Autism and thimerosal-containing vaccines: lack of consistent evidence for an association

Paul Stehr-Green¹, Peet Tull, Michael Stellfeld, Preben-Bo Mortenson, Diane Simpson

PMID: 12880876 DOI: 10.1016/s0749-3797(03)00113-2

Abstract

Background: In 1999, concerns were raised that vaccines containing the preservative Thimerosal might increase the risk of autism and/or other neurodevelopmental disorders.

Methods: Between the mid-1980s through the late-1990s, we compared the prevalence/incidence of autism in California, Sweden, and Denmark with average exposures to Thimerosal-containing vaccines. Graphic ecologic analyses were used to examine population-based data from the United States (national immunization coverage surveys and counts of children diagnosed with autism-like disorders seeking special education services in California); Sweden (national inpatient data on autism cases, national vaccination coverage levels, and information on use of all vaccines and vaccine-specific amounts of Thimerosal); and Denmark (national registry of inpatient/outpatient-diagnosed autism cases, national vaccination coverage levels, and information on use of all vaccines and vaccine-specific amounts of Thimerosal).

Results: In all three countries, the incidence and prevalence of autism-like disorders began to rise in the 1985-1989 period, and the rate of increase accelerated in the early 1990s. However, in contrast to the situation in the United States, where the average Thimerosal dose from vaccines increased throughout the 1990s, Thimerosal exposures from vaccines in both Sweden and Denmark-already low throughout the 1970s and 1980s-began to decrease in the late 1980s and were eliminated in the early 1990s.

Conclusions: The body of existing data, including the ecologic data presented herein, is not consistent with the hypothesis that increased exposure to Thimerosal-containing vaccines is responsible for the apparent increase in the rates of autism in young children being observed worldwide.

“Financial support for the compilation of the data used in this investigation and the preparation of this report was provided by the National Immunization Program, Centers for Disease Control and Prevention. We are grateful to Victoria Romanus of the Swedish Institute for Infectious Disease Control, Ingrid Trolin of the Swedish Medical Products Agency, Anne-Marie Plesner and Peter Andersen of the Danish Statens Serum Institut Institut [Denmark’s largest vaccine company], and Roger Bernier and Susan Chu of the Centers for Disease Control and Prevention for their contributions in the design and conduct of this investigation, and in the preparation and review of this manuscript.”

14studies.com

Sometimes called the “Swedish Study.” A summary paper that used the same methodologically flawed approach used in the original Danish study published in Pediatrics, which we discuss as study #2. Shockingly, Sweden’s autism rate is noted to be 1 in 10,000, which is 60 times lower than the U.S. rate, but the authors don’t address this discrepancy.

Actual Question This Study Asked & Answered:

Q: Did the discontinuation of thimerosal use in vaccines in Denmark, Sweden, and the U.S. lead to a decrease in autism?

A: No.

Did the study look at unvaccinated children?

No.

Conflict of Interest (from the study itself):

Ability to Generalize:

None. As SafeMinds noted:

“Stehr-Green et al. 1 have misrepresented my work and confused the debate over autism and mercury exposure in the United States with ecological data from Sweden and Denmark. Their uninformative article in AJPM should not delay efforts by independent researchers to carry out the investigations into mercury and neuro-developmental disorders recommended by the Institute of Medicine (IOM).2 Their report has many flaws, but four stand out..”

Post-Publication Criticism:

Very high.

Scoring (Out of 40 possible points):

Asked the Right Question: 0

Ability to Generalize: 0

Conflict of Interest: 0

Post-Publication Criticism: 0

Total Score: 0

Choice Excerpt from the Study:

“Prior to 1992, the data in the national register did not include cases diagnosed in one large clinic in Copenhagen (which accounts for approximately 20% of cases occurring nationwide). Prior to 1995, the autism cases reported to the national register reflected only cases diagnosed in inpatient settings.”

Meaning:

Highlights the “fatal flaw” of the Danish data set, that many autism cases simply were not counted until after 1995, when Thimerosal was removed from vaccines.

This is the equivalent of doing a study on “Divorce Rates in North America” and counting Mexico and Canada only for the first few years, then adding in the United States, and noting that divorce rates went up. To compound the problem, Denmark also changed the diagnostic code they used, to the more universal ICD10 code, beginning in 1993, which would have further raised the rates.

