Medscape Medical news, October 2, 2007


[Rachel's introduction: Paul A. Offitt, MD (who serves as an advisor to Merck Pharmaceutical), calls the fallout from the decision to withdraw thimerosal from vaccines a "cautionary tale:" "Although the precautionary principle assumes that there is no harm in exercising caution, the alarm caused by the removal of thimerosal from vaccines has been quite harmful," he writes. [Of course the precautionary principle assumes no such thing -- it assumes all alternatives are carefully weighed. This is just another typical attack on precaution - -distorting it in order to bash it. -- RPR Editors.]]

By Susan Jeffrey

A new study from the Centers for Disease Control and Prevention (CDC) does not appear to support a causal association between early exposure to mercury from thimerosal-containing vaccines or immune globulins and deficits in neuropsychological functioning among children now aged 7 to 10 years.

Out of 328 tests assessing these outcomes, the number of significant associations was about 5%, as would be expected for a chance finding, lead author William W. Thompson, PhD, from the CDC's Vaccine Safety Datalink Team, told Medscape Neurology & Neurosurgery.

"So at the end of the day, we think the weight of the evidence does not support a causal association between thimerosal exposure and 42 neuropsychological outcomes that we tested," Dr. Thompson said.

Their report is published in the September 27 issue of the New England Journal of Medicine.

However, the authors point out that their study did not look at autism spectrum disorders and so cannot answer the thorny question of a causal link there that has been the focus of litigation. This question is also the subject of 2 Perspective articles in the same issue of the Journal.

"We have a separate autism case-control study that we're doing that's assessing whether thimerosal from vaccines is associated with the risk for autism," Dr. Thompson noted. "That study is ongoing, and we hope to have a manuscript submitted for publication in the next year."

Thimerosal Removed From Vaccines

Thimerosal has been used as a preservative in vaccines since the 1930s, the researchers write. It is 49.6% mercury by weight and is metabolized into ethyl mercury and thiosalicylate.

In 1999, the Food and Drug Administration (FDA) estimated that infants immunized according to the recommended schedule could receive amounts of mercury in excess of limits set by the Environmental Protection Agency for exposure to methyl mercury, they note. "As a precautionary measure, the Public Health Service and the American Academy of Pediatrics [AAP] urged vaccine manufacturers to remove thimerosal from all infant vaccines as soon as was practical and recommended that studies be carried out to understand better the risks associated with mercury exposure from thimerosal-containing vaccines," the authors write.

This study is a follow-up to a previous analysis by the CDC published in 2003, Dr. Thompson said. Using computerized databases from 3 large health maintenance organizations (HMOs), the previous researchers found increasing exposure to thimerosal was associated with a greater likelihood of tics in 1 population and of language delay in another, but no significant associations were found in the third population (Verstraeten T. et al. Pediatrics. 2003;112:1039-1048).

In the current study, the authors aimed to have a more rigorous and comprehensive approach using a similar design to previous studies of prenatal exposure to methyl mercury from fish consumption, Dr. Thompson said.

"Our study improved on previous thimerosal studies by enrolling children on the basis of thimerosal exposure, independent of health status; prospectively assessing neuropsychological functioning independently of exposure and healthcare-seeking behavior; and collecting extensive information on potential confounders, including medical history and socioeconomic and educational factors that could influence a child's health and development," the authors write.

They also sought the advice of a panel of external experts, including vaccine advocacy groups, to compile the outcomes of interest. "In the end, we had 42 neuropsychological outcomes that we looked at and had extensive information on vaccine histories," Dr. Thompson said. The panel also had significant input on review of the results and draft of the final manuscript, he noted.

In all, 1047 children between the ages of 7 and 10 years were enrolled from 4 HMOs that participate in the CDC's Vaccine Safety Datalink. Exposure to thimerosal was determined using computerized health records, medical records, personal immunization records, and maternal interviews. They assessed the association between current neuropsychological performance and exposure to mercury in the prenatal period, birth to 28 days, and the first 7 months of life.

