Association between thimerosal-containing vaccine and autism
Anders Hviid 1 , Michael Stellfeld, Jan Wohlfahrt, Mads Melbye
JAMA. 2003 Oct 1;290(13):1763-6.
doi: 10.1001/jama.290.13.1763.
| AAP: A study of 467,000 children born in Denmark between 1990 and 1996 compared children who were vaccinated with a thimerosal-containing vaccine to children who received a thimerosal-free formulation of the same vaccine. The risk of autism spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine. The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autism spectrum disorders. |
Abstract
Context: Mercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, contains ethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmental disorders such as autism.
Objective: To determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism.
Design, setting, and participants: Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31, 1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of the same vaccine.
Main outcome measures: Rate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury.
Results: During 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval [CI], 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 microg of ethylmercury, 0.98 [95% CI, 0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders).
Conclusion: The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders.
| Role of Study Sponsors: Members of the funding organization (AAP) and its sponsor (CDC) participated along with experts in virology and neurovirology, autism pathogenesis, and vaccine design and safety; representatives of the autism advocacy community; and study collaborators in an Oversight Committee that reviewed and agreed to all aspects of study design prior to data collection.” |
14Studies.com
The second “Denmark study”. The conclusions appear to be based on lost data. SafeMinds re-ran their numbers, and found that autism rates and thimerosal levels were actually highly correlated.
Actual Question This Study Asked & Answered:
Q: Did the discontinuation of thimerosal use in vaccines in Denmark lead to a decrease in autism?
A: No.
Did the study look at unvaccinated children?
No.
Conflict of Interest (from the study itself):
“Author Affiliations: Danish Epidemiology Science Centre,Department of Epidemiology Research (Messrs Hviid, Wohlfahrt, and Dr Melbye) and Medical Department (Dr Stellfeld), Statens Serum Institut [a vaccine manufacturer], Copenhagen, Denmark.”
Ability to Generalize:
None. As SafeMinds noted:
“A large percentage of diagnosed autism cases are lost from the Danish registry each year. In the ten years preceding 2000, 815 cases were lost, more than the 710 remaining in the registry in 2000. The vast majority of those lost cases would represent older children in the 2000 registry. Since the relative risk of the Hviid study is based on finding fewer older thimerosal-exposed children than younger unexposed children, the validity of their conclusion exonerating thimerosal in autism is questionable. More likely, the finding is a result of missing records rather than true lower incidence rates among the exposed group.”
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: 1
Total Score: 1
Choice Excerpt from the Study:
“As shown in Figure 2, the incidence of autism diagnosed among Swedish inpatients aged 2 to 10 years old began to increase in the mid to late 1980s, rising from a rate of 5 to 6 inpatient-diagnosed cases per 100,000 person-years before 1985 to a peak rate of 9.2/100,000 in 1993.”
Meaning:
The authors are saying that Sweden has an autism rate of 1 in 10,000, which is SIXTY times lower than the U.S. rate of 1 in 150, which the authors don’t appear to consider or discuss. Isn’t anyone curious why Sweden’s autism rate is SIXTY times lower that ours?
Guest Critic #1: SafeMinds
Safe Minds Analysis of Denmark Data Finds Dramatic Drop in Autism Rates After Thimerosal Removal from Vaccines, Finds Flaw in Study Appearing in JAMA, Invalidating its Conclusions
Analysis provides further substantiation of role of thimerosal in autism, sheds more light on vaccine conflicts of interest A newly released analysis of autism registry data from Denmark by Safe Minds, a non-profit autism organization, shows that the rate of autism declined from an incidence of 1 in 500 prior to 1992 to 1 in 1,500 today. This decline in the incidence of autism follows the removal of thimerosal from infant vaccines in that country in 1992. The analysis also uncovered a flaw in the methodology of Danish investigators publishing in the October issue of JAMA (Hviid et al), who utilized the same Danish registry data and concluded that autism rates in Denmark rose after thimerosal removal from vaccines.
“In our review of the Danish data we identified a flaw which resulted in a substantial loss of autism case records from the registry which essentially renders the findings from the JAMA study by Hviid and colleagues invalid”, said Sallie Bernard, executive director of Safe Minds. “The registry allows 10-25% of diagnosed autism cases to be lost from its records each year. The effect of this loss is such that the records will disappear from older age groups to a much greater degree than from younger age groups in any given registry year.”
The Hviid findings are based on finding fewer older children in their 2000 registry cohort than younger ones. Since the older children received thimerosal vaccines and the younger ones did not, Hviid falsely concluded that thimerosal is not a factor in autism. The Safe Minds analysis shows instead that the decline is likely due to the loss of records of older children from the registry records, rather than a true decline in autism rates in the older group.
Safe Minds reanalyzed the Denmark registry data and used an alternative method to avoid the record removal bias. The analysis looked at same-age children – 5-9 year olds – but from different registry years: 1992, when all of the children received thimerosal-containing vaccines, and 2002, when none of the children received vaccines with thimerosal. After adjusting for the lack of outpatient records in the 1992 registry, the analysis found a 2.3 higher number of autism cases among the 1992 thimerosal-exposed group relative to the 2002 non-exposed group.
