June 1999: Report of the
working party on MMR vaccine
1. Background
On the basis of their research
findings, doctors at the Royal Free Hospital
led by Dr. Andrew Wakefield have suggested
that both measles and measles vaccines may be
causally associated with Crohn's disease (a
serious form of inflammatory bowel disease)
and MMR vaccine with the development of
autism (a developmental disorder usually,
diagnosed in the second year of life). MMR
vaccine was introduced into routine UK
immunisation programmes in 1988, following
which it has been given to millions of
children at the age of 13-15 months.
1.1 Sources of
information
During 1996-7 the MHRA
(medicines) (MHRA) was informed by a firm of
solicitors that they had received several
hundred reports of children who had developed
autism, Crohn's disease or similar disorders
after immunisation with measles, mumps and
rubella (MMR) vaccine or, much less
frequently, measles rubella (MR) vaccine.
Such reports were continuing to accumulate
and a wide variety of other conditions had
also been reported.
In order that more information
could be obtained about these possible
adverse effects, purpose-designed
questionnaires were sent to parents via the
solicitors. To validate information received
from parents, further questionnaires were
sent to the doctors (the GP and at least one
specialist) who had cared for these children.
1.2 Formation and remit
of Working Party
In 1998, on the advice of the
Committee on Safety of Medicines, an ad hoc
Working Party was formed to assess these
parent reports together with medical evidence
received from GPs and specialists. The
Working Party included members with
specialist expertise in the fields of adult
and paediatric gastroenterology, general
paediatrics, paediatric neurology and child
psychiatry. Its membership and remit are
given at Annex 1.
1.3 Meetings of the
Working Party
The first meeting took place on
27 February 1998. At this meeting members of
the Working Party recognised that there were
marked limitations in studying the selected
group of children that had been identified by
the firm of solicitors involved. The children
had been brought to the notice of the
solicitors because of a reported association
between the administration of MMR or MR
vaccine and the appearance of certain
symptoms and signs. They were not a randomly
selected or population-based group and there
were no controls. Because of the way in which
children had been selected, it seemed likely
that there would be a temporal association
between administration of the vaccine and the
appearance of symptoms in the group, and it
would be difficult to draw conclusions about
that association. However, in view of the
concerns that had been raised about the
children identified by the solicitors, the
Working Party considered that it was
appropriate to evaluate the information that
was available about these children.
In particular, it was important
to assess whether or not there was
information in medical records to support the
parental concerns, to look for evidence of
unusual features suggestive of a novel
syndrome and to see whether there was any
evidence of acute neurological events
associated with immunisation which might have
predisposed children to subsequent autism. In
searching for features that might indicate a
link with immunisation, the Working Party
agreed to systematically examine evidence
relating to medical confirmation of the
diagnosis, temporal association between
immunisation and onset, prior history and
potential alternative causes. In doing so it
recognised that, even when these criteria
were met, they would not necessarily be
sufficient to define a causal association.
The Working Party considered the
diagnostic criteria which should be used for
autism, pervasive developmental disorder
(PDD), developmental delay, encephalitis,
different types of inflammatory bowel disease
and other types of bowel disorder. Also, they
advised on the drafting of the evaluation
form which would be used to collate the
information provided by the parents and
doctors for an individual case. At the first
meeting it was decided that a pilot study
using a sample of 20 reports of all types of
reactions would be performed to develop the
evaluation form. These were chosen at random
from the first 90 reports containing
responses from both GPs and specialists.
The second meeting of the
Working Party took place on 1 July 1998 when
the results of the pilot study were
discussed. Members amended the assessment
form to improve precision. It was noted that
adequate supporting information was
frequently not available, either because
details had not been entered on
questionnaires or because the information was
not available at source. By July 1998
information from 180 cases had been received
for which parents suspected autism as a
possible adverse effect, of which 52 also had
a gastrointestinal disorder mentioned as an
additional possible adverse effect to MMR
vaccine. It was agreed that further reports,
not included in the pilot study, should be
examined. Each report was to be evaluated
independently by an individual member of the
Working Party and an MHRA physician using the
revised assessment form.
