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No Evidence for a New Variant of Measles-Mumps-Rubella–Induced Autism

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No Evidence for a New Variant of Measles-Mumps-Rubella–Induced Autism No Evidence for A New Variant of Measles-Mumps-Rubella–Induced Autism Eric Fombonne, FRCPsych*, and Suniti Chakrabarti, FRCPCH, MRCP‡ ABSTRACT. Objective. A link has been postulated estimates and is not suggestive of an increased frequency between measles-mumps-rubella (MMR) vaccine and a of this form of pervasive developmental disorder in sam- form of autism that is a combination of developmental ples of children who are immunized with MMR. There regression and gastrointestinal symptoms that occur was no difference in the mean age at first parental con- shortly after immunization. This hypothesis has in- cern between the 2 samples exposed to MMR (19.3 and volved 3 separate claims: 1) that there is new phenotype 19.2 months) and the pre-MMR sample (19.5 months). of autism involving regression and gastrointestinal Thus, MMR immunization was not associated with a symptoms, 2) that this new variant is responsible for the shift toward an earlier age for first parental concerns. alleged rise of autism rates, and 3) that this phenotype is Similarly, the rate of developmental regression reported associated with biological findings suggestive of the per- in the post-MMR sample (15.6%) was not different from sistence of measles infection. We tested the first of these that in the pre-MMR sample (18.4%); therefore, there was claims. If this new “autistic enterocolitis” syndrome had no suggestion that regression in the developmental some validity, then 1 or several of the following 6 pre- course of autism had increased in frequency since MMR dictions should be supported by empirical data: 1) child- was introduced. In the epidemiologic sample, the subset hood disintegrative disorder has become more frequent, of autistic children with regression had no other devel- 2) the mean age of first parental concern for autistic opmental or clinical characteristics, which would have children who are exposed to MMR is closer to the mean argued for a specific, etiologically distinct phenotype. immunization age than in children who are not exposed Parents of autistic children with developmental regres- to MMR, 3) regression in the development of children sion detected the first symptoms at a very similar age with autism has become more common in MMR-vacci- (19.8 months) to those of autistic children without regres- nated children, 4) the age of onset for autistic children sion (19.3 months). Moreover, the mean intervals from with regression clusters around the MMR immunization MMR immunization to parental recognition of autistic date and is different from that of autistic children with- symptoms were comparable in autistic children with or out regression, 5) children with regressive autism have without regression (248 vs 272 days; not significant). In distinct symptom and severity profiles, and 6) regressive the epidemiologic sample, gastrointestinal symptoms autism is associated with gastrointestinal symptoms were reported in 18.8% of children. Constipation was the and/or inflammatory bowel disorder. most common symptom (9.4%), and no inflammatory Methods. Three samples were used. Epidemiologic bowel disorder was reported. Furthermore, there was no data on 96 children (95 immunized with MMR at a me- association between developmental regression and gas- dian age of 13.5 months) who were born between 1992 trointestinal symptoms (odds ratio: 0.63; 95% confidence and 1995 and had a pervasive developmental disorder interval: 0.06–3.2; not significant), and only 2.1% of the diagnosis as reported in a recent UK survey (post-MMR sample experienced both problems, a rate that did not sample) were compared with data from 2 previous clini- exceed chance expectations. ؍ ؍ cal samples (1 pre-MMR [n 98] and 1 post-MMR [n Conclusions. No evidence was found to support a 68]) of autistic patients. All patients were assessed with distinct syndrome of MMR-induced autism or of “autis- the standardized Autism Diagnostic Interview (ADI), al- tic enterocolitis.” These results add to the recent accumu- lowing rigorous comparison of age at first parental con- lation of large-scale epidemiologic studies that all failed cerns and rates of regression across samples. Reliability to support an association between MMR and autism at was excellent on ADI scores, age of parental concern, and population level. When combined, the current findings developmental regression. Furthermore, data on bowel do not argue for changes in current immunization pro- symptoms and disorders were available in the epidemi- grams and recommendations. Pediatrics 2001;108(4). ologic survey from both pediatric and parental sources, URL: http://www.pediatrics.org/cgi/content/full/108/4/ and immunization