Title: MMR vaccination and autism
Letter
Authors: Dr Andrew J Wakefield MB,BS., FRCS., FRCPath and Dr Carol Stott PhD
Response to: D’Souza et al. No evidence of persisting measles virus in peripheral blood mononuclear cells from children with autism spectrum disorder. Pediatrics. 2006;118:1664-75.
Dear Sir,
The merit of D’Souza et al’s use of a study of peripheral blood mononuclear cells to dismiss findings in intestinal biopsies is questionable (1). A recent US study using nested PCR and sequencing confirmed the fidelity of the original Uhlmann F-gene primers in the detection of measles virus in intestinal biopsies from children with autism (2).
D’Souza et al claim that, among other things, the ‘epidemiological burden of evidence against such an [causal] association between MMR and autism is overwhelming”. They fail to reference the authoritative Cochrane review of this epidemiology (3) which dismissed much of it as being of insufficient quality to merit consideration, including Fombonne’s own work (4) of which they said, “the number and possible impact of biases in this study was so high that interpretation of the results was difficult.” Even the Cochrane review failed to note that another of Fombonne’s studies using the UK General Practice database (GPRD)(5) tested the wrong hypothesis and lacked sufficient power to detect an association between MMR and regressive autism.
So which studies are sufficient to overwhelm? Several have looked at age of exposure to MMR vaccine and risk of autism. Such a hypothesis is merited on the basis that younger age of exposure to measles virus is associated with an increased risk of adverse outcome including persistent infection and delayed disease. Richler et al posed the question of whether there is an autism phenotype characterized by regression associated with significant intestinal symptoms following MMR vaccine, in a previously developmentally normal or near-normal child (6). Children meeting these criteria were compared with all other autistic children in their study cohort. In this, the only epidemiologic study to at least attempt to segregate this sentinel autism phenotype, age-of-exposure to MMR vaccine was significantly lower (mean age 14.38 months) when compared with the remaining autistic population (mean age 17.71 months; (p<0.05). Strangely - and at odds with their own reported findings - the authors concluded that, ‘there was no evidence that onset of autistic symptoms or of regression was related to MMR vaccination’.
Three further aspects of age-of-exposure to MMR and autism have been
reported: DeStefano and colleagues performed a case-control study comparing
age at first MMR vaccination in children from the Atlanta metro area (7).
By 36 months of age, significantly more cases with autism (93%) had
received MMR than controls (91%)(Odds Ratio 1.49; 95% confidence interval
[CI] 1.04-2.14). This association was strongest in the 3 to 5-year age
group with an Odds Ratio of 2.34. Due to diagnostic delay, a significant
proportion of this group had yet to be diagnosed with autism, potentially
underestimating this risk. Moreover, in a subgroup analysis looking at
children with different disease characteristics, they found a significant
association between MMR vaccination by 36 months and autistic children with
no evidence of mental retardation (IQ>70; OR 2.54 [1.20-5.00]). The odds
ratios were increased to 3.55 in a subgroup analysis adjusted for birth
weight, multiple gestation, maternal age and maternal education, thus
strengthening the association between age-of-exposure to MMR and autism. It
is interesting that their ‘regressive group’ did not show this effect
although the interpretation of this finding is severely constrained by
their retrospective ascertainment of regression from medical records.
First, regression did not form part of the diagnostic algorithm for autism
and second, the concept of regression conflicted, until very recently, with
the beliefs of most autism diagnosticians. IQ, on the other hand, is an
objective measure and a normal IQ appears to be an increasingly common
feature among recent cohorts of affected children (8). An IQ within the
normal range may well reflect a period of normal cerebral development and
in this instance, be a better marker of the late-onset phenotype than
retrospective record review. Having tested a hypothesis and found a
significant association between autism and age of first MMR exposure, the
authors, somewhat curiously, ascribe this effect to an ‘artifact of
immunization requirements for pre-school special education attendance in
case children’. Such an interpretation would only possibly be valid if the
immunization mandate for normal pre-school children were different from
that of special education children; it is not. Moreover, the special
education group, with a likely excess of contraindications to MMR
vaccination such as seizures, should have a lesser exposure to MMR. In
addition, if there were no true association, lower exposure in the special
education group would be expected in light of higher levels of parental
concern and consequent rates of abstention in this group, a possibility
that could have been easily checked by comparing the proportions of
exemption filings held by law in all state schools. This notwithstanding,
the data of DeStefano et al are not consistent with the author’s post hoc
rationalization.
Second, Edwardes and Baltzan (9) reanalyzed the California autism data of
Dales and colleagues (10), confirming that the age of MMR immunization was
becoming younger between 1981 and 1993. The ratio of children immunized
before age 17 months to those immunized between age 17 and 24 months
increased 200% from 1981 to 1993, and the rate of early MMR immunization is
correlated with the incidence of autism. This is an important factor in
light of DeStefano et al’s observation of a greater statistically
significant association between autism and MMR vaccination by 36 months in
more recent birth cohorts (7).
