FW: Drug Co Time Trend Study: No MMR, Vaccine Connection

[Guest guest]

Drug Co Time Trend Study: No MMR, Vaccine Connection

FEAT DAILY NEWSLETTER Sacramento, California http://www.feat.org

" Healing Autism: No Finer a Cause on the Planet "

______________________________________________________

February 9, 2001 Search www.feat.org/search/news.asp

Drug Co Time Trend Study: No MMR, Vaccine Connection

Mumps, measles, and rubella vaccine and the incidence of autism recorded by

general practitioners: a time trend analysis.

http://www.bmj.com/cgi/content/full/322/7283/DC1

A Kaye, del Mar Melero-Montes, Hershel Jick

Boston Collaborative Drug Surveillance Program, Boston University

School of Medicine, 11 Muzzey Street, Lexington, MA 02421, USA

A Kaye epidemiologist del Mar Melero-Montes epidemiologist

Hershel Jick associate professor of medicine

Correspondence to: J A Kaye jkaye@...

Abstract

Objective To estimate changes in the risk of autism and assess the

relation of autism to the mumps, measles, and rubella (MMR) vaccine.

Design Time trend analysis of data from the UK general practice

research database (GPRD).

Setting General practices in the United Kingdom.

Subjects Children aged 12 years or younger diagnosed with autism

1988-99, with further analysis of boys age 2 to 5 years born 1988-93.

Main outcome measures Annual and age specific incidence for first

recorded diagnoses of autism (that is, when autism was first recorded) in

the children aged 12 years or younger; annual, birth cohort specific risk of

autism diagnosed in the 2 to 5 year old boys; coverage (prevalence) of MMR

vaccination in the same birth cohorts.

Results The incidence of newly diagnosed autism increased sevenfold,

from 0.3 per 10 000 person years in 1988 to 2.1 per 10 000 person years in

1999. The peak incidence was among 3 and 4 year olds, and 83% (254/305) of

cases were boys. In an annual birth cohort analysis of 114 boys born in

1988-93, the risk of autism in 2 to 5 year old boys increased nearly

fourfold over time, from 8 (95% confidence interval 4 to 14) per 10 000 for

boys born in 1988 to 29 (20 to 43) per 10 000 for boys born in 1993. For the

same annual birth cohorts the prevalence of MMR vaccination was over 95%.

Conclusions Because the incidence of autism among 2 to 5 year olds

increased markedly among boys born in each year separately from 1988 to 1993

while MMR vaccine coverage was over 95% for successive annual birth cohorts,

the data provide evidence that no correlation exists between the prevalence

of MMR vaccination and the rapid increase in the risk of autism over time.

The explanation for the marked increase in risk of the diagnosis of autism

in the past decade remains uncertain.

Introduction

The possibility that the mumps, measles, and rubella (MMR) vaccine may

be causally related to the risk of autism is currently causing substantial

concern. This proposition originated primarily from a publication by

Wakefield et al in 1998 that described 12 case reports of children who were

diagnosed with ileal-lymphoid-nodular hyperplasia followed by behaviour

disorders that were clinically diagnosed as representing autism. (1) In

eight of 12 children the behaviour disorder was " linked " in time by the

parents or the child’s physician.

In June 1999 et al published in the Lancet the results of a

study in which they identified children diagnosed as having autism in the

North East Thames region for birth cohorts from 1979 to 1992. (2) They

reported that the incidence of autism started to increase in children born

in the late 1980s and increased dramatically in those born from 1989 to

1992. They also provided estimates of the coverage (prevalence) of MMR

vaccination from 1987 to 1995, which rose to over 90% by 1988-9. They found

no temporal association between MMR vaccination and the incidence of autism

within one to two years of vaccination, and there was no " clustering " of

cases in the two to four months after vaccination.

In a subsequent letter to the Lancet's editor Wakefield described the

study by et al (2) as containing a " fundamental flaw " and provided

data from the United Kingdom (north west London) and the United States

(California) based on the time trend of autism occurrence by birth cohort in

relation to the introduction of the MMR vaccine. (3) In both areas a

dramatic increase in the incidence of autism was reported in temporal

association with the rapid introduction of the vaccine.

We used the UK general practice research database (GPRD) to evaluate

further the temporal relation of MMR vaccine and the incidence of autism.