Guest Critic #1: SafeMinds, Mark Blaxill

FULL RESPONSE TO STEHR-GREEN PAPER IN AMERICAN JOURNAL OF PREVENTIVE MEDICINE

by Mark Blaxill, Safe Minds

Concerns continue over mercury and autism

To the editors,

Stehr-Green et al. 1 have misrepresented my work and confused the debate over autism and mercury exposure in the United States with ecological data from Sweden and Denmark. Their uninformative article in AJPM should not delay efforts by independent researchers to carry out the investigations into mercury and neuro-developmental disorders recommended by the Institute of Medicine (IOM).2 Their report has many flaws, but four stand out.

Their erroneous description of the California data promotes complacency regarding autism rates.

For an IOM review, I presented an ecological analysis of autism rates and thimerosal exposure in vaccines that demonstrated an association between rising autism rates in California and thimerosal exposure in childhood vaccines. I neverattempted to publish these findings, since ecological analysis, as the IOM summary pointed out, is generally uninformative. I simply made the case for concern and more (and independent) research. In their re-use of my charts, the authors err in describing the rates of autism reported therein as rates for the larger class of “autism-like disorders.” This is not true. California prevalence rates are reported based only on DSM IV autism cases.3,4 By suggesting these rates belong to a broader category, the authors’ description minimizes the severity of the situation in California. These high and rising autism rates point to an urgent public health crisis, one that requires accurate measurement and precise classification.
Their new autism trend analyses account for only a fraction of the autism population.

The large majority of autism cases are found in outpatient populations. Yet, their autism analyses in Sweden (exclusively) and Denmark (for two-thirds of the study period) rely on inpatient populations for disease frequency calculations. One recent study5 in Denmark reported that over 93% of autistic children were outpatients. Clearly, this small minority of inpatient autism cases has little value for purposes of trend assessment. Investigating restricted populations for purposes of causal inference is a fool’s errand.
Their rate and exposure assessments contain multiple errors, inconsistencies and misrepresentations.

For example, in addition to the inpatient population problem: they measure autism case counts, not rates in Denmark; they mischaracterize their autism cohorts in Sweden as birth year cohorts when they are actually moving average cohorts of 2-10 year olds; they report vaccine compliance levels in Denmark (over 90%) that are inconsistent with the mercury exposures in their display; they represent the Danish pertussis doses as standard when they are highly unusual (and therefore suspect); they acknowledge non-standard and changing diagnostic criteria and incomplete institutional coverage in their Danish case count, without attempting correction; and they report time at diagnosis, not year of birth, in their Danish autism population, a common mistake. Despite these flaws, they claim, inappropriately, that their choice of Swedish and Danish sources was based on “high quality records.”
Their interpretation of the autism-mercury hypothesis is incorrect.

Based on these flawed trend assumptions, the authors use the shift in Sweden and Denmark from comparatively low thimerosal exposures to thimerosal-free vaccines in an attempt to falsify the autism-mercury hypothesis. Absent a clear increase in autism rates in Denmark and Sweden, this attempt at falsification fails. The autism-mercury hypothesis I tested was that increases in mercury exposure are associated with increases in autism rates. Reductions in comparatively low thimerosal exposures need not produce decreasing autism rates in stable, low-prevalence populations for the autism-mercury hypothesis to hold. Having performed the ecological analysis with which the authors started, I fully recognize its failings. Most notably: I could not match the exposure population with the affected autism population (a revision I have since made with little impact on the results); I could not measure administration of thimerosal-containing vaccines, only their sales; and I did not correct for lagged ascertainment of autism cases. Compared to the problems in the Danish and Swedish analyses, these are minor issues.

I do not, however, wish to stand in defense of ecological analysis. The authors’ awkward attempts at trend analysis stand as eloquent testimony to the potential misuse of ecological analysis, especially when based on shifting data sources and incomplete time series. Instead, resources should flow to more informative, original research. Credible evidence points to rapidly rising U.S. autism rates.4 Mercury exposure is temporally,1 epidemiologically,6 and clinically7 associable with U.S. autism cases and may help explain these increases. The IOM has called for an active research program that did not include additional ecological speculations. Independent scientists should heed their recommendations, remain concerned over the connection between autism and mercury and investigate the connection further with proper methods.

