reasons for examining the relationship between pater- nal age and ASD is that it may provide elues to the bio- logical pathways leading to ASD. ‘Suggestions ofan association between paternal ageand ASD can be traced back to the 1970s," and stud= ies?!" of ASD have reported paternal age Irequen- cies among numerous other variables. However, few stud- ies have systematically examined this association in rigorous designs that included adjustment for maternal age. The results of 3 recent case-control studies were mixed: 2 studies" found advancing paternal age to be a risk factor for ASD, while the other study" did not The present investigation was ahistorical population- based cohort study specifically designed for a rigorous test of the hypothests that advaneing paternal age is as- sociated with inereased risk of ASD in offspring. The co- hhort members were born in Israel during 6 consecutive years and were assessed by the Israeli dralt board at age 17 years. To our knowledge, this isthe first epidemio logical study using an entire cohort and focusing on the paternal age hypothesis. Our analyses ineluded adjust- ‘ment for maternal age and other potential confounders. ss} This study i based on a cohort of Jewish persons born in Is rael during@ consecutive yearsin the 1980s A toal of 378801 individuals in this o-year birth cohort were assessed by the l= rac draft board at age 17 yeas. Linkage tothe lrall Bureau of Statics indicated that 98% ofthe boysand 75% ofthe gels i the cohort wh had survived the fst year of lie were in cluded the draft board egity. The proportion sloweramong, women because orthodox Jewish women (about 25% of wom fn) are exempted rom military induction, The draft board de- termines intelectual, medical, and psychiatric ligt Tor com palsory mary service. The drat bord etry data Were used Ty oan dato paren at ith and wo ob tain the diagnose outcomes among te cohort tage 17 yeas ts descbed herein. * “_ ‘Aller receiving local human subjects committe approval a dwafile of the fll cohort was crated by the managers of the dattboard registry database. The data ile was stripped of den ttle; only dedenfied data were used by the investigators PARENTAL AGE AT BIRTH Israeli citizens are given a unique identification number at birth borat award ofleracli eitizenship. The draft board data for an in- dluctee often include the identification numbers ofthe indict ces parents. In these instances, the identification numbers ofthe parents were linked to the parents draft boatd assessments at age (aernosrep) ARGH GEN PNCHIATRUVOL ST, SEP 17 yearsand, when appa, othe pres military servi les With the inductees dae of bith and the maternal nd paternal ics obi is posable o compte the patel mer tal age atthe time ef bith ofthe induce, Gt 378901 cohort members assessed by the draft board 318506 (41%) had data on pateral age a birth (herater, the larger cohord. There were 2 reasons for missing dts on Paternal age. First, individuals emigrating to sacl after age 33 Jearsare oc required to repor tothe drat board. Secon the Saft board inte computerized databases nly inthe 1960s Inlight ofthese reasons We suspect tht paternal age data were tore likely to be missing for cohort members with alder lc thers than for those wth younger fathers Data on maternal age at birth were ebtaned for 132271 (415%) ofthe cohort members wth paternal age dats (here aftr, the smaller coho). There were 2 main reasons why i tras much more difficult to obtain data on maternal age than On paternal age at bith First, when dat board data om par nis were unavailable the parental data could be obtained rom theses kept onsndivials native military service (eo ‘he reserve Fores) ths pertained mainly o mien beense ince women Were notinacivewrice, Secale oted ea ler, orthodox Jewish women (abot 25% of women) are ex- tmp fom malay service andareunassssed bythe dra bord ASD OUTCOMES ‘The draft board assigns ICD-10 diagnoses. Paychiatricdiag- noses are assigned by 2 board-certified psychiatrist expert- ced in reatingadolescent.Thestandart procedure or psy chiatric dlagnosis includes face-to-face assesment as descrbed ideal elsewhere For individuals with developmental ds- abilities (including ASD), the standard procedure ts modified. ‘Atage 17 years, thelr medical status ts reported in detal to the draft board by government agencies and other organizations respontable for her care snd protection. uch reports include the current diagnosis according to