Subjects and methods

The data in the UK general practice research database are firmly

established in numerous publications to be of high quality and completeness

(4) and, in particular, the recording of vaccinations in this database has

been found to be virtually complete (H Jick et al unpublished data). (5) (6)

We initially tried to conduct a case-control analysis comparing children who

received the MMR vaccine and those not vaccinated in relation to the

diagnosis of autism. Only about 3% of cases and controls, however, did not

receive the vaccine, and therefore there was too little information to

provide a meaningful estimate of relative odds. We therefore conducted a

time trend analysis to explore the relation of the MMR vaccine and the

diagnosis of autism over time.

We identified 305 children aged 12 or younger whose diagnosis of

autism was first recorded (first recorded diagnosis) during the years 1988

to 1999 (from among 3 092 742 person years of observation in the base

population). We reviewed the detailed computer recorded information for each

of these children. We estimated annual incidence (regardless of age at first

recorded diagnosis) and age specific incidence (regardless of year of first

recorded diagnosis). Some practices stopped providing information before

1999, and therefore the person-time available in the later years was smaller

than that in the earlier years.

Subsequent analyses were restricted to 114 boys born in 1988-93 who

had a first recorded diagnosis of autism at age 2 to 5 years (24-71

months)—that is, during 1990-9. Annual birth cohorts were analysed

separately. For each annual birth cohort, we estimated the four year

cumulative incidence (risk) of diagnosed autism with the exponential

formula: cumulative incidence=1- exp(- S IkDt), where Ik represents the

estimated age specific annual incidences for the individual birth cohort and

D t is one year. The prevalence of MMR vaccination among children registered

in the general practice research database within 60 days of birth who had at

least two years of recorded follow up was also calculated separately for

each annual birth cohort. Statistical analyses were performed using STATA,

version 7.0 (Stata Corporation, College Station, Texas).

Results

The estimated yearly incidence of diagnosed autism among children aged

12 years or younger (305 cases) increased sevenfold, from 0.3 per 10 000

person years in 1988 to 2.1 per 10 000 person years in 1999. The median age

at first recorded diagnosis of autism was 4.6 years and did not vary

substantially over time (table). The peak ages at first recorded diagnosis

were 3 years and 4 years (fig 1). Two hundred and fifty four of the cases

were male. About 81% (248/305) of the cases were referred to a specialist

for evaluation of the diagnosis.

[Tables and Chart at: http://www.bmj.com/cgi/content/full/322/7283/DC1 ]

Table 1 Number of cases, person years at risk, and mean age of

cases, according to year of diagnosis of autism in 305 children aged 12

years or younger.

(F1) Fig 1 Incidence of autism in children registered in UK general

practice research database, by age at diagnosis (total observation time was

3 092 744 person years)

To assess more precisely the possibility of a temporal association

between MMR vaccination and the risk of autism, we analysed data for

consecutive annual birth cohorts of boys born during 1988-93. For each

annual birth cohort, we estimated the four year cumulative incidence (risk)

of a first recorded diagnosis of autism at age 2-5 years. One hundred and

fourteen boys were included in this analysis. The four year risk of

diagnosed autism increased nearly fourfold, from 8 (95% confidence interval

4 to 14) per 10 000 for boys born in 1988 to 29 (20 to 43) per 10 000 for

boys born in 1993 (P<0.0001 by score test for trend in odds (Fig 2)). In

contrast, the prevalence of MMR vaccination among children registered in the

general practice research database with at least two years of follow up was

virtually constant (about 97%) for each successive annual birth cohort (fig

2 (2)) and was similar among males and females (data not shown).

Fig 2 Four year risk of autism (with 95% confidence intervals) among

boys aged 2 to 5 years and prevalence of MMR vaccine, by annual birth cohort

Among the vaccinated children, the median age at first MMR vaccination

was 14 months, and 95% of those vaccinated received their first MMR

vaccination by age 20 months. Among 110 cases of autism in boys aged 2 to 5

years born in 1988-93 for whom MMR vaccination could be assessed, the

distribution of age at first MMR vaccination was nearly identical to that of

the population as a whole, and 109 (99%) were vaccinated, a prevalence

nearly identical to that in the general population.

Discussion

Previous publications have reported that the overall incidence of

clinically diagnosed autism began to rise in the late 1980s, and that the

incidence occurs predominantly in boys. (2)(3) (6) This study shows that the

incidence has continued to increase during the past decade. Our analysis of

the risk of diagnosed autism for boys aged 2 to 5 years showed a progressive

increase for each successive birth cohort from 1988 to 1993, during which

time the prevalence of MMR vaccination was over 95%. It should be noted that

the MMR vaccine is given first at about 15 months of age and that autism is

not typically diagnosed until age 2 years or later.