This set should include a large
sample of cases recorded as autism without
bowel disease (fifty were selected, which
with the 5 cases from the pilot study
represented over 40% of such cases available
at the time), all the cases with possible
autism associated with bowel disease and all
possible cases of Crohn's disease for which
information from both GP and specialist had
been received by 1 August 1998.
The third meeting of the Working
Party took place on 5 November 1998. At this
meeting differences of view between members
and the MHRA evaluator regarding individual
cases were resolved. The Working Party also
considered an overall assessment of the cases
of autism and Crohn's disease which had been
evaluated in detail, considered what further
steps were appropriate and began to formulate
its conclusions. Subsequently a draft report
was prepared and circulated to members for
comments.
At its fourth meeting on 5 March
1999 the Working Party discussed in detail a
draft report of its findings. A fifth meeting
was held on 10 May 1999 to finalise the
report.
2. Methods of
investigation
Blank questionnaires were
provided to the firm of solicitors who
distributed them to parents. Completed parent
questionnaires were normally returned
directly to MHRA. They were classified and
entered onto a specially designated area of
the ADROIT computerised database (see Figure
1). This system was specifically designed for
the purpose of handling large numbers of
individual case reports. Medical
questionnaires were subsequently sent to GPs
and specialists. Because of the importance of
supporting medical information for
evaluation, this process was restricted to
cases for whom medical information was
received from both these sources. The cases
were initially distributed equally and
randomly amongst experts on the Working Party
(one per case) but subsequently, where
necessary, the evidence for each diagnosis
was further reviewed by a member with
relevant specialist expertise. A single MHRA
physician also reviewed all the cases. The
two evaluators initially worked independently
of each other using the evaluation forms
developed for this purpose.
The Working Group focused its
attention on three groups of children i.e.
those with autism, those with Crohn's disease
and those who had both autism and a
gastrointestinal disorder. Fifty reports of
autism alone (in addition to five included in
the pilot study), all the reports of Crohn's
disease, and all cases of autism associated
with any gastrointestinal disorder were
evaluated in detail. Members of the Working
Group were sent all the information available
from these reports. Where a selection had to
be made (as for the possible cases of autism
alone), this was done on the basis of earlier
receipt of medical follow-up information.
The conclusions of the Working
Party member and MHRA evaluator were
summarised in a table at the end of each
assessment form in the following four
categories :
A. Have
either the diagnosis or clinically relevant
signs and symptoms been confirmed medically ?
YES (Y) NO (N) UNSURE (U)
B. Was
the onset of the possible adverse effect
within six weeks of immunisation with MMR ?
Parent=YES (Y) NO (N) NOT KNOWN (NK)
Health Professional=YES (Y) NO (N) NOT KNOWN
(NK)
C. Was
there history prior to immunisation relevant
to the possible adverse effect?
YES (Y) NO (N) UNSURE (U)
D. Was
there evidence of other causes for the
possible adverse effect ?
YES (Y) NO (N) UNSURE (U)
Six weeks after immunisation was
chosen as a cut-off point for a close
temporal association because this is the
maximum period in which viral replication can
be detected after immunisation [1]. This
cut-off point has been used previously in
epidemiological studies [2,3]. No minimum
time period after vaccination was used,
although recognising that cases would be
included with histories of symptom onset
interval too short to be likely to be
vaccine-related. In respect of the timing of
onset of each adverse effect, the parental
information took priority over the doctor's
(reflecting normal clinical practice because
the doctor would normally rely on the
parent's account of symptom onset).
Each report was subsequently
categorised with the letters Y or N for each
of the four categories above. Those cases
which at least one evaluator judged fulfilled
the following specific criteria: (a) medical
confirmation of diagnosis (b) onset within 6
weeks following immunisation (c) no relevant
prior history (d) absence of an alternative
cause, i.e. those that were categorised as
YYNN, were reviewed at a meeting of the
Working Party in order to reach an agreed
evaluation. As indicated above, such a
categorisation focuses on more immediate
events but is insufficient to define a causal
association.
For all other cases, differences
between the evaluations of the Working Party
member and the MHRA physician were resolved
between them.