contemporary criteria, The original childhood diagnose ad subsequent eine sony ‘ptoage 17 yearearealeo commonly reported. The daft board generally assigns adiagnoss based om review ofthese matei- Ae rather than face-tovfaceasessnen For individuals with ASD, the responsible agency isthe not- for profi israel Sotety for Autistic Chldren (SAC). The SAC twas established in 1974, and its services recive wide publicy de media coverage, emphasizing ther nonselective svallbi- iy, ligt for specialized heath services ofr any other form o federal support including tax credits, depends on reporting to the SAC: Consequently, virtually all children and alee Cente diagnosed as having ASD are egstered wih the ISAC. In- dividuals are generally refered to the ISAC by specialists at child development center. Israel has universal heath insurance overage that guaranees equal accesso health services, eg ies of employment status orsocoeconomic statu. al infants and preschool children are regularly seen at well-child care cin- ics and undergo routine medical and developmental screening Those withsuspeced developmental disables re efered for assessment at acid development centr where chldren with $spected ASD are evaluate by bosndcetiied clinica spe- Gializing in childhood developmental disorders, Diagnose ‘yplaly made by atm that includes apeyehatit, clin py chologist, and speech pathologist or occupational therapist de- pending on clinal manfetatons. Theinsruments include pa ental ierviews diect testing ofthe child, and observations in faturalsic settings including the home or educational loca tion. At the time of tial dagnossof cases in the present co- hor the standard insirument for diagnosis nse eae was the Childhood Autism Rating Seale" Inividals who ae diag- bose as having ASD ae thes regsered withthe ISAC or on (©2006 American Medical Association. AI rights reserved, ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/18914/ on 05/08/2017 {going care and evaluation, At age 17 years their medical status fe reported to the draft board “The draft board regsry docs not diferente the specific {cD-I0diagioses within ASD, which include nism, atypical a tim, Aspenger syndrome, Rt syndrome, ovrreactve disorder, childhood disintegrate disorder, and pervasive developmental tlsordes. For resons, however, ssa to scume ta mos individuals with ASD daghoses met [CD-10 exterior a dig toss of aut pre, First, thee Individual were orignal di ‘gnosed and followed up during the 1980s and early 19905 when ihe diagnosis of ais was narow and uncommon, and dig: nowesof ASD such ax Asperger syndrome were rt Asperger sy dome was asgned aunque Icb-10diaposiclstication code only in 1902), The ISAC records of individuals eisteed during the childhood years of he cohort almost exclusively indicates dlagnosis of autism, Second, although we were unable to eas sesraubjectsinourcohiort beease coor mnembersin ths study are anonymous, ve have ben ascertaining subjects with asm from the ISAC reiry a part of another study. The Autism Di agnostic Interven Revised i administered to these subjects “Twenty-wo such subjects were born during the years fhe pre- sent siudy cohort, and diagnostic ceria for autism acconding tothe Aus Diagnostic Interview-Revised algorithm were u He or all 32 subject. * " PATTERN OF MISSING DATA ternal age was mare likly tobe missing fr ASD than non ASD cohort members 35% vs 10%; xi 84 75, P= 001). Thi would beeapeced sugested cae indiidals toler tnhers were more ikl abe missing datacom pacrnal age and i Gas suggested by our result) individuals with olde fathers reveal ki tohave a0 forsee eso he com Binaion of having both ASD and an alder ater was associ sted with aving sing dalam pera ge, this would is reels toward the nll of no asoeation beeen paternal ge tnd ASD, Maternal age wa slay mlsingfor ASD sad not ASD cohort members GOK v= 38% 71-0008, P89), Linkage tothe lracl Bure of Slate nda that the itr tom of maternal age nour cohort was smi othe tb ton of eatrnal agen the elie cohort born during the tel vant ents, wih isin nderepresctiation folder mabe DATA ANALYSIS ‘The primary data analysis was conducted in the smaller subset 32271). Logistic regression analysis was used to exam- ine the associations between parental age and isk of ASD. When adjusting paternal age for maternal age, or vice versa, paternal age and maternal age were consistently defined (ie, both were treated as continuous or categorical variables i the regression