The analysis then determined an autism incidence rate for the non-thimerosal group of 1 in 1,500, while the thimerosal-exposed group had an incidence of 1 in 500, a 3-fold increase. The higher figure is comparable to the 1 in 500 incidence level for core autism recently found in England and the 1 in 250 incidence level recently calculated for the US. The thimerosal exposure level and timing in pre-1992 Denmark was comparable to that in England, while that for the US was somewhat more aggressive.
The Safe Minds analysis also revealed how small shifts in study design using the Denmark data can result in large changes to the results. The volatility stems from the many changes that the data set has gone through in the past decade. This makes the data set especially prone to possible bias.
“In the Hviid study in JAMA we can clearly see how the data was misinterpreted so a conclusion could be drawn to clear thimerosal from any role in autism,” said Lyn Redwood, president of Safe Minds. “This misinterpretation is not surprising given the authors’ employment with the manufacturer and promoter of vaccines in Denmark, Statens Serum Institut. This conflict of interest should have been stated by JAMA.”
Safe Minds is calling for a complete analysis of the Denmark autism registry data set by independent, unbiased epidemiologists who have no involvement in vaccine development, production, promotion, or administration.
Click HERE fo Safe Minds analysis.
Guest Critic #2: Bernard Rimland, Autism Research Institute
To the Editor: In their article on the association between thimerosal-containing vaccines and autism, Dr Hviid and colleagues1 acknowledged their affiliations with Statens Serum Institut, Copenhagen, Denmark, but did not disclose that the institute is a for-profit, state-owned enterprise with roughly $120 million in annual revenue. According to its 2002 Annual Report,2 vaccines represent approximately one half of Statens Serum Institut’s revenues and more than 80% of its profits. Furthermore, Statens Serum Institut manufactured the now discontinued monocomponent pertussis vaccine that contained thimerosal under investigation in their study. They were also the providers of diphtheria and tetanus components of a major thimerosal-containing diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP) vaccine sold in the United States.3
Bernard Rimland, PhD
Autism Research Institute
San Diego, Calif
CRITIQUES OF THE STUDY
■ Mercury Cannot Be “Protective” – The data in this study show that mercury is beneficial to infant children. Those in the thimerosal group had a relative risk of 0.85 for autism, compared with the mercury free group, suggesting a substantial (though not significant) protective effect for thimerosal. This finding is suspicious, and runs counter to all knowledge, science and common sense. More to the point, the outcome suggests the presence of unexamined or unreported bias in the study design and data management that suggest the researchers were prejudiced in a way that makes them unreliable investigators.
■ Older Children’s Records Missing – SafeMinds identified a flaw that could well have produced a significant loss of autism case records from the Danish register, rendering the Hviid et al. findings invalid. “The registry allows 10-25% of diagnosed autism cases to be lost from its records each year,” the group wrote in a letter to JAMA.[55] “The effect of this loss is such that the records will disappear from older age groups to a much greater degree than from younger age groups in any given registry year.” Older children were underrepresented in the cohort, even though they were the ones who received thimerosal-containing vaccines before 1992.
■ Reanalysis Finds More Autism in Exposed Children – In the same letter to JAMA, SafeMinds reanalyzed the Denmark data using an alternative method to avoid the “record removal bias.” Instead, they looked at same-age children – 5-to-9 year olds – but from two different registry years: 1992, when all of the children received thimerosal-containing pertussis vaccines; and 2002, when none of the children received thimerosal. “After adjusting for the lack of outpatient records in the 1992 registry, the analysis found a 2.3 times higher number of autism cases among the 1992 thimerosal-exposed group relative to the 2002 non-exposed group,” SafeMinds said.
■ No Tracking of Birth Cohorts – The researchers failed to classify autism cases by birth year. There is often a gap between the number of children diagnosed with autism from any given birth cohort and the number of autism cases reported in any given calendar year. Analyzing the data according to birth cohort would have painted a far more accurate picture, because it would have reduced or eliminated the gap between diagnoses of ASD and reporting of cases.
■ Undisclosed Conflict of Interest – “In the Hviid study in JAMA we can clearly see how the data was misinterpreted so a conclusion could be drawn to clear thimerosal from any role in autism,” a SafeMinds statement said. “This misinterpretation is not surprising, given the authors’ employment at Statens Serum Institut, a conflict of interest that should have been disclosed.”
WHAT THE AUTHORS SAID
The authors wrote that a “possible weakness” of their paper was that “the date of diagnosis used as the incidence date may differ significantly from the ‘onset of symptoms’ date.” Diagnosis autism is often “a lengthy process,” they wrote, and this is “reflected in the mean ages of diagnoses in this study (4.7 years for autism and 6.0 years for other autistic-spectrum disorders).” Such a limitation, however, “is more likely to be a problem in an incidence study than in a risk factor study.”
WHAT THE IOM SAID
Although the committee considered the study as having “strong internal validity” it also identified various limitations, “including its time-series design,” (as pointed out by SafeMinds), and the “generalizability of the study’s findings to the U.S. situation, especially with regard to the different dosing schedule used in Denmark and the relative genetic homogeneity of the Danish population.”
SUMMARY: This study was marked by missing records, a failure to track birth cohorts, and undisclosed conflicts of interest. Reanalysis of the data actually showed an increased risk of ASD following thimerosal exposure. It also concluded that mercury had a protective effect on the neurodevelopment of children, which flies in the face of all logic and all previous studies of mercury and children.