Medical confirmation of
the diagnoses of autism/PDD and Crohn's
disease
The diagnostic criteria used for
pervasive developmental disorder (PDD) and
autism are given in Annex 2. Autism is a more
specific diagnosis than PDD. Although
parental reports invariably mentioned autism
rather than PDD, evidence to support the more
specific diagnosis was often lacking.
Since fulfillment of the
diagnostic criteria for autism was more
likely to reflect the nature of the
information available than true differences,
this report presents the evidence for both
categories combined i.e. autism/PDD.
Statements relating to "autism"
have been retained where they reflect
parental reports rather than medical
diagnoses.
If the criteria for PDD or
autism were met, or the evidence supported
Crohn's disease for the possible adverse
effect, this led to a categorisation of YES
for "Has the diagnosis been confirmed
medically?" If the evaluator was
uncertain about the diagnosis then UNSURE was
categorised. If the evidence did not support
the diagnosis then NO was categorised.
The evaluator was also asked to
indicate on the assessment form if there were
any extraordinary features about each
individual case.
Classification of onset
of possible adverse effect
Two values for time of onset for
signs and symptoms according to the parent
and doctor were available for evaluation. If
either the parent or doctor indicated that
the onset of the possible adverse effect was
at any time within 6 weeks following
immunisation then this was classified as YES.
If both the parent and doctor indicated that
the onset of the possible adverse effect was
later than six weeks than this was
categorised as a NO. If neither the parent
nor doctor indicated a time of onset for the
possible adverse effect, then this was
categorised as NOT KNOWN. The evaluators
exercised clinical judgement in deciding
whether reported symptoms and signs were
relevant to the possible adverse effect. For
example, in a case of autism, behavioural
symptoms soon after vaccination would have
been considered relevant but non-specific
symptoms such as pyrexia alone would not have
led to a classification of YES.
History relevant to
possible effect prior to immunisation
For children who had signs and
symptoms of the possible adverse effect which
were usually not recognised as such by the
parent, but were noted by the health
professional, a categorisation of YES was
used when the reporting doctor was confident
about this evidence and UNSURE when there was
doubt. NO was chosen to indicate no relevant
past history had been reported by both the
child's parents and doctors.
Evidence of other causes
for main possible adverse effect
Evidence of other causes applied
in particular to children with autism/PDD.
The main evidence was that of a first
generation (i.e. parents or siblings) family
history of speech or behavioural disorders
which might indicate a genetic component to
the adverse effect [4,5]. More distant family
history only was not considered evidence.
Evaluation of obstetric
history
Obstetric history was primarily
sought to see if there was evidence of
neonatal encephalopathy which might also be
an alternative cause. As details confirming a
normal obstetric history were needed, it was
not considered adequate evidence of a normal
obstetric history for a doctor just to circle
YES or NO on the questionnaire without
supporting information. An obstetric history
was considered adequate only if the child's
doctor(s) had provided details.
Evaluation of signs and
symptoms of encephalitis and encephalopathy
Both the Working Group and MHRA
evaluators were provided with checklists of
signs, symptoms and investigations for
serious acute neurological events which might
indicate encephalitis or encephalopathy. If
either condition occurred, this might be a
relevant cause of autism/PDD.
Inclusion of reports for
evaluation
By mid-1998 about 1200 parent
questionnaires had been distributed by
solicitors. On 21 October 1998, 531 parent
reports had been received and added to the
ADROIT database. Of the 531 children, 231
were classified as having autism (with or
without gastrointestinal disorders) and 20
classified as Crohn's disease (one of whom
also had autism). Medical information had
been received from GPs and specialists for
218 cases in total. The Working Party
considered it was not feasible to review all
the less commonly reported effects because
the body of information available for the
individual problems was insufficient to
permit meaningful analysis. In reaching this
conclusion, the Working Party took account of
the fact that all the less frequently
reported possible effects were of symptoms,
signs or illnesses which are encountered
naturally in children in this age group.
