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Is There a 'Regressive Phenotype' of Autism Spectrum Disorder Associated with the Measles-Mumps-Rubella Vaccine?

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Is There a 'Regressive Phenotype' of Autism Spectrum Disorder Associated with the Measles-Mumps-Rubella Vaccine? Journal of Autism and Developmental Disorders, Vol. 36, No. 3, April 2006 (Ó 2006) DOI 10.1007/s10803-005-0070-1 Published Online: April 28, 2006 Is There a ‘Regressive Phenotype’ of Autism Spectrum Disorder Associated with the Measles-Mumps-Rubella Vaccine? A CPEA Study Jennifer Richler,1 Rhiannon Luyster,1 Susan Risi,1 Wan-Ling Hsu,1 Geraldine Dawson,2 Raphael Bernier,2 Michelle Dunn,3 Susan Hepburn,4 Susan L. Hyman,5 William M. McMahon,6 Julie Goudie-Nice,6 Nancy Minshew,7 Sally Rogers,8 Marian Sigman,9 M. Anne Spence,10 Wendy A. Goldberg,10 Helen Tager-Flusberg,11 Fred R. Volkmar,12 and Catherine Lord13 A multi-site study of 351 children with Autism Spectrum Disorders (ASD) and 31 typically developing children used caregiver interviews to describe the children’s early acquisition and loss of social-communication milestones. For the majority of children with ASD who had experienced a regression, pre-loss development was clearly atypical. Children who had lost skills also showed slightly poorer outcomes in verbal IQ and social reciprocity, a later mean age of onset of autistic symptoms, and more gastrointestinal symptoms than children with ASD and no regression. There was no evidence that onset of autistic symptoms or of regression was related to measles-mumps-rubella vaccination. The implications of these findings for the existence of a ‘regressive phenotype’ of ASD are discussed. KEY WORDS: Autism spectrum disorder; language development; regression; Autism Diagnostic Interview - Revised (ADI-R); measles-mumps-rubella (MMR) vaccine; gastrointestinal disorders. While most children with Autism Spectrum Dis- orders (ASD) are described as showing developmental differences from birth or early in infancy, a substantial 1 University of Michigan, Ann Arbor, USA. 2 minority (20–40%) of parents of children with ASD University of Washington, Seattle, USA. report that their children initially seemed to acquire 3 Albert Einstein College of Medicine, Bronx, USA. 4 University of Colorado Health Sciences Center, Aurora, USA. some social and communicative skills that they subse- 5 University of Rochester, Rochester, USA. quently lost, typically between 15 and 24 months of 6 University of Utah, Salt Lake City, USA. age (Davidovitch, Glick, Holtzman, Tirosh, & Safir, 7 University of Pittsburgh, Pittsburgh, USA. 8 2000; Goldberg et al., 2003). These losses can occur in a University of California-Davis, Davis, USA. range of skills, from using eye contact and gestures to 9 University of California-Los Angeles, Los Angeles, USA. 10 University of California-Irvine, Irvine, USA. producing meaningful words to participating in 11 Boston University, Boston, USA. reciprocal games like ‘‘peek-a-boo.’’ 12 Yale University, New Haven, USA. In recent years, researchers have become inter- 13 Correspondence should be addressed to: Catherine Lord, Aut- ested in the question of whether children with ASD ism and Communication Disorders Center, University of who experience a regression manifest a new variant or Michigan, 1111 East Catherine Street, Ann Arbor, MI, 48109- 2054, USA; Tel: +1-734-936-8600; Fax: +1-734-936-0068; phenotype of the disorder. In order to address this e-mail: [email protected]. question, investigators have examined whether 299 0162-3257/06/0400-0299/0 Ó 2006 Springer ScienceþBusiness Media, Inc. 300 Richler et al. children with ASD and regression differ from chil- by losses in language and other skills. Eight of the dren with ASD and no regression in terms of skill 12 children were described as having lost skills development and severity of autistic symptoms, both within days after being vaccinated; the interval in the early years and later on in life. Luyster et al. ranged from 24 hours to 2 months. In most cases, (2005) found that children with regression had parents and/or physicians attributed onset of symp- superior social and communicative skills prior to loss toms to the MMR vaccine. All of the children had compared to children with ASD and no regression. GI abnormalities (diarrhea, abdominal pain, bloat- At the same time, however, studies have consistently ing, and food intolerance) and most had received a found that children with ASD and regression were clinical diagnosis of autism. The authors suggested not developing like typical children prior to loss that the MMR vaccine might have triggered bowel (Lord, Shulman, & DiLavore, 2004; Siperstein & dysfunction; accompanying neurodevelopmental Volkmar, 2004; Werner, Dawson, Munson, & dysfunction, they posited, would have resulted from Osterling, 2005). an excessive absorption of gut-derived peptides from Findings on social and communicative