Mark F. Blaxill
Director
Safe Minds

References:

1. Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D. Autism and thimerosalcontaining vaccines: lack of consistent evidence for an association. Am J Prev Med. 2003;25(2):101-106.

2. Institute of Medicine. Immunization Safety Review: Thimerosal Containing Vaccines and Neurodevelopmental Disorders. Stratton K, Gable A, and McCormick M, eds. Washington, D.C.: National Academy Press; 2001

3. California Department of Developmental Services. Changes in the population of persons with autism and pervasive developmental disorders in California’s Developmental Services System: 1987 through 1998. A Report to the Legislature, Department of Developmental Services, California Health and Human Services Agency, State of California, Sacramento. 1999.

4. California Department of Developmental Services. Autistic spectrum disorders: changes in the California caseload, an update: 1999 through 2002. Department of Developmental Services, California Health and Human Services Agency, State of California, Sacramento. 2003.

5. Madsen KM, Hviid A, Vestergaard M, Schendel D, Wohlfahrt J, Thorsen P, Olsen J, Melbye M. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002;347(19):1477-82.

6. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med. 2003;228(6):660-664

7. Holmes AS, Blaxill MF, Haley BE. Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxic. 2003;111(4):277-285

CRITIQUES OF THE STUDY

Critics point to this study’s most glaring flaw, which appears in the Denmark section. The authors relied on autism prevalence data as reported in the Danish Psychiatric Central Register. But the way in which Denmark diagnosed and tracked autism patients had changed radically over the course of their investigation. This created an important alteration in the study’s entry criteria midway through the study period.

■ Changing Danish Population – From 1983-1992, the Danish register only listed autism cases that were diagnosed in an inpatient (hospital) setting. But in 1992 data from a large, state-of-the-art autism clinic in Copenhagen, which was diagnosing about 20% of all cases in the country was added to the national register. That year, the same year that thimerosal was removed from childhood vaccines, the number of reported autism cases, not surprisingly, saw a significant spike.

■ Adding Outpatient Cases – In 1995, for reasons that went unexplained, the national register began including all autism cases diagnosed in Denmark, including those diagnosed in outpatient settings. Most people with autism are diagnosed in clinics and private offices, not in hospitals. SafeMinds and other organizations point to a large 2002 study in Denmark – on autism and the MMR vaccine by Madsen et al. (see MMR section) – showing that outpatient-diagnosed cases outnumbered inpatient cases by a 13.5-to-1 ratio in Denmark, accounting for 93% of all autism cases.[47]

■ New Diagnostic Criteria – A third change in methodology occurred during the study period as well. In 1993, Denmark updated its psychiatric diagnostic codes and adopted new diagnoses for autistic-related disorders. Government workers conducted training seminars with clinicians in order to promote the new coding system, and an increase in autism and other reported diagnosis was to be fully expected.

■ Denmark: An Artificial Increase? This study “manipulates the incidence of autism in an attempt to clear thimerosal-containing vaccines of any role in the etiology of the disease,” a SafeMinds said in a statement. The increase reported in Denmark was “falsely created by the authors’ use of techniques which artificially boosted the number of cases identified.”

■ Sweden: Inpatient Cases Only – By counting only inpatient cases in Sweden, the reliability of that country’s data is also called into question. This limitation (counting a minority of the total number of cases) likely accounted for the erratic swings in the annual numbers of autism cases reported in that country.

■ California: Increase is Real – Sterh-Green et al. erred by writing that California’s Department of Developmental Services used a “vague” and difficult to verify autism definition. Their speculation that “changes in diagnostic criteria,” including PDD, “accounted for the largest increases” is not supported by the evidence. California’s data included only full-blown cases of autism, and not PDD. If anything, diagnostic criteria for “classic” autism became narrower over the years. And the suggestion that changes in criteria or “diagnostic substitution” (from mental retardation to autism) could explain the reported 800% increase in California has been disproven in several published papers. No retraction or correction of the authors’ erroneous claims was made.