On the basis described in
section 1.3 above, one hundred and twenty-six
reports were evaluated in detail by a member
of the Working Party and the MHRA physician,
as follows: autism only (55); autism and
gastrointestinal disease (52) and Crohn's
disease only (19). Twelve reports of autism
with gastrointestinal disorder and 3 of
Crohn's disease had to be excluded from the
full analysis because there was insufficient
medical information available to make an
evaluation. During the evaluation it emerged
that one of the cases of "autism
only" did have gastrointestinal
symptoms. Thus, a total of 95 reports of
children with autism were fully evaluated, of
whom 54 had no gastrointestinal problem and
41 had both autism and a gastrointestinal
disorder. In addition, 16 reports of children
who had Crohn's disease reported alone were
fully evaluated. Whilst all information
received from both parents and doctors
relating to reports not selected for detailed
evaluation has been entered onto the ADROIT
database, the Working Party has not reviewed
these cases individually.
3. Results
3.1 Autism/PDD
3.1.1 Confirmation of
diagnosis
Of the 95 cases of reported
autism evaluated, the diagnosis was
considered confirmed as autism/PDD in 81,
possible in 11 and not confirmed in 3. The
three unconfirmed reports were all considered
to be cases of global developmental delay.
These three reports are not considered in the
summary statistics below. The 92 reports of
autism/PDD considered confirmed or possible
included 78 (85%) males and 14 (15%) females
and are summarised below.
3.1.2 Immunisation
history
All but one of the 92 children
with confirmed or possible autism/PDD had
received MMR vaccine, the exception having
received monocomponent measles vaccine. Using
information relating to the date of
immunisation (Urabe strain vaccines were
withdrawn in the UK in September 1992) and
batch numbers, it was determined that the
mumps component of the vaccine was Jeryl-Lynn
strain for 59 children, Urabe strain for 11
and uncertain or unknown in 21.
3.1.3 Onset of symptoms
of autism in relation to immunisation
Information on the timing of
onset of autism in relation to immunisation
as provided by parents and doctors is
summarised in Figure 2. Some 42% of parents
reported onset of first symptoms within six
weeks following immunisation, 47% reported
onset more than 6 weeks following
immunisation and 11% did not indicate the
time of onset. In only 6% of cases were
reporting health professionals made aware of
the child's symptoms for the first time
within six weeks following immunisation. For
37% of reports, the time of onset quoted by
parents and the time a health professional
became aware were similar.
Comparison of the children whose
onset of autism was within 6 weeks following
immunisation with those for whom it began
later showed no differences in respect of the
proportions who had prior abnormalities,
relevant family history and a confirmed
diagnosis.
3.1.4 Previous medical
history suggesting behavioural abnormalities
Doctors reported a previous
behavioural abnormality in 24 (26%), and a
possible behavioural abnormality in a further
12 (13%) children prior to immunisation.
However, parents had only indicated a
possible pre-existing behavioural problem in
one child.
3.1.5 Family history
In total, a family history of
speech and/or behavioural difficulties was
reported by health professionals for 42 (46%)
of cases. For 28 children (30%), this
included at least one first-generation
relative (i.e. parent or sibling), as
follows:
Sibling only (in 5 cases it
was a twin) 12
Parent only 5
Mother, uncle and brother 1
Mother and brother 1
Father and uncle 1
Father and cousin 1
Father and grandmother 1
Both parents and brother 1
Father, aunt and cousin 1
Father and aunt 1
Brother and cousin 1
Brother and multiple family members 1
Father and multiple family members 1
3.1.6 Obstetric history
Adequate information to be
confident that the mother's obstetric history
was normal was presented in only 23 reports
(25%). For 7 reports (8%), complications of
pregnancy were reported, as follows: cord
around neck (3), fetal distress requiring
Caesarean section (2), varicella in pregnancy
(1), and a twin born second as a breech with
Apgar scores of 5 at 2 minutes and 9 at 5
minutes (1). However, none of these was
considered as evidence of another cause for
autism/PDD.
3.1.7 Signs and symptoms
of encephalopathy
One child with possible autism
was reported by a parent to have had a
convulsion within 6 weeks after immunisation
but no medical confirmation was provided. For
none of the other cases of autism/PDD did the
parent or doctor report any clinical signs or
symptoms suggesting a diagnosis of
encephalopathy or encephalitis. One child
developed autism/PDD concurrently with
myoclonic seizures with an onset greater than
six weeks following immunisation.