If the MMR vaccine were a major cause of the increasing incidence of

autism then the risk of autism in successive birth cohorts would be expected

to stop rising within a few years of the vaccine being in full use. This was

not the case in our study as the cumulative incidence for boys ages 2 to 5

years rose almost fourfold in the 1993 birth cohort (with follow up to 1999)

compared with the 1988 birth cohort, whereas the prevalence of MMR

vaccination was over 95%. Thus no time correlation exists between the

prevalence of MMR vaccination and the incidence of autism in each birth

cohort from 1988 to 1993.

We recognise that the diagnosis of autism in our study was not

confirmed from original records but consider that differential

misclassification of the diagnosis in vaccinated and unvaccinated children

is unlikely to vary over the period of the study.

Time trend analysis for the evaluation of the relation of an exposure

to an illness is a relatively crude method. This is particularly true where

the exposure and the illness are both rising during the period of study as

such a correlation may be coincidental and due to changes in other factors

that are correlated over time with the outcome illness. Nevertheless, when

the incidence of an illness is rising rapidly in each birth year cohort at

the same time that an exposure is steady and almost universal, the exposure

cannot be the explanation for the rapid increase in incidence that was

observed.

The increase in recorded diagnoses of autism that we observed in the

UK general practice research database could be due to increased awareness of

the condition among parents and general practitioners, changing diagnostic

criteria, or environmental factors not yet identified.

A strength of our study is that we were able to use population based

data in the general practice research database to estimate the birth cohort

specific incidence of autism recorded by general practitioners as well as

the prevalence of MMR vaccination. A limitation is that we have not yet

obtained and evaluated full clinical record information from general

practitioners to describe more fully the characteristics of children

diagnosed as having autism and to explore other possible explanations for

the marked increase in the incidence of this illness during the past decade.

Nevertheless, these results provide evidence against a causal relation

between MMR vaccination and the risk of autism.

What is already known on this topic

The incidence of autism in the United Kingdom has increased markedly

over the past decade.

Some have proposed that this may be related to introduction of the

mumps, measles, and rubella (MMR) vaccine in 1988

What this study adds

The authors conducted a detailed analysis of time trends in the

coverage (prevalence) of MMR vaccination and the risk of autism among boys

aged 2 to 5 years born in 1988-93 and registered in the UK general practice

research database

The risk of autism increased nearly fourfold among annual birth

cohorts during these years, whereas the prevalence of MMR vaccination was

over 95% and virtually constant

These data provide evidence against a causal association between MMR

vaccination and the risk of autism

We appreciate the helpful comments of M on an earlier

draft of the manuscript.

Contributors: JAK participated in the study design, analysed the data,

and drafted the manuscript. MdelMM-M helped in assembling the data for

analysis and contributed to writing the manuscript. HJ participated in the

study design and revising the manuscript. JAK and HJ are guarantors for the

paper.

Funding: No specific funding.

Competing interests: The Boston Collaborative Drug Surveillance

Program is supported in part by grants from AstraZeneca, Berlex

Laboratories, Boehringer Ingelheim Pharmaceuticals, Boots Healthcare

International, Bristol-Myers Squibb Pharmaceutical Research Institute,

GlaxoWellcome, Hoffmann-La Roche, Janssen Pharmaceutica Products, R W

Pharmaceutical Research Institute; McNeil Consumer Products, and

Novartis Farmaceutica. JAK is a and Virginia Taplin fellow at the

Harvard School of Public Health and is supported by a training fellowship in

cancer epidemiology from the National Cancer Institute (T32-CA 09001).

Wakefield AJ, Murch SH, A, Linell J, Casson DM, Malik M, et

al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive

developmental disorder in children. Lancet 1998;351:637-41.

B, E, Farrington CP, Petropoulos M-C, Favot-Mayaud I, Li

J, et al. Autism and measles, mumps, and rubella vaccine: no epidemiological

evidence for a causal association. Lancet 1999;353:2026-9.

Wakefield AJ. MMR vaccination and autism. Lancet 1999;354:949-50.

Jick H. A database worth saving. Lancet 1997;350:1045-6.

Jick H, Withers JM, Dean AD. Haemophilus influenza vaccine [letter].

Br J Gen Pract 1995;45:107.

Wing L. The autistic spectrum. Lancet 1997;350:1761-6.

>> DO SOMETHING ABOUT AUTISM NOW <<

Subscribe, Read, then Forward the FEAT Daily Newsletter.

To Subscribe go to www.feat.org/FEATnews No Cost!

_______________________________________________________

Lenny Schafer, Editor PhD Ron Sleith Kay Stammers

Editor@... Unsubscribe: FEATNews-signoff-request@...