WHAT THE STUDY SAID

■ Inpatient v Outpatient Cases – The authors noted that the switch from counting inpatient cases only, to counting all cases “Changes over time in the rates of diagnosis of autism-like disorders in inpatient versus outpatient settings may have affected the ascertainment of cases,” the authors said, adding that these very significant changes “may have spuriously increased the apparent number of autism cases.”

■ Weakness of Ecological Studies – The authors also noted the inherent weaknesses of relying on large epidemiology investigations called “ecological” studies, in which the unit of analysis is a population group and not individuals. They conceded that these studies are inherently limited in their ability to prove or disprove causation. “Such studies can be useful in exploring possible associations, (and) searching for areas of possible further study,” they wrote. “However, the greatest difficulty in interpreting ecologic studies is that of adequately controlling confounding factors due to unavailability of data and/or methodological limitations.”

WHAT THE CDC SAID ABOUT ECOLOGICAL STUDIES

An unpublished 2008 report from the CDC to the US House of Representatives Appropriations Committee concurs that ecological studies are far from ideal when using computerized population data – in this case the federal Vaccine Safety Datalink (VSD) – to determine an association between vaccines and autism.[48]

“CDC concurs that conducting an ecologic analysis using VSD administrative data to address potential associations between thimerosal exposure and risk of AD/ASD is not useful,” said the CDC paper, which was signed by then Director Julie Gerberging, MD, now President of the Vaccine Division at Merck & Co., Inc. Such an evaluation, she added, “would be uninformative and potentially misleading.

WHAT THE IOM COMMITTEE SAID:

■ Shifting Study Population – In its 2004 report, the Immunization Safety Review Committee agreed that “possible reasons” for the autism increase in Denmark “may be due to the changes in the inclusion criteria in the national register, diagnostic changes (from ICD-8 diagnostic coding to ICD-10), and the fact that, prior to 1992, cases diagnosed in one large clinic (about 20 percent of all cases) were not included.”

■ Weakness of Ecological Studies – The committee likewise conceded that “The ecological nature of the study limits the study’s contribution to causality.”

■ Swedish Contribution is Limited – As for the Swedish data, “which only reflected cases diagnosed in inpatient settings” the IOM committee admitted that the reported increase might have been caused by “changes in diagnostic criteria and increasing awareness of autism and related disorders.” The Sweden section, likewise, was an ecological analysis, which again “limits the study’s contribution to causality.”

CRITIQUE BY MARK D. NOBLE – PROFESSOR OF GENETICS AND OF NEUROBIOLOGY AND ANATOMY, UNIVERSITY OF ROCHESTER MEDICAL CENTER[49]

One hypothesis to explain the sudden increase in prevalence is that changes in diagnosis and increased interest in autism caused an enhanced recognition of children with these syndromes. Thus, we know that the reported prevalence from 1971 to 1990 is artificially low, because it doesn’t include children who were given a different diagnosis. That means that in its current form, the comparison between the 1971-1990 cohort and later cohorts is fundamentally flawed, because they represent different kinds of information. There is quite an explosive change that is going on between 1995 and 2000. What could explain this? When you read the actual details of this manuscript (Madsen et al., 2003) you find out that, in 1995, a change was made in the information contained in the Danish registry. Prior to 1995 this registry only contained inpatient data, but after 1995 it also included data from outpatients.

In fact, the paper states that this change introduced 4-6 times as many total individuals into the registry. But it did not increase for a biological reason – it increased because they simply were obtaining cases from 4-6 times as many total people. At least in the years 1991-1998, 93.1% of the autism cases were treated only as outpatients. Thus, the addition of outpatients to the analysis in 1995 may have added 13.5 times as many cases of autism to the number of cases reported. If we apply even the most conservative correction factor for non-biological contributions, then a reasonable interpretation … is that the biological prevalence of PDD fell by 30-40% after the removal of thimerosal from vaccines. Even the application of the lower end of the possible correction factors leads to the conclusion that there was a fall in autism prevalence after thimerosal was removed from vaccines.

SUMMARY: This weak review analyzed data from three different countries where mercury exposures were vastly different, and where autism cases were counted in very different ways. In addition, over the study period, the Danish autism registry switched from counting only inpatient-diagnosed cases (about 13% of the total) to counting both inpatient and outpatient cases (100% of the total). This accounted for most if not all of the “increase” in cases observed after the removal of thimerosal from Danish vaccines.