3.1.8 Other potentially
relevant history
Three children had head
circumferences larger than the 97th
percentile. Six children had viral illnesses
which either the parent or the doctor thought
might be relevant to developing PDD or
autism, as follows: unspecified viral illness
(3), bronchiolitis due to respiratory
syncytial virus (1), rubella (1), measles
(1). One parent had informed the doctor that
the child had started to lose skills after a
minor head injury pre-dating immunisation.
3.1.9 Reports initially
classified as YYNN by at least one evaluator
There were 18 reports of
autism/PDD where at least one of the
evaluators initially classified a report as
YYNN (which means confirmed diagnosis of PDD,
symptom onset according to parents within six
weeks following immunisation, no relevant
prior history and no evidence for alternative
causes). However, in most reports there were
factors identified which raised some doubts
about either the diagnosis, presence of
preceding speech problems, time of onset or
other causes.
For six of these 18 reports
there was complete agreement between the
evaluators. After discussion of the 12 other
cases by the Working Party a further two
cases were considered to be YYNN. None of the
eight cases considered to be YYNN had
extraordinary features suggestive of a novel
syndrome. Of the 10 cases that were not
ultimately considered to be YYNN, doubt
related to the time of onset in 5, relevant
prior history in 3 and the diagnosis not
being confirmed in 2.
3.1.10 Interobserver
variation
For all 92 reports of confirmed
or possible autism/PDD, there was complete
agreement on all four categories between the
external and MHRA evaluators for 22 reports
(24%). Of the 70 reports where there was
disagreement, this was for one category in 36
(39%), two categories in 21 (23%), three
categories in 9 (10%) and four categories in
4 (4%). Differences arose over the certainty
of the diagnosis in 21 cases, time of onset
(28), presence of relevant prior history
(37), and existence of alternative causes
(35).
3.2 Cases of Crohn's
disease without autism
Sufficient information to make
an evaluation was available for 16 reports of
Crohn's disease.
3.2.1 Confirmation of
diagnosis
The diagnosis was supported by
adequate information in 12 of the 16 cases.
In three cases the diagnosis was considered
possible, as follows: histological findings
consistent with but not diagnostic of Crohn's
disease (1); no histological evidence but the
child had an ileostomy (1); orofacial
granulomatosis proven but no bowel histology
(1). For one case, Crohn's disease was
considered unconfirmed, the available
evidence being consistent with a diagnosis of
constipation. The following information
summarises the 15 reports considered
confirmed or possible.
3.2.2 Immunisation
history
For the 15 children where
Crohn's disease was considered confirmed or
possible, the parents suspected MR vaccine in
9 cases and MMR vaccine in 6 cases. Of the 9
children where MR vaccine was suspected, 6
had previously received MMR vaccine, 1 had
previously received measles vaccine, 1 had
previously received both measles and MMR
vaccine, and 1 had previously received
measles vaccine and rubella vaccine
separately.
3.2.3 Onset of symptoms
of Crohn's disease
Information on timing of the
onset of Crohn's disease as provided by
parents and doctors is summarised in Figure
3. For five of the 15 reports the onset
according to the parent was within six weeks
of immunisation with MMR vaccine. One child
developed arthritis between six weeks and six
months following immunisation although bowel
symptoms started over six months later.
3.2.4 Classification of
cases of Crohn's disease
There were 4 reports of Crohn's
disease where both the MHRA evaluator and the
Working Group member classified a report as
YYNN. None of these cases had extraordinary
features suggestive of a novel syndrome. For
all 15 reports of confirmed or possible
Crohn's disease, there was complete agreement
on all four categories between the external
and MHRA evaluators for 10 reports. Of the 5
reports where there was disagreement, this
was for one category in 2, two categories in
2, three categories in none and four
categories in 1. Differences arose over the
certainty of the diagnosis in 2 cases, time
of onset (2), presence of relevant prior
history (4), and existence of alternative
causes (2).