"Among the 42 neuropsychological outcomes, we detected only a few significant associations with exposure to mercury from thimerosal," the authors write.

"We present 378 tests in the manuscript, and when you run that many statistical tests, you're likely to get some chance findings," Dr. Thompson noted. Of the 378 tests, there were 19 statistically significant associations; 12 of these showed better outcomes with increasing thimerosal exposure, and 7 associated poorer outcomes with increasing exposure. The differences were small and mostly sex- specific.

Statistical significance on 19 tests, about 5% of the total, "is exactly what you would expect by chance," he said.

However, some of these associations may require further investigation, he added. One of these was an association of thimerosal exposure and tics among boys, important because a similar relationship was also seen in 2 previous studies, including the one by Verstraeten et al.

"We're in ongoing discussions within the CDC and with the National Center for Birth Defects and Developmental Disabilities regarding whether we should follow up on that or not," he said. Results from another ongoing study, called the Thimerosal Italy Study, which is also assessing tics as an outcome, will give more information on how to proceed on that finding, he noted.

Thimerosal has been removed from all vaccines with the exception of some influenza vaccines, Dr. Thompson said. However, parents can request thimerosal-free vaccines for their children.

Perspectives: Thimerosal and Autism

Researchers in the current study emphasize that their study did not assess autism spectrum disorders in relation to thimerosal exposure. In the 2 Perspective articles, a lawyer and a physician look at the impact that the fear of a potential link with autism has had on the use of vaccines and on litigation related to this question of causation.

In one of these, Paul A. Offitt, MD, chief of the division of infectious diseases at the Children's Hospital of Philadelphia, in Pennsylvania, calls the fallout from the decision to withdraw thimerosal from vaccines a "cautionary tale."

"Although the precautionary principle assumes that there is no harm in exercising caution, the alarm caused by the removal of thimerosal from vaccines has been quite harmful," he writes. "For instance, after the July 1999 announcement by the CDC and AAP, about 10% of hospitals suspended use of the hepatitis-B vaccine for all newborns, regardless of their level of risk. One 3-month-old child born to a Michigan mother infected with hepatitis-B virus died of overwhelming infection."

And there has been other fallout, he writes. The idea that thimerosal causes autism has given rise to a "cottage industry of charlatans offering false hope, partly in the form of mercury-chelating agents."

Many parents choose not to have their children immunized for influenza because some preparations of vaccine still contain thimerosal. "By choosing not to vaccinate their children, these parents have elevated a theoretical (and now disproved) risk above the real risk of being hospitalized or killed by influenza.

"During the next few years, thimerosal will probably be removed from influenza vaccines and the court cases will probably settle down," Dr. Offitt concludes. "But the thimerosal controversy should stand as a cautionary tale of how not to communicate theoretical risks to the public; otherwise, the lesson inherent in the collateral damage caused by its precipitous removal will remain unlearned."

In a second Perspective, Stephen D. Sugarman, JD, professor at the University of California, Berkley School of Law, outlines some of the process and current state of suits related to the causation question between childhood vaccines and autism.

Thousands of autism claims are pending, he writes. "In 2002, to resolve such claims more expeditiously, the VICP [Vaccine Injury Compensation Program] announced that some test cases would examine the general causation question, putting aside the question of harm to any particular child. Although this process was supposed to take only 2 years, the first of 9 test cases was heard just this past summer, with many witnesses testifying on each side. A special section of the US Court of Federal Claims administers the VICP, and judges running this so-called vaccine court are not expected to begin to decide these cases until 2008. Department of Justice lawyers appear in opposition to the claimants."

The study was supported by the Centers for Disease Control and Prevention, in Atlanta, Georgia. Dr. Thompson reports being a former employee of Merck; disclosures for other coauthors appear in the paper. Dr. Offit reports serving on the scientific advisory board of Merck and being the coinventor of the bovine-human reassortant rotavirus vaccine, RotaTeq, on which he holds a patent.

N Engl J Med. 2007;357:1281-1292, 1275-1277, 1278-1279.