Third, Suissa pointed out that according to the Danish data of Madsen et al
(11) the rates of autistic disorder by age at vaccination, are 18.9, 14.8,
24.6, and 26.9 per 105 per year respectively for ages <15, 15-19, 20-24,
25-35, falling to 12.0 per 105 with age at vaccination >35 months, compared
with the overall rate of 11.0 for the reference group of no vaccination,
over all ages (12). Suissa considered it somewhat implausible for the
age-adjusted rate ratio to fall below 1 (as presented), unless the risk
profile by age in the unvaccinated is vastly different than in the
vaccinated. Thus, rather than an apparent association between exposure and
outcome being a spurious result of confounding, this would actually
represent effect modification. The data support the hypothesis of an
association between exposure and outcome, modified, rather than confounded
by, age of exposure.
While an effect of age of exposure to MMR vaccine on autism risk is evident
from these studies, the nature of that risk is not known.
Aside from the issue of age of exposure, Taylor et al found a significant
clustering of parental concern within 6 months of MMR vaccination
(p=0·03)(13) and, as was later pointed out, a step-up in number of autism
diagnoses associated with the introduction of MMR vaccination in the UK
(14). A similar step up in the autism rate with introduction of MMR was
observed in Denmark (12).
Overwhelmed, D’Souza et al claim that the hypothesized link between MMR and
ASD is spurious. With respect, we disagree.
Andrew J Wakefield MB,BS., FRCS., FRCPath and Carol Stott Ph.D
References
1. D'Souza Y, Fombonne E, Ward BJ. No evidence of persisting measles virus
in peripheral blood mononuclear cells from children with autism spectrum
disorder. Pediatrics. 2006;118:1664-75.
2. Walker SJ, Hepner K, Segal J, Krigsman A. Persistent ileal measles virus
in a large cohort of regressive autistic children with ileocolitis and
lymphnodular hyperplasia: re-visitation of an earlier study [abstract].
International Meeting for Autism Research (IMFAR) 2006,
http://www.cevs.ucdavis.edu/Cofred/Public/Aca/WebSec.cfm?confid=238&webid=12 45.
3. Cochrane. Demicheli V, Jefferson T, Rivetti A, Price D. Vaccines for
measles, mumps and rubella in children (Review) The Cochrane Library. John
Wiley & Sons, Ltd. 2005, Issue 4.
http://www.thecochranelibrary.com 4. Fombonne E, Chakrabarti S. No evidence for a new variant of
measles-mumps-rubella-induced autism. Pediatrics 2001;108:E58
5. Smeeth L, Cook C, Fombonne E, Heavey L, Rodrigues L, Smith P, Hall A.
MMR vaccination and pervasive developmental disorders: a case-control
study. Lancet 2004, 364:963-969
6. Richler J, Luyster R, Risi S, Hsu Wan-Ling, Dawson G, Bernier R, et al .
Is there a ‘regressive phenotype’ of autistic spectrum disorder associated
with the measles-mumps-rubella vaccine? a CPEA study. Autism Dev. Dis.
2006, 36:299-316.
7. DeStefano F, Bhasin TK, Thompson WW, Yeargin-All–sopp M, Boyle C. Age at
first measles-mumps-–rubella vaccination in children with autism and
school-mat–ched control subjects: a population-based study in metro–politan
Atlanta. Pediatrics 2004, 113:259–266.
8. Autistic Spectrum Disorders: changes in the California caseload. An
update: 1999 through 2002. California Department of Developmental Services.
A Report to the Legislature, Department of Developmental Services.
Sacramento, Calif.: www.dds.ca.gov. Accessed Oct, 2006.
9. Edwardes M, Baltzan M. MMR Immunization and Autism. JAMA 2001,
285:2852-2853
10. Dales L, Hammer SJ, Smith NJ. Time trends in autism and MMR
immunization coverage in California. JAMA 2001, 285:1183-1185
11. Madsen MK., Hviid A., Vestergaard M., Schendel D., Wohlfarht J.,
Thorsen P., et al. A population-based study of measles mumps rubella
vaccination and autism. NEJM 2002, 347:1478-1482.
12. Stott CA; Blaxill M, Wakefield AJ. MMR and Autism in Perspective: the
Denmark Story. Journal of American Physicians and Surgeons. 2004;9:89-91
13. Taylor B, Miller E, Farrington P, et al. Autism and measles, mumps,
rubella vaccine: no epidemiological evidence for a causal association.
1999;353:2026-2029.
14. Wakefield AJ.MMR vaccine and autism. 1999;354:950-951.
Potential conflicts.
The authors have acted as paid experts in the UK MMR vaccine litigation.
AJW is a named inventor on two viral diagnostic patents.