3.3 Other bowel
disorders associated with cases of autism
The single case reported on the
parent questionnaire as having both autism
and Crohn's disease was considered to have a
confirmed diagnosis of autism but not of
Crohn's disease, the medical evidence being
consistent with a diagnosis of constipation.
Thus there was no case for which both
disorders were confirmed. Of the 41cases of
autism with a bowel disorder, the following
gastrointestinal diagnoses were confirmed:
lymphonodular hyperplasia (9 cases: 4 alone,
4 with microscopic colitis and one with
giardiasis), constipation (5), diarrhoea of
unknown cause (2), gastroenteritis (2),
clostridium difficile diarrhoea (1),
cryptosporidiosis (1), recurrent
intussusception (1), lactose intolerance (1)
and coeliac disease (1). In all but two cases
the onset of the gastrointestinal disorder
was uncertain or greater than 6 months after
immunisation with MMR vaccine. For the
remaining 18 cases the diagnosis of a
gastrointestinal disorder was not medically
confirmed.
4. Discussion
The original remit of the
Working Party envisaged that it might place
its findings in the context of all the
available relevant evidence but this report
only considers evidence derived from the
evaluation of parental and medical
questionnaires. A wide variety of possible
adverse effects after MMR or MR vaccines had
been reported through solicitors. The remit
of the Working Party was to consider
"any of the reported effects" but
the Working Party, having reviewed the full
range of possible adverse effects reported by
parents of 531 children, decided to consider
those which had been most frequently reported
and had caused most concern to parents i.e.
autism/PDD and gastrointestinal disorders,
particularly Crohn's disease.
The Working Party recognised
that there were marked limitations in
studying the group of children that had been
identified by the solicitors involved. These
children were not a randomly selected or
population-based group and there were no
controls. They had been reported to
solicitors because of a perceived association
between the administration of MMR or MR
vaccine and the occurrence of various
illnesses.
A sample of 95 cases with
reported autism were selected from the
original 180 reports for detailed evaluation.
For cases of autism/PDD with gastrointestinal
disorders and Crohn's disease, all the cases
with follow-up information available by
1/8/98 were included. For cases of autism/PDD
alone, selection was made on the basis of
earlier receipt of follow-up information.
This may have led to some sampling bias but
it is, however, likely that any bias
introduced by this process will be for more
plausibly linked cases to be included.
For 85% of the children reviewed
whose parents reported autism, the available
medical information supported a diagnosis of
PDD or autism. Autism/PDD was considered
possible in a further 12% of cases.
Developmental assessments and clinical
examinations were normally provided. Results
of investigations such as hearing tests and
chromosome analyses were often reported. The
confirmed cases showed no extraordinary
characteristics and there was no evidence to
support a novel syndrome associated with MMR
vaccine.
In assessing the temporal
significance of reports in relation to
vaccination, a period of onset within six
weeks was considered of particular interest
because this is the maximum period in which
viral replication can be detected after
immunisation [1] and has been used previously
used for some of the principal
epidemiological studies of MMR vaccine [2,3].
For 42% of cases of autism, relevant symptoms
were first observed within six weeks
following vaccination according to the
parents. It is noteworthy that parents were
much more likely to indicate that symptom
onset was within this interval than were
doctors. Only 5 of these children were seen
by doctors within six weeks of immunisation.
Where there was disagreement between parents
and doctors we used the parental report in
our analysis although it would be reasonable
to assume that a dramatic and acute
deterioration in a child's neurological,
behavioural or cognitive state would have
prompted medical consultation. Often the
doctor only provided the date of the first
consultation when symptoms were first
reported to him or her, rather than the
actual time of onset. Because of the gradual
way in which autistic features evolve in a
child, it is not surprising that the time of
onset was not known for many children.
Comparisons of the
characteristics of children whose symptoms
were reported to have had an onset within or
greater than 6 weeks following immunisation
revealed no differences. For the assessment
of cases of autism/PDD there was some
interobserver variation, with complete
agreement on all four categories for 24% of
cases and all but one category for 63%.
Differences were fairly evenly spread amongst
the four categories and are likely to reflect
the considerable difficulty involved in
interpreting the variable and often limited
information reviewed.
