Neurologic Disorders After Measles-Mumps-Rubella Vaccination
Annamari Mäkelä, MD; J. Pekka Nuorti, MD; Heikki Peltola, MD
| AAP: In a study of 535,544 children aged 1-7 years who were vaccinated between November 1982 and June 1986 in Finland, no association was found between MMR vaccination and encephalitis, aseptic meningitis or autism. |
Objective. The possibility of adverse neurologic events has fueled much concern about the safety of measles-mumps-rubella (MMR) vaccinations. The available evidence concerning several of the postulated complications is controversial. The aim of this study was to assess whether an association prevails between MMR vaccination and encephalitis, aseptic meningitis, and autism.
Methods. A retrospective study based on linkage of individual MMR vaccination data with a hospital discharge register was conducted among 535 544 1- to 7-year-old children who were vaccinated between November 1982 and June 1986 in Finland. For encephalitis and aseptic meningitis, the numbers of events observed within a 3-month risk interval after vaccination were compared with the expected numbers estimated on the basis of occurrence of encephalitis and aseptic meningitis during the subsequent 3-month intervals. Changes in the overall number of hospitalizations for autism after vaccination throughout the study period were searched for. In addition, hospitalizations because of inflammatory bowel diseases were checked for the children with autism.
Results. Of the 535 544 children who were vaccinated, 199 were hospitalized for encephalitis, 161 for aseptic meningitis, and 352 for autistic disorders. In 9 children with encephalitis and 10 with meningitis, the disease developed within 3 months of vaccination, revealing no increased occurrence within this designated risk period. We detected no clustering of hospitalizations for autism after vaccination. None of the autistic children made hospital visits for inflammatory bowel diseases.
Conclusions. We did not identify any association between MMR vaccination and encephalitis, aseptic meningitis, or autism.
| “Dr Makela was partially supported by a grant from Merck & Co. [the manufacturer of the MMR vaccine].” |
F. Edward Yazbak, MD, FAAP TL:
RE Neurologic Disorders After Measles-Mumps-Rubella Vaccination. Annamari Mäkelä, MD, J. Pekka Nuorti, MD and Heikki Peltola, MD
My first reaction when I saw the above title in your newsletter was “Oh God! Not again!” I then read the abstract and all I could think of was “déjà vu”. It would be nice to know how many of your readers also wondered, “Did I see this before?” All these studies from Finland are just so much alike and so predictable.
Once more, let us all remember that:
1. The original Peltola study, from which all these mini studies are sprouting, was over by 1996, two full years before Wakefiled’s first paper;
2. That Peltola said on BBC that his main study did not look for
autism and IBD; and
3. That many knowledgeable epidemiologists, including the authors of the latest study from Denmark (Medgaard Madsen et al) have criticized the methodology of previous “Peltola Team” studies.
Makela and Associates were so intent on shooting down Wakefield’s work that even in a paper titled “Neurologic disorders after MMR”, they found a way to mention that no hospitalized children with autism had IBD. (I can’t help but wonder whether Peltola’s Holiday Greeting cards mention IBD). Regardless of what Makela says, the fact is that the number of individuals who received assistance for IBD from the Social Security Institution in Finland doubled in nine years (9,737 in 1992 to 20,807 in 2001).
Another fact is that autism is as prevalent in Finland now as it is in the rest of the western world. Thank God a large number of their poor children are high functioning. (http://www.jabs.org.uk).
It is not clear why 352 children with autism were hospitalized during the study period. In the US, affected children are not usually hospitalized with a diagnosis of autism. Indeed, over here, such a diagnosis often compromises payment by certain HMOs.
The whole Makela study is based on ONE comparison: ” For encephalitis and aseptic meningitis, the numbers of events observed within a 3-month risk interval after vaccination were compared with the expected numbers estimated on the basis of occurrence of encephalitis and aseptic meningitis during thesubsequent 3-month intervals”. If the children in the first group developed symptoms of encephalitis and meningitis within two weeks of vaccination, then causation is implied (medically and medico-legally). In this case, a comparison with the control group is meaningless and the author’s conclusion is unwarranted.
This study by Makela, Nuorti and Peltola will not be remembered for any convincing or striking finding. But it will be quoted though for another reason: By stating, “The aim of this study was to assess whether an association prevails between MMR vaccination and encephalitis, aseptic meningitis, and autism” in an article titled “Neurologic Disorders after Measles-Mumps-Rubella Vaccination” the authors assert that autism is a neurological complication of MMR vaccination. Now that, we will not forget!
F. Edward Yazbak, MD, FAAP TL Autism Research, Falmouth, Massachusetts
WHAT CRITICS SAID:
F. Edward Yazbak, MD: Makela et al. were so intent on shooting down Wakefield’s work that even in a paper titled “Neurologic disorders after MMR,” they found a way to mention that no hospitalized children with autism had IBD. But regardless of what Makela says, the fact is that the number of individuals who received assistance for IBD from the Social Security Institution in Finland doubled in nine years (from 9,737 in 1992 to 20,807 in 2001).
The whole study is based on ONE comparison. If the children in the first group developed symptoms of encephalitis and meningitis within two weeks of vaccination, then causation is implied (medically and medico-legally). In this case, a comparison with the control group is meaningless and the author’s conclusion is unwarranted.[8]
WHAT THE COCHRANE REVIEW SAID:
■ This study suffered from a “moderate” risk of bias.
■ It was “weakened” by the loss of 14% of the original birth cohort and the effects of the rather long time frame of follow up. What the impact of either of these factors was in terms of confounders is open to debate.
■ The long follow up for autism was due to the lack of a properly constructed causal hypothesis.
■ The study failed to report complete vaccine identification information, including lot numbers, adjuvants, preservatives, strains, product and manufacturer.
■ There was a lack of adequate description of exposure (vaccine content and schedules).
■ The authors provided “inadequate” explanations for missing information, even though there were clearly missing unintended-event data on as many as 20% of the participants.
■ The study had discrepancies in reporting of denominators and was classified to be at moderate risk of bias.
What the IOM said: The study suffered from one primary limitation: its exclusive reliance on hospitalization records. This made it impossible to identify children with ASD who were not hospitalized, but rather seen in an outpatient setting. The IOM went on to say that “While the authors stated that it is common in Finland for children with autism to be admitted to the hospital for observation and testing, a diagnosis of autism does not always involve hospitalization.”[9]
What Science-Based Medicine.com said: “Using ‘hospitalizations’ as criteria for finding children with autism (is) not a good way to find autism cases, I agree.”[10]
SUMMARY:
The “Finnish MMR study” fails to make explicit the exact definition of ‘caseness’, particularly with respect to autism. The criticisms leveled at the study are crucially important in this respect. First, there is a failure to differentiate between autism per se, and the sub-group who are proposed to be at increased risk (i.e. those with regressive onset). There is also a degree of circularity in the statement that those whose encephalitis was ‘unrelated to vaccination’ were excluded. To deselect particular cases before analysis, on the basis of a proposed non-relationship between exposure and outcome is poor epidemiological practice. Further, it implies that decisions about causality were made after the event, on the basis of criteria which were not made explicit to the reader. At face value, the exclusion of these cases would appear to work in favor of those proposing a possible association between exposure and hospitalization; but this would only be the case if the lack of association was real. No evidence is presented which allows formulation of an opinion on this. The most problematic factor, however, is in the assumption that children hospitalized ‘for autism’ somehow represent the very well defined group of children that are proposed to be at risk of an adverse event following vaccination. This assumption simply has no validity, and neither, therefore, do any conclusions based on data related to this group.