models). Odds ratios (ORs) and 95% confidence intervals (CIs) were computed. P values were calculated using Wald x, and the significance level was se at P=05 (2sided). All analyses were conducted using SAS statistical software (SAS Institute Cary, NC) at the Department of Mental Health ofthe Medical Corps, Israel Defense Forces. MODELING OF PATERNAL AGE We first examined paternal age using categorical measure to allow fora nonlinear elfet of paternal age on the tsk of ASD. Paternal age was divided into the following 4 age categories: 15 10 29 years (referent category), 301039 yeas, 40 10 49 years, and 50 years or older. For the unadjusted result, we ited pa- ternal age as the only predictor of ASD. For the adjusted 1e- sult, we also included in the model the following 3 variables (aernosrep) ARGH GEN NCHIATRUVOL ST, EPS found tobe associated with both paternal age and risk of ASD (ie, potential confounders): year of birth? socioeconomic ta- tus and maternal age" Socioeconomic status was based on paternal years of educational achievement which was avall- SHE from the draft bord, Because of statstial power constd- erations the oldest paternal ge categories (40-49 and =50 years) swere combined in te adjusted analysis, We used the Cochran [Armitage rend testo examine linear tend in the relatonship ietween paternal age and sk of ASD. We then examined pa ternal age asa continious variable. For ease of interpretation, results forage se continuous variable are presented in terms ofa 10-year increase in paternal age. MODELING OF MATERNAL AGE “The same procedures were repeated to assess the association be- ‘ween maternal ageand ASD. Therefore, maternal age was mod- cled first as «categorical variable. We divided maternal age into the following 3 age groups consistent wit the paternal age cat fegories: 15 to 20 years, 30 to 39 years, and 40 years or olde, ‘Maternal age was then analyzed as. continuous variable (OFFSPRING SEX We then examined resis for male and female ofsring sep rately. This as done in pat because dierent eiclogies ay Pertan to male and female subjects wth ASD. was aso done {safeguard against bss duc to lost ellow-up. As noted tari almost amen but only about three quarters of women inthe birth cohort were ascertained bythe dal bard tage 17 years An analysis restrcied onal ollpring would be ne aMfected by bus due to loss to fllow-ap, SENSITIVITY ANALYSES For? sensitivity analyses, we used the lagersubsl (n=318500) These analyses were designed to gage potential bas nthe pri- tnaryanalysiedue to he exclusion of individuals missing daton tnateral age.” Fis, na caegorical da analysis, we imputed tnssingmnteral age with values obtained by mean of linea tn- {erpolationbased on paternal age. We regressed maternal agen paternal age in he cor th complet parenl age dat pre~ Ucted maternal age values were based on this linear reresion ‘model, Second, aa further safeguard, we simulated an exreme ‘cenariof confounding hy maternal age although the pattern of Iissingdataon maternal ge doesnot suggest diferent lows for [ASD cates all non-ASD cohort members wih misig data on tnateral ge were randomly sxigned o maternal age categories inracs th eroured ta he dtibuton of teed oe the subst withpateral age dala wasequivaent tothe censusbureat dlsibutiowofmateralageat fri in the cohort years: The ASD ohor members with missing dataon maternal age-were then as- signed to maternal ageestegories bced onthe Caney premise {hatmaternalagewas much moreliely tobe missing forthe old- tstiaternal ge group (=40 years) For heanahysig we assumed 4 10-old higher rate of ASD inthis group than that observed in thecohort wed forthe primary analyse The emalning subjects ‘with ASD with missing dala onmateralagewereasgnedinqua Proportions tothe other 2 maternal age categories. EE The risk of ASD was 8 4cases per 10 000 persons (310 eases) among all individuals in the cohort who were assessed by the draft board, 8.3 cases per 10000 persons (110 cases) (©2006 American Medical Association. AI rights reserved, ‘Downloaded From: http:/jamanetwork.com/pdfaccess.ashx?url=/data/journals/psych/18914/ on 05/08/2017 Table 1. Associations Between Paternal Age and Risk of Aullsm Spectrum Disorder (ASD) Inthe Smaller Subset With Data on Both Paternal and Maternal Age ‘Unaahsted oF ise (exec) value Pan a 10000 4.00 700 @ 810000 © 1.64(1.08-250) 2162 (000265) 06 % a2joom © SaS(28e-1071) © <0 752651246 ©

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