In the children with confirmed
or possible autism there was no evidence
suggestive of a preceding acute neurological
event such as encephalitis or encephalopathy,
either before or after MMR vaccine. With
regard to previous medical history suggestive
of behavioural difficulties, there was a
marked contrast between the frequency
estimated from information provided by
parents (1%) and doctors (39%).
There were 28 cases (30%)
recorded of speech or behavioural
difficulties in childhood affecting
first-degree relatives of autistic children
(with multiple instances in some families).
There were also seven children with abnormal
obstetric histories and six with a preceding
possible viral illness which had been
considered relevant either by the parent or
the reporting doctor.
When considering the bowel
symptoms associated with autism, there were
no consistent clinical features or evidence
of a close temporal relationship with MMR
vaccine. Some of the findings described on
endoscopy such as lymphonodular hyperplasia
may be normal features [6]. In particular,
there were no reports with adequate evidence
to support a diagnosis of inflammatory bowel
disease occurring in association with autism.
No consistent recognised or novel
gastrointestinal syndrome could be defined in
these children with autism/PDD and
gastrointestinal symptoms.
Crohn's disease was usually well
documented diagnostically and was considered
confirmed or possible in 15 cases. Five cases
of Crohn's disease had an onset of symptoms
within six weeks after vaccination according
to the parents. Four of the cases were
categorised as "YYNN" but no
differences in characteristics between these
children and the others with Crohn's disease
were identified.
The Working Party carefully
considered whether further evaluation of
cases of reported autism/PDD and Crohn's
disease not yet reviewed in detail should be
undertaken. Taking into account the high
proportions of cases already sampled with the
diagnoses of particular concern, the absence
of findings suggesting a causal association
and the limitations of the evidence (in
particular selection bias leading to an
expected temporal association), the Working
Party considered that further detailed
evaluation is not warranted.
5. Conclusions of the
Working Party
Based on their review of
information described above, the Working
Party reached the following conclusions :
5.1 The
exercise undertaken in respect of cases of
children with adverse effects attributed by
parents to MMR or MR vaccines and reported to
a firm of solicitors has yielded a
considerable volume of medical information
which was extremely variable in quality and
completeness.
5.2 The
information evaluated has important intrinsic
limitations as regards assessing whether the
vaccines are, or are not, causally associated
with the attributed adverse effects. Notably
these are bias in the selection of cases for
which it would be impossible to compensate,
and the lack of any control (unimmunised)
group with which the frequency and
characteristics of the attributed illnesses
could be compared. Also there was frequent
divergence between parents and doctors
regarding specific details of the illnesses.
5.3 Detailed
evaluation of 92 cases with autism/PDD and
all 15 cases with confirmed Crohn's disease
revealed no extraordinary features which
suggested a novel syndrome, nor did it
support causal associations with MMR or MR
vaccines. In particular, no case of
autism/PDD developed following an acute
unexpected and/or unexplained neurological
event in the post-vaccination period.
5.4 For
only eight cases of the 92 with autism and
four of the 15 with Crohn's disease was
satisfactory evidence available to infer (i)
medical confirmation of the diagnosis (ii) a
close temporal association between
administration of the vaccine and onset of
the illness (iii) no relevant prior history
and (iv) absence of an alternative cause. The
numbers of such cases identified was
therefore small. Furthermore these factors
alone are insufficient to prove causation,
particularly as the onset of autism is
frequently recognised around the time MMR
vaccine is given. The pattern of the
illnesses reported for the 8 cases with
autism and 4 with Crohn's disease cited above
did not appear to differ from that of other
children with these disorders. There was no
evidence to suggest that administration of
MMR or MR vaccine was associated with
particular variants of pervasive
developmental disorder or inflammatory bowel
disease.
5.5 It was
impossible to prove or refute the suggested
associations between MMR vaccine and
autism/PDD or inflammatory bowel disease
because of the nature of the information, the
self-selection of cases and the lack of
comparators. Nevertheless, the Working Party
found that the information available did not
support the suggested causal associations or
give cause for concern about the safety of
MMR or MR vaccines.
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