Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis
BMJ 2001; 322 doi: https://doi.org/10.1136/bmj.322.7284.460 (Published 24 February 2001) Cite this as: BMJ 2001;322:460
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Kaye et al. argue that the increase in the detected incidence of autism in the UK, at a time of steady "ceiling" uptake of MMR vaccine, provides evidence against a causal link between them. Whilst their data certainly does not confirm any such link, it may simply be evidence of improved case ascertainment (i.e. diagnosis) of those with autism.
The current climate of concern about MMR vaccination ironically may create a much better study environment in which to prove or disprove any link. In the coming years one can expect to see declining vaccine uptake - especially amongst those at possibly increased pre-existing risk of the disease (younger siblings of autistic children). At the same time case ascertainment rates of autism should continue to improve (or at least plateau). Only under that situation can a continual rise in the recorded incidence of autism truly be used as an argument against the link - whilst a drop in observed incidence rates would be stronger evidence in its favour
Competing interests: No competing interests
The study by James A Kaye and colleagues (1) clearly indicates that
the fast and gradual rise in risk of diagnosed autism for boys born from
1988 to 1993 cannot be explained by changes in the prevalence of MMR
vaccination in the UK.
The practical conclusion is that we must look at early environmental
factors that have been actually altered during this 6 year period. This
was the very time when the rates of births in physiological conditions
have been gradually and rapidly shrinking (rising rates of epidural
anaesthesia and caesarean sections). Today it would be relevant to save
from oblivion studies suggesting that there are risk factors for autism in
the perinatal period (2,3). I previously instanced such studies to
introduce the concept of "cul-de-sac epidemiology" (4). Who will break
through the dead end of the cul-de-sac?
References:
-1- Kaye JA, Melero-Montes M, Jick H. Mumps, measles, and rubella
vaccine and the incidence of autism recorded by general practitioners: a
time trend analysis. BMJ 2001; 322: 460-3.
-2- Tinbergen N, Tinbergen A. Autistic children. Allen and Unwin.
London 1983.
-3- Hattori R, Desimaru M, Nagayama I, Inoue K. Autistic and
developmental disorders after general anaesthetic delivery. Lancet 1991;
337: 1357-58.
-4- Odent M. Between circular and cul-de-sac epidemiology. Lancet
2000; 355: 1371.
Competing interests: No competing interests
The Kaye et el statistical analysis leaves us now with the task of
determing what has changed environmentally or mode of treatment which
might account for this rapid rise in the diagnosis of autism.
Might I suggest it could be time to look at the rising use of H2
blockers and proton pump inhibitors for gastric reflux which many of these
children have suffered prior to the diagnosis of autism. I note that usage
of the first of these drugs commenced in the late 70's.
The fact that some children are secretin responders might alert us to
the fact that reducing these levels as a consequence of drug treatment is
inadvisable.
Mary Reid
Competing interests: No competing interests
Dear Editor
Four questions-
Firstly, could I please ask Kaye et al whether they have also carried out a similar time trend analysis in California and in Boston?
Secondly, have they studied also the relationship, if any, between MMR vaccination and ileal lymphoid nodular hyperplasia?
Thirdly, have our paediatric psychiatrists any information or views on the subject?
Finally, I would ask paediatric gastroenterologists whether they have encountered ileal lymphoid hyperplasia following MMR. If so, what is the incidence, please?
JK Anand
Competing interests: No competing interests
Kaye et al's statistical analysis offers good evidence that MMR is
unlikely to be the sole cause of the huge increase in autism that has
occurred over the last twenty years or so. However, as far as I am aware,
those who suggest that there may be a link between MMR and autism are not
necessarily making such a suggestion. What they are saying is that there
is strong anecdotal evidence that MMR may be the trigger to autism in some
cases, and that there is a plausible explanatory mechanism whereby it
could be such a trigger. I have spoken to the parents of three children
in whom the MMR vaccination was followed by an immediate, quite severe,
reaction and a sudden subsequent descent into autism. Large scale
epidemiological proofs that MMR cannot be the sole cause of autism are, I
presume, insufficient to gainsay them entirely.
Competing interests: No competing interests
It is gratifying to see this paper using the GPRD primary care
database to study the possible relationship between MMR vaccination and
autism. The database is one of the best sources of patient records in
general practice in England and can, with some justification, claim to be
particularly good for preventive medical procedures. It is, therefore,
all the more disappointing that Kaye et al have apparently missed the
opportunity to make full use of the database.
I have personal experience with GPRD for clinical research purposes
so have first hand knowledge of its strengths and weaknesses. In the
years since it was created as VAMP about 8 million patients have, at one
time or another, been registered on the database of which about half have
dropped out leaving about 4 million at the present time. The paper quotes
that the data was derived from a total of 3 092 742 person years of
observation. As the database has been recording data for more than 10
years this means that it contains 20 million or more person years of
observation. With the estimate of the total data used apparently accurate
to one person year in 3 million it would be helpful to know what happened
to the other 17 million or so that were in the database. Is this
selection intentional, accidental or enforced by circumstance? Why are
the excluded person years of observation assumed to be of no importance to
the study?