dates were obtained from computer- e58; autism, immunization, MMR, regression, epidemiol- ized records. ogy. Results. The prevalence of childhood disintegrative disorder was 0.6/10 000 (95% confidence interval: 0.02– 3.6/10 000); this very low rate is consistent with previous ABBREVIATIONS. PDD, pervasive developmental disorders; CDD, childhood disintegrative disorder; ADI-R, Autism Diagnos- tic Interview-Revised; MHC, Maudsley Hospital Clinical; MFS, From the *Institute of Psychiatry, Department of Child and Adolescent Maudsley Family Study; SD, standard deviation. Psychiatry, King’s College London, London, United Kingdom; ‡Child De- velopment Center, Central Clinic, Stafford, United Kingdom. Received for publication Mar 26, 2001; accepted May 25, 2001. utism is a severe developmental disorder that Reprint requests to (E.F.) Department of Child Psychiatry, Montreal Chil- involves delay and deviance in the develop- dren’s Hospital, 4018 Saint Catherine West, Montreal, Quebec H3Z 1P2, ment of language and communication and of Canada. A PEDIATRICS (ISSN 0031 4005). Copyright © 2001 by the American Acad- social interaction and reciprocity, and restricted pat- emy of Pediatrics. terns of play, interests, and behaviors.1,2 Autism is a http://www.pediatrics.org/cgi/content/full/108/4/Downloaded from www.aappublications.org/newse58 byPEDIATRICS guest on September Vol. 30, 108 2021 No. 4 October 2001 1of8 disorder that belongs to a larger group of conditions argued by Wakefield et al,12,13 a new syndrome has referred to as pervasive developmental disorders appeared, then precise delineation of its clinical and (PDD), which also include less severe autistic pat- developmental characteristics is required to validate terns of development, such as atypical autism and and research it. Asperger syndrome. A very rare PDD, childhood dis- Unfortunately, the precise phenotype has not been integrative disorder (CDD), applies to children who described clearly yet. In the most recent series of 60 develop normally up to age 2 (and more often 3) and patients13 (which includes all children of the first present subsequently with a profound behavioral dis- report12), 57 children had a PDD diagnosis but 3 integration followed by severe autism and intellectual children with other diagnoses were included (1 dys- impairments. Autism is associated with mental retar- lexia, 1 schizophrenia, 1 attention-deficit/hyperac- dation in 70% of cases, and males are 4 times more tivity disorder), raising serious questions about the likely than females to be affected.3 Twin and family specificity of the hypothesis under investigation. The studies have accumulated evidence for a strong genetic male:female ratio otherwise was typical of autism component in cases of idiopathic autism.4,5 samples, but it is worth noting that no quantitative In a small proportion not exceeding 10%,3,6 autism data were available on intellectual functioning, lan- and autistic syndromes occur in conjunction with guage level, severity of autistic symptomatology, known medical disorders that are likely to be caus- and associated neurologic signs. Normal electroen- ally associated with the syndrome. Prime examples cephalograms, brain magnetic resonance imaging, of these medical conditions are tuberous sclerosis,7 and cerebrospinal fluid profiles in the first series12 fragile X,8 and congenital rubella.9,10 When autism were not particularly suggestive of brain pathology. occurs as a result of these medical conditions, a dis- Three features, however, could act as pointers to- tinct behavioral phenotype has been reported. Thus, ward a specific variant of autism. First, 2 children autistic individuals with tuberous sclerosis have el- had a diagnosis of CDD; as CDD is extremely rare,3 evated rates of epilepsy and mental retardation and (E. Fombonne, submitted) it raised the possibility brain and skin lesions, and the male:female ratio in that CDD might be part of this new phenotype. affected individuals is closer to unity.7 Autistic indi- Second, based on retrospective parental accounts, viduals with fragile X have high levels of social anx- developmental regression was reported in almost all iety and avoidance (rather than aloofness) and of cases.13 Regression, however, was defined loosely as overactivity and attention deficits, and males almost loss of acquired skills after a period of normal devel- always have intellectual impairments and present opment as determined by the presence of uneventful specific physical features.11 Autistic children with general practitioner and health visitor records up to congenital rubella have specific congenital abnor- the first birthday. Onset of behavioral symptoms malities,9 and autistic symptoms tend to improve in occurred within 2 weeks of MMR immunization in 8 the longer term.10 Thus, variants of autism associated patients from the first
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