outcomes food, which might disrupt normal brain develop- in children with ASD and regression have been less ment. It should be noted, however, that 10 of the 13 consistent. Kurita (1985) found that, at 38 months, authors recently retracted this interpretation of the children with autism and speech loss had a significantly findings (Murch et al., 2004). lower developmental quotient than children without More recently, researchers have begun to examine speech loss, suggesting that language loss may be the evidence for a link between the MMR vaccine and related to poorer outcome, at least in the shorter term. autism. Chen, Landau, Sham, and Fombonne (2004) Brown and Prelock (1995) found that individuals with examined the association between the prevalence of ASD and a history of regression showed poorer social autism and exposure to measles infection and the communication skills later in life than did individuals MMR vaccine in the UK and found no evidence for with ASD and no history of regression. Several studies such a relationship. Wilson, Mills, Ross, McGowan, have found that, at approximately 6 years of age, and Jadad (2003) reviewed four studies on the rela- children with autism who had a history of regression tionship between ASD and the MMR vaccine, none of had a lower IQ than those children who did not which found any evidence for a link. For example, one experience a regression (Burack & Volkmar, 1992; study followed up 31 vaccinated children reported to Kobayashi & Murata, 1998; Kurita, 1996). However, have GI tract symptoms and found that none of the other studies have found no differences between children went on to receive a diagnosis of ASD (Peltola children with ASD with and without regression on et al., 1998). Another study did not find an increased various outcome variables (Lord et al., 2004). rate of GI symptoms or regression in children with Another way to examine the issue of whether autism after the MMR vaccine was introduced to a regressive autism constitutes a distinct phenotype is population in the UK (Taylor et al., 2002). to determine whether it is characterized by a distinct One of the studies reviewed by Wilson et al. symptom profile. Some researchers have suggested (2003), conducted by Fombonne and Chakrabarti that regressive autism is associated with an increased (2001), provided the focus for the present study. The frequency of gastrointestinal (GI) disorders and authors asked two questions: First, does regressive symptoms (Wakefield et al., 1998). Recent studies, autism represent a new ‘phenotype’ of ASD? Second, however, have found no evidence for an increased is regressive autism associated with the MMR vac- risk of GI dysfunction among children with ASD and cine? If regressive autism truly is a new, MMR- regression as compared to children with ASD and no induced phenotype of the disorder, Fombonne and regression (Fombonne & Chakrabarti, 2001; Molloy & Chakrabarti argued, then one would expect, among Manning-Courtney, 2003). other things, that children with regressive autism Several years ago, Wakefield et al. (1998) sug- would have different symptom and severity profiles gested that both regression and GI dysfunction in and a higher rate of GI abnormalities than children children with ASD could be ‘triggered’ by the with ASD and no regression. If a particular pheno- measles-mumps-rubella (MMR) vaccine. In one of type of autism were associated with the MMR the earliest studies on this topic, Wakefield et al. vaccine, then the age of onset for these children (with (1998) examined a group of 12 patients referred to a ASD and regression) would follow age at vaccination pediatric gastroenterology unit who were reported to and would differ from the age of onset for children have had a history of normal development followed without regression. Regressive Phenotype 301 In the Fombonne and Chakrabarti (2001) study, parental concern from the ADI-R as the measure of children with pervasive developmental disorders onset. Most of the parents in the study, then, were (PDD) (including autism, atypical autism, Pervasive reporting about events that had taken place many Developmental Disorder – Not Otherwise Specified, years ago; for example, of the three samples in the PDD-NOS, Asperger syndrome, and Childhood Dis- study, one consisted entirely of parents of individuals integrative Disorder, CDD) and a history of regres- over 22 years old. Due to a ‘‘telescoping effect’’ sion were compared to a sample of children with observed in other studies (Cooper, Kim, Taylor, & PDD and no history of regression. No differences Lord, 2001), it is possible that the mean age of first were found in any of the areas examined, leading concern would have been lower had the participants Fombonne and Chakrabarti (2001) to conclude that (i.e. the ‘‘subjects’’ whose parents described them in there was no evidence for a new ‘‘regressive pheno- the interviews) been
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