It is also stated by the authors that analyses were restricted to 114
out of 254 males although it is not at all clear why 140 were excluded
and, presumably, considered irrelevant. No reason is given for the
exclusion of all 51 females. It is stated that the investigation of a
possible association with MMR vaccination was restricted to those patients
with at least two years follow-up but this was not stated to be the
criterion for the selected males. Diligence in the keeping of patient
records is certainly a factor likely to reflect general practitioner
characteristics and thus impose some bias on the patient population
recorded.
The limitations of this study have to be borne in mind when drawing
conclusions with regard to any possible association of MMR vaccination and
the development of an autistic disorder.
A Peter Fletcher
Competing interests: No competing interests
Dear Sir
Kaye et al (1) undertook an ecological study comparing the time trend
in mumps-measles-rubella (MMR) vaccine coverage to the time trend in
diagnoses of autism. They found a marked increase in the incidence of
autism codes in childrens' electronic general practice records over an 11
year period. We agree with their conclusion that MMR cannot be the cause
of this observed increase, since the vaccine coverage remained constant
during the same time period. There have been changes in the classification
of autistic diseases and in the likelihood of case ascertainment in recent
years, and a more rigorous review of cases may clarify whether some of the
increase was due to alterations in diagnostic practice.(2) Only 81% of
cases were reported to have been referred to a specialist, raising
questions about the validity of the diagnoses used by Kaye et al. Children
with medical conditions present from birth and known to be associated with
an increased risk of autism (fragile X disorder, tuberous sclerosis,
phenylketonuria, and congenital rubella) were not excluded.
The failure to find an association between the time trends in vaccine
coverage and the incidence of autism codes in childrens' electronic
general practice records does not exclude a causal association. Whether
exposure to MMR vaccination increases the risk of autism is of great
public health importance and can be usefully investigated using the
general practice research database (GPRD). We have been funded by the
United Kingdom Medical Research Council to undertake an investigation of
the causes of autism, including an assessment of the potential role of MMR
vaccine using case-control and case series approaches. The electronic
general practice records in the GPRD will be supplemented by a full record
review of all cases and questionnaires to parents of both affected
children and to controls. We will undertake a detailed validation and
classification of all cases and establish the date of onset of symptoms.
In addition we will obtain information on potential confounding factors
from both cases and controls. A detailed protocol of our study has been
published (3).
1. Kaye JA, del Melero-Montes M, Jick H. Mumps, measles, rubella
vaccine and the incidence of autism recorded by general practitioners: a
time trend analysis. BMJ 2001;322:in press.
2. Fombonne E. Is There an epidemic of autism? Pediatrics 2001;107
(2):411-413.
3. Smeeth L, HallAJ, Fombonne E, Rodrigues LC, Huang X, Smith PG. A
case-control study of autism and mumps-measles-rubella vaccination using
the general practice research database: design and methodology. BMC Public
Health 2001,1:2.
Dr Liam Smeeth(1)
Prof Andrew J Hall(2)
Dr Eric Fombonne(3)
Dr Laura C Rodrigues(2)
Xiangning Huang(2)
Prof Peter G Smith(2)
1 Department of Epidemiology and Population Health,
2 Department of Infectious and Tropical Diseases,
London School of Hygiene and Tropical Medicine
Keppel Street, London WC1E 7HT, UK
3 Institute of psychiatry/King's College London,
Department of Child and Adolescent Psychiatry,
MRC Child Psychiatry Unit,
London SE5 8AF, UK
Competing interests: No competing interests
As Ms. White wisely points out, it is time to end the sophistry that
invokes increased awareness and diagnosis as explanations for the
increased incidence of kids being diagnosed with autistic spectrum
disorders (ASD). These kids, even the mildly effected ones, require
special attention and could not be shuffled through the regular school
systems.
The increased incidence of ASD is a real biological phenomena
attributable, in large part, to an environmental factor(s).
Competing interests: No competing interests
Do the authors know if the vaccine manufacturers made any changes to
the content or structure of the MMR vaccine during the time period covered
by the study?
Competing interests: No competing interests
Response to Rapid Responses
We appreciate the attention given to our recent publication on autism
and the measles, mumps, and rubella (MMR) vaccine (1) and wish to respond
to several of the scientific questions and comments submitted by readers.
To Hilary Butler: We studied the question of a link between autism
and the MMR vaccine because our group has long been interested in
evaluating the safety of medical therapies, and the specific question of a
connection between the MMR vaccine and autism is an important public
health issue. The reasons we used the General Practice Research Database
(GPRD) to study this question are that the GPRD is an excellent source of
information for such studies and we already had the information available
(as we hold a license to use of the GPRD for research purposes). One of
the advantages of this computer-based data source is that it can be used
relatively quickly and inexpensively to evaluate drug and vaccine safety
issues when they arise. The information in the GPRD is recorded by
general practitioners in the course of their daily encounters with
patients - without regard to any particular research hypothesis - and this
reduces certain forms of bias in observational studies, especially when
one is evaluating a question that has received a great deal of public
attention. We did not include controls in our published study because
there were not enough unvaccinated children during the period we
investigated to allow such a comparison.
To Mark Berelowitz: Our report focused on how frequently general
practitioners recorded a diagnosis of autism in the medical record of 2-
to 5-year old boys born in 1988-1993. We acknowledged in the paper that
we are not certain that all the diagnoses were confirmed. We did not
state or intend to imply that the observed trend in incidence will
continue in the future, as suggested in your comment.
To Cort Wrotnowski: The main analysis was restricted to children
born 1988-1993 so that children would have adequate follow-up in the
database for us to evaluate the risk of autism being diagnosed by age 5.
Because girls make up only about one fifth of the children who are
diagnosed as having autism, an estimate of the risk for girls is less
reliable and was, in our judgment, not stable enough statistically for us
to report. The findings we presented in the paper relate to boys.
To Liam Smeeth and colleagues: We disagree with applying the term
"ecological" to our study. An ecological study is one in which "…the
units of analysis are populations or groups of people, rather than
individuals." (2). It is true that we explicitly contrasted in Figure 2
the increase in risk of autism being diagnosed among 2- to 5-year olds
born in 1988-1993 (n=114) with the prevalence of MMR vaccination by age 2
in the corresponding GPRD birth cohorts (which are the source population).
However, we also noted in the text that the vaccine prevalence for the 114
boys diagnosed as having autism was similar to that of the whole
population. We agree, as we stated in the paper, that some
misclassification of cases is probable since we relied only on the first
recorded diagnosis of autism by general practitioners as a criterion for
inclusion, but it is unimportant that a small number of children with
conditions predisposing to autism were not excluded from our study since
we were evaluating the risk of being diagnosed with autism per se. We
agree that further work is needed to evaluate possible causes of the
recent rapid increase in the diagnosis of autism other than the MMR
vaccine and look forward to learning the results of your more extensive
planned investigation.
To Bert Castle: About 86% of the MMR vaccine used in the UK until
October 1992 was either Pluserix (SmithKline Beecham) or Immravax
(Merieux), and the remainder was MMR II (Merck Sharp & Dohme; now
produced by Aventis Pasteur MSD) (Elizabeth Miller, personal
communication, 22 February, 2001). After Pluserix and Immravax were
withdrawn in 1992 due to a risk of aseptic meningitis attributed to the
mumps component (3), only MMR II was used. Immravax and Pluserix
contained the same measles component (Schwartz strain), while the measles
component of MMR II is different (Enders attenuated Edmonston strain).
To Dr A Peter Fletcher: The total of 3,092,742 person-years in the
GPRD refers to children age 12 or younger (see Figure 1 of our paper).
This represents only a small portion of the total person-time in the GPRD
(which also includes data on individuals older than age 12), but since we
were interested in the first time a diagnosis of autism was recorded in
relation to MMR vaccination, we focused our attention on children. The
reason we studied 114 boys from age 2 to age 5 who were born in 1988-1993
is discussed above, as is our reason for not reporting an estimate of risk
for girls. We did not explicitly state that the 114 boys had been
followed for at least 2 years from birth in the GPRD, but that is implicit
in our presenting an estimate of their risk of being diagnosed with autism
starting at age 2 (since children who stopped contributing information to
the database before reaching 2 years of age - for whatever reason - would
not be included in this calculation).
References
1. Kaye JA, Melero-Montes MM, Jick H. Mumps, measles, and rubella vaccine
and the incidence of autism recorded by general practitioners: a time
trend analysis. BMJ 2001;322:460-463
2. Last JM (ed). A Dictionary of Epidemiology (Third Edition). Oxford
University Press, New York, 1995
3. Miller E, Goldacre M, Pugh S, Colville A, Farrington P, Flower A, Nash
J, MacFarlane L, Tettmar R. Risk of aseptic meningitis after measles,
mumps, and rubella vaccine in UK children. Lancet 1993;341:979-982
James A. Kaye, epidemiologist; Maria del Mar Melero-Montes,
epidemiologist; Hershel Jick, Associate Professor of Medicine; Boston
Collaborative Drug Surveillance Program, Boston University School of
Medicine, 11 Muzzey Street, Lexington, MA 02421, USA
